Process for the preparation of heterocyclic ketone compounds and their azabicyclic intermediates

Abstract

The present disclosure relates to a process for the synthesis of a heterocyclic ketone compound, and in particular a 3'-substituted-3-hydroxy-(8-azabicyclo[3.2.1]oct-8-yl)-[5-(1 h-pyrazol-4-yl)-thiophen-3-yl]-methanone compound and azabicyclic intermediates thereof. In particular, the present disclosure also relates to a process for the synthesis of Xanamem. The present disclosure also relates to a process for the synthesis of optionally protected azabicyclic intermediate compounds. The present disclosure also relates to 3'-substituted-3-hydroxy-(8-azabicyclo[3.2.1]oct-8-yl)-[5-(1 h-pyrazol-4-yl)-thiophen-3-yl]-methanone compounds and azabicyclic intermediate compounds thereof.

Description

Technical Field

[0001] This disclosure generally relates to a process for synthesizing heterocyclic ketone compounds, and particularly to 3'-substituted-3-hydroxy-(8-azabicyclo[3.2.1]oct-8-yl)-[5-(1h-pyrazol-4-yl)-thiophen-3-yl]-ketone compounds and their azabicyclo intermediates. In particular, this disclosure also relates to a process for synthesizing Xanamem. This disclosure also relates to a process for synthesizing optionally protected azabicyclo intermediate compounds. This disclosure further relates to 3'-substituted-3-hydroxy-(8-azabicyclo[3.2.1]oct-8-yl)-[5-(1h-pyrazol-4-yl)-thiophen-3-yl]-ketone compounds and their azabicyclo intermediate compounds, which have been prepared by any of the processes of this disclosure. This disclosure also relates to pharmaceutical compositions comprising 3'-substituted-3-hydroxy-(8-azabicyclo[3.2.1]oct-8-yl)-[5-(1h-pyrazol-4-yl)-thiophen-3-yl]-methyl ketone compounds, and particularly Xanamem. Background Technology

[0002] Xanamem, also known as UE2343, is a potent inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Due to its inhibitory effect and associated reduction in cortisol levels, Xanamem has been proposed as a treatment for Alzheimer's disease.

[0003]

[0004] To date, the only reported process for the preparation of Xanamem comes from the international PCT publication WO2011135276. According to the reported preparation process, before the final amide coupling reaction in dichloromethane to generate Xanamem using 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (HATU) as a coupling agent, carboxylic acid derivatives (left-handed) and amine bicyclic derivatives (right-handed) of the molecule are synthesized separately.

[0005] A specific drawback of the reported process identified by the inventors lies in the synthesis of the right-hand side of Xanamem, particularly the coupling of the pyrimidine moiety with the nortropinone moiety. This reaction involves the use of the highly reactive, auto-igniting reagent, n-butyllithium. Therefore, the reaction must be carefully maintained at low temperatures, specifically -95°C. The addition of n-butyllithium to the reaction mixture results in an exothermic reaction, thus raising the temperature of the reaction mixture upon addition. Therefore, the reaction requires the slow addition of n-butyllithium, with careful monitoring of the reaction temperature throughout the process. While this reaction may be suitable for small-scale synthesis, it is not inherently suitable for large-scale production of Xanamem.

[0006] Another specific drawback of the reported process identification by the inventors lies in the final amide coupling reaction of thiophene carboxylic acid and nortropinoneamine. The reaction using the HATU coupling reagent produces tetramethylurea (TMU) as a byproduct, which is itself a potentially genotoxic compound. Furthermore, this TMU byproduct is difficult to separate from Xanamem during purification. Moreover, while this reaction and the associated post-reaction purification steps may be suitable for small-scale synthesis of Xanamem, the reaction is not suitable for large-scale production of Xanamem.

[0007] Therefore, there remains a need for safe, efficient, and scalable synthesis of high-purity Xanamem and related analogues, in which the generation of any undesirable byproducts is significantly reduced or avoided. Summary of the Invention

[0008] The subject matter of this disclosure is partly based on the surprising discovery that the Grignard reaction conditions of the reaction system can eliminate the need for low-temperature reaction conditions in the preparation of azabicyclic intermediates, and / or that the specific amide coupling reaction conditions for the preparation of heterocyclic ketones can avoid the genotoxic tetramethylurea (TMU) byproduct, thus also leading to the efficient and scalable synthesis of Xanamem.

[0009] This disclosure also relates to a process for preparing azabicyclic compounds, the process comprising a Grignard reaction of a nortropinone compound with a halogenated compound. This disclosure further relates to a process for preparing heterocyclic ketone compounds, the process comprising an amide coupling reaction of a heterocyclic carboxylic acid compound with an azabicyclic compound, wherein one or both compounds may be provided as starting materials for the coupling reaction in the form of a salt. This disclosure also relates to compounds prepared by any of the processes described herein and any compositions comprising such compounds.

[0010] Therefore, in one aspect, a process for preparing the protected azabicyclic compound of formula 4 is provided.

[0011]

[0012] The process includes the nortropinone compound of formula 5.

[0013]

[0014] Grignard reaction with the halo compounds of Formula 6,

[0015] XR]

[0016] Formula 6

[0017] in

[0018] R 1 Selected from carbocyclic or heterocyclic groups, wherein each carbocyclic and heterocyclic group is a monocyclic or bicyclic group, and each monocyclic or bicyclic group is either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogens, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -CN, -NR 3 R 4 -COR 3 -CO2R 3 And each R 3 and R 4 Independently select from the following groups: hydrogen and -C 1-6 alkyl;

[0019] R 2 It is an amine protecting group; and

[0020] X is a halogen.

[0021] On the other hand, a process for preparing heterocyclic ketone compounds of formula 1 is provided.

[0022]

[0023] The process involves using a carboxylic acid compound of formula 2 or a salt thereof.

[0024]

[0025] The reaction with an amine compound of formula 3 or a salt thereof in the presence of at least one coupling agent selected from oxime coupling agents and carbodiimide coupling agents,

[0026]

[0027] in

[0028] R 1 Selected from carbocyclic or heterocyclic groups, wherein each carbocyclic and heterocyclic group is a monocyclic or bicyclic group, and each monocyclic or bicyclic group is either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogens, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -CN, -NR 3 R 4 -COR 3 -CO2R 3 And each R 3 and R4 Choose independently the following groups: hydrogen and C 1-6 alkyl;

[0029] R 5 It is a hydrogen or amine protecting group.

[0030] On the other hand, a process for preparing heterocyclic ketone compounds of formula 1 is provided.

[0031]

[0032] The process involves using a carboxylic acid compound of formula 2 or a salt thereof.

[0033]

[0034] The single or double salt of the amine compound of formula 3 reacts in the presence of at least one amide coupling agent.

[0035]

[0036] in

[0037] R 1 Selected from carbocyclic or heterocyclic groups, wherein each carbocyclic and heterocyclic group is a monocyclic or bicyclic group, and each monocyclic or bicyclic group is either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogens, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -CN, -NR 3 R 4 -COR 3 -CO2R 3 And each R 3 and R 4 Choose independently the following groups: hydrogen and C 1-6 alkyl;

[0038] R 5 It is a hydrogen or amine protecting group.

[0039] The scope of this invention is not limited to the specific embodiments described herein, which are intended for illustrative purposes only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention as described herein.

[0040] Throughout this specification, unless otherwise specifically stated or required by the context, references to a single step, substance composition, group of steps, or group of substance compositions shall be understood to encompass one or more of such steps, substance compositions, group of steps, or group of substance compositions. Attached Figure Description

[0041] While it should be understood that various embodiments of this disclosure may be utilized, several instances of this disclosure are described below with reference to the accompanying drawings.

[0042] Figure 1 The HPLC chromatogram of the crude compound A8 reaction mixture is shown 1.5 hours after Grignard reaction with i-PrMgBr, tert-butyloxycarbonyl-nortropinone and THF containing LaCl3.

[0043] Figure 2 The HPLC chromatogram of crude compound A8 after Grignard reaction with i-PrMgBr, tert-butyloxycarbonyl-nortropinone and LaCl3-containing THF is shown.

[0044] Figure 3 The HPLC chromatogram of purified compound A8 after Grignard reaction with i-PrMgBr, tert-butyloxycarbonyl-nortropinone and LaCl3-containing THF is shown.

[0045] Figure 4 The HPLC chromatogram of the crude compound A8 after a Grignard reaction with excess i-PrMgBr (1.7 equivalents) is shown.

[0046] Figure 5 The Grignard reaction of crude compound A8 with excess i-PrMgBr (1.7 equivalents) is shown on a scale-up basis. 1 H NMR spectrum.

[0047] Figure 6 The HPLC chromatogram of the crude compound A8 after a Grignard reaction with insufficient i-PrMgBr (1.3 equivalents) is shown.

[0048] Figure 7 The Grignard reaction of crude compound A8 with insufficient i-PrMgBr (1.3 equivalents) is shown on a scale-up basis. 1 H NMR spectrum.

[0049] Figure 8 The HPLC chromatogram of the p-TSA salt of compound A9 after scale-up (30 g to 50 g) condensation reaction is shown.

[0050] Figure 9 The benzoate of compound A9 after salt screening is shown. 1 H NMR spectrum.

[0051] Figure 10 The p-TSA salt of compound A9 after salt screening is shown. 1 H NMR spectrum.

[0052] Figure 11 The components of the mixture from which compound A9 was extracted are shown. 1 The 1H NMR spectrum showed TsOH retention.

[0053] Figure 12 The HPLC chromatogram of purified compound 1 after amide coupling reaction with compound A9 in p-TSA is shown.

[0054] Figure 13 The HPLC chromatogram of purified compound 1 after amide coupling reaction with Oxymapure and EDC-containing THF is shown.

[0055] Figure 14 The HPLC chromatogram of compound 1 purified by recrystallization from EtOH / H2O 1:1 is shown. Detailed Implementation

[0056] General definition

[0057] Unless otherwise specifically defined, all technical and scientific terms used herein should be understood to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., chemistry, biochemistry, medicinal chemistry, microbiology, etc.).

[0058] As used herein, the term “and / or”, such as “X and / or Y”, should be understood to mean “X and Y” or “X or Y”, and should be understood to provide explicit support for both meanings or either meaning, such as A and / or B including options i) A, ii) B or iii) A and B.

[0059] As used herein, unless otherwise stated, the term “about” means + / - 20% of the specified value, typically + / - 10%, typically + / - 5%.

[0060] As used herein, the terms “a,” “an,” and “the” include both singular and plural aspects unless the context clearly indicates otherwise.

[0061] The compounds disclosed herein may contain a chiral (asymmetric) center, or the molecule as a whole may be chiral. Individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are within the scope of this invention.

[0062] As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0063] As used herein, the term "alkyl" encompasses both straight-chain (i.e., linear) and branched hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, pentyl, and hexyl groups. In one instance, the alkyl group has 1 to 6 carbon atoms (i.e., C64-C ... 1-6 alkyl).

[0064] As used herein, the term "carbocyclic group" refers to an aromatic or non-aromatic cyclic group containing a carbon atom. Carbocyclic groups can be, for example, monocyclic or polycyclic (i.e., bicyclic, tricyclic). Polycyclic carbocyclic groups can contain fused rings. In one example, a carbocyclic group has 3 to 10 carbon atoms (i.e., C atoms). 3-10 (Carbocyclic group). Examples of monocyclic non-aromatic carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl groups. Aromatic carbocyclic groups include phenyl and naphthyl groups.

[0065] As used herein, the term "heterocyclic group" refers to an aromatic or non-aromatic cyclic group that resembles a carbocyclic group, but in which one to three carbon atoms are replaced by one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. Heterocyclic groups can be, for example, monocyclic or polycyclic (e.g., bicyclic). Polycyclic heterocyclic groups can, for example, contain fused rings. In bicyclic heterocyclic groups, one or more heteroatoms may be present in each ring, or a heteroatom may be present in only one ring. The heteroatom may be N, O, or S. Heterocyclic groups containing a suitable nitrogen atom include corresponding N-oxides. In one example, the heterocyclic group has 3 to 10 atoms (i.e., a 3 to 10-membered heterocyclic group). Examples of monocyclic non-aromatic heterocyclic groups include acridine, aziridine, pyrrolidinyl, imidazoalkyl, pyrazolyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and aziridineheptyl. Examples of bicyclic heterocyclic groups in which one ring is non-aromatic include dihydrobenzofuranyl, indanyl, dihydroindolyl, isodihydroindolyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, and benzozaheptanyl. Examples of monocyclic aromatic heterocyclic groups (also known as monocyclic heteroaryl groups) include furanyl, thiopheneyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiazolyl, pyridinyl, triazolyl, triazinyl, pyridazinyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidine. Examples of bicyclic aromatic heterocyclic groups (also known as bicyclic heteroaryl groups) include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiopheneyl, benzoimidazolyl, naphridinyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridinyl, pyridopyrimidinyl, isoquinolinyl, and benzohydrooxazolyl.

[0066] As used herein, the term "anion" refers to a negatively charged ion. Similarly, as used herein, the term "cation" refers to a positively charged ion.

[0067] This disclosure relates to compounds of Formula 1 and their salts. In the cases of compounds of Formula 1 containing suitable acidic or basic groups, salts can be formed. Suitable salts of compounds of Formula 1 include salts formed with organic or inorganic acids or bases. As used herein, the phrase "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt. Exemplary acid addition salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucuronides, saccharin salts, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthyl) salts (i.e., 1,1'-methylene-bis(2-hydroxy-3-naphthylcarbamate)). Exemplary base addition salts include, but are not limited to, ammonium salts, alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts with organic bases such as dicyclohexylamine, N-methyl-D-glucosamine, morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di-, or tri-lower alkylamines such as ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl-, or dimethyl-propylamine, or mono-, di-, or trihydroxy lower alkylamines such as mono-, di-, or tri-ethanolamine. Pharmaceutically acceptable salts may involve another molecule such as an acetate ion, a succinate ion, or other counterions. Counterions can be any organic or inorganic part that stabilizes the charge on the parent compound. Furthermore, pharmaceutically acceptable salts may have more than one charged atom in their structure. Cases where multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counterions. Therefore, pharmaceutically acceptable salts may have one or more charged atoms and / or one or more counterions. It should also be understood that non-pharmaceutically acceptable salts also fall within the scope of this disclosure, as these may be used as intermediates in the preparation of pharmaceutically acceptable salts or may be used in storage or transportation processes.

[0068] Those skilled in the art of organic and / or medicinal chemistry will understand that many organic compounds can form complexes with solvents in which they react, precipitate, or crystallize. These complexes are called “solvents.” For example, a complex with water is called a “hydrate.” As used herein, the phrase “pharmaceutically acceptable solvate” or “solvent” refers to the association of one or more solvent molecules with a compound of this disclosure. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. It should be understood that this disclosure covers solvated forms of compounds of Formula 1 and their salts, including hydrates.

[0069] Those skilled in the art of organic and / or medicinal chemistry will understand that compounds of Formula 1 and their salts can exist in amorphous or crystalline forms. It should be understood that this disclosure covers all forms and polymorphs of compounds of Formula 1 and their salts.

[0070] It should be understood that, for clarity, certain features described herein in the context of individual embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, the various features described in the context of a single embodiment may also be provided individually or in any sub-combination.

[0071] Throughout this specification, various aspects and components of the invention may be presented in a range format. The inclusion of a range format is for convenience and should not be construed as an inflexible limitation of the scope of the invention. Therefore, a description of a range should be considered to specifically disclose all possible subranges and individual numerical values ​​within that range, unless specifically indicated. For example, a description of a range such as 1 to 5 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 5, 3 to 5, etc., and individual and partial numbers within the listed ranges, such as 1, 2, 3, 4, 5, 5.5, and 6, unless the context requires or implies integers. This applies regardless of the magnitude of the disclosed range. Where specific values ​​are required, these will be specified in the specification.

[0072] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” shall be understood to mean including the stated elements, whole or steps, or groups of elements, whole or steps, but not excluding any other elements, whole or steps, or groups of elements, whole or steps.

[0073] It should be clearly understood that although many prior art publications are cited in this document, such citations do not constitute an admission that any of these publications constitute common knowledge in the field in Australia or any other country.

[0074] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. While similar or equivalent methods and materials to those described herein may be used in the practice or testing of this invention, suitable methods and materials are described below. In case of conflict, this specification (including definitions) shall prevail. Furthermore, materials, methods, and examples are illustrative only and not restrictive.

[0075] Process for preparing Xanamem

[0076] The subject matter of this disclosure is based in part on the surprising discovery of an efficient and scalable process for the preparation of Xanamem. Scheme 1 below provides a non-limiting example of an efficient and scalable process for the preparation of Xanamem and related compounds (compounds of Formula 1).

[0077]

[0078] A general schematic diagram of the process for preparing compounds of formula 1 using scheme 1.

[0079] The above process is further described below for each step of the process. Each step may be provided as its own independent process aspect, example, or instance for the preparation of the intermediate or the compound itself, or as another example or instance of another process aspect or example described herein. For each compound, composition, and / or its process, each intermediate or compound prepared in each step may also be provided as its own independent aspect, example, or instance.

[0080] Synthesis of compound A3

[0081] In some embodiments, compound A3 is prepared by reacting compound A1 with compound A2.

[0082]

[0083] As used herein, the term "LG" refers to a "leaving group" and can be any molecular fragment that detaches a pair of electrons during heterolytic bond cleavage. In some embodiments, the leaving group (LG) is an anion. In some embodiments, the leaving group (LG) is a cation. In some embodiments, the leaving group (LG) is a neutral molecular fragment. Examples of anionic leaving groups (LG) include, but are not limited to, halides. In some embodiments, the leaving group (LG) is a halide. In some embodiments, the leaving group (LG) is a halide and is selected from the group consisting of chlorine (Cl... - ), bromine (Br) - ) and iodine (I - In one instance, LG is chlorine (Cl). -In one instance, LG is bromine (Br). - In one instance, LG is iodine (I). - In some embodiments, LG is a borate ester derivative. Borate ester derivatives can be introduced via the Miyaura borylation reaction. In one example, LG is a borate ester derivative having the following structure:

[0084]

[0085] R 5 It can be a hydrogen or amine protecting group. In some embodiments, R 5 It is hydrogen. In some embodiments, R 5 It is an amine protecting group. As used herein, the term "protecting group" refers to a molecular segment whose functional group is chemically modified to obtain chemoselectivity in a subsequent chemical reaction. Specifically, the term "amine protecting group" refers to a protecting group whose functional group is chemically modified to obtain chemoselectivity in a subsequent chemical reaction. Examples of amine protecting groups include, but are not limited to, urethane, amide, benzyl, benzylene, toluenesulfonyl, and triphenylmethyl protecting groups. In some embodiments, R 5 The protecting group is an amino group selected from the group consisting of: urethane, amide, benzyl, benzylene, toluenesulfonyl, and triphenylmethyl protecting groups. Examples of urethane protecting groups include, but are not limited to, methyl and ethyl groups, 9-fluorenylmethyl, 9-fluorenylmethoxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), benzyl carbamate (Cbz), and p-methoxybenzylcarbonyl (MeOZ) groups. In some embodiments, R 5 It is a tert-butyloxycarbonyl (Boc) protecting group. Examples of amide protecting groups include, but are not limited to, acetyl (Ac), benzamide, trifluoroacetamide, trichloroacetamide, phenylacetamide, pyridine amide, and phthalimide groups. Other examples of amino protecting groups include, but are not limited to, benzoyl, benzyl, benzylene, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), toluenesulfonyl (Ts), trichloroethyl chloroformate (Troc), toluenesulfonyl, triphenylmethyl, and triphenylmethyl groups.

[0086] In some embodiments, R 5 It is the tetrahydropyran (THP) moiety, which is:

[0087]

[0088] In some embodiments, compound A1 is:

[0089]

[0090] X can be a functional group capable of reacting with the leaving group (LG) of compound A1 to form a carbon-carbon single bond. In some embodiments, X is a halide. In some embodiments, X is selected from the group consisting of chlorine, bromine, and iodine. In one example, X is chlorine. In one example, X is bromine. In one example, X is iodine.

[0091] R 6 It can be a hydrogen or ester protecting group. In some embodiments, R 6 It is hydrogen. In some embodiments, R 6 It is an ester protecting group. As used herein, the term "ester protecting group" refers to a molecular fragment in which the ester functional group is chemically modified to obtain chemoselectivity in subsequent chemical reactions. In some embodiments, R 6 It is a straight-chain or branched alkyl chain. In some embodiments, R 6 Is it a straight chain or a branched chain C? 1-6 Alkyl chain. In some embodiments, R 6 It is C 1-6 Alkyl aryl group. In some embodiments, R 6 Choose from the group consisting of: methyl (CH3), ethyl (CH2CH3), propyl (CH2CH2CH3), benzyl, and tert-butyl (C(CH3)3). In one example, R 6 It is a methyl group. In one example, R 6 It is an ethyl group. In one example, R 6 It is a benzyl group.

[0092] In some embodiments, compound A2 is:

[0093]

[0094] Under suitable conditions understood by those skilled in the art, compound A1 reacts with compound A2 to form compound A3. Various carbon-carbon bond formation reaction conditions are known in the art. In some embodiments, compound A1 reacts with compound A2 under Suzuki reaction conditions to yield compound A3. Suzuki reaction conditions may also be referred to as Suzuki-Miyaura reaction conditions, or Suzuki coupling. As those skilled in the art will understand, the Suzuki reaction is a cross-coupling reaction in which the coupling partners are boric acid / ester derivatives and organohalides, thereby catalyzing the reaction by a metal catalyst in the presence of a base.

[0095] The metal catalyst is typically a palladium catalyst, but it can also be a nickel catalyst. In some embodiments, the reaction is catalyzed by a palladium catalyst. In some embodiments, the reaction is catalyzed by a nickel catalyst. In some embodiments, the reaction is catalyzed by a catalyst selected from the group consisting of: Pd(Amphos)₂Cl₂, Pd(PPh₃)₄, Pd₂(dba)₃, Pd(OAc)₂, PdCl₂(dppf), Ni(cod)₂, NiCl₂-glycol dimethyl ether, NiCl₂(PCy₃)₂, NiCl₂(dppp), and NiCl₂(PPh₃)₂. In one example, the metal catalyst is Pd(Amphos)₂Cl₂. In some embodiments, about 0.01 to 0.1 equivalents, about 0.01 to 0.05 equivalents, or about 0.02 to 0.025 equivalents of the metal catalyst are used in the reaction relative to compound A₂.

[0096] This reaction can be further catalyzed by phosphine ligand derivatives. Examples of such ligands include, but are not limited to, BrettPhos, AdBrettPhos, tBuBrettPhos, RuPhos, CPhos, AlPhos, SPhos, XPhos, MePhos, JohnPhos, CyJohnPhos, XantPhos, and DavePhos.

[0097] The base is typically a water-soluble base. In some embodiments, the base is selected from the group consisting of: potassium carbonate (K₂CO₃), potassium tert-butoxide (KOtBu), cesium carbonate (Cs₂CO₃), tripotassium phosphate (K₃PO₄), sodium hydroxide (NaOH), and triethylamine (NEt₃). In one example, the base is potassium carbonate (K₂CO₃). In some embodiments, about 1 to 5 equivalents, about 1 to 2 equivalents, or about 1 to 1.5 equivalents of the base are used in the reaction relative to compound A₂.

[0098] As those skilled in the art will understand, the reaction can be carried out in a variety of suitable solvent systems. In some embodiments, the solvent is an aqueous solvent, such as a mixture comprising water. In some embodiments, the solvent is a two-phase mixture comprising water. In some embodiments, the solvent is a two-phase mixture comprising water and one or more ether solvents. Aqueous solvents or two-phase mixtures may comprise or consist of solvents selected from or composed of water, polar ether solvents, nonpolar ether solvents, or combinations thereof. The use of two-phase mixtures unexpectedly provides additional advantages, such as further reduction of any trace impurities, such as catalysts (e.g., palladium).

[0099] In some embodiments, the reaction is carried out in a polar solvent, such as a polar protic solvent, a polar aprotic solvent, or a combination thereof. In some embodiments, the reaction is carried out in a nonpolar solvent, such as a nonpolar aprotic solvent. Examples of polar protic solvents include, but are not limited to, water, alcohols, and glycols. Examples of alcohols include, but are not limited to, methanol (MeOH), ethanol (EtOH), 1-propanol, isopropanol (2-propanol, iPrOH, or IPA), 1-butanol, 2-butanol, tert-butanol (t-BuOH), 1-pentanol, 3-methyl-1-butanol, and 2-methyl-1-propanol. Examples of glycols include, but are not limited to, ethylene glycol. Examples of polar aprotic solvents include, but are not limited to, halogenated hydrocarbons, ketones, nitriles, esters, carbonates, ethers, sulfoxides, sulfones, amides, nitroalkanes, and pyrrolidines. Examples of ketones include, but are not limited to, acetone, methyl ethyl ketone (MEK), methyl butyl ketone (MBK), methyl isobutyl ketone (MIBK), and methyl isopropyl ketone. Examples of nitriles include, but are not limited to, acetonitrile (MeCN). Examples of esters include, but are not limited to, ethyl formate, methyl acetate (MeOAc), ethyl acetate (EtOAc), propyl acetate, isopropyl acetate (iPAC), n-butyl acetate, and isobutyl acetate. Examples of carbonates include, but are not limited to, dimethyl carbonate (DMC) and propylene carbonate (PC). Examples of polar and nonpolar ethers include, but are not limited to, methyl tert-butyl ether (MTBE), diethyl ether, 1,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol, dimethoxyethane (DME or monoethylene glycol dimethyl ether), 1,1-dimethoxymethane, 2,2-dimethoxypropane, 1,1-diethoxypropane, isopropyl ether, petroleum ether, cyclopentylmethyl ether (CPME), anisole (methoxybenzene), methyltetrahydrofuran (MeTHF), and tetrahydrofuran (THF). Examples of sulfoxides include, but are not limited to, dimethyl sulfoxide (DMSO). Examples of sulfones include, but are not limited to, sulfolane. Examples of amides include, but are not limited to, formamide, N,N-dimethylacetamide, and N,N-dimethylformamide (DMF). Examples of nitroalkanes include, but are not limited to, nitromethane. Examples of pyrrolidines include, but are not limited to, N-methylpyrrolidone (NMP). Examples of polar and nonpolar halogenated hydrocarbons (such as chlorinated hydrocarbons) include, but are not limited to, dichloromethane (DCM), chloroform, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1-dichloroethylene, and 1,2-dichloroethylene. In one example, the reaction is carried out in an ether, such as CPME and MeTHF.

[0100] In some embodiments, the solvent comprises water and one or more polar aprotic ether solvents (such as CPME and MeTHF) or is composed thereof.

[0101] In one example, the reaction conditions used Pd(Amphos)₂Cl₂ as a catalyst, potassium carbonate (K₂CO₃) as a base, and ether / water as a solvent. The ether can be a polar ether according to any example described herein, such as CPME and / or MeTHF.

[0102] Compound A3 is formed through a reaction, wherein R 5 and R 6 As described in this article. In one example, compound A3 is:

[0103]

[0104] In the synthesis of Xanamem and its analogues, compound A3 can be used in successive synthetic steps without purification (i.e., obtained and reacted as a crude product), or it can be isolated and / or purified first. Suitable isolation and / or purification techniques will be understood by those skilled in the art.

[0105] Synthesis of compound A4

[0106] In some embodiments, compound A4 is transmitted via R 5 It is prepared by deprotection of compound A3.

[0107]

[0108] R 5 and R 6 As described herein, and as those skilled in the art will understand, compound A3 reacts under suitable reaction conditions to form compound A4. 5 Deprotection yields the free secondary amine (-N(H)-) of compound A4.

[0109] In some embodiments, R 5 yes:

[0110]

[0111] And acidic reaction conditions are required to react R. 5 The attached amine is deprotected. In one example, the acidic reaction conditions include hydrochloric acid (HCl). An excess of hydrochloric acid may be required. In some embodiments, at least about 1.5, 2, 3, 4, or 5 equivalents of hydrochloric acid (HCl) relative to compound A3 are used in the reaction. In one example, about 4 equivalents of hydrochloric acid (HCl) relative to compound A3 are used in the reaction.

[0112] Those skilled in the art will understand that a variety of suitable solvents can be used for this reaction. Any one or more of the solvents described above for the preparation of compound A3 can be used for the reaction to prepare compound A4. In one example, the solvent is a biphasic solvent according to any example described herein. In one example, the solvent includes esters and / or ethers. In another example, the solvent includes ethers such as cyclopentylmethyl ether (CPME) and 2-methyltetrahydrofuran (2-MeTHF).

[0113] Those skilled in the art will understand that heat may need to be applied to promote the reaction. In some embodiments, the reaction is heated to about 30°C to 80°C, about 40°C to 70°C, or about 45°C to 55°C. In one example, the reaction is heated to about 50°C.

[0114] Purification can be provided by recrystallization, which in some instances can be achieved using solvents selected from esters and / or ethers.

[0115] Synthesis of compound A5

[0116] In some embodiments, compound A5 is obtained by hydrolyzing R from compound A4. 6 To prepare.

[0117]

[0118] R 6 As described herein, and as those skilled in the art will understand, compound A4 reacts under suitable reaction conditions to hydrolyze R. 6 This yields compound A5. In some embodiments, the reaction is an ester hydrolysis reaction. 6 Hydrolysis of the group yields a carboxylic acid group on compound A5.

[0119] Hydrolysis can be acid-catalyzed or base-catalyzed. In some embodiments, the hydrolysis is acid-catalyzed. In some embodiments, the hydrolysis is base-catalyzed. Examples of suitable acids include, but are not limited to, hydrochloric acid (HCl). Examples of suitable bases include, but are not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), and lithium hydroxide (LiOH). In some embodiments, the hydrolysis is catalyzed by a lithium hydroxide (LiOH) base. In one example, the base is in the form of lithium hydroxide monohydrate (LiOH·H₂O).

[0120] Those skilled in the art will understand that a variety of suitable solvents can be used for this reaction. Any one or more of the solvents described above for the preparation of compound A3 or compound A4 can be used for the reaction to prepare compound A5. In one example, the solvent is a biphasic solvent according to any example described herein. In one example, the solvent includes esters and / or ethers. In another example, the solvent includes ethers such as cyclopentylmethyl ether (CPME) and 2-methyltetrahydrofuran (2-MeTHF).

[0121] Those skilled in the art will understand that heat may need to be applied to promote the reaction. In some embodiments, the reaction is heated to about 30°C to 70°C, about 30°C to 50°C, or about 30°C to 40°C. In one example, the reaction is heated to about 35°C.

[0122] Synthesis of compound A8

[0123] In some embodiments, compound A8 is prepared by reacting compound A6 with compound A7.

[0124]

[0125] In some embodiments, a process is provided for preparing a protected amine compound A8 of formula 4.

[0126]

[0127] The process includes the nortropinone compound A7 of formula 5.

[0128]

[0129] Grignard reaction with halo compound A6 of formula 6.

[0130] XR 1

[0131] Formula 6

[0132] In some embodiments, R 1 It is a carbocyclic or heterocyclic group. In one example, R 1 It is a carbocyclic group. In one example, R 1 It is a heterocyclic group. In some embodiments, each carbocyclic or heterocyclic group is a monocyclic or bicyclic group. In one example, the carbocyclic group is a monocyclic group. In one example, the carbocyclic group is a bicyclic group. In one example, the heterocyclic group is a monocyclic group. In one example, the heterocyclic group is a bicyclic group. In some embodiments, each carbocyclic and heterocyclic group is a monocyclic or bicyclic group, which is either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogen, -OH, -C. 1-6 Alkyl, -OC1-6 Alkyl, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -CN, -NR 3 R 4 -COR 3 -CO2R 3 In some embodiments, each carbocyclic and heterocyclic group is a respective unsubstituted monocyclic or bicyclic group. In some embodiments, each carbocyclic and heterocyclic group is a monocyclic or bicyclic group, each of which is substituted by one or more substituents selected from the group consisting of: halogen, -OH, -C. 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -CN, -NR 3 R 4 -COR 3 -CO2R 3 .

[0133] In some embodiments, R 1 It is a monocyclic or bicyclic heteroaryl group, wherein each monocyclic or bicyclic heteroaryl group is either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogen, -OH, -C. 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Haloalkyl. In some embodiments, R 1 It is a pyrimidine that is either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogens, -OH, -C. 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups, -OC 1-6 Haloalkyl. In some embodiments, R 1 It is an unsubstituted pyrimidine.

[0134] In some embodiments, R 2 It is an amine protecting group as described in this article. In one example, R 2The protecting group is selected from the group consisting of: urethane esters (e.g., tert-butylcarbamate (BOC), tert-butyl carbamate (BOC), 9-fluorenylmethyl carbamate (FMOC), benzyl carbamate (CBZ), amides (e.g., acetamide Ac, trifluoroacetamide, phthalimide), benzyl, benzylene, tosyl (e.g., toluene sulphonyl), and trimethylol (e.g., triphenylmethyl). In one example, R 2 It is a tert-butyloxycarbonyl (BOC) group.

[0135] In some embodiments, R 3 and R 4 Choose independently the following groups: hydrogen and C 1-6 Alkyl group. In one example, R 3 It is hydrogen. In one instance, R 3 It is C 1-6 Alkyl group. In one example, R 4 It is hydrogen. In one instance, R 4 It is C 1-6 alkyl.

[0136] In some embodiments, X is a halogen. In some embodiments, X is selected from the group consisting of chlorine, bromine, and iodine. In some embodiments, X is chlorine. In some embodiments, X is bromine. In some embodiments, X is iodine.

[0137] In some embodiments, the Grignard reaction includes the following steps: i) a halogen-metal exchange reaction involving a Grignard reagent and ii) a coupling reaction involving LaCl3.

[0138] In some embodiments, the Grignard reagent is selected from the group consisting of i-PrMgBr, i-PrMgCl·LiCl (“Turbo Grignard” reagent), and bis-BuMgCl·LiCl. In one instance, the Grignard reagent is i-PrMgBr.

[0139] In some embodiments, the halogen-metal exchange reaction advantageously eliminates the need for low-temperature cooling conditions. In some embodiments, the halogen-metal exchange reaction comprising i-PrMgBr is carried out at about -40°C to 20°C, about -30°C to 10°C, or about -20°C to 0°C. In one example, the halogen-metal exchange reaction comprising i-PrMgBr is carried out at about -20°C to 0°C. In one example, the halogen-metal exchange reaction comprising i-PrMgBr is carried out at about -20°C to -15°C. In some embodiments, i-PrMgBr is added to the reaction mixture at about -20°C to -15°C.

[0140] In some embodiments, a halogen-metal exchange reaction involving i-PrMgBr is carried out using about 1 to 3 equivalents of i-PrMgBr, about 1 to 2 equivalents of i-PrMgBr, or about 1.1 to 1.5 equivalents of i-PrMgBr. In some instances, a halogen-metal exchange reaction involving i-PrMgBr is carried out using at least about 1, 1.1, 1.2, 1.3, 1.4, or 1.5 equivalents of i-PrMgBr. In some instances, a halogen-metal exchange reaction involving i-PrMgBr is carried out using less than about 3, 2.5, 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, or 1.2 equivalents of i-PrMgBr. In some instances, a halogen-metal exchange reaction involving i-PrMgBr is carried out using an equivalent of i-PrMgBr in amounts between any two of the aforementioned upper and / or lower limits.

[0141] In some embodiments, after complete addition of i-PrMgBr, the reaction mixture is stirred for t minutes, and then the mixture is heated to approximately 0°C. In some embodiments, t is approximately 5 to approximately 60 minutes, approximately 10 to 45 minutes, or approximately 20 to 40 minutes. In some embodiments, t is approximately 5 minutes, approximately 10 minutes, approximately 20 minutes, approximately 30 minutes, approximately 45 minutes, or approximately 60 minutes. In one example, t is approximately 30 minutes. That is, in one example, the duration of the halogen-metal exchange reaction is approximately 30 minutes.

[0142] Once the reaction mixture is heated to approximately 0°C, a coupling reaction comprising LaCl3 is carried out. In some embodiments, the coupling reaction occurs at approximately 0°C, approximately 1°C, approximately 2°C, approximately 3°C, approximately 4°C, or approximately 5°C. In some embodiments, the coupling reaction occurs at approximately 0°C to 20°C, approximately 0°C to 10°C, or approximately 0°C to 5°C. In one example, the coupling reaction occurs at approximately 0°C to 5°C.

[0143] In some embodiments, the amount of LaCl3 used in the reaction is about 1 to 3 equivalents, about 1.1 to 2 equivalents, about 1.2 to 1.8 equivalents, or about 1.4 to 1.6 equivalents. In one example, the amount of LaCl3 used in the reaction is about 1.5 equivalents.

[0144] In one instance, LaCl3 is LaCl3·2LiCl.

[0145] Those skilled in the art will understand that a variety of suitable solvents can be used for this reaction. Any one or more of the solvents described above for the preparation of compounds A3, A4, or A5 can be used for the reaction to prepare compound A8. In one example, the solvent includes esters and / or ethers. In another example, the solvent includes ethers such as cyclopentylmethyl ether (CPME) and 2-methyltetrahydrofuran (2-MeTHF). The solvent can be present in the reaction in any suitable amount to allow the reaction to proceed. In some examples, the solvent can be anhydrous. For example, the amount of water in the solvent can be less than about (in ppm) 500, 400, 300, 200, 100, 75, 50, 25, 10, 5, or 1.

[0146] In some embodiments, Grignard quenching of the reaction can be monitored before complete conversion to compound A8, such as when an amount of Grignard reagent is added to achieve a conversion of at least 50%, 75%, 90%, or 95%. The reaction mixture can be quenched by pouring it onto an acid (such as an aqueous solution containing citric acid).

[0147] In some embodiments, compound A8 of formula 4 is a compound of formula 4a.

[0148]

[0149]

[0150] Furthermore, the process includes using compound A7 of formula 5a.

[0151]

[0152] It reacts with compound A6 of formula 6a.

[0153]

[0154] In the synthesis of Xanamem and its analogues, compound A8 of Formula 4 may or may not be purified before proceeding to subsequent synthetic steps or reactions. In one example, compound A8 of Formula 4 is purified. Conventional purification by column chromatography is suitable for separating compound A8 of Formula 4 in good purity. In one example, compound A8 is purified by column chromatography. In another example, compound A8 is not purified before proceeding to subsequent synthetic reactions. That is, the crude material is reacted directly in the synthesis of compound A9 of Formula 3. This carrying of the crude material is referred to in the art as “cascading” the crude material into subsequent chemical reactions.

[0155] Synthesis of compound A9

[0156] In some embodiments, compound A9 causes R to... 2The preparation is carried out by deprotecting compound A8 and optionally forming a salt of compound A9. The salt can be formed as a single salt or a double salt, for example as follows:

[0157]

[0158] R 1 and R 2 It may be provided according to any embodiment or instance thereof as described herein.

[0159] In some embodiments, a process is provided for preparing a nitrogen-containing bicyclic compound A9 of formula 3 or a salt thereof.

[0160]

[0161] The process includes removing the amine protecting group from compound A8 of formula 4, and optionally salting it.

[0162] Compound A8 can be used as a crude product from its previous reaction as described, for example, directly condensed into a starting material in compound A9 of formula 3.

[0163] It should be understood that, depending on the nature of the protecting group, the amine protecting group can be removed by any suitable method known in the art. In some embodiments, the amine protecting group is removed under acidic conditions, such as with an acid including hydrochloric acid, acetic acid, or sulfonic acid. In one example, the protecting group is a BOC protecting group, and it is removed under acidic conditions. In another example, the protecting group is a BOC protecting group, and it is removed under aqueous hydrochloric acid (HCl) solution conditions. In another example, the protecting group is a BOC protecting group, and it is removed under trifluoroacetic acid (TFA) conditions. In one example, the acidic conditions include sulfonic acid. The sulfonic acid can be an optionally substituted alkyl or aromatic sulfonic acid, such as p-toluenesuphonic acid (also known as tosylic acid TsOH). In one example, the protecting group is a BOC protecting group, and it is removed under sulfonic acid conditions, such as with p-toluenesuphonic acid (TsOH). The use of sulfonic acid can provide additional advantages, such as rapid precipitation of the reaction product to form mono- or ditoluenesulfonates.

[0164] Compound A9 of Formula 3 may optionally undergo salt formation. As used herein, the term "salt formation" refers to the conversion of a chemical into its salt form. In some embodiments, compound A9 of Formula 3 reacts in its salt form in subsequent chemical reactions. Conversion of compound A9 of Formula 3 into its salt can produce a more stable intermediate (e.g., less prone to degradation). Those skilled in the art will understand that many suitable salts can be utilized. In one example, a sulfonic acid (such as p-toluenesulfonic acid (p-TSA or TsOH)) is used to prepare a salt to form a toluenesulfonate of compound A9 of Formula 3. Sulfonic acids have been found to effectively provide the dual function of deprotection of amine protecting groups and salt formation of the resulting deprotected compound. Salt formation can provide a single or double salt, such as a ditoluenesulfonate (e.g., pTSA:nortropinone in the range of 1:1 to 2:1). Salt formation has been found to provide additional advantages in purification, where rapid crystallization and precipitation from solution provides a stable salt compound that can be used directly (e.g., without further purification) in subsequent amide coupling reactions, particularly when prepared as a double salt.

[0165] Those skilled in the art will understand that a variety of suitable solvents can be used for this reaction. Any one or more of the solvents described above for the preparation of compounds A3, A4, A5, or A8 can be used for the reaction to prepare compound A9. In one example, the solvent is selected from the group consisting of water, alcohols, esters, ethers, or combinations thereof. The solvent can be an aqueous solvent. The solvent can include an acid according to any of the examples described above. In one example, the solvent includes ethers such as cyclopentylmethyl ether (CPME) and 2-methyltetrahydrofuran (2-MeTHF). In another example, the solvent includes alcohols such as isopropanol (IPA). The solvent can be present in the reaction in any suitable amount to allow the reaction to proceed. The acid can be present in the reaction in an amount of about 0.1 to 2, 0.2 to 1, or 0.3 to 0.7 mol / L. The acid may be present in a molar equivalent amount of compound A9 of formula 3 in a reaction at least 1, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5 or 5, and / or in an amount less than about 5.5, 5.0, 4.5, 4.0, 3.5, 3.0, 2.5, 2.0 or 1.5, or in a range provided by any two of these upper and / or lower limits, such as 2 to 5 or 2.5 to 4.5.

[0166] Synthesis of Compound 1

[0167] In some embodiments, heterocyclic ketone compound 1 is prepared by an amide coupling reaction between carboxylic acid compound A5 or a salt thereof and a aziridine compound A9 or a salt thereof.

[0168] In some embodiments, a process for preparing heterocyclic ketone compound 1 of formula 1 is provided.

[0169]

[0170] Where R 1 It is any embodiment or instance thereof as defined herein;

[0171] The process involves using a carboxylic acid compound of formula 2 or a salt thereof.

[0172]

[0173] It reacts with nitrogen-containing bicyclic compounds of formula 3, as prepared herein, or their salts.

[0174]

[0175] In some embodiments, carboxylic acid compound A5 is provided as a salt, such as a halide salt (e.g., a chloride).

[0176] In some embodiments, the azabicyclic compound A9 is provided as a salt, such as a monosalt, a disalt, or a combination thereof, as follows:

[0177]

[0178]

[0179] In some instances, the single or double salts of the azabicyclic compound A9 are sulfonates, such as the toluenesulfonate described herein according to any of its examples.

[0180] In some instances, compound A9 of formula 3 is a disulfonate of formula 3a:

[0181]

[0182] R is selected from alkyl, aryl, and alkylaryl, each of which may be optionally substituted.

[0183] Examples of sulfonates include mesylate, trifluoromethanesulfonate, ethanesulfonate, p-toluenesulfonate, benzenesulfonate, closilate, camphorsulfonate, p-iodobenzenesulfonate, or nitrobenzenesulfonate. In one instance, the sulfonate is toluenesulfonate.

[0184] In some embodiments, an equimolar or excess molar equivalent of a carboxylic acid compound A5 or a salt thereof is used relative to the azabicyclic compound A9 or a salt thereof. For example, the molar equivalent of the carboxylic acid compound A5 or a salt thereof relative to the azabicyclic compound A9 or a salt thereof is at least 1, 1.05, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, or 1.5.

[0185] In some embodiments, a process for preparing heterocyclic ketone compounds of formula 1 is provided:

[0186]

[0187] The process involves using a carboxylic acid compound of formula 2 or a salt thereof.

[0188]

[0189]

[0190] It reacts with an amine compound of Formula 3 or a salt thereof in the presence of at least one coupling agent selected from oxime coupling agents and carbodiimide coupling agents.

[0191]

[0192] R in Equation 3 1 The groups may be selected from carbocyclic or heterocyclic groups, wherein each carbocyclic or heterocyclic group is a monocyclic or bicyclic group, and each monocyclic or bicyclic group is either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogens, -OH, -C. 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -CN, -NR 3 R 4 -COR 3 -CO2R 3 And each R 3 and R 4 Choose independently the following groups: hydrogen and C 1-6 Alkyl. According to any embodiment or example thereof described herein, R 5 It can be a hydrogen or amine protecting group.

[0193] In some embodiments, R 1 It is a carbocyclic or heterocyclic group. In some embodiments, each carbocyclic or heterocyclic group is a monocyclic or bicyclic group. In one example, the carbocyclic group is a monocyclic group. In one example, the carbocyclic group is a bicyclic group. In one example, the heterocyclic group is a monocyclic group. In one example, the heterocyclic group is a bicyclic group. In some embodiments, each carbocyclic and heterocyclic group is a monocyclic or bicyclic group, each of which is unsubstituted or substituted by one or more substituents selected from the group consisting of: halogen, -OH, -C. 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -CN, -NR 3 R 4 -COR 3 -CO2R 3 In some embodiments, each carbocyclic and heterocyclic group is a respective unsubstituted monocyclic or bicyclic group. In some embodiments, each carbocyclic and heterocyclic group is a monocyclic or bicyclic group, each of which is substituted by one or more substituents selected from the group consisting of: halogen, -OH, -C. 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -CN, -NR 3 R 4 -COR 3 -CO2R 3 .

[0194] In some embodiments, R 1 It is a monocyclic or bicyclic heteroaryl group, wherein each monocyclic or bicyclic heteroaryl group is either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogen, -OH, -C. 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Haloalkyl, -OC 1-6Haloalkyl. In some embodiments, R 1 It is a pyrimidine that is either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogens, -OH, -C. 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups, -OC 1-6 Haloalkyl. In some embodiments, R 1 It is an unsubstituted pyrimidine.

[0195] As used herein, the term "coupling agent" refers to a compound that can form a chemical bond between two chemical moieties. In one example, the coupling agent is an "amide coupling agent," which provides a chemical bond between the carboxylic acid moiety and the amine moiety, thereby forming an amide bond. The coupling agent may optionally be accompanied by one or more additives or one or more base compounds to promote the coupling reaction.

[0196] In some embodiments, the amide coupling agent is at least one coupling agent selected from the group consisting of carbodiimide coupling agents and oxime coupling agents. In some embodiments, the amide coupling agent is a carbodiimide coupling agent. In some embodiments, the carbodiimide coupling agent is selected from the group consisting of DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), EDAC.HCl (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.HCl), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), and combinations thereof. In one example, the carbodiimide coupling agent is EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide). In one example, the carbodiimide coupling agent is DIC (diisopropylcarbodiimide).

[0197] In some embodiments, the coupling agent is an oxime coupling agent. In some embodiments, the oxime coupling agent is selected from the group consisting of: OxymaPure (2-cyano-2-(hydroxyimino)acetate), K-Oxyma (potassium 2-cyano-2-(hydroxyimino)acetate), COMU (1-[(1-(cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-methylene)]methylammonium hexafluorophosphate), PyOxym-M, PyOxim (O-[(cyano(ethoxycarbonyl)-methylene)amino]oxytripyrrolidinylphosphine hexafluorophosphate), HONM (isonitrosoMissell acid), Ocyma-B, Oxyma-T, Amox, HMMU, Fmoc-Amox, and combinations thereof. In one example, the oxime coupling agent is OxymaPure (2-cyano-2-(hydroxyimino)acetate).

[0198] In some embodiments, an amide coupling agent is used in the reaction in an amount of at least 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, or 3.5 equivalents relative to compound A5. In some embodiments, an amide coupling agent is used in the reaction in an amount of less than 5, 4.5, 4, 3.5, 3, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2, 1.9, 1.8, 1.6, or 1.5 equivalents relative to compound A5 or Formula 2. The equivalent amount of the amide coupling agent used in the reaction relative to compound A5 or Formula 2 can be provided within a range between any two of these upper and / or lower limits, for example, between about 1 and 3, 1.2 and 2, or 1.3 and 1.7. It should be understood that, in one instance, the amide coupling agent is a carbodiimide coupling agent (e.g., DIC), and according to any instance thereof as described herein, the process may optionally also include one or more additives (e.g., HOPO and / or DIPEA).

[0199] Additives can be used with amide coupling reagents. Additives can be any reagent that promotes / catalyzes the amide coupling reaction. In one example, the additive is an N-oxide reagent, such as 2-hydroxypyridine-N-oxide (HOPO). It should be understood that N-oxide reagents have N... + -O - The bond, for example, optionally substituted pyridine N-oxides, such as HOPO. For example, the reagent may include a carbodiimide coupling agent and optional additives, or consist of a carbodiimide coupling agent and optional additives.

[0200] In some embodiments, an additive (e.g., HOPO) is used in the reaction at an amount of at least 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, or 3.5 equivalents of compound A5. In some embodiments, an additive is used in the reaction at an amount of less than 5, 4.5, 4, 3.5, 3, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2, 1.9, 1.8, 1.6, or 1.5 equivalents of compound A5. The amount of additive used in the reaction relative to compound A5 can be provided within a range between any two of these upper and / or lower limits, for example, between about 1 and 4, 1.1 and 3, or 1.2 and 2.

[0201] In some embodiments, the base is present in an amount less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, or 0.1 equivalents relative to the molar amount of compound A5. In some embodiments, the base is present in an amount greater than about 0.1, 0.3, 0.5, 0.7, 1, 1.5, 2, 2.5, 3, or 3.5 equivalents relative to the molar amount of compound A5. In some embodiments, the base is present in a range provided by any two of the above-described upper and / or lower limits of the additive, such as 1 to 7, 2 to 6, or 2.5 to 4.5.

[0202] In another example, the reagent may include a carbodiimide coupling agent and optionally one or more additives, or may consist of a carbodiimide coupling agent and optionally one or more additives. In one example, the additive is an N-oxide agent, such as 2-hydroxypyridine-N-oxide (HOPO). In one example, the additive is a base, such as an amine (e.g., DIPEA). In one example, the reagent includes or consists of a carbodiimide coupling agent (e.g., diisopropylcarbodiimide), an N-oxide additive (e.g., 2-hydroxypyridine-N-oxide), and a base additive (e.g., DIPEA).

[0203] In some embodiments, the coupling agent is selected from at least one oxime coupling agent and at least one carbodiimide coupling agent, each of which may be provided according to any of the embodiments or examples thereof as described herein. In one example, the coupling agent is selected from the group consisting of: OxymaPure (2-cyano-2-(hydroxyimino)acetate), EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), and 2-hydroxypyridine-N-oxide (HOPO). It should be understood that one or more optional additives may also be used according to any of the examples described herein.

[0204] It has been surprisingly found that the use of at least one carbodiimide coupling agent enables amide coupling reactions to occur without any significant formation of any undesirable byproducts (e.g., tetramethylurea, TMU). In some embodiments, the process involves a specific combination of at least one carbodiimide coupling agent, optionally at least one additive (e.g., N-oxide, such as HOPO), and optionally at least one base (e.g., DIPEA), wherein the presence of undesirable byproducts (e.g., tetramethylurea, TMU) is significantly reduced or avoided. In some embodiments, the process involves the optional use of DIC with HOPO and / or DIPEA.

[0205] Those skilled in the art will understand that a variety of suitable solvents can be used for this reaction. Any one or more of the solvents described above for the preparation of compounds A3, A4, A5, A8, or A9 can be used for the reaction to prepare compounds of formula 1. In one example, the solvent is selected from the group consisting of water, alcohols, esters, ethers, nitriles, or combinations thereof. The solvent can be an aqueous solvent. In one example, the solvent includes ethers such as cyclopentylmethyl ether (CPME) and 2-methyltetrahydrofuran (2-MeTHF). In another example, the solvent includes alcohols such as isopropanol (IPA). In another example, the solvent includes nitriles such as acetonitrile. In yet another example, the solvent includes acetonitrile. The solvent can be present in the reaction in any suitable amount to allow the reaction to proceed. In one example, the solvent in an aqueous solvent includes water and one or more organic solvents (e.g., nitrile solvents such as acetonitrile) as described herein in any example.

[0206] In some embodiments, the reaction includes an organic solvent, which is a polar protic or aprotic solvent. Examples of polar aprotic solvents include, but are not limited to, acetonitrile (ACN), dimethylformamide (DMF), dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate (EtOAc), dimethyl sulfoxide (DMSO), acetone, hexamethylphosphoric triamine (HMPT), dimethyl ketone, and methyl ethyl ketone. In one example, the organic solvent is a polar aprotic solvent, namely acetonitrile (ACN). In another example, the organic solvent is Me-THF.

[0207] In some embodiments, the reaction is provided in an aqueous solvent, such as water and a water-miscible solvent (such as acetonitrile). Examples of suitable water-miscible solvents include alcohols, ethers, and nitriles. In one example, the aqueous solvent is a mixture of water and acetonitrile, such as in a ratio of about 1:3 to about 3:1 or about 1:1.

[0208] In some embodiments, after the reaction is substantially complete, an additional solvent is added to the reaction mixture to promote the precipitation of compounds of Formula 1, such as alcohols (e.g., ethanol).

[0209] In some instances, the reaction mixture comprising compound A5, a carbodiimide coupling agent, and an additive selected from HOPO and DIPEA is stirred for about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, or about 6 hours prior to the addition of compound A9. In some embodiments, the reaction mixture is heated to a temperature of about 30 to 90°C, 40 to 80°C, or 50 to 70°C. Examples of solvents include aqueous solvents, such as water and acetonitrile (e.g., about 1:1).

[0210] In some embodiments, compound A9 of Formula 3 is a secondary amine salt according to any of the examples described herein. In one example, compound A9 of Formula 3 is a secondary amine sulfonate, such as a p-toluenesulfonic acid (p-TSA) salt.

[0211] In some embodiments, a process is provided in which the compound of formula 1 is a compound of formula 1a:

[0212]

[0213] The process involves using a carboxylic acid compound of formula 2a or a salt thereof.

[0214]

[0215] The sulfonic acid (e.g., p-TSA) salt compound of formula 3a reacts with a carbodiimide coupling agent and optionally one or more additives.

[0216]

[0217] R is selected from alkyl, aryl, and alkylaryl, each of which may be optionally substituted.

[0218] In some embodiments, the carboxylic acid compound of Formula 2 is prepared by saponification of the ester compound of Formula 7 with a base.

[0219]

[0220] Where R 5 It is a hydrogen or amine protecting group and R 6 It is an ester protecting group, as described in this article.

[0221] It should be understood that R 6 The compound of formula 7 can be cleaved by base-catalyzed hydrolysis. In some embodiments, the base is selected from the group consisting of sodium hydroxide (NaOH), lithium hydroxide (LiOH), and potassium hydroxide (KOH). In one instance, the base is lithium hydroxide (LiOH). Alternatively, it should be understood that R 6 The compound of formula 7 can be cleaved by acid-catalyzed hydrolysis.

[0222] In some embodiments, R in the compound of formula 7 is removed before preparing the carboxylic acid compound of formula 2. 5 Amine protecting group.

[0223] Scale up

[0224] The process described herein allows for the scalable synthesis and manufacture of compounds of Formula 1. When compared with the process described in International Patent Application WO2011135276, the described process provides an increased overall yield of Compound 1, scalable reaction conditions, and eliminates the generation of potentially toxic byproducts.

[0225] In some embodiments, the process is carried out on a small scale (e.g., from 20 mg to 1 gram), which is suitable for research and development purposes. However, in some other embodiments, the process is carried out on a large scale (e.g., greater than 1 gram, particularly greater than 50 grams), which is suitable for manufacturing purposes. The synthesis or one or more steps thereof may occur in a batch process.

[0226] In some embodiments, the process for preparing the compound of formula 4 occurs with a starting material amount of at least 1 g, at least 10 g, at least 50 g, at least 100 g, at least 500 g, at least 1 kg, or at least 10 kg of a compound of formula 5 or a compound of formula 6. That is, the process for preparing the compound of formula 4 occurs on a scale of at least 1 g, at least 10 g, at least 50 g, at least 100 g, at least 500 g, at least 1 kg, or at least 10 kg. In one example, the process for preparing compound A8 occurs with a starting material amount of at least 1 g, at least 10 g, at least 50 g, at least 100 g, at least 500 g, at least 1 kg, or at least 10 kg of a compound of formula A7 or a compound of formula A6. That is, the process for preparing compound A8 occurs on a scale of at least 1 g, at least 10 g, at least 50 g, at least 100 g, at least 500 g, at least 1 kg, or at least 10 kg.

[0227] In some embodiments, as measured by HPLC, the process provides a conversion of at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, or at least 80% of the compound of Formula 5 to the compound of Formula 4. It should be understood that the conversion of the reaction can be measured at any point during the reaction by any suitable technique, such as TLC or HPLC. Typically, aliquots of the reaction mixture are subjected to HPLC, where relevant component peaks are identified and integrated relative to each other. In some embodiments, the Grignard reaction as described herein provides a conversion of at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, or at least 80% of the compound of Formula 5 to the compound of Formula 4, as measured by HPLC.

[0228] As used herein and as understood by those skilled in the art, the term “yield” will be understood to mean the amount of crude or purified compound obtained from a reaction, measured as a percentage of the theoretical yield of the compound in the reaction.

[0229] In some embodiments, the process provides at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% yield of the compound of Formula 4, as determined based on the starting materials of the compounds of Formula 5 and Formula 6. That is, in some embodiments, the Grignard reaction as described herein provides at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% yield of the compound of Formula 4. In some embodiments, the Grignard reaction as described herein provides about 20% to 80%, about 30% to 70%, or about 50% to 70% yield of the compound of Formula 4. In one example, the Grignard reaction as described herein provides at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% yield of compound A8. In some embodiments, the Grignard reaction as described herein provides about 20% to 80%, about 30% to 70%, or about 50% to 70% yield of compound A8.

[0230] In some embodiments, the process described herein provides compounds of Formula 4 with high purity. As will be understood by those skilled in the art, purity is a measure independent of yield. That is, a compound can have high purity despite a low yield. As used herein, the term "high purity" means that at least 80% of the final material obtained is the desired compound (e.g., Formula 4), which can be measured, for example, by HPLC methods. The purity of a compound can be measured based on the crude reaction mixture, the product separated from the reaction mixture (i.e., after post-reaction processing), or the purified product (i.e., after chromatography, recrystallization, etc.).

[0231] In some embodiments, the Grignard reaction as described herein provides a compound of formula 4 with a purity of at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, or 95%. In one example, the Grignard reaction as described herein provides a compound of formula 4 in a crude reaction mixture with a purity of at least 30%, 40%, or 50%. In one example, the Grignard reaction as described herein provides a compound of formula 4 in a product separated from the reaction mixture (i.e., after post-reaction treatment) with a purity of at least 50%. In one example, the Grignard reaction as described herein provides a compound of formula 4 with a purity of at least 95% after purification. In one example, the Grignard reaction as described herein provides a compound of formula 4 with a purity of at least 95% after recrystallization. In one example, the Grignard reaction as described herein provides a compound of formula 4 with a purity of at least 95% after column chromatography.

[0232] In some embodiments, a process for preparing a nitrogen-containing bicyclic compound of formula 4 is provided.

[0233]

[0234] The process includes the nortropinone compound of formula 5.

[0235]

[0236] Grignard reaction with the halo compounds of Formula 6,

[0237] XR 1

[0238] Formula 6

[0239] Where R 1 Selected from carbocyclic or heterocyclic groups, wherein each carbocyclic and heterocyclic group is a monocyclic or bicyclic group, and each monocyclic or bicyclic group is either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogens, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -CN, -NR 3 R 4 -COR 3 -CO2R 3 And each R 3 and R 4 Independently select from the following groups: hydrogen and -C 1-6 Alkyl; R 2 X is an amine protecting group; and X is a halogen; and the yield of the compound of formula 4 is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%.

[0240] In some embodiments, the process for preparing the compound of formula 1 occurs using a compound of formula 2 or formula 3 with a starting material amount of at least 1 g, at least 10 g, at least 50 g, at least 100 g, at least 500 g, at least 1 kg, or at least 10 kg. That is, the process for preparing the compound of formula 1 occurs on a scale of at least 1 g, at least 10 g, at least 50 g, at least 100 g, at least 500 g, at least 1 kg, or at least 10 kg. In one example, the process for preparing compound 1 occurs using compound A5 or compound A9 with a starting material amount of at least 1 g, at least 10 g, at least 50 g, at least 100 g, at least 500 g, at least 1 kg, or at least 10 kg. That is, the process for preparing compound 1 occurs on a scale of at least 1 g, at least 10 g, at least 50 g, at least 100 g, at least 500 g, at least 1 kg, or at least 10 kg.

[0241] In some embodiments, as measured by HPLC, the process provides a conversion of at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, or at least 80% of the compound of Formula 2 to the compound of Formula 1. In some embodiments, as measured by HPLC, the process provides a conversion of at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, or at least 80% of the compound of Formula 3 to the compound of Formula 1. In some embodiments, the amide coupling reaction as described herein provides a conversion of at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, or at least 80% of the compound of Formula 2 to the compound of Formula 1, as measured by HPLC. In some embodiments, the amide coupling reaction as described herein provides a conversion of at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, or at least 80% of the compound of Formula 3 to the compound of Formula 1, as measured by HPLC.

[0242] In some embodiments, the process provides at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% yield of the compound of Formula 1, as determined according to the starting materials of the compounds of Formula 2 and Formula 3. That is, in some embodiments, the amide coupling reaction as described herein provides at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% yield of the compound of Formula 1. In some embodiments, the amide coupling reaction as described herein provides about 20% to 80%, about 30% to 70%, or about 50% to 70% yield of the compound of Formula 1. In one example, the amide coupling reaction as described herein provides at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80% yield of compound 1. In some embodiments, the amide coupling reaction as described herein provides about 20% to 80%, about 30% to 70%, or about 50% to 70% yield of compound 1.

[0243] In some embodiments, the process described herein provides compounds of Formula 1 with high purity. In some embodiments, the amide coupling reaction described herein provides compounds of Formula 1 with a purity of at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%. In one example, the amide coupling reaction described herein provides a compound of Formula 1 in a crude reaction mixture with a purity of at least 80%. In one example, the amide coupling reaction described herein provides a compound of Formula 1 in a product separated from the reaction mixture (i.e., after post-reaction treatment) with a purity of at least 80%. In one example, the amide coupling reaction described herein provides a compound of Formula 1 with a purity of at least 95% after purification. In one example, the amide coupling reaction described herein provides a compound of Formula 1 with a purity of at least 95% after recrystallization. In one example, the amide coupling reaction described herein provides a compound of Formula 1 with a purity of at least 95% after column chromatography.

[0244] In some embodiments, a process for preparing heterocyclic ketone compounds of formula 1 is provided.

[0245]

[0246] The process involves using a carboxylic acid compound of formula 2 or a salt thereof.

[0247]

[0248] It reacts with the amine bicyclic compound of Formula 3 or its salt in the presence of at least one coupling agent.

[0249]

[0250] Where R 1 Selected from carbocyclic or heterocyclic groups, wherein each carbocyclic and heterocyclic group is a monocyclic or bicyclic group, and each monocyclic or bicyclic group is either unsubstituted or substituted by one or more substituents selected from the group consisting of: halogens, -OH, -C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OC 1-6 Halogenated alkyl groups, -CN, -NR 3 R 4 -COR 3 -CO2R 3 And each R 3 and R 4 Choose independently the following groups: hydrogen and C 1-6 Alkyl; R 5It is a hydrogen or amine protecting group; wherein the yield of the compound of formula 1 is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%.

[0251] compound

[0252] In some embodiments, compounds of Formula 1 are provided:

[0253]

[0254] Where R 1 Prepared as described herein by any of the processes described herein.

[0255] In some embodiments, compounds of formula 1a are provided:

[0256]

[0257] Prepared by any of the processes described herein.

[0258] In some embodiments, compounds of formula 4 are provided:

[0259]

[0260] Where R 1 Prepared as described herein by any of the processes described herein.

[0261] In some embodiments, compounds of formula 4a are provided:

[0262]

[0263] Prepared by any of the processes described herein.

[0264] In some embodiments or examples, one or more intermediate compounds as described herein may be provided at any step of the process.

[0265] Composition

[0266] While compounds of Formula 1 or salts thereof may be administered alone in some embodiments, they are more commonly administered as part of a pharmaceutical composition or formulation. Therefore, this disclosure also provides pharmaceutical compositions comprising compounds of Formula 1 or salts thereof and pharmaceutically acceptable excipients. The pharmaceutical compositions include one or more pharmaceutically acceptable diluents, carriers, or excipients (collectively referred to herein as “excipient” materials).

[0267] This disclosure also provides pharmaceutical formulations or compositions for veterinary and human medical use, comprising a compound of formula 1 of this disclosure or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable carriers, and optionally any other therapeutic ingredient, stabilizer, etc. The carrier must be pharmaceutically acceptable in the sense of compatibility with the other components of the formulation and not unduly harmful to the recipient.

[0268] Examples of pharmaceutical preparations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, and intra-articular), inhalation (including fine particulate powders or nebulizers that can be produced by various types of metered-dose pressurized aerosols), nebulizers or blowpipes, rectal, intraperitoneal, and topical (including skin, mouth, sublingual, and intraocular) administration, although the most appropriate route may depend on, for example, the recipient's condition and impairment.

[0269] Pharmaceutical formulations can be conveniently present in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. All methods involve the step of combining a compound of formula (I) or a salt thereof with an excipient constituting one or more essential components. Typically, formulations are prepared by uniformly and tightly binding the active ingredient to a liquid carrier or a finely dispersed solid carrier, or both, and then, if desired, shaping the product into the desired formulation.

[0270] In some embodiments, the composition is formulated for oral delivery. For example, pharmaceutical formulations of the present invention suitable for oral administration may exist as discrete units, such as capsules, pouches, pills, or tablets each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids, such as elixirs, tinctures, suspensions, or syrups; or as oil-in-water or water-in-oil liquid emulsions. The compounds of Formula 1 may also exist as large pills, saccharides, or pastes.

[0271] Tablets can be prepared, for example, by compression or molding with one or more excipients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (such as powder or granules) optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant in a suitable machine. Molded tablets can be prepared by molding a mixture of powder compounds wetted with an inert liquid diluent in a suitable machine. Tablets can be optionally coated or scored and can be formulated to provide a slow or controlled release of the compound of Formula 1. The compound of Formula 1 can be administered, for example, in a form suitable for immediate or sustained release. Immediate or sustained release can be achieved by using a suitable pharmaceutical composition comprising the compound of Formula 1, or, particularly in the case of sustained release, by using a device such as a subcutaneous implant or an osmotic pump. The compound of Formula 1 can also be administered liposomes.

[0272] Exemplary compositions for oral administration include suspensions that may contain, for example, microcrystalline cellulose for volume impartation, alginate or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavorings, such as those known in the art; and immediate-release tablets that may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and / or lactose and / or other excipients, binders, expanders, disintegrants, diluents, and lubricants, such as those known in the art. Suitable binders include starch, gelatin, natural sugars (such as glucose or β-lactose), corn sweeteners, natural and synthetic gums (such as gum arabic, tragacanth, or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc.). Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc. Compounds of Formula 1 can also be delivered orally via sublingual and / oral administration. Molded tablets, compressed tablets, or lyophilized tablets are exemplary forms that can be used. Exemplary compositions include those formulated with compounds of Formula 1 and rapidly dissolving diluents (such as mannitol, lactose, sucrose, and / or cyclodextrin). Such formulations may also include high molecular weight excipients, such as cellulose (microcrystalline cellulose). Viagra) or polyethylene glycol (PEG). Such formulations may also include excipients that promote mucosal adhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers, and release-controlled agents, such as polyacrylic acid copolymers. Lubricants, flow aids, flavoring agents, colorants, and stabilizers may also be added for ease of manufacture and use. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. For oral administration in liquid form, the oral drug component can be combined with any orally administered, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerin, water, etc.

[0273] In some embodiments, the composition is formulated for parenteral delivery. Formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners. The formulation may be present in a single dose or in multi-dose containers, such as sealed ampoules and vials, and may be stored under lyophilized conditions, requiring only the addition of a sterile liquid carrier, such as saline or water for injection, just before use. Temporary injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets of the aforementioned types. Exemplary compositions for parenteral administration include injectable solutions or suspensions that may contain, for example, suitable non-toxic, parenteral-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersants or wetting agents and suspending agents, including synthetic monoglycerides or diglycerides and fatty acids, including oleic acid or cremaphores.

[0274] For example, in one embodiment, the formulation may be a sterile lyophilized composition adapted to be reconstituted in an aqueous carrier prior to injection. In one embodiment, a formulation suitable for parenteral administration conveniently comprises a sterile aqueous formulation of a compound of formula 1, which may, for example, be formulated to be isotonic with the recipient's blood.

[0275] The compounds of Formula 1 disclosed herein can, for example, be formulated into compositions comprising those suitable for inhalation into the lungs via aerosol or parenteral (including intraperitoneal, intravenous, subcutaneous, or intramuscular) administration. The compositions can be conveniently present in unit dosage forms and can be prepared by any method well known in the pharmaceutical field. All methods involve the step of binding a compound of Formula 1 to a carrier constituting one or more excipients. Typically, the compositions are prepared by binding a compound of Formula 1 to a liquid carrier to form a solution or suspension, or by binding a compound of Formula 1 to a formulation component suitable for forming a solid, optionally a particulate product, and then, if desired, shaping the product into a desired delivery form. When in particulate form, the solid dosage forms of this disclosure will typically comprise particles ranging in size from about 1 nanometer to about 500 micrometers. Typically, for solid dosage forms intended for intravenous administration, the particle diameter typically ranges from about 1 nm to about 10 micrometers. The composition may contain a compound of Formula 1 disclosed herein, which is nanoparticle with the following particle diameters: less than 1000 nm, for example 5 to 1000 nm, especially 5 to 500 nm, more especially 5 to 400 nm, such as 5 to 50 nm, and especially 5 to 20 nm. In one example, the composition contains a compound of Formula 1 with an average size between 5 nm and 20 nm. In some embodiments, the compound of Formula 1 is polydispersed in the composition, wherein the PDI is between 1.01 and 1.8, especially between 1.01 and 1.5, and more especially between 1.01 and 1.2. In one example, the compound of Formula 1 is monodispersed in the composition.

[0276] It should be understood that, in addition to the ingredients specifically mentioned above, the formulation may include other conventional reagents in the art that take into account the type of formulation discussed, such as flavoring agents, those suitable for oral administration.

[0277] The compositions disclosed herein may further include polymeric excipients / additives or carriers, such as polyvinylpyrrolidone, derived cellulose (such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose), Ficolls (polymeric sugars), hydroxyethyl starch (HES), glucose binders (e.g., cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin), polyethylene glycol, and pectin. The compositions may also include diluents, buffers, citrates, trehalose, binders, disintegrants, thickeners, lubricants, preservatives (including antioxidants), inorganic salts (e.g., sodium chloride), antimicrobial agents (e.g., benzalkonium chloride), sweeteners, antistatic agents, sorbitol esters, lipids (e.g., phospholipids, such as lecithin and other phosphatidylcholine, phosphatidylethanolamine, fatty acids and fatty esters, steroids (e.g., cholesterol)), and chelating agents (e.g., EDTA, zinc, and other such suitable cations). Other pharmaceutical excipients and / or additives suitable for the compositions according to this disclosure are listed in Remington: The Science & Practice of Pharmacy, 19th Edition, Supplement, edited by Williams & Williams, (1995); in Physician's Desk Reference, 52nd Edition, Supplement, Medical Economics, edited by Montvale, NJ (1998); and in Handbook of Pharmaceutical Excipients, 3rd Edition, edited by AHKibbe, Pharmaceutical Press, 2000.

[0278] In some embodiments, compounds of formula 1a are provided with a purity of at least about 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99.5, or 99.9 (wt%, based on the total composition comprising compounds of formula 1a):

[0279]

[0280]

[0281] For compounds of formula 1a, high purity can be defined as the amount (by weight %) of any impurities present being less than about 5, 4, 3, 2, 1, 0.5, 0.1, 0.05, 0.01, 0.05, 0.001, 0.005, or 0.0001. The compound may be substantially free of any impurities. Impurities may be selected from any one or more byproducts or reagents used in the process described herein, such as TMU, THP, and / or iodopyrimidine. In one example, the impurity (if present) is TMU. High-purity compounds can be obtained from the crude reaction composition of the amide coupling reaction step for preparing compounds of formula 1a. The compound can be purified from the crude reaction composition (e.g., washing and / or solvent extraction). According to any of the embodiments or examples described herein, high-purity compounds of formula 1a may be provided in pharmaceutical compositions comprising one or more pharmaceutically acceptable excipients.

[0282] In some embodiments, a composition comprising a compound of formula 1a according to any embodiment or example thereof described herein and one or more excipients is provided:

[0283]

[0284] The amount (by weight %) of any impurity (if present) is less than about 5, 4, 3, 2, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001, 0.0005, or 0.0001. The composition may be substantially free of any impurities. Impurities may be selected from any one or more byproducts or reagents used in the process described herein, such as TMU, THP, DIPU, and / or iodopyrimidine. In one example, the impurity (if present) is TMU. The composition may be a crude reaction composition of the amide coupling reaction step of a compound of formula 1a. The composition may be a purified (e.g., washed and / or solvent-extracted) crude reaction composition. According to any of the embodiments described herein or examples thereof, the composition may be a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients.

[0285] The present disclosure will now be described with reference to the following examples, which illustrate some specific aspects of the disclosure. However, it should be understood that the specificity of the following description of the disclosure does not replace the generality of the foregoing description of the disclosure.

[0286] Example

[0287] Overview: Materials and Methods

[0288] Unless otherwise stated, all solvents and reagents are commercially available.

[0289] Table 1. Abbreviations

[0290] API active pharmaceutical ingredients

[0291] Aq. Water-based

[0292] Boc tert-butyloxycarbonyl protecting group

[0293] Brine saturated sodium chloride aqueous solution

[0294] BRP Batch Record Production

[0295] nBuLi n-Butyllithium

[0296] CPME cyclopentylmethyl ether

[0297] Eq. equivalent

[0298] GC gas chromatography

[0299] HATU hexafluorophosphate aziridinetriazole tetramethylurea

[0300] HCl hydrochloric acid

[0301] HFR High Force Research

[0302] HPLC (High Performance Liquid Chromatography)

[0303] IT internal temperature

[0304] JT Jacket Temperature

[0305] MeCH methylcyclohexane

[0306] 2-MeTHF 2-Methyltetrahydrofuran

[0307] MPLC (Medium-Pressure Liquid Chromatography)

[0308] NAC N-acetyl-L-cysteine

[0309] NaOH (sodium hydroxide)

[0310] qNMR quantitative nuclear magnetic resonance

[0311] RT room temperature

[0312] THF Tetrahydrofuran

[0313] TLC (Thin Layer Chromatography)

[0314] TFA (trifluoroacetic acid)

[0315] THP Tetrahydropyran

[0316] TMU Tetramethylurea

[0317] Example 1: Synthesis of compound A3

[0318]

[0319] A1 (43.3 g) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (933 mg) were charged into a reactor. A solution of dioxane (582 mL), ethyl 5-bromothiophene-3-carboxylate (31 g), and K2CO3 (42.8 g) in water (95.9 mL) was added. The reaction mixture was heated to 85 °C. After 4 hours, IPC showed complete conversion (HPLC showed no residual A1, A3: 89 area%) and the reaction mixture was cooled to 25 °C (IT). Brine (110 mL) was added, the mixture was clarified and filtered, the phases were separated, and the organic phase was evaporated under reduced pressure. The aqueous phase was extracted with 2-MeTHF (31 mL). The dioxane phase was evaporated under reduced pressure and 2-MeTHF (167 mL) was added and combined with the 2-MeTHF extraction. The combined organic phase was washed with NaHCO3 (115 mL) and brine (110 mL). The product solution was stored at 2 to 8 °C for the next step. For yield determination, aliquots were taken, evaporated, and analyzed. The calculated yield of crude A3 was determined to be 58.9 g (146%). The yield was corrected for NMR content determination to be 93%. The purity determination was 85.5% (area%).

[0320] Example 2: Synthesis of compound A4

[0321]

[0322] A solution of 2-methyltetrahydrofuran containing A3 was added to a reaction vessel. The solution was heated to 50°C and 4 equivalents of hydrochloric acid were slowly added. After addition, the suspension was cooled to 0°C and stirred cold for 30 minutes. The suspension was then filtered, and the solid was dried under reduced pressure. The light brown solid was suspended in 1 volume equivalent of 2-methyltetrahydrofuran, and potassium carbonate solution was added dropwise until the pH reached 10 to 12. The layers were separated from the two-phase solution. The solvent in the organic layer was removed under reduced pressure. The brown solid was suspended in 5 volume equivalents of isopropyl acetate and heated to reflux, then clarified and filtered. The clarified solution was gradually cooled to 0°C and stirred overnight. The light brown suspension was filtered, and the solid was dried to obtain A4.

[0323] Cleavage of THP protecting groups

[0324] Screening was conducted to determine which acid, in what quantity, and at what temperature was preferred for the cleavage of the tetrahydropyran (THP) group. Results showed that excess hydrochloric acid in water or isopropanol for approximately 55°C for about 24 hours resulted in good cleavage of the THP group. H₂SO₄ and ethanol for approximately 80°C for about 48 hours also resulted in good cleavage of the THP group; however, some saponification of the ester was also observed. Finally, hydrochloric acid was preferred as the reagent for cleaving the THP group. Furthermore, an organic hydrochloric acid solution was chosen to prevent the A4 salt from entering the solution, allowing for clean filtration and preventing the development of equilibrium.

[0325] recrystallization

[0326] The crystals were tested on a small scale in isopropanol and isopropyl acetate under the following conditions. 48 mg of A4 was added to two vials and diluted in 0.73 mL (15 volume equivalents) of isopropanol and isopropyl acetate, respectively. Both were heated to reflux (until both became clear brown solutions) and then allowed to cool slowly to room temperature.

[0327] Both were filtered at room temperature, analyzed by HPLC, and the yield was determined.

[0328]

[0329] Due to the better yield and the absence of new impurities, it was decided to recrystallize in isopropyl acetate.

[0330] The remainder from crude A4 was diluted in 10 volume equivalents of isopropyl acetate and heated to reflux. The substance dissolved at approximately 10°C before reflux. The solution was gradually cooled to 20°C, then the solid was filtered and dried under reduced pressure at 50°C. The yield of large-scale recrystallization was 77%.

[0331] The recrystallization was further optimized using the already purified material. A4 was dissolved in 5 volume equivalents of isopropyl acetate under reflux. The mixture was then clarified, filtered, and cooled. A solid with a purity >98% was obtained.

[0332] Example 3: Synthesis of compound A5

[0333]

[0334] Saponification using lithium hydroxide monohydrate

[0335] A solution of A4 in 2-methyltetrahydrofuran (2-Me-THF) and a solution of lithium hydroxide monohydrate (3 equivalents) in water (5 volume equivalents) were placed together in a reaction vessel. The mixture was stirred overnight at 35°C. Complete conversion to A5 was observed. No post-treatment or purification was performed.

[0336] Saponification using sodium hydroxide solution

[0337] Solubility tests showed that A5 was soluble in water at pH 4. Saponification of A4 was carried out under aqueous conditions.

[0338] Add A4 to a solution of sodium hydroxide suspended in water (7.3 volume equivalents) and an aqueous solution of sodium hydroxide consisting of 1.3 volume equivalents dissolved in 3 volume equivalents of water. The mixture was then heated to 65°C. Complete conversion was observed after 1 hour. The mixture was cooled to 45°C and HCl was added dropwise until the pH reached 5. The resulting suspension was cooled to 10°C and filtered. The solid was dried and analyzed by HPLC (97.86%). Yield: 86.91%.

[0339] Example 4: Synthesis of Compound A8

[0340]

[0341] Halogen-metal exchange reaction

[0342] A screening of reagents for halogen-metal exchange reactions was conducted, including the following Grignard reagents:

[0343] ·i-PrMg.LiCl (“Turbo Grignard”);

[0344] ·i-PrMgBr; and

[0345] ·Second-BuMgCl.LiCl.

[0346] Based on screening, all of the above Grignard reagents showed complete consumption of compound A6 by HPLC-UV at about 0°C for 0.5 to 1 hour (i.e., no residual starting material was detected), with about 1.05 to 1.11 equivalents of Grignard reagent being preferred.

[0347] Coupling reaction

[0348] Screening was conducted to investigate coupling with tert-butyloxycarbonyl-nortropinone, including p-tolyl magnesium bromide. Seven reactions with different additives (reagents and equivalences) were then screened at room temperature, including:

[0349] Additives: CeCl3, LaCl3·2LiCl, MnCl2; and

[0350] • Equivalent: 1.5, 2.0.

[0351] LaCl3 exhibits a transformation independent of the equivalence used.

[0352] Overview

[0353] The halogen-metal exchange reactions of compound A6 with various Grignard reagents progressed well. Coupling with tert-butyloxycarbonyl-nortropinone using LaCl3·2LiCl provided a favorable conversion to compound A8.

[0354] The next step is to combine these two steps and study the coupling of tert-butyloxycarbonyl-nortropinone with compound A6 using different combinations of Grignard reagents / additives.

[0355] Screening of Grignard reagent / additive combinations

[0356] The table below provides a summary of the various filtering criteria:

[0357]

[0358]

[0359] *Comparative Examples

[0360] Overall Results

[0361] Based on experiments, the combination of i-PrMgBr and LaCl3 was determined to be the preferred method for synthesizing compound A8. Dioxane and Me-THF also showed good reaction results.

[0362] Screening of addition order, addition time, and mixing time

[0363] Further screening was conducted to evaluate the effect of the order of reagent addition on the reaction.

[0364] The order of addition of different reagents / reagent mixtures at room temperature (addition time 1 hour). The last reagent added to the mixture is listed:

[0365] • Add nortropinone (all other reagents are already present);

[0366] • Add compound A6+i-PrMgBr+LaCl3;

[0367] • Add nortropinone + LaCl3; and

[0368] • Add compound A6+i-PrMgBr.

[0369] Three special addition sequences at room temperature and -78°C:

[0370] • Compound A6->LaCl3->i-PrMgBr->nortropinone;

[0371] • i-PrMgBr->LaCl3->compound A6->nortropinone; and

[0372] One-pot reaction (at room temperature).

[0373] Reaction time of compound A6+i-PrMgBr (with and without LaCl3):

[0374] ·30 minutes; and

[0375] • 16 hours.

[0376] Screening with an addition time of 1 hour showed no significant difference, with conversions of 54% to 64% for compound A8. The addition sequence of the first two tests was strongly exothermic and resulted in conversions of only 30% to 35%, with very low IPC HPLC purities of 11.6% and 24.0% at room temperature. The reaction did not occur at -78°C. Only when heated to room temperature did reactions occur with conversions of 61% to 73%. Even though the conversions appeared promising, the cumulative safety risks were considered too high to be carried out on a larger scale. One-pot reactions (with i-PrMgBr added as the final reagent) contained various byproducts.

[0377] The reaction time after the Grignard reagent i-PrMgBr was added to compound A6 was investigated. Reactions with a 30-minute reaction time prior to the addition of tert-butyloxycarbonyl-nortropinone showed better conversion than those with a 16-hour reaction time. LaCl3 also affected conversion and purity. Reactions in which LaCl3 was present from the outset proceeded worse than reactions in which LaCl3 was added simultaneously with or directly before nortropinone. Therefore, LaCl3 should be added shortly before or simultaneously with nortropinone.

[0378] Screening by Equivalent and Temperature

[0379] First, an initial screening was conducted to investigate the effect of different equivalents of LaCl3 (0.2 / 1.5 / 2.0 / 2.5) at room temperature. The best results in terms of conversion and purity were obtained with 1.5 equivalents of LaCl3. Otherwise, 2.0 equivalents of LaCl3 showed slightly better conversion, but poorer purity.

[0380] The next step is to screen four different parameters, each with three different setpoints, generating a total of nine reactions to determine the optimal conditions:

[0381] • Equivalent weight of i-PrMgBr: 1.2 / 1.5 / 1.8;

[0382] • Equivalent weight of LaCl3: 0.5 / 1.0 / 1.5;

[0383] • Halogen-metal exchange temperature: -20℃ / 0℃ / room temperature; and

[0384] • Reaction temperature: -20℃ / 0℃ / room temperature.

[0385] The results show that the following parameters describe the optimal conditions:

[0386] •i-PrMgBr: 1.5 equivalents;

[0387] • LaCl3: 1.5 equivalents;

[0388] • HM - Exchange temperature: -20℃; and

[0389] • Reaction temperature: 0℃.

[0390] Validation reaction: Validation experiment was conducted on 2.0 g of tert-butyloxycarbonyl-nortropinone using optimized conditions.

[0391] Compound A6 was loaded, diluted with 2-Me-THF, and cooled to -20°C. i-PrMgBr was added at -20 to -15°C, yielding a yellow suspension. After stirring for 30 minutes, the mixture was heated to 0°C. A solution of tert-butyloxycarbonyl-nortropinone and LaCl3 in THF was added dropwise over 30 minutes at 0 to 5°C. IPC after 1.5 hours showed 35% tert-butyloxycarbonyl-nortropinone / 65% compound A8 and an IPC HPLC purity of 51.2% (see [link to HPLC]). Figure 1 The reaction was quenched with an aqueous solution of citric acid (5%), extracted with 2-Me-THF, and the organic phase was washed with an aqueous solution of sodium chloride (5%). The organic phase was evaporated to dryness to obtain an HPLC purity of 31.0% and 19.4% (9.7% nortropinone and the remaining 68.1% of compound A6) (see [reference]). Figure 2 4.1 g of crude product was obtained. Crystallization from heptane yielded 0.55 g (yield: 20.1%) of pure product with an HPLC purity of 99.3% (see [reference]). Figure 3 (HPLC chromatogram of the purified product).

[0392] Screening of scale-up reactions

[0393] For most previous tests, 2.0 equivalents of compound A6 were used to ensure complete conversion of the available (undeprotonated) tert-butyloxycarbonyl-nortropinone. Since compound A6 is an expensive starting material, it was decided to test the reaction with a lower amount of compound A6 (1.5 equivalents). Furthermore, checking for excess or deficiency of i-PrMgBr (relative to compound A6) was better for scale-up: two experiments were conducted at a scale of 2.0 g. The reaction conditions were similar to those described above (1.0 equivalents of nortropinone / 1.5 equivalents of LaCl3 / -20°C to 0°C). The differences were the equivalents of i-PrMgBr (1.7 and 1.3 equivalents, respectively, relative to 2.0 equivalents) and compound A6 (from 2.0 equivalents to 1.5 equivalents).

[0394] In the first experiment, an excess of i-PrMgBr (1.7 equivalents) was used. After stirring overnight at 0°C, IPC showed that the ratio of compound A6 to nortropinone was 62.4% to 37.6%, with an HPLC purity of 37.3 area % (after 2 hours, the purity was 43.3% => degradation overnight due to side reactions with residual i-PrMgBr). After post-treatment, 5.86 g of crude product was obtained with an HPLC purity of 20.9% (by qNMR) and 60.7 area % (32.7% nortropinone and 3.2% compound A6). The calculated maximum yield after content correction was 45.4% (see [reference]). Figure 4 HPLC chromatogram of the crude product, and Figure 5 Quantitative NMR).

[0395] In the second experiment, a deficiency of i-PrMgBr (1.3 equivalents) was used. After stirring overnight at 0°C, IPC showed a ratio of compound A6 to nortropinone of 60% to 40%, and an HPLC purity of 44.9 area % (compound A6 was not integrated due to excess). 5.47 g of crude product was obtained with an HPLC-purity of compound A8 (14.6% nortropinone and 52.1% compound A6) of 24.0% as determined by NMR and 25.2 area % as determined by NMR. The calculated maximum yield, corrected for determination, was 48.3% (see [link to experimental data]). Figure 6 HPLC chromatogram of the crude product and Figure 7 : NMR crude product).

[0396] Based on these results, scale-up was achieved using approximately 1.3 equivalents of i-PrMgBr to prevent degradation after “complete” conversion. Reducing the equivalent of compound A6 had no negative impact on the conversion but a positive impact on manufacturing costs (requiring less compound A6), thus this was also possible.

[0397] Realization of conditions for scaling up

[0398] Compound A6 was loaded, diluted with 2-Me-THF, and cooled to -20°C. i-PrMgBr was added at -20 to -15°C, yielding a yellow suspension. After stirring for 30 minutes, the mixture was heated to 0°C. A solution of tert-butyloxycarbonyl-nortropinone and LaCl3 in THF was added dropwise over 30 minutes at 0 to 5°C. After 2.5 hours, the IPC showed 47% tert-butyloxycarbonyl-nortropinone / 53% compound A8 and an HPLC purity of 42.9. The reaction was quenched with an aqueous citric acid solution (5%), extracted with 2-Me-THF, and the organic phase was washed with an aqueous sodium chloride solution (5%). The organic phase was aliquoted into two fractions of similar size. The organic phase was evaporated to dryness to obtain 24.5 g and 25.0 g of crude product, respectively. The NMR content was 35.9% and 34.6% (content-corrected yield: 43.2% / 42.6%), and the HPLC purity was 24.6 area % (21.2 area % nortropinone and the remaining 52.3% A6).

[0399] Purification of compound A8: Compound A8 was purified by chromatography using a heptane / EtOAc gradient (yield: 33%, purity: 93.8 area%) and crystallized from heptane (overall yield: 28%, purity: 97.2%).

[0400] Overview of the development of the Grignard pathway

[0401] More than 100 reactions were conducted in total to develop an alternative Grignard pathway. Finally, reaction conditions were developed that showed reaction curves and yields quite similar to the literature BuLi process, but without requiring a low temperature.

[0402] For scale-up, a process that does not involve chromatography is preferred (i.e., condensing compound A8 into compound A9). To avoid the formation of new impurities during scale-up, iodopyrimidine is removed by extraction or derivatization.

[0403] To avoid purification difficulties, it was decided to condense the crude compound A8 into compound A9 and then purify it after this step.

[0404] Example 5: Synthesis of Compound A9

[0405]

[0406] Scale-up condensation reaction

[0407] Crude compound A8 was condensed into a tert-butyloxycarbonyl cleavage reaction. Sulfonic acid was also used for tert-butyloxycarbonyl deprotection and to generate stable deprotected salt compounds. Crude compound A8 (50 g) was dissolved in an aqueous solution of 4-toluenesulfonic acid (p-TSA or TsOH) monohydrate (0.5 M, 3.5 equivalents). The mixture was heated to 50 °C and stirred for 1 to 2 hours. After IPC showed complete consumption of compound A8 in the supernatant, the turbid mixture was cooled to room temperature. The resulting precipitate was filtered off and washed with MeTHF. After vacuum drying at room temperature, a pTSA salt of compound A9 was obtained as a colorless to grayish-white solid (36.9% yield at >99% purity, see [reference]). Figure 9 The salt was also identified to reveal a 2:1 pTSA composition: compound A9. The NMR purity of the salt was determined to be 99.6%.

[0408] Example 6: Synthesis of Compound 1

[0409]

[0410] DIPEA (3.5 equivalents) was added to a suspension of compound A5a (1.00 equivalents), compound A9 (EU1H2*2pTSA (1.10 equivalents), and HOPO (1.50 equivalents) in acetonitrile / water (1:1 v / v, 31.0 v / w), and the mixture was stirred for 5 minutes. DIC (1.50 equivalents) was added, and the mixture was heated to 60°C and stirred until complete consumption of EU1D2 was observed (6 to 19 hours). Acetonitrile was distilled off, and the mixture was cooled to room temperature. The acetonitrile was then slowly added by adding 2M... The aqueous layer was acidified with HCl (1.0 equivalent) and washed with iPrOAc (3 × 21.3 v / w). EtOH (7.5 v / w) was added to the aqueous layer and the mixture was heated to 45 °C. Sodium hydroxide (30%, 1.00 equivalent) was added dropwise until the pH reached 12. The crystalline material was used for purification of the product, followed by drying to remove the solvent. After evaporation under reduced pressure, compound 1 (20.1 g, 82.4%) with a purity of 99.7% by area was obtained as an off-white solid (see [link to product description]). Figure 12 ).

[0411] Oxymapure and EDC were also used in the amide coupling reaction. 6.5 g of compound A5 was dissolved in 13 volume equivalents of acetonitrile. Oxymapure was added and the suspension was cooled to -10°C. EDC×HCl was added and the mixture was stirred for 30 minutes. Then DIPEA and compound A9 were added. The mixture was heated to room temperature. The mixture became a solution over time. After the reaction was complete, half of the reaction mixture was taken to test the proposed aqueous post-treatment. Post-treatment: Water was added dropwise to three times the volume of acetonitrile to obtain a light suspension. Solid sodium carbonate was added until the pH was 9 to 12. The solvent was then removed under reduced pressure and washed twice with 2 volume equivalents of water. The solid was suspended in water and 60% H2SO4 was added until the pH was 0. The solution was then washed twice with Me-THF to remove the coupling agent. Concentrated sodium hydroxide solution was added until the pH was 11. The mixture was heated to 50°C and saturated with Na2SO4. The mixture was then extracted twice with a Me-THF / EtOH (3 / 1) mixture. The organic layer was then dried under reduced pressure to give an orange solid as the crude product. HPLC: 97.71 area %. qNMR: 41.47%. NMR analysis of the reaction mixture showed 79% theoretical amount of compound 1 in acetonitrile solution. Crude compound 1 was suspended in 6 volume equivalents of EtOH / H2O 1 / 1 and heated to 82 °C. The mixture was then cooled to 0 °C and filtered. The solid was then stirred at 0 °C with 2 volume equivalents of water for 30 min before filtration again. The solid was dried under reduced pressure at 50 °C to give 3.24 g of gray solid as pure compound 1. HPLC area %. 98.53%. qNMR: 97.67% (see [reference]). Figure 14 ).

Claims

1. A process for preparing a nitrogen-containing bicyclic compound of formula 4, Formula 4 The process includes the nortropinone compound of Formula 5. Formula 5 Grignard reaction with halo compounds of formula 6, Formula 6 in R 1 It is an unsubstituted monocyclic or bicyclic heteroaryl group; R 2 The amine protecting group is selected from the group consisting of: urethane, amide, benzyl, benzylene, toluenesulfonyl, and triphenylmethyl; and X is a halogen. And the Grignard reaction includes the following steps: i) Halogen-metal exchange reactions involving Grignard reagents, wherein the Grignard reagent includes i-PrMgBr; and ii) Coupling reaction in the presence of LaCl3, The coupling reaction occurs at a temperature between 0°C and 20°C.

2. The process according to claim 1, wherein R 1 It is a pyrimidine.

3. The process according to claim 1, wherein R 2 It is a tert-butyloxycarbonyl (BOC) group.

4. The process according to claim 1, wherein X is iodine.

5. The process according to claim 1, wherein the halogen-metal exchange reaction occurs at a temperature between -30°C and 10°C.

6. The process according to claim 1, wherein the azabicyclic compound of formula 4 is a protected amine compound of formula 4a: Equation 4a; The process includes using a tropinone compound of formula 5a. Formula 5a Reaction with halogenated compounds of formula 6a Equation 6a.

7. The process according to claim 1, further comprising using sulfonic acid to remove the amine protecting group from the azabicyclic compound of formula 4 to prepare a salt of the amine bicyclic compound of formula 3: Formula 3.

8. The process according to claim 7, wherein salt formation includes using... p -TSA is prepared using formula 3. p -TSA salt.

9. The process according to claim 8, wherein formula 3... p -TSA salt is a double salt of formula 3. p -TSA salt.

10. The process according to claim 7, further comprising using a salt of the amine bicyclic compound of formula 3. Formula 3 With carboxylic acid compounds of formula 2 or their salts, Formula 2 The reaction is carried out in the presence of at least one coupling agent to form a heterocyclic ketone compound of formula 1. Formula 1 in R 1 It is an unsubstituted monocyclic or bicyclic heteroaryl group; R 5 It is a hydrogen or amine protecting group.

11. The process according to claim 10, wherein the coupling agent comprises an oxime coupling agent, and the oxime coupling agent comprises ethyl cyano (hydroxyimino) acetate.

12. The process according to claim 10, wherein the coupling agent comprises a carbodiimide coupling agent selected from the group consisting of: dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide·HCl and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

13. The process according to claim 10, wherein the coupling agent is a carbodiimide coupling agent selected from diisopropylcarbodiimide.

14. The process according to claim 10, wherein the reaction between the salt of formula 3 and the carboxylic acid compound of formula 2 or a salt thereof further comprises one or more additives.

15. The process according to claim 14, wherein the additive is selected from N-oxide reagents and bases.

16. The process according to claim 15, wherein the N-oxide reagent is 2-hydroxypyridine-N-oxide.

17. The process according to claim 15, wherein the alkali is N,N -Diisopropylethylamine.

18. The process according to claim 10, wherein the reaction between the salt of formula 3 and the carboxylic acid compound of formula 2 or a salt thereof occurs in an aqueous solvent.

19. The process according to claim 10, wherein R in formula 3 1 It is a pyrimidine.

20. The process according to claim 10, wherein R 5 It is an amine protecting group, THP.

21. The process according to claim 10, wherein R 5 It is hydrogen.

22. The process according to claim 10, wherein the compound of formula 3 is a sulfonate.

23. The process according to claim 10, wherein the compound of formula 3 is a disulfonate.

24. The process according to claim 10, wherein the compound of formula 3 is a 4-toluenesulfonate of formula 3.

25. The process according to claim 10, wherein the compound of formula 3 is prepared according to any one of claims 7 to 9.

26. The process according to claim 10, wherein the heterocyclic ketone compound of formula 1 is a compound of formula 1a: Equation 1a; The process described herein includes using a carboxylic acid compound of formula 2a or a salt thereof. Equation 2a The sulfonate of formula 3a reacts with the carbodiimide coupling agent in the presence of the sulfonate. Equation 3a R is selected from alkyl, aryl, and alkylaryl, each of which may be optionally substituted.

27. The process according to claim 10, wherein the carboxylic acid compound of formula 2 is prepared by saponification with a base of an ester compound of formula 7. Formula 7 Where R 5 It is a hydrogen or amine protecting group and R 6 It is an ester protecting group.

28. The process according to claim 27, wherein R in the ester compound of formula 7 6 It is C 1-10 alkyl.

29. The process according to claim 27, wherein R in the compound of formula 7 is removed prior to the preparation of the carboxylic acid compound of formula 2. 5 Amine protecting group.

30. The process according to claim 10, wherein the amount of the heterocyclic ketone compound of formula 1 prepared in each reaction batch is at least 50 g.

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