TW202000201A - Process for preparing 1-arylsulfonyl-pyrrolidine-2-carboxamide Transient Receptor Potential channel antagonist compounds and crystalline forms thereof - Google Patents

Abstract

The invention relates generally to methods of preparing 1-arylsulfonyl-pyrrolidine-2-carboxamide Transient Receptor Potential channel antagonist compounds of the following structure (I): The invention further relates to solvate and co-crystal polymorphs of crystalline formula (I), and methods of preparation thereof.

Description

Method for preparing 1-arylsulfonyl-pyrrolidine-2-carboxamide transient receptor potential channel antagonist compound and its crystal form

。 本發明之領域另外係關於結晶式(I)之溶劑合物及共晶體多晶型物及其製備方法。The field of the present invention generally relates to a method for preparing 1-arylsulfonyl-pyrrolidine-2-carboxamide transient receptor potential channel antagonist compounds of the following structure (I):

. The field of the invention additionally relates to crystalline solvates and eutectic polymorphs of formula (I) and methods for their preparation.

The transient receptor potential (TRP) channel is a type of ion channel found on the plasma membrane of various (and other animal) cell types. There are at least 28 known human TRP channels that are broken into multiple families or groups based on sequence homology and function. Transient receptor potential cation channel, subgroup A member 1 (TRPA1) is a non-selective cation conduction channel that regulates membrane potential via sodium, potassium, and calcium flux. TRPA1 has been shown to be highly expressed in human dorsal root ganglion neurons and peripheral sensory nerves. In humans, TRPA1 is activated by a variety of reactive compounds (such as acrolein, allyl isothiocyanate, ozone) and non-reactive compounds (such as nicotine and menthol), and is therefore considered to act as a chemical sensor Device.

Many known TRPA1 agonists are irritants that cause pain, irritation, and neuropathic inflammation in humans and other animals. Therefore, it is expected that TRPA1 antagonists or agents that block the biological effects of TRPA1 channel activators will be suitable for the treatment of diseases such as asthma and its exacerbation, chronic cough and related diseases, and for the treatment of acute and chronic pain. Recently, products of tissue damage and oxidative stress (such as 4-hydroxynonenal and related compounds) have also been shown to activate TRPA1 channels. The results of this study provide the effectiveness of small molecule TRPA1 antagonists in the treatment of diseases related to tissue damage, oxidative stress and bronchial smooth muscle contraction, such as asthma, chronic obstructive pulmonary disease (COPD), occupational asthma, and virus-induced pneumonia Extra basic principles. In addition, recent research results are related to activation of TRPA1 channel and increased pain perception (Kosugi et al., J. Neurosci 27, (2007) 4443-4451; Kremayer et al., Neuron 66 (2010) 671-680; Wei et al., Pain 152 (2011) 582-591); Wei et al., Neurosci Lett 479 (2010) 253-256)), providing additional rationale for the effectiveness of small molecule TRPA1 inhibitors in the treatment of pain disorders

自國際公開案第WO 2016/128529號已知，其以全文引用的方式併入本文中。可使用(2S ,4R ,5S )-4-氟-1-((4-氟苯基)磺醯基)-5-甲基-N -((5-(三氟甲基)-2-(2-(三氟甲基)嘧啶-5-基)吡啶-4-基)甲基)吡咯啶-2-甲醯胺之替代名稱，但以所示化學結構為準。WO 2016/128529公開案揭示適用於製備化合物I(a)之方法。方法示於圖4中。然而，先前技術方法之步驟4所產生之中間物以鹽酸鹽型式分離，且步驟3及4之組合的產率係約17%。此外，在先前技術方法中化合物I(a)以非晶固體型式分離。此外，先前技術方法需要多個層析純化步驟以獲得所需純度。TRP channel antagonist compound (2 S ,4 R ,5 S )-4-fluoro-1-((4-fluorophenyl)sulfonyl)-5-methyl- N -( (5-(Trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide:

It is known from International Publication No. WO 2016/128529, which is incorporated herein by reference in its entirety. (2 S ,4 R ,5 S )-4-fluoro-1-((4-fluorophenyl)sulfonyl)-5-methyl- N -((5-(trifluoromethyl)- Alternative name for 2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide, but subject to the chemical structure shown. The WO 2016/128529 publication discloses a method suitable for preparing compound I(a). The method is shown in Figure 4. However, the intermediate produced in step 4 of the prior art method is separated in the form of hydrochloride, and the yield of the combination of steps 3 and 4 is about 17%. In addition, in the prior art method, the compound I(a) is isolated as an amorphous solid. In addition, prior art methods require multiple chromatographic purification steps to obtain the required purity.

Therefore, there is a need to prepare TRP antagonist compounds of structure (I), such as (2 S ,4 R ,5 S )-4-fluoro-1-((4-fluorophenyl)sulfonyl)-5-methyl- N -((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide and its intermediate Compound improvement methods.

In addition, there is a need for a crystalline form of compound (I) that can provide improved characteristics such as one or more of stability, solubility, dissolution rate, hardness, compressibility, and melting point.

。In some embodiments, methods for preparing compound 3 are provided. The method includes reacting compound 1 with a sulfonating agent in a solvent to form compound 2 according to the following step 1, wherein Y is arylsulfonyl or alkylsulfonyl:

.

。The method further includes reacting compound 2 with a nitrogen source in a solvent according to the following step 2 to form compound 3:

.

Compound 3 is the free base. Based on compound 1, the yield of compound 3 is at least 30%. R ^{1 is} selected from halo, halo-C _1-4 alkyl-, halo-C _1-4 alkoxy- and -CN. R ^{2 is} selected from H and cyclopropyl-.

The group Y can be introduced by the reaction of Compound 1 with a sulfonating agent such as sulfonate, arylsulfonyl halide or lower alkylsulfonyl halide. Exemplary sulfonating agents include tosyl (tosyl) chloride and mesyl (tosyl) chloride. The nitrogen source may be ammonia or an ammonium salt, which reacts with compound 2 to displace the Y-O- group and obtain amine compound 3.

。In some other embodiments, a method of preparing crystalline Compound I or a solvate or co-crystal thereof is provided. The method comprises reacting compound 6 (in acid salt form), compound 7 and base in a solvent system to form compound (I) as follows

.

R ^{1 is} selected from halo, halo-C _1-4 alkyl-, halo-C _1-4 alkoxy- and -CN. R ^{2 is} selected from H and -cyclopropyl. R ³ is C _1-4 alkyl-, and R ^{4 is} selected from H and -F, or R ³ and R ⁴ together with the ring atoms to which they are attached form a three-membered carbocyclic ring. R ⁵ is a halogen group. X ₁ and X _{2 are} each C, or one of X ₁ and X ₂ is N, and the other is C. n系1 or 2. The asterisks indicate the palm center.

The method further includes moving the solvent system of the reaction step from the solvent system of the reaction step to an organic solvent selected from the following by the compound (I) by solvent exchange to form a solution of the compound (I): (a) a nonpolar solvent having a dielectric constant greater than 2 ; (B) polar aprotic solvents; or (c) polar protic solvents.

The method further includes contacting the solution of compound (I) with an anti-solvent to form a slurry of crystalline compound (I).

In some other embodiments, a crystalline (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl- N -((5-(三Fluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide compound.

In some other embodiments, there is provided a pharmaceutical composition comprising a compound of the present invention and at least one pharmaceutically acceptable excipient, diluent, and/or carrier.

In some other embodiments, a compound E (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl is provided as a free base anhydrous crystal -N -((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide, which The characteristic is that the X-ray powder diffraction peak contains three, four or five peaks selected from the following: 7.5°±0.2°, 8.2°±0.2°, 12.6°±0.2°, 13.1°±0.2°, 13.4°± 0.2°, 14.7°±0.2°, 15.1°±0.2°, 15.5°±0.2°, 16.1°±0.2°, 16.6°±0.2°, 18.2°±0.2°, 18.9°±0.2°, 19.9°±0.2° , 20.4°±0.2°, 21.0°±0.2°, 21.5°±0.2°, 21.8°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 24.3°±0.2°, 25.0°±0.2°, 25.4 °±0.2° and 28.4°±0.2°.

In some other embodiments, there is provided (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl which is a free base anhydrous crystalline form E -N -((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide and at least A pharmaceutical composition of pharmaceutically acceptable excipients, diluents and/or carriers.

In some other embodiments, a method for preparing (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl which is a free base anhydrous crystalline form E is provided -Method of N -((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide .

The method includes making (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl- N -((5-(trifluoromethyl)-2 -(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide free base starting material is mixed with dichloromethane to form a solution with at least 50 mg/ (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl- N -((5-(trifluoromethyl)-2-( 2-(Trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide concentration solution.

The method further includes making the (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl- N -((5-(trifluoromethyl) A solution of -2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide and a non-polar antisolvent with a dielectric constant of less than 2 The combined volume ratio of dichloromethane to anti-solvent is about 1:1.5 to about 1:10 to form crystalline E-type (2 S ,4 R ,5 S )-4-fluoro-1 containing free base anhydrous -(4-fluorobenzenesulfonyl)-5-methyl- N -((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridine-4- Base) methyl) pyrrolidine-2-carboxamide slurry.

The method further includes separating free base anhydrous crystalline E-type (2 S , 4 R , 5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl- N- ( (5-(Trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide.

Cross-reference of related applications

This application claims the priority of US Provisional Application No. 62/632,653 filed on February 20, 2018, the disclosure content of which is incorporated herein by reference.

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. Although the invention will be described in conjunction with the listed embodiments, it should be understood that it is not intended to limit the invention to those embodiments. On the contrary, the present invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the scope of the patent application. Those skilled in the art should be able to identify various methods and materials similar or equivalent to those described herein, which can be used in the practice of the present invention. The present invention is by no means limited to the methods and materials. One or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including but not limited to the defined terms, term usage, the described technology, or the like) Below, the application shall prevail. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned are incorporated by reference in their entirety.

化合物(I) 。The present invention provides an improved method for preparing compound (I):

Compound (I).

The present invention further provides the crystalline form of compound (I). The present invention further provides various crystalline polymerization forms of compound (I). The present invention further provides an improved method for preparing compound (I) and a method for preparing various crystal polymerization types of compound (I).

definition

When indicating the number of substituents, the terms "at least one" and "one or more" refer to the range of one substituent to the highest possible number of substitutions, that is, replacement of one hydrogen to replacement of all hydrogens by the substituent. The term "substituent" indicates an atom or group of atoms that replaces a hydrogen atom on the parent molecule. The term "substituted" indicates a designated group with one or more substituents. Where any group may carry multiple substituents and provide multiple possible substituents, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from the group of possible substituents. When indicating the number of substituents, the terms "at least one" and "one or more" mean one substituent to the highest possible number of substitutions, that is, replacement of one hydrogen to replacement of all hydrogens by the substituents.

As used herein, "alkyl" refers to a monovalent straight or branched chain saturated hydrocarbon moiety consisting solely of carbon and hydrogen atoms and having one to twelve carbon atoms. "Lower alkyl" refers to an alkyl group having one to six carbon atoms, or one to four carbon atoms, such as a C _1-4 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, second butyl, third butyl, pentyl, n-hexyl, octyl, dodecyl And similar groups. The alkyl group is optionally substituted with one or more substituents.

As used herein, the terms "halo" and "halogen" refer to chlorine, fluorine, bromine, and iodine.

As used herein, the term "haloalkyl" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms are replaced by the same or different halogen. Exemplary haloalkyl groups include halo-C _1-4 alkyl groups, such as -CH ₂ Cl, -CH ₂ CF ₃ , -CH ₂ CCl ₃ , -CF ₃ and -CHF ₂ .

As used herein, the term "alkoxy" refers to the moiety of the structure -OR, where R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, and isopropoxy.

As used herein, the term "haloalkoxy" refers to an alkoxy group as defined herein, wherein one or more hydrogen atoms are replaced by the same or different halogen. Exemplary haloalkoxy groups include halo-C _1-4 alkoxy groups, such as -OCH ₂ Cl, -OCH ₂ CF ₃ , -OCH ₂ CCl ₃ , -OCF ₃ and -OCHF ₂ .

As used herein, the terms "cycloalkyl" and "carbocycle" refer to a monovalent saturated carbocyclic moiety containing 3 to 12 carbon atoms and consisting of a monocyclic or bicyclic ring. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including their partially unsaturated (cycloalkenyl) derivatives.

As used herein, "leaving group" refers to an atom or a group of atoms that is replaced with a stable species in a chemical reaction. Suitable leaving groups are well known in the art, see for example March's Advanced Organic Chemistry, Supplement 5th Edition, Editors: Smith, M. B and March, J., John Wiley & Sons, New York: 2001 and TW Greene , Protective Groups in Organic Synthesis , John Wiley & Sons, New York, 1991, the entire contents of each of which are incorporated herein by reference. Such leaving groups include (but are not limited to) halogen, alkoxy, sulfonyloxy, optionally substituted alkylsulfonyl, optionally substituted alkenylsulfonyl, optionally substituted Arylsulfonyl and diazo moieties. Some examples of leaving groups include chlorine, iodine, bromine, fluorine, methanesulfonyl (methanesulfonyl), tosylate, triflate, nitro-benzenesulfonyl (nitrobenzenesulfonate) (Acyl) and bromo-benzenesulfonyl (bromobenzenesulfonyl).

As used herein, "protecting group" refers to a group used to protect a remote functional group (eg, primary or secondary amine) of an intermediate. The need for such protection will vary depending on the nature of the remote functional group and the conditions of the preparation method. Suitable amine protecting groups include acetyl, trifluoroacetyl, third butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz), and 9- stilboxymethyleneoxycarbonyl (Fmoc). For a general description of protecting groups and their uses, see March and Green.

As used herein, "deprotection agent" refers to a compound that will cleave a protection group as defined herein.

六氟磷酸鹽(HBTU)；N,N'-二環己基碳化二亞胺(DCC)；苯并三唑-1-基氧基)參(二甲胺基)鏻六氟磷酸鹽(BOP)；苯并三唑-1-基-氧基三吡咯啶基鏻六氟磷酸鹽(PyBOP)；1,1'-羰基二咪唑(CDI)；1-乙基-3-(3-二甲胺基丙基)碳化二亞胺(EDC)及羥基苯并三唑(HOBt)；及EDC及4-二甲胺基吡啶(DMAP)。As used herein, "coupling agent" refers to an agent that promotes the formation of amides from amines and carboxylic acids. Examples of coupling agents include, but are not limited to, propanephosphonic anhydride (T3P®); 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b Pyridinium 3-oxide hexafluorophosphate (HATU); 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl

Hexafluorophosphate (HBTU); N,N'-dicyclohexylcarbodiimide (DCC); benzotriazol-1-yloxy) ginseng (dimethylamino) phosphonium hexafluorophosphate (BOP) ; Benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP); 1,1'-carbonyldiimidazole (CDI); 1-ethyl-3-(3-dimethylamine Propyl) carbodiimide (EDC) and hydroxybenzotriazole (HOBt); and EDC and 4-dimethylaminopyridine (DMAP).

As used herein, the term "free base" refers to the parent compound (I) different from any of its salts.

As used herein, the term "organic base" refers to an organic compound that contains one or more nitrogen atoms and acts as a base. Examples of organic bases include (but are not limited to) tertiary amine bases. Examples of organic bases include, but are not limited to, N-methyl-morpholine (NMM), diisopropylethylamine (DIPEA), and triethylamine (TEA).

As used herein, the term "inorganic base" refers to a base that contains inorganic components. Examples of inorganic bases include, but are not limited to, alkali metal hydroxides, ammonium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate.

As used herein, the term "organic acid" refers to an organic compound that acts as an acid. Examples of organic acids include, but are not limited to, carboxylic acids. Examples of organic acids include, but are not limited to, formic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, succinic acid, adipic acid, tartaric acid, and citric acid.

As used herein, the term "inorganic acid" refers to an acid containing inorganic components. Examples of inorganic acids include inorganic acids, including but not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and boric acid.

As used herein, the term "polar aprotic solvent" refers to any polar solvent that does not have proton donating ability. Examples without any limitation include 2-methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, propyl acetate (e.g. isopropyl acetate), acetone, dimethylsulfoxide, N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoramide and propylene carbonate.

As used herein, the term "polar protic solvent" refers to any polar solvent with proton donating ability. Examples include, but are not limited to, water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, formic acid, nitromethane, and acetic acid. Organic polar protic solvents do not include any effective amount of water.

As used herein, the term "polar organic solvent" refers to polar aprotic and polar protic solvents, excluding water.

As used herein, the term "nonpolar solvent" refers to a solvent that contains bonds between atoms with similar electronegativity, such as carbon and hydrogen, so that the charge on the molecules is evenly distributed. Non-polar solvents are characterized by a low dielectric constant. Examples include (but are not limited to) pentane (e.g. n-pentane), hexane (e.g. n-hexane), heptane (e.g. n-heptane), cyclopentane, methyl tertiary butyl ether, diethyl ether, toluene, Benzene, 1,4-dioxane, carbon tetrachloride, chloroform and dichloromethane (DCM). In some aspects, the non-polar solvent has a dielectric constant of less than 2, and examples thereof include, but are not limited to, n-pentane, n-hexane, and n-heptane. Compared with other non-polar solvents, DCM exhibits a certain degree of polarity at the bond level (that is, between carbon and chlorine), but due to the symmetry-based polarity cancellation only exhibits a small degree of polarity at the molecular level.

As used herein, the term "solvent" refers to polar aprotic solvents, polar protic solvents, and nonpolar solvents.

As used herein, the term "anti-solvent" refers to a solvent that has poor solubility of the mentioned compound and induces precipitation or crystallization of the compound from solution.

As used herein, "ammonium salt" refers to a salt having an ammonium cation. Examples include, but are not limited to, ammonium carbonate, ammonium chloride, and ammonium nitrate.

As used herein, "polymorph" or "polymorphism" refers to the ability of a substance to exist in more than one crystal form, where different crystal forms of a particular substance are called "polymorphs." In general, Xianxin polymorphism can be affected by the ability of material molecules to change their configuration or form different intermolecular or intramolecular interactions, especially hydrogen bonding, which is reflected in the different crystal lattices of different polymorphs Atomic arrangement. Different polymorphs of matter can have different lattice energies, and therefore, in the solid state they can exhibit different physical properties, such as type, density, melting point, color, stability, solubility, dissolution rate, etc., which in turn can affect factors such as It is not limited to the following characteristics: stability, dissolution rate and/or bioavailability of a given polymorph and its suitability for use as a medicament and in a pharmaceutical composition.

As used herein, "morphology" refers to the external shape and existing plane of a crystal, without reference to the internal structure. Crystals can exhibit different morphologies according to different conditions such as growth rate, agitation, and the presence of impurities.

As used herein, "solvate" refers to any type of compound (I) bonded to another molecule (such as a polar solvent) by a non-covalent bond. Such solvates are usually crystalline solids with a substantially fixed solute to solvent molar ratio. Representative solvents include n-heptane, N,N-dimethylacetamide, anisole, ethanol, toluene, 2-propanol, 1-butanol, 2-methyltetrahydrofuran, tetrahydrofuran, isobutanol and di Jia Yajie.

As used herein, the term "seed" can be used as a noun to describe one or more crystals of a crystalline compound (I) (eg, compound I (a) polymorph E form). The term "inoculation" can also be used as a verb to describe the introduction of the one or more crystals of the crystalline compound (I) into the environment (including but not limited to, for example, solutions, mixtures, suspensions or dispersions) thereby making the formation of more The action of crystals of polycrystalline compound (I).

Compounds with the same molecular formula but different bonding properties or order of their atoms or their arrangement in space are called "isomers". Isomers with different arrangement of atoms in space are called "stereoisomers". A diastereoisomeric system has stereoisomers of opposite configuration at one or more opposite centers, which are not enantiomers. The stereoisomers with one or more asymmetric centers that are not overlapping mirror images of each other are called "enantiomers". When the compound has an asymmetric center, for example, if the compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomeric systems is possible. Enantiomers can be characterized by the absolute configuration of one or more asymmetric centers, and described by the R- and S-sequencing rules of Cahn, Ingold, and Prelog, or by means of molecules rotating the plane of polarization , And designated as right-handed or left-handed (that is, designated as (+)-isomer or (-)-isomer, respectively). Dipalmitic compounds can exist in the form of individual enantiomers or in the form of mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture". In certain embodiments, the compound is enriched in at least about 90% by weight of individual diastereomers or enantiomers. In other embodiments, the compound is enriched in at least about 95%, 98%, or 99% by weight of individual diastereomers or enantiomers.

The compounds of the present invention may contain asymmetric or contra palm centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention including, but not limited to, diastereomers, enantiomers and delayed isomers and mixtures thereof (such as racemic mixtures) form part of the invention . In some cases, stereochemistry has not been determined or has been provisionally designated. Many organic compounds exist in optically active forms, that is, they can rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule around its palm center.

As used herein, the terms "about" and "about" refer to values of 90%, 95%, or 99% of the reference value.

The term "therapeutically effective amount" of a compound means the amount of the compound that is effective to prevent, alleviate or ameliorate the symptoms of the disease or prolong the survival of the treated individual. The determination of the therapeutically effective amount is within the skill in this technology. The therapeutically effective amount or dose of the compound according to the invention can vary within wide limits and can be determined in a manner known in the art.

Preparation of compounds (I) Method

According to one aspect of the present invention, the TRP antagonist compound (I) can be prepared according to the method shown in FIG. 1.

In some aspects, compound 3 having a 5-(pyridin-2-yl)pyrimidine core can be prepared from compound 1 through steps 1 and 2 as follows.

In step 1, compound 1 is reacted with a sulfonating agent as a source of part Y in a solvent to form compound 2 as follows:

R ^{1 is} selected from halo, halo-C _1-4 alkyl-, halo-C _1-4 alkoxy- and -CN. In some aspects, R ^{1 is} selected from —F, —CF ₃ , —CHF ₂ , —OCF ₃ , —OCHF ₂ , —OCH ₂ CF ₃ and —CN. In some other aspects, R ¹ is -CF ₃ .

R ^{2 is} selected from H and -cyclopropyl. In some aspects, R ² is H.

The group Y may be, for example, arylsulfonyl or alkylsulfonyl, and may be obtained by compound 1 and an arylsulfonyl halide reagent such as tosyl chloride (tosyl chloride) or such as mesylate ( (Methanesulfonyl chloride) is introduced by the reaction of the lower alkyl sulfonyl halide reagent.

In some embodiments, the step 1 solvent comprises or is a polar aprotic solvent. In some such aspects, the solvent is selected from one or more of the following: 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), ethyl acetate, propyl acetate, acetone, dimethylformamide ( DMF), acetonitrile and dimethyl sulfoxide (DMSO). In some aspects, the polar aprotic solvent is selected from MeTHF and THF. In some aspects, the polar aprotic solvent is MeTHF.

In general, a polar aprotic solvent can be added to a container such as a jacketed reactor, and then compound 1 is added with stirring. The concentration of Compound 1 may suitably be about 0.05 to about 2 kg/L, such as about 1 kg/L. The organic base can then be added with stirring, and the reactor contents are cooled to a temperature below about 25°C, such as from about 0°C to about 10°C. The base can generally be present in excess of Compound 1 molar. The source of the arylsulfonyl halide or lower alkylsulfonyl halide of the group Y can then be added with stirring while maintaining the temperature to form a reaction mixture. The aryl sulfonyl halide or the lower alkyl sulfonyl halide may generally be present in excess of Compound 1 molar, and the base may be in molar excess of the source of the leaving group. The reaction mixture can be maintained at a certain temperature with stirring, and reacted until a step 1 reaction product mixture comprising compound 2 is formed, which contains less than 5%, less than 2%, less than 1%, or less than 0.5% of starting compound 1. The analysis can be performed by HPLC as described elsewhere herein.

The reaction product mixture of Step 1 containing Compound 2 may be washed with an aqueous acid solution or an aqueous salt solution at least once or sequentially in any order. In some such aspects, the reaction product mixture comprising Compound 2 may be washed with an aqueous solution of acid (eg, citric acid) from about 2 wt% to about 10 wt%, such as about 5 wt%. In some aspects, the volume ratio of the aqueous acid solution to the reaction product mixture may suitably be about 0.5:1 to about 5:1, about 0.5:1 to about 2:1, such as about 1:1. In some aspects, the reaction product mixture comprising Compound 2 may be washed with an aqueous solution of salt (eg, sodium chloride) of about 5 wt% to about 40 wt%, such as about 25 wt%. In some aspects, the volume ratio of the aqueous salt solution to the reaction product mixture may suitably be about 0.5:1 to about 3:1, about 0.5:1 to about 2:1, such as about 0.75:1.

In some aspects, the solvent exchange of the polar aprotic solvent to the second solvent in the reaction product mixture of step 1 can be achieved. In some aspects, the second solvent is a polar aprotic solvent. In some specific aspects, the second solvent comprises or is ethyl acetate. In some aspects, a second solvent may be added to the reaction product mixture of step 1, followed by one or more optional washing steps as described elsewhere herein, such as after acid washing and before salt washing. The volume ratio of the second solvent to the solvent in Step 1 may suitably be about 1.5:1 to about 5:1, such as about 3:1. In some aspects, after the second solvent is added to the reaction product mixture of step 1 and at least one washing step, a second solvent may be added, followed by distillation. In some such aspects, the volume ratio of the second solvent to the solvent in step 1 may be from about 0.5:1 to about 2:1, such as about 0.75:1. Distillation may be performed under reduced pressure to produce a mixture containing concentrated compound 2, for example, compound 2 concentration is about 0.25 g/mL to about 1 g/mL, such as about 0.5 g/mL. The distillation temperature may suitably be below about 50°C.

Solid compound 2 can be formed by adding an anti-solvent to the reaction product mixture containing compound 2 or any solution of compound 2. In some aspects, the anti-solvent has a dielectric constant of less than 2. In some aspects, the anti-solvent is selected from one or more of n-pentane, n-hexane, n-heptane, and cyclopentane. In some aspects, the anti-solvent comprises or is n-heptane. In some aspects, the distillation is performed after the anti-solvent is added. In some such distillation aspects, the volume ratio of the anti-solvent to the solvent in Step 1 may suitably be about 0.25:1 to about 2:1, about 0.25:1 to about 1:1, such as about 0.5:1. Distillation may be performed under reduced pressure to produce a mixture containing concentrated compound 2, for example, compound 2 concentration is about 0.25 g/mL to about 1 g/mL, such as about 0.5 g/mL. The distillation step can be repeated one or more times. After the final distillation step, an anti-solvent can be added to produce a slurry that can be easily transferred and filtered. For example, the compound 2 concentration in the slurry may suitably be about 0.05 to about 0.5 g/mL, about 0.1 to about 0.3 g/mL, such as about 0.2 g/mL.

The solid compound 2 can be separated by techniques known in the art, including filtration, centrifugation, and Shendian. The separated solid compound 2 is optionally washed with an anti-solvent and/or mother liquor, and then dried as appropriate. Drying can be performed by techniques known in the art, including vacuum drying at high temperatures such as about 30°C to about 50°C.

The yield of compound 2 based on compound 1 is at least 85%, at least 90% or at least 95%, for example 90% or 95%. The purity as measured by the HPLC method described elsewhere herein is at least 95%, at least 96%, or at least 97%, such as about 97% or about 97.5%.

化合物1(a)。In some aspects, compound 1 is the following compound 1(a), (5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methanol :

Compound 1(a).

化合物2(a)。In some aspects, compound 2 is the following compound 2(a), methanesulfonic acid (5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridine-4- Base) methyl ester:

Compound 2(a).

。In step 2, compound 2 and the nitrogen source in the solvent react as follows to form compound 3:

.

R ¹ and R ^{2 are} as previously described.

In step 2, compound 2 and the solvent are combined in the reactor with stirring until a solution is formed. In some aspects, the solvent includes or is a polar organic solvent. In some aspects, the polar organic solvent may be selected from one or more of the following: methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, formic acid, acetic acid, MeTHF, THF, ethyl acetate , Propyl acetate, acetone, DMF, acetonitrile and DMSO. In some aspects, the polar organic solvent is selected from one or more of THF and MeTHF. In some aspects, the solvent is THF. In some aspects, the nitrogen source is ammonia or ammonium salt. The concentration of compound 2 in the solution may suitably be about 0.05 to about 1.0 g/mL, about 0.05 to about 0.5 g/mL, or about 0.1 g/mL to about 0.3 g/mL, such as about 0.2 g/mL. The solution of Compound 2 is combined with ammonia or an ammonium salt to form a reaction mixture containing Compound 2. In some aspects, the ammonia or ammonium salt may be a solution in an organic polar protic solvent selected from methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, formic acid , Nitromethane and acetic acid. In some aspects, the organic polar protic solvent is selected from methanol, ethanol, 1-propanol, and 2-propanol. In some aspects, the organic polar protic solvent comprises or is methanol. In any such aspect, the solution may be an ammonia or ammonium salt having a concentration of about 3 mol to about 9 mol, such as a concentration of about 7 mol. The volume of the ammonia or ammonium salt solution and the compound 2 solution may be about 1:1 to about 10:1, or about 4:1 to about 8:1, such as about 5:1, such as about 6:1. The reaction mixture is heated to form a reaction product mixture containing compound 3. A suitable reaction temperature may be about 30°C to about 60°C, about 30°C to about 50°C, or about 35°C to about 45°C. The reaction mixture may be maintained at a certain temperature with stirring, and react until a step 2 reaction product mixture comprising compound 3 is formed, which contains less than 0.5%, less than 0.2%, or less than 0.1% of compound 2. The analysis can be performed by HPLC as described elsewhere herein.

In some aspects, step 2 may optionally include a purification step. In some such aspects, the purification step may include: (i) exchanging the solvent from step 2 into a non-polar solvent having a dielectric constant greater than 2 to form a first solution of compound 3 in the non-polar solvent; (ii) The solid compound 3 is precipitated from the solution by adding an acid, and then the solid compound 3 and optionally the separated solid compound 3 are washed; (iii) the compound 3 is dissolved in a non-polar solvent with a dielectric constant greater than 2 by adding a base To form a second solution of compound 3 in a non-polar solvent; (iv) by adding an anti-solvent, the solid compound 3 free base is precipitated from the second solution, concentrated by removing the non-polar solvent, or a combination thereof; And (v) isolated and purified compound 3 free base.

In some such purification aspects, a step 2 reaction product solvent exchange/washing step from a polar organic solvent to a non-polar solvent having a dielectric constant greater than 2 may be performed. Suitable non-polar solvents include methyl tertiary butyl ether (MTBE), diethyl ether, toluene, benzene, 1,4-dioxane, carbon tetrachloride, chloroform and dichloromethane. In some aspects, the non-polar solvent contains or is MTBE. In such an aspect, the reaction product mixture of step 2 and the non-polar solvent may be from about 1.25:1 to about 4:1, from about 1:5:1 to about 3:1, such as from about 2:1 to a polar organic The volume ratio of the solvent is blended. The resulting combination can be further blended with an inorganic alkaline aqueous solution. In some aspects, the base is selected from alkali metal hydroxides, ammonium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate. In some aspects, the base may be potassium bicarbonate or sodium bicarbonate. The aqueous inorganic base solution may suitably be about 2 wt% to about 30 wt% base. For weak bases such as potassium bicarbonate or sodium bicarbonate, the concentration may suitably be about 15 wt% to about 30 wt% or about 20 wt% to about 25 wt%. In this aspect, the phases are separated and the lower aqueous phase is removed. The aqueous phase can be formed with a non-polar solvent from about 0.5:1 to about 4:1, about 1:5:1 to about 3:1, such as about 0.5:1 or 2:1, and a non-polar solvent used to form step 2(a ) The volume ratio of the polar organic solvent of the reaction mixture is washed at least once. The organic phases from each washing step are combined. In some aspects, two washing steps are performed at a solvent volume ratio of about 2:1, followed by one washing step at a solvent volume ratio of about 0.5:1. The combined organic layer containing Compound 3 may be distilled under reduced pressure to concentrate Compound 3 to a concentration such as about 0.03 g/mL to about 0.2 g/mL, such as about 0.07 g/mL. Distillation temperatures below about 50°C are suitable for practicing the present invention.

In some such purification aspects, step compound 3 or its concentrate may be blended with a solution of an acid such as an organic acid in a solvent such as a non-polar solvent. In some aspects, the organic acid is a carboxylic acid. In some aspects, the carboxylic acid is selected from one or more of formic acid, oxalic acid, malonic acid, succinic acid, glutaric acid succinic acid, and adipic acid. In some aspects, the organic acid comprises or is oxalic acid. The non-polar solvent system is as described elsewhere herein. In some aspects, the non-polar solvent contains or is MTBE. The concentration of the organic acid in the non-polar solvent may suitably be about 0.02 g/mL to about 0.1 g/mL, such as about 0.03 g/mL, such as about 0.04 g/mL. The blend can be agitated at about room temperature for at least about 1 hour to form solid compound 3. Solid compound 3 can be isolated by methods described elsewhere herein, and optionally washed with a non-polar solvent.

In some such purification aspects, solid compound 3 can be combined with additional non-polar solvents (eg, MTBE) to about 0.05 g/mL to about 0.5 g/mL, or about 0.1 g/mL to about 0.2 with stirring g/mL of compound 3 concentration. The compound 3 mixture may use an inorganic base aqueous solution as previously described with an inorganic base solution of about 0.5:1 to about 5:1, about 1:1 to about 3:1, or about 1:1 to about 1.5:1 with additional non- Wash by volume ratio of polar solvents. The phases are separated, and the lower aqueous phase is removed, and optionally washed with additional non-polar solvent as previously described at least once. The combined organic phase containing Compound 3 is distilled under reduced pressure to produce a mixture containing concentrated Compound 3, for example, Compound 3 concentration is about 0.25 g/mL to about 1 g/mL, such as about 0.5 g/mL. The distillation temperature is suitably below about 50°C.

In the final purification step, an anti-solvent, such as a non-polar anti-solvent with a dielectric constant of less than 2 (such as n-heptane) as described elsewhere herein is added to the compound 3 concentrate to form a compound 3 concentration of about 0.05 Compound 3 free base slurry to about 0.5 g/mL, about 0.1 to about 0.3 g/mL, such as about 0.2 g/mL.

化合物3(a)。In some aspects, compound 3 is compound 3(a), (5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl amine

Compound 3(a).

In some aspects, solid compound 3 can be isolated by methods described elsewhere herein. The isolated compound 3 is washed with a non-polar solvent as appropriate. Compound 3 solids can be optionally dried by techniques known in the art, including vacuum drying at high temperatures such as about 20°C to about 50°C.

The yield of compound 3 based on compound 2 is at least 70%, at least 75%, or at least 80%, such as 80% or 85%. The percentage of analysis (w/w) as measured by the HPLC method described elsewhere herein is at least 90% or at least 95%, such as about 95% or about 96%. The purity as measured by the HPLC method described elsewhere herein is at least 97%, at least 98%, or at least 99%, such as about 99% or about 99.5%.

The yield of compound 3 based on compound 1 is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%.

In step 3, according to step 3, compound 3, compound 4 and the coupling agent are reacted in a solvent to form compound 5 as follows:

R ¹ and R ^{2 are} as previously described.

In some aspects, R ³ is -C _1-4 alkyl. In some aspects, R ³ is -CH ₃ .

In some aspects, R ^{4 is} selected from H and F. In some other aspects, R ⁴ is F.

In some other aspects, R ³ and R ⁴ together with the ring atoms to which they are attached form a three-membered carbocyclic ring.

Each asterisk refers to the palm center.

PG means amine protecting group. In some aspects, PG is selected from the group consisting of acetyl, trifluoroacetyl, third butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-茀ylmethyleneoxycarbonyl (Fmoc) . In some aspects, PG is BOC.

化合物4(a)。In some aspects, compound 4 is the following compound 4(a), (2S,4R,5S)-1-(third butoxycarbonyl)-4-fluoro-5-methylpyrrolidine-2-carboxylic acid :

Compound 4(a).

化合物5(a)。In some aspects, compound 5 is the following compound 5(a), (2S,3R,5S)-3-fluoro-2-methyl-5-((5-(trifluoromethyl)-2-(2 -(Trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methylaminecarboxamide)pyrrolidine-1-carboxylic acid third butyl ester:

Compound 5(a).

六氟磷酸鹽(HBTU)；N,N'-二環己基碳化二亞胺(DCC)；苯并三唑-1-基氧基)參(二甲胺基)鏻六氟磷酸鹽(BOP)；苯并三唑-1-基-氧基三吡咯啶基鏻六氟磷酸鹽(PyBOP)；1,1'-羰基二咪唑(CDI)；1-乙基-3-(3-二甲胺基丙基)碳化二亞胺(EDC)及羥基苯并三唑(HOBt)；及EDC及4-二甲胺基吡啶(DMAP)。在一些態樣中，偶合劑係T3P®。偶合劑可視情況呈於有機溶劑中之溶液，例如50 wt%之T3P®於乙酸乙酯中之溶液。In some aspects, the coupling agent may be selected from: propanephosphonic anhydride (T3P®); 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5 -b]pyridine 3-oxide hexafluorophosphate (HATU); 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl

Hexafluorophosphate (HBTU); N,N'-dicyclohexylcarbodiimide (DCC); benzotriazol-1-yloxy) ginseng (dimethylamino) phosphonium hexafluorophosphate (BOP) ; Benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP); 1,1'-carbonyldiimidazole (CDI); 1-ethyl-3-(3-dimethylamine Propyl) carbodiimide (EDC) and hydroxybenzotriazole (HOBt); and EDC and 4-dimethylaminopyridine (DMAP). In some aspects, the coupling agent is T3P®. The coupling agent may optionally be present in a solution in an organic solvent, such as 50 wt% T3P® in ethyl acetate.

In some aspects, the reaction mixture used to form compound 5 further comprises a base. In some aspects, the base is an organic base. In some other aspects, the base is a tertiary amine base. In some other aspects, the base is selected from N-methyl-morpholine (NMM), diisopropylethylamine (DIPEA), and triethylamine (TEA). In some other aspects, the base comprises or is NMM.

In some aspects, the solvent used to form the reaction mixture of compound 5 comprises or is a polar aprotic solvent. In some aspects, the polar aprotic solvent is selected from one or more of MeTHF, THF, ethyl acetate, propyl acetate, isopropyl acetate, acetone, DMF, acetonitrile, and DMSO. In some aspects, the polar aprotic solvent is selected from one or both of ethyl acetate and propyl acetate.

The reaction mixture used in Step 3 can be formed by combining Compound 3, Compound 4 and the solvent in the reactor with stirring until a solution is formed. The order of addition is strictly not critical. The reaction can use the approximate stoichiometric equivalent ratio of compounds 3 and 4. The concentration of Compound 3 may suitably be about 0.03 g/mL to about 0.3 g/mL, about 0.05 g/mL to about 0.15 g/mL, such as about 0.1 g/mL. Next, a base is added to the solution of compounds 3 and 4. The base is usually present in excess of compound 3 molar, such as a molar ratio between 1:1 and 3:1, ranging from about 1.1:1 to about 2:1, about 1.2:1 to about 1.5:1, such as about 1.3: 1. The coupling agent is then added to form the reaction mixture. In some aspects, the equivalent amounts of base and coupling agent are present in approximately stoichiometric equivalent amounts.

The reaction mixture is heated so as to reach at least 40°C, such as about 40°C to about 70°C or about 50°C to about 60°C. The reaction mixture may be kept at a certain temperature with stirring, and react until a reaction product mixture of step 3 (a) containing compound 5 is formed, which contains less than 5%, less than 2%, less than 1%, or less than 0.5% of starting compound 4 And/or compound 3. The analysis can be performed by HPLC as described elsewhere herein. The reaction time is usually at least 1 hour, at least 2 hours, or at least 3 hours. If the reaction product mixture contains more than 5% of compound 4, additional coupling agent can be added and the reaction can continue.

In some aspects, step 3 may further include: (i) a solvent exchange step from a solvent (eg, polar aprotic solvent) used in the compound 5 reaction mixture to a second solvent (eg, polar protic solvent); and (ii ) Precipitation step, in which solid compound 5 is produced by adding an anti-solvent. In some aspects, the solvent exchange step may include a base, such as an inorganic base. In some aspects, the base is selected from one or more of the following: alkali metal hydroxide, ammonium hydroxide, potassium carbonate, and sodium carbonate. In some aspects, the base is a strong base. In some aspects, the base is sodium hydroxide or potassium hydroxide. In some aspects, the base is an aqueous solution.

In some aspects, the second solvent in the solvent exchange is a polar protic solvent. In such aspects, the polar protic solvent may be selected from one or more of the following: methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, formic acid, and acetic acid. In some aspects, the polar protic solvent is selected from one or more of the following: methanol, ethanol, 1-propanol, and 2-propanol. In some aspects, the polar protic solvent comprises or is ethanol.

In the solvent exchange step, an aqueous alkali solution is optionally added to the reaction product mixture of step 3 containing compound 5 with stirring. Agitation was stopped and the phases were separated, and the lower aqueous phase was removed from the reactor. The remaining organic phase containing compound 5 was distilled under reduced pressure while adding a polar protic solvent in the solvent exchange step while maintaining a substantially constant volume. Continue solvent exchange until the content of polar aprotic solvent as measured by GC as described elsewhere herein is less than 2%. Compound 5 was produced in solid form by adding water. Water may then be added to the reactor, and the reaction product mixture may be heated so as to reach at least 40 °C, such as about 40 °C to about 75 or about 50 °C to about 70 °C. The amount of water based on the weight of the starting compound 3 may be suitably about 0.5 mL/g to about 2 mL/g, about 0.5 mL/g to about 1.5 mL/g, such as about 1 mL/g. The reaction product mixture can then be cooled to below about 35°C, such as from about 5°C to about 30°C or from about 10°C to about 25°C. Water may then be added, where the amount of water may suitably be about 2 mL/g to about 10 mL/g, about 4 mL/g to about 8 mL/g, such as about 6 mL/g based on the weight of the starting compound 3 g.

The solid compound 5 can be isolated by techniques known in the art as described elsewhere herein. The separated solid compound 5 is washed with a polar protic solvent and water as appropriate, and then dried as appropriate. Drying can be performed by techniques known in the art, including vacuum drying at high temperatures such as about 40°C to about 60°C.

The yield of compound 5 based on compound 3 is at least 80%, at least 85%, or at least 90%, such as 85% or 90%. The purity as measured by the HPLC method described elsewhere herein is at least 95%, at least 97%, or at least 99%, such as about 99% or about 99.5%.

In step 4, compound 5 and the acidic deprotecting base agent are reacted in a solvent as follows to deprotect the compound 5 and form compound 6:

PG, R ¹ , R ² , R ³ and R ^{4 are} as previously described.

化合物6(a)In some aspects, compound 5 is compound 5(a) disclosed elsewhere herein. In some such aspects, compound 6 is the following compound 6(a) (2S,4R,5S)-4-fluoro-5-methyl-N-((5-(trifluoromethyl)-2-( Acid salt of 2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide:

Compound 6(a)

The acidic deprotection base agent may be an organic acid or an inorganic acid. In some aspects, the acidic deprotecting base agent is an acyl halide or an inorganic acid. In some aspects, the acidic deprotecting base agent is selected from the following acyl chlorides: acetyl chloride, methyl chloride, propyl chloride, and butyl chloride, or inorganic acids selected from hydrochloric acid and sulfuric acid. In some aspects, the acidic deprotection base is acetyl chloride, so that compound 6(a) is the acetate salt. In certain embodiments, the acidic deprotection base is hydrochloric acid, so that compound 6(a) is the hydrochloride salt.

In some aspects, the solvent used in step 4 contains or is a polar protic solvent. In some aspects, the polar protic solvent is selected from one or more of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, formic acid, and acetic acid. In some aspects, the polar protic solvent is selected from one or more of the following: methanol, ethanol, 1-propanol, and 2-propanol. In some aspects, the polar protic solvent comprises or is 1-propanol.

In step 4, the solvent, compound 5 and acidic deprotection base are combined in the reactor with stirring to form a reaction mixture. The acidic deprotection base compound is 5 equivalent excess. In some aspects, the molar ratio of the acidic deprotecting base agent to Compound 5 may be between 1:1 and 5:1, ranging from about 1.5:1 to about 4:1, or from about 2:1 to about 3 :1, such as about 2.5:1. The concentration of compound 5 in the reaction mixture may suitably be about 0.05 g/mL to about 1 g/mL, about 0.075 g/mL to about 0.5 g/mL, or about 0.1 g/mL to about 0.3 g/mL, such as about 0.2 g/mL. The reaction mixture is heated to at least 40°C with stirring, such as about 40°C to about 75°C or about 50°C to about 70°C, and is left to stand until a reaction product mixture comprising Compound 6, which contains less than 5%, less than 2% , Less than 1% or less than 0.5% of the starting compound 5. The analysis can be performed by HPLC as described elsewhere herein. The reaction time is usually at least 1 hour, at least 2 hours, or at least 3 hours.

In some aspects, the reaction product mixture containing Compound 6 may be distilled under reduced pressure while adding a non-polar anti-solvent (eg, n-heptane) having a dielectric constant of less than 2 while maintaining a substantially constant volume. An anti-solvent is added to form solid compound 6 in the reaction product mixture. Distillation is continued until a volume ratio of non-polar antisolvent to polar protic solvent present in the reaction mixture of step 4 of at least about 0.5:1, 0.75:1 or 1:1, such as about 1:1 to about 4:1, about 1.5:1 to about 3:1, such as about 2:1. The reactor contents are then cooled to below about 40°C, such as from about 5°C to about 30°C, and Compound 6 solids are separated by methods as described elsewhere herein. The isolated compound 6 solid is optionally washed with a combination of polar protic solvent and non-polar anti-solvent.

Compound 6 solid may be dried as appropriate. Drying can be performed by techniques known in the art, including vacuum drying at high temperatures such as about 30°C to about 40°C.

The yield of compound 6 based on compound 5 is at least 80%, at least 85%, or at least 90%, such as 85% or 90%. The purity as measured by the HPLC method described elsewhere herein is at least 96%, at least 97%, or at least 98%, such as about 98% or about 98.5%.

In step 5, the acid salt of compound 6, compound 7 and base are reacted in a solvent system as follows to form compound (I):

R ¹ , R ² , R ³ and R ^{4 are} as previously described.

R ⁵ is a halogen group. In some aspects, R ⁵ is F.

n系1 or 2. In some aspects, n is 1.

X ₁ and X _{2 are} each C, or one of X ₁ and X ₂ is N and the other is C. In some aspects, X ₁ and X _{2 are} each C. In some aspects, X ₁ is C and X ₂ is N. In some aspects, X ₁ is N and X ₂ is C.

化合物I(a)。In some aspects, compound 6 is compound 6(a) disclosed elsewhere herein. In some such aspects, compound (I) is the following compound I(a), (2S,4R,5S)-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl-N -((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide:

Compound I(a).

In step 5, compound 6, a solvent system containing a non-polar solvent, a base, and compound 7 are combined with stirring to form a reaction mixture, and then allowed to react to form a reaction product mixture containing compound (I). In some aspects, the reaction mixture is formed by combining Compound 6 with a non-polar solvent, then adding a polar protic solvent as appropriate, and then adding an aqueous alkaline solution.

The base used in step 5 may be an organic base or an inorganic base. In some aspects, the base is an inorganic base. In some aspects, the alkali is an inorganic alkali aqueous solution. In some such aspects, the base is selected from aqueous solutions of alkali metal hydroxides, ammonium hydroxide, potassium carbonate, and sodium carbonate. In some aspects, the alkali is an aqueous solution of potassium carbonate or sodium carbonate.

The solvent system used in step 5 contains a non-polar solvent with a dielectric constant greater than 2. In some aspects, the non-polar solvent is selected from one or more of the following: methyl tertiary butyl ether, diethyl ether, 1,4-dioxane, and chloroform. In some aspects, the non-polar solvent is selected from methyl tert-butyl ether and diethyl ether. In some aspects, the solvent comprises or is methyl tertiary butyl ether. The solvent system may further include a polar protic solvent selected from one or more of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, formic acid, and acetic acid as the case may be. In some aspects, the polar protic solvent is selected from one or more of the following: methanol, ethanol, 1-propanol, and 2-propanol. In some aspects, the polar protic solvent comprises or is ethanol. The volume ratio of the non-polar solvent to the optional polar protic solvent may be suitably about 1:1 to about 20:1, about 1:2 to about 20:1, about 5:1 to about 15:1, such as About 10:1. The equivalent ratio of base to compound 6 may be greater than 1:1, between about 1:1 and about 4:1, ranging from about 1.5:1 to about 3:1, such as about 2:1.

In the reaction mixture, the concentration of the compound (I) in the non-polar solvent may be suitably about 0.05 g/mL to about 1 g/mL, about 0.1 g/mL to about 0.75 g/mL, about 0.15 g/mL to about 0.4 g/mL, about 0.2 g/mL to about 0.3 g/mL, such as about 0.25 g/mL. In the aspect involving an aqueous solution of an inorganic base, the volume ratio of water to non-polar solvent in the reaction mixture may be suitably about 0.25:1 to about 4:1, about 0.5:1 to about 2:1, such as about 1: 1.

The reaction mixture is maintained at a certain temperature for a certain period of time sufficient to produce a reaction product mixture comprising Compound (I) and less than about 5% of Compound 6, as measured by HPLC as described elsewhere herein. The reaction temperature is suitably about 10°C to about 60°C, about 10°C to about 50°C, or about 15°C to about 40°C. The reaction time is usually at least 1 hour, at least 2 hours, or at least 3 hours.

In the aspect of the present invention where the reaction product mixture contains water, the phases are separated, and the lower aqueous phase is removed. In any of the various aspects, water can be added to the organic mixture in the reactor with stirring to separate the phases and remove the lower aqueous phase. Additional water washing steps or washing with saline solution are within the scope of the present invention. The remaining organic phase containing compound (I) can be distilled under reduced pressure to reduce the volume and form a concentrate of the reaction product mixture containing compound (I). In some aspects, the distillation may continue until the minimum stirring volume is reached.

A solvent exchange step may be performed to exchange the solvent in the concentrate of the reaction product mixture containing compound (I) with a novel solvent selected from the following: (i) a second non-polarity having a dielectric constant greater than 2 as described elsewhere herein Solvents; (ii) polar aprotic solvents as described elsewhere herein; or (iii) polar protic solvents as described elsewhere herein, and thereby form a solution of compound (I) in a novel solvent. The solvent exchange can be suitably performed by adding the novel solvent to the reaction product mixture concentrate containing the compound (I), followed by distillation under reduced pressure while adding the novel solvent while maintaining a substantially constant volume.

A non-polar anti-solvent (such as n-heptane) as described elsewhere herein can then be added to the distilled mixture containing compound (I) with stirring, and the blend can be suitably heated to about 40°C to about 85°C or about 50°C to about 80°C, and then cooled to less than 20°C, such as about -10°C to about 15°C or about -5°C to about 10°C to form a second nonpolar with a dielectric constant greater than 2 The solvent, the polar aprotic solvent or the solid crystalline compound (I) exchanged as a solvate of the polar protic solvent of the solvent in the reaction mixture of step 5. A suitable concentration of compound (I) in the anti-solvent may be about 0.025 to about 1 g/mL or about 0.05 to about 0.5 g/mL. The crystalline compound (I) can be isolated by methods described elsewhere herein. The isolated compound (I) may be known in the art described elsewhere herein at high temperatures such as about 30°C to about 70°C or about 40°C to about 60°C, such as about 50°C to about 60°C Technical drying. Compound (I) can be dried until the non-polar antisolvent content is less than 0.5% as measured by GC as described elsewhere herein. The yield of compound (I) based on compound 6 is at least 80%, at least 85% or at least 90%, for example 85% or 90%. The analysis measured by the HPLC method described elsewhere is at least 85% or at least 90%, such as about 90% or about 92%. The purity as measured by the HPLC method described elsewhere herein is at least 97%, at least 98%, or at least 99%, such as about 98.5% or about 99%.

In the aspect of the novel solvent DMAc in the solvent exchange step, the crystalline compound (I) is designated as the C-type DMAc solvate. In the aspect of the novel solvent anisole, the crystalline compound (I) is designated as the D-type anisole solvate. In the aspect of the novel solvent-based ethanol, the crystalline compound (I) is designated as the F-type ethanol solvate. In the aspect of the novel solvent-based toluene, the crystalline compound (I) is designated as the G-type toluene solvate. In the aspect of the novel solvent system 2-propanol, the crystalline compound (I) is designated as H-type 2-propanol solvate. In the aspect of the novel solvent system 1-butanol, the crystalline compound (I) is designated as the type I 1-butanol solvate. In the aspect of the novel solvent system MeTHF, the crystalline compound (I) is designated as the J-type MeTHF solvate. In the aspect of the novel solvent system THF, the crystalline compound (I) is designated as the K-type THF solvate. In the case of the novel solvent system isobutanol, the crystalline compound (I) is designated as the L-type isobutanol solvate. In the aspect of the novel solvent system DMSO, the crystalline compound (I) is designated as the M-type DMSO solvate. In the aspect of the novel solvent system 2-pentanol, the crystalline compound (I) is designated as the 2-pentanol solvate of the BK type. In the aspect of the novel solvent system isopropyl acetate, the crystalline compound (I) is designated as a BK type isopropyl acetate solvate.

In some aspects, Form F can be obtained by slowly evaporating a solution of Compound (I) in ethanol. In some other aspects, Form H can be obtained by slowly evaporating the solution of compound (I) in IPA or by slowly evaporating the solution of compound (I) in MTBE and IPA.

In some aspects of the invention, the crystalline compound (I) Form E can be prepared from the amorphous compound (I) or from any of a variety of crystalline hydrate types. In such aspect, the compound (I) is dissolved in DCM at a temperature below about 50°C to form a solution. The temperature is suitably about 5°C to about 50°C, about 10°C to about 40°C, or about 10°C to about 30°C. The concentration of compound (I) in DCM may suitably be about 0.05 g/mL to about 2 g/mL, about 0.1 g/mL to about 1 g/mL, or about 0.1 g/mL to about 0.5 g/mL. Add a non-polar anti-solvent (such as n-heptane) with a dielectric constant of less than 2 as described elsewhere in this article to the compound (I) solution to induce crystallization of the crystalline compound (I) Form E and form its slurry . The volume ratio of total antisolvent to DCM may suitably be about 1:1 and about 5:1, about 1.5:1 to about 4:1, or about 1.5:1 to about 3:1, such as about 2:1. In some aspects, the initial anti-solvent addition is performed, followed by addition in increments over an addition period such as about 1 hour to about 5 hours or about 2 hours to about 4 hours. After the initial anti-solvent addition and before one or more other anti-solvent additions, the crystalline compound (I) E-type seed crystal is optionally added.

The solid crystalline compound (I) Form E can be separated from the slurry by techniques known in the art as described elsewhere herein, with the concomitant production of mother liquor. The separated solids are washed with mother liquor and/or anti-solvent as appropriate, and then dried as appropriate. The crystalline compound (I) Form E can be used in such techniques as described elsewhere herein at high temperatures such as about 30°C to about 70°C, or about 40°C to about 60°C, such as about 45°C to about 55°C Known techniques to dry. Compound (I) is dried until the DCM content is less than 600 ppm and the non-polar anti-solvent content is less than 0.45%, as measured by GC as described elsewhere herein. The yield of compound (I) based on compound 6 is at least 80%, at least 85% or at least 90%, for example 85% or 90%. The purity as measured by the HPLC method described elsewhere herein is at least 98%, at least 99%, or at least 99.5%, such as about 99%, about 99.5%, or about 99.9%.

Compound 1 can be prepared according to the three-step method shown in FIG. 2 and further referring to examples.

。In the first step, compound 10A, an alkyl ester-forming agent and a base are reacted in a solvent according to the following to form compound 10B:

.

The alkyl ester-forming agent may be an alkylating agent, and in many embodiments, may be a methylating agent, such as methyl tosylate.

The reaction mixture is formed of compound 10A, a solvent, an alkylating agent, a methylating agent, and a base, and the reaction mixture is reacted at a temperature of about 25°C to about 60°C or about 30°C to about 50°C to form a reaction including compound 1B Product mixture. In some aspects, the solvent comprises or is a polar aprotic solvent. R ¹ and R ² , polar aprotic solvents, methylating agents, and bases are as described elsewhere herein. In some aspects, the polar aprotic solvent comprises or is DMF. In some aspects, the alkylating agent may be a methylating agent selected from methyl iodide, methyl tosylate, and methyl methanesulfonate. In some aspects, the base is an inorganic base, or an inorganic base selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate. The reaction product mixture may be combined with water and a non-polar solvent having a dielectric constant greater than 2 (eg MTBE) as described elsewhere herein, followed by phase separation to remove the aqueous phase. The aqueous phase can be washed one or more times with additional non-polar solvents. The organic phase containing Compound 1B can be combined with a polar aprotic solvent (such as THF) and distilled to a Compound 1B concentration of about 0.1 to about 2 g/mL or about 0.25 to about 0.75 g/mL.

In some embodiments, the methylating agent can be replaced with other lower alkyl reagents so that compound 10B is a lower alkyl ester other than the methyl ester as shown.

。In the second step, compound 1B and the reducing agent are reacted in a solvent according to the following to form compound 1C:

.

Forming a reaction mixture of compound 1B contained in a solvent (eg THF), additional solvent (eg THF), water and a reducing agent, and reacting at a temperature below 25°C, such as from about 5°C to about 20°C to form The reaction product mixture of compound 1C. In some aspects, the solvent is a polar aprotic solvent. R ¹ and R ² and polar aprotic solvents are as described elsewhere herein. In some aspects, the reducing agent is a borohydride compound, such as sodium borohydride NaBH ₄ . The pH value of the reaction product mixture is adjusted to about 1 with an inorganic acid (eg, HCl), and the adjusted reaction product mixture is stirred at a certain temperature, for example, for at least 1 hour or at least 4 hours. The phases were separated, and the lower aqueous phase was removed, leaving the organic phase containing compound 1C. The aqueous phase can be washed at least once again with a polar aprotic solvent (such as ethyl acetate) as described elsewhere herein. The combined organic phases containing compound 1C can be washed one or more times with an inorganic base aqueous solution (eg sodium bicarbonate or potassium bicarbonate) and/or saline solution (eg NaCl). The washed organic phase is combined with a non-polar solvent (such as n-heptane) having a dielectric constant of less than 2 as described elsewhere herein, and then distilled under reduced pressure at a temperature below about 70°C. A further non-polar solvent can be added, and the mixture is cooled to below about 20°C, such as from about -5°C to about 5°C. The solid compound 1C can be separated from the slurry by techniques known in the art as described elsewhere herein. The separated solids are optionally washed with anti-solvent, and then optionally dried by techniques known in the art described elsewhere herein. The yield of compound 1C based on compound 1B is at least 70%, at least 75%, or at least 80%, for example 80%. The purity as measured by the HPLC method described elsewhere herein is at least 98% or at least 99%, such as about 99% or about 99.4%.

。In the third step, compound 1C, compound 8, catalyst and base are reacted in a solvent according to the following to form compound 1:

.

Forming a reaction mixture comprising Compound 1C, Compound 8, solvent, catalyst, and base, and reacting at a temperature of about 65°C to about 90°C, about 70°C to about 85°C, or about 75°C to about 80°C to form an inclusion The reaction product mixture of compound 1. In some aspects, the solvent is a non-polar solvent with a dielectric constant greater than 2. R ¹ and R ² , the base and the non-polar solvent are as described elsewhere herein. In some aspects, the solvent comprises or is 1,4-dioxane. In some aspects, the base is an inorganic base, or is selected from potassium bicarbonate and sodium bicarbonate. In some aspects, the catalyst is a palladium catalyst, such as (but not limited to) Pd(dppf)Cl ₂ . The reaction was continued until the compound 1C content was less than 5% as measured by HPLC as described elsewhere herein. After the reaction is complete, the reaction product mixture can be distilled to reduce the volume, and the resulting concentrate containing Compound 1 is combined with water and a non-polar solvent (eg, MTBE) having a dielectric constant greater than 2. The phases were separated, and the lower aqueous phase was removed, leaving the organic phase containing Compound 1. The aqueous phase can be washed at least once again with a non-polar solvent (eg MTBE) having a dielectric constant greater than 2. Mix the combined organic phase with a non-polar anti-solvent (such as n-heptane) having a dielectric constant of less than 2 as described elsewhere herein, and then distill under reduced pressure at a temperature below about 70°C to reduce the volume . At least one more non-polar anti-solvent addition and distillation steps can be performed. A non-polar solvent (eg, DCM) may be added, and the mixture is cooled to below about 40°C, such as from about 20°C to about 35°C. Solid compound 1 can be separated from the slurry by techniques known in the art as described elsewhere herein. The separated solid can be washed with anti-solvent and non-polar solvent with a dielectric constant greater than 2 as appropriate. Compound 1 is then optionally dried by techniques known in the art described elsewhere herein. The yield of compound 1 based on compound 1C is at least 70% or at least 75%, for example 75% or 78%. The purity as measured by the HPLC method described elsewhere herein is at least 97%, at least 98%, or at least 98.5%, such as about 98% or about 98.7%.

。In some aspects, compound 10A is the following compound 10A(i), 2-chloro-5-methylisonicotinic acid:

.

。In some aspects, compound 10B is the following compound 10B(i), 2-chloro-5-methyl isonicotinic acid methyl ester:

.

。In some aspects, compound 10C is the following compound 10C(i), (2-chloro-5-methylpyridin-4-yl)methanol:

.

酸酯化合物8：

。The following compound 8 can be prepared from compound 8A 5-bromo-2-iodopyrimidine as follows: by introducing trifluoromethyl to form compound 8(b) (5-bromo-2-(trifluoromethyl)pyrimidine), which According to the two-step method shown in FIG. 2 and further referring to the following example, it is converted to

Ester compound 8:

.

Polar aprotic solvents are described elsewhere in this article. In some aspects, the solvent used in Step 1 contains or is DMF, and the solvent used in Step 2 contains or is THF.

In some aspects of the invention, compound 4(a) (2S,4R,5S)-1-(third butoxycarbonyl)-4-fluoro-5-methylpyrrolidine-2-carboxylic acid can be obtained from compound 4A It was prepared according to the 7-step method shown in FIG. 3 and with further reference to the examples.

Chemical compound (I) Polymorph and preparation method

Provided herein are crystalline forms of compound (I) (eg, compound I(a)) and pharmaceutical compositions comprising the crystalline forms of compound (I). Certain crystalline polymorphic salts of compound (I) are also within the scope of the present invention. It has been found that the crystal form of compound (I) can be prepared in one or more polymorphic forms, including hydrate, solvate and salt forms. These polymorphic forms exhibit novel physical properties compared to prior art amorphous forms, which can be used to obtain novel pharmacological properties and can be used in the development of pharmaceutical substances and drugs. More specifically, the crystalline form of Compound (I) and its pharmaceutical composition are suitable for preventing, ameliorating, or treating diseases mediated by TRPA1.

Contrary to the amorphous form of the compound (I) free base, the crystalline form is characterized by the presence of observable peaks in the powder X-ray diffraction (PXRD) pattern measured by the crystalline form. The measured or calculated PXRD patterns of the salt and crystal types reported herein represent fingerprint patterns that can be compared to other experimentally determined patterns to find matching fingerprints. The consistency of the individual crystalline patterns has been determined by the overlapping or matching of the PXRD patterns determined experimentally and the PXRD patterns of the crystalline patterns reported herein. In various embodiments, the salt and crystal forms are characterized by exhibiting at least one of the PXRD peaks reported here. Therefore, in various embodiments, the salt or crystalline pattern is characterized by a match of two or more peaks, a match of 3 or more peaks, a match of 4 or more peaks, or 5 from each PXRD pattern Matching of one or more peaks, etc.

In some embodiments, the percent crystallinity of any of the salts or crystal forms of Compound (I) described herein may vary according to the total amount of Compound (I). In particular, certain embodiments provide at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the crystallinity percentage of the salt or crystal form of Compound (I). In some embodiments, the percentage of crystallinity may be substantially 100%, where substantially 100% indicates that the entire amount of compound (I) appears to be crystalline, as determined best using methods known in the art. Therefore, the therapeutically effective amount of the pharmaceutical composition and compound (I) may include an amount of change in crystallinity. Such cases include the use of compound (I) as a variety of formulations and active pharmaceutical ingredients (API) in solid form, including the sequential dissolution, partial dissolution or suspension or dispersion of a certain amount of compound (I) in solid form The situation in the liquid.

As mentioned, in some embodiments, an API composition comprising compound (I) is provided, wherein at least a portion of compound (I) in the API composition is in one of a salt or a crystalline form. For example, the API composition containing compound (I) is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, At least 95% or at least 99% of the compounds of the composition are in one of the salt or crystalline forms. In some embodiments, substantially 100% of the API formulation of compound (I) is in the salt or crystalline form as described herein.

Any of the crystalline forms (including salts and solvated forms) of Compound (I) can be used as an API for preparing a pharmaceutical composition. The solvated version can be applied as a process intermediate in the preparation of the solvent-free version as indicated above. Compound (I) salts and crystalline forms can be used to prepare pharmaceutical compositions suitable for various routes of administration (including oral) to subjects in need. Therefore, in some embodiments, a pharmaceutical composition comprising a crystalline form of compound (I) and one or more pharmaceutically acceptable excipients is provided.

In some embodiments, the salt or crystalline form of compound (I) includes the following salt or crystalline form: (1) compound with PXRD pattern A (I) free base hydrate; (2) compound with PXRD pattern E ( I) Free base anhydrous; (3) Compound with PXRD pattern C (I) Free base N,N-dimethylacetamide solvate; (4) Compound with PXRD pattern D (I) Free base benzene Methyl ether solvate; (5) compound with pattern F (I) free base ethanol solvate; (6) compound with PXRD pattern G (I) free base toluene solvate; (7) with PXRD pattern H Compound (I) free base 2-propanol solvate; (8) compound with PXRD pattern I (I) free base 1-butanol solvate; (9) compound with PXRD pattern J (I) free Base 2-methyltetrahydrofuran solvate; (10) Compound with PXRD pattern K (I) Free base tetrahydrofuran solvate; (11) Compound with PXRD pattern L (I) Isobutanol solvate; (12 ) Compound with PXRD pattern M (I) DMSO solvate; (13) Compound with eutectic PXRD pattern A (I) Anhydrogen gentisic acid co-crystal; (14) Compound with eutectic PXRD pattern B (I) Anhydrous gentisic acid co-crystal; (15) compound with co-crystal PXRD pattern C (I) hydrated pyridine-carboxamide co-crystal; (16) compound with PXRD pattern AL (I) free base anhydrous; (17) with PXRD pattern BO compound (I) free base hydrate; (18) compound (I) free base n-heptane solvate PXRD pattern BP; (19) compound (I) free base 2-pentanol solvate PXRD pattern BK; (20) Compound (I) free base 1-propanol solvate PXRD pattern AX; (21) Compound (I) free base m-xylene solvate PXRD pattern Q; (22) Compound (I) free base 2-Methoxyethanol solvate PXRD pattern P; and (23) Compound (I) free base second butyl ethanol solvate PXRD pattern AQ.

Based on certain attributes and in some aspects, the crystalline Compound I(a) free base anhydrous E form is the preferred polymorphic form. For example, the E type is the only anhydrous found. The grinding evaluation indicates that the E-type does not form any significant amorphous material after jet grinding. When evaluated by XRPD and HPLC, Type E exhibits good physical and chemical stability under conditions of 80°C (sealed)/24 hours, 25°C/60% RH/6 days and 40°C/75% RH/6 days Sex. In addition, Type E showed no type change after DVS evaluation at 25°C. In addition, Form E production can be easily scaled up by anti-solvent crystallization in DCM/n-heptane at room temperature.

In certain embodiments of the methods described herein, the solvate version of compound (I) can be obtained by exposing the compound to a continuous solvent to form crystals of compound (I). For example, but not limited to, compound (I) may be dissolved in a first solvent (such as dichloromethane), and then crystallization is induced by adding an anti-solvent (such as n-heptane). In any of a number of aspects, crystals can be separated by techniques known in the art, including filtration, centrifugation, and Shendian. The separated crystals are optionally washed with anti-solvent and then dried. Drying can be performed by techniques known in the art, including vacuum drying at high temperatures such as about 35°C to about 60°C.

Compound (I) (eg Compound I(a)) free base anhydrous form E can be prepared from a solution of compound (I) free base in dichloromethane (DCM). The concentration of compound (I) in the solution is suitably at least 50 g/L at room temperature, such as about 200 g/L, about 150 g/L, about 300 g/L, about 350 g/L, or about 400 g/ L and its range, such as about 200 g/L to about 400 g/L or about 250 g/L to about 350 g/L. Then add n-heptane in the following volume of DCM and n-heptane: volume ratio: about 1:2, about 1:2.5, about 1:3, about 1:3.5, about 1:4 or about 1:5 and its range , Such as about 1:2 to about 1:5, or about 1:2.5 to about 1:3.5. E-type seeds of Compound (I) may be added as appropriate to induce and/or enhance crystallization.

Optionally, crystalline compound (I) (for example, compound I(a)) free base anhydrous form E can be prepared by solid phase transformation. In one such aspect, Form E can be prepared by heating the solid compound (I) free base anisole form D solvate to greater than about 100°C, such as about 110°C. In another such aspect, Form E can be prepared by heating the solid compound (I) free base ethanol Type F solvate to greater than about 100°C, such as about 105°C. In another such aspect, Form E can be prepared by heating the solid compound (I) free base toluene type G solvate to greater than about 100°C, such as about 110°C. In another such aspect, Form E can be prepared by heating the solid compound (I) free base 2-propanol form H solvate to greater than about 110°C, such as about 125°C.

In the state where the crystalline compound I(a) is designated as the free base anhydrous of type E, the type E can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by the Type E has characteristic peaks at angles expressed as 2θ degrees as follows: 7.5°±0.2°, 8.2°±0.2°, 12.6°±0.2°, 13.1°±0.2 °, 13.4°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 15.5°±0.2°, 16.1°±0.2°, 16.6°±0.2°, 18.2°±0.2°, 18.9°±0.2°, 19.9°±0.2°, 20.4°±0.2°, 21.0°±0.2°, 21.5°±0.2°, 21.8°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 24.3°±0.2°, 25.0° ±0.2°, 25.4°±0.2° and 28.4°±0.2°. The endothermic peak (start) of type E was determined to be 147.0°C. In another aspect, the E-type free base anhydrate exhibits an XRPD pattern that is substantially consistent with FIG. 10. In another aspect, the E type exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 11. In another aspect, Type E exhibits an NMR spectrum that is substantially consistent with FIG. 12. In another aspect, the E-type exhibits a DVS isotherm that is substantially consistent with FIG. 13.

The crystalline compound (I) free base hydrate form A can be prepared from a solution, which is dissolved at 60°C from an E-shaped or amorphous material at 125 mg/mL in methanol, after which 5-20% (v/v) is added Water, and then cooled to 10°C. The solid was then collected by vacuum filtration and dried at ambient room temperature and pressure.

In the aspect that the crystalline compound I(a) is a form of free base hydrate A, it can be identified according to the characteristic peak in XRPD analysis. In one such aspect, the XRPD pattern exhibited by Type A has characteristic peaks at angles expressed as 2θ degrees as follows: 7.2°±0.2°, 12.2°±0.2°, 14.0°±0.2°, 14.2°±0.2 °, 15.5°±0.2°, 15.8°±0.2°, 17.0°±0.2°, 17.2°±0.2°, 18.4°±0.2°, 21.3°±0.2°, 21.6°±0.2°, 22.2°±0.2°, 23.4°±0.2°, 24.4°±0.2° and 25.2°±0.2°. The endothermic peak (start) of type A was determined to be 98.0°C. In another aspect, Type A free base hydrate exhibits an XRPD pattern substantially consistent with FIG. 6. In another aspect, Type A exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 7. In another aspect, Type A exhibits an NMR spectrum that is substantially consistent with FIG. 8. In another aspect, Type A exhibits a DVS isotherm that is substantially consistent with FIG. 9.

The crystalline compound (I) free base N,N-dimethylacetamide (DMAc) solvate form C can be prepared from a solution of compound (I) in DMAc by adding a water antisolvent. Optionally, type C crystals can be prepared by evaporating DMAc from the solution and/or by cooling the solution below about 10°C, such as from about 0°C to about 5°C. Optionally, Compound (I) DMAc solvate C-type seeds are added to induce and/or enhance crystallization.

In the aspect that the crystalline compound I(a) is the DMAc solvate form C, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by Type C has characteristic peaks at angles expressed as 2θ degrees as follows: 10.8°±0.2°, 12.1°±0.2°, 12.3°±0.2°, 13.6°±0.2 °, 13.8°±0.2°, 14.9°±0.2°, 16.0°±0.2°, 16.2°±0.2°, 17.1°±0.2°, 18.2°±0.2°, 21.2°±0.2°, 21.5°±0.2°, 22.4°±0.2°, 21.2°±0.2°, 23.5°±0.2°, 24.2°±0.2°, 25.2°±0.2°, 27.2°±0.2° and 27.9°±0.2°. The endothermic peak (start) of type C was determined to be 100.4°C. In another aspect, the C-type DMAc solvate exhibits an XRPD pattern that is substantially consistent with FIG. 25. In another aspect, Type C exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 26. In another aspect, Form C exhibits an NMR spectrum that is substantially consistent with FIG. 27.

The crystalline compound (I) (for example, compound I(a)) free base anisole solvate Form D can be prepared from a solution of compound (I) in anisole by adding anisole in n-heptane antisolvent. In some aspects, a solution of compound (I) in anisole can be contacted with n-heptane vapor to form water. Optionally, D-type crystals can be prepared by evaporating anisole from the solution and/or by cooling the solution to below about 10°C, such as from about 0°C to about 5°C. The anisole solvate D-type seeds of compound (I) may be added as appropriate to induce and/or enhance crystallization.

In the state where the crystalline compound I(a) is designated as the free base anisole solvate of type D, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by the D pattern has characteristic peaks at angles expressed as 2θ degrees as follows: 5.7°±0.2°, 12.8°±0.2°, 15.4°±0.2°, 17.1°±0.2 °, 18.1°±0.2° and 20.8°±0.2°. The endothermic peak (start) of type D was determined to be 94.9°C. In another aspect, the D-anisole solvate exhibits an XRPD pattern substantially consistent with FIG. 28. In another aspect, the D-type exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 29. In another aspect, the D-form exhibits an NMR spectrum that is substantially consistent with FIG. 30.

The crystalline Compound (I) (eg Compound I(a)) free base ethanol solvate Form F can be prepared from a solution of Compound (I) in ethanol by adding n-heptane antisolvent. Optionally, type F crystals can be prepared by evaporating ethanol from the solution and/or by cooling the solution to below about 10°C, such as from about 0°C to about 5°C. Optionally, the compound (I) ethanol solvate F-type seed crystal is added to induce and/or enhance crystallization.

In the state where the crystalline compound I(a) is designated as the free base ethanol solvate of type F, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by the Type F has characteristic peaks at angles expressed as 2θ degrees as follows: 11.7°±0.2°, 12.9°±0.2°, 13.3°±0.2°, 17.4°±0.2 °, 18.5°±0.2°, 19.4°±0.2°, 23.5°±0.2°, 24.3°±0.2° and 25.9°±0.2°. The endothermic peaks (start) of type F were measured at 100.3°C and 36.4°C. In another aspect, the F-type free base ethanol solvate exhibits an XRPD pattern substantially consistent with FIG. 32. In another aspect, the F-type exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 33. In another aspect, Form F exhibits an NMR spectrum that is substantially consistent with FIG. 34.

Crystalline Compound (I) (eg Compound I(a)) free base toluene solvate Form G can be prepared from a solution of Compound (I) in toluene by cooling the solution to below about 10°C, such as from about 0°C to about 5 ℃ to prepare. Optionally, G-type crystals can be prepared by evaporating toluene from the solution and then cooling. Optionally, a compound (I) toluene solvate G type seed crystal is added to induce and/or enhance crystallization.

In the aspect that the crystalline compound I(a) is designated as the free base toluene solvate of type G, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by the Type G has characteristic peaks at angles expressed as 2θ degrees as follows: 13.8°±0.2°, 16.7°±0.2°, 17.6°±0.2°, 17.8°±0.2 °, 18.8°±0.2°, 22.5°±0.2° and 25.1°±0.2°. The endothermic peak (start) of type G was determined to be 106.3°C. In another aspect, the G-type free base toluene solvate exhibits an XRPD pattern substantially consistent with FIG. 36. In another aspect, the G-type exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 37. In another aspect, Form G exhibits an NMR spectrum that is substantially consistent with FIG. 38.

The crystalline Compound (I) (eg Compound I(a)) free base 2-propanol solvate Form H can be prepared from a solution of Compound (I) in MTBE by adding 2-propanol antisolvent. The compound (I) 2-propanol solvate H-type seed crystal may be added as appropriate to induce and/or enhance crystallization.

In the aspect that the crystalline compound I(a) is designated as the free base 2-propanol solvate of the H form, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by the H pattern has characteristic peaks at angles expressed as 2θ degrees as follows: 11.5°±0.2°, 12.8°±0.2°, 13.1°±0.2°, 17.5°±0.2 °, 18.2°±0.2°, 22.3°±0.2°, 23.2°±0.2° and 24.0°±0.2°. The endothermic peak (start) of the H type was determined to be 116.3°C. In another aspect, the H-type free base 2-propanol solvate exhibits an XRPD pattern substantially consistent with FIG. 40. In another aspect, the H-type exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 41. In another aspect, the H-form exhibits an NMR spectrum that is substantially consistent with FIG. 42.

The crystalline Compound (I) (eg Compound I(a)) free base 1-butanol solvate Form I can be crystallized from Form A at a temperature greater than about 35°C, such as about 40°C, about 50°C or about 60°C The slurry is prepared. Compound (I) 1-propanol solvate type I seeds may be added as appropriate to induce and/or enhance crystallization.

In the state where the crystalline compound I(a) is designated as the free base 1-butanol solvate of type I, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by Type I has characteristic peaks at angles expressed as 2θ degrees as follows: 12.0°±0.2°, 12.4°±0.2°, 12.6°±0.2°, 13.3°±0.2 °, 14.0°±0.2°, 15.1°±0.2°, 17.2°±0.2°, 17.9°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, 23.1°±0.2°, 24.3°±0.2°, 25.4°±0.2°, 25.9°±0.2° and 27.3°±0.2°. The endothermic peak (start) of type I was determined to be 90.0°C. In another aspect, the Type I free base 1-butanol solvate exhibits an XRPD pattern substantially consistent with FIG. 44. In another aspect, Type I exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 45. In another aspect, Type I exhibits an NMR spectrum that is substantially consistent with FIG. 46.

Crystalline compound (I) (eg compound I(a)) free base 2-methyltetrahydrofuran (MeTHF) solvate Form J can be prepared from a slurry of Form A crystals in MeTHF and n-heptane at about room temperature . A suitable volume ratio of MeTHF to n-heptane is about 1:1.1 to about 1:5, such as about 1:1.15, 1:2, 1:2.5 or 1:3. Optionally, compound (I) MeTHF solvate J-type seeds are added to induce and/or enhance crystallization.

In the aspect that the crystalline compound I(a) is designated as the J-type free base MeTHF solvate, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by the J pattern has characteristic peaks at angles expressed as 2θ degrees as follows: 11.8°±0.2°, 13.1°±0.2°, 14.5°±0.2°, 16.8°±0.2 °, 18.4°±0.2°, 19.4°±0.2°, 20.7°±0.2°, 21.8°±0.2°, 24.3°±0.2° and 26.4°±0.2°. The endothermic peak (start) of the J type was determined to be 82.2°C. In another aspect, the J-type free base MeTHF solvate exhibits an XRPD pattern substantially consistent with FIG. 47. In another aspect, the J-type exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 48. In another aspect, the J-form exhibits an NMR spectrum that is substantially consistent with FIG. 49.

Crystalline Compound (I) (eg Compound I(a)) free base THF solvate form K can be prepared from a slurry of form A crystals in THF and n-heptane at about room temperature. A suitable volume ratio of THF to n-heptane is about 1:1.1 to about 1:5, such as about 1:1.15, 1:2, 1:2.5 or 1:3. Optionally, compound (I) THF solvate K-type seeds are added to induce and/or enhance crystallization.

In the state where the crystalline compound I(a) is designated as the K-type free base THF solvate, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by the K-type has characteristic peaks at angles expressed as 2θ degrees as follows: 11.0°±0.2°, 12.0°±0.2°, 12.4°±0.2°, 12.6°±0.2 °, 13.3°±0.2°, 13.5°±0.2°, 14.1°±0.2°, 14.7°±0.2°, 17.2°±0.2°, 18.5°±0.2°, 19.5°±0.2°, 20.9°±0.2°, 21.4°±0.2°, 21.6°±0.2°, 22.0°±0.2°, 22.2°±0.2°, 22.9°±0.2°, 24.8°±0.2°, 27.1°±0.2°, 27.4°±0.2° and 28.3° ±0.2°. The endothermic peak (start) of K-type was determined to be 86.8°C. In another aspect, the K-type free base THF solvate exhibits an XRPD pattern substantially consistent with FIG. 50. In another aspect, the K-type exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 51. In another aspect, the K-type exhibits an NMR spectrum that is substantially consistent with FIG. 52.

The crystalline compound (I) (eg, compound I(a)) free base isobutanol solvate L form can be prepared from a slurry of anhydrous compound (I) or form A crystals in isobutanol at about room temperature. The L-type seed crystal of compound (I) isobutanol solvate may be added as appropriate to induce and/or enhance crystallization.

In the state where the crystalline compound I(a) is designated as the L-type free base isobutanol solvate, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by the L-shape has characteristic peaks at angles expressed as 2θ degrees as follows: 11.6°±0.2°, 12.8°±0.2°, 13.1°±0.2°, 14.2°±0.2 °, 17.5°±0.2°, 18.1°±0.2°, 22.8°±0.2°, 23.1°±0.2°, 24.0°±0.2° and 25.3°±0.2°. The L-shaped endothermic peak (start) was measured to be 106.8°C. In another aspect, the L-type free base isobutanol solvate exhibits an XRPD pattern substantially consistent with FIG. 53. In another aspect, the L-shape exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 54. In another aspect, the L-form exhibits an NMR spectrum that is substantially consistent with FIG. 55.

Crystalline Compound (I) (Compound I(a)) free base DMSO solvate Form M can be prepared from a slurry of Form E crystals in DMSO and water at about room temperature. A suitable volume ratio of THF to n-heptane is about 1:2 to about 2:1, such as about 1:2, 1:1.5, 1:1, 1.5:1 or 2:1. Optionally, the compound (I) DMSO solvate M-type seed crystal is added to induce and/or enhance crystallization.

In the state where the crystalline compound I(a) is designated as the M-type free base DMSO solvate, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by the M-type has characteristic peaks at angles expressed as 2θ degrees as follows: 12.1°±0.2°, 13.4°±0.2°, 14.7°±0.2°, 18.4°±0.2 °, 20.9°±0.2°, 21.5°±0.2°, 24.9°±0.2°, 26.8°±0.2° and 27.6°±0.2°. The endothermic peak (start) of the M type was determined to be 110.7°C. In another aspect, the M-type free base DMSO solvate exhibits an XRPD pattern substantially consistent with FIG. 56. In another aspect, the M-type exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 57. In another aspect, the M-type exhibits an NMR spectrum that is substantially consistent with FIG. 58.

Compound (I) (e.g. Compound I(a)) free base anhydrous Form AL can be prepared from a slurry of Form E crystals in EtOAc and n-heptane. A suitable volume ratio of EtOAc to n-heptane EtOAc may be about 2:1 to about 1:5, such as about 2:1, 1:1, 1:2, 1:3, 1:4 or 1:5. Compound (I) AL type seed crystals may be added as appropriate to induce and/or enhance crystallization. The crystallization temperature may be suitably about 15°C to about 60°C or about 50°C to about 60°C, such as about 15°C, 25°C, 35°C, 45°C, 50°C, 55°C or 60°C. The crystallization time may be at least about 12 hours, such as 12 hours, 1 day, 3 days, 5 days, or longer.

In the state where the crystalline compound I(a) is designated as the free base anhydrous of type AL, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by the AL type has characteristic peaks at angles expressed as 2θ degrees as follows: 7.6°±0.2°, 8.4°±0.2°, 13.2°±0.2°, 13.8°±0.2 °, 14.8°±0.2°, 15.2°±0.2°, 15.6°±0.2°, 15.9°±0.2°, 16.9°±0.2°, 18.1°±0.2°, 20.5°±0.2° and 21.3°±0.2°. The endothermic peaks (start) of the AL type were measured at 93.3°C and 147.5°C. In another aspect, the M-type free base anhydrous exhibits an XRPD pattern that is substantially consistent with FIG. 81. In another aspect, the AL type exhibits TGA and DSC spectral curves substantially consistent with FIG. 82. In another aspect, the AL type exhibits an NMR spectrum that is substantially consistent with FIG. 83.

The crystalline compound (I) (for example, compound I(a)) free base hydrate BO form can be prepared from a solution of E form crystals in methanol and water. A suitable volume ratio of methanol to water may be about 3:1 to about 1:3, such as about 3:1, 2:1, 1:1, 1:2, or 1:3. The dissolution temperature may be about 30°C to about 70°C or about 50°C to about 60°C, such as about 30°C, 40°C, 50°C, 55°C, 60°C, 65°C or 70°C. The crystallization temperature may be less than about 60°C , Such as about 60 ℃, 50 ℃, 40 ℃, 30 ℃, 20 ℃, 10 ℃ or 5 ℃. The crystallization time may be at least about 12 hours, such as 12 hours, 1 day, 2 days, 3 days, or longer. Based on XPRD comparison, the BN type of the compound I(a) crystal system was determined according to FIG. 84. The BO type is obtained after drying the BN type crystals under ambient conditions for at least about one hour.

In the state where the crystalline compound I(a) is the free base hydrate BO type, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by the BO type has characteristic peaks at angles expressed as 2θ degrees as follows: 12.1°±0.2°, 12.4°±0.2°, 13.9°±0.2°, 15.0°±0.2 °, 15.4°±0.2°, 17.1°±0.2°, 18.3°±0.2°, 21.5°±0.2°, 22.1°±0.2°, 24.4°±0.2°, 25.1°±0.2°, 26.2°±0.2° and 26.3°±0.2°. The endothermic peaks (start) of the BO type were measured at 86.2°C and 148.3°C, and the exothermic peaks were measured at 136.4°C. In another aspect, the BO-type free base hydrate exhibits an XRPD pattern substantially consistent with FIG. 84. In another aspect, the BO type exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 85. In another aspect, the BO type exhibits an NMR spectrum that is substantially consistent with FIG. 86.

Crystalline compound (I) (for example, compound I(a)) free base n-heptane solvate BP type can be a slurry of E-type crystals in (i) isopropyl acetate and n-heptane, followed by E-type crystals (ii) Prepared by slurry in isobutyl acetate and n-heptane. A suitable volume ratio of each of isopropyl acetate and n-heptane and isobutyl acetate and n-heptane may be about 3:1 to about 1:3, such as about 3:1, 2:1, 1:1 , 1:2 or 1:3. The slurry temperature may be about 30°C to about 80°C or 65°C to about 75°C, such as about 30°C, 40°C, 50°C, 60°C, 65°C, 70°C, 75°C or 80°C.

The crystalline Compound I(a) is the free base n-heptane solvate BP type, which can be identified according to the characteristic peak in XRPD analysis. In one such aspect, the XRPD pattern exhibited by the BP type has characteristic peaks at angles expressed as 2θ degrees as follows: 8.5°±0.2°, 12.9°±0.2°, 17.6°±0.2°, 18.1°±0.2 °, 19.4°±0.2°, 20.8°±0.2°, 21.2°±0.2°, 22.9°±0.2° and 24.0°±0.2°. The endothermic peaks (start) of the BP type were measured at 122.5°C and 147.3°C. In another aspect, the BP-type free base n-heptane solvate exhibits an XRPD pattern substantially consistent with FIG. 87. In another aspect, the BP type exhibits TGA and DSC spectral curves substantially consistent with FIG. 88. In another aspect, the BP type exhibits an NMR spectrum substantially consistent with FIG. 89.

The crystalline compound (I) (for example, compound I(a)) free base 2-pentanol solvate form BK can be prepared from a slurry of form E crystals in 2-pentanol and n-heptane. A suitable volume ratio of each of isopropyl acetate and n-heptane and isobutyl acetate and n-heptane may be about 4:1 to about 1:2, such as about 4:1, 3:1, 2:1 , 1:1 or 1:2. The slurry temperature may be about 30°C to about 70°C or about 45°C to about 55°C, such as about 30°C, 40°C, 45°C, 50°C, 55°C, 60°C or 70°C.

In the form of the crystalline compound I(a) which is the free base 2-pentanol solvate type BK, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by the BK type has characteristic peaks at angles expressed as 2θ degrees as follows: 11.9°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 14.7°±0.2 °, 16.9°±0.2°, 17.9°±0.2°, 19.3°±0.2°, 21.8°±0.2°, 22.7°±0.2°, 23.9°±0.2°, 24.6°±0.2° and 26.1°±0.2°. The endothermic peak (start) of the BK type was determined to be 71.5°C. In another aspect, the BK-type free base 2-pentanol solvate exhibits an XRPD pattern substantially consistent with FIG. 90. In another aspect, the BK type exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 91. In another aspect, the BK type exhibits an NMR spectrum that is substantially consistent with FIG. 92.

The crystalline compound (I) (eg compound I(a)) free base 1-propanol solvate form AX can be prepared by rapidly evaporating a solution of compound (I) in a solution of 1-propanol and isopropyl acetate. A suitable volume ratio of 1-propanol to isopropyl acetate may be about 3:1 to about 1:3, such as about 3:1, 2:1, 1.25:1, 1:1, 1:2, or 1:3 . The evaporation may be performed under partial vacuum, and the evaporation temperature may be about 15°C to about 60°C or about 20°C to about 35°C, such as about 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 50 ℃ or 60℃.

In the aspect that the crystalline compound I(a) is the free base 1-propanol solvate type AX, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by the AX type has characteristic peaks at angles expressed as 2θ degrees as follows: 11.5°±0.2°, 12.9°±0.2°, 13.1°±0.2°, 17.4°±0.2 °, 18.2°±0.2°, 23.1°±0.2°, 23.9°±0.2° and 25.9°±0.2°. The endothermic peaks (start) of type AX were measured at 113.5°C and 122.0°C. In another aspect, the AX-type free base 1-propanol solvate exhibits an XRPD pattern substantially consistent with FIG. 93. In another aspect, the AX type exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 94. In another aspect, the AX type exhibits an NMR spectrum that is substantially consistent with FIG. 95.

Crystalline Compound (I) (e.g. Compound I(a)) free base m-xylene solvate Form Q can be prepared by rapidly evaporating a solution of compound (I) in a solution of methyl acetate and m-xylene. A suitable volume ratio of methyl acetate to m-xylene may be about 3:1 to about 1:3, such as about 3:1, 2:1, 1.25:1, 1:1, 1:2, or 1:3. The evaporation may be performed under partial vacuum, and the evaporation temperature may be about 15°C to about 60°C or about 20°C to about 35°C, such as about 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 50 ℃ or 60℃.

The crystalline compound I(a) is a form Q of free base meta-xylene solvate, which can be identified according to the characteristic peak in XRPD analysis. In one such aspect, the XRPD pattern exhibited by the Q pattern has characteristic peaks at angles expressed as 2θ degrees as follows: 5.5°±0.2°, 12.5°±0.2°, 15.0°±0.2°, 17.6°±0.2 °, 20.2°±0.2°, 22.1°±0.2°, 22.8°±0.2° and 26.6°±0.2°. The Q-type endothermic peak (start) was measured to be 78.8°C. In another aspect, the Q-type free base meta-xylene solvate exhibits an XRPD pattern substantially consistent with FIG. 96. In another aspect, the Q-type exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 97. In another aspect, the Q-type exhibits an NMR spectrum that is substantially consistent with FIG. 98.

The crystalline Compound (I) (eg Compound I(a)) free base 2-methoxyethanol (EGME) solvate Form P can be prepared by rapidly evaporating a solution of Compound (I) in EGME and n-heptane. A suitable volume ratio of EGME to n-heptane may be about 3:1 to about 1:3, such as about 3:1, 2:1, 1.25:1, 1:1, 1:2, or 1:3. The evaporation may be performed under partial vacuum, and the evaporation temperature may be about 15°C to about 60°C or about 20°C to about 35°C, such as about 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 50 ℃ or 60℃.

In the form of the crystalline compound I(a) which is the free base EGME solvate P type, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by the P-type has characteristic peaks at angles expressed as 2θ degrees as follows: 11.9°±0.2°, 12.3°±0.2°, 12.7°±0.2°, 14.0°±0.2 °, 17.1°±0.2°, 20.0°±0.2°, 23.9°±0.2°, 24.1°±0.2°, 25.5°±0.2°, 25.8°±0.2° and 27.2°±0.2°. The P-type endothermic peaks (start) were measured at 104.7°C and 142.0°C. In another aspect, the P-type free base EGME anhydrous exhibits an XRPD pattern that is substantially consistent with FIG. 99. In another aspect, the P-type exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 100. In another aspect, the P-type exhibits an NMR spectrum that is substantially consistent with FIG. 101.

The crystalline compound (I) (eg compound I(a)) free base second butanol solvate form AQ can be prepared by rapidly evaporating a solution of compound (I) in second butanol and MTBE. A suitable volume ratio of second butanol to MTBE may be about 3:1 to about 1:3, such as about 3:1, 2:1, 1.25:1, 1:1, 1:2, or 1:3. The evaporation may be performed under partial vacuum, and the evaporation temperature may be about 15°C to about 60°C or about 20°C to about 35°C, such as about 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 50 ℃ or 60℃.

In the aspect that the crystalline compound I(a) is designated as the free base second butanol solvate of the AQ type, it can be identified according to the characteristic peak in the XRPD analysis. In one such aspect, the XRPD pattern exhibited by the AQ type has characteristic peaks at angles expressed as 2θ degrees as follows: 11.5°±0.2°, 12.7°±0.2°, 12.9°±0.2°, 14.1°±0.2 °, 17.4°±0.2°, 17.9°±0.2°, 21.9°±0.2°, 22.7°±0.2°, 23.1°±0.2°, 23.5°±0.2°, 23.9°±0.2°, 25.5°±0.2° and 27.6°±0.2°. The endothermic peaks (start) of the AQ type were determined to be 99.7°C and 110.8°C. In another aspect, the AQ-type free base second butanol solvate exhibits an XRPD pattern substantially consistent with FIG. 102. In another aspect, the AQ type exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 103. In another aspect, the AQ type exhibits an NMR spectrum that is substantially consistent with FIG. 104.

Compound (I) (eg Compound I(a)) gentisic acid anhydrous co-crystal form A can be prepared from a solution of compound (I) free base and gentisic acid in ethyl acetate (EtOAc). The concentration of the compound (I) is suitably about 20 g/L to about 100 g/L, about 30 g/L to about 75 g/L, or about 50 g/L. Compound (I) and gentisic acid are present in approximately stoichiometric amounts. An anti-solvent such as n-heptane is added to the solution to induce crystallization. The volume ratio of EtOAc to anti-solvent is suitably about 1:1.1 to about 1:5, such as about 1:1.15, 1:2, 1:2.5 or 1:3. Optionally, compound (I) gentisic acid anhydrous eutectic type A seed crystal is added to induce and/or enhance crystallization. The slurry can be cooled so as to reach less than 10°C, such as about 0°C to about 5°C, to induce further crystallization. Compound (I) gentisic acid anhydrous co-crystal form A can be collected by methods known in the art as described elsewhere herein, and dried at about room temperature as described elsewhere herein.

In another aspect, Compound I(a) gentisic acid anhydrate eutectic Form A exhibits an XRPD pattern substantially consistent with FIG. 66. In other aspects, the characteristic peak is 2θ degrees at the following angles: 12.5°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 15.7°±0.2°, 17.5°±0.2°, 21.7°±0.2 °, 25.5°±0.2° and 26.3°±0.2°. In another aspect, the eutectic type A exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 67. In another aspect, eutectic Form A exhibits an NMR spectrum that is substantially consistent with FIG. 68.

Compound (I) (eg Compound I(a)) free base anhydrous co-crystal form B can be prepared from a solution of compound (I) free base and gentisic acid in THF. The concentration of the compound (I) is suitably about 20 g/L to about 100 g/L, about 30 g/L to about 75 g/L, or about 50 g/L. Compound (I) and gentisic acid are present in approximately stoichiometric amounts. An anti-solvent such as n-heptane is added to the solution to induce crystallization. The volume ratio of THF to anti-solvent is suitably about 1:1.1 to about 1:5, such as about 1:1.15, 1:2, 1:2.5 or 1:3. Optionally, compound (I) gentisic acid anhydrous eutectic B-type seed crystal is added to induce and/or enhance crystallization. The slurry can be cooled so as to reach less than 10°C, such as about 0°C to about 5°C, to induce further crystallization. Compound (I) gentisic acid anhydrous eutectic Form B can be collected by methods known in the art as described elsewhere herein, and dried at approximately room temperature as described elsewhere herein.

In another aspect, Compound I(a) gentisic acid anhydrate eutectic Form B exhibits an XRPD pattern substantially consistent with FIG. 69. In another aspect, the characteristic peak is the following 2θ degrees: 6.6°±0.2°, 7.9°±0.2°, 12.2°±0.2°, 12.4°±0.2°, 14.0°±0.2°, 15.1°±0.2 °, 16.3°±0.2°, 21.1°±0.2°, 25.3°±0.2° and 25.6°±0.2°. In another aspect, the eutectic type B exhibits TGA and DSC spectral curves that are substantially consistent with FIG. 72. In another aspect, the eutectic type B exhibits an NMR spectrum that is substantially consistent with FIG. 73.

Compound (I) (e.g. Compound I(a)) pyridylcarboxamide hydrate co-crystal form A can be prepared from compound (I) free base and a solution of pyridylcarboxamide in EtOAc. The concentration of the compound (I) is suitably about 20 g/L to about 100 g/L, about 30 g/L to about 75 g/L, or about 50 g/L. The compound (I) and picolinamide are present in approximately stoichiometric amounts to a slight molar excess of picolinamide, such as from about 1:1 to about 1:4, such as about 1:2. An anti-solvent such as n-heptane is added to the solution to induce crystallization. The volume ratio of EtOAc to anti-solvent is suitably about 1:1.1 to about 1:5, such as about 1:1.15, 1:2, 1:2.5 or 1:3. The compound (I) hydrate co-crystal A type seed crystal may be added as appropriate to induce and/or enhance crystallization. The slurry can be cooled so as to reach less than 10°C, such as about 0°C to about 5°C, to induce further crystallization. Compound (I) pyridylcarboxamide hydrate co-crystal form A can be collected by methods known in the art as described elsewhere herein, and dried at about room temperature as described elsewhere herein.

In another aspect, Compound I(a) pyridylcarboxamide hydrate co-crystal form A exhibits an XRPD pattern substantially consistent with FIG. 74. The characteristic peaks of 2θ degrees are at the following angles: 12.1°±0.2°, 12.4°±0.2°, 14.5°±0.2°, 15.8°±0.2°, 18.1°±0.2°, 19.1°±0.2°, 22.0°±0.2 °, 24.5°±0.2°, 25.6°±0.2° and 26.6°±0.2°. In another aspect, the eutectic type A exhibits TGA and DSC spectral curves substantially consistent with FIG. 75. In another aspect, eutectic Form A exhibits an NMR spectrum that is substantially consistent with FIG. 76.

Pharmaceutical composition

The invention also provides compositions and medicaments comprising compound (I) and at least one pharmaceutically acceptable carrier. The composition of the present invention can be used to selectively inhibit TRPA1 in patients, such as humans. As used herein, the term "composition" is intended to encompass products that contain the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from a combination of the specified ingredients in the specified amounts.

In one aspect, the invention provides compounds (I) (eg compound I(a)) or examples thereof (and their stereoisomers, solvates, metabolites or pharmaceutically acceptable salts thereof) And pharmaceutical compositions or drugs of pharmaceutically acceptable carriers, diluents or excipients. In another embodiment, the present invention provides the preparation of a composition (or drug) comprising a compound of the present invention. In another embodiment, the present invention provides the administration of compound (I) (eg compound I(a)) or embodiments thereof and compositions comprising compound (I) or embodiments thereof to patients in need (eg human patients) versus.

The composition is formulated, administered and administered in a manner consistent with good medical practice. Factors considered in this context include the specific condition being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of drug delivery, the method of administration, the time of administration, and other factors known to medical practitioners . The effective amount of the compound to be administered will be controlled by such considerations, and is the minimum amount required to inhibit TRPA1 activity as required to prevent or treat undesirable diseases or conditions such as pain. For example, such amounts may be generally lower than those that are toxic to normal cells or mammals.

The compounds of the present invention can be administered by any suitable means, including oral, superficial (including buccal and sublingual), transrectal, transvaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal , Intrathecal and epidural and intranasal, and if local treatment is required, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, intracerebral, intraocular, intralesional, or subcutaneous administration.

As an API, the crystalline form of compound (I) free base or a mixture thereof may have an advantage over the amorphous form. For example, the purification of the API to the high purity required by most regulatory agencies can be more efficient and therefore cost less, where the API is in a crystalline form opposite to the amorphous form. The physical and chemical stability of crystalline API solids, and therefore the shelf life can also be better than the amorphous form. The ease of handling can be improved relative to the amorphous form that can be oily or viscous. Compared to the case of amorphous materials, drying can be simpler and easier to control in the case of crystalline materials, it can have a well-defined drying or desolvation temperature, and the amorphous material can have a greater effect on organic solvents Affinity and no clearly defined drying temperature. Subsequent processing using crystalline API can further permit enhanced process control. In the preparation of liquid formulations (for example, solutions in lipid carriers), the crystalline compound (I) can dissolve faster, and gels may not be easily formed during dissolution. These advantages are illustrative and non-limiting.

The pharmaceutical composition containing the crystalline compound (I) free base, or using the crystalline compound (I) free base or a salt of the compound (I) as an API contains a pharmaceutical composition that can be treated when administered to an individual in need according to an appropriate protocol An effective amount of compound (I). Unless the context requires otherwise, dosages are expressed herein as free base equivalents. Generally, in the case of oral or parenteral administration to adults weighing approximately 70 kg, the unit dose (a single dose) can be administered at an appropriate frequency (for example, twice a day to once a week) A daily dose of about 0.1 mg to about 5,000 mg, about 1 mg to about 1,000 mg, about 7 mg to about 1,400 mg, or about 1 mg to 100 mg may be appropriate, but if specified, the lower and upper limits may also be exceeded. In other words, the therapeutically effective amount of the compound of the present invention administered parenterally per dose will be in the range of about 0.01 to 100 mg, about 0.01 to 100 mg, or about, for example, 0.1 to 20 mg per kg of patient's body weight per day. The typical initial range of compounds is 0.3 to 15 mg/kg/day. This dosage regimen can be adjusted to provide the best therapeutic response. The compound can be administered 1 to 4 times a day, preferably once or twice a day. The daily dose can be administered as a single dose or in divided doses, or for parenteral administration, which can be provided as a continuous infusion.

The compound of the present invention can be administered in any convenient administration form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, and the like. Such compositions may contain conventional components in pharmaceutical preparations, such as diluents, carriers, pH modifiers, sweeteners, bulking agents, and other active agents.

Examples of suitable oral administration forms are lozenges, which contain about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 300 mg and 500 mg of the compound of the invention with about 90 to 30 mg of anhydrous lactose, about 5 to 40 mg of croscarmellose sodium, about 5 to 30 mg of polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mg of stearic acid Magnesium compound. The powdered ingredients are mixed together first, and then mixed with the solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate and compressed into a tablet form using conventional equipment. Examples of aerosol formulations can be prepared by dissolving, for example, 5 to 400 mg of the compound of the present invention in a suitable buffer solution (e.g. phosphate buffer) and adding a tonicity agent (e.g. salt such as sodium chloride) if necessary . The solution can be filtered, for example, using a 0.2 micron filter to remove impurities and contaminants.

For the treatment of eyes or other external tissues (eg mouth and skin), it is preferred to apply the formulation in the form of a surface ointment or cream containing the active ingredient in an amount of, for example, 0.075 to 20% w/w. When formulated as an ointment, the active ingredient can be used with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated as a cream with an oil-in-water cream base. If necessary, the water phase of the cream base may include a polyhydric alcohol, that is, an alcohol having two or more hydroxyl groups, such as propylene glycol, 1,3-butanediol, mannitol, sorbitol, glycerin And polyethylene glycol (including PEG 400) and mixtures thereof. Surface formulations may suitably include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include DMSO and related analogs.

For surface formulations, an effective amount of the pharmaceutical composition according to the present invention needs to be administered to a target area, such as the skin surface, mucous membranes and the like, which is close to the peripheral neurons to be treated. Depending on the area to be treated, whether the use is diagnostic, prophylactic or therapeutic, the severity of the symptoms and the nature of the surface vehicle used, this amount will generally be about 0.0001 mg to about 1 g per administration Within the scope of the compounds of the present invention. A preferred surface preparation is an ointment, wherein about 0.001 to about 50 mg of active ingredient is used per cc of ointment base. The pharmaceutical composition can be formulated as a transdermal composition or a transdermal delivery device ("patch"). Such compositions include, for example, backings, active compound reservoirs, control films, liners, and contact adhesives. Such transdermal patches can be used to provide continuous action, or to deliver the compounds of the present invention as needed.

The composition containing the compound (I) is usually formulated into a pharmaceutical composition according to standard medical practice. Typical formulations are prepared by mixing the compounds of the invention with diluents, carriers or excipients. Suitable diluents, carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004 ; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005.

The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light shielding agents, slip agents, processing aids, colorants, Sweeteners, fragrances, flavoring agents, diluents, and other known additives that make medicines (ie, compounds of the present invention or pharmaceutical compositions thereof) delicately present or aid in the manufacture of pharmaceutical products (ie, medicines). Suitable carriers, diluents and excipients are well known to those skilled in the art and include buffers such as phosphates, citrates and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives ( Such as octadecyldimethylbenzylammonium chloride; hexahydroxyammonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butanol or benzyl alcohol; alkyl parabens such as Methyl hydroxybenzoate or propyl parahydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptide; Proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamate, aspartame, histidine, spermine Acid or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming relative Ions, such as sodium; metal complexes (eg, Zn-protein complexes); and/or nonionic surfactants, such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG). The compound (I) of the present invention can also be coated in the prepared microcapsules by, for example, coagulation technology or by interfacial polymerization, for example, in a colloidal drug delivery system (such as liposomes, albumin microspheres, microemulsion, Nanoparticles and nanocapsules) or hydroxymethyl cellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules in giant emulsions. Such techniques are disclosed in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005) 21st Edition, Lippincott Williams & Wilkins, Philidelphia, PA. The specific carrier, diluent or excipient used will depend on the manner and purpose of administration of the compound of the invention. Solvents are generally selected based on solvents that are known to be safe (GRAS) by those skilled in the art to be administered to mammals. In general, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (eg PEG 400, PEG 300), etc. and mixtures thereof. Acceptable diluents, carriers, excipients and stabilizers are non-toxic to the recipient at the dosage and concentration used.

A sustained-release preparation of the compound (I) of the present invention can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing Compound (I), which matrices are in the form of shaped articles, such as films or microcapsules. Examples of sustained-release matrix include polyester, hydrogel (e.g. poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide (US Patent No. 3,773,919), L- Copolymers of glutamic acid and γ-ethyl-L-glutamic acid (Sidman et al., Biopolymers 22:547, 1983), non-decomposable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater. Res. 15:167, 1981), decomposable lactic acid-glycolic acid copolymers (such as LUPRON DEPOT™ (injectable microspheres consisting of lactic acid-glycolic acid copolymers and leuprolide acetate)) and poly-D-(-) -3-hydroxybutyric acid (EP 133,988A). Sustained-release compositions also include compounds coated with liposomes, which can be prepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci. USA 82:3688, 1985; Hwang et al., Proc Natl. Acad. Sci. USA 77:4030, 1980; US Patent Nos. 4,485,045 and 4,544,545; and EP 102,324A). Generally, liposomes are small (approximately 200 to 800 Angstroms) unilamellar in which the lipid content is greater than approximately 30 mole% cholesterol, and the selected ratio is adjusted for optimal therapy.

In one example, the compound (I) can be prepared by using a physiologically acceptable carrier (i.e., in a galenical administration form) at ambient temperature, at an appropriate pH, and at a desired purity. Carriers that are not toxic to the recipient at the dosage and concentration used in the formula) are mixed for formulation. The pH of the formulation depends mainly on the specific application and the concentration of the compound, but is preferably any value in the range of about 3 to about 8. In one example, compound (I) is formulated at pH 5 in an acetate buffer. In another embodiment, compound (I) is sterile. The compounds can be stored, for example, in the form of solid or amorphous compositions, in the form of lyophilized formulations or aqueous solutions.

Formulations suitable for oral administration of compound (I) can be prepared as discrete units, such as pills, capsules, cachets, or lozenges, each containing a predetermined amount of a compound of the present invention.

Compressed lozenges can be prepared by compressing in a suitable machine the active ingredients of a free-flowing type (such as powder or granules) mixed with binders, lubricants, inert diluents, preservatives, surfactants or dispersants. . Molded lozenges can be manufactured by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. The lozenges can be coated or scored as appropriate and formulated as appropriate to provide slow or controlled release of the active ingredient from it.

Tablets, dragees, buccal tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules (eg gelatin capsules), syrups or elixirs can be prepared for oral use. The formulation of the compound (I) intended for oral use can be prepared according to any method known in the art of manufacturing pharmaceutical compositions, and such compositions may contain one or more agents including sweeteners, flavoring agents, coloring agents And preservatives to provide palatable preparations. Lozenges containing active ingredients mixed with pharmaceutically acceptable non-toxic excipients are acceptable, and the excipients are suitable for the manufacture of lozenges. Such excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin or Acacia; and lubricants such as magnesium stearate, stearic acid or talc. Lozenges may be uncoated or they may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, time delay materials such as glyceryl monostearate or glyceryl distearate can be used alone or with wax.

Examples of suitable oral administration forms are lozenges, which contain about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 300 mg and 500 mg of the compound of the invention with about 90 to 30 mg of anhydrous lactose, about 5 to 40 mg of croscarmellose sodium, about 5 to 30 mg of polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mg of stearic acid Magnesium compound. The powdered ingredients are mixed together first, and then mixed with the solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate and compressed into a tablet form using conventional equipment. Examples of aerosol formulations can be prepared by dissolving, for example, 5 to 400 mg of the compound of the present invention in a suitable buffer solution (e.g. phosphate buffer) and adding a tonicity agent (e.g. salt such as sodium chloride) if necessary . The solution can be filtered, for example, using a 0.2 micron filter to remove impurities and contaminants.

The formulation can be packaged in unit-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored in freeze-dried (lyophilized) conditions, just add a sterile liquid carrier such as water just before use injection. Temporary injection solutions and suspensions can be prepared from sterile powders, granules, and lozenges of the kind previously described. A preferred unit dose formulation is a formulation containing the daily dosage or unit daily sub-dose or an appropriate portion of the active ingredient as described above.

When the binding target is located in the brain, some embodiments of the present invention provide a compound (I) capable of crossing the blood-brain barrier. Certain neurodegenerative diseases are associated with increased permeability of the blood-brain barrier, so that the compound (I) can be easily introduced into the brain. When the blood-brain barrier remains intact, there are several methods known in the art for transporting molecules through the blood-brain barrier, including (but not limited to) physical methods, lipid-based methods, and receptor and channel-based methods.

Physical methods of transporting the compound (I) across the blood-brain barrier include, but are not limited to, completely avoiding the blood-brain barrier or by creating an opening in the blood-brain barrier.

Circumvention methods include (but are not limited to) direct injection into the brain (see, for example, Papanastassiou et al., Gene Therapy 9:398-406, 2002), interstitial infusion/convection enhanced delivery (see, for example, Bobo et al., Proc. Natl. Acad. Sci. USA 91: 2076-2080, 1994) and implantation of delivery devices in the brain (see, for example, Gill et al., Nature Med. 9:589-595, 2003; and Gliadel Wafers™, Guildford.

Methods for forming openings in the barrier include (but are not limited to) ultrasound (see, for example, U.S. Patent Publication No. 2002/0038086), osmotic pressure (for example, by administering high osmolarity mannitol (Neuwelt, EA, Implication of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2, Plenum Press, NY, 1989)) and penetration by, for example, bradykinin or penetrant A-7 (see, for example, U.S. Patent No. 5,112,596, Nos. 5,268,164, 5,506,206 and 5,686,416).

Lipid-based methods for delivering compound (I) across the blood-brain barrier include, but are not limited to, encapsulating compound (I) in liposomes coupled to antibody-binding fragments that bind to blood vessel of blood-brain barrier Receptor on the endothelium (see, for example, U.S. Patent Application Publication No. 2002/0025313) and applying compound (I) to low-density lipoprotein particles (see, for example, U.S. Patent Application Publication No. 2004/0204354) or apolipolipid Protein E (see, eg, US Patent Application Publication No. 2004/0131692).

Receptor and channel-based methods for delivering compound (I) across the blood-brain barrier include (but are not limited to) the use of glucocorticoid blockers to increase the permeability of the blood-brain barrier (see, eg, US Patent Application Publication No. 2002/0065259 No. 2003/0162695 and 2005/0124533); activated potassium channels (see, eg, US Patent Application Publication No. 2005/0089473), inhibiting ABC drug transporters (see, eg, US Patent Application Publication No. 2003/0073713) No.); coating compound (I) with transferrin and modulating the activity of one or more transferrin receptors (see, eg, US Patent Application Publication No. 2003/0129186) and cationizing antibodies (see, eg, US Patent No. 5,004,697).

Regarding intracerebral use, in certain embodiments, the compound may be continuously administered by infusion into the CNS reservoir, but rapid injection may be acceptable. The inhibitor can be administered into the ventricle or otherwise introduced into the CNS or spinal fluid. The administration can be performed by using an indwelling catheter and a continuous administration member such as a pump; or it can be administered by implantation, for example, by implanting a sustained-release vehicle into the brain. More specifically, the inhibitor may be injected through a long-term implanted cannula or long-term infusion by means of an osmotic micropump. A subcutaneous pump can be used, which delivers the protein to the ventricle via a small tube. The highly precise pump can be refilled through the skin and its delivery rate can be set without surgical intervention. Examples of suitable administration protocols and delivery systems involving continuous intraventricular infusion of a hypodermic pump device or a fully implanted drug delivery system are used for Alzheimer's disease patients and Parkinson's disease ( Parkinson's disease) animal model administration dopamine, dopamine accelerators and choline stimulating accelerators and other administration programs and delivery systems, such as Harbaugh, J. Neural Transm. Supplement 24:271, 1987; and DeYebenes and others , Mov. Disord. 2: 143, 1987.

Indications and treatment

Representative compounds of the invention have been shown to modulate TRPA1 activity (see for example WO 2016/128529). Therefore, the compounds of the present invention are suitable for the treatment of diseases and conditions mediated by TRPA1 activity. Such diseases and conditions include (but are not limited to): pain (acute, chronic, inflammatory or neuropathic pain); itching or various inflammatory conditions; inner ear disorders; fever or other temperature regulation disorders; tracheobronchial or diaphragm dysfunction ; Gastrointestinal or urinary tract disorders; chronic obstructive pulmonary disease; incontinence; and disorders related to decreased blood flow to the CNS or CNS hypoxia.

In a particular embodiment, the compounds of the present invention can be administered to treat pain, including but not limited to neuropathic and inflammatory pain and other pain. Some types of pain can be considered as diseases or conditions, while other types can be considered as symptoms of multiple diseases or conditions, and pain can include multiple pathogenic sources. Exemplary types of pain treatable with TRPA1 modulators according to the present invention include pain related to, caused by, or caused by: osteoarthritis, tendon cuff disorders, arthritis (eg, rheumatoid arthritis or inflammatory) Arthritis; see Barton et al. Exp. Mol. Pathol. 2006, 81(2), 166-170), muscle fiber pain, migraine and headache (such as cluster headache, sinus headache or tension headache; see Godsby Curr . Pain Headache Reports 2004, 8, 393), sinusitis, oral mucositis, toothache, tooth injury, tooth extraction, tooth infection, burns (Bolcskei et al., Pain 2005, 117(3), 368-376), sunburn, Dermatitis, psoriasis, eczema, insect stings or bites, musculoskeletal disorders, fractures, ligament sprains, plantar fasciitis, costochonditis, tendonitis, bursitis, tennis elbow, pitcher elbow, patellar tendonitis, Repetitive strain, myofascial syndrome, muscle sprain, myositis, temporomandibular joint disease, resection, lower back pain, spinal cord injury, neck pain, neck injury, bladder spasm, gastrointestinal disorders, cystitis, interstitial Cystitis, cholecystitis, urinary tract infection, urethral colic, renal colic, pharyngitis, cold sores, stomatitis, otitis media, otitis media (Chan et al., Lancet, 2003, 361, 385), oral burning syndrome, mucositis , Esophageal pain, esophageal cramps, abdominal disorders, gastroesophageal reflux disease, pancreatitis, enteritis, irritable bowel disease, inflammatory bowel disease, Crohn's disease (Crohn's disease), ulcerative colitis, colon dilation, abdomen Contractions, diverticulosis, diverticulitis, intestinal gas, hemorrhoids, anal fissure, anorectal disease, prostatitis, epididymitis, testicular pain, proctitis, rectal pain, labor pain, labor, endometriosis, menstrual pain spasms , Pelvic pain, vulvar pain, vaginitis, mouth and genital infections (such as herpes simplex virus), pleurisy, pericarditis, non-cardiothoracic pain, contusion, abrasions, skin incisions (Honore, P. et al., J Pharmacal Exp Ther., 2005, 314, 410-21), postoperative pain, peripheral neuropathy, central neuropathy, diabetic neuropathy, acute herpes neuralgia, post-herpetic neuralgia, trigeminal neuralgia, glossopharyngeal neuralgia, atypical facial pain, nerve Root disease (gradiculopathy), HIV-related neuropathy, physical nerve damage, cauteric neuralgia, reflex sympathetic dystrophy, sciatica, cervical spine, chest or lumbar radiculopathy, brachial plexus disease, lumbar plexus disease, nerve Degenerative disorders, occipital neuralgia, intercostal neuralgia, supraorbital neuralgia, inguinal neuralgia, abnormal femoral pain, reproductive femoral neuralgia, carpal tunnel syndrome, Morton's neuroma, postoperative mastectomy syndrome, open Thoracic surgery Posterior syndrome, post-polio syndrome, Guillain-Barre syndrome, Raynaud's syndrome, coronary artery spasm (Printzmetal's or variant angina), visceral hyperalgesia (Pomonis, JD et al. J. Pharmacal. Exp. Ther. 2003, 306, 387; Walker, KM et al., J. Pharmacal. Exp. Ther. 2003, 304(1), 56-62), thalamic pain, cancer (E.g. pain caused by cancer (including osteolytic sarcoma) obtained by treatment of cancer by radiation or chemotherapy or by nerve or bone lesions associated with cancer (see Menendez, L. et al., Neurosci. Lett. 2005, 393 (1), 70-73; Asai, H. et al., Pain 2005, 117, 19-29) or bone destruction pain (see Ghilardi, JR et al., J. Neurosci. 2005, 25, 3126-31)) , Infection or metabolic diseases. In addition, the compounds can be used to treat pain indications such as visceral pain, eye pain, heat pain, tooth pain, capsaicin-induced pain (as well as other symptomatic conditions induced by capsaicin, such as cough, tearing, and bronchospasm).

In another particular embodiment, the compounds of the present invention can be administered to treat itching, which can be caused by a variety of sources, such as skin or inflammatory conditions.

In another specific embodiment, the compounds of the present invention can be administered to treat inflammatory disorders, including disorders selected from the group consisting of renal or hepatobiliary disorders, immune disorders, drug reactions, and unknown/idiopathic disorders. Inflammatory conditions that can be treated with the agent of the present invention include, for example, inflammatory bowel disease (IBO), Crohn's disease, and ulcerative colitis (Geppetti, P. et al., Br. J. Pharmacal. 2004, 141, 1313-20 ; Yiangou, Y. et al., Lancet 2001, 357, 1338-39; Kimball, ES et al., Neurogastroenterol. Motif., 2004, 16, 811), osteoarthritis (Szabo, A. et al., J. Pharmacal. Exp Ther. 2005, 314, 111-119), psoriasis, psoriatic arthritis, rheumatoid arthritis, myasthenia gravis, multiple sclerosis, scleroderma, spheroid nephritis, pancreatitis, inflammatory hepatitis, asthma , Chronic obstructive pulmonary disease, allergic rhinitis, uveitis, and cardiovascular inflammation, including atherosclerosis, myocarditis, pericarditis, and vasculitis.

In another specific embodiment, the compounds of the present invention can be administered to treat inner ear disorders. Such conditions include, for example, hearing allergies, tinnitus, vestibular hypersensitivity, and intermittent dizziness.

For example, the compounds of the present invention can be administered to treat tracheobronchial and septal dysfunction, including, for example, asthma and allergy-related immune responses (Agopyan, N. et al., Am. J. Physiol. Lung Cell Mol. Physiol. 2004, 286, L563-72; Agopyan, N. et al., Toxicol. Appl. Pharmacal. 2003, 192, 21-35), cough (for example, acute or chronic cough, or cough caused by gastroesophageal reflux disease stimulation; see Lalloo, UG et al., J. Appl. Physiol. 1995, 79(4), 1082-7), bronchospasm, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, and continuous hiccups (hiccups, hiccups).

In another specific embodiment, the compounds of the present invention can be administered to treat gastrointestinal and urinary tract disorders such as overactive bladder, inflammatory hyperalgesia, hypervisceral reflex of the bladder, hemorrhagic cystitis (Dinis, P. et al., J Neurosci., 2004, 24, 11253-11263), interstitial cystitis (Sculptoreanu, A. et al., Neurosci Lett., 2005, 381, 42-46), inflammatory prostate disease, prostatitis (Sanchez, M . Et al., Eur J Pharmacal., 2005, 515, 20-27), nausea, vomiting, intestinal cramps, intestinal bloating, bladder spasm, urgency, urgency, and impulsive incontinence.

In another specific embodiment, the compounds of the present invention can be administered to treat conditions associated with reduced blood flow to the CNS or CNS hypoxia. Such conditions include, for example, head trauma, spinal injury, thromboembolism or hemorrhagic stroke, transient ischemic attack, cerebral vasospasm, hypoglycemia, cardiac arrest, persistent epilepsy, perinatal asphyxia, Alzheimer's Disease and Huntington's Disease.

In other embodiments, the compounds of the present invention may be administered to treat other diseases, disorders or conditions mediated by TRPA1 activity, such as anxiety; learning or memory disorders; eye-related disorders (such as glaucoma, vision loss, intraocular pressure Elevation and conjunctivitis); Baldness (for example by stimulating hair growth); Diabetes (including insulin-resistant diabetes or diabetic conditions mediated by insulin sensitivity or secretion); Obesity (for example by appetite suppression); Indigestion; Biliary colic; renal colic; painful bladder syndrome; inflammation of the esophagus; upper respiratory tract disease; urinary incontinence; acute cystitis; and stinging effects (such as marine life, snake or insect stings or bites, including jellyfish, spiders, or stingrays) Fish sting poison effect).

In a particular embodiment, the compounds of the present invention are administered to treat pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), arthritis, itching, cough, asthma or inflammatory bowel disease.

In another embodiment, the present invention provides a method for treating neuropathic pain or inflammatory pain, comprising the step of administering a therapeutically effective amount of a compound as described herein to an individual in need.

In another embodiment, the present invention provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in modulating TRPA1 activity.

In another embodiment, the present invention provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in medical therapy.

In another embodiment, the present invention provides a method for treating a respiratory tract disorder selected from chronic obstructive pulmonary disease (COPD), asthma, allergic rhinitis and bronchospasm, comprising administering a therapeutically effective amount such as The steps of the compounds described herein.

In another embodiment, the present invention provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of respiratory disorders.

In another embodiment, the present invention provides the use of a compound as described herein or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of respiratory disorders.

In another embodiment, the present invention provides a method for treating a respiratory disorder of a mammal (eg, a human), which comprises administering to a mammal a compound as described herein or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method for modulating TRPA1 activity, which comprises contacting TRPA1 with a compound as described herein or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound as described herein or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of diseases or conditions mediated by TRPA1 activity. In the aspect of this embodiment, the disease or condition is pain (including but not limited to acute, chronic, neuropathic or inflammatory pain), itching, inflammatory disorders, inner ear disorders, fever or other temperature regulation disorders, Tracheobronchial or diaphragm dysfunction, gastrointestinal or urinary tract disorders, chronic obstructive pulmonary disease, incontinence, or disorders related to reduced blood flow to the CNS or CNS hypoxia. Within certain aspects of this embodiment, where the disease or condition is pain (including but not limited to acute, chronic, neuropathic, and inflammatory pain), arthritis, itching, cough, asthma, inflammatory bowel disease, or inner ear disease.

In another embodiment, the present invention provides the use of a compound as described herein or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of a disease or condition mediated by TRPA1 activity. In the aspect of this embodiment, the disease or condition is pain (including but not limited to acute, chronic, neuropathic or inflammatory pain), itching, inflammatory disorders, inner ear disorders, fever or other temperature regulation disorders, Tracheobronchial or diaphragm dysfunction, gastrointestinal or urinary tract disorders, chronic obstructive pulmonary disease, incontinence, or disorders related to reduced blood flow to the CNS or CNS hypoxia. Within the aspect of this embodiment, the disease or condition is pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), arthritis, itching, cough, asthma, inflammatory bowel disease or inner ear disorders .

In another embodiment, the present invention provides a method for treating a disease or condition mediated by TRPA1 activity in a mammal (eg, a human), which comprises administering to the mammal a compound as described herein or a pharmaceutical Acceptable salt. In certain aspects of this embodiment, the disease or condition is pain (including but not limited to acute, chronic, neuropathic, or inflammatory pain), itching, inflammatory disorders, inner ear disorders, fever, or other temperature regulation Disorders, tracheobronchial or diaphragm dysfunction, gastrointestinal or urinary tract disorders, chronic obstructive pulmonary disease, incontinence, or disorders related to reduced blood flow to the CNS or CNS hypoxia. In certain aspects of this embodiment, the disease or condition is pain (including but not limited to acute, chronic, neuropathic and inflammatory pain), arthritis, itching, cough, asthma, inflammatory bowel disease or inner ear disorders . In some embodiments, the disease or condition is asthma.

Combination therapy

In the treatment of diseases and conditions mediated by ion channels, the compounds of the present invention can be effectively combined with one or more other compounds of the present invention or one or more other therapeutic agents or as any combination thereof. For example, the compounds of the present invention can be administered simultaneously, sequentially, or separately in combination with other therapeutic agents, including (but not limited to) the following.

Opioid analgesics, such as morphine, heroin, cocaine, oxymorphine, levorphanol, levallorphan, oxycodone, cocaine Codeine, dihydrocodeine, propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone, melipid Meripidine, methadone, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, butorphanol nalbuphine) and pentazocine.

Non-opioid analgesics, such as acetomeniphen and salicylates (such as aspirin).

Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, fenoprofen, ketoprofen, celecoxib, diclofenac ), diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, Indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone (nabumetone), naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone ( phenylbutazone), piroxicam (piroxicam), sulfasalazine (sulfasalazine), sulindac (sulindac), tolmetin (tolmetin) and zomepiric acid (zomepirac).

Antispasmodic agents such as carbamazepine, oxcarbazepine, lamotrigine, valproate, topiramate, gabapentin, and pregabalin ).

Antidepressants, such as tricyclic antidepressants, such as amitriptyline, clomipramine, despramine, imipramine, and nortriptyline ( nortriptyline).

COX-2 selective inhibitors, such as celecoxib, celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etaxibu (etoricoxib) and lumiracoxib.

Alpha adrenergic drugs, such as doxazosin, doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil (modafinil) and 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinolin-2-yl)-5- (2-pyridyl) quinazoline.

Barbiturate sedatives, such as amobarbital (amobarbital), aprobarbital (aprobarbital), butabarbital (butabarbital), butabital (butabital), metobarbital (mephobarbital), Methobarbital, methohexital, pentobarbital, phenobartital, phenobartital, secobarbital, talbutal, and cyprol Miller (theamylal) and thiopental (thiopental).

Tachykinin (NK) antagonists, especially NK-3, NK-2 or NK-1 antagonists, such as (aR, 9R)-7-[3,5-bis(trifluoromethyl)benzyl)] -8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazepine[2,1-g][1 ,7]-㖠idine-6-13-dione (TAK-637), 5-[[2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethylphenyl ]Ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK- 869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy5-(trifluoromethoxy)phenyl]-methylamino]- 2-phenylpiperidine (2S, 3S).

Coal tar analgesics, such as paracetamol.

Serotonin reuptake inhibitors such as paroxetine, sertraline, norfluoxetine (fluoxetine demethyl metabolite), metabolite demethylsertraline , '3 fluvoxamine,'paroxetine, paroxetine, citalopram, citalopram metabolite norcitapram, escitalopram oxalate (escitalopram), d,l-fluoroamphetamine , Femoxetine, ifoxetine, cyanodothiepin, litodoxiepin, litoxetine, dapoxetine, nefazodone, cephalosporin Reliamine (cericlamine), trazodone (trazodone) and fluoxetine (fluoxetine).

Norepinephrine (norepinephrine) reuptake inhibitors, such as maprotiline (lopropramine), lofepramine, mirtazepine, oxaprotiline, non-levolamin (fezolamine), tomoxetine, mianserin, buproprion, buproprion, hydroxybutamine acetone, nomifensine and vero Viloxazine (Vivalan®)), especially selective norepinephrine reuptake inhibitors, such as reboxetine, especially (S,S)-reboxetine, and venlafaxine Duloxetine is a sedative/anxiolytic agent.

Double serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desvenlafaxine, clomipramine, clomipramine metabolite norclomipramine Ming, duloxetine, milnacipran and imipramine.

Acetylcholinesterase inhibitors, such as donepezil.

5-HT3 antagonists, such as ondansetron.

Metabolic glutamate receptor (mGluR) antagonist.

Local anesthetics such as mexiletine and lidocaine.

Corticosteroids, such as dexamethasone.

Antiarrhythmic drugs, such as mexiletine and phenytoin.

Muscarinic antagonists such as tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, tilmi Temiverine and ipratropium.

Cannabinoid.

Vanilla extract receptor agonists (such as resinferatoxin) or antagonists (such as capsazepine).

Sedatives, such as glutetimide, meprobamate, methaqualone, and dichloralphenazone.

Anxiolytics, such as benzodiazepines.

Antidepressants, such as mirtazapine.

Topical agents, such as lidocaine, capsaicin and resiniferotoxin.

Muscle relaxants, such as benzodiazepine, chloramphenicol, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol and o-toluate Ming (orphrenadine).

Antihistamine or H1 antagonist.

NMDA receptor antagonist.

5-HT receptor agonist/antagonist.

PDEV inhibitor.

Tramadol®.

Choline-induced (nicotine) analgesics.

α-2-δ ligand.

Prostaglandin E2 subtype antagonist.

Leukotriene B4 antagonist.

5-lipoxygenase inhibitor.

5-HT3 antagonist.

As used herein, "combination" refers to any mixture or replacement of one or more compounds of the invention and one or more other compounds of the invention or one or more additional therapeutic agents. Unless the context dictates otherwise, "combination" may include the simultaneous or sequential delivery of a compound of the invention and one or more therapeutic agents. Unless the context dictates otherwise, "combination" may include a dosage form of a compound of the invention and another therapeutic agent. Unless the context dictates otherwise, "combination" may include the route of administration of a compound of the invention with another therapeutic agent. Unless the context dictates otherwise, "combination" may include the formulation of a compound of the invention with another therapeutic agent. Dosage forms, administration routes, and pharmaceutical compositions include, but are not limited to, the dosage forms, administration routes, and pharmaceutical compositions described herein.

Examples

Example 1: Preparation of (2S,4R,5S)-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl-N-((5-(trifluoromethyl)) of formula (I) -2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide

Example 1A: Preparation of compound formula (I) from compound 1

Example 1A analysis method

Referring to FIG. 1, compound I(a) is prepared from compound 1 according to the following steps 1 to 5.

Example 1A Step 1: Mesylate

。Compound 2(a) (5-(4-(methoxymethyl)-5-(trifluoromethyl)pyridin-2-yl)-2-(trifluoromethyl)pyrimidine) is as follows from compound 1(a ) ((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methanol) preparation, where MS stands for mesylate (methanesulfonyl) base):

.

2-Methyltetrahydrofuran (147.7 kg, 8.54 kg/kg Compound 1(a)) was added to the inertization reactor with stirring, and then Compound 1(a) (17.3 kg, 53.53 mol) was added. Triethylamine (7.03 kg, 0.407 kg/kg Compound 1(a)) was added to the reactor and the contents were cooled to 0°C to 10°C. Methanesulfonyl chloride (methasulfonyl chloride) (7.36 kg, 0.425 kg/kg Compound 1(a)) was slowly added to the reactor to keep the temperature below 10°C. The reactor contents were agitated at this temperature for at least 2 hours. The reactor contents were sampled and the content of compound 1(a) was tested by HPLC method-012. Continue sampling and LC testing (at 1 hour intervals) until the content of compound 1(a) is less than 5.0%.

A 5% citric acid aqueous solution (173 kg, 10 kg/kg Compound 1(a)) was added to the reactor and the reactor contents were stirred at 25°C for at least 30 minutes. Ethyl acetate (77.6 kg, 5.94 kg/kg compound 1(a)) was added to the reactor and the reactor contents were stirred for at least 30 minutes. The stirring was stopped to allow the phases to separate, and the lower aqueous phase was removed. A 25% aqueous NaCl solution (102.8 kg, 5.94 kg/kg Compound 1(a)) was added to the organic phase in the reactor and the reactor contents were stirred for at least 10 minutes. The stirring was stopped to allow the phases to separate, and the lower aqueous phase was removed. The remaining organic phase was distilled under reduced pressure at a temperature of less than 50°C to a volume of 2 liters/kg of Compound 1(a). Ethyl acetate (77.6 kg, 5.94 kg/kg Compound 1(a)) was added to the reactor with stirring and the contents of the reactor were distilled under reduced pressure to a volume of 2 liters/kg Compound 1 at a temperature of less than 50°C. (a). Add n-heptane (59.2 kg, 3.42 kg/kg Compound 1(a)) to the reactor with stirring and distill the contents of the reactor under reduced pressure to a volume of 2 liters/kg Compound 1 at a temperature of less than 50°C (a). Add n-heptane and repeat the distillation twice. Add n-heptane (47.3 kg, 2.73 kg/kg Compound 1(a)) to the reactor and stir the contents at 25°C to 30°C for at least 2 hours. The reactor contents were filtered to collect the solid compound 2(a), and the reactor was washed with n-heptane (23.7 kg, 1.37 kg/kg compound 1(a)) to continue through the collected compound 2(a) solids. The solid compound 2(a) was dried in a vacuum oven at 30°C to 40°C for at least 14 hours to obtain compound 2(a) (21.85 kg, yield 95%). The HPLC purity obtained by the method HPLC-012 was 97.66%, and the impurity was 2.61%.

Example 1A Step 2: Amine formation

。Compound 3(a) (5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methanamine is as follows from compound 2(a) 5-( 4-(Methoxymethyl)-5-(trifluoromethyl)pyridin-2-yl)-2-(trifluoromethyl)pyrimidine Preparation:

.

To the inertization reactor, compound 2(a) (11 kg, 27.41 moles) and THF (48.9 kg, 4.45 kg/kg) were sequentially added with stirring until a solution was formed. Combine the solution of compound 2(a) with NH ₃ /MeOH (7M methanol solution, 257.1 kg, 23.4 kg/kg) with stirring, slowly heat to 35°C to 45°C, and age at this temperature for at least 2 hours to Compound 3 is formed. The reactor contents were sampled and the compound 2(a) content was tested by HPLC method-014. Continue sampling and LC testing (at 1 hour intervals) until the content of compound 1(a) is less than 5.0%.

The contents of the reactor containing compound 3 were combined with MTBE (81.4 kg, 7.4 kg/kg compound 2(a)) and 20% aqueous KHCO ₃ solution (27.3 kg, 2.48 kg/kg compound 2(a)) with stirring . Stop stirring and allow the mixture to phase separate for at least 10 minutes. The lower aqueous phase was removed and combined with MTBE (81.4 kg, 7.4 kg/kg Compound 2(a)) with stirring, and mixed for at least 10 minutes. Stop stirring and allow the mixture to phase separate for at least 10 minutes. In the second washing step, the lower aqueous phase was removed and combined with MTBE (81.4 kg, 7.4 kg/kg Compound 2(a)) with stirring, and mixed for at least 10 minutes. Stop stirring and allow the mixture to phase separate for at least 10 minutes. In the third washing step, the lower aqueous phase was removed and combined with MTBE (40.7 kg, 3.7 kg/kg Compound 2(a)) with stirring, and mixed for at least 10 minutes. The stirring was stopped, the mixture phase was separated for at least 10 minutes, and the lower aqueous phase was removed.

Four organic phases containing compound 3 were combined in the reactor and distilled under reduced pressure at a temperature of less than 50°C to reach a volume of 15 L/kg of compound 2(a). Combine a solution of oxalic acid (1.73 kg, 0.157 kg/kg Compound 2(a)) in MTBE (40.7 kg, 3.7 kg/kg) with the organic phase of distillation over 3 hours while maintaining the temperature at 20°C to 30°C Next, to form a slurry containing compound 3, and then to age for at least 20 minutes after the oxalic acid addition is complete. The slurry was filtered to collect the solid crude compound 3 oxalate, and the reactor was washed with MTBE (16.3 kg, 1.48 kg/kg compound 2(a)) and continued through the collected solids.

Crude compound 3 and MTBE (81.4 kg, 7.4 kg/kg compound 2(a)) were combined in the reactor with stirring, after which 25% (w/w) KHCO ₃ aqueous solution (57.1 kg, 5.19 kg) was added with stirring /kg Compound 2(a)) while maintaining the temperature at 20°C to 30°C. The contents of the reactor were aged for 30 minutes with stirring, the stirring was stopped, and the mixture was phase separated for at least 10 minutes. The lower aqueous phase was removed and combined with MTBE (81.4 kg, 7.4 kg/kg Compound 2(a)) with stirring, and mixed for at least 10 minutes. In the second washing step, the lower aqueous phase was removed and combined with MTBE (40.7 kg, 3.7 kg/kg Compound 2(a)) with stirring, and mixed for at least 10 minutes. The stirring was stopped, the mixture phase was separated for at least 10 minutes, and the lower aqueous phase was removed.

Three organic phases containing compound 3 were combined in the reactor and distilled under reduced pressure at a temperature of less than 50°C to reach a volume of 2 L/kg of compound 2(a). Add n-heptane (30.1 kg, 2.74 kg/kg Compound 2(a)) to the reactor with stirring and distill the contents of the reactor under reduced pressure at a temperature of less than 50 °C to reach a volume of 2 L/kg Compound 2(a). N-Heptane (30.1 kg, 2.74 kg/kg Compound 2(a)) was added to the reactor with stirring and the reactor contents were kept at 20°C to 30°C for 3 hours. The reactor contents were filtered to isolate solid compound 3, and the reactor was washed with n-heptane (15 kg, 2.74 kg/kg compound 2(a)) and continued through the collected solids. The solid compound 3 was dried in a vacuum oven at 30°C to 40°C for at least 14 hours to obtain compound 3 (7.2 kg, yield 82%) as a light brown solid. The identification obtained by 1H NMR indicates that compound 3 is consistent with the standard of compound 3. The HPLC analysis system was 95.9%, and the HPLC purity system was 99.42%.

Example 1A Step 3: Condensation reaction to form amide

。Compound 5(a) (2S,3R,5S)-3-fluoro-2-methyl-5-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidine-5- Yl)pyridin-4-yl)methylaminemethanyl)pyrrolidine-1-carboxylic acid tert-butyl ester is as follows from compound 3(a) (5-(trifluoromethyl)-2-(2-(trifluoro (Methyl)pyrimidin-5-yl)pyridin-4-yl)methylamine and compound 4(a) (2S,4R,5S)-1-(third butoxycarbonyl)-4-fluoro-5-methyl Preparation of pyrrolidine-2-carboxylic acid:

.

With stirring, compound 3(a) (13 g, 40.4 mmol) and compound 4(a) (10.0 g, 40.4 mmol) were reacted with isopropyl acetate (90 mL, 9.0 mg/kg compound 4(a)) Until the solution is formed. To the reactor, N-methylmorpholine (5.3 g, 0.58 mL/g Compound 4, 52.5 mmol) and T3P® in ethyl acetate (33.4 g, 3.12 mL/g Compound 4 ( a), 3.34 g/g compound 4, 52.5 mmol). The reactor contents are heated to 50°C to 60°C. Flush the reactor with isopropyl acetate (10 mL, 1.0 mL/g compound 3(a), 0.87 g/g compound 4(a)), and keep the reactor contents at this temperature for at least 3 hours to form Compound 5(a). The contents of the reactor were sampled and the content of compound 3(a) was tested by LC method-V1.0. Continue sampling and LC testing (at 1 hour intervals) until the content of compound 3(a) is less than 5.0%.

The contents of the reactor containing compound 5(a) were combined with 2N NaOH (54 g, 5.4 g/g compound 4(a)) with mixing and mixed at 40°C to 60°C for at least 10 minutes. Stop stirring and allow the mixture to phase separate for at least 10 minutes, 40°C to 60°C. Remove the lower aqueous phase. The contents of the reactor were distilled under reduced pressure (100 to 400 mbar) to a total volume of 9 to 11 mL/g of compound 4(a). The reactor contents were distilled under further reduced pressure (100 to 400 mbar) while adding ethanol (300 mL, 30 mL/g compound 4(a)) while maintaining a constant volume of 9 to 11 mL/g compound 4(a ). The reactor contents were sampled and the isopropyl acetate content was tested by GC. Continue to use ethanol solvent exchange until the isopropyl acetate content is less than 2.0%.

Add water (20 mL to 55°C (57 mL, 5.7 mL/g Compound 4(a)) to the reactor with stirring and heat to 55°C to 65°C for at least 10 minutes, then cool to 15 over 1 to 3 hours ℃ to 25 ℃. The contents of the reactor were kept at 15°C to 25°C for 1 hour with stirring to form a slurry containing solid compound 5(a). The solid was collected by filtration, and the collected solid was washed with mother liquor. The ethanol used in water 50 v/v% (4 mL/g compound 4(a)) was washed in the reactor and continued through the collected solids. The washed solid compound 5(a) is dried in a vacuum oven (<100 mbar at 30°C) for at least 6 hours. The compound 5(a) was sampled, and the water was tested by Karl Fischer method. Continue to dry until the water content is less than 1. The identity label obtained by 1H NMR indicates that compound 5(a) is consistent with the standard of compound 5(a). Compound 5(a) was produced as a brown/orange solid (20.1 g, 90% yield). The purity obtained by HPLC was 99.28%.

Example 1A Step 4: Deprotection

。Compound 6(a), (2S,4R,5S)-4-fluoro-5-methyl-N-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidine-5 -Yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide hydrochloride is as follows from compound 5(a) (2S,3R,5S)-3-fluoro-2-methyl-5-( (5-(Trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methylamine formamide)pyrrolidine-1-carboxylic acid tert-butyl ester preparation:

.

Add 1-propanol (58.6 mL, 3.77 mL/g compound 5(a)) to the reactor and cool to -5°C to 5°C, then add acetyl chloride (5.3 mL, 73.4 mmol, 0.34 mL) with stirring /g compound 5(a)) while keeping the temperature below 40°C. The mixture is aged at this temperature for at least 10 minutes. Compound 5(a) (15.56 g, 28.2 mmol) was added to the reactor, followed by 1-propanol (31 mL, 2 mL/g compound 5(a)). The reaction mixture was heated to 55°C to 65°C with stirring and maintained at this temperature for at least 3 hours to produce compound 6. The contents of the reactor were sampled and the content of compound 5(a) was tested by LC method-V1.0. Continue sampling and LC testing (at 1 hour intervals) until the content of compound 5(a) is less than 5.0%.

The reactor contents were distilled under reduced pressure (100 to 400 mbar) while adding n-heptane (187 mL, 12 mL/g compound 5(a)) while maintaining a constant volume of about 7 mL/g compound 5(a ). The reactor contents were sampled and the 1-propanol content was tested by GC. The reactor contents were cooled to 15°C to 25°C and stirred for at least 1 hour. The reactor contents were filtered to collect the solid compound 6(a), and the reactor was washed with the mother liquor to continue to pass through the collected compound 6(a) solids. The collected solid was further washed with a mixture of 1-propanol (10.9 mL, 0.7 mL/g compound 5(a)) and n-heptane (43.6 mL, 2.8 mL/g compound 5(a)). The solid compound 6(a) was dried in a vacuum oven (less than 100 mbar) at 50°C for at least 6 hours to obtain compound 6(a) as a brown/orange solid (20.1 g, yield 90%). The HPLC purity obtained by the method HPLC-012 was 97.66%, and the impurity was 2.61%. The dried material was sampled and tested for 2-propanol and n-heptane content by GC. Continue to dry until the contents of 1-propanol and n-heptane are less than 0.5% each. The purity of compound 6(a) obtained by HPLC was 98.81%.

Example 1A Step 5: Preparation of compound (I)a

。Compound (I)(a), (2S,4R,5S)-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl-N-((5-(trifluoromethyl)- 2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide is as follows from compound 6(a) (2S,4R,5S)-4 -Fluoro-5-methyl-N-((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidine- 2-Methylamine hydrochloride and compound 7(a) 4-fluorobenzene-1-sulfonyl chloride were prepared as ethanol solvates:

.

To the reactor were added middle compound 6(a) (10 g, 20.5 mmol) and MTBE (15 mL, 1.5 ml g compound 6a)) with stirring. Ethanol (4 mL, 0.4 mL/g compound 6(a)) and 10% K ₂ CO ₃ aqueous solution (38.2 mL, 3.82 mL/g compound 6(a)) were added to the reactor with stirring, and then compound 7 was added (a) A solution in MTBE (4.4 g compound 7(a), 0.44 g/g compound 6(a), 22.6 mmol; 21 mL MTBE 2.6 mL/g compound 6(a)). The reaction mixture is mixed at 15°C to 40 for at least 2 hours to form compound I(a). The contents of the reactor were sampled and the content of compound 6(a) was tested by LC method-V1.0. Continue sampling and LC testing (at 1 hour intervals) until the content of compound 6(a) is less than 5.0%. The stirring was stopped to allow the phases to separate, and the lower aqueous phase was removed. Water (20 mL, 2.0 mL/g compound 6(a)) was added to the reactor with stirring and mixed for at least 10 minutes. The stirring was stopped to allow the phases to separate, and the lower aqueous phase was removed.

The contents of the reactor containing compound I(a) were distilled to a minimum stirring volume under reduced pressure (100 to 400 mbar). Ethanol (10 to 50 mL, 1 to 5 mL/g compound 6(a)) was added to the reactor to a total volume of 4 to 5 mL/g compound 6(a). The reactor contents were distilled under reduced pressure (100 to 400 mbar) while adding ethanol (60 mL, 6.0 mL/g compound 6(a)) to maintain a constant volume of about 4.5 mL/g compound (a). The reactor contents were sampled and MTBE was evaluated by GC. Add n-heptane (100 mL, 10.0 mL/g compound 6(a)) to the reactor and heat to 60°C to 70°C, followed by stirring for at least 15 minutes. The reaction mixture was cooled to -5°C to 5°C over 1 to 3 hours and aged with stirring for 30 minutes. The reactor contents were filtered to collect the solid compound I(a), and the reactor was washed with the mother liquor to continue to pass through the collected compound I(a) solid. Washing the reactor with n-heptane (20 mL, 2 mL/g compound 6(a)) continued through the collected compound 6(a) solids. The solid compound I(a) was dried in a vacuum oven at 50°C to 60°C for at least 18 hours to obtain the compound I(a) as an off-white to brown solid (11.7 g, yield 94%). The dried material was sampled and tested for n-heptane content by GC. Continue to dry until the n-heptane content is less than 0.5%. The analysis of compound I(a) by HPLC was 92.81% and the purity by HPLC was 98.99%. Compound I(a) was identified as Form F of the crystalline free base ethanol solvate of Compound I(a).

Example 1A: Preparation of crystalline compound I (a) free base anhydrous form E

The solid crystalline free base Compound I(a) ethanol solvate (10.0 g) and DCM (25 mL, 2.5 mL/g Compound I(a)) were stirred at 15°C to 25°C to form a solution. The solution was filtered through a 0.45 μm filter cartridge into the reactor, where it was combined with n-heptane (22 mL, 2.2 mL/g Compound I(a)) with stirring. The crystalline Compound I(a) free base anhydrous E-type seed crystals were added to the reactor for at least 30 minutes under stirring at 15-25°C. N-Heptane (16 mL, 1.6 mL/g compound 6(a)) was added to the reactor over 2.5 to 3.5 hours with stirring. With stirring, n-heptane (16 mL, 1.6 mL/g compound 6(a)) was added to the reactor over 1.5 to 2.5 hours. With stirring, n-heptane (16 mL, 1.6 mL/g compound 6(a)) was added to the reactor over 0.5 to 1.5 hours. The crystalline Compound I(a) free base anhydrous type E solid was collected by filtration, and the reactor was washed with the mother liquor to continue passing through the collected solid. The reactor was washed with n-heptane (20 mL/g, 2.0 mL/g compound 6(a)) and continued through the collected solids. The washed crystalline Compound I(a) free base anhydrous Form E is dried in a vacuum oven (<20 mbar at 45°C to 55°C) for at least 18 hours. The dried material (8.4 g, 90% yield) was sampled and tested for DCM and n-heptane content by GC. Continue drying until the DCM content is less than 600 ppm and the n-heptane content is less than 0.45%. The identification obtained by 1H NMR indicates that the compound I(a) free base anhydrous is consistent with the compound I(a) free base anhydrous standard. The HPLC purity is 99.87%.

Example 1B: Preparation of compound 1(c) of (5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methanol.

Compound 1(c) was prepared according to the method depicted in Figure 2.

Example 1B analysis method

Referring to FIG. 2, compound 1(a) is prepared from compound 10A and compound 8 according to the following steps 1 to 3.

Example 1B Step 1

。Compound 10B(i) 2-chloro-5-methyl isonicotinic acid methyl ester was prepared from compound 10A(i) 2-chloro-5-methyl isonicotinic acid as follows:

.

To the inertized first reactor, dimethylformamide (99.3 kg, 4.75 kg/kg compound 10A(i)) was added and stirred. To the reactor, add compound 10A(i) (20.9 kg, 92.7 mol), sodium bicarbonate (15.6 kg, 0.745 kg/kg compound 10A(i)) and methyl tosylate (22.4 kg, 1.07 kg/ kg compound 10A(i)). The reaction mixture is heated to 35 to 45°C to maintain at this temperature for at least 4 hours. The sample was removed from the reaction mixture and diluted with acetonitrile. The reactor contents were sampled and the compound 10A(i) content was tested by HPLC method-008. Continue sampling and LC testing (at 1 hour intervals) until the content of compound 10A(i) is less than 5.0%. The reaction mixture was cooled to 20 to 30°C.

Water (313.5 kg, 15.0 kg/kg compound 10A(i)) was added to the inertized second reactor and stirred. The contents of the first reactor were added to the second reactor over a period of 1 hour while maintaining the temperature below 25°C. The mixture was stirred for at least 10 minutes, after which methyl tert-butyl ether (77.3 kg, 3.70 kg/kg compound 10A(i)) was added, after which the mixture was allowed to stand for 10 minutes. The bottom water layer was removed and transferred to the first container, and the organic layer was drained and transferred to the second container. Add the contents of the first vessel containing the aqueous phase to the second reactor, and then add methyl tertiary butyl ether (77.3 kg, 3.70 kg/kg compound 10A(i)) to the second reaction器中. Stir the mixture for at least 10 minutes, stop stirring, and let the mixture stand for at least 10 minutes. The bottom water layer was removed and transferred to the first container, and the organic layer was drained and transferred to the second container. Add the contents of the first vessel containing the aqueous phase to the second reactor, and then add methyl tertiary butyl ether (77.3 kg, 3.70 kg/kg compound 10A(i)) to the second reaction器中. Stir the mixture for at least 10 minutes, stop stirring, and let the mixture stand for at least 10 minutes. Remove the bottom water layer and transfer to the first container.

To the second reactor, the organic phase and the saline solution (3.4 M sodium chloride, 125 kg, 5.98 kg/kg compound 10A(i)) in the second vessel were added in order. The contents of the second reactor were stirred for at least 10 minutes, after which the mixture was allowed to stand for at least 10 minutes. Remove the bottom water layer and transfer as waste. To the second reactor was added saline solution (3.4 M sodium chloride, 125 kg, 5.98 kg/kg compound 10A(i)), and the contents of the second reactor were stirred for at least 10 minutes, after which the mixture was allowed to stand Set at least 10 minutes. Remove the bottom water layer and transfer as waste.

The contents of the second reactor were distilled under reduced pressure to a volume of 2 L/kg, while keeping the temperature of the reactor below 45°C. Tetrahydrofuran (37.2 kg, 1.78 kg/kg compound 10A(i)) was added to the second reactor, and the contents of the reactor were distilled under reduced pressure to reach a volume of 2 L/kg (where compound 10B(i) was Solution type) while keeping the temperature of the reactor below 45°C to maintain the temperature at 20°C to 30°C for the next step.

Example 1B Step 2

。Compound 10C(i) (2-chloro-5-methylpyridin-4-yl)methanol was prepared from compound 10B(i) 2-chloro-5-methylisonicotinic acid methyl ester as follows:

.

To the stirred inertization reactor was added compound 10B(i) (42 L, 1.9 L/kg) as a tetrahydrofuran solution. Tetrahydrofuran (167.4 kg, 7.6 kg/kg compound 10B(i)) and water (14.6 kg, 0.7 kg/kg compound 10B(i)) were added to the reactor and the mixture was cooled to 10 to 20°C. Lithium chloride (5.9 kg, 0.265 kg/kg compound 10B(i)) was added to the reactor while maintaining the temperature below 25°C, after which sodium borohydride (3.5 kg, 0.16 kg/ kg compound 10B(i)) while keeping the temperature below 25°C. The reaction mixture is kept at 15 to 25°C for at least 5 hours. The reactor contents were sampled and the compound 10B(i) content was tested by HPLC method-008. Continue sampling and LC testing (at 1 hour intervals) until the content of compound 10B(i) is less than 5.0%

Hydrochloric acid (2N, 230 L, 10.4 L/kg) was added to the reactor to obtain a pH of about 1, while maintaining the reactor temperature below 20°C to stirring for at least 4 hours. Stop the agitation and let the mixture sit for at least 10 minutes. Transfer the aqueous layer to the first container and the organic layer to the second container. Aqueous layer, ethyl acetate (94 kg, 4.2 kg/kg compound 10B(i)) were added to the reactor sequentially, and the mixture was stirred for at least 10 minutes. Stop the agitation, let the mixture stand for at least 10 minutes, and drain the aqueous phase into waste. Sodium bicarbonate (115 kg, 5.18 kg/kg compound 10B(i)) was added to the reactor and the mixture was stirred for at least 10 minutes. Stop the agitation and let the mixture sit for at least 10 minutes. Transfer the aqueous layer to the first container and the organic layer to the second container. Aqueous layer, ethyl acetate (94 kg, 4.2 kg/kg compound 10B(i)) were added to the reactor sequentially, and the mixture was stirred for at least 10 minutes. Stop the agitation, let the mixture stand for at least 10 minutes, and drain the aqueous phase into waste.

To the second reactor, the organic phase and the saline solution (3.4 M sodium chloride, 125 kg, 5.63 kg/kg compound 10B(i)) in the second vessel were added in sequence. Stir the mixture for at least 10 minutes, stop the agitation, and let the mixture stand for at least 10 minutes. Remove the water layer and transfer to waste. Repeat this drying process a second time. The contents of the vacuum distillation reactor to reach a volume of 2 L/kg while keeping the temperature of the reactor below 60°C. Add heptane (71 kg, 3.2 L/kg, 3.2 kg/kg compound 10B(i)) to the reactor and distill the contents of the reactor under reduced pressure to a volume of 2 L/kg, while keeping the temperature of the reactor low At 60°C. Heptane (71 kg, 3.2 L/kg, 3.2 kg/kg compound 10B(i)) was added to the reactor, and the reactor contents were cooled to 0°C and aged for at least 1 hour while keeping the reaction temperature at − Between 5 and 5°C. The solid was filtered and the reactor and filter cake were washed twice with heptane (14.2 kg, 3.2 L/kg, 0.64 kg/kg compound 10B(i)). The product was dried in a vacuum oven to a constant weight of compound 10C(i) as an off-white solid (15.8 kg, yield 81%, in two steps). The purity of the compound 10C(i) product was determined to be 99.38 A% using analytical HPLC method-009.

Example 1B Step 3

酸製備：

。Compound 1(a) (5-methyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methanol is as follows from compound 10C(i) (2-chloro-5-methyl Pyridin-4-yl)methanol and compound 8 2-(trifluoromethyl)pyrimidin-5-yl

Acid preparation:

.

Add 1,4-dioxane (52.73 kg, 7.22 kg/kg compound 10C(i)) and water (36.5 kg, 5 kg/kg compound 10C(i)) to the first stirred inertization reactor and Stir. To the first reactor, potassium carbonate (11.9 kg, 1.63 kg/kg compound 10C(i)) and compound 10C(i) (7.3 kg, 93 mol) were added in sequence. Adjust the temperature of the mixture to 25 to 30°C and further add [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.505 kg, 0.07 kg) in the first reactor /kg compound 10C(i)). Nitrogen was bubbled through the solution for 1 to 2 hours, after which the solution was heated to 75 to 80°C and stirred for 2 hours. The contents of the first reactor were sampled and the compound 10C(i) content was tested by HPLC method-011. Continue sampling and LC testing (at 30-minute intervals) until the compound 10C(i) content is less than 5.0%.

The reaction mixture was cooled to 45°C and the contents of the first reactor were distilled under reduced pressure to reach a volume of 3 L/kg, while keeping the temperature of the reactor below 60°C. To the first reactor, add water (58.4 kg, 8.0 kg/kg compound 2C), methyl tert-butyl ether (54 kg, 7.4 kg/kg compound 10C(i)) in sequence, and stir the mixture for at least 10 minute. Stop the agitation and let the mixture sit for at least 10 minutes. The bottom water layer was removed and transferred to the first container, and the organic layer was discharged into the second container. To the first reactor, the aqueous phase, methyl tert-butyl ether (27 kg, 3.7 kg/kg compound 10C(i)) were added in sequence, and the mixture was stirred for at least 10 minutes. Stop the agitation and let the mixture sit for at least 10 minutes. The bottom water layer was removed and transferred to the first container, and the organic layer was discharged into the second container. To the first reactor, the aqueous phase, methyl tert-butyl ether (27 kg, 3.7 kg/kg compound 10C(i)) were added in sequence, and the mixture was stirred for at least 10 minutes. Stop the agitation and let the mixture sit for at least 10 minutes. Remove the bottom water layer and transfer to the first container.

To the first reactor, add the organic phase and silicone rubber (3.65 kg, 0.50 kg/kg compound 10C(i)) in the second container in sequence, and stir the reactor contents at 25 to 30°C for at least 2 hour. The reactor contents were filtered and the filtrate was collected in a third container. The first reactor was rinsed with methyl tert-butyl ether (27 kg, 3.7 kg/kg compound 10C(i)), then filtered through a filter cake and collected in a third container. Take the filtrate from the third container and add it to the second reactor.

The contents of the second reactor were distilled under reduced pressure to reach a volume of 2 L/kg, while keeping the temperature of the reactor below 50°C. Heptane (25 kg, 3.42 kg/kg compound 10C(i)) was added to the second reactor, and the contents of the second reactor were distilled under reduced pressure to reach a volume of 4 L/kg while maintaining The temperature of the reactor is below 50°C. Add heptane in the second reactor and repeat the distillation of the reactor contents twice as described. Dichloromethane (14.56 kg, 2.0 kg/kg compound 10C(i)) was then added in the second reactor, and the mixture was stirred at 25 to 30°C for at least 2 hours. Filter the contents of the second reactor and wash the filter with a mixture of dichloromethane (3.24 kg, 0.44 kg/kg compound 10C(i)) and heptane (3.32 kg, 0.45 kg/kg compound 10C(i)) Cake and reactor. The filter cake was vacuum dried at 30 to 40°C for 14 hours to obtain crude compound 1(a) (about 10 kg). In the third inertized reactor, dichloromethane (26.6 kg, 3.64 kg/kg compound 10C(i)) and crude compound 1(a) (about 10 kg) were added in this order. Heat the reactor contents to 35 to 45°C and stir for at least 2 hours. Over a period of 3 hours, heptane (27.36, 3.75 kg/kg compound 10C(i)) was added to the third reactor. The mixture was cooled to a temperature of 20 to 30°C and maintained at this temperature for at least 2 hours. The solid was filtered and the filter cake was washed with a mixture of dichloromethane (4.44 kg, 0.61 kg/kg compound 10C(i)) and heptane (4.55 kg, 0.62 kg/kg compound 10C(i)). The solid was dried in a vacuum oven at 30 to 40°C for at least 14 hours to obtain compound 1(a) (8.53 kg, yield 78%). The purity of the product was 98.71 A% by analytical HPLC method-011.

酸(化合物8)Example 1C: Preparation (2-(trifluoromethyl)pyrimidin-5-yl)

Acid (Compound 8)

Example 1C analysis method

酸如下由化合物8A 5-溴-2-碘嘧啶及8B 5-溴-2-(三氟甲基)嘧啶製備：

。Compound 8 2-(trifluoromethyl)pyrimidin-5-yl

The acid is prepared from compounds 8A 5-bromo-2-iodopyrimidine and 8B 5-bromo-2-(trifluoromethyl)pyrimidine as follows:

.

In Step 1, DMF (149.6 kg, 7 L/kg compound 8A) was added to the inertization reactor with stirring. To the reactor, add compound 8A (22.5 kg, 78.98 moles, 1 equivalent), CuI (6 kg, 0.4 equivalent, 2.674 kg/kg compound 8A) and MeO ₂ CCF ₂ SO ₂ F (21.2 kg, 0.944 kg /kg compound 8A). The reactor contents were stirred at 80 to 90°C for at least 3 hours to form a reaction product mixture containing compound 8B. The reactor was sampled and the compound 8A content was tested by LC, where the limit was compound 8A <5%. Continue mixing at 80 to 90°C until the compound 8A content is <5%. NaHCO ₃ (371.3 kg, 16.5 kg/kg, compound 8A) at a concentration of 25 mol was combined with the reaction product mixture and kept under stirring at 20° C. to 30° C. for 6 hours. MTBE (116.6 kg, 5.18 kg/kg compound 8A) was combined with the reaction product, followed by diatomite filter aid (22.5 kg, 1 kg/kg compound 8A). The reaction product mixture was stirred at 20 to 30°C for 15 minutes, filtered and the filtrate was collected. The filter cake was washed with MTBE (33.3 kg, 1.48 kg/kg compound 8A) and the filtrates were combined.

The collected filtrate was allowed to stand for at least 10 minutes and the bottom water layer was removed. The aqueous layer was washed twice with MTBE (116.6 kg, 5.18 kg/kg Compound 8A), where phase separation and aqueous layer removal were performed after each MTBE wash. The three organic layers were combined and further combined with 5 molar NaCl aqueous solution (212 kg, 9.42 kg/kg Compound 8A) and stirred for at least 10 minutes. Let the blend stand for at least 10 minutes and remove the bottom water layer. The organic layer was combined with 5 molar NaCl aqueous solution (212 kg, 9.42 kg/kg Compound 8A) and stirred for at least 10 minutes. Let the blend stand for at least 10 minutes and remove the bottom water layer. The remaining organic layer in the reactor was distilled under atmospheric pressure to reduce the volume to the minimum stirring volume (about 1 L/kg compound 8A). Then the contents of the reactor were distilled under further reduced pressure (50 to 100 mbar), and compound 8B was collected as a fraction of 80 to 90°C. The yield of compound 8A was 76.6%, and the HPLC purity obtained by method MTH-003 by HPLC method 003 V01 was 95.71%.

In step 2, add THF (179.4 kg, 7.12 kg/kg compound 8B), compound 8B (25.2 kg, 111 mol) and B(Oi-Pr) ₃ (31.3 kg, 12.43 kg) to the inertization reactor in this order /kg compound 8B) and cooled to -70 to -80°C. N-BuLi (39.7 kg, 1.58 kg/kg Compound 8B) was added dropwise to the reactor over 6 hours to form a reaction mixture, followed by stirring for at least 1 hour to form a reaction product mixture containing Compound 8. The reaction product mixture was sampled and tested for compound 8B content by HPLC method 007 V01. The reaction was continued until the content of compound 8B was less than 5%.

A solution of water (7 kg, 0.28 kg/kg Compound 8B) in THF (22.4 kg, 0.88 kg/kg Compound 8B) was added to the reaction product mixture with stirring, while maintaining the temperature of -55 to -65°C, while stirring The reaction product mixture is kept at this temperature for at least 30 minutes. The reaction product was heated to 0°C over 1 to 2 hours and then water (376 kg, 13 kg/kg compound 8B) was combined with the reaction product mixture while maintaining the temperature at 10°C and the reaction product mixture under these conditions At least 30 minutes. Allow the blend to stand for at least 10 minutes and remove the bottom aqueous layer containing compound 8. The water layer was blended with MTBE (93.2 kg, 3.7 kg/kg compound 8B) and stirred for at least 10 minutes. Allow the blend to stand for at least 10 minutes and remove the bottom aqueous layer containing compound 8. The pH of the aqueous layer was adjusted to 1 to 2 with concentrated HCl (12.35 kg, 0.49 kg/kg Compound 8B) at a temperature less than 25°C.

The pH-adjusted aqueous phase was blended with MTBE (93.2 kg, 3.7 kg/kg compound 8B) and stirred for at least 10 minutes. The blend was allowed to stand for at least 10 minutes and the bottom water layer was removed, leaving the organic layer containing compound 8. The water layer was blended with MTBE (93.2 kg, 3.7 kg/kg Compound 8B) and stirred for at least 10 minutes, and the blend was allowed to stand for at least 10 minutes, and the bottom water layer was removed. Repeat the steps of blending the water layer, and discard the water layer. The organic layer was combined in the reactor and distilled under reduced pressure at a temperature of less than 45°C to reduce the volume to about 3 L/kg of compound 8B. 1,4-Dioxane (130.16 kg, 5.17 kg/kg Compound 8B) was added to the reactor with stirring and the reactor contents were distilled under reduced pressure to reduce the volume to about 3 L/kg Compound 8B. The reactor contents were cooled to 25°C to obtain a solution of compound 8 in 1,4-dioxane (71.3 kg, yield 82%). The analysis determined that it was 24.5 w/w% compound 8.

Example 1D: Preparation of compound 4(a)

Compound 4(a) (2S,4R,5S)-1-(third butoxycarbonyl)-4-fluoro-5-methylpyrrolidine-2-carboxylic acid was prepared according to the method depicted in Figure 3 and described below .

Example 1D analysis method

Example 1D Step 1.

。Compound 4B (2S,4S)-1-(third butoxycarbonyl)-4-(third butyldimethylsilyloxy)pyrrolidin-2-carboxylic acid is as follows from compound 4A (2S,4S)-1 -(Third butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid preparation:

.

To a glass-lined reactor containing DCM (279 L), compound 4A (65.2 kg) and imidazole (37.8 kg, 0.580 kg/kg compound 4A) were added. To the reaction mixture, tributyldimethylsilyl chloride (46.2 kg, 0.709 kg/kg compound 4A) was added dropwise at 10 to 15°C over a period of 2.5 to 3 hours. The reaction mixture was stirred at 25 to 30°C for 5 hours. The reactor contents were sampled and the compound 4A content was tested by HPLC method-001. Continue sampling and testing until the content of compound 4A is less than 0.1%.

The reaction mixture was cooled to 10 to 15°C, filtered and washed three times with 15 L DCM. The phases were separated and the organic phase was washed twice with 5 w% citric acid (80 kg) and stirred for 20 minutes. The organic phase was then washed twice with brine (80 kg) and stirred for 20 minutes. The organic phase was then dehydrated over anhydrous sodium sulfate (approximately 25 kg), filtered with 100 mesh non-woven filter cloth, and washed three times with DCM (10 L). The dissolved fraction was concentrated in vacuo at 40 to 45°C. Ethyl acetate (130 kg, 2.0 kg/kg compound 4A) was added to the reactor, and the dissolved fraction was concentrated at 45°C over 5 hours to obtain compound 4A (142.5 kg) in ethyl acetate as a pale yellow solution. ). The HPLC purity obtained by HPLC method-001 was 98.6%, and the impurity was 0.6%. The crude product was used directly in Step 2 of Example ID.

Example 1D Step 2.

。Compound 4C (2S, 4S)-1-(third butoxycarbonyl)-4-(third butyldimethylsilyloxy)-5- pendant pyrrolidine-2-carboxylic acid is as follows from compound 4B ( Preparation of 2S,4S)-1-(third butoxycarbonyl)-4-(third butyldimethylsilyloxy)pyrrolidine-2-carboxylic acid:

.

Water (650 kg, 19.8 kg/kg Compound 4B) and sodium periodate (58.7 kg, 1.79 kg/kg Compound 4B) were added to the stirred reactor. After stirring for 10 minutes, a yellow solution was obtained, which was then combined with ethyl acetate reactant (245 kg, 7.47 kg/kg compound 4B). A solution of compound 4B in ethyl acetate (16 kg) (49 kg, 67 w%) was added to the reactor over 30 minutes. Ruthenium dioxide (770 g, 0.0235 kg/kg compound 4B) was added to the reactor, and the contents of the reactor were purged with nitrogen three times, and stirred under nitrogen at 50 to 55° C. for 24 hours to form a reaction product mixture . The reactor contents were sampled and the compound 4B content and compound 4C content were tested by HPLC method-001. Continue sampling and testing until the compound 4B content is less than 0.24% and the compound 4C content exceeds 95.0%.

The reaction product mixture was cooled to room temperature (about 25°C) and filtered through a pad of celite. The resulting filter cake was washed with ethyl acetate (20 kg). The phases were separated and the aqueous phase was extracted with ethyl acetate (120 kg). The organic phases were combined, cooled to below 10°C, and slowly added to a 10 wt% sodium bisulfite aqueous solution (120 kg, pH=7, adjusted with 120 kg 10 wt% NaOH) to keep the internal temperature below 10°C. The phases were separated and the organic phase was extracted with 10 w% aqueous sodium bisulfite solution (pH = 7, adjusted with 80 kg 10 wt% NaOH). The organic phase was washed twice with brine (50 kg), dehydrated with anhydrous sodium sulfate (about 35 kg), and filtered with a 100-mesh non-woven filter cloth. The resulting filter cake was washed with ethyl acetate (25 kg). The filtrate and concentrate were combined and concentrated in vacuo at 40 to 45°C for 8 hours. The crude compound 4C (55 kg) was obtained as a yellow oil.

Compound 4C was crystallized as follows. Heptane (2 L/kg, 137 kg) was added to 110 kg of crude compound 4C, and the reaction mixture was concentrated to about 1 L/kg at 40 to 45°C over 6 hours. Heptane (2 L/kg, 137 kg) was added and the reaction mixture was sampled and subjected to GC test (GC, EA: 0.17A%). Heptane (3.75 L/kg, 263 kg) was added to the reaction mixture, and cooled to 15°C with an ice water bath over a period of 1 hour, so that a solid compound 4C precipitated from the solution. The mixture was stirred at 15 to 20°C for 30 minutes, cooled to 5°C with an ice water bath over a period of 2 hours, and stirred at 5 to 10°C for 30 minutes. The reaction mixture was filtered to obtain wet crude compound 4C. The wetted crude material was dried under vacuum at 25° C. for 6 hours to produce 67.8 kg of compound 4C from 101 kg of wetted solid, and the LC purity was 98.1 A%. The isolated yield obtained was 64.4% (calculated by LC analysis).

The mother liquor was concentrated in vacuo at 40 to 45°C for 6 hours, yielding about 90 kg of crude compound 4C as a yellow oil. The crude compound 4C was dissolved in n-heptane (137 kg, 2 L/kg), and the mixture was cooled to 5°C with an ice water bath over a period of 2 hours and stirred at 0 to 5°C for 30 minutes. The mixture was filtered to obtain the wet crude material of compound 4C (about 9 kg, LC purity 95.6 C%). The wetted crude material was dried under vacuum at 25°C for 6 hours to produce 6.9 kg of compound 4C from 9 kg of wetted solid, with an LC purity of 96.9 A%. The isolated yield was 6.5% (calculated by LC analysis).

The second mother liquor was concentrated in vacuo at 40 to 45°C and poured onto silica (20 kg, 200 to 300 mesh, 2.5 kg/kg). The silica was washed with a solution of petroleum ether and ethyl acetate (10/1, v/v, 100 L), and the filtrate was collected and concentrated to dryness in vacuo at 45°C. Heptane (3 L/kg) was added to the crude oil of compound 4C, and the mixture was cooled from room temperature to 15°C with an ice water bath over a period of 1 hour, resulting in the formation of a precipitate. The mixture was stirred at 15 to 20°C for 30 minutes, cooled to 5°C with an ice water bath over a period of 2 hours, and stirred at 5 to 10°C for 30 minutes. The reaction mixture was filtered to obtain wet crude compound 4C. The crude material was dried under vacuum at 25°C for 6 hours to produce 3.3 kg of compound 4C with an LC purity of 95.3 A%. The isolated yield was 64.4% (calculated by LC analysis). The total of the obtained compound 4C was 78 kg, and the isolated yield was 77.4% (calculated by LC analysis).

Example 1D Step 3

。Compound 4D (2S, 4S)-1-(third butoxycarbonyl)-4-(third butyldimethylsilyloxy)-5-methylenepyrrolidine-2-carboxylic acid is as follows from compound 4C ( Preparation of 2S,4S)-1-(third butoxycarbonyl)-4-(third butyldimethylsilyloxy)-5- pendant pyrrolidine-2-carboxylic acid:

.

To the reactor, add dimethyl titanocene (289 kg, 8.9 wt% in toluene, 1.28 kg/kg compound 4C), titanocene dichloride (0.803 kg, 0.040 kg/kg compound 4C) and 20.1 kg Compound 4C to produce a red mixture. The reactor was purged with nitrogen 5 times, and the reaction mixture was successively stirred for 8 hours while maintaining the internal temperature at 75 to 80°C. A sample of the reaction mixture was removed, diluted with acetonitrile, and analyzed by HPLC using method-001. This method demonstrates that 90.6% of compound 4D is produced and 0.34% of compound 4C is retained.

The reaction mixture was cooled to 25°C and concentrated in vacuo to dryness at 45°C over a period of 14 hours to produce approximately 60 kg of solid crude material. Heptane (114 kg) was added to the above residue under stirring at 5 to 10°C for 1 hour. The mixture was filtered and the filter cake was washed with heptane (about 50 kg). The filtrate and concentrate were combined under vacuum at 45°C for a period of 7 hours to dryness, yielding approximately 30 kg of crude solid material. Heptane (28.4 kg) was added under stirring at 5 to 10°C for 1 hour. The mixture was filtered and the filter cake was washed with heptane (about 10 kg) to produce a solution of compound 4D and heptane (62 kg). Add silicon dioxide (14 kg, 60 to 100 mesh) to the above solution over a period of 30 minutes, while stirring the solution at a temperature of 25 to 30°C. The solution was poured into silica (35 g, 200 to 300 mesh) under vacuum (petroleum ether/ethyl acetate=20/1). Combine the filtrate and concentrate in vacuo at 45°C to dryness. 17.1 kg of compound 4D was obtained, the LC purity was 92.8 A% and the yield was 85.5%.

Example 1D Step 4.

。Compound 4E (2S, 4S, 5S)-1-(third butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-5-methylpyrrolidine-2-carboxylic acid is as follows from compound 4D Preparation of (2S,4S)-1-(third butoxycarbonyl)-4-(third butyldimethylsilyloxy)-5-methylenepyrrolidine-2-carboxylic acid:

.

Add compound 4D (17.1 kg, 46.1 mol), methanol (136 kg, 7.68 kg/kg compound 4D) and activated carbon (1.7 kg, 0.1 kg/kg compound 4D) to the reactor and stir at 25 to 30°C for 1 hour. The reaction mixture was then filtered and activated carbon (1.7 kg) was added. The resulting filter cake was washed twice with methanol (10). Collect approximately 20 kg of filtrate. The filtrate was stirred at 25 to 30°C for 1 hour, filtered (about 220 L), and combined with wetted palladium/carbon (5 wt%, 4.25 kg). The filter cake was washed twice with methanol (10 L), and approximately 30 kg of filtrate was collected. The reactor containing this solution was purged with hydrogen three times, and the solution was stirred under a hydrogen atmosphere (P = 1 atm) at 25 to 30°C for 18 hours. The contents of the reactor were sampled and the content of compound 4E was tested by HPLC method-001, and the content of compound 4E was shown to be 95.3 A%.

The mixture was filtered and washed with methanol (about 25 L). The filtrate and washing solution were combined and concentrated in vacuo to about 15 L at 45°C. Activated carbon (0.3 kg, 0.18 kg/kg Compound 4D) was added to the concentrate, and the mixture was stirred at 25 to 30°C for 1 hour, filtered (about 15 L) and wetted palladium/carbon (5 wt%, 0.556) was added kg). The reactor containing this solution was purged with hydrogen three times, and the solution was stirred under a hydrogen atmosphere (P = 1 atm) at 25 to 30°C for 18 hours. The contents of the reactor were sampled and the content of compound 4E was tested by HPLC method-001, and the content of compound 4E was shown to be 95.3 A%.

The mixture was filtered and washed with methanol (about 5 L) and concentrated to dryness in vacuo at 45°C. 14.4 kg of compound 4E (yield=84%) was obtained with a purity of 97.3 A%.

Example 1D Step 5.

。Compound 4F (2S, 4S, 5S)-1-(third butoxycarbonyl)-4-hydroxy-5-methylpyrrolidine-2-carboxylic acid is as follows from compound 4E (2S,4S,5S)-1-( Third butoxycarbonyl)-4-(third butyldimethylsilyloxy)-5-methylpyrrolidine-2-carboxylic acid Preparation:

.

Compound 4E (30.3 kg, 81.11 mol) and tetrahydrofuran (135 kg, 4.46 kg/kg compound 4E) were added to the reactor and stirred for 10 minutes. The mixture was cooled to 20 to 25°C, after which tetrabutylammonium fluoride trihydrate (25.6 kg, 0.845 kg/kg compound 4E) was added to form a reaction mixture. The reactor was purged with nitrogen three times, followed by stirring at 20 to 30°C for 1 hour to form a reaction product mixture containing compound 4F. The contents of the reactor were sampled and the content of compound 4F was tested by HPLC method-001, and the content of compound 4F was shown to be 83.6 A%.

The reaction product mixture was cooled to 10°C, mixed with water (130 kg, 4.29 kg/kg Compound 4E, about 10°C) and stirred for 10 minutes. The organic phase of the mixture was extracted three times with ethyl acetate (108 kg, 81 kg and 54 kg). The extracted organic phases were combined and washed twice with brine (120 kg, 20 wt%). The mixture was dried with anhydrous sodium sulfate (50 kg). The solid was collected by filtration and washed twice with ethyl acetate (25 kg). The filtrate was concentrated in vacuo at 50°C. HPLC analysis showed that the content of ethyl acetate was 0.6 A%. Petroleum ether (40 kg, 1.3 kg/kg compound 4E) and water (90 kg, 3.0 kg/kg compound 4E) were added to the residue and stirred vigorously at 5 to 15°C for 30 minutes. The solid was collected by filtration and washed twice with pre-cooled water (28 kg). 27.1 kg of wetting product was obtained. The wetting product was dissolved in DCM (143 kg, 4.72 kg/kg compound 4E), and the mixture was washed with brine (54 kg, 20 w%). The phases were separated and the organic phase was dried over anhydrous sodium sulfate (21 kg), followed by stirring for 10 minutes. Anhydrous magnesium sulfate (10.8 kg) was added and the mixture was stirred for 30 minutes, filtered and washed twice with DCM (20 kg). The mixture was concentrated in vacuo at 45 to 55°C. 20.3 kg of compound 4F was obtained with an LC purity of 97.8 A% and an uncorrected yield of 96.6%.

Example 1D Step 6.

。Compound 4G (2S, 4S, 5S)-1-(third butoxycarbonyl)-4-fluoro-5-methylpyrrolidine-2-carboxylic acid is as follows from compound 4F (2S,4S,5S)-1-( Third butoxycarbonyl)-4-(third butyldimethylsilyloxy)-5-methylpyrrolidine-2-carboxylic acid Preparation:

.

To the reactor, compound 4F (20.3 kg, 78.29 mol), THF (110 kg, 5.4 kg/kg compound 4F) and TEA (19.8 kg, 0.975 kg/kg compound 4F) were added. The mixture was cooled to 10°C with an ice bath, and then the reactor was purged with nitrogen three times. Triethylamine trihydrofluoride (10.1 kg, 0.498 kg/kg compound 4F) was added dropwise at 10 to 20°C, followed by perfluoro-1-butane sulfonyl fluoride (52.06 kg, 2.56 kg/kg compound 4F) ), which is also added dropwise at 10 to 20°C. The reaction mixture was stirred at 10 to 30°C for 12 hours. The sample was removed from the reaction mixture and diluted with acetonitrile for analysis. Analysis by HPLC method-001 showed that the content of compound 4G was 40.6 A% and 0.53 A% of compound 4F was retained.

The mixture was cooled to 10°C. Aqueous potassium permanganate (150 kg, 3.22 wt%) was added dropwise at 10 to 20°C to purify any removal products. The reaction mixture was stirred at 10 to 20°C for 1 hour. The sample was removed from the reaction mixture and diluted with acetonitrile for analysis. Analysis by HPLC method-001 showed that the content of compound 4G was 50.3 A% and the removal product was not retained.

Sodium bicarbonate (10.15 kg, 0.5 kg/kg Compound 4F, pH = 7 to 8) was added portionwise at 5 to 10° C. and stirred for 10 minutes. Toluene (18 kg, 0.89 kg/kg compound 4F) was added, and the mixture was stirred for 5 minutes and filtered through celite (13 kg, 0.64 kg/kg compound 4F). The collected filter cake was then washed twice with 30 kg toluene and then with 20 kg toluene. The organic phase was separated and extracted three times with toluene (87 kg, 4.3 kg/kg compound 4F). The organic phases were combined, washed with 20 wt% brine (165 kg, 8.1 kg/kg Compound 4F), and dehydrated over anhydrous sodium sulfate (41.2 kg, 2.03 kg/kg Compound 4F). The mixture was then washed twice with toluene (20 kg) and concentrated in vacuo at 60°C. LC analysis showed that 60 A% of toluene was retained.

Petroleum ether (65 kg, 3.2 kg/kg compound 4F) and silicone gel (20 kg, 200 to 300 mesh) were added to the residue and stirred for 10 minutes. The mixture was filtered through silica gel (40 kg, 200 to 300 mesh) and dissolved with a solution of ethyl acetate and petroleum ether (1:10, 1.7 L). The mixture was concentrated in vacuo at 45°C. 13.1 kg of compound 4G was obtained, the LC purity was 90.2 A% and the uncorrected yield was 63.7%.

Example 1D Step 7.

。Compound 4(a) (2S,4R,5S)-1-(third butoxycarbonyl)-4-fluoro-5-methylpyrrolidine-2-carboxylic acid is as follows from compound 4G (2S,4S,5S)- Preparation of 1-(third butoxycarbonyl)-4-fluoro-5-methylpyrrolidine-2-carboxylic acid:

.

To the reactor, compound 4G (13 kg, 49.75 mol), methanol (83 kg, 6.4 kg/kg compound 4G) and THF (92.5 kg, 7.1 kg/kg compound 4G) were added. The mixture was cooled to 10°C with an ice bath. Lithium hydroxide (2.7 kg, 0.27 kg/kg compound 4G) in water (105 kg, 8.1 kg/kg compound 4G) was added dropwise to the reaction mixture. The mixture was gradually warmed to 25 to 30°C over a period of 1 hour, and stirred at this temperature for 12 hours to form a reaction product mixture containing compound 4(a). The sample was removed from the reaction mixture and diluted with acetonitrile for analysis. Analysis by HPLC method-002 showed that the content of compound 4(a) was 84.5 A% and retained 1.45 A% of compound 4G.

The mixture was concentrated in vacuo at 45°C and the residue (about 120 kg) was cooled to 20°C, washed twice with 80 kg DCM and once with 47 kg DCM. Collect the organic phase. The aqueous phase was cooled to 10°C, and 1M HCl (about 65 kg, 0 to 10°C) was added dropwise to the reaction mixture over a period of approximately 2.5 hours to adjust the pH to 2 to 3. A white precipitate formed in the reaction mixture. The reaction mixture was continuously stirred at 0 to 10°C for 30 minutes, filtered, and the collected solid was washed twice with cold water (18 kg). The solid was then dried under vacuum at 60°C for 7 hours to obtain 10.1 kg of crude product compound 4(a) (yield = 82.1%) with an LC purity of 99.6 A%.

Example 2: Preparation of crystalline form

Example 2-A: Polymorph screening

Compound I(a) starting material by X-ray powder diffraction (XRPD) (see Figure 6), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) (see Figure 7), proton nuclear magnetic resonance ( 1H NMR) (see Figure 8) and dynamic gas phase adsorption (DVS) (see Figure 9). The characterization results show that the starting material is a slightly hygroscopic hydrate, designated as type A.

Using Form A as the starting material, polymorph screening is performed via vapor diffusion, anti-solvent addition, slurry conversion, slow evaporation, and slow cooling. Through screening and subsequent research, a total of 14 crystal types were found, including anhydrous E type, hydrate A type, 10 solvate types and two transient types (converted to A type A0 and B type under environmental conditions) . The characterization results of the 14 crystal types are summarized in Table 1 below, and the interconversion diagrams are shown in FIG. 5. Amorphous formation was observed after magnetic stirring of type A in water.

Table 1: Characterization results of crystal types

Hydrate type A and anhydrous type E were selected to increase proportionally for further evaluation. Types A and E were suspended in water at room temperature (RT, about 25°C) and 50°C using magnetic stirring and shaking, respectively. For Types A and E, magnetic stirring caused significant amorphous formation, however, no decrease in crystallinity was observed via oscillation, indicating a mechanical stability problem. The kinetic solubility of Forms A and E was measured at 37°C in HPLC water, pH 6.5 phosphate buffer and 0.01 N HCl. Solubility samples were taken at the end points of 1, 2, 4, and 24 hours, as well as filter cakes for XRPD testing and supernatants for HPLC and pH analysis. The results show that both types have no type change, and that in all three aqueous media, type A exhibits a higher total solubility than type E, indicating that type E may be more thermodynamically stable than type A at 37°C.

Further study the proportional increase of E type and the feasibility of jet grinding. After the mixture of form A and E was magnetically stirred in DCM/n-heptane (v/v, 1:3) at room temperature, pure form E was obtained, indicating that form E could be directly separated. By anti-solvent crystallization in DCM/n-heptane in the presence of seed crystals at room temperature, a 3-g scale of Form E was successfully prepared and by XRPD, TGA, DSC, polarized microscopy (PLM), particle size distribution ( PSD) and gas chromatography (GC) are fully characterized, as indicated in more detail in the examples below. Long needle-like crystals were observed, and the two solvent residues were below 50 ppm. After 2.86 g Type E jet milling, a limited sample (<50 mg) was collected and characterized by XRPD, DSC, PLM and PSD. No obvious amorphous was detected in the jet milled product.

Example 2-B: Polymorph screening

Analytical methods for polymorphic studies.

X-ray powder diffraction (XRPD)

For XRPD analysis, PANalytical and Bruker X-ray powder diffractometers were used. The XRPD parameters used are listed below, where the measured temperature is 25°C.

Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

TGA data was collected using TA Q500/Q5000 TGA from TA Instruments. DSC and mDSC were performed using TA Q200/Q2000 DSC from TA Instruments. The detailed parameters used are listed below.

Proton Nuclear Magnetic Resonance ( ¹ H NMR)

¹ H NMR data was collected by Bruker 400M NMR spectrometer using DMSO-d6.

Dynamic Vapor Phase Adsorption (DVS) DVS is measured by SMS (Surface Measurement System) DVS Intrinsic instrument. The DVS test parameters are listed below.

High pressure liquid chromatography (HPLC)

Detailed chromatography conditions using Agilent 1100 HPLC and dissolution measurements are listed below.

Particle size distribution (PSD)

PSD data was collected using laser diffraction particle size S-3500, and the parameters are listed below.

Gas chromatography (GC)

The solvent residue was measured using an Agilent 7820A GC system with an Agilent 7697A headspace. The detailed parameters used are listed below.

Example 2-B(1)-Anti-solvent addition experiment

The solubility of Compound I(a) Form A was estimated in 22 solvents at room temperature. Approximately 2 mg of solid was added to a 3 mL glass vial. Next, the solvents in Table 2 were gradually added to the vial in the order of 50, 50, 200, and 700 µL until the solids dissolved or the total volume reached 1 mL. The results summarized in Table 2 are used to guide solvent selection in polymorph screening.

Table 2: Overview of solubility experiments

A total of 16 anti-solvent addition experiments were conducted. For each experiment, weigh approximately 15 mg of Compound I(a) Type A into a 20 mL glass vial, and then add 0.3 to 1.0 mL of the corresponding solvent. The mixture was then magnetically stirred at 500 RPM to obtain a clear solution at room temperature. Subsequently, the relevant anti-solvent is added to the solution to induce precipitation or until the total amount of anti-solvent reaches 10.0 mL. The clear solution was transferred to beating at 5°C. If no precipitation occurs, the solution is then transferred to room temperature and slowly evaporated. The solid was isolated for XRPD analysis. The results summarized in Table 3 show that types B, C, D, F, H and K are produced.

*：固體經由在5℃下攪拌獲得。 **：固體經由在室溫下緩慢蒸發獲得。Table 3: Overview of anti-solvent addition experiment

*: The solid was obtained by stirring at 5°C. **: The solid is obtained via slow evaporation at room temperature.

Example 2-B(2)-Solid Vapor Diffusion Experiment

The solid vapor diffusion experiment was conducted using 11 solvents. For each experiment, approximately 10 mg of Compound I(a) Form A was weighed into a 3 mL vial and placed in a 20 mL vial with 4 mL of corresponding solvent. The 20 mL vial was sealed with a cap and kept at room temperature for 12 days to allow the solvent vapor to interact with the solid sample. The isolated solids were tested by XRPD. The results are summarized in Table 4 and indicate that types A, B and F were obtained.

Table 4: Overview of solid vapor diffusion experiments

Example 2B-(3)-Slow evaporation experiment

The slow evaporation experiment was performed under 12 conditions. For each experiment, weigh approximately 15 mg of Compound I(a) Type A into a 3 mL glass vial, and then add the corresponding solvent or solvent mixture to obtain a clear solution. Subsequently, the vial was covered with a parafilm with 3 to 4 pinholes and kept at room temperature to allow the solution to evaporate slowly. The isolated solids were tested by XRPD. As outlined in Table 5, types A, E, F and H are generated.

Table 5: Overview of the slow evaporation experiment

Example 2-B(4)-Slurry conversion experiment at room temperature

Slurry conversion experiments were carried out in different solvent systems at room temperature. For each experiment, approximately 20 mg of Compound I(a) Form A was suspended in a 0.3 mL corresponding solvent in a 1.5 mL glass vial. After the suspension was magnetically stirred at room temperature for 9 days, the remaining solid was separated for XRPD analysis. The results summarized in Table 6 show that types A, F, G, H and J were obtained.

Table 6: Overview of slurry conversion experiments

Example 2-B(5)-Slurry conversion experiment at 50℃

The slurry conversion experiment was conducted at 50°C in different solvent systems. For each experiment, approximately 20 mg of Compound I(a) Form A was suspended in a 0.3 mL corresponding solvent in a 1.5 mL glass vial. After the suspension was magnetically stirred at 50°C for 9 days, the remaining solid was separated for XRPD analysis. The results summarized in Table 7 indicate the generation of D, F, G, H and I types.

Table 7: Summary of slurry conversion experiment at 50℃

Example 2-B(6)-Liquid vapor diffusion

14 liquid vapor diffusion experiments were conducted. For each experiment, approximately 15 mg of Compound I(a) Form A was dissolved in a corresponding solvent of 0.5 to 1.0 mL in a 3 mL vial to obtain a clear solution. Subsequently, the solution was placed in a 20 mL vial with 4 mL of relevant anti-solvent. The 20 mL vial is sealed with a cap and kept at room temperature, allowing sufficient time for the solvent vapor to interact with the solution. The solid was isolated for XRPD analysis. The results summarized in Table 8 show that types B, D, E and H were obtained.

Table 8: Overview of liquid vapor diffusion experiments

Example 2-B(7)-Slow cooling

The slow cooling experiment was conducted in 14 solvent systems. For each experiment, approximately 20 mg of Compound I(a) Form A was suspended in 1.0 mL of the corresponding solvent in a 3 mL glass vial at room temperature. The suspension was transferred to beating at 500 RPM via a magnetic stirrer at 50°C. The sample was equilibrated at 50°C for 2 hours and filtered using 0.45 μm Nylon membrane. Subsequently, the filtrate was slowly cooled from 50°C to 5°C at a rate of 0.1°C/min. The samples were stored at 5°C before XRPD analysis. The results summarized in Table 9 indicate that types G and H were obtained.

Table 9: Overview of the slow cooling experiment

Example 2-C: Co-crystal screening

Based on the approximate solubility data of the free base, four solvent systems were used in the screening. For each solvent acetone, THF and EtOAc, a free base stock solution with a concentration of 30 mg/mL was prepared individually. In each experiment, 0.5 mL of the stock solution and the corresponding acid were mixed at a feed ratio of 1:1 molar concentration, and stirred overnight at room temperature. For the conditions under IPA/H2O (19:1, v/v), add the solvent to the mixture of free base solid and acid at a molar ratio of 1:1 and feed ratio, and stir the obtained suspension at room temperature Overnight. Heating-cooling (65°C to 5°C) was applied to the suspension obtained before the solid was centrifuged and dried under vacuum at room temperature. For samples without any solids, the clear solution was transferred to 5°C and stirred for 2.5 days. If no solid is still obtained, 1.0 mL of H2O is added to the acetone clear solution, and heating-cooling (65°C to 5°C) is applied to the obtained emulsion; 1.0 mL of n-heptane is added to the THF/EtOAc solution and then Transfer to 5°C. Finally, the clear solution obtained after the addition of the anti-solvent was transferred to room temperature and evaporated.

As outlined in Table 10, a total of three crystal hits were isolated, and their characteristic data are summarized in Table 11.

N/A：觀察到無固體或有限量之固體。 *：觀察到有限之繞射峰。Table 10: Overview of eutectic screening

N/A: No solid or limited amount of solid is observed. *: A limited diffraction peak was observed.

N/A：觀察到無固體或有限量之固體。 *：在¹ H NMR中未偵測到明顯信號。觀察到有限之繞射峰。Table 11: Overview of eutectic data

N/A: No solid or limited amount of solid is observed. *: No obvious signal was detected in ¹ H NMR. A limited diffraction peak was observed.

Example 2-D: Preparation of compound I(a) by the prior art method of WO 2016/128529

Compound I(a) was prepared by the method disclosed in WO 2016/128529 and characterized by XRPD and considered to be amorphous. See Figures 59 and 61. The TGA and DSC results of this compound are also shown in FIG. 62. The HPLC results of this compound are shown in Figure 63.

Example 2-E: Compound I(a) Hydrate Form A

Compound I(a) starting material was characterized by XRPD, TGA, DSC, 1H NMR and DVS. The XRPD results in Figure 6 indicate that the starting material is crystalline Form A. TGA and DSC data are shown in Figure 7. A weight loss of 3.3% at up to 130°C was observed in TGA, and DSC results showed a relatively broad endothermic peak at 98.0°C (initial temperature). Other XRPD results showed no pattern change after heating Type A to 80°C under nitrogen protection, cooling to 30°C and then exposure to air. In addition, as shown in FIG. 8, the process solvent MeOH was not detected by ¹ H NMR, indicating type A hydrate.

To further identify Type A and study its dehydration characteristics, DSC under open conditions was tested to test whether the relatively broad endothermic peak observed in Figure 7 was caused by overlapping dehydration peaks and melting peaks, and temperature-variable XRPD (VT-XRPD) was performed To observe the dehydration pattern of type A. The uncapped DSC results of another Type A batch showed an endothermic peak of 56.4°C (peak temperature) due to dehydration before melting at 101.6°C (peak temperature). Under the condition that the dehydration temperature is known, VT-XRPD is performed under a nitrogen atmosphere at a temperature increased to 80 and returned to 30°C. A unique XRPD was observed after Type A dehydration at 70°C, and this novel type was designated Type A0. After exposure to ambient conditions for about 30 minutes, Type A0 is converted to Type A. Therefore, it is considered that the A0 type system can be protected from moisture at the moment when the anhydrous substance is observed.

To evaluate the hygroscopicity and physical stability of Type A at different humidity, DVS data was collected at 25°C after the sample was equilibrated at an ambient humidity of 70% RH. As shown in Fig. 9, at a relative humidity higher than 10% RH and a moisture absorption system of 0.3%, the water absorption rate was slowly increased to 80% RH, indicating that the type A sample was slightly hygroscopic. Dehydration occurs at 0% RH, indicating that the critical water activity of Types A and A0 at 25°C is between 0% RH and 10% RH.

Example 2-F: Compound I(a) Anhydrate Form E

Compound I (a) Form E was obtained by slow evaporation in DCM/n-heptane (v/v, 1:1) at room temperature. The XRPD pattern is shown in FIG. 10, and the TGA/DSC curve is shown in FIG. The results indicated that the E-type system had a weight loss of 1.7% before 140°C in TGA and a sharp melting endothermic peak in DSC at 147.0°C (initial temperature). No obvious solvent signal was detected by ¹ H NMR as shown in FIG. 12, indicating that the E type is anhydrous.

Compound I(a) Form E was re-prepared to a 100 mg scale via slow evaporation in DCM/n-heptane (v/v, 1:2) at room temperature, and needle-like crystals were observed. To evaluate the hygroscopicity of Form E, DVS data was collected at 25°C after the sample was pre-equilibrated at 0% RH to remove unbound water. The DVS results shown in Fig. 13 show a water absorption of 0.3% at 25°C/80% RH, indicating that the sample of formula E is slightly hygroscopic. The XRPD results show no pattern changes after the DVS test, as shown in Figure 71.

Example 2-G: Evaluation of type A and type E

Based on the type identification results, types A and E were selected and re-prepared for further evaluation, including mechanical stability studies, critical water activity measurements, and kinetic dissolution measurements.

Form A was re-prepared as follows.

Compound I(a) hydrate form A was reconstituted into 1 g by drying the filter cake of type B (prepared from amorphous compound I(a)) at 60°C for evaluation. 1.0 g of amorphous compound I(a) solid was weighed into a 20 mL glass vial. 8 mL of MeOH was added to the vial under mechanical stirring at room temperature overnight to form a suspension. The suspension was sampled for XPRD and the resulting pattern corresponds to type B. The suspension was evaporated at room temperature to induce additional precipitation. After the solvent was removed, the solid was dried at 60°C overnight. The XRPD result is shown in FIG. 20 and indicates that Type A is made. According to the TGA and DSC results shown in Fig. 21, a 2.1% weight loss at 80°C and a wide endothermic peak at 98.1°C were observed.

Form E was re-prepared as follows.

Compound I(a) Form E was prepared by adding an anti-solvent in DCM/n-heptane at room temperature, and then evaporated to dryness to prepare 1 g. 1.0 g of amorphous compound I(a) solid was weighed into a 20 mL glass vial. Add 4 mL DCM and stir at room temperature to get a clear solution. 4 mL of n-heptane was added to the solution, and then about 1 mg of Compound I(a) Type E seed crystal was added. The solution became cloudy immediately. Continue stirring for 6 hours. The suspension was evaporated at room temperature to induce further crystallization. After the solvent was removed, the solid was dried at 60°C overnight. The XRPD results shown in Figure 22 show that the E-type was successfully re-prepared. According to the TGA and DSC data shown in FIG. 23, a weight loss of 0.4% at 145°C and a sharp melting endothermic peak of 145.9°C (initial temperature) were observed.

The magnetic stirring of the re-prepared Forms A and E in water led to the formation of amorphous, however, no decrease in crystallinity was observed through shaking, indicating a problem of mechanical stability. The kinetic solubility results in three aqueous media (HPLC water, pH 6.5 phosphate buffer and 0.01N HCl) showed that type A exhibited a higher total solubility than type E at 37°C for up to 24 hours at 37°C The lower E type may be more thermodynamically stable than the A type.

Example 2-G(1): Stability of mechanical force in water

After magnetic stirring in water at room temperature and 50°C for nine days, the hydrate form A is easily transformed into amorphous. ^{The 1} H NMR results show that there is no obvious chemical degradation of the slurry sample at room temperature. In order to study the reasons for the formation of amorphous, magnetic stirring and shaking were used to suspend A and E types in water at room temperature and 50°C, respectively. The results are summarized in Table 12 (where "Exp" refers to the experiment, "S. Form" refers to the initial type, "Load" refers to the solid loading (mg/mL), and "Method" refers to the beating method, ""Temp." refers to the temperature in ℃, "time" refers to the sampling time in days and "solid type" refers to the solid type obtained after beating. As shown by the XRPD results, the amorphous is obtained at room temperature, And after stirring E-type magnetic force in water at 50°C for seven days, an amorphous halo was observed. The mixture of type A and A and E was shaken in water for three days at room temperature. XRPD results showed no significant crystallinity decrease, indicating magnetic The mechanical grinding effect of stirring contributes to the formation of amorphous in water.

Table 12: Overview of Type A and Type E Beating Experiments

Example 2-G(2): critical water activity

In order to determine the critical water activity between Forms A and E, an attempt was made to perform slurry conversion by shaking method in three solvent-water systems (including acetone, ACN and DMSO) at room temperature, where no screening from polymorphs was observed To solvate.

In detail, approximately 40 mg of solid was shaken at a rate of 500 RPM in a 1 mL solvent mixture. The results are summarized in Table 13. Types A and E were converted into oil after shaking in acetone/H2O (v/v, 1:2) and ACN/H2O (v/v, 1:2) at room temperature, but in DMSO/H2O (v /v, 1:2) The novel DMSO solvate M type was observed.

Table 13: Overview of Type A and Type E water activity experiments

Example 2-G(3): Kinetic solubility

To compare the in vitro dissolution between types A and E, the kinetics in water (HPLC grade), pH 6.5 phosphate buffer and 0.01N HCl at 37°C at the endpoints of 1, 2, 4, and 24 hours were measured. Learn solubility. The suspension was mixed in a 4 mL plastic vial and rolled (25 RPM) in a thermostat at 37° C. The initial solid loading was 5 mg/mL. At the end points of 1, 2, 4 and 24 hours, the suspension was separated by high-speed centrifugation at 14000 RPM. The solid was characterized by XRPD, and the supernatant was analyzed by HPLC and pH test. It was observed that there was no pattern change in types A and E for up to 24 hours in all three media. The results are summarized in Table 14 (where "Phos." refers to phosphate, "S" refers to solubility in μg/mL, "pH" refers to the final pH, and "FC" refers to the type change). Type A showed higher total solubility than Type E in all three aqueous media, indicating that Type E may be more thermodynamically stable than Type A at 37°C.

Table 14:

Example 2-H: Proportional increase of E type and the feasibility of jet grinding

Example 2-H(1): Competition experiment of beating of hydrate type A and anhydrous type E in DCM/n-heptane

Perform beating competition experiment of hydrate type A and anhydrous E. A saturated solution of Compound I(a) Form A in DCM/n-heptane (1:3 v/v) was prepared at room temperature with stirring for 30 minutes. Approximately 5 mg of each of Compound I (a) Form A and Form E was placed in an HPLC vial. The Type A solution was filtered through a PTFE filter into a vial to form a mixture, and the contents were magnetically stirred at room temperature. After equilibrating overnight, the mixture was centrifuged and sampled for XRPD analysis. The XRPD results are depicted in Figure 14.

Example 2-H(2): Anti-solvent crystallization in DCM/n-heptane

Compound I (a) Anhydrous Form E is scaled up to 3 g as follows. 2.89 g of amorphous Compound I(a) solid was placed in a 100 mL reactor and combined with 10 mL DCM with stirring to obtain a clear solution. The n-heptane was added in 3 mL increments until turbidity was observed after 9 mL of n-heptane had been added. With stirring, 0.40 g of Compound I(a) Form E seed crystals were added and aged for 1 hour. 21 mL of n-heptane was added with a syringe pump over 4 hours, and stirring was continued overnight. The crystals were separated by filtration and dried in a vacuum oven at 50°C overnight. The yield of 3.01 g of dried solid was about 93.3%. The initial concentration of compound I(a) is about 280 mg/mL; the seed loading system is 14%; the inoculation point occurs at DCM/n-heptane 10:9 v/v; the final DCM/n-heptane ratio is 1:3 v /v; mother liquor concentration is 3.1 mg/mL; needle-like crystal morphology is observed; crystal type is E-type; and melting point is 147.5°C; residual solvent is <32 ppm DCM and 19.4 ppm n-heptane. The particle size distribution data (PSD) are shown in Table 15 below.

Table 15: Compound I(a) E-type particle size distribution

The XRPD results shown in Fig. 15 indicate that type E was obtained. According to the TGA and DSC data in Fig. 16, the weight loss before 145°C was observed to be 0.8% and the sharp endothermic peak was at 147.5°C (initial temperature). The PSD data shows a bimodal distribution of particle size, and the second maximum is attributed to small agglomerates because it decreases after ultrasound treatment.

Example 2-H(3): Jet grinding research

Jet milling was performed on 2.86 g of Compound I(a) Type E to investigate any possible mechanical effects. In this study, 2.86 g Type E was ground at 0.7 mPa and a feed rate of 2 kg/h. PSD characteristic data (without ultrasonic processing) are summarized in Table 16. PSD characteristic data (with ultrasound processing) are summarized in Table 17

Table 16: Jet grinding data (without ultrasonic processing)

Table 16: Jet grinding data (without ultrasonic processing)

As shown in the XRPD results shown in FIG. 17, no change in the type of jet mill product or significant amorphous halo was observed. DSC results Figure 18 shows a broadened endothermic peak at 140.8°C (starting temperature). The ground product consists of small particles, small agglomerates and a small amount of long needles. The PSD data summarized in Table 16 shows an irregular particle size distribution, and the maximum decrease (>10 µm) after ultrasound treatment is attributed to small agglomerates.

Example 2-I: Compound I(a) Form A0

Type A0 is obtained by dehydrating Type A under the protection of nitrogen, and the XRPD pattern is shown in FIG. 24. Xianxin A0 type is a transient type because it is converted to type A after being exposed to environmental conditions.

Example 2-J: Compound I(a) Type B

Type B can be obtained by MeOH-mediated crystallization or solid phase transformation. As shown in FIG. 19, a representative XRPD pattern of type B was collected in transmission mode, which was obtained through the interaction of type A solid with MeOH vapor. A rapid form conversion of Forms B to A was observed after air drying within 10 minutes. Considering the formation of solvates from multiple alcohols, it is speculated that the B-type transient MeOH solvates.

Example 2-K: Compound I(a) Form C

Form C can be reproducibly obtained by adding H ₂ O to the DMAc solution. The XRPD results in Figure 25 show that Form C has high crystallinity. The TGA and DSC results in FIG. 26 show a considerable weight loss of 12.3% before 200°C and a sharp endothermic peak of 100.4°C (initial temperature) before decomposition. As shown in the ¹ H NMR result shown in FIG. 27, 0.90 equivalents of DMAc (11.4%) relative to Compound I(a) was detected, which was consistent with the TGA weight loss. In addition, XRPD results show that Form C was converted to amorphous after being heated to 105°C under nitrogen and cooled to 30°C and exposed to air. Therefore, Xianxin C-type DMAc solvate.

Example 2-L: Compound I(a) Form D

Form D is obtained through anisole-mediated crystallization. Form D was obtained through the interaction of anisole solution and n-heptane vapor, and its XRPD is shown in FIG. 28. The TGA and DSC results in Figure 29 show a considerable weight loss of 20.7% before 200°C and a sharp endothermic peak at 94.9°C (starting temperature). As a result of ¹ H NMR shown in FIG. 30, 0.84 equivalents of anisole (13.0%) relative to Compound I(a) was detected and no significant amount of n-heptane was detected. In addition, after the type D was heated to 100°C under nitrogen protection, cooled to 30°C and exposed to air, several characteristic peaks of the type E were observed, as shown by XRPD in Fig. 31. Therefore, Xianxin D type anisole solvate.

Example 2-M: Compound I(a) Form F

Type F can be obtained by EtOH-mediated crystallization or solid phase transformation. Form F was obtained by slowly evaporating the EtOH solution at room temperature, and its XRPD is shown in FIG. 32. The TGA and DSC results in Figure 33 show a weight loss of 8.3% before 200°C and a sharp endothermic peak of 100.3°C, followed by a small endothermic peak of 136.4°C (starting temperature). As a result of ¹ H NMR shown in FIG. 34, 0.88 equivalents of EtOH (6.2%) relative to Compound I(a) was detected. In addition, after the F-type was heated to 105° C. under nitrogen, cooled to 30° C. and exposed to air, several characteristic peaks of the E-type were observed, as shown by XRPD in FIG. 35. Therefore, Xianxin F type EtOH solvate.

Example 2-N: Compound I(a) Form G

Form G can be obtained by toluene-mediated crystallization. Form G was obtained by slowly cooling the toluene solution from 50°C to 5°C, and its XRPD is shown in Fig. 36. The TGA and DSC results in Figure 37 show a weight loss of 17.8% before 200°C and a sharp endothermic peak of 106.3°C (starting temperature). ¹ H NMR results Figure 38 shows that 0.82 equivalents of toluene (11.0%) relative to compound I(a) was detected. In addition, the G-type switch was heated to 110 under the protection of nitrogen, cooled to 30°C and exposed to air and then transformed into the E-type, as shown by XRPD in FIG. 39. Therefore, Xianxin G type toluene solvate.

Example 2-O: Compound I(a) H type

Type H can be obtained by IPA-mediated crystallization or phase transformation. Form H was obtained by slowly evaporating MTBE/IPA (v/v, 1:1) at room temperature, and its XRPD is shown in FIG. 40. The TGA and DSC results in Figure 41 show a 15.8% weight loss before 200°C and a sharp endothermic peak of 116.3°C (starting temperature). ¹ H NMR results Figure 42 shows that 1.02 equivalents of IPA (9.1%) relative to compound I(a) was detected, and no significant amount of MTBE was detected. In addition, the H type is heated to 125°C under nitrogen protection, cooled to 30°C and exposed to air and then converted to the E type, as shown by XRPD in Fig. 43. Therefore, Xianxin H-type IPA solvate.

Example 2-P: Compound I(a) Form I

Type I is obtained by slurry conversion of Type A in 1-butanol at 50°C. The XRPD results in Figure 44 show that Type I has high crystallinity. The TGA and DSC results in Figure 45 show a 13.7% weight loss before 200°C and a sharp endothermic peak at 90.0°C (starting temperature). ¹ H NMR results Figure 46 shows that 1.13 equivalents of 1-butanol (12.1%) relative to compound I(a) were detected. In addition, Type I was heated to 95°C under nitrogen protection, cooled to 30°C and then transformed into amorphous after being exposed to air. Therefore, Xianxin Type I is a 1-butanol solvate.

Example 2-Q: Compound I(a) Type J

Form J was obtained by beating form A in MeTHF/n-heptane (v/v, 1:2) at room temperature. The XRPD results in Figure 47 show that the J-type has high crystallinity. The TGA and DSC results in Figure 48 show a weight loss of 14.4% before 200°C and a sharp endothermic peak of 82.2°C (starting temperature). ¹ H NMR results Figure 49 shows that 0.93 equivalents of MeTHF (11.6%) to compound I(a) was detected, and no significant amount of n-heptane was detected. In addition, the J-type was heated to 85°C under nitrogen, cooled to 30°C and exposed to air to produce a significant amount of amorphous. Therefore, Xianxin J-type MeTHF solvate.

Example 2-R: Compound I(a) Type K

Form K was obtained by beating form A in THF/n-heptane (v/v, 1:2) at -20°C. The XRPD results in Figure 50 show that the K-type has high crystallinity. The TGA and DSC results in Figure 51 show a weight loss of 10.0% before 200°C and a sharp endothermic peak of 86.8°C (initial temperature). ¹ H NMR results Figure 52 shows that 0.76 equivalents of THF (8.3%) relative to compound I(a) were detected. In addition, the K-type was heated to 90°C under nitrogen protection, cooled to 30°C and exposed to air to produce a significant amount of amorphous. Therefore, Xianxin K-type THF solvate.

Example 2-S: Compound I(a) L form

The L form is obtained by beating amorphous compound I(a) in isobutanol at room temperature. The XRPD results in Figure 53 show that the L-type has high crystallinity. The TGA and DSC results in Figure 54 show a considerable weight loss of 11.2% before 200°C and a sharp endothermic peak of 106.8°C (initial temperature). ¹ H NMR results Figure 55 shows that 0.97 equivalents of isobutanol (10.6%) relative to compound I(a) was detected. In addition, the L-form was heated to 110°C under the protection of nitrogen, cooled to 30°C and then transformed into amorphous after being exposed to air. Therefore, Xianxin L-type isobutanol solvate.

Example 2-T: Compound I(a) Form M

The M form was obtained by shaking the E form in DMSO/water (v/v, 1:1) at room temperature. The XRPD results in Figure 56 show that the M-type has high crystallinity. The TGA and DSC results in Figure 57 show a considerable weight loss of 10.7% before 200°C and a sharp endothermic peak of 110.7°C (initial temperature). From ¹ H NMR chart 58, 0.90 equivalents of DMSO (10.4%) relative to compound I(a) was detected, which was consistent with the TGA weight loss. In addition, the M type was heated to 115°C under the protection of nitrogen, cooled to 30°C, and then transformed into amorphous after being exposed to air. Therefore, Xianxin M-type DMSO solvate.

Example 2-U: Compound I(a) Form E grows proportionally from amorphous starting material

Compound I(a) Form E was prepared from amorphous compound I(a) via anti-solvent crystallization at room temperature in DCM/n-heptane with seed crystals. 66.6 g of amorphous compound I(a) was added to the 1 L reactor. 220 mL of DCM was added to the reactor with stirring at room temperature to obtain a clear solution. 125 mL of n-heptane was added, followed by about 5 mg of Compound I(a) Form E seed crystals. Slowly dissolve the seed crystal. Then, 5 mL of n-heptane and 2.6 g of Compound I(a) E type seed crystals were added sequentially. Most seed crystals dissolved and only limited needle-like crystals were observed on the reactor wall during stirring. 530 mL of n-heptane was added with a syringe pump over 4 hours. After an additional 20 mL of n-heptane was added, turbidity was observed. After aging overnight, the crystalline solid was collected by filtration and washed with n-heptane. The filter cake was oven dried at 50°C under vacuum overnight. 62.6 g of solid was collected with a yield of about 93.4%.

*：此時2.6 g晶種之大多數溶解，且在22:15之DCM/正庚烷之溶劑比率下觀察到顯而易見的混濁。 **：起始物質之HPLC純度係99.18面積%。Long needle crystals were observed. During the stirring most of the seeds dissolve, however, good quality attributes of the E-type product are still obtained. Therefore, the antisolvent crystallization method in DCM/n-heptane is commercially practical under limited seed crystals. The XRPD results shown in Figure 64 show that Form E was obtained by antisolvent crystallization. According to the TGA and DSC data shown in FIG. 65, a 1.2% weight loss at 145°C was observed in the TGA, and the DSC results showed a sharp melting endothermic peak of 147.3°C (initial temperature). The product was characterized by XRPD, TGA, DSC, PLM, HPLC and GC. The results are summarized in the table below.

*: Most of the 2.6 g seed crystals were dissolved at this time, and a clear turbidity was observed at a solvent ratio of DCM/n-heptane of 22:15. **: The HPLC purity of the starting material is 99.18 area%.

Example 2-V: Anhydrous compound I(a) gentisic acid co-crystal type A

Compound I(a) free base (300.1 mg) and gentisic acid (76.1 mg) were combined in a 20 mL glass vial and then 6.0 mL of EtOAc was added to form a clear solution. To the vial, 8.0 mL of n-heptane, about 50 mg of Compound I(a) gentisic acid co-crystal type A seed crystals were sequentially added, and a cloudy solution was observed. 5.0 mL of n-heptane was added to the vial and the suspension was observed after stirring at room temperature for 2 hours. The suspension was cooled to 5°C and stirred for 17 hours to induce additional crystallization. The suspension was filtered and the collected crystals were dried under vacuum at room temperature for 4 hours to obtain a yield of 66.5%. The XRPD results are shown in Figure 66. The characteristic peak is at 2θ degrees of the following angles: 12.5°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 15.7°±0.2°, 17.5°±0.2°, 21.7°±0.2°, 25.5°±0.2 ° and 26.3°±0.2°. As shown in FIGS. 67 and 70, a weight loss of 2.5% at 110°C was observed in TGA, and the DSC results showed an endothermic peak at 170.8°C (initial temperature). The stoichiometric ratio was determined to be 1.00 (acid/free base) and no significant solvent signal was detected by 1H NMR, as shown in Figure 68. According to the collected characteristic data, Xianxin gentisic acid eutectic type A is anhydrous.

The kinetic solubility of gentisic acid co-crystal type A in water and three biological related media (SGF, FaSSIF and FeSSIF) was measured at 37°C using Compound I (a) free base type E as a control. All solubility samples (the initial solid loading was about 10 mg/mL) were kept rolling at 25 rpm on a rolling incubator at 37°C, and samples were taken at 1, 2, 4, and 24 hours, respectively. After centrifugation, the supernatant was collected for HPLC and pH testing, and the wet filter cake was collected for XRPD characterization. Compared with the free base form E, gentisic acid co-crystal form A exhibited increased solubility (two-fold) in FaSSIF/FeSSIF and comparable solubility in SGF/water. In addition, no type change was observed after 24 hours of gentisic acid co-crystal type A or free base type E suspended in water and three biological media (SGF/FaSSIF/FeSSIF).

Evaluation of gentisic acid co-crystal form A at 80°C (sealed)/24 hours, 25°C/60% RH/6 days and 40°C/75% RH/6 days under compound I(a) free base E form as a control Solid state stability. Stability samples are characterized by XRPD checking any solid type changes and HPLC checking purity changes. After performing stability tests based on XRPD and HPLC results, no solid type change or significant HPLC purity reduction was observed, indicating that gentisic acid co-crystal type A and free base type E were physically and chemically stable under the test conditions.

In order to study the stability of the solid type that changes with humidity, the DVS isotherm data was collected at 25°C to show that compound I(a) gentisic acid co-crystal type A and compound I(a) free base type E were slightly hygroscopic Performance and no solid type change after DVS test.

In order to evaluate its mechanical stability, compound I(a) gentisic acid co-crystal type A was suspended in H ₂ O and n-heptane under magnetic stirring and using compound I(a) free base type E as a control in. After magnetic stirring at room temperature in free base form E in H ₂ O for 6 days, an amorphous solid was observed by XRPD test, however, crystalline samples were still observed for each of the following: (i) in n-heptane Free base form E with magnetic stirring for 6 days; (ii) Compound I with magnetic stirring in n-heptane (a) Form A of gentisic acid co-crystal; and (iii) Compound I with magnetic stirring in H ₂ O for 6 days (a) Gentianic acid co-crystal type A. Therefore, the mechanical stability of the gentisic acid eutectic type A exhibited in H ₂ O is better than that of the free base type E.

Example 2-W: Anhydrous compound I(a) gentisic acid co-crystal B type

Anhydrous compound I(a) gentisic acid co-crystal form B can be prepared by a method similar to the method of preparing compound I(a) gentisic acid co-crystal form A, but in which EtOAc is replaced with THF. The XRPD results are shown in Figure 69. The characteristic peak data in 2θ degrees is displayed at the following angles: 6.6°±0.2°, 7.9°±0.2°, 12.2°±0.2°, 12.4°±0.2°, 14.0°±0.2°, 15.1°±0.2°, 16.3 °±0.2°, 21.1°±0.2°, 25.3°±0.2° and 25.6°±0.2°. The TGA/DSC data for Type B is shown in Figure 72. A weight loss of 8.6% at 160°C was observed in TGA, and DSC results showed multiple thermal events before melting/decomposition. The stoichiometric determination was 0.95 (acid/free base) and 6.6% THF was detected by 1H NMR as shown in FIG. 73 (the molar ratio to the free base was 0.60), indicating that type B may be a THF solvate.

Example 2-X: Hydrate Compound I(a) Pyridinamide Co-crystal Form A

Compound I(a) free base (200.9 mg) and pyridylformamide (40.3 mg) were combined in a 20 mL glass vial, and then 2.0 mL of EtOAc was added to form a clear solution. To the vial, 8.0 mL of n-heptane, about 10 mg of Compound I (a) pyridylcarboxamide co-crystal type A seed crystals were sequentially added, and a turbid solution was observed. 10.0 mL of n-heptane was added to the vial and the suspension was observed after stirring at room temperature for 28 hours. Rapid evaporation at room temperature with stirring for 17 hours to induce further crystallization. The suspension was filtered and the collected crystals were dried under vacuum at room temperature for 6 hours. The XRPD results are shown in Figure 74 and Figure 78. As shown in FIGS. 75 and 79, a weight loss of 3.5% at 65°C was observed in TGA and DSC results showed a wide endothermic peak of 64.6°C (initial temperature). The stoichiometric determination was 1.19 (acid/free base) and no significant solvent signal was detected by 1H NMR, as shown in Figure 76 and Figure 80. As shown in Fig. 77, the sample became amorphous after being heated to 75°C. According to the collected characteristic data, Xianxin pyridinecarboxamide co-crystal type A hydrate, with the loss of water due to degradation and melting.

Example 2-Y: Preparation of crystalline compound I(a) free base anhydrous AL form

The crystalline compound I (a) of the AL type free base anhydrous was obtained by beating the E form in EtOAc/n-heptane (v/v, 1:3) at 50°C for five days. The XRPD pattern is shown in FIG. 81, and the TGA/DSC curve is shown in FIG. 82. The AL type exhibits characteristic peaks of 2θ degrees at the following angles: 7.6°±0.2°, 8.4°±0.2°, 13.2°±0.2°, 13.8°±0.2°, 14.8°±0.2°, 15.2°±0.2°, 15.6 °±0.2°, 15.9°±0.2°, 16.9°±0.2°, 18.1°±0.2°, 20.5°±0.2° and 21.3°±0.2°. The results indicated that the AL type system had a weight loss of 1.1% before 150°C in TGA and two endothermic peaks crystallized at 93.3 and 147.5°C (beginning) in DSC (with closed cap). When the DSC test is performed with the lid open, the endothermic peak at about 93.3°C disappears, indicating that the first endothermic peak cannot be generated by strongly bonded water/solvent. As shown in the ¹ H NMR spectrum in Figure 83, no EtOAc/n-heptane signal was detected. Therefore, based on a possible theory, the first endothermic peak observed in Xianxin 82 can be produced by surface water.

Type AL is converted to anhydrous type E after three days of exposure to environmental conditions (23±2℃, 70% RH), indicating that anhydrous type E is more thermodynamically stable at room temperature (23±2℃) than type AL . This result may clarify the fact that when a sample of type AL was heated to 120°C and cooled to 30°C under a nitrogen blanket and then exposed to air, an anhydrous type E was observed.

Example 2-Z: Preparation of crystalline compound I(a) free base hydrate BO type

Compound I(a) E-type crystals were slurried in MeOH/H ₂ O (v/v, 1:1) at 60° C. to form a clear solution. Solid material was observed after two days. According to XRPD comparison, the obtained wet solid material is a novel crystal type, designated as BN type. The BO type was obtained after air-drying the solid BN type at ambient conditions for about 1.5 hours. The XRPD pattern is shown in FIG. 84. The characteristic peaks expressed in 2θ degrees are at the following angles: 12.1°±0.2°, 12.4°±0.2°, 13.9°±0.2°, 15.0°±0.2°, 15.4°±0.2°, 17.1°±0.2°, 18.3° ±0.2°, 21.5°±0.2°, 22.1°±0.2°, 24.4°±0.2°, 25.1°±0.2°, 26.2°±0.2° and 26.3°±0.2°. The DSC curve of the BO model is shown in FIG. 85. The results indicated that the BO-type system crystallized, an overlapping endothermic peak at 84.2°C (start), and an exothermic peak at 128.5°C (start), and then a sharp endothermic peak at 148.3°C (peak). Since the amorphous material is obtained after heating the BO type to 120°C and the MeOH signal is not detected by the ¹ H NMR shown in FIG. 86, Xianxin BO type hydrates.

Example 2-AA: Preparation of crystalline Compound I(a) free base n-heptane solvate BP type

Compound I (a) E-type crystals were slurried in isopropyl acetate/n-heptane at 70°C and isobutyl acetate/n-heptane at 90°C, respectively. The obtained solid material was characterized by XRPD and TGA/DSC and designated as BP type, and the results are shown in FIG. 87 and FIG. 88. The characteristic peaks expressed in 2θ degrees are at the following angles: 8.5°±0.2°, 12.9°±0.2°, 17.6°±0.2°, 18.1°±0.2°, 19.4°±0.2°, 20.8°±0.2°, 21.2° ±0.2°, 22.9°±0.2° and 24.0°±0.2°. The BP type crystallizes at a weight loss of 3.0% in TGA up to 140°C and in DSC before a sharp melting/decomposition signal at 147.3°C (peak) at 122.5°C. Anhydrous E type was observed after the BP type sample was heated to 130°C under a nitrogen blanket and cooled to 30°C and exposed to air. As shown in the ¹ H NMR spectrum in FIG. 89, the stoichiometric ratio of n-heptane:API is 0.16:1 (2.6 wt%). Combined with the type change after heating, Xianxin BP type is n-heptane solvate.

Example 2-AB: Preparation of crystalline compound I(a) free base 2-pentanol solvate form BK

Compound I (a) E-type crystals were beaten in 2-pentanol/n-heptane (v/v, 2:1) at 50°C. The obtained solid material was characterized by XRPD and TGA/DSC and designated as type BK. The results are shown in FIG. 90 and FIG. 91. The characteristic peaks expressed in 2θ degrees are at the following angles: 11.9°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 14.7°±0.2°, 16.9°±0.2°, 17.9°±0.2°, 19.3° ±0.2°, 21.8°±0.2°, 22.7°±0.2°, 23.9°±0.2°, 24.6°±0.2° and 26.1°±0.2°. The results indicated that the BK type system was 11.6% by weight loss in TGA before 120°C and a sharp melting endothermic peak crystallized at 71.5°C (peak) in DSC. To further identify the BK type, the heating experiment was conducted at 89°C and the results indicated that the BK type was converted to the amorphous type after heating. In addition, about 0.92 mole equivalent of 2-pentanol (15.5 wt%) was detected by ¹ H NMR shown in FIG. 92 in the sample. Combined with the type change after heating, Xianxin BK type 2-pentanol solvate.

Example 2-AC: Preparation of crystalline Compound I(a) free base 1-propanol solvate form AX

Form AX was obtained by rapid evaporation of compound I(a) in 1-propanol/isopropyl acetate (v/v, 5:4) at room temperature. The obtained solid material was characterized by XRPD and TGA/DSC and designated as AX type, and the results are shown in FIG. 93 and FIG. 94. The characteristic peaks expressed in 2θ degrees are at the following angles: 11.5°±0.2°, 12.9°±0.2°, 13.1°±0.2°, 17.4°±0.2°, 18.2°±0.2°, 23.1°±0.2°, 23.9° ±0.2° and 25.9°±0.2°. The results indicate that the AX type system crystallized in the TGA before 150°C with a weight loss of 11.0% and the endothermic peaks before decomposition in DSC at 113.5°C and 122.0°C (peak value). To further identify the AX type, a heating experiment was performed at 118°C and the results indicated that the AX type was converted to an amorphous type after heating. In addition, about 0.94 mole equivalent of 1-pentanol (11.3 wt%) was detected by ¹ H NMR shown in FIG. 95 in the sample. Combined with heating experiment results, Xianxin AX type 1-propanol solvate.

Example 2-AD: Preparation of crystalline Compound I (a) free base m-xylene solvate Form Q

Form Q was obtained by rapid evaporation of compound I(a) in methyl acetate/m-xylene (v/v, 5:4) at room temperature. The obtained solid material was characterized by XRPD and TGA/DSC and designated as type Q, and the results are shown in FIG. 96 and FIG. 97. The characteristic peaks expressed in 2θ degrees are shown at the following angles: 5.5°±0.2°, 12.5°±0.2°, 15.0°±0.2°, 17.6°±0.2°, 20.2°±0.2°, 22.1°±0.2°, 22.8 °±0.2° and 26.6°±0.2°. The results indicate that the Q-type system crystallizes in a two-step weight loss system of 13.7% before 200°C in TGA and an endothermic peak at 78.8°C (peak) before decomposition in DSC. To further identify the Q-type, a heating experiment was conducted at 80°C and the results indicated that the Q-type was converted to an amorphous type after heating. In addition, about 0.73 mole equivalent of xylene (14.9 wt%) was detected in the sample by ¹ H NMR shown in FIG. 98. Combined with heating experiment results, Xianxin Q-type xylene solvate.

Example 2-AE: Preparation of crystalline compound I(a) free base EGME solvate form P

Form P was obtained by rapid evaporation of compound I(a) in EGME/m-xylene (v/v, 1:1) at room temperature. The obtained solid material was characterized by XRPD and TGA/DSC and designated as P-type, and the results are shown in FIG. 99 and FIG. 100. The characteristic peaks expressed in 2θ degrees are shown at the following angles: 11.9°±0.2°, 12.3°±0.2°, 12.7°±0.2°, 14.0°±0.2°, 17.1°±0.2°, 20.0°±0.2°, 23.9 °±0.2°, 24.1°±0.2°, 25.5°±0.2°, 25.8°±0.2° and 27.2°±0.2°. The results indicate that the P-type system crystallizes in the TGA before 150°C with a weight loss of 13.8% and in DSC before decomposition in the two endothermic peaks at 104.7 and 142.0°C (peak). To further identify the P-type, a heating experiment was conducted at 105°C and the results indicated that the P-type was converted to an amorphous form after heating. In addition, about 1.03 mole equivalent of EGME (15.1 wt%) was detected by ¹ H NMR shown in FIG. 101 in the sample. Combined with heating experiment results, Xianxin P-type EGME solvate.

Example 2-AF: Preparation of crystalline compound I(a) free base second butanol solvate form AQ

Form AQ was obtained by rapid evaporation of compound I(a) in second butanol/MTBE (v/v, 5:4) at room temperature. The obtained solid material was characterized by XRPD and TGA/DSC and designated as AQ type, and the results are shown in FIG. 102 and FIG. 103. The characteristic peaks expressed in 2θ degrees are shown at the following angles: 11.5°±0.2°, 12.7°±0.2°, 12.9°±0.2°, 14.1°±0.2°, 17.4°±0.2°, 17.9°±0.2°, 21.9 °±0.2°, 22.7°±0.2°, 23.1°±0.2°, 23.5°±0.2°, 23.9°±0.2°, 25.5°±0.2° and 27.6°±0.2°. The results indicate that the AQ type system crystallizes in the TGA at a weight loss of 16.3% before 120°C and two endothermic peaks at 99.7°C and 110.8°C (peak) before decomposition. To further identify the AQ type, a heating experiment was conducted at 108°C and the results indicated that the AQ type was converted to an amorphous type after heating. In addition, about 0.92 mole equivalent of second butanol (13.1 wt%) was detected by ¹ H NMR shown in FIG. 104 in the sample. Combined with heating experiment results, Xianxin AQ type is the second butanol solvate.

This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the present invention is defined by the scope of the patent application, and may include other examples conceived by those skilled in the art. If these other examples have structural elements that are not different from the literal language of the patent scope, or if they include equivalent structural elements that are not materially different from the literal language of the patent scope, the examples are intended to be within the scope of the patent application Within the category.

Fig. 1 shows a method of the present invention for preparing a TRP antagonist compound (I).

Figure 2 shows a method of the invention for preparing intermediate compound 1 and a method of the invention for preparing intermediate compound 8.

3 shows a method of the present invention for preparing intermediate compound 4(a) corresponding to compound 4 of FIG. 1, wherein R ³ is -CH ₃ , R ⁴ is F and PG is the third butoxycarbonyl (BOC).

Figure 4 shows the preparation of amorphous (2 S ,4 R ,5 S )-4-fluoro-1-((4-fluorophenyl)sulfonyl)-5-methyl- N -((5-(trifluoro Prior art method of methyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide (compound I(a)).

Figure 5 shows the interconversion relationship between the crystal forms of compound I(a).

Figure 6 shows the XRPD pattern of crystalline Compound I(a) Type A.

Figure 7 shows the TGA and DSC curves of crystalline Compound I(a) Form A.

Fig. 8 shows the ¹ H NMR spectrum of the crystalline compound I(a) Form A.

Figure 9 shows the DVS curve of crystalline Compound I(a) Form A.

Fig. 10 shows the XRPD pattern of the crystalline compound I(a) E type.

Fig. 11 shows the TGA and DSC curves of the crystalline compound I(a) E form.

Figure 12 shows the ¹ H NMR spectrum of the crystalline compound I(a) Form E.

Figure 13 shows the DVS curve of the crystalline compound I(a) Form E.

Figure 14 shows an XRPD overlay of samples of Compound I (a) Type A and Type E slurries.

Figure 15 shows the XRPD pattern of crystalline compound I(a) E type.

Fig. 16 shows the TGA and DSC curves of the crystalline Compound I(a) Form E.

Figure 17 shows the XRPD pattern of crystalline compound I(a) Form E before and after jet milling.

Figure 18 shows the DSC curve of crystalline compound I(a) Form E after jet milling.

Figure 19 shows XRPD overlays of crystalline Compound I(a) Form B before and after air drying.

Figure 20 shows the XRPD overlay of the re-prepared crystalline Compound I(a) Form A before and after drying.

Figure 21 shows the TGA and DSC curves of the newly prepared crystalline compound I(a) Form A.

Fig. 22 shows the XRPD pattern of the newly prepared crystalline compound I(a) E type.

Figure 23 shows the TGA and DSC curves of the newly prepared crystalline Compound I(a) Form E.

FIG. 24 shows the XRPD pattern of crystalline compound I(a) A0 type.

Figure 25 shows the XRPD pattern of crystalline Compound I(a) Type C.

Figure 26 shows the TGA and DSC curves of the crystalline Compound I(a) Form C.

Fig. 27 shows the ¹ H NMR spectrum of the crystalline compound I(a) Form C.

Figure 28 shows the XRPD pattern of the crystalline compound I(a) D form.

Figure 29 shows the TGA and DSC curves of the crystalline Compound I(a) D form.

Fig. 30 shows the ¹ H NMR spectrum of the crystalline compound I(a) Form D.

Figure 31 shows an XRPD overlay of crystalline Compound I(a) Form D before and after heating.

Figure 32 shows the XRPD pattern of crystalline Compound I(a) F type.

Fig. 33 shows the TGA and DSC curves of the crystalline compound I(a) F type.

Fig. 34 shows the ¹ H NMR spectrum of the crystalline compound I(a) Form F.

Figure 35 shows an XRPD overlay of crystalline Compound I(a) Form F before and after heating.

Figure 36 shows the XRPD pattern of crystalline Compound I(a) Type G.

Figure 37 shows the TGA and DSC curves of the crystalline Compound I(a) Form G.

Fig. 38 shows the ¹ H NMR spectrum of the crystalline compound I(a) Form G.

Figure 39 shows an XRPD overlay of crystalline Compound I(a) Form G before and after heating.

Fig. 40 shows the XRPD pattern of the crystalline compound I(a) H type.

Figure 41 shows the TGA and DSC curves of the crystalline compound I(a) H form.

Figure 42 shows the ¹ H NMR spectrum of the crystalline compound I(a) H form.

Figure 43 shows an XRPD overlay of crystalline Compound I(a) Form H before and after heating.

Figure 44 shows the XRPD pattern of crystalline Compound I(a) Type I.

Figure 45 shows the TGA and DSC curves of crystalline Compound I(a) Type I.

Fig. 46 shows the ¹ H NMR spectrum of the crystalline compound I(a) Type I.

Fig. 47 shows the XRPD pattern of the crystalline compound I(a) J type.

Fig. 48 shows the TGA and DSC curves of the crystalline compound I(a) J type.

Fig. 49 shows the ¹ H NMR spectrum of the crystalline compound I(a) Form J.

Fig. 50 shows the XRPD pattern of the crystalline compound I(a) type K.

Fig. 51 shows the TGA and DSC curves of the crystalline Compound I(a) Type K.

Fig. 52 shows the ¹ H NMR spectrum of the crystalline compound I(a) Type K.

Fig. 53 shows the XRPD pattern of the crystalline compound I(a) L type.

Figure 54 shows the TGA and DSC curves of the crystalline compound I(a) L-form.

Figure 55 shows the ¹ H NMR spectrum of the crystalline compound I(a) L form.

Figure 56 shows the XRPD pattern of the crystalline compound I(a) M type.

Figure 57 shows the TGA and DSC curves of the crystalline compound I(a) M form.

Fig. 58 shows the ¹ H NMR spectrum of the crystalline compound I(a) M type.

Fig. 59 shows the XRPD pattern of the amorphous compound I(a) prepared by the prior art method.

Fig. 60 shows the TGA and DSC curves of the amorphous compound I(a) free base prepared by the prior art method.

FIG. 61 shows the XRPD pattern of the amorphous compound I(a) free base prepared by the prior art method.

Fig. 62 shows the TGA and mDSC curves of the amorphous compound I(a) prepared by the prior art method.

Fig. 63 shows an HPLC chromatogram of amorphous compound I(a) prepared by the prior art method.

FIG. 64 shows XRPD patterns of crystalline compound I(a) E-type and E-type seed materials.

Figure 65 shows the TGA and DSC curves of the crystalline compound I(a) E form.

Figure 66 shows an XRPD overlay of gentisic acid-compound I(a) co-crystal form A.

Figure 67 shows the TGA and DSC curves of gentisic acid-compound I(a) co-crystal form A.

Figure 68 shows the ¹ H NMR spectrum of gentisic acid-compound I(a) co-crystal form A.

Figure 69 shows an XRPD overlay of gentisic acid-compound I(a) co-crystals A and B.

Figure 70 shows the TGA and DSC curves of gentisic acid-compound I(a) co-crystal form A.

Figure 71 shows the XPRD overlay of the pattern of crystalline compound I(a) Form E before and after the DVS test.

Figure 72 shows the TGA and DSC curves of the gentisic acid-compound I(a) co-crystal B form.

Fig. 73 shows the ¹ H NMR spectrum of gentisic acid-compound I(a) co-crystal B type.

Fig. 74 shows the XRPD overlay of the pyridine formamide compound I(a) eutectic Form A.

Fig. 75 shows the TGA and DSC curves of the co-crystal Form A of the pyridylcarboxamide compound I(a).

Fig. 76 shows the ¹ H NMR spectrum of the pyridine formamide compound I(a) eutectic Form A.

Figure 77 shows the XRPD overlay of pyridylcarboxamide compound I(a) eutectic Form A before and after heating.

Fig. 78 shows the XRPD pattern of the co-crystal form A of pyridylcarboxamide compound I(a).

Fig. 79 shows the TGA and DSC curves of the co-crystal Form A of the pyridylcarboxamide compound I(a).

Fig. 80 shows the ¹ H NMR spectrum of the form A co-crystal of the pyridylcarboxamide compound I(a).

Fig. 81 shows the XRPD pattern of crystalline compound I(a) AL type.

Figure 82 shows the TGA and DSC curves of the crystalline compound I(a) AL form.

Fig. 83 shows the ¹ H NMR spectrum of the crystalline compound I(a) AL form.

Fig. 84 shows an XRPD overlay of the crystalline compound I(a) BO type and BN type.

Fig. 85 shows the TGA and DSC curves of the crystalline compound I(a) BO type.

Fig. 86 shows the ¹ H NMR spectrum of the crystalline compound I(a) BO type.

Fig. 87 shows the XRPD pattern of the BP type of the crystalline compound I(a).

Fig. 88 shows the TGA and DSC curves of the BP type of the crystalline compound I(a).

Fig. 89 shows the ¹ H NMR spectrum of the BP type of the crystalline compound I(a).

Fig. 90 shows the XRPD pattern of the crystalline compound I(a) BK type.

Figure 91 shows the TGA and DSC curves of the crystalline compound I(a) BK type.

Fig. 92 shows the ¹ H NMR spectrum of the crystalline compound I(a) BK type.

Figure 93 shows the XRPD pattern of crystalline compound I(a) AX type.

Fig. 94 shows TGA and DSC curves of AX type crystalline compound I(a).

FIG. 95 shows the ¹ H NMR spectrum of AX type crystalline compound I(a).

Fig. 96 shows the XRPD pattern of the crystalline compound I(a) Q type.

Fig. 97 shows the TGA and DSC curves of the Q type of crystalline compound I(a).

Fig. 98 shows the ¹ H NMR spectrum of the crystalline compound I(a) Q type.

Fig. 99 shows the XRPD pattern of the crystalline compound I(a) P type.

Figure 100 shows the TGA and DSC curves of the crystalline compound I(a) P-type.

Fig. 101 shows the ¹ H NMR spectrum of the crystalline compound I(a) P type.

Fig. 102 shows the XRPD pattern of the crystalline compound I(a) AQ type.

Fig. 103 shows the TGA and DSC curves of the crystalline compound I(a) AQ type.

Fig. 104 shows the ¹ H NMR spectrum of the crystalline compound I(a) AQ type.

Claims (156)

A method for preparing compound 3, which comprises: (i) reacting compound 1 with a sulfonating agent in a solvent according to step 1 to form compound 2, wherein Y is arylsulfonyl or alkylsulfonyl

; And (ii) reacting compound 2 with a nitrogen source in a solvent according to step 2 to form compound 3,

, Where: Compound 3 is the free base; based on compound 1, the yield of compound 3 is at least 30%; R ^{1 is} selected from halo, halo-C _1-4 alkyl-, halo-C _1-4 alkyl Oxygen- and -CN; and R ^{2 are} selected from H and cyclopropyl-. The method of claim 1, wherein R ^{1 is} selected from -F, -CF ₃ , -CHF ₂ , -OCF ₃ , -OCHF ₂ , -OCH ₂ CF ₃ and -CN. The method of claim 2, wherein R ¹ is -CF ₃ . The method according to any one of claims 1 to 3, wherein R ² is H. The method according to any one of claims 1 to 4, wherein the sulfonating agent: (i) is a sulfonate; (ii) is selected from mesylate chloride and tosylate chloride; or (iii) is mesylate chlorine. The method according to any one of claims 1 to 5, wherein the step 1 reaction further comprises a base. The method of claim 6, wherein the base in step 1 is (i) an amine base or (ii) an amine base selected from trimethylamine, diisopropylethylamine, tributylamine, and octylamine. The method according to any one of claims 1 to 7, wherein the solvent in step 1: (i) contains or is a polar aprotic solvent; (ii) is selected from one or more of the following: 2-methyltetrahydrofuran, Tetrahydrofuran, ethyl acetate, propyl acetate, acetone, dimethylformamide, acetonitrile, and dimethylsulfoxide; (iii) selected from 2-methyltetrahydrofuran and tetrahydrofuran; or (iv) 2-methyltetrahydrofuran. The method according to any one of claims 1 to 8, wherein the nitrogen source of step 2 is ammonia or ammonium salt. The method according to any one of claims 1 to 9, wherein the solvent in step 2: (i) contains or is a polar organic solvent; (ii) is selected from one or more of the following: methanol, ethanol, 1-propane Alcohol, 2-propanol, 1-butanol, formic acid, acetic acid, 2-methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, propyl acetate, acetone, dimethylformamide, acetonitrile and dimethylsulfoxide; (iii ) Is selected from one or more of the following: methanol, ethanol, 1-propanol and 2-propanol; or (iv) methanol. The method according to any one of claims 1 to 10, further comprising a purification step, wherein compound 3 is purified by: (i) from the step 2 solvent exchange to a non-polar solvent with a dielectric constant greater than 2 to form the first solution of compound 3 in the non-polar solvent; (ii) by adding an acid, the solid compound 3 is precipitated from the first solution, and then the solid compound 3 is separated and the separated solid compound 3 is optionally washed; (iii) by adding a base, compound 3 is dissolved in a non-polar solvent with a dielectric constant greater than 2 to form a second solution of compound 3 in the non-polar solvent; (iv) by adding an anti-solvent, the solid compound 3 free base is precipitated from the second solution, or concentrated by removing the non-polar solvent, or a combination thereof; and (v) Separation and purification of compound 3 in free base form. The method of claim 11, wherein the non-polar solvent having a dielectric constant greater than 2: (i) is selected from one or more of the following: methyl tertiary butyl ether, diethyl ether, toluene, 1,4-bis Oxane and chloroform; (ii) one or both selected from methyl tertiary butyl ether and diethyl ether; or (iii) methyl tertiary butyl ether. The method of claim 11 or 12, wherein the acid that precipitates compound 3: (i) is an organic acid; (ii) is a carboxylic acid; (iii) is selected from one or more of the following: formic acid, oxalic acid, propylene Diacid, succinic acid, glutaric acid, succinic acid and adipic acid; or (iv) oxalic acid. The method according to any one of claims 11 to 13, wherein the antisolvent: (i) has a dielectric constant of less than 2; (ii) is selected from one or more of the following: n-pentane, n-hexane, n-hexane Heptane and cyclopentane; or (iii) n-heptane. The method according to any one of claims 1 to 14, wherein the yield of the compound 3 is at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% based on the compound 1. The method according to any one of claims 1 to 15, further comprising forming compound 6 from compound 3 by a method including: (i) reacting compound 3, compound 4 and the coupling agent in a solvent according to step 3; Formation of compound 5

Where each asterisk indicates a palmarity center, and PG indicates an amine protecting group; and (ii) according to the following step 4, compound 5 and an acidic deprotecting group reacting in a solvent to form compound 6

Where R ³ is C _1-4 alkyl- and R ^{4 is} selected from H and -F, or R ³ and R ⁴ together with the ring atoms to which they are attached form a three-membered carbocyclic ring. The method of claim 16, wherein R ³ is -CH ₃ and R ⁴ is -F. The method according to claim 16 or 17, wherein the step 3 reaction further comprises a base and the amine protecting group: (i) is selected from acetyl, trifluoroacetyl, third butoxycarbonyl, benzyloxycarbonyl And 9-oxylmethyleneoxycarbonyl; or (ii) is the third butoxycarbonyl group. The method according to claim 18, wherein the base in step 3: (i) is an organic base; (ii) is a tertiary amine base; (iii) is selected from N-methyl-morpholine, diisopropylethylamine and Triethylamine; or (iv) N-methyl-morpholine. The method according to any one of claims 16 to 19, wherein the coupling agent: (i) is selected from propanephosphonic anhydride; 1-[bis(dimethylamino)methylene]-1H-1,2,3- Triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl

Hexafluorophosphate; N,N'-dicyclohexylcarbodiimide; benzotriazol-1-yloxy) ginseng (dimethylamino)phosphonium hexafluorophosphate; benzotriazol-1-yl -Oxytripyrrolidinylphosphonium hexafluorophosphate; 1,1'-carbonyldiimidazole; 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and hydroxybenzotriazole; And 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and 4-dimethylaminopyridine; or (ii) propanephosphonic anhydride. The method according to any one of claims 16 to 20, wherein the solvent in step 3: (i) contains or is a polar aprotic solvent; (ii) is selected from one or more of the following: 2-methyltetrahydrofuran , Tetrahydrofuran, ethyl acetate, propyl acetate, acetone, dimethylformamide, acetonitrile, and dimethyl sulfoxide; or (iii) one or both selected from ethyl acetate and propyl acetate. The method of claim 21, wherein step 3 further comprises: (i) exchange of the polar aprotic solvent into a polar protic solvent; and (ii) The solid compound 5 is precipitated by adding an anti-solvent. The method of claim 22, wherein the polar protic solvent: (i) is selected from one or more of the following: methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, formic acid, and acetic acid; (ii) one or more selected from methanol, ethanol, 1-propanol and 2-propanol; or (iii) ethanol. The method according to any one of claims 16 to 23, wherein the acidic deprotecting base agent is: (i) an organic acid or an inorganic acid; (ii) an acyl halide or an inorganic acid; (iii) selected from acetyl Chloride, methyl chloride, propyl chloride and butyl chloride's acetyl chloride or inorganic acid selected from hydrochloric acid and sulfuric acid; or (iv) is acetyl chloride. The method according to any one of claims 16 to 24, wherein the solvent of step 4 (i) contains or is a polar protic solvent; (ii) is selected from one or more of the following: methanol, ethanol, 1-propane Alcohol, 2-propanol, 1-butanol, formic acid, and acetic acid; (iii) one or more selected from the group consisting of methanol, ethanol, 1-propanol, and 2-propanol; or (iv) 1- Propanol. The method of any one of claims 16 to 25, wherein compound 6 is in the form of a solution and step 4 further comprises forming a slurry of solid compound 6 by adding an anti-solvent, wherein the anti-solvent: (i) has less than 2 Electrical constant; (ii) one or more selected from the group consisting of n-pentane, n-hexane, n-heptane, and cyclopentane; or (iii) n-heptane. The method according to any one of claims 16 to 26, further comprising forming crystalline compound 1 or a solvate or co-crystal thereof from compound 6 by a method comprising: (i) according to the following step 5, compound 6, Compound 7 and base react in a solvent system to form compound (I)

Wherein: R ⁵ is a halogen group; X ₁ and X _{2 are} each C, or one of X ₁ and X ₂ is N and the other is C; and n is 1 or 2. The method of claim 27 further includes: (i) The compound (I) is transferred from the solvent system to the organic solvent selected from the following by solvent exchange to form a solution of the compound (I): (a) Non-polar solvents with a dielectric constant greater than 2, (b) polar aprotic solvents, or (c) polar protic solvents; and (ii) contacting the solution of the compound (I) with an antisolvent to form a slurry of the solvate of the crystalline compound (I) and the nonpolar solvent, polar aprotic solvent or polar protic solvent with a dielectric constant greater than 2 . The method of claim 27 or 28, wherein the anti-solvent has a dielectric constant of less than 2, or is selected from n-pentane, n-hexane, and n-heptane, or is n-heptane. The method according to any one of claims 27 to 29, wherein the base: (i) is an aqueous solution of an inorganic base; (ii) is an aqueous solution selected from alkali metal hydroxides, ammonium hydroxide, potassium carbonate, and sodium carbonate; or (iii) is an aqueous solution of potassium carbonate or sodium carbonate. The method according to any one of claims 27 to 30, wherein the solvent system of step 5: (i) contains or is a non-polar solvent having a dielectric constant greater than 2; (ii) is selected from one or more of the following: Methyl tertiary butyl ether, diethyl ether, 1,4-dioxane and chloroform; (iii) selected from methyl tertiary butyl ether and diethyl ether; or (iv) methyl tertiary butyl ether. The method according to any one of claims 28 to 31, wherein the organic solvent used for the solvent exchange and forming a solution of compound (I) is selected from: (i) N,N-dimethylacetamide and form a crystalline compound (I) N,N-dimethylacetamide solvate Form C; (ii) anisole and form crystalline compound (I) anisole solvate form D; (iii) Ethanol, and form crystalline compound (I) ethanol solvate Form F; (iv) Toluene, and form crystalline compound (I) Toluene solvate Form G; (v) 2-propanol, and form a crystalline compound (I) 2-propanol solvate form H; (vi) 1-butanol and form crystalline compound (I) 1-butanol solvate Form I; (vii) 2-methyltetrahydrofuran, and the crystalline compound (I) 2-methyltetrahydrofuran solvate Form J is formed; (viii) Tetrahydrofuran, and form crystalline compound (I) Tetrahydrofuran solvate form K; (ix) Isobutanol and form crystalline compound (I) I-butanol solvate L form; and (x) Dimethyl sulfoxide and form crystalline compound (I) Dimethyl sulfoxide solvate M type. The method according to any one of claims 28 to 32, wherein the organic solvent used for the solvent exchange and forming the solution of the compound (I) is ethanol. The method according to any one of claims 28 to 33, further comprising: (i) dissolving the compound (I) solvate in dichloromethane and (ii) dissolving the compound (I) in dichloromethane The solution is contacted with the antisolvent to form the solvate of the crystalline compound (I) and the slurry of the antisolvent, Wherein the anti-solvent: (i) is a non-polar surfactant having a dielectric constant of less than 2; (ii) is selected from n-pentane, n-hexane and n-heptane; or (iii) is n-heptane. The method of claim 34, wherein the organic solvent used for the solvent exchange and forming a solution of compound (I) is ethanol, the antisolvent is n-heptane, and the crystalline compound (I) is free base anhydrous form E. The method according to any one of claims 16 to 35, wherein: (i) Compound 4 has the structure 4(a)

Compound 4(a); (ii) Compound 5 has structure 5(a)

Compound 5(a); and (iii) Compound 6 has structure 6(a)

Compound 6(a). The method according to any one of claims 27 to 36, wherein the compound (I) has the structure I(a):

Compound I(a). A method for preparing crystalline compound I or a solvate or co-crystal thereof, the method comprising: (i) subjecting compound 6 acid salt, compound 7 and base to the following reaction in a solvent system to form compound I

Wherein R ^{1 is} selected from halo, halo-C _1-4 alkyl-, halo-C _1-4 alkoxy- and -CN, R ^{2 is} selected from H and -cyclopropyl, R ³ is C _1-4 alkyl-, and R ^{4 is} selected from H and -F, or R ³ and R ⁴ together with the ring atoms to which they are attached form a three-membered carbocycle, R ⁵ is a halo group, X ₁ and X _{2 are} each C, or one of X ₁ and X ₂ is N and the other is C, n is 1 or 2, and each asterisk indicates a palmarity center; (ii) by compound (I) by solvent exchange, from The solvent system of reaction step (i) is moved to an organic solvent selected from the following to form a solution of compound (I): (a) a non-polar solvent with a dielectric constant greater than 2, (b) a polar aprotic solvent, or (c) Polar protic solvent; and (iii) contacting the solution of compound (I) with an anti-solvent to form a slurry of crystalline compound (I). The method of claim 38, wherein the crystalline compound (I) is a solvate with the nonpolar solvent, polar aprotic solvent, or polar protic solvent having a dielectric constant greater than 2. The method of claim 38 or 39, wherein R ^{1 is} selected from the group consisting of —F, —CF ₃ , —CHF ₂ , —OCF ₃ , —OCHF ₂ , —OCH ₂ CF ₃ and —CN. The method of claim 40, wherein R ¹ is -CF ₃ . The method according to any one of claims 38 to 41, wherein R ² is H. The method of any one of claims 38 to 42, wherein R ³ is -CH ₃ and R ⁴ is -F. The method according to any one of claims 38 to 43, wherein R ⁵ is -F, X ₁ and X _{2 are} each C, and n is 1. The method according to any one of claims 38 to 44, wherein the anti-solvent has a dielectric constant of less than 2, or is selected from n-pentane, n-hexane, and n-heptane, or is n-heptane. The method according to any one of claims 38 to 45, wherein the base: (i) is an aqueous solution of an inorganic base; (ii) is an aqueous solution selected from alkali metal hydroxides, ammonium hydroxide, potassium carbonate, and sodium carbonate; or (iii) is an aqueous solution of potassium carbonate or sodium carbonate. The method according to any one of claims 38 to 40, wherein the solvent system for forming compound (I): (i) contains or is a non-polar solvent having a dielectric constant greater than 2; (ii) selected from the following One or more: methyl tertiary butyl ether, diethyl ether, 1,4-dioxane, and chloroform; (iii) selected from methyl tertiary butyl ether and diethyl ether; or (iv) The third butyl ether. The method according to any one of claims 38 to 47, wherein the organic solvent used for the solvent exchange and forming a solution of compound (I) is selected from: (i) N,N-dimethylacetamide and form a crystalline compound (I) N,N-dimethylacetamide solvate Form C; (ii) anisole and form crystalline compound (I) anisole solvate form D; (iii) Ethanol, and form crystalline compound (I) ethanol solvate Form F; (iv) Toluene, and form crystalline compound (I) Toluene solvate Form G; (v) 2-propanol, and form a crystalline compound (I) 2-propanol solvate form H; (vi) 1-butanol and form crystalline compound (I) 1-butanol solvate Form I; (vii) 2-methyltetrahydrofuran, and the crystalline compound (I) 2-methyltetrahydrofuran solvate Form J is formed; (viii) Tetrahydrofuran, and form crystalline compound (I) Tetrahydrofuran solvate form K; (ix) Isobutanol and form crystalline compound (I) I-butanol solvate L form; and (x) Dimethyl sulfoxide and form crystalline compound (I) Dimethyl sulfoxide solvate M type. The method of any one of claims 38 to 48, wherein the organic solvent used for the solvent exchange and forming a solution of compound (I) is ethanol. The method according to any one of claims 38 to 49, further comprising: (i) dissolving the compound (I) or a solvate thereof in methylene chloride and (ii) dissolving the compound (I) in dichloromethane The solution in methane contacts the antisolvent to form the solvate of the crystalline compound (I) and the slurry of the antisolvent, Wherein the anti-solvent: (i) is a non-polar surfactant with a dielectric constant of less than 2; (ii) is selected from n-pentane, n-hexane and n-heptane; or (iii) is n-heptane. The method of claim 50, wherein the organic solvent used for the solvent exchange and forming the solution of compound (I) is ethanol, the antisolvent is n-heptane, and the crystalline compound (I) is free base anhydrous form E. The method of any one of claims 38 to 51, further comprising forming compound 6, the method comprising: (i) reacting compound 3, compound 4, and a coupling agent in a solvent to form compound 5 according to the following steps

Where PG represents an amine protecting group; and (ii) react compound 5 with an acidic deprotecting group agent in a solvent according to the following steps to form compound 6

. The method of claim 52, wherein the reaction to form compound 5 further comprises a base, and the amine protecting group: (i) is selected from the group consisting of acetyl, trifluoroethoxy, third butoxycarbonyl, and benzyloxy Carbonyl and 9- stilbene methyleneoxycarbonyl; or (ii) is the third butoxycarbonyl. The method of claim 53, wherein the base: (i) is an organic base; (ii) is a tertiary amine base; (iii) is selected from N-methyl-morpholine, diisopropylethylamine and triethylamine ; Or (iv) is N-methyl-morpholine. The method according to any one of claims 52 to 54, wherein the coupling agent: (i) is selected from propanephosphonic anhydride; 1-[bis(dimethylamino)methylene]-1H-1,2,3- Triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl

Hexafluorophosphate; N,N'-dicyclohexylcarbodiimide; benzotriazol-1-yloxy) ginseng (dimethylamino)phosphonium hexafluorophosphate; benzotriazol-1-yl -Oxytripyrrolidinylphosphonium hexafluorophosphate; 1,1'-carbonyldiimidazole; 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and hydroxybenzotriazole; And 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and 4-dimethylaminopyridine; or (ii) propanephosphonic anhydride. The method according to any one of claims 52 to 55, wherein the solvent forming Compound 5: (i) is a polar aprotic solvent; (ii) is selected from one or more of the following: 2-methyltetrahydrofuran, tetrahydrofuran, Ethyl acetate, propyl acetate, acetone, dimethylformamide, acetonitrile, and dimethyl sulfoxide; or (iii) one or both selected from ethyl acetate and propyl acetate. The method of claim 56, wherein the step of forming compound 5 further comprises: (i) exchange of the polar aprotic solvent into a polar protic solvent, and (ii) The solid compound 5 is precipitated by adding an anti-solvent. The method of claim 57, wherein the polar protic solvent in the step of forming compound 5: (i) is selected from one or more of the following: methanol, ethanol, 1-propanol, 2-propanol, 1- Butanol, formic acid and acetic acid; (ii) one or more selected from the group consisting of methanol, ethanol, 1-propanol and 2-propanol; or (iii) ethanol. The method according to any one of claims 52 to 58, wherein the acidic deprotecting base agent is: (i) an organic acid or an inorganic acid; (ii) an acyl halide or an inorganic acid; (iii) selected from acetyl Chloride, methyl chloride, propyl chloride and butyl chloride's acetyl chloride or inorganic acid selected from hydrochloric acid and sulfuric acid; or (iv) is acetyl chloride. The method according to any one of claims 52 to 59, wherein the solvent for deprotecting compound 5: (i) contains or is a polar protic solvent; (ii) is selected from one or more of the following: methanol, Ethanol, 1-propanol, 2-propanol, 1-butanol, formic acid and acetic acid; (iii) one or more selected from the group consisting of methanol, ethanol, 1 -propanol and 2-propanol; or ( iv) is 1-propanol. The method of any one of claims 52 to 60, wherein compound 6 is in the form of a solution and the method further comprises forming a slurry of solid compound 6 by adding an anti-solvent, wherein the anti-solvent: (i) has less than 2 Electrical constant; (ii) one or more selected from the group consisting of n-pentane, n-hexane, n-heptane, and cyclopentane; or (iii) n-heptane. The method of any one of claims 52 to 61, further comprising forming compound 3, the method comprising: (i) reacting compound 1 with a sulfonating agent in a solvent to form compound 2 according to the following step 2, wherein Y Arylsulfonyl or alkylsulfonyl

; And (ii) according to the following steps, reacting compound 2 with a nitrogen source in a solvent to form compound 3, wherein compound 3 is the free base

. The method of claim 62, wherein the sulfonating agent: (i) is a sulfonate; (ii) is selected from mesylate chloride and tosylate chloride; or (iii) is mesylate chloride. The method of claim 62 or 63, wherein the mixture of compound 2 is formed further comprising a base. The method of claim 64, wherein the base is an amine base, or an amine base selected from trimethylamine, diisopropylethylamine, tributylamine, and octylamine. The method according to any one of claims 62 to 65, wherein the solvent for the reaction for forming Compound 2: (i) is a polar aprotic solvent; (ii) is selected from one or more of the following: 2-methyltetrahydrofuran , Tetrahydrofuran, ethyl acetate, propyl acetate, acetone, dimethylformamide, acetonitrile, and dimethylsulfoxide; (iii) selected from 2-methyltetrahydrofuran, tetrahydrofuran; or (iv) 2-methyltetrahydrofuran . The method according to any one of claims 62 to 66, wherein the nitrogen source of the compound 3 forming reaction is ammonia or ammonium salt. The method according to any one of claims 62 to 67, wherein the solvent for the reaction of forming compound 3: (i) contains or is a polar organic solvent; (ii) is selected from one or more of the following: methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, formic acid, acetic acid, 2-methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, propyl acetate, acetone, dimethylformamide, acetonitrile and dimethylsulfoxide ; (Iii) one or more of the following: methanol, ethanol, 1-propanol and 2-propanol; or (iv) methanol. The method according to any one of claims 62 to 68, further comprising a purification step, wherein compound 3 is purified by the following sequence of steps: (i) The solvent of the reaction to form compound 3 is exchanged into a non-polar solvent having a dielectric constant greater than 2 to form a first solution of compound 3 in the non-polar solvent; (ii) By adding an acid, the solid compound 3 is precipitated from the solution, and then the solid compound 3 is separated and the separated solid compound 3 is optionally washed; (iii) by adding a base, compound 3 is dissolved in a non-polar solvent with a dielectric constant greater than 2 to form a second solution of compound 3 in the non-polar solvent; (iv) by adding an anti-solvent, the solid compound 3 free base is precipitated from the second solution, concentrated by removing the non-polar solvent, or a combination thereof; and (v) Separation and purification of compound 3 free base. The method of claim 69, wherein the non-polar solvent having a dielectric constant greater than 2: (i) is selected from one or more of the following: methyl tertiary butyl ether, diethyl ether, toluene, 1,4-bis Oxane and chloroform; (ii) one or both selected from methyl tertiary butyl ether and diethyl ether; or (iii) methyl tertiary butyl ether. The method of claim 69 or 70, wherein the acid that precipitates compound 3 is: (i) an organic acid; (ii) a carboxylic acid; (iii) one or more selected from the group consisting of formic acid, oxalic acid, and propylene Diacid, succinic acid, glutaric acid, succinic acid and adipic acid; or (iv) oxalic acid. The method according to any one of claims 69 to 71, wherein the antisolvent: (i) has a dielectric constant less than 2; (ii) is selected from one or more of the following: n-pentane, n-hexane, n-hexane Heptane and cyclopentane; or (iii) n-heptane. The method of any one of claims 62 to 72, wherein the yield of compound 3 based on compound 1 is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%. The method according to any one of claims 52 to 73, wherein: (i) Compound 4 has the structure 4(a)

Compound 4(a); and (ii) Compound 5 has structure 5(a)

Compound 5(a). The method according to any one of claims 38 to 74, wherein: (i) Compound 6 has the structure 6(a)

Compound 6(a); and (ii) Compound (I) has structure I(a):

Compound I(a). A crystal (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl- N -((5-(trifluoromethyl)-2-( 2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide compound. A compound as claimed in claim 76, wherein the compound is the free base anhydrous polymorph E, and exhibits an XRPD pattern having at least three, at least four, or at least five features at the following angles expressed in degrees 2θ Peak: 7.5°±0.2°, 8.2°±0.2°, 12.6°±0.2°, 13.1°±0.2°, 13.4°±0.2°, 14.7°±0.2°, 15.1°±0.2°, 15.5°±0.2°, 16.1°±0.2°, 16.6°±0.2°, 18.2°±0.2°, 18.9°±0.2°, 19.9°±0.2°, 20.4°±0.2°, 21.0°±0.2°, 21.5°±0.2°, 21.8° ±0.2°, 22.4°±0.2°, 22.7°±0.2°, 24.3°±0.2°, 25.0°±0.2°, 25.4°±0.2° and 28.4°±0.2°. A compound according to claim 76 or 77, wherein the compound is a free base anhydrous polymorph E form having a powder X-ray diffraction pattern according to FIG. The compound according to any one of claims 76 to 78, wherein the compound is a free base anhydrous polymorph E form having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 11. A compound as claimed in claim 76, wherein the compound is free base hydrate polymorph Form A, and exhibits an XRPD pattern having at least three, at least four, or at least five features at an angle expressed as 2θ degrees as follows Peak: 7.2°±0.2°, 12.2°±0.2°, 14.0°±0.2°, 14.2°±0.2°, 15.5°±0.2°, 15.8°±0.2°, 17.0°±0.2°, 17.2°±0.2°, 18.4°±0.2°, 21.3°±0.2°, 21.6°±0.2°, 22.2°±0.2°, 23.4°±0.2°, 24.4°±0.2° and 25.2°±0.2°. A compound according to claim 76 or 80, wherein the compound is a free base hydrate polymorph Form A having a powder X-ray diffraction pattern according to FIG. 6. The compound of any one of claims 76, 80, or 81, wherein the compound is a free base hydrate polymorph Form A having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 7. The compound according to claim 76, wherein the compound is the free base dimethylacetamide solvate polymorph Form C, which exhibits at least three, at least four, or at least five XRPD patterns at 2θ as follows Characteristic peaks at angles expressed in degrees: 10.8°±0.2°, 12.1°±0.2°, 12.3°±0.2°, 13.6°±0.2°, 13.8°±0.2°, 14.9°±0.2°, 16.0°±0.2° , 16.2°±0.2°, 17.1°±0.2°, 18.2°±0.2°, 21.2°±0.2°, 21.5°±0.2°, 22.4°±0.2°, 21.2°±0.2°, 23.5°±0.2°, 24.2 °±0.2°, 25.2°±0.2°, 27.2°±0.2°. The compound according to claim 76 or 83, wherein the compound is a free base dimethylacetamide solvate polymorph Form C having a powder X-ray diffraction pattern according to FIG. 25. The compound according to any one of claims 76, 83, or 84, wherein the compound is a free base dimethylacetamide solvate having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 26 Polymorph C type. A compound as claimed in claim 76, wherein the compound is the free base anisole solvate polymorph Form D, which exhibits at least three, at least four, or at least five XRPD patterns expressed as 2θ degrees below Characteristic peaks at angles: 5.7°±0.2°, 12.8°±0.2°, 15.4°±0.2°, 17.1°±0.2°, 18.1°±0.2° and 20.8°±0.2°. A compound according to claim 76 or 86, wherein the compound is a free base anisole solvate polymorph D form having a powder X-ray diffraction pattern according to FIG. 28. The compound according to any one of claims 76, 86, or 87, wherein the compound is a free base anisole solvate polymorph having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 29 Type D. A compound as claimed in claim 76, wherein the compound is a free base ethanol solvate polymorph Form F, which exhibits at least three, at least four, or at least five XRPD patterns at an angle expressed as 2θ degrees as follows The characteristic peaks: 11.7°±0.2°, 12.9°±0.2°, 13.3°±0.2°, 17.4°±0.2°, 18.5°±0.2°, 19.4°±0.2°, 23.5°±0.2°, 24.3°±0.2 ° and 25.9°±0.2°. A compound according to claim 76 or 89, wherein the compound is a free base ethanol solvate polymorph Form F having a powder X-ray diffraction pattern according to FIG. 32. The compound according to any one of claims 76, 89, or 90, wherein the compound is a free base ethanol solvate polymorph F having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 33 type. The compound of claim 76, wherein the compound is the free base toluene solvate polymorph Form G, which exhibits at least three, at least four, or at least five XRPD patterns at an angle expressed as 2θ degrees as follows The characteristic peaks: 13.8°±0.2°, 16.7°±0.2°, 17.6°±0.2°, 17.8°±0.2°, 18.8°±0.2°, 22.5°±0.2° and 25.1°±0.2°. A compound according to claim 76 or 92, wherein the compound is a free base toluene solvate polymorph Form G having a powder X-ray diffraction pattern according to FIG. 36. The compound according to any one of claims 76, 92 or 93, wherein the compound is a free base toluene solvate polymorph G having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 37 type. A compound as claimed in claim 76, wherein the compound is a free base isopropanol solvate polymorph Form H, which exhibits at least three, at least four, or at least five XRPD patterns expressed in 2θ degrees as follows Characteristic peaks at angles: 11.5°±0.2°, 12.8°±0.2°, 13.1°±0.2°, 17.5°±0.2°, 18.2°±0.2°, 22.3°±0.2°, 23.2°±0.2° and 24.0° ±0.2°. A compound according to claim 76 or 95, wherein the compound is a free base isopropyl alcohol solvate polymorph H form having a powder X-ray diffraction pattern according to FIG. 40. The compound according to any one of claims 76, 95, or 96, wherein the compound is a free base isopropyl alcohol solvate polymorph having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 41物H型。 Type H. The compound according to claim 76, wherein the compound is the free base 1-butanol solvate polymorph Form I, which exhibits an XRPD pattern with at least three, at least four, or at least five expressed in 2θ degrees as follows Characteristic peaks at angles: 12.0°±0.2°, 12.4°±0.2°, 12.6°±0.2°, 13.3°±0.2°, 14.0°±0.2°, 15.1°±0.2°, 17.2°±0.2°, 17.9 °±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, 23.1°±0.2°, 24.3°±0.2°, 25.4°±0.2°, 25.9°±0.2° and 27.3°± 0.2°. A compound according to claim 76 or 98, wherein the compound is a free base 1-butanol solvate polymorph Form I having a powder X-ray diffraction pattern according to FIG. 44. A compound according to any one of claims 76, 98 or 99, wherein the compound is the free base 1-butanol solvate polymorph according to the thermogravimetric analysis curve and/or the differential scanning calorimetry curve of FIG. 45物I型。 Type I. The compound of claim 76, wherein the compound is the free base 2-methyltetrahydrofuran solvate polymorph Form J, which exhibits an XRPD pattern with at least three, at least four, or at least five at 2θ degrees as follows Characteristic peaks at the indicated angles: 11.8°±0.2°, 13.1°±0.2°, 14.5°±0.2°, 16.8°±0.2°, 18.4°±0.2°, 19.4°±0.2°, 20.7°±0.2°, 21.8°±0.2°, 24.3°±0.2° and 26.4°±0.2°. A compound according to claim 76 or 101, wherein the compound is a free base 2-methyltetrahydrofuran solvate polymorph Form J having a powder X-ray diffraction pattern according to FIG. 47. The compound according to any one of claims 76, 101 or 102, wherein the compound is a free base 2-methyltetrahydrofuran solvate having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 48 Crystal type J. A compound as claimed in claim 76, wherein the compound is the free base tetrahydrofuran solvate polymorph Form K, and exhibits an XRPD pattern having at least three, at least four, or at least five at an angle expressed as 2θ degrees as follows The characteristic peaks: 11.0°±0.2°, 12.0°±0.2°, 12.4°±0.2°, 12.6°±0.2°, 13.3°±0.2°, 13.5°±0.2°, 14.1°±0.2°, 14.7°±0.2 °, 17.2°±0.2°, 18.5°±0.2°, 19.5°±0.2°, 20.9°±0.2°, 21.4°±0.2°, 21.6°±0.2°, 22.0°±0.2°, 22.2°±0.2°, 22.9°±0.2°, 24.8°±0.2°, 27.1°±0.2°, 27.4°±0.2° and 28.3°±0.2°. The compound according to claim 76 or 104, wherein the compound is a free base tetrahydrofuran solvate polymorph K form having a powder X-ray diffraction pattern according to FIG. 50. The compound according to any one of claims 76, 104, or 105, wherein the compound is a free base tetrahydrofuran solvate polymorph K having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 51 type. A compound as claimed in claim 76, wherein the compound is the free base isobutanol solvate polymorph L form, which exhibits at least three, at least four, or at least five XRPD patterns expressed as 2θ degrees below Characteristic peaks at angles: 11.6°±0.2°, 12.8°±0.2°, 13.1°±0.2°, 14.2°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 22.8°±0.2°, 23.1° ±0.2°, 24.0°±0.2° and 25.3°±0.2°. A compound according to claim 76 or 107, wherein the compound is a free base isobutanol solvate polymorph L form having a powder X-ray diffraction pattern according to FIG. 53. A compound according to any one of claims 76, 107 or 108, wherein the compound is a free base isobutanol solvate polymorph having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 54物L型。 Object L type. A compound as claimed in claim 76, wherein the compound is the free base dimethyl sulfoxide solvate polymorph Form M, which exhibits at least three, at least four, or at least five XRPD patterns expressed as 2θ degrees below Characteristic peaks at angles: 12.1°±0.2°, 13.4°±0.2°, 14.7°±0.2°, 18.4°±0.2°, 20.9°±0.2°, 21.5°±0.2°, 24.9°±0.2°, 26.8 °±0.2° and 27.6°±0.2°. The compound of claim 76 or 110, wherein the compound is a free base dimethyl sulfoxide solvate polymorph M form having a powder X-ray diffraction pattern according to FIG. 56. The compound according to any one of claims 76, 110 or 111, wherein the compound is a free base dimethyl sulfoxide solvate polycrystal having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 57 Type M type. The compound of claim 76, wherein the compound is an anhydrous gentisic acid eutectic polymorph Form A, and exhibits an XRPD pattern having at least three, at least four, or at least five at an angle expressed by 2θ degrees as follows The characteristic peaks: 12.5°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 15.7°±0.2°, 17.5°±0.2°, 21.7°±0.2°, 25.5°±0.2° and 26.3°±0.2 °. A compound as claimed in claim 76 or 113, wherein the compound is an anhydrous gentisic acid eutectic polymorph Form A having a powder X-ray diffraction pattern according to FIG. 66. The compound according to any one of claims 76, 113 or 114, wherein the compound is an anhydrous gentisic acid co-crystal polymorph A having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 67 type. The compound of claim 76, wherein the compound is an anhydrous gentisic acid eutectic polymorph Form B, and exhibits an XRPD pattern having at least three, at least four, or at least five at an angle expressed by 2θ degrees as follows Characteristic peaks: 6.6°±0.2°, 7.9°±0.2°, 12.2°±0.2°, 12.4°±0.2°, 14.0°±0.2°, 15.1°±0.2°, 16.3°±0.2°, 21.1°±0.2 °, 25.3°±0.2° and 25.6°±0.2°. A compound as claimed in claim 76 or 116, wherein the compound is an anhydrous gentisic acid eutectic polymorph Form B having a powder X-ray diffraction pattern according to FIG. 69. A compound as claimed in claim 76, wherein the compound is hydrated pyridomethanamine co-crystal polymorph Form A, and exhibits an XRPD pattern having at least three, at least four, or at least five angles expressed in degrees 2θ as follows Characteristic peaks at: 12.1°±0.2°, 12.4°±0.2°, 14.5°±0.2°, 15.8°±0.2°, 18.1°±0.2°, 19.1°±0.2°, 22.0°±0.2°, 24.5°± 0.2°, 25.6°±0.2° and 26.6°±0.2°. A compound as claimed in claim 76 or 118, wherein the compound is a form A hydrated pyridylcarboxamide eutectic polymorph having a powder X-ray diffraction pattern according to FIG. 78. The compound according to any one of claims 76, 118 or 119, wherein the compound is a pyridylformamide hydrate co-crystal polymorph having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 79 Type A. A compound as claimed in claim 76, wherein the compound is the free base anhydrous polymorph AL, and exhibits an XRPD pattern having at least three, at least four, or at least five features at an angle expressed by 2θ degrees as follows Peak: 7.6°±0.2°, 8.4°±0.2°, 13.2°±0.2°, 13.8°±0.2°, 14.8°±0.2°, 15.2°±0.2°, 15.6°±0.2°, 15.9°±0.2°, 16.9°±0.2°, 18.1°±0.2°, 20.5°±0.2° and 21.3°±0.2°. A compound according to claim 76 or 121, wherein the compound is a free base anhydrous polymorph AL form having a powder X-ray diffraction pattern according to FIG. 81. The compound according to any one of claims 76, 121, or 122, wherein the compound is a free base anhydrous polymorph AL form having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 82. A compound as claimed in claim 76, wherein the compound is the free base hydrate polymorph BO form, which exhibits an XRPD pattern having at least three, at least four, or at least five features at an angle expressed by 2θ degrees as follows Peak: 12.1°±0.2°, 12.4°±0.2°, 13.9°±0.2°, 15.0°±0.2°, 15.4°±0.2°, 17.1°±0.2°, 18.3°±0.2°, 21.5°±0.2°, 22.1°±0.2°, 24.4°±0.2°, 25.1°±0.2°, 26.2°±0.2° and 26.3°±0.2°. A compound according to claim 76 or 124, wherein the compound is a free base hydrate polymorph BO form having a powder X-ray diffraction pattern according to FIG. 84. The compound of any one of claims 76, 124, or 125, wherein the compound is a free base hydrate polymorph BO form having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 85. A compound according to claim 76, wherein the compound is the free base n-heptane solvate polymorph BP form, which exhibits an XRPD pattern having at least three, at least four, or at least five expressed as 2θ degrees as follows Characteristic peaks at angles: 8.5°±0.2°, 12.9°±0.2°, 17.6°±0.2°, 18.1°±0.2°, 19.4°±0.2°, 20.8°±0.2°, 21.2°±0.2°, 22.9° ±0.2° and 24.0°±0.2°. The compound according to claim 76 or 127, wherein the compound is a free base n-heptane solvate polymorph BP form having a powder X-ray diffraction pattern according to FIG. 87. The compound according to any one of claims 76, 127, or 128, wherein the compound is a free base n-heptane solvate polymorph having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 88 BP type. A compound as claimed in claim 76, wherein the compound is the free base 2-pentanol solvate polymorph form BK, which exhibits an XRPD pattern with at least three, at least four, or at least five expressed in 2θ degrees as follows Characteristic peaks at angles: 11.9°±0.2°, 13.0°±0.2°, 14.4°±0.2°, 14.7°±0.2°, 16.9°±0.2°, 17.9°±0.2°, 19.3°±0.2°, 21.8 °±0.2°, 22.7°±0.2°, 23.9°±0.2°, 24.6°±0.2° and 26.1°±0.2°. A compound according to claim 76 or 130, wherein the compound is a free base 2-pentanol solvate polymorph BK form having a powder X-ray diffraction pattern according to FIG. 90. The compound according to any one of claims 76, 130, or 131, wherein the compound is a free base 2-pentanol solvate polycrystal having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 91 Type BK type. A compound as claimed in claim 76, wherein the compound is the free base n-amyl alcohol solvate polymorph Form AX, which exhibits at least three, at least four, or at least five XRPD patterns expressed in 2θ degrees as follows Characteristic peaks at angles: 11.5°±0.2°, 12.9°±0.2°, 13.1°±0.2°, 17.4°±0.2°, 18.2°±0.2°, 23.1°±0.2°, 23.9°±0.2° and 25.9° ±0.2°. A compound according to claim 76 or 133, wherein the compound is a free base n-amyl alcohol solvate polymorph AX form having a powder X-ray diffraction pattern according to FIG. 93. The compound according to any one of claims 76, 133, or 134, wherein the compound is a free base n-amyl alcohol solvate polymorph having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 94 AX type. A compound as claimed in claim 76, wherein the compound is the free base meta-xylene solvate polymorph Form Q, which exhibits an XRPD pattern with at least three, at least four, or at least five expressed as 2θ degrees as follows Characteristic peaks at angles: 5.5°±0.2°, 12.5°±0.2°, 15.0°±0.2°, 17.6°±0.2°, 20.2°±0.2°, 22.1°±0.2°, 22.8°±0.2° and 26.6° ±0.2°. The compound as claimed in claim 76 or 136, wherein the compound is a free form meta-xylene solvate polymorph Form Q having a powder X-ray diffraction pattern according to FIG. 96. The compound according to any one of claims 76, 136, or 137, wherein the compound is a free base metaxylene solvate polymorph having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 97 Type Q. The compound according to claim 76, wherein the compound is the free base 2-methoxyethanol solvate polymorph Form P, which exhibits an XRPD pattern having at least three, at least four, or at least five in the following 2θ Characteristic peaks at angles expressed in degrees: 11.9°±0.2°, 12.3°±0.2°, 12.7°±0.2°, 14.0°±0.2°, 17.1°±0.2°, 20.0°±0.2°, 23.9°±0.2° , 24.1°±0.2°, 25.5°±0.2°, 25.8°±0.2° and 27.2°±0.2°. The compound according to claim 76 or 139, wherein the compound is a free base 2-methoxyethanol solvate polymorph P form having a powder X-ray diffraction pattern according to FIG. 99. The compound according to any one of claims 76, 139, or 140, wherein the compound is a free base 2-methoxyethanol solvate having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 100 Polymorph P type. A compound as claimed in claim 76, wherein the compound is the free base second butanol solvate polymorph AQ form, which exhibits an XRPD pattern having at least three, at least four, or at least five expressed in 2θ degrees as follows Characteristic peaks at angles: 11.5°±0.2°, 12.7°±0.2°, 12.9°±0.2°, 14.1°±0.2°, 17.4°±0.2°, 17.9°±0.2°, 21.9°±0.2°, 22.7 °±0.2°, 23.1°±0.2°, 23.5°±0.2°, 23.9°±0.2°, 25.5°±0.2° and 27.6°±0.2°. The compound according to claim 76 or 142, wherein the compound is a free base second butanol solvate polymorph AQ form having a powder X-ray diffraction pattern according to FIG. 102. The compound according to any one of claims 76, 142, or 143, wherein the compound is a free base second butanol solvate polycrystal having a thermogravimetric analysis curve and/or a differential scanning calorimetry curve according to FIG. 103 Type AQ type. A pharmaceutical composition comprising the compound according to any one of claims 76 to 144 and at least one pharmaceutically acceptable excipient, diluent and/or carrier. An E-type compound (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl- N -((5-( Trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide, characterized by X-ray powder diffraction peaks Contains three, four or five peaks selected from 7.5°±0.2°, 8.2°±0.2°, 12.6°±0.2°, 13.1°±0.2°, 13.4°±0.2°, 14.7°±0.2°, 15.1 °±0.2°, 15.5°±0.2°, 16.1°±0.2°, 16.6°±0.2°, 18.2°±0.2°, 18.9°±0.2°, 19.9°±0.2°, 20.4°±0.2°, 21.0°± 0.2°, 21.5°±0.2°, 21.8°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 24.3°±0.2°, 25.0°±0.2°, 25.4°±0.2° and 28.4°±0.2° . The compound of claim 146 is characterized by a powder X-ray diffraction pattern according to FIG. The compound of claim 146 or 147 is characterized by the thermogravimetric analysis curve and/or the differential scanning calorimetry curve according to FIG. 11. A pharmaceutical composition comprising the compound according to any one of claims 146 to 148 and at least one pharmaceutically acceptable excipient, diluent and/or carrier. Preparation of (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl- N -((5-( A method of trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide, which includes: (1) mixing (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl- N -((5-(trifluoromethyl)-2-(2- (Trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide free base starting material and dichloromethane to form containing (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl- N -((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidine-5 -Yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide concentration is at least 50 mg/mL solution; (2) make the (2 S ,4 R ,5 S )-4-fluoro- 1-(4-fluorobenzenesulfonyl)-5-methyl- N -((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridine-4 -Yl)methyl)pyrrolidine-2-carboxamide solution combined with a non-polar antisolvent having a dielectric constant of less than 2 to achieve a total volume ratio of methylene chloride to antisolvent of about 1:1.5 to about 1 :10, to form an E-type (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl- N -((5 -(Trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide slurry; and (3) The free base anhydrous crystalline E-type (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl- N -((5 -(Trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide. The method of claim 150, wherein the anti-solvent is n-heptane. The method of claim 150 or 151, wherein the mixing step (1) and the combining step (2) are performed at about 15°C to about 35°C. The method of any one of claims 150 to 152, wherein the volume ratio of dichloromethane to antisolvent is about 1:2 to about 1:4, or about 1:3. The method according to any one of claims 150 to 153, wherein step (2) further comprises crystallizing the free base anhydrous E-type (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzene Sulfonyl)-5-methyl- N -((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrole Seed crystals of pyridin-2-carboxamide added to (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5-methyl- N -((5-( Trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidin-2-carboxamide in the combined solution. The method according to any one of claims 150 to 154, wherein the starting material is an amorphous solid (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5 -Methyl- N -((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide Amine free base. The method according to any one of claims 150 to 155, wherein the starting material is type F (2 S ,4 R ,5 S )-4-fluoro-1-(4-fluorobenzenesulfonyl)-5- Methyl- N -((5-(trifluoromethyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-4-yl)methyl)pyrrolidine-2-carboxamide Free base.

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