Process of manufacture of p2x3 antagonists including camlipixant

Abstract

A process for the preparation of a compound of Formula (A), wherein R1 and R2 are independently selected from hydrogen, halo and C1-3 alkyl; R3, R4, R5 and R6 are independently selected from hydrogen, halo and C1-3 alkyl; X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rb and -SO2NRaRb; and Ra and Rb are independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

Description

[0001] PROCESS OF MANUFACTURE OF P2X3 ANTAGONISTS INCLUDING CAMLIPIXANT

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to processes for the preparation of certain P2X3 antagonists, including camlipixant, and to processes for preparing intermediates useful in the preparation of certain P2X3 antagonists, including camlipixant. In particular, the process disclosed herein can be used for commercial manufacture of certain P2X3 antagonists, including camlipixant The present invention also relates to intermediates useful in the manufacture of certain P2X3 antagonists, including camlipixant.

[0004] BACKGROUND TO THE INVENTION

[0005] P2X3 antagonists are useful in the treatment of various diseases, particularly in the treatment of refractory chronic cough. One particular P2X3 antagonist in development is known as camlipixant. Processes for the preparation of camlipixant can be found in WO 2014 / 117274, WO 2021 / 161109 and WO 2023 / 021328.

[0006] There exists the need for an alternative process for the preparation of camlipixant and analogues thereof. In particular, a process that offers advantages over those previously described in WO 2014 / 117274, WO 2021 / 161109 and WO 2023 / 021328, for example such that the process can be carried out successfully at manufacturing scale, while reducing the cost of goods.

[0007] SUMMARY OF THE INVENTION

[0008] In a first aspect of the invention, there is provided a process for the preparation of a compound of Formula (A), wherein

[0009] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl; R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0010] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (15) to a compound of Formula (A) wherein

[0011] R7is independently selected from C1-3 alkyl; and

[0012] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and X1may be the same or different.

[0013] In a second aspect of the invention, there is provided a process for the preparation of a compound of Formula (A), wherein

[0014] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0015] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0016] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (14) to a compound of Formula (15) wherein

[0017] R7is C1-3 alkyl; and

[0018] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and X1may be the same or different.

[0019] In a third aspect of the invention, there is provided a process forthe preparation of a compound of Formula (A), wherein

[0020] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0021] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0022] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (V) to a compound of Formula (14) wherein

[0023] R7is C1-3 alkyl; and

[0024] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and X1may be the same or different.

[0025] In a fourth aspect of the invention, there is provided a process for the preparation of a compound of Formula (A), wherein

[0026] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0027] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0028] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (VI) to a compound of Formula (V) wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband-SO2NRaRb, where

[0029] X and X1may be the same or different; and

[0030] LG is a suitable leaving group.

[0031] In a fifth aspect of the invention, there is provided a process for the preparation of a compound of Formula (A), wherein

[0032] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0033] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0034] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (VII) to a compound of Formula (VI) wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband-SO2NRaRb, where X and X1may be the same or different.

[0035] In a sixth aspect of the invention, there is provided a process forthe preparation of a compound of Formula (A), wherein

[0036] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0037] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0038] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (13) wherein Y is a suitable amine group bound through nitrogen or a suitable trialkylphosphine group bound though phosphorus to a compound of Formula (VII) wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband-SO2NRaRb, where X and X1may be the same or different.

[0039] In a seventh aspect of the invention, there is provided a process for the preparation of a compound of Formula (A), wherein

[0040] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0041] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0042] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (VII) to a compound of Formula (13)

[0043] In an eighth aspect of the invention, there is provided a process for the preparation of a compound of Formula (A), wherein

[0044] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0045] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0046] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of to a compound of Formula (X)

[0047] In a tenth aspect of the invention, there is provided a compound of Formula (VI), Formula (VII), Formula (V), Formula (V-l), Formula (14) or (14-l), Formula (15) or (15-1), Formula (13) or (13-

[0048] I) wherein

[0049] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0050] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0051] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb;

[0052] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; and LG is a suitable leaving group, where present.

[0053] In an eleventh aspect of the invention, there is provided a compound having one of the following structures

[0054]

[0055] DETAILED DESCRIPTION OF THE INVENTION

[0056] Definitions

[0057] As used herein, the term “halo” refers to chloro, fluoro, bromo, or iodo substituents.

[0058] As used herein, the term “alkyl” refers to a saturated hydrocarbon radical, straight or branched, having the specified number of carbon atoms. For example, the term “C1-3 alkyl” refers to an alkyl group having 1 to 3 carbon atoms. Exemplary groups include, methyl, ethyl and propyl (n-propyl and isopropyl).

[0059] As used herein, the term “cycloalkyl” refers to a non-aromatic, saturated monocyclic hydrocarbon ring containing the specified number of carbon atoms. For example, the term “C3- 6 cycloalkyl” refersto a cycloalkyl group having 3 to 6 carbon atoms. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0060] As used herein, the term “chiral catalyst” refersto a catalyst comprising a transition metal and a chiral ligand. As used herein, the term “API” refers to active pharmaceutical ingredient and is intended to refer to drug substance, optionally comprising process-related impurities, that is suitable for formulation into tablets, for example for use in patients.

[0061] As used herein, the term “protecting group” refers to a group of atoms that mask, reduce or prevent the reactivity of the functional group when attached to a reactive functional group in a molecule. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in "Protective Groups in Organic Synthesis”, T.W. Greene and P.G.M. Wuts, Wiley- Interscience, 2006, and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Functional groups that can have a protecting group include, but are not limited to, hydroxy, amino, and carboxy groups.

[0062] As used herein, “leaving group” may be referred to as “LG” and is defined as a term that would be understood by one of ordinary skill in the art; that is, an atom or group of atoms that readily detaches from the main or residual part of a substrate during a reaction or elementary step of a reaction. Examples of suitable leaving groups include halogens and — S(O)2R where R is, for example optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. Those of skill in the art of organic synthesis will readily identify suitable leaving groups to perform a desired reaction under different reaction conditions. Non-limiting characteristics and examples of leaving groups can be found, for example in Organic Chemistry, 2nd ed., Francis Carey (1992), pages 328-331 ; Introduction to Organic Chemistry, 2d ed., Andrew Streitwieser and Clayton Heathcock (1981), pages 169-171 ; and Organic Chemistry, 5th Ed., John McMurry, Brooks / Cole Publishing (2000), pages 398 and 408., such as a nucleophilic substitution reaction. Suitable leaving groups are known in the art.

[0063] In general, solvents with dielectric constants greater than about 5 are considered "polar" and those with dielectric constants less than 5 are considered "non-polar."

[0064] Statement of Invention

[0065] The invention relates to two alternative processes (Process A and Process B) for the preparation of P2X3 antagonists defined by Formula (A) wherein

[0066] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0067] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0068] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0069] Each process will be described below with reference to Process A and Process B.

[0070] Process A

[0071] The present invention provides a process for the preparation of a compound of Formula (A), wherein

[0072] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0073] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0074] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (15) to a compound of Formula (A) wherein

[0075] R7is independently selected from C1-3 alkyl; and

[0076] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and X1may be the same or different.

[0077] In an embodiment R7is ethyl or methyl.

[0078] In an embodiment, R7is methyl.

[0079] In an embodiment, said conversion comprises contacting a compound of Formula (15) with a suitable acid, followed by a suitable reducing agent.

[0080] In an embodiment, the suitable acid is selected from the group consisting of a sulfonic acid, sulfuric acid, trimethylsilyl trifluoromethanesulfonate, triflic acid, boron trifluoride etherate, hydrogen chloride, hydrogen bromide, and trifluoroacetic acid.

[0081] In an embodiment, the suitable acid is p-toluenesulfonic acid or methanesulfonic acid.

[0082] In an embodiment, the suitable acid is methanesulfonic acid.

[0083] In an embodiment, the suitable reducing agent is tetramethyldisiloxane (TMDS), hydrogen, polymethylhydrogen siloxane, or triethylsilane.

[0084] In an embodiment, the suitable reducing agent is hydrogen, and the reaction is catalysed by Pd / C. In an embodiment, the suitable acid is p-toluenesulfonic acid, the suitable reducing agent is hydrogen, and the reaction is catalysed by Pd / C.

[0085] In an embodiment, the suitable reducing agent is tetramethyldisiloxane (TMDS).

[0086] In an embodiment, the suitable acid for the conversion of a compound of Formula (15) to a compound of Formula (A) is methanesulfonic acid and the suitable reducing agent is tetramethyldisiloxane (TMDS).

[0087] In an embodiment, the process for the preparation of a compound of Formula (A) by conversion of a compound of Formula (15) is carried out in the presence of a suitable solvent. For example, the solvent may be selected from the group consisting of tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-MeTHF), ethyl acetate, acetonitrile (MeCN), dimethyl sulfoxide (DMSO), dimethylformamide (DM F), dimethylacetamide (DMAc), isopropyl acetate (IPAc), dichloromethane (DCM), and N-Methyl-2-pyrrolidone (NMP). In an embodiment, the solvent is acetonitrile (MeCN).

[0088] The process for the conversion of a compound of Formula (15) to a compound of Formula (A) may additionally result in the formation of process-related impurities. For example, the process for the conversion of a compound of Formula (15) to a compound of Formula (A) may additionally result in formation of a compound of Formula (15) to a compound of Formula (17) and / or a compound of Formula (18) under certain reaction conditions / workup conditions, for example wherein conversion of a compound of Formula (15) to a compound of Formula (A) comprises contacting a compound of Formula (15) with a suitable acid, followed by a suitable reducing agent, particularly wherein the suitable acid is methanesulfonic acid and the suitable reducing agent is tetramethyldisiloxane (TMDS).

[0089] A compound of Formula (17) is as follows wherein

[0090] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0091] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0092] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0093] A compound of Formula (18) is as follows wherein

[0094] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0095] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0096] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0097] Therefore, also provided herein is API (active pharmaceutical ingredient) comprising: pharmaceutically acceptable salt thereof, wherein

[0098] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0099] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0100] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0101] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; and

[0102] (ii) a compound of Formula (17) wherein each R1, R2, R3, R4, R5and R6, Raand Rb, and X group is the same as those in defined according to Formula (A).

[0103] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (17) in an amount of from about 0.01 wt% and less than about 1 wt%, particularly in an amount of from about 0.01 wt% and less than about 0.5 wt% based on total weight of the API composition.

[0104] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (17) in an amount of from about 0.01 % area by HPLC and less than about 1 % area by HPLC, particularly in an amount of from about 0.01 % area by HPLC and less than about 0.5% area by HPLC.

[0105] In an embodiment, there is provided API comprising: pharmaceutically acceptable salt thereof, wherein

[0106] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0107] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0108] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0109] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; and

[0110] (ii) a compound of Formula (17) in an amount of up to about 0.3 wt% based on the total weight of the composition, particularly in an amount of up to about 0.15 wt% based on the total weight of the API composition or in an amount of up to about 0.1 wt% based on the total weight of the API composition, and wherein each R1, R2, R3, R4, R5and R6, Raand Rb, and X group is the same as those in defined according to Formula (A).

[0111] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (17) in an amount of from about 0.01 wt% and less than about 0.3 wt% based on the total weight of the API composition.

[0112] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (17) in an amount of from about 0.01 wt% and less than about 0.15 wt% based on the total weight of the API composition.

[0113] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (17) in an amount of from about 0.01 wt% and less than about 0.1 wt% based on the total weight of the API composition.

[0114] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (17) in an amount of up to about 0.3 wt%, up to about 0.15 wt%, particularly up to about 0.1 wt% based on the total weight of the API composition.

[0115] In an embodiment, the compound according to Formula (A) is camlipixant, i.e. wherein R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X is -C(O)NHCH3, i.e. Rais hydrogen and Rbis CHs.

[0116] In an embodiment, there is provided API comprising: pharmaceutically acceptable salt thereof, wherein

[0117] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0118] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0119] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0120] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; and (ii) a compound of Formula (17) in an amount of up to about 0.3% area by HPLC, particularly in an amount of up to about 0.15% area by HPLC, or in an amount of up to about 0.1 % area by HPLC. and wherein each R1, R2, R3, R4, R5and R6, Raand Rb, and X group is the same as those in defined according to Formula (A).

[0121] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (17) in an amount of from about 0.01 % and less than about 0.3% area by HPLC.

[0122] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (17) in an amount of from about 0.01 % and less than about 0.15% area by HPLC.

[0123] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (17) in an amount of from about 0.01 % and less than about 0.1 % area by HPLC

[0124] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (17) in an amount of up to about 0.3%, up to about 0.15%, particularly up to about 0.1 % area by HPLC.

[0125] In an embodiment, the compound according to Formula (A) is camlipixant, i.e. wherein R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X is -C(O)NHCH3, i.e. Rais hydrogen and Rbis CHs.

[0126] Therefore, in an aspect of the invention, when Formula (A) is camlipixant, there is provided camlipixant API comprising pharmaceutically acceptable salt thereof; and

[0127] In an embodiment, there is provided API comprising pharmaceutically acceptable salt thereof; and in an amount of less than about 0.3 wt% based on the total weight of the API composition, particularly in an amount of less than about 0.15 wt% based on the total weight of the API composition or in an amount of less about than 0.1 wt% based on the total weight of the API composition. In an embodiment, there is provided API comprising in an amount of less than about 0.3% area by HPLC, particularly in an amount of less than about 0.15% area by HPLC or in an amount of less about than 0.1% area by HPLC.

[0128] In an embodiment, there is provided API comprising pharmaceutically acceptable salt thereof; and in an amount of up to about 0.3 wt% based on the total weight of the composition, particularly in an amount of up to about 0.15 wt% based on the total weight of the composition or in an amount of up to about 0.1 wt% based on the total weight of the composition.

[0129] In an embodiment, there is provided camlipixantAPI comprising a compound of Formula (A); and a compound of Formula (17-a) in an amount of from about 0.01 wt% and less than about 0.3 wt% based on the total weight of the composition.

[0130] In an embodiment, there is provided camlipixantAPI comprising a compound of Formula (A); and a compound of Formula (17-a) in an amount of from about 0.01 wt% and less than about 0.15 wt% based on the total weight of the composition.

[0131] In an embodiment, there is provided camlipixantAPI comprising a compound of Formula (A); and a compound of Formula (17-a) in an amount of from about 0.01 wt% and less than about 0.1 wt% based on the total weight of the composition.

[0132] In an embodiment, there is provided camlipixantAPI comprising a compound of Formula (A); and a compound of Formula (17-a) in an amount of up to about 0.3 wt%, up to about 0.15 wt%, particularly up to about 0.1 wt% based on the total weight of the composition.

[0133] In an embodiment, there is provided API comprising pharmaceutically acceptable salt thereof; and in an amount of up to about 0.3% area by HPLC, particularly in an amount of up to about 0.15% area by HPLC or in an amount of up to about 0.1 % area by HPLC. In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); and a compound of Formula (17-a) in an amount of from about 0.01 % and less than about 0.3% area by HPLC.

[0134] In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); and a compound of Formula (17-a) in an amount of from about 0.01 % and less than about 0.15% area by HPLC.

[0135] In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); and a compound of Formula (17-a) in an amount of from about 0.01 % and less than about 0.1 % area by HPLC.

[0136] In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); and a compound of Formula (17-a) in an amount of up to about 0.3%, up to about 0.15%, particularly up to about 0.1 % area by HPLC.

[0137] In an embodiment, also provided herein is API comprising: pharmaceutically acceptable salt thereof, wherein

[0138] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0139] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0140] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0141] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; and

[0142] (ii) a compound of Formula (18) wherein each R1, R2, R3, R4, R5and R6, Raand Rb, and X group is the same as those in defined according to Formula (A).

[0143] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (18) in an amount of from about 0.01 wt% and less than about 1 wt%

[0144] In an embodiment, there is provided API comprising: pharmaceutically acceptable salt thereof, wherein

[0145] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0146] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0147] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0148] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; and

[0149] (ii) a compound of Formula (18) in an amount of up to about 0.3 wt% based on the total weight of the API composition, particularly in an amount of up to about 0.15 wt% based on the total weight of the API composition or in an amount of up to about 0.1 wt% based on the total weight of the API composition, and wherein each R1, R2, R3, R4, R5and R6, Raand Rb, and X group is the same as those in defined according to Formula (A). In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (18) in an amount of from about 0.01 wt% and less than about 0.3 wt% based on the total weight of the API composition.

[0150] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (18) in an amount of from about 0.01 wt% and less than about 0.15 wt% based on the total weight of the API composition.

[0151] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (18) in an amount of from about 0.01 wt% and less than about 0.1 wt% based on the total weight of the API composition.

[0152] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (18) in an amount of up to about 0.3 wt%, particularly up to about 0.15 wt% based on the total weight of the API composition.

[0153] In an embodiment, there is provided API comprising: pharmaceutically acceptable salt thereof, wherein

[0154] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0155] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0156] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0157] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; and

[0158] (ii) a compound of Formula (18) in an amount of up to about 0.3% area by HPLC, particularly in an amount of up to about 0.15% area by HPLC or in an amount of up to about 0.1 % area by HPLC, and wherein each R1, R2, R3, R4, R5and R6, Raand Rb, and X group is the same as those in defined according to Formula (A).

[0159] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (18) in an amount of from about 0.01 % and less than about 0.3% area by HPLC.

[0160] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (18) in an amount of from about 0.01 % and less than about 0.15% area by HPLC.

[0161] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (18) in an amount of from about 0.01 % and less than about 0.1 % area by HPLC.

[0162] In an embodiment, there is provided API comprising a compound of Formula (A); and a compound of Formula (18) in an amount of up to about 0.3%, particularly up to about 0.15% area by HPLC.

[0163] In an embodiment, the compound according to Formula (A) is camlipixant, i.e. wherein R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X is -C(O)NHCH3, i.e. Rais hydrogen and Rbis CHs.

[0164] Therefore, in an aspect of the invention, when Formula (A) is camlipixant, there is provided a camlipixant API comprising pharmaceutically acceptable salt thereof; and

[0165] In an embodiment, there is provided camlipixant API comprising in an amount of up to about 0.3 wt% based on the total weight of the API composition, particularly in an amount of up to about 0.15 wt% based on the total weight of the API composition or in an amount of up to about 0.1 wt% based on the total weight of the API composition.

[0166] In an embodiment, there is provided camlipixant API comprising pharmaceutically acceptable salt thereof; and in an amount of less than about 0.15 wt% based on the total weight of the composition.

[0167] In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); and a compound of Formula (18-a) in an amount of from about 0.01 wt% and less than about 0.3 wt% based on the total weight of the composition.

[0168] In an embodiment, there is provided camlipixantAPI comprising a compound of Formula (A); and a compound of Formula (18-a) in an amount of from about 0.01 wt% and less than about 0.15 wt% based on the total weight of the composition.

[0169] In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); and a compound of Formula (18-a) in an amount of from about 0.01 wt% and less than about 0.1 wt% based on the total weight of the composition.

[0170] In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); and a compound of Formula (18-a) in an amount of up to about 0.3 wt%, particularly up to about 0.15 wt% based on the total weight of the composition.

[0171] In an embodiment, there is provided camlipixant API comprising pharmaceutically acceptable salt thereof; and in an amount of up to about 0.3% area by HPLC, particularly in an amount of up to about 0.15% area by HPLC or in an amount of up to about 0.1% area by HPLC.

[0172] In an embodiment, there is provided camlipixant API comprising in an amount of less than about 0.15% area by HPLC.

[0173] In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); and a compound of Formula (18-a) in an amount of from about 0.01 % and less than about 0.3% area by HPLC.

[0174] In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); and a compound of Formula (18-a) in an amount of from about 0.01% and less than about 0.15% area by HPLC.

[0175] In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); and a compound of Formula (18-a) in an amount of from about 0.01% and less than about 0.1% area by HPLC. In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); and a compound of Formula (18-a) in an amount of up to about 0.3%, particularly up to about 0.15% area by HPLC.

[0176] In an embodiment, also provided herein is API comprising: wherein

[0177] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0178] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0179] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl;

[0180] (ii) a compound of Formula (17)

[0181] (iii) a compound of Formula (18) wherein each R1, R2, R3, R4, R5and R6, Raand Rb, and X group in a compound of Formula (17) and a compound of Formula (18) is the same as those in defined according to Formula (A).

[0182] In an embodiment, there is provided API comprising a compound of Formula (A); a compound of Formula (17); and a compound of Formula (18), wherein the compound of Formula (17) and compound of Formula (18) are each present in an amount of from about 0.01 wt% and less than about 1 wt%, particularly in an amount of from about 0.01 wt% and less than about 0.5 wt% based on the total weight of the API composition.

[0183] In an embodiment, there is provided API comprising a compound of Formula (A); a compound of Formula (17); and a compound of Formula (18), wherein the compound of Formula (17) and compound of Formula (18) are each present in an amount of from about 0.01 % and less than about 1 %, particularly in an amount of from about 0.01 % and less than about 0.5% area by HPLC.

[0184] In an embodiment, also provided herein is API comprising: pharmaceutically acceptable salt thereof, wherein

[0185] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0186] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0187] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl;

[0188] (ii) a compound of Formula (17)

[0189] in an amount of up to about 0.3 wt% based on the total weight of the API composition, particularly in an amount of up to about 0.15 wt% based on the total weight of the API composition or in an amount of up to about 0.1 wt% based on the total weight of the API composition; and

[0190] (iii) a compound of Formula (18) in an amount of up to about 0.3 wt% based on the total weight of the API composition, particularly in an amount of up to about 0.15 wt% based on the total weight of the API composition or in an amount of up to about 0.1 wt% based on the total weight of the API composition, wherein each R1, R2, R3, R4, R5and R6, Raand Rb, and X group in a compound of Formula (17) and a compound of Formula (18) is the same as those in defined according to Formula (A).

[0191] In an embodiment, there is provided API comprising a compound of Formula (A); a compound of Formula (17) in an amount of from about 0.01 wt% and less than about 0.3 wt% based on the total weight of the API composition; and a compound of Formula (18) in an amount of from about 0.01 wt% and less than about 0.3 wt% based on the total weight of the API composition.

[0192] In an embodiment, there is provided API comprising a compound of Formula (A); a compound of Formula (17) in an amount of from about 0.01 wt% and less than about 0.15 wt% based on the total weight of the API composition; and a compound of Formula (18) in an amount of from about 0.01 wt% and less than about 0.15 wt% based on the total weight of the API composition.

[0193] In an embodiment, there is provided API comprising a compound of Formula (A); a compound of Formula (17) in an amount of from about 0.01 wt% and less than about 0.1 wt% based on the total weight of the API composition; and a compound of Formula (18) in an amount of from about 0.01 wt% and less than about 0.1 wt% based on the total weight of the API composition

[0194] In an embodiment, there is provided API comprising a compound of Formula (A); a compound of Formula (17) in an amount of up to about 0.3 wt%, up to about 0.15 wt%, particularly up to about 0.1 wt% based on the total weight of the API composition; and a compound of Formula (18) in an amount of up to about 0.3 wt%, up to about 0.15 wt%, particularly up to about 0.1 wt% based on the total weight of the API composition

[0195] In an embodiment, also provided herein is API comprising: pharmaceutically acceptable salt thereof, wherein

[0196] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0197] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0198] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0199] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; and

[0200] (ii) a compound of Formula (17) in an amount of up to about 0.3% area by HPLC, particularly in an amount of up to about 0.15% area by HPLC or in an amount of up to about 0.1 % area by HPLC; and

[0201] (iii) a compound of Formula (18) in an amount of up to about 0.3% area by HPLC, particularly in an amount of up to about 0.15% area by HPLC or in an amount of up to about 0.1 % area by HPLC, wherein each R1, R2, R3, R4, R5and R6, Raand Rb, and X group in a compound of Formula (17) and a compound of Formula (18) is the same as those in defined according to Formula (A).

[0202] In an embodiment, there is provided API comprising a compound of Formula (A); a compound of Formula (17) in an amount of from about 0.01 % and less than about 0.3% area by HPLC; and a compound of Formula (18) in an amount of from about 0.01 % and less than about 0.3% area by HPLC.

[0203] In an embodiment, there is provided API comprising a compound of Formula (A); a compound of Formula (17) in an amount of from about 0.01 % and less than about 0.15% area by HPLC; and a compound of Formula (18) in an amount of from about 0.01 % and less than about 0.15% area by HPLC.

[0204] In an embodiment, there is provided API comprising a compound of Formula (A); a compound of Formula (17) in an amount of from about 0.01 % and less than about 0.1 % area by HPLC; and a compound of Formula (18) in an amount of from about 0.01 % and less than about 0.1 % area by HPLC.

[0205] In an embodiment, there is provided API comprising a compound of Formula (A); a compound of Formula (17) in an amount of up to about 0.3%, up to about 0.15%, particularly up to about 0.1 % based on the total weight of the API composition; and a compound of Formula (18) in an amount of up to about 0.3%, up to about 0.15%, particularly up to about 0.1 % area by HPLC. In an embodiment, the compound according to Formula (A) is camlipixant, i.e. wherein R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X is -C(O)NHCH3, i.e. Rais hydrogen and Rbis CH3.

[0206] Therefore, in an aspect of the invention, when Formula (A) is camlipixant, there is provided camlipixant API comprising pharmaceutically acceptable salt thereof;

[0207] In an embodiment, when Formula (A) is camlipixant, there is provided camlipixant API comprising pharmaceutically acceptable salt thereof; in an amount of less than about 0.3 wt% based on the total weight of the API composition, particularly in an amount of less than about 0.15 wt% based on the total weight of the composition or in an amount of less about than 0.1 wt% based on the total weight of the API composition; and in an amount of less than about 0.3 wt% based on the total weight of the API composition, particularly in an amount of less than about 0.15 wt% based on the total weight of the API composition or in an amount of less about than 0.1 wt% based on the total weight of the API composition.

[0208] In an embodiment, when Formula (A) is camlipixant, there is provided camlipixant API comprising pharmaceutically acceptable salt thereof; in an amount of up to about 0.3 wt% based on the total weight of the API composition, particularly in an amount of up to about 0.15 wt% based on the total weight of the API composition or in an amount of up to about 0.1 wt% based on the total weight of the API composition; and in an amount of up to about 0.3 wt% based on the total weight of the API composition, particularly in an amount of up to about 0.15 wt% based on the total weight of the API composition or in an amount of up to about 0.1 wt% based on the total weight of the API composition.

[0209] In an embodiment, there is provided camlipixantAPI comprising a compound of Formula (A); a compound of Formula (17-a) in an amount of from about 0.01 wt% and less than about 0.3 wt% based on the total weight of the API composition; and a compound of Formula (18-a) in an amount of from about 0.01 wt% and less than about 0.3 wt% based on the total weight of the API composition. In an embodiment, there is provided camlipixantAPI comprising a compound of Formula (A); a compound of Formula (17-a) in an amount of from about 0.01 wt% and less than about 0.15 wt% based on the total weight of the API composition; a compound of Formula (18-a) in an amount of from about 0.01 wt% and less than about 0.3 wt% based on the total weight of the API composition.

[0210] In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); a compound of Formula (17-a) in an amount of from about 0.01 wt% and less than about 0.1 wt% based on the total weight of the API composition; and a compound of Formula (18-a) in an amount of from about 0.01 wt% and less than about 0.3 wt% based on the total weight of the API composition

[0211] In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); a compound of Formula (17-a) in an amount of up to about 0.3 wt%, up to about 0.15 wt%, particularly up to about 0.1 wt% based on the total weight of the API composition; and a compound of Formula (17-a) in an amount of up to about 0.3 wt%, up to about 0.15 wt%, particularly up to about 0.1 wt% based on the total weight of the API composition.

[0212] In an embodiment, when Formula (A) is camlipixant, there is provided camlipixant API comprising pharmaceutically acceptable salt thereof; in an amount of less than about 0.3% area by HPLC, particularly in an amount of less than about 0.15% area by HPLC or in an amount of less about than 0.1 % area by HPLC; and in an amount of less than about 0.3% area by HPLC, particularly in an amount of less than about 0.15% area by HPLC or in an amount of less about than 0.1% area by HPLC.

[0213] In an embodiment, when Formula (A) is camlipixant, there is provided camlipixant API comprising pharmaceutically acceptable salt thereof; in an amount of up to about 0.3% area by HPLC, particularly in an amount of up to about 0.15% area by HPLC or in an amount of up to about 0.1% area by HPLC; and in an amount of up to about 0.3% area by HPLC, particularly in an amount of up to about 0.15% area by HPLC or in an amount of up to about 0.1 % area by HPLC.

[0214] In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); a compound of Formula (17-a) in an amount of from about 0.01 % and less than about 0.3% area by HPLC; and a com pound of Formula (18-a) in an amount of from about 0.01 % and less than about 0.3% area by HPLC.

[0215] In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); a compound of Formula (17-a) in an amount of from about 0.01 % and less than about 0.15% area by HPLC; a compound of Formula (18-a) in an amount of from about 0.01 % and less than about 0.3% area by HPLC.

[0216] In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); a compound of Formula (17-a) in an amount of from about 0.01 % and less than about 0.1 % area by HPLC; and a com pound of Formula (18-a) in an amount of from about 0.01 % and less than about 0.3% area by HPLC.

[0217] In an embodiment, there is provided camlipixant API comprising a compound of Formula (A); a compound of Formula (17-a) in an amount of up to about 0.3%, up to about 0.15%, particularly up to about 0.1 % area by HPLC; and a compound of Formula (17-a) in an amount of up to about 0.3%, up to about 0.15%, particularly up to about 0.1 % area by HPLC.

[0218] In an embodiment, there is also provided API composition comprising a compound of Formula (A) and which comprises process-related impurities, wherein the process-related impurities are a compound of Formula (17) and / or (18), wherein a compound of Formula (17) is present in an amount of from 0.01 to 0.5% area by HPLC, and wherein a compound of Formula (18) is present in an amount of from 0.01 to 1 % area by HPLC.

[0219] In an embodiment, there is also provided camlipixant API composition comprising a compound of camlipixant and which comprises process-related impurities, wherein the process-related impurities are a compound of Formula (17-a) and / or (18-a), wherein a compound of Formula (17-a) is present in an amount of from 0.01 to 0.5% area by HPLC, and wherein a compound of Formula (18-a) is present in an amount of from 0.01 to 1% area by HPLC.

[0220] In an embodiment, there is also provided API composition comprising a compound of Formula (A) and which comprises process-related impurities, wherein the process-related impurities are a compound of Formula (17) and / or (18), wherein a compound of Formula (17) is present in an amount of from 0.01 to 0.5 wt% based on the total weight of the API composition, and wherein a compound of Formula (18) is present in an amount of from 0.01 to 1 wt% based on the total weight of the API composition.

[0221] In an embodiment, there is also provided camlipixant API composition comprising a compound of camlipixant and which comprises process-related impurities, wherein the process-related impurities are a compound of Formula (17-a) and / or (18-a), wherein a compound of Formula (17-a) is present in an amount of from 0.01 to 0.1 wt% based on the total weight of the API composition, and wherein a compound of Formula (18-a) is present in an amount of from 0.01 to 0.1 wt% based on the total weight of the composition.

[0222] In an embodiment, there is also provided API composition comprising a compound of Formula (A) and which comprises process-related impurities, wherein the process-related impurities are a compound of Formula (17) and / or (18), wherein a compound of Formula (17) is present in an amount of from 0.01 to 0.1 % area by HPLC, and wherein a compound of Formula (18) is present in an amount of from 0.01 to 0.1 % area by HPLC.

[0223] In an embodiment, there is also provided camlipixant API composition comprising a compound of camlipixant and which comprises process-related impurities, wherein the process-related impurities are a compound of Formula (17-a) and / or (18-a), wherein a compound of Formula (17-a) is present in an amount of from 0.01 to 0.1 % area by HPLC, and wherein a compound of Formula (18-a) is present in an amount of from 0.01 to 0.1 % area by HPLC.

[0224] In an embodiment, there is also provided API composition comprising a compound of Formula (A) and which comprises process-related impurities, wherein the process-related impurities are a compound of Formula (17) and / or (18), wherein a compound of Formula (17) is present in an amount of from 0.01 to 0.1 wt% based on the total weight of the API composition, and wherein a compound of Formula (18) is present in an amount of from 0.01 to 0.1 wt% based on the total weight of the API composition.

[0225] In an embodiment, there is also provided camlipixant API composition comprising a compound of camlipixant and which comprises process-related impurities, wherein the process-related impurities are a compound of Formula (17-a) and / or (18-a), wherein a compound of Formula (17-a) is present in an amount of from 0.01 to 0.1 wt% based on the total weight of the API composition, and wherein a compound of Formula (18-a) is present in an amount of from 0.01 to 0.1 wt% based on the total weight of the composition.

[0226] In an embodiment, when Formula (A) is camlipixant, camlipixant may be purified to API by recrystallisation in methanol and water. In particular, it is possible to reduce the amount of a compound of Formula (18-a) in the API material by recrystallisation in methanol and water. In particular, it is possible to reduce the amount to about 0.01 % area as measured by HPLC to about 0.1 % area as measured by HPLC. In an embodiment, it is possible to reduce the amount to about 0.01 wt%to about 0.1 wt% based on the total weight of the API. The resultant camlipixant active pharmaceutical ingredient may then be jet-milled following recrystallisation.

[0227] In an embodiment, the compound according to Formula (A) is camlipixant, i.e. wherein R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X is -C(O)NHCH3, i.e. Rais hydrogen and Rbis CHs. It follows that the relevant groups defined in relation to a compound of Formula (17) or (18) are the same as those in camlipixant.

[0228] In an embodiment, R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X is -SO2NH2, i.e. Rais hydrogen and Rbis hydrogen.

[0229] In an embodiment, R1is chloro, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X is -SO2NH2, i.e. Rais hydrogen and Rbis hydrogen.

[0230] In an embodiment, R1is methyl, R2is hydrogen, R3, R4and R6are fluoro, R5is hydrogen and X is -C(O)NHCH3, i.e. Rais hydrogen and Rbis CH3.

[0231] In an embodiment, R1is chloro, R2is hydrogen, R3, R4and R6are fluoro, R5is hydrogen and X is -C(O)NHCH3, i.e. Rais hydrogen and Rbis CH3.

[0232] In an embodiment, R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X is -NHC(O)-cyclopropyl, i.e. Rais hydrogen and Rbis cyclopropyl.

[0233] In an embodiment, X and X1are the same.

[0234] In an embodiment, X and X1are -C(O)NHCH3, i.e. Rais hydrogen and Rbis CH3.

[0235] In an embodiment, the process further comprises contacting a compound of Formula (14)

[0236] with a suitable reducing agent to provide a compound of Formula (15), wherein R1, R2, R3, R4, R5, R6, and X1are as previously defined.

[0237] In an embodiment R7is ethyl or methyl.

[0238] In an embodiment, R7is methyl.

[0239] In an embodiment, R7is methyl in a compound of Formula (14) and a compound of Formula (15).

[0240] Therefore, in an embodiment, there is provided a process for the preparation of a compound of Formula (A) as defined above, wherein the process comprises conversion of a compound of Formula (15-1) to a compound of Formula (A), wherein R1, R2, R3, R4, R5, R6, and X1are as previously defined.

[0241] In an embodiment, it follows that the process further comprises contacting a compound of Formula (14-1)

[0242] with a suitable reducing agent to provide a compound of Formula (15-1), wherein R1, R2, R3, R4, R5, R6, and X1are as previously defined.

[0243] In an embodiment, the reducing agent is a chiral reducing agent.

[0244] In an embodiment, the chiral reducing agent is a ketoreductase enzyme in the presence of a cofactor.

[0245] In an embodiment, the cofactor is NADP+.

[0246] Alternatively, the chiral reducing agent comprises a ruthenium -based catalyst and a suitable source of hydrogen. In an embodiment, the chiral reducing agent comprises a chiral catalyst.

[0247] In an embodiment, the suitable source of hydrogen is formic acid and a suitable amine, wherein the suitable amine is a tertiary amine, optionally selected from the group consisting of triethylamine, N-methyl dicyclohexylamine, N-methyl morpholine, N,N- dimethylaminoethanol, TMEDA, (-)-sparteine and isopropylamine.

[0248] In an embodiment, the amine is triethylamine such that the compound of Formula (14) or (14-1) is contacted with a chiral catalyst (such as a ruthenium-based catalyst), formic acid and triethylamine.

[0249] In an embodiment, the ratio of formic acid to triethylamine is 1 :1 to 5:2. In an embodiment, the ratio is 5:2.

[0250] In an embodiment, the chiral catalyst is a ruthenium-based chiral catalyst.

[0251] In an embodiment, the chiral catalyst is a Noyori catalyst.

[0252] In an embodiment, the ruthenium-based chiral catalyst is selected from [(R)-BINAP RuCI (p- cymene)] Cl, [(S)-BINAP RuCI (p-cymene)] Cl, [(S)-BINAP RuCI (benzene)]CI, [(R)-BINAP RuCI (benzene)]CI, (S)-XylPPhos RuCI2 (S,S)-DPEN, (R)-XylPPhos RuCI2 (R,R)-DPEN, (R)- BINAP RuCI2 (R,R)-DPEN, (S)-BINAP RuCI2 (S,S)-DPEN, (R.R)-TsDPEN RuCI (p-cymene), (S.S)-TsDPEN RuCI (p-cymene), (R.R)-MsDPEN RuCI (p-cymene), (S,S)-MsDPEN RuCI (p- cymene), (R.R)-TsDPEN RuCI (mesitylene), (S.S)-TsDPEN RuCI (mesitylene), (R,R)- TsDACH RuCI (p-cymene), (S,S)-TsDACH RuCI (p-cymene), C4-[(R,R)-teth-TrisDPEN RuCI], C4-[(S,S)-teth-TrisDPEN RuCI], C3-[(R,R)-teth-MtsDPEN RuCI] and C3-[(S,S)-teth-MtsDPEN RuCI],

[0253] In an embodiment, the ruthenium -based chiral catalyst is selected from one of the following:

[0254] In an embodiment, the ruthenium-based chiral catalyst is C3-[(R,R)-teth-TsDPEN RuCI] or C3- [(S,S)-teth-TsDPEN RuCI]. In an embodiment, the ruthenium-based chiral catalyst is (S,S)- Ts-DENEB RuCI.

[0255] In an embodiment, the ruthenium -based chiral catalyst is selected from (R.R)-Ts-DENEB, (S.S)-Ts-DENEB, (R.R)-Ms-DENEB and (S,S)-Ms-DENEB, depicted as follows.

[0256] In an embodiment, the ruthenium-based chiral catalyst is present in an amount of from about 0.5 to about 10 mol%.

[0257] In an embodiment, the ruthenium-based chiral catalyst is present in an amount of from about 2 to about 6 mol%.

[0258] In an embodiment, the ruthenium -based chiral catalyst is present in an amount of about 5 mol%. When the process for the preparation of a compound of Formula (15) or (15-1) is carried out using a ruthenium -based chiral catalyst, the process may be carried out in a suitable solvent selected from acetonitrile, an ethereal solvent (for example methyl tert-butyl ether, tetrahydrofuran, 2-m ethyltetrahydrofuran or dioxane) or a polar aprotic solvent (for example dimethylformamide, dimethylacetamide or DMSO). In an embodiment, the solvent is acetonitrile. In another embodiment, the solvent is tetrahydrofuran or 2-m ethyl tetrahydrofuran (2-MeTHF). In an embodiment, the solvent is tetrahydrofuran.

[0259] In an embodiment, the compound of Formula (14) or (14-1) is contacted with a chiral catalyst suitable to provide a compound of Formula (15) or (15-1) having an enantiomeric excess of at least 70% to at least 99%, particularly at least 80 to at least 99%, particularly at least 90% to at least 99%, particularly at least 95% to at least 99%.

[0260] In an embodiment, the process further comprises contacting a compound of Formula (V) with a compound of Formula (16) followed by an agent selected from methyl chloroformate, dimethyl carbonate and dimethyl dicarbonate to provide a compound of Formula (14), optionally in the presence of a suitable base, wherein LG is a suitable leaving group and wherein R1, R2, R3, R4, R5, R6, and X1are as previously defined.

[0261] In an embodiment, the agent is methyl chloroformate.

[0262] In an embodiment, LG is a leaving group selected from the group consisting of halo, tosylate, mesylate and triflate.

[0263] In an embodiment, LG is halo.

[0264] In an embodiment, LG is chloro. Therefore, in an embodiment, the process further com prises contacting a compound of Formula (V-l) with a compound of Formula (16) followed by an agent selected from methyl chloroformate, dimethyl carbonate and dimethyl dicarbonate to provide a compound of Formula (14), optionally in the presence of a suitable base, wherein R1, R2, R3, R4, R5, R6, and X1are as previously defined.

[0265] In an embodiment R7is ethyl or methyl.

[0266] In an embodiment, R7is methyl.

[0267] In an embodiment, R7is methyl in a compound of Formula (14) and a compound of Formula (15) and (16).

[0268] In an embodiment, the suitable base is triethylamine.

[0269] In an embodiment, the process of contacting a compound of Formula (V) or (V-l) with a compound of Formula (16) to provide of a compound of Formula (14) may be carried out in a suitable solvent. For example, the solvent may be selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAc), isopropyl acetate (IPAc), N-methyl-2- pyrrolidone (NMP), methyl tert-butyl ether, acetonitrile, acetone, water and dichloromethane. In an embodiment, the solvent is dimethylacetamide (DMAc) or N-methyl-2-pyrrolidone (NMP). In a particular embodiment, the solvent is dimethylacetamide (DMAc).

[0270] In an embodiment, the process further comprises contacting a compound of Formula (VI) with a hydrogen halide, to provide a compound of Formula (V) or (V-l), wherein R1, R2, R3, R4, R5, R6, and X1are as previously defined.

[0271] In an embodiment, where LG is chloro, the hydrogen halide is hydrochloric acid.

[0272] In an embodiment, the hydrochloric acid is prepared by a combination of lithium chloride, tetrabutylammonium chloride or magnesium chloride and methanesulfonic acid. In an embodiment, the hydrochloric acid is prepared by a combination of lithium chloride and methanesulfonic acid.

[0273] In an embodiment, where LG is bromo or iodo, the hydrogen halide is hydrobromic acid or hydroiodic acid, respectively.

[0274] In an embodiment, the process of contacting a compound of Formula (VI) with hydrogen halide to provide a compound of Formula (V) or (V-l) may be carried out in the presence of a suitable solvent, wherein the solvent is an ethereal solvent or polar aprotic solvent. For example, the solvent may be selected from the group consisting of tetrahydrofuran, 2- methyltetrahydrofuran, ethyl acetate, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAc), isopropyl acetate (IPAc), N-methyl-2-pyrrolidone (NMP), methyl tert-butyl ether, acetonitrile, acetone, water and dichloromethane. In an embodiment, the solvent is dimethylacetamide (DMAc) or N-methyl-2-pyrrolidone (NMP). In a particular embodiment, the solvent is dimethylacetamide (DMAc).

[0275] For example, the solvent may be selected from the group consisting of tetrahydrofuran, 2- methyltetrahydrofuran, methyl tert-butyl ether, dioxane, dimethylformamide, dimethylsulfoxide and dimethylacetamide.

[0276] In an embodiment, the solvent is dimethylacetamide.

[0277] In an embodiment, the process further comprises contacting a compound of Formula (VII) with a trimethylsulfoxonium halide in the presence of a coupling reagent and a suitable base, to provide a compound of Formula (VI), wherein R1, R2, R3, R4, R5, R6, and X1are as previously defined.

[0278] In an embodiment, the trimethylsulfoxonium halide is trimethylsulfoxonium chloride. In an embodiment, the coupling reagent is selected from oxalyl chloride, thionyl chloride, hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), N,N’-dicyclohexylcarbodiimide (DCC) and carbonyldiimidazole (CDI).

[0279] In an embodiment, the coupling reagent is CDI.

[0280] In an embodiment, the suitable base used in the preparation of a compound of Formula (VI) is selected from the group consisting of potassium tert-butoxide, sodium hydride, lithium bis(trimethy Isily l)amide, sodium bis(trimethy Isily l)amide and a guanidine-based base.

[0281] In an embodiment, the base is potassium tert-butoxide.

[0282] In an embodiment, the process for the preparation of a compound of Formula (VI) by contacting a compound of Formula (VII) with a trimethylsulfoxonium halide in the presence of a coupling agent and suitable base, is carried out in the presence of a suitable solvent. The solvent may be selected from the group consisting of tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, 2-m ethyltetrahydrofuran, acetonitrile, isopropyl acetate, dichloromethane, N-methyl-2-pyrrolidone (NMP) and ethyl acetate. In an embodiment, the solvent is tetrahydrofuran or dimethyl sulfoxide. In an embodiment, the solvent is tetrahydrofuran. In an embodiment, the solvent is dimethyl sulfoxide. In an embodiment, the solvent is a combination of tetrahydrofuran and dimethyl sulfoxide.

[0283] In an embodiment the process further comprises contacting a compound of Formula (13) with a compound of Formula (VIII) in the presence of a suitable acid, to provide a compound of Formula (VII), wherein Y is a suitable amine group bound through nitrogen or a suitable trialkylphosphine group bound though phosphorus, wherein R1, R2, R3, R4, R5, R6, and X1are as previously defined.

[0284] In an embodiment, R1is methyl and R2is H. In an embodiment, the process for contacting a compound of Formula (13) with a compound of Formula (VIII) is carried out in the presence of a suitable solvent. In an embodiment, the solvent is a polar aprotic solvent in combination with acetic acid. In an embodiment, suitable solvent polar aprotic solvents may be toluene or acetonitrile. In an embodiment, the solvent is acetonitrile (MeCN). In an embodiment, the ratio of acetic acid to acetonitrile is 2:3 or 1 :3. In an embodiment, the ratio of acetic acid to acetonitrile is 1 :3.

[0285] In an embodiment, the process further comprises contacting a compound of Formula (IX) ormula (X) in the presence of a suitable nitrogen- or trialkylphosphorous-containing nucleophile to provide a compound of Formula (13) wherein Y is a suitable amine group bound through nitrogen or a suitable trialkylphosphine group bound through phosphorous, wherein R1, R2, R3, R4, R5, R6, and X1are as previously defined.

[0286] In an embodiment, the suitable nitrogen- or trialkylphosphorous-containing nucleophile is a nitrogen-containing nucleophile. In an embodiment, the nitrogen-containing nucleophile is selected from the group consisting of piperidine, 1 -methylimidazole, imidazole, 4- dimethylaminopiperidine (DMAP) and pyrrolidine. In an embodiment, the nitrogen-containing nucleophile is imidazole.

[0287] Therefore, it follows that, in an embodiment, Y is selected from piperidinyl, 1 -methylimidazolyl, imidazolyl, pyrrolidinyl and dimethylaminopiperidinyl. In particular, Y is imidazolyl, particularly N-linked imidazolyl. In an embodiment Y is

[0288] Therefore, in an embodiment, the process comprises contacting a compound of Formula (IX) ormula (X) in the presence of imidazole (i.e. wherein the nitrogen- or trialkylphosphorous-containing nucleophile is imidazole) to provide a compound of Formula (13-1) 1are as previously defined.

[0289] In an embodiment, the process of contacting a compound of Formula (IX) with a compound of Formula (X) in the presence of a nitrogen- or trialkylphosphorous-containing nucleophile to provide a compound of Formula (13) or (13-1) is carried out in the presence of a suitable solvent. For example, the solvent may be selected from the group consisting of tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-MeTHF), ethyl acetate, acetonitrile, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAc), isopropyl acetate (IPAc), dichloromethane (DCM), and N-Methyl-2-pyrrolidone (NMP). In an embodiment, the solvent is THF.

[0290] In an embodiment, the process further comprises contacting the compound of Formula (13) or (13-1) with a compound of Formula (VIII) in the presence of a suitable acid to provide a compound of Formula (VII), wherein R1and R2, are as previously defined.

[0291] In an embodiment, the suitable acid is formic acid or acetic acid. In an embodiment, the suitable acid is acetic acid.

[0292] In an embodiment, the process of contacting a compound of Formula (13) or (13-1) with a compound of Formula (VIII) to provide a compound of Formula (VII) is carried out in the presence of a suitable solvent. In an embodiment, the solvent is a polar aprotic solvent in combination with acetic acid. In an embodiment, suitable solvent polar aprotic solvents may be toluene or acetonitrile. In an embodiment, the solvent is acetonitrile (MeCN). In an embodiment, the ratio of acetic acid to acetonitrile is 2:3 or 1 :3. In an embodiment, the ratio of acetic acid to acetonitrile is 1 :3.

[0293] In an embodiment the process further comprises contacting a compound of Formula (XI) with a suitable acid, to provide a compound of Formula (X), wherein R' is C1-3 alkyl, and wherein R3, R4, R5, R6, and X1are as previously defined.

[0294] In an embodiment, the suitable acid is selected from the group consisting of hydrochloric acid, methanesulfonic acid, acetic acid or formic acid, or a combination thereof.

[0295] In an embodiment, the acid is formic acid.

[0296] In an alternative embodiment, the acid is a combination of methanesulfonic acid and formic acid.

[0297] In an embodiment, R' is methyl or ethyl. In an embodiment, R' is ethyl.

[0298] In an embodiment, the process of contacting a compound of Formula (XI) with a suitable acid to provide a compound of Formula (X) is carried out in the absence of a solvent.

[0299] In an embodiment, where X and X1is -C(O)NHCH3, i.e. , where Raand Rbare hydrogen and - CH3, the process further comprises contacting a compound of Formula (19) with methylamine hydrochloride in the presence of a suitable base and suitable coupling reagent, to provide a compound of Formula (Xl-I) wherein R' is C1-3 alkyl, and wherein R3, R4, R5and R6are as previously defined.

[0300] In an embodiment, the suitable base for the formation of a compound of Formula (Xl-I) is selected from the group consisting of imidazole, triethylamine, Hunig’s base, pyridine, potassium carbonate and sodium carbonate. In an embodiment, the suitable base is imidazole.

[0301] In an embodiment, the coupling reagent for the formation of a compound of Formula (Xl-I) is selected from oxalyl chloride, thionyl chloride, hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N,N’- dicyclohexylcarbodiimide (DCC) and carbonyldiimidazole (CDI).

[0302] In an embodiment, the suitable coupling reagent for the formation of a compound of Formula (Xl-I) is selected from the group consisting of hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and carbonyldiimidazole (CDI). In an embodiment, the suitable coupling reagent is CDI.

[0303] In an embodiment, the suitable base is imidazole and the suitable coupling reagent is CDI.

[0304] In an embodiment, the process of contacting a compound of Formula (19) with methylamine hydrochloride in the presence of a suitable base and suitable coupling reagent to provide a compound of Formula (Xl-I) is carried out in the presence of a suitable solvent. In an embodiment, the solvent is a polar aprotic solvent. For example, the solvent may be selected from the group consisting of tetrahydrofuran (THF), 2-m ethyl tetrahydrofuran (2-MeTHF), ethyl acetate, acetonitrile, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAc), isopropyl acetate (IPAc), dichloromethane (DCM), and N-Methyl- 2-pyrrolidone (NMP). In an embodiment, the solvent is DMSO.

[0305] In a further embodiment, the process further comprises contacting a compound of Formula (XII) (Xi is -CO2H) with a suitable base and ethyl diethoxyacetate (where R' is ethyl) or methyl dimethoxyacetate (where R' is methyl) to provide a compound of Formula (XI) or a salt thereof, optionally in the presence of a suitable solvent (such as THF), wherein R3, R4, R5and R6, are as previously defined.

[0306] In an embodiment, the suitable base is butyl lithium (BuLi) or lithium diisopropyl amide (LDA).

[0307] It will be understood by those skilled in the art that a suitable protecting group strategy may be employed to facilitate the conversion of the compound of Formula (Xll-I) to a compound of Formula (XI). For example, suitable protecting groups included tert-butyloxycarbonyl (Boc) and triisopropylsilyl. These groups may be removed by several methods well known to those skilled in the art (for examples see "Protective Groups in Organic Synthesis”, T.W. Greene and P.G.M. Wuts, Wiley- Interscience, 2006), for example Boc may be removed by conventional acid hydrolysis with, for example trifluoroacetic acid. Triisopropylsilyl may be removed, for example, by imidazole.

[0308] In an alternative embodiment, X1is CO2H and the process further comprises contacting a compound of Formula (XII) with tri methylol propane (TMP) in the presence of a suitable base (such as nBuLi) and tetramethylethylenediamine (TMEDA) followed by ethyl diethoxyacetate to provide a compound of Formula (19-1), i.e., where R’ is ethyl, wherein R3, R4, R5and R6are as previously defined.

[0309] In an alternative embodiment, the process further comprises contacting a compound of Formula (XII) with triisopropylsilyl chloride and N-m ethylmorpholine, followed by ethyl diethoxyacetate in the presence of lithium diisopropylamide, followed by imidazole, to provide a compound of Formula (20) wherein R3, R4, R5and R6are as previously defined.

[0310] In a further embodiment, the process comprises contacting a compound of Formula (XII) with butyl lithium, lithium 2, 2, 6, 6-tetram ethylpiperidine (LiTMP), and tetramethylethylenediamine (TMEDA), followed by ethyl diethoxyacetate to provide a compound of Formula (19-1), optionally in the presence of a suitable solvent (such as THF), wherein R3, R4, R5and R6are as previously defined. In an embodiment, the process further comprises contacting a compound of Formula (19) or (19-1), with a suitable coupling reagent and methylamine to provide a compound of Formula (Xl-I), i.e. , where R’ is ethyl. In an embodiment, the suitable coupling reagent is CDI. The process of contacting a compound of Formula (19) or (19-1), with a suitable coupling reagent and methylamine to provide a compound of Formula (Xl-I) may be carried out in the presence of a suitable solvent, such as DMSO.

[0311] In an alternative embodiment, the process further comprises contacting a compound of Formula (XII) with Boc anhydride, 4-dim ethylaminopyridine, and triethylamine followed by ethyl diethoxyacetate in the presence of and lithium diisopropylamide, followed by trifluoroacetic acid, to provide a compound of Formula (19), wherein R3, R4, R5and R6are as previously defined.

[0312] In an alternative embodiment, where X1is Br, the process further comprises contacting a compound of Formula (21) with a suitable base (for example LDA - lithium diisopropylamide) and ethyl diethoxyacetate (where R' is ethyl) or methyl dim ethoxy acetate (where R' is methyl) to provide a compound of Formula (XI), where X1is Br and wherein R3, R4, R5and R6are as previously defined.

[0313] The steps outlined above under Process A may also be used in the preparation of a compound of Formula (A'), i.e. having the opposite stereochemistry to a compound of Formula (A)

[0314] For example, the present invention may also comprise, in another aspect, a process for the preparation of a compound of Formula (A’) wherein

[0315] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0316] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0317] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (15') to a compound of Formula (A) wherein

[0318] R7is independently selected from C1-3 alkyl; and

[0319] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and X1may be the same or different. The further additional steps are the same as hereinbefore described except that in the step comprising the preparation of a compound of Formula (15'), a suitable reducing agent is used to install a chiral centre in a compound of Formula (15').

[0320] The steps outlined above under Process A may also be used in the preparation of a compound of Formula (A"), i.e. a racemic version of a compound of Formula (A) wherein

[0321] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0322] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0323] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (15") to a compound of Formula (A’) wherein

[0324] R7is independently selected from C1-3 alkyl; and

[0325] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and X1may be the same or different.

[0326] The further additional steps are the same as hereinbefore described except that in the step comprising the preparation of a compound of Formula (15"), a suitable reducing agent is used which provides a racemic OH-group. As defined above, there is provided herein, a process for the preparation of a compound of Formula (A) wherein

[0327] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0328] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0329] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (14) to a compound of Formula (15) wherein

[0330] R7is C1-3 alkyl; and

[0331] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and

[0332] X1may be the same or different. As defined above, there is provided herein, a process for the preparation of a compound of Formula (A) wherein

[0333] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0334] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0335] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (V) to a compound of Formula (14) wherein

[0336] R7is C1-3 alkyl; and

[0337] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and

[0338] X1may be the same or different.

[0339] As defined above, there is provided herein, a process for the preparation of a compound of Formula (A)

[0340] wherein

[0341] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0342] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0343] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (VI) to a compound of Formula (V) wherein

[0344] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and

[0345] X1may be the same or different; and

[0346] LG is a suitable leaving group.

[0347] In an embodiment, LG is chloro such that there is provided a process for the preparation of a compound of Formula (A)

[0348] wherein

[0349] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0350] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0351] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (VI) to a compound of Formula (V-l) wherein

[0352] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and X1may be the same or different.

[0353] As defined above, there is provided herein, a process for the preparation of a compound of Formula (A)

[0354] wherein

[0355] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0356] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0357] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (VII) to a compound of Formula (VI) wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband-SO2NRaRb, where X and X1may be the same or different.

[0358] As defined above, there is provided herein, a process for the preparation of a compound of Formula (A)

[0359] wherein

[0360] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0361] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0362] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (13) wherein Y is a suitable amine group bound through nitrogen or a suitable trialkylphosphine group bound though phosphorus to a compound of Formula (VII) wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband-SO2NRaRb, where X and X1may be the same or different.

[0363] In an embodiment, Y is imidazolyl, such that there is provided a process for the conversion of a compound of Formula (13) to a compound of Formula (VII) wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband-SO2NRaRb, where X and X1may be the same or different.

[0364] As defined above, there is provided herein a process for the preparation of a compound of Formula (A) wherein

[0365] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0366] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0367] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (X) to a compound of Formula (13) wherein

[0368] Y is a suitable amine group bound through nitrogen or a suitable trialkylphosphine group bound though phosphorus; and

[0369] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and X1may be the same or different.

[0370] In an embodiment, Y is imidazolyl, such that there is provided, a process for the preparation of a compound of Formula (A) wherein

[0371] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0372] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0373] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (X) to a compound of Formula (13-1) wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband-SO2NRaRb, where X and X1may be the same or different.

[0374] As defined above, there is provided a process for the preparation of a compound of Formula (A) wherein

[0375] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0376] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0377] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (XI) to a compound of Formula (X) wherein R' is C1-3 alkyl; and X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and X1may be the same or different.

[0378] In an embodiment, conversion of a compound of Formula (XI) to a compound of Formula (X) comprises contacting a compound of Formula (XI) with a suitable acid as previously described, for example hydrochloric acid, methanesulfonic acid, acetic acid or formic acid, particularly a combination of methanesulfonic acid and formic acid.

[0379] In an embodiment, R' is methyl or ethyl. In an embodiment, R' is ethyl.

[0380] Therefore, in an embodiment, there is provided a process for the preparation of a compound of Formula (A), the process comprising conversion of a compound of Formula (Xl-I) to a compound of Formula (X), wherein R3, R4, R5, R6and X1are as previously defined.

[0381] Reaction conditions for each of the described conversions are as previously described.

[0382] In any one of the above aspects or embodiments, in a compound of Formula (A), (A’) or (A”), R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen, X is -C(O)NHCH3, i.e. Rais hydrogen and Rbis CH3.

[0383] In any one of the above aspects or embodiments, in a compound of Formula (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen, X1is -C(O)NHCH3, i.e. Rais hydrogen and Rbis CH3.

[0384] In an embodiment, the compound according to Formula (A) is camlipixant, i.e. wherein R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X is -C(O)NHCH3, i.e. Rais hydrogen and Rbis CH3. It follows from this that the corresponding intermediates used in the process for the preparation of camlipixant will have corresponding R1, R2, R3, R4, R5and R6.

[0385] In any one of the above aspects or embodiments, the compound according to Formula (A) is camlipixant, i.e. wherein R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X1is -C(O)NHCH3, i.e. depicted by the following structure

[0386] Therefore, in an embodiment, the present invention provides a process for the preparation of a compound of Formula (A), the process comprising contacting a compound of Formula (15-a) with a suitable acid (such as, for example, methanesulfonic acid), followed by a suitable reducing agent (such as, for example, tetramethyldisiloxane wherein

[0387] R7is independently selected from C1-3 alkyl.

[0388] In an embodiment, the process further comprises contacting a compound of Formula (14-a) with a suitable reducing agent (such as a chiral reducing agent, for example a ketoreductase enzyme in the presence of a cofactor or a ruthenium-based catalyst in the presence of a suitable source of hydrogen) to provide a compound of Formula (15-a).

[0389] In an embodiment, the suitable reducing agent for contacting a compound of Formula (14-a) to provide a compound of Formula (15-a) is a ketoreductase enzyme in the presence of a cofactor, wherein the cofactor is NADP+.

[0390] In an embodiment, the process further comprises contacting a compound of Formula (V-a) with a compound of Formula (16) followed by an agent selected from methyl chloroform ate, dimethyl carbonate and dimethyl dicarbonate to provide a compound of Formula (14), optionally in the presence of a suitable base, wherein LG is a suitable leaving group, to provide a compound of Formula (14-a).

[0391] In an embodiment, the agent is methyl chloroformate and the suitable base is triethylamine.

[0392] In an embodiment, LG is selected from the group consisting of halo, tosylate, mesylate and triflate.

[0393] In an embodiment, LG is halo. In an embodiment, LG is chloro.

[0394] In an embodiment, the compound of Formula (V-a) is a compound of Formula (V-la), wherein

[0395] LG is chloro la). Therefore, in a particular embodiment, the process further comprises contacting a compound of Formula (5-la) with a compound of Formula (16) followed by an agent selected from methyl chloroform ate, dimethyl carbonate and dimethyl dicarbonate to provide a compound of Formula (14), optionally in the presence of a suitable base,

[0396] In an embodiment, the agent is methyl chloroformate and the suitable base is triethylamine.

[0397] In an embodiment, the process further comprises contacting a compound of Formula (Vl-a) with a hydrogen halide, to provide a compound of Formula (V-a).

[0398] In an embodiment, the hydrogen halide is hydrochloric acid, which is prepared by a combination of lithium chloride and methanesulfonic acid.

[0399] In an embodiment, the process further comprises contacting a compound of Formula (Vll-a) with a trimethylsulfoxonium halide in the presence of a coupling reagent and a suitable base, to provide a compound of Formula (Vl-a). In an embodiment, the trimethylsulfoxonium halide is trimethylsulfoxonium chloride, the coupling reagent is CDI and the suitable base is potassium tert-butoxide.

[0400] In an embodiment the process further comprises contacting a compound of Formula (13-a) with a compound of Formula (Vlll-a)

[0401] XX (Vlll-a) in the presence of a suitable acid (such as acetic acid), to provide a compound of Formula

[0402] (Vll-a), wherein Y is a suitable amine group bound through nitrogen or a suitable trialkylphosphine group bound though phosphorus.

[0403] In an embodiment, Y is imidazolyl, i.e. the process further comprises contacting a compound of Formula (13-la) with a compound of Formula (Vlll-a)

[0404] ^VNH2 X (Vlll-a) in the presence of a suitable acid (such as acetic acid), to provide a compound of Formula (Vll-a).

[0405] In an embodiment the process further comprises contacting a compound of Formula (IX) with a compound of Formula (X-a) in the presence of a suitable nitrogen-containing or phosphorous-containing nucleophile, to provide a compound of Formula (13-a).

[0406] In an embodiment, the suitable nitrogen-containing nucleophile is imidazole, such that the compound of Formula (13-a) is a compound of Formula (13-la)

[0407] In an embodiment the process further comprises contacting a compound of Formula (Xl-a) with a suitable acid (such as methanesulfonic acid, formic acid, or a combination thereof), to provide a compound of Formula (X-a), wherein R' is selected from C1-3 alkyl.

[0408] In an embodiment, R’ is ethyl.

[0409] In an embodiment, the process further comprises contacting a compound of Formula (Xll-a) with a suitable base and ethyl diethoxyacetate (where R' is ethyl) or methyl dim ethoxy acetate (where R' is methyl) to provide a compound of Formula (Xl-a).

[0410] In an embodiment, the suitable base is butyl lithium (BuLi) or lithium diisopropyl amide (LDA). It will be understood by those skilled in the art that a suitable protecting group strategy may be employed to facilitate the conversion of the compound of Formula (Xll-a) to a compound of Formula (Xl-a), as described above.

[0411] In an alternative embodiment, the process further comprises contacting a compound of Formula (Xll-a) with triisopropylsilyl chloride and N-m ethylmorpholine, followed by ethyl diethoxyacetate in the presence of lithium diisopropylamide, followed by imidazole in the presence of methylcyclohexane, to provide a compound of Formula (20-a)

[0412] In an alternative embodiment, the process further comprises contacting a compound of

[0413] Formula (Xll-a) with Boc anhydride, 4-dim ethylaminopyridine, and triethylamine followed by ethyl diethoxyacetate in the presence of LDA, followed by trifluoroacetic acid, to provide a compound of Formula (19-la) la). In a particular embodiment, the process further com prises contacting a compound of Formula (Xll-a) with butyl lithium, lithium 2, 2, 6, 6-tetram ethylpiperidine (LiTMP), and tetramethylethylenediamine (TMEDA, followed by ethyl diethoxyacetate to provide a compound of Formula (19-la).

[0414] Process B

[0415] An alternative process for the preparation of a compound of Formula (A) is provided below.

[0416] Disclosed herein is a process for the preparation of a compound of Formula (A), wherein

[0417] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0418] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0419] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0420] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (I) to a compound of Formula (II) wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband-SO2NRaRb, where X and X1may be the same or different.

[0421] In an embodiment, the process for the preparation of a compound of Formula (A) comprises contacting a compound of Formula (I) with 2-aminoethyl hydrogen sulfate in the presence of a suitable base to provide a compound of Formula (II), wherein the base may be selected from the group consisting of 1 ,8-diazabicyclo(5.4.0)undec-7-ene (DBU), triethylamine, isopropylamine, n-m ethylmorpholine, pyridine, potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide. In an embodiment, the base is any suitable tertiary amine. In an embodiment, the base is DBU.

[0422] In an embodiment, the process for the preparation of a compound of Formula (A) comprises contacting a compound of Formula (I) with 2-aminoethyl hydrogen sulfate in the presence of 1 ,8-diazabicyclo(5.4.0)undec-7-ene (DBU) to provide a compound of Formula (II).

[0423] In some embodiments, following addition of 2-aminoethyl hydrogen sulfate, sodium hydroxide is added.

[0424] In an alternative embodiment, the process forthe preparation of a compound of Formula (A) comprises contacting a compound of Formula (I) with ethanolamine in the presence of a suitable activating agent, wherein the activating agent may be tosyl chloride or mesyl chloride.

[0425] In an alternative embodiment, the process forthe preparation of a compound of Formula (A) comprises contacting a compound of Formula (I) with ethanolamine in the presence of diethyl azodicarboxylate and triphenyl phosphine (also known as a Mitsonobu reaction) to provide a compound of Formula (II).

[0426] In an embodiment, the process for the preparation of a compound of Formula (A) by conversion of a compound of Formula (I) to a compound of Formula (II) is carried out in the presence of a suitable solvent. In an embodiment, the solvent is an ethereal or alcohol-based solvent. In an embodiment, the solvent is selected from the group consisting of tetrahydrofuran, 2-m ethyltetrahydrofuran, dioxane and methyl tert-butyl ether. Alternatively, the solvent is an alcohol-based solvent, such as methanol or ethanol. In an embodiment, the solvent is ethanol.

[0427] In an embodiment, the compound according to Formula (A) is camlipixant, i.e. wherein R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X is -C(O)NHCH3, i.e. Rais hydrogen and Rbis CH3.

[0428] In an embodiment, R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X is -SO2NH2, i.e. Rais hydrogen and Rbis hydrogen.

[0429] In an embodiment, R1is chloro, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X is -SO2NH2, i.e. Rais hydrogen and Rbis hydrogen.

[0430] In an embodiment, R1is methyl, R2is hydrogen, R3, R4and R6are fluoro, R5is hydrogen and X is -C(O)NHCH3, i.e. Rais hydrogen and Rbis CH3.

[0431] In an embodiment, R1is chloro, R2is hydrogen, R3, R4and R6are fluoro, R5is hydrogen and X is -C(O)NHCH3, i.e. Rais hydrogen and Rbis CH3.

[0432] In an embodiment, R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X is -NHC(O)-cyclopropyl, i.e. Rais hydrogen and Rbis cyclopropyl.

[0433] In an embodiment, X and X1are the same.

[0434] In an embodiment, X and X1are -C(O)NHCH3, i.e. Rais hydrogen and Rbis CH3.

[0435] In an embodiment, the process for the preparation of a compound of Formula (A) further comprises contacting a compound of Formula (II) with methyl chloroform ate, dimethyl carbonate or dimethyl dicarbonate optionally in the presence of a suitable base, such as triethylamine, Hunig’s base, pyridine, potassium carbonate or sodium carbonate, to provide a compound of Formula (A). In an embodiment, the base is triethylamine. In an embodiment, the addition of methyl chloroformate, dimethyl carbonate or dimethyl dicarbonate is carried out in the presence of a suitable solvent selected from the group consisting of tetrahydrofuran, 2- m ethyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, acetone, water and dichloromethane. In an embodiment, the solvent is a mixture of acetone and water.

[0436] In an embodiment, the process further comprises contacting a compound of Formula (III) with a quaternary ammonium salt in the presence of a suitable base, to provide a compound of Formula (I).

[0437] In an embodiment, the quaternary ammonium salt is a tetraalkylammonium halide.

[0438] In an embodiment, the tetraalkylammonium halide is a tetrabutylammonium halide.

[0439] In an embodiment, the tetrabutylammonium halide is tetrabutylammonium bromide (TBAB) and the suitable base is sodium hydroxide, potassium hydroxide or lithium hydroxide. In an embodiment, the base is potassium hydroxide.

[0440] In an alternative embodiment, the compound of Formula (I) is prepared by contacting a compound of Formula (III) with a base selected from the group consisting of sodium hydride, lithium bis(trimethylsilyl)am ide and potassium bis(trimethylsilyl)amide.

[0441] The process for the conversion of a compound of Formula (III) to a compound of Formula (I) may be carried out in a suitable solvent selected from the group consisting of dichloromethane, dichloroethane and tetrahydrofuran. In an embodiment, the solvent is dichloromethane (DCM).

[0442] In an embodiment, the process further comprises contacting a compound of Formula (VI) with a chiral catalyst and a suitable source of hydrogen, to provide a compound of Formula (III), wherein R1, R2, R3, R4, R5, R6and X1are as previously defined.

[0443] In an embodiment, the source of hydrogen is formic acid and a suitable amine. In an embodiment, the amine for use in the preparation of a compound of Formula (III) with a chiral catalyst and formic acid is a tertiary amine, wherein the tertiary amine may be selected from the group consisting of triethylamine, N-methyl dicyclohexylamine, N-methyl morpholine, N,N-dim ethylaminoethanol, TMEDA, (-)-sparteine and isopropylamine. In an embodiment, the amine is triethylamine such that the compound of Formula (III) is prepared by contacting a compound of Formula (VI) with a chiral catalyst, formic acid, and triethylamine.

[0444] In an embodiment, the ratio of formic acid to triethylamine is 1 :1 to 5:2. In an embodiment, the ratio is 5:2.

[0445] In an embodiment, the chiral catalyst is a ruthenium -based chiral catalyst.

[0446] In an embodiment, the chiral catalyst is a Noyori catalyst.

[0447] In an embodiment, the ruthenium-based chiral catalyst is selected from [(R)-BINAP RuCI (p- cymene)] Cl, [(S)-BINAP RuCI (p-cymene)] Cl, [(S)-BINAP RuCI (benzene)JCI, [(R)-BINAP RuCI (benzene)JCI, (S)-XylPPhos RuCI2 (S,S)-DPEN, (R)-XylPPhos RuCI2 (R,R)-DPEN, (R)- BINAP RuCI2 (R,R)-DPEN, (S)-BINAP RuCI2 (S,S)-DPEN, (R.R)-TsDPEN RuCI (p-cymene), (S.S)-TsDPEN RuCI (p-cymene), (R.R)-MsDPEN RuCI (p-cymene), (S,S)-MsDPEN RuCI (p- cymene), (R.R)-TsDPEN RuCI (mesitylene), (S.S)-TsDPEN RuCI (mesitylene), (R,R)- TsDACH RuCI (p-cymene), (S,S)-TsDACH RuCI (p-cymene), C4-[(R,R)-teth-TrisDPEN RuCI], C4-[(S,S)-teth-TrisDPEN RuCI], C3-[(R,R)-teth-MtsDPEN RuCI] and C3-[(S,S)-teth-MtsDPEN RuCI],

[0448] In an embodiment, the ruthenium -based chiral catalyst is selected from one of the following:

[0449] In an embodiment, the ruthenium-based chiral catalyst is C3-[(R,R)-teth-TsDPEN RuCI] or C3- [(S,S)-teth-TsDPEN RuCI]. In an embodiment, the ruthenium-based chiral catalyst is (S,S)- Ts-DENEB RuCI.

[0450] In an embodiment, the ruthenium -based chiral catalyst is selected from (R.R)-Ts-DENEB, (S.S)-Ts-DENEB, (R.R)-Ms-DENEB and (S,S)-Ms-DENEB, depicted as follows.

[0451] (R.R)-Ms-DENEB (S.S)-Ms-DENEB.

[0452] In an embodiment, the ruthenium -based chiral catalyst is present in an amount of from about 0.5 to about 10 mol%.

[0453] In an embodiment, the ruthenium-based chiral catalyst is present in an amount of from about 2 to about 6 mol%.

[0454] In an embodiment, the ruthenium -based chiral catalyst is present in an amount of about 5 mol%.

[0455] The process for the preparation of a compound of Formula (III) may be carried out in a suitable solvent selected from acetonitrile, an ethereal solvent (for example methyl tert-butyl ether, tetrahydrofuran, 2-m ethyltetrahydrofuran or dioxane) or a polar aprotic solvent (for example dimethylformamide, dimethylacetamide or DMSO). In an embodiment, the solvent is acetonitrile. In another embodiment, the solvent is tetrahydrofuran.

[0456] In an embodiment, the compound of Formula (VI) is contacted with a chiral catalyst suitable to provide a compound of Formula (III) having an enantiomeric excess of at least 70% to at least 99%, particularly at least 80 to at least 99%, particularly at least 90% to at least 99%, particularly at least 95% to at least 99%.

[0457] In an alternative embodiment, the process further comprises contacting a compound of Formula (IV) with a quaternary ammonium salt in the presence of a suitable base, to provide a compound of Formula (I), wherein R1, R2, R3, R4, R5, R6and X1are as previously defined. wherein LG is a suitable leaving group.

[0458] In an embodiment, LG is a leaving group selected from the group consisting of halo, tosylate, mesylate and triflate.

[0459] In an embodiment, the compound of Formula (IV) is a compound of Formula (I V-l), wherein LG is chloro wherein R1, R2, R3, R4, R5, R6and X1are as previously defined.

[0460] Therefore, in a particular embodiment, the process further com prises contacting a compound of Formula (IV-I) with a quaternary ammonium salt in the presence of a suitable base, to provide a compound of Formula (I), wherein R1, R2, R3, R4, R5, R6and X1are as previously defined.

[0461] In an embodiment, the quaternary ammonium salt is a tetraalkylammonium halide.

[0462] In an embodiment, the tetraalkylammonium halide is a tetrabutylammonium halide. In an embodiment, the tetrabutylammonium halide is tetrabutylammonium bromide (TBAB) and the suitable base is sodium hydroxide, potassium hydroxide or lithium hydroxide. In an embodiment, the base is potassium hydroxide.

[0463] The process for the conversion of a compound of Formula (I V-l ) to a compound of Formula (I) may be carried out in a suitable solvent selected from the group consisting of dichloromethane, dichloroethane and tetrahydrofuran. In an embodiment, the solvent is dichloromethane (DCM).

[0464] In an embodiment, the process further comprises contacting a compound of Formula (V) with a ketoreductase enzyme; or a chiral catalyst and a suitable source of hydrogen, to provide a compound of Formula (IV), wherein LG is a suitable leaving group as previously defined, i.e. halo, tosylate, mesylate or triflate, wherein R1, R2, R3, R4, R5, R6and X1are as previously defined.

[0465] In an embodiment, the source of hydrogen is formic acid and a suitable amine.

[0466] In an embodiment, the amine is a tertiary amine, wherein the tertiary amine may be selected from the group consisting of triethylamine, N-methyl dicyclohexylamine, N-methyl morpholine, N,N-dim ethylaminoethanol, TMEDA, (-)-sparteine and isopropylamine. In an embodiment, the amine is triethylamine such that the compound of Formula (IV) is prepared by contacting a compound of Formula (V) with a chiral catalyst, formic acid, and triethylamine.

[0467] In an embodiment, the compound of Formula (V) is a compound of Formula (V-l), wherein LG is chloro wherein R1, R2, R3, R4, R5, R6and X1are as previously defined. Therefore, in a particular embodiment, the process further com prises contacting a compound of Formula (V-l) with a ketoreductase enzyme; or a chiral catalyst and a suitable source of hydrogen, to provide a compound of Formula (IV-I), wherein R1, R2, R3, R4, R5, R6and X1are as previously defined.

[0468] In an embodiment, the source of hydrogen is formic acid and a suitable amine.

[0469] In an embodiment, the amine is a tertiary amine, wherein the tertiary amine may be selected from the group consisting of triethylamine, N-methyl dicyclohexylamine, N-methyl morpholine, N,N-dim ethylaminoethanol, TMEDA, (-)-sparteine and isopropylamine. In an embodiment, the amine is triethylamine such that the compound of Formula (IV-I) is prepared by contacting a compound of Formula (V-l) with a chiral catalyst, formic acid, and triethylamine.

[0470] In an embodiment, the chiral catalyst is a ruthenium-based chiral catalyst. In an embodiment, the chiral catalyst is a Noyori catalyst. In an embodiment, the ruthenium-based chiral catalyst is as described above.

[0471] In an embodiment, the process further comprises contacting a compound of Formula (VI) with a suitable acid, to provide a compound of Formula (V) or Formula (V-l), wherein R1, R2, R3, R4, R5, R6and X1are as previously defined.

[0472] In an embodiment, where LG is chloro, the acid is hydrochloric acid. In an embodiment, the hydrochloric acid is prepared by a combination of lithium chloride, tetrabutylammonium chloride or magnesium chloride and methanesulfonic acid. This process may be carried out in the presence of a suitable solvent, wherein the solvent is an ethereal solvent or polar aprotic solvent. For example, the solvent may be selected from the group consisting of tetrahydrofuran, 2-m ethyltetrahydrofuran, methyl tert-butyl ether, dioxane, dimethylformamide, dimethylsulfoxide and dimethylacetamide.

[0473] In an embodiment, where LG is bromo or iodo, the acid is HBr or HI, respectively.

[0474] In an embodiment, where LG is selected from tosylate, mesylate and triflate, the process may further com prise contacting a compound of Formula (Vl) with basic water, for exam pie sodium bicarbonate or sodium hydroxide to provide an alpha hydroxy ketone, followed by contacting the alpha hydroxy ketone with mesyl chloride or tosyl chloride to provide the corresponding mesylate or triflate LG, respectively.

[0475] In an embodiment, the process further comprises contacting a compound of Formula (VII) with trim ethylsulf oxonium chloride in the presence of a coupling reagent and a suitable base, to provide a compound of Formula (VI), wherein R1, R2, R3, R4, R5, R6and X1are as previously defined.

[0476] In an embodiment, the coupling reagent is selected from oxalyl chloride, thionyl chloride, hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), N,N’-dicyclohexylcarbodiimide (DCC) and carbonyldiimidazole (CDI).

[0477] In an embodiment, the coupling reagent is selected from hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) and carbonyldiimidazole (CDI).

[0478] In an embodiment, the coupling reagent is CDI.

[0479] In an embodiment, the base used in the preparation of a compound of Formula (VI) is selected from the group consisting of potassium tert-butoxide, sodium hydride, lithium bis(trimethylsilyl)am ide, sodium bis(trimethylsilyl)am ide and a guanidine-based base.

[0480] In an embodiment, the base is potassium tert-butoxide.

[0481] In another aspect of the invention, there is provided a process for the preparation of a compound of Formula (I) wherein

[0482] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0483] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0484] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0485] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising contacting a compound of Formula (VII) with trim ethylsulf oxonium chloride in the presence of a coupling reagent and a suitable base, to provide a compound of Formula (VI)

[0486] In an embodiment, the coupling reagent is selected from oxalyl chloride, thionyl chloride, hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), N,N’-dicyclohexylcarbodiimide (DCC) and carbonyldiimidazole (CDI).

[0487] In an embodiment, the coupling reagent used in the preparation of a compound of Formula (I) (by conversion of a compound of Formula (VII) to a compound of Formula (VI)) is selected from hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) and carbonyldiimidazole (CDI). In an embodiment, the coupling reagent is CDI.

[0488] In an embodiment, the base used in the preparation of a compound of Formula (I) is selected from potassium tert-butoxide and tetramethylguanidine. In an embodiment, the base is potassium tert-butoxide.

[0489] The process for the preparation of a compound of Formula (I) comprising contacting a compound of Formula (VII) with trim ethylsulf oxonium chloride in the presence of a coupling reagent, may be carried out in the presence of a suitable solvent selected from the group consisting of tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, 2- m ethyltetrahydrofuran, acetonitrile, isopropyl acetate and ethyl acetate. In an embodiment, the solvent is tetrahydrofuran.

[0490] In an embodiment, the process further comprises contacting a compound of Formula (VIII) with a compound of Formula (IX) and a compound of Formula (X) to provide a com pound of Formula (VI I), wherein R1, R2, R3, R4, R5, R6and X1are as previously defined.

[0491] The process for the preparation of Formula (VII) may be carried out in the presence of a suitable solvent selected from the group consisting of acetonitrile, dimethylacetamide, cyrene (dihydrolevoglucosenone), tert-amyl alcohol, dimethylsulfoxide, dimethylformamide or acetic acid. In an embodiment, the solvent is acetonitrile or dimethylacetamide. In an embodiment, the solvent is dimethylacetamide. In an embodiment, the solvent is acetic acid. It has been found that when the solvent is acetic acid, the reaction proceeds faster.

[0492] The compound of Formula (IX) is also known as Meldrum’s acid.

[0493] In an embodiment, the process further comprises contacting a compound of Formula (XI) with a suitable acid to provide a compound of Formula (X), wherein R' is independently selected from C1-3 alkyl and wherein R3, R4, R5, R6and X1are as previously defined.

[0494] In an embodiment, the acid is selected from the group consisting of hydrochloric acid, methanesulfonic acid, acetic acid or formic acid.

[0495] In an embodiment, the acid is formic acid.

[0496] In an alternative embodiment, the acid is methanesulfonic acid and acetic acid.

[0497] In an embodiment, R' is methyl or ethyl. In an embodiment, R' is ethyl.

[0498] In an embodiment, when X is -C(O)NHCH3 and R' is ethyl, the process further comprises contacting a compound of Formula (20) with methylammonium chloride in the presence of a coupling reagent (for example, hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) or carbonyldiimidazole (CDI)), to provide a compound of Formula (XI), wherein R3, R4, R5and R6are as previously defined.

[0499] In an embodiment, the coupling reagent for the preparation of a compound of Formula (XI) is CDI.

[0500] In an embodiment, the process further comprises contacting a compound of Formula (XII) with triisopropylsilyl chloride and N-m ethylmorpholine, followed by ethyl diethoxyacetate in the presence of lithium diisopropylamide, followed by imidazole in the presence of methylcyclohexane, to provide a compound of Formula (XII), wherein R3, R4, R5and R6are as previously defined.

[0501] In an alternative embodiment, where X1is Br, the process further comprises contacting a compound of Formula (21) with a suitable base (for example LDA - lithium diisopropylamide) and ethyl diethoxyacetate (where R' is ethyl) or methyl dim ethoxy acetate (where R' is methyl) to provide a compound of Formula (XI) where X1is Br and wherein R3, R4, R5and R6are as previously defined.

[0502] In another aspect of the invention, there is provided a process for the preparation of a compound of Formula (I) wherein

[0503] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0504] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0505] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0506] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising contacting a compound of Formula (III) with a quaternary ammonium salt in the presence of a suitable base, to provide a compound of Formula (II).

[0507] In an embodiment, the quaternary ammonium salt is a tetraalkylammonium halide.

[0508] In an embodiment, the tetraalkylammonium halide is a tetrabutylammonium halide. In an embodiment, the tetrabutylammonium halide is tetrabutylammonium bromide (TBAB) and the suitable base is sodium hydroxide, potassium hydroxide or lithium hydroxide. In an embodiment, the base is potassium hydroxide.

[0509] The process for the preparation of a compound of Formula (I) comprising contacting a compound of Formula (III) with a quaternary ammonium salt may be carried out in the presence of a suitable solvent selected from the group consisting of dichloromethane, dichloroethane and tetrahydrofuran. In an embodiment, the solvent is dichloromethane.

[0510] In an alternative embodiment, the compound of Formula (I) is prepared by contacting a compound of Formula (III) with a base selected from the group consisting of sodium hydride, lithium bis(trimethylsilyl)am ide and potassium bis(trimethylsilyl)am ide.

[0511] In another aspect of the invention, there is provided a process for the preparation of a compound of Formula (III) wherein

[0512] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0513] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl; X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0514] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising contacting a compound of Formula (VI) with a chiral catalyst and a suitable source of hydrogen.

[0515] In an embodiment, the source of hydrogen is formic acid and a suitable amine.

[0516] In an embodiment, the amine for use in the preparation of a compound of Formula (III) with a chiral catalyst and formic acid is a tertiary amine, wherein the tertiary amine may be selected from the group consisting of triethylamine, N-methyl dicyclohexylamine, N-methyl morpholine, N,N-dim ethylaminoethanol, TMEDA, (-)-sparteine and isopropylamine. In an embodiment, the amine is triethylamine such that the compound of Formula (III) is prepared by contacting a compound of Formula (VI) with a chiral catalyst, formic acid, and triethylamine.

[0517] The processforthe preparation of a compound of Formula (III) may be carried out in a suitable solvent selected from acetonitrile, an ethereal solvent (for example methyl tert-butyl ether, tetrahydrofuran, 2-m ethyltetrahydrofuran or dioxane) or a polar aprotic solvent (for example dimethylformamide, dimethylacetamide or DMSO). In an embodiment, the solvent is acetonitrile. In another embodiment, the solvent is tetrahydrofuran.

[0518] An appropriate chiral catalyst for the preparation of a compound of Formula (III) is any of those previously defined.

[0519] In an embodiment, the chiral catalyst is a ruthenium -based chiral catalyst.

[0520] In an embodiment, the chiral catalyst is a Noyori catalyst.

[0521] In an embodiment, the ruthenium -based chiral catalyst is selected from any one of those previously defined.

[0522] In an embodiment, the ruthenium-based chiral catalyst is C3-[(R,R)-teth-TsDPEN RuCI] or C3- [(S,S)-teth-TsDPEN RuCI]. In an embodiment, the ruthenium-based chiral catalyst is (S,S)- Ts-DENEB RuCI. In an embodiment, the ruthenium -based chiral catalyst is present in an amount of from about 0.5 to about 10 mol%.

[0523] In an embodiment, the ruthenium -based chiral catalyst is present in an amount of from about 2 to about 6 mol%.

[0524] In an embodiment, the ruthenium-based chiral catalyst is present in an amount of about 5 mol%.

[0525] In another aspect of the invention, there is provided a process for the preparation of a compound of Formula (I) wherein

[0526] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0527] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0528] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0529] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising contacting a compound of Formula (VI) with a chiral catalyst and a suitable source of hydrogen, to provide a compound of Formula (III)

[0530] In an embodiment, the source of hydrogen is formic acid and a suitable amine.

[0531] In an embodiment, the amine for use in the preparation of a compound of Formula (III) with a chiral catalyst and formic acid is a tertiary amine, wherein the tertiary amine may be selected from the group consisting of triethylamine, N-methyl dicyclohexylamine, N-methyl morpholine,

[0532] N,N-dim ethylaminoethanol, TMEDA, (-)-sparteine and isopropylamine. In an embodiment, the amine is triethylamine such that the compound of Formula (III) is prepared by contacting a compound of Formula (VI) with a chiral catalyst, formic acid, and triethylamine.

[0533] In an embodiment, the process for the preparation of a compound of Formula (I) comprising contacting a compound of Formula (VI) with a chiral catalyst and a suitable source of hydrogen, may be carried out in the presence of a suitable solvent selected from the group consisting of acetonitrile, an ethereal solvent (for example methyl tert-butyl ether, tetrahydrofuran, 2-m ethyltetrahydrofuran or dioxane) and a polar aprotic solvent (for exam pie dimethylformamide, dimethylacetamide or DMSO). In an embodiment, the solvent is acetonitrile. In another embodiment, the solvent is tetrahydrofuran.

[0534] In an embodiment, the catalyst is a ruthenium -based chiral catalyst.

[0535] In an embodiment, the chiral catalyst is a Noyori catalyst.

[0536] In an embodiment, the ruthenium -based chiral catalyst is selected from any one of those previously defined.

[0537] In an embodiment, the ruthenium-based chiral catalyst and ligand is C3-[(R,R)-teth-TsDPEN RuCI] or C3-[(S,S)-teth-TsDPEN RuCI]. In an embodiment, the ruthenium-based chiral catalyst is (S,S)-Ts-DENEB RuCI.

[0538] In an embodiment, the ruthenium -based chiral catalyst is present in an amount of from about

[0539] O.5 to about 10 mol%.

[0540] In an embodiment, the ruthenium -based chiral catalyst is present in an amount of from about 2 to about 6 mol%. In an embodiment, the ruthenium-based chiral catalyst is present in an amount of about 5 mol%.

[0541] In another embodiment of the invention, there is provided a process for the preparation of a compound of Formula (A) wherein

[0542] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0543] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0544] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0545] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising contacting a compound of Formula (VII) with trim ethylsulf oxonium chloride in the presence of a coupling reagent and a suitable base, to provide a compound of Formula (VI) wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband-SO2NRaRb, where X and X1may be the same or different.

[0546] In an embodiment, the coupling reagent is selected from oxalyl chloride, thionyl chloride, hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), N,N’-dicyclohexylcarbodiimide (DCC) and carbonyldiimidazole (CDI).

[0547] In an embodiment, the coupling reagent is selected from hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) and carbonyldiimidazole (CDI). In an embodiment, the coupling reagent is CDI.

[0548] In an embodiment, the base used in the preparation of a compound of Formula (VI) is selected from the group consisting of potassium tert-butoxide, sodium hydride, lithium bis(trimethylsilyl)am ide, sodium bis(trimethylsilyl)amide and a guanidine-based base. In an embodiment, the base is potassium tert-butoxide.

[0549] In another embodiment of the invention, there is provided a process for the preparation of a compound of Formula (A) wherein

[0550] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0551] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0552] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0553] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising contacting a compound of Formula (VI) with a suitable acid, to provide a compound of Formula (V-l) wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband-SO2NRaRb, where X and X1may be the same or different.

[0554] In an embodiment, the acid is hydrochloric acid. In an embodiment, the hydrochloric acid is prepared by a combination of lithium chloride, tetrabutylammonium chloride or magnesium chloride and methanesulfonic acid. This process may be carried out in the presence of a suitable solvent, wherein the solvent is an ethereal solvent or polar aprotic solvent. For example, the solvent may be selected from the group consisting of tetrahydrofuran, 2- methyltetrahydrofuran, methyl tert-butyl ether, dioxane, dimethylformamide, dimethylsulfoxide and dimethylacetamide. In an embodiment, the solvent is 2-m ethyltetrahydrofuran.

[0555] In another embodiment of the invention, there is provided a process for the preparation of a compound of Formula (A) wherein

[0556] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0557] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl; X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (VI) to a compound of Formula (I) wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband-SO2NRaRb, where X and X1may be the same or different.

[0558] In another embodiment of the invention, there is provided a process for the preparation of a compound of Formula (A) wherein

[0559] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0560] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0561] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (VI) to a compound of Formula (I) wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband-SO2NRaRb, where X and X1may be the same or different.

[0562] In another embodiment of the invention, there is provided a process for the preparation of a compound of Formula (A) wherein

[0563] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0564] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0565] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (V-l) to a compound of Formula (II) wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband-SO2NRaRb, where X and X1may be the same or different.

[0566] In an embodiment, there is provided a process for the preparation of a compound of Formula (V-l) wherein

[0567] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0568] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0569] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0570] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising contacting a compound of Formula (VI) with a suitable acid (for exam pie, hydrochloric acid), in the presence of a suitable solvent (for example, tetrahydrofuran, 2-m ethyltetrahydrofuran, methyl tert-butyl ether, dioxane, dimethylformamide, dimethylsulfoxide or dimethylacetamide, particularly 2- m ethyltetrahydrofuran).

[0571] In an embodiment, there is provided a process for the preparation of a compound of Formula (VI) wherein

[0572] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0573] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0574] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and

[0575] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising contacting a compound of Formula (VII) with trimethylsulfoxonium chloride in the presence of a coupling reagent (for example, hexafluorophosphate azabenzotriazole tetramethyl uranium (HATU), 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) or carbonyldiimidazole (CDI), particularly CDI) and a suitable base (for example, potassium tert-butoxide, sodium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)am ide or a guanidine-based base, particularly potassium tert-butoxide), to provide a compound of Formula (VI).

[0576] In an embodiment, there is provided a process for the preparation of a compound of Formula (VII), the process comprising contacting a compound of Formula (X) with a compound of Formula (IX) and a compound of Formula (VIII) in the presence of a suitable solvent (acetonitrile, dimethylacetamide, cyrene (dihydrolevoglucosenone), tert-amyl alcohol, dimethylsulfoxide, dimethylformamide or acetic acid, particularly acetic acid in which it has been found that the reaction proceeds faster), wherein R1, R2, R3, R4, R5, R6and X1are as previously defined.

[0577] In any one of the above aspects or embodiments, the compound according to Formula (A) is camlipixant, i.e. wherein R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X1is -C(O)NHCH3, i.e. depicted by the following structure

[0578] Therefore, in an embodiment, the invention relates to a process for the preparation of cam lipixant, wherein a compound of Formula (V-la) is converted to cam lipixant la).

[0579] In an embodiment, the process for the preparation of cam lipixant further com prises contacting a compound of Formula (V-a) with hydrochloric acid in the presence of a suitable alcohol (such as ethanol or iso-propanol) and in the presence of a suitable solvent (such as DM SO), to provide a compound of Formula (V-la).

[0580] In an embodiment, the process forthe preparation of cam lipixant further com prises contacting a compound of Formula (Vll-a) with trim ethylsulf oxonium chloride in the presence of a suitable coupling reagent (such as HATU, EDC or CDI, particularly CDI) and a suitable base (such as potassium tert-butoxide, sodium hydride, lithium bis(trimethylsilyl)am ide or a guanidine-based base, particularly potassium tert-butoxide) and a suitable solvent (such as THF), to provide a compound of Formula (Vl-a)

[0581] In an embodiment, the process forthe preparation of cam lipixant further com prises contacting a compound of Formula (Vlll-a) ormula (IX) and a compound of Formula (X-a) to provide a compound of Formula (Vll-a).

[0582] In an embodiment, the process forthe preparation of cam lipixant further com prises contacting a compound of Formula (Xl-a) with a suitable acid (such as hydrochloric acid, methanesulfonic acid, acetic acid or formic acid, or a combination thereof, particularly a combination of methanesulfonic acid and acetic acid), to provide a compound of Formula (X-a), wherein, R' is independently selected from C1-3 alkyl

[0583] Compounds of the invention according to Process A or Process B In an aspect of the invention, there is provided a compound of Formula (I) wherein

[0584] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0585] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0586] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl. In another aspect of the invention, there is provided a compound of Formula (VI) wherein

[0587] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0588] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0589] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0590] In another aspect of the invention, there is provided a compound of Formula (VII) wherein

[0591] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0592] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl; X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0593] In another aspect of the invention, there is provided a compound of Formula (V) wherein

[0594] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0595] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0596] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb;

[0597] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; and LG is a suitable leaving group.

[0598] In another aspect of the invention, there is provided a compound of Formula (V-l) wherein

[0599] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0600] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0601] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0602] In another aspect of the invention, there is provided a compound of Formula (VII) wherein

[0603] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0604] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0605] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0606] In another aspect of the invention, there is provided a compound of Formula (IV-I) wherein

[0607] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0608] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0609] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0610] In another aspect of the invention, there is provided a compound of Formula (13) wherein

[0611] Y is a suitable amine group bound through nitrogen or a suitable trialkylphosphine group bound though phosphorus; and

[0612] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0613] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb;

[0614] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0615] In another aspect of the invention, there is provided a compound of Formula (13-1) wherein

[0616] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0617] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0618] In another aspect of the invention, there is provided a compound of Formula (14) wherein

[0619] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0620] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0621] R7is independently selected from C1-3 alkyl;

[0622] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0623] In another aspect of the invention, there is provided a compound of Formula (14-1) wherein

[0624] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0625] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl; X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0626] In another aspect of the invention, there is provided a compound of Formula (15) wherein

[0627] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0628] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0629] R7is independently selected from C1-3 alkyl;

[0630] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0631] In another aspect of the invention, there is provided a compound of Formula (15-1) wherein

[0632] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0633] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0634] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0635] In any one of the above aspects or embodiments, in a compound of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen, X1is -C(O)NHCH3, i.e. Rais hydrogen and Rbis CH3. Thus, in another aspect, there is provided a compound according to one of the following structures:

[0636] In an embodiment, there is provided a compound according to one of the following structures:

[0637] In any one of the above aspects or embodiments, in a compound of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X1is -SO2NH2.

[0638] Thus, in another embodiment, there is provided a compound according to one of the following structures:

[0639] In any one of the above aspects or embodiments, in a compound of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, R1is chloro, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X1is -SO2NH2. Thus, in another embodiment, there is provided a compound according to one of the following structures:

[0640] In any one of the above aspects or embodiments, in a compound of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, R1is methyl, R2is hydrogen, R3, R4and R6are fluoro, R5is hydrogen and X1is -C(O)NHCH3.

[0641] Thus, in another embodiment, there is provided a compound according to one of the following structures:

[0642] In any one of the above aspects or embodiments, in a compound of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, R1is chloro, R2is hydrogen, R3, R4and R6are fluoro, R5is hydrogen and X1is -C(O)NHCH3. Thus, in another embodiment, there is provided a compound according to one of the following structures:

[0643] In any one of the above aspects or embodiments, in a compound of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X1is -NHC(O)-cyclopropyl.

[0644] Thus, in another embodiment, there is provided a compound according to one of the following structures:

[0645] In any one of the above aspects or embodiments, in a compound of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X1is Br. Thus, in another embodiment, there is provided a compound according to one of the following structures:

[0646] In any one of the above aspects or embodiments, in a compound of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, R1is chloro, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X1is -Br. Thus, in another embodiment, there is provided a compound according to one of the following structures:

[0647] In any one of the above aspects or embodiments, in a compound of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, R1is methyl, R2is hydrogen, R3, R4and R6are fluoro, R5is hydrogen and X1is Br.

[0648] Thus, in another embodiment, there is provided a compound according to one of the following structures:

[0649] In any one of the above aspects or embodiments, in a compound of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, R1is chloro, R2is hydrogen, R3, R4and R6are fluoro, R5is hydrogen and X1is Br.

[0650] Thus, in another embodiment, there is provided a compound according to one of the following structures:

[0651] In certain embodiments where X or X1is bromo, it is understood by a person skilled in the art that it is possible to convert the bromo group to either -C(O)NHCH3 or -SO2NH2. In other words, in any one of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (XI- I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where X1is bromo, it is possible to convert that particular group to either -C(O)NHCH3 or - SO2NH2 at any stage.

[0652] For example, where X1is bromo and X is -SO2NH2, a compound of any one of Formulae (A), may be contacted with a suitable base (for example, nBuLi), SO2 and SO2CI, followed by NH4OH or ammonia.

[0653] In an embodiment, where X is bromo, the invention includes a process where a compound having Formula (A-l) is converted to a compound of Formula (A), where X is -SO2NH2

[0654] The conversion of a compound of Formula (A-l) to a compound of Formula (A), where X is - SO2NH2, is carried out by contacting a compound of Formula (A-l) with a suitable base (for example, nBuLi), SO2 and SO2CI, followed by NF OH or ammonia. The conversion may also be carried out by analogous methods disclosed in WO 2020 / 135771 (see, for example, Examples 171 and 172).

[0655] In any one of the above aspects or embodiments, in a compound of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, R1is methyl, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X1is CO2H.

[0656] Thus, in another embodiment, there is provided a compound according to one of the following structures:

[0657] In any one of the above aspects or embodiments, in a compound of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, R1is chloro, R2is hydrogen, R3and R4are fluoro, R5and R6are hydrogen and X1is CO2H. Thus, in another embodiment, there is provided a compound according to one of the following structures:

[0658] In any one of the above aspects or embodiments, in a compound of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, R1is methyl, R2is hydrogen, R3, R4and R6are fluoro, R5is hydrogen and X1is CO2H.

[0659] Thus, in another embodiment, there is provided a compound according to one of the following structures:

[0660] In any one of the above aspects or embodiments, in a compound of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, R1is chloro, R2is hydrogen, R3, R4and R6are fluoro, R5is hydrogen and X1is CO2H.

[0661] Thus, in another embodiment, there is provided a compound according to one of the following structures:

[0662] In certain embodiments where X1or X is CO2H or CO2Ra, it is understood by a person skilled in the art that it is possible to convert the CO2H or CCteR3group to either -C(O)NHCH3 or - SO2NH2. In other words, in any one of Formulae (A), (I), (II), (III), (IV), (IV-I), (V), (V-l) (VI), (VII), (VIII), (IX), (X), (XI) or (XII) where X1or X is CO2H or CO2Ra, it is possible to convert that particular group to either -C(O)NHCH3 or -SO2NH2 at any stage.

[0663] In certain embodiments where X1or X is CO2H or CO2Ra, it is understood by a person skilled in the art that it is possible to convert the CO2H or CCteR3group to either -C(O)NHCH3 or - SO2NH2. In other words, in any one of Formula (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21), where present, where X1or X is CO2H or CO2Ra, it is possible to convert that particular group to either -C(O)NHCH3 or -SO2NH2 at any stage.

[0664] The present invention also includes enantiomers of a compound of any one of Formulae (A), (I), (III), (15), or (15-1). Enantiomers can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate enantiomeric variations of suitable reagents. Thus, in another aspect, there is provided a compound according to one of the following structures:

[0665] In an embodiment, when Formula (A) is camlipixant, camlipixant may be purified by recrystallisation in methanol and water. The resultant camlipixant active pharmaceutical ingredient may then be jet-milled following recrystallisation.

[0666] The present invention also includes all suitable isotopic variations of a compound of any one of Formulae (A), (A’), (A”), (I), (II) (III), (IV), (IV-I), (V), (V-l), (VI), (VII), (VIII), (X), (XI), (Xl-I), (XII), (13), (13-1), (14), (14-1), (15), (15’), (15”), (15-1), (17), (18), (19), (19-1), (20) or (21). An isotopic variation is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 170, 180, 18F and 36CI, respectively. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred fortheir ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Thus, in one embodiment, the present invention includes cam lipixant wherein one or more hydrogen atoms attached to carbon atoms are replaced by deuterium. Isotopic variations can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.

[0667] Embodiments of the Invention

[0668] Embodiment 1 :

[0669] A process for the preparation of a compound of Formula (A), wherein

[0670] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0671] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0672] X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (1) to a compound of Formula (2) wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband-SO2NRaRb, where X and X1may be the same or different.

[0673] Embodiment2: A process according to embodiment 1 , wherein said conversion comprises (1) contacting a compound of Formula (I) with 2-aminoethyl hydrogen sulfate in the presence of a suitable base, (2) contacting a compound of Formula (I) with ethanolamine in the presence of a suitable activating agent, or (3) contacting a compound of Formula (I) with ethanolamine in the presence of diethyl azodicarboxylate and triphenyl phosphine. Embodiment 3: A process according to embodiment 2, wherein the suitable base is selected from the group consisting of DBU, triethylamine, isopropylamine, n-methylmorpholine, pyridine, potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide.

[0674] Embodiment 4: A process according to embodiment 2, wherein the suitable activating agent is tosyl chloride or mesyl chloride.

[0675] Embodiment 5: A process according to any one of the preceding embodiments, wherein the process is carried out in the presence of a suitable solvent.

[0676] Embodiment 6: A process according to embodiment 5, wherein the suitable solvent is an ethereal or alcohol-based solvent.

[0677] Embodiment 7: A process according to any one of the preceding embodiments, further comprising contacting a compound of Formula (II) with methyl chloroform ate, dimethyl carbonate or dimethyl dicarbonate to provide a compound of Formula (A), optionally in the presence of a suitable base.

[0678] Embodiment 8: A process according to any one of the preceding embodiments, further comprising contacting a compound of Formula (III) with a quaternary ammonium salt in the presence of a suitable base, to provide the compound of Formula (I).

[0679] Embodiment 9: A process according to embodiment s, wherein the quaternary ammonium salt is a tetraalkylammonium halide.

[0680] Embodiment 10: A proceed according to embodiment 8 or 9, wherein the quaternary ammonium salt is tetrabutylammonium bromide.

[0681] Embodiment 11 : A process according to any one of embodiments 8 to 10, wherein the suitable base is sodium hydroxide, potassium hydroxide or lithium hydroxide.

[0682] Embodiment 12: A process according to any one of embodiments 8 to 11 , further comprising contacting a compound of Formula (VI) with a chiral catalyst and a suitable source of hydrogen, to provide a compound of Formula (III).

[0683] Embodiment 13: A process according to embodiment 12, wherein the suitable source of hydrogen is formic acid and a suitable amine, wherein the suitable amine is a tertiary amine, optionally selected from the group consisting of triethylamine, N-methyl dicyclohexylamine, N- methyl morpholine, N,N-dim ethylaminoethanol, TMEDA, (-)-sparteine and isopropylamine.

[0684] Embodiment 14: A process according to any one of embodiments 1 to 7, further comprising contacting a compound of Formula (4) with a quaternary ammonium salt in the presence of a suitable base, to provide a compound of Formula (I), wherein LG is a suitable leaving group.

[0685] Embodiment 15: A process according to embodiment 14, wherein the quaternary ammonium salt is a tetraalkylammonium halide.

[0686] Embodiment 16: A proceed according to embodiment 14 or 15, wherein the quaternary ammonium salt is tetrabutylammonium bromide.

[0687] Embodiment 17: A process according to any one of embodiments 14 to 16, wherein the suitable base is sodium hydroxide, potassium hydroxide or lithium hydroxide.

[0688] Embodiment 18: A process according to any one of embodiments 14 to 17, further com prising contacting a compound of Formula (V) with a ketoreductase enzyme; or a chiral catalyst and suitable source of hydrogen, to provide a compound of Formula (VI).

[0689] Embodiment 19: A process according to embodiment 18, wherein the suitable source of hydrogen is formic acid and a suitable amine, wherein the suitable amine is a tertiary amine, optionally selected from the group consisting of triethylamine, N-methyl dicyclohexylamine, N- methyl morpholine, N,N-dim ethylaminoethanol, TMEDA, (-)-sparteine and isopropylamine.

[0690] Embodiment 20: A process according to any one of embodiments 12 to 19, wherein the chiral catalyst is a ruthenium -based catalyst.

[0691] Embodiment21 : A process according to any one of embodiments 18 to 20, further com prising contacting a compound of Formula (VI) with a suitable acid, to provide a compound of Formula (V).

[0692] Embodiment 22: A process according to embodiments or embodiment 21 , further comprising contacting a compound of Formula (VII) with trimethylsulfoxonium chloride in the presence of a coupling reagent and a suitable base, to provide a compound of Formula (VI). Embodiment 23: A process according to embodiment 22, wherein the coupling reagent is HATLI, EDC or CDI.

[0693] Embodiment24: A process according to embodiment 23, wherein the coupling reagent is CDI.

[0694] Embodiment 25: A process according to any one of embodiments 22 to 24, wherein the suitable base is potassium tert-butoxide, sodium hydride, lithium bis(trimethylsilyl)am ide or a guanidine-based base.

[0695] Embodiment 26: A process according to embodiment 25, wherein the suitable base is potassium tert-butoxide.

[0696] Embodiment 27: A process according to any one of the preceding embodiments, further comprising contacting a compound of Formula (VIII)

[0697] Rl / \ NH2

[0698] Y

[0699] R2^ (Viii) with a compound of Formula (IX) and a compound of Formula (X) to provide a compound of Formula (VII).

[0700] Embodiment 28: A process according to embodiment 27, further comprising contacting a compound of Formula (XI) with a suitable acid, to provide a compound of Formula (X), wherein, R' is independently selected from C1-3 alkyl.

[0701] Embodiment 29: A process according to embodiment 28, wherein the suitable acid is hydrochloric acid, methanesulfonic acid, acetic acid or formic acid, or a combination thereof.

[0702] Embodiment 30: A process according to embodiment 29, wherein the suitable acid is a combination of methanesulfonic acid and acetic acid.

[0703] Embodiment 31 : A process according to any one of the preceding embodiments, wherein the compound of Formula (A) is camlipixant.

[0704] Embodiment 32: A compound of Formula (I) wherein

[0705] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0706] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0707] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0708] Embodiment 33: A compound of Formula (VI) wherein

[0709] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0710] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0711] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0712] Embodiment 34: A compound of Formula (VII) wherein

[0713] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0714] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0715] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0716] Embodiment 35: A compound of Formula (V) wherein

[0717] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0718] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0719] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb;

[0720] Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; and LG is a suitable leaving group.

[0721] Embodiment 36: A compound of Formula (V-l) wherein

[0722] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0723] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0724] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0725] Embodiment 36: A compound of Formula (13) wherein

[0726] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0727] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0728] Embodiment 37: A compound of Formula (14) wherein

[0729] R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0730] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0731] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0732] Embodiment 38: A compound of Formula (15) wherein R1and R2are independently selected from hydrogen, halo and C1-3 alkyl;

[0733] R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;

[0734] X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

[0735] Embodiment 39: A process or com pound according to any one of the preceding embodiments, wherein R1is CH3, R2is hydrogen, R3and R4are fluoro, and R5and R6are hydrogen.

[0736] Embodiment 40: A process or com pound according to any one of the preceding embodiments, wherein X and / or X1is -C(O)NHCH3.

[0737] EXAMPLES

[0738] The invention is illustrated in the following examples.

[0739] NMR spectra were recorded on BrukerAVIII 500 MHz spectrometer or a BrukerNeo 600 MHz spectrometer and calibrated using residual deuterated solvent as an internal reference (DMSO-d6 @ 2.50 ppm for1H NMR spectra, DMSO-d6 at 39.5 ppm for13C NMR spectra). Spectra were collected at 25 °C unless otherwise noted. The following abbreviations (or com binations thereof) were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. High-resolution mass spectra (HRMS) were recorded on a Thermo Fisher Scientific Orbitrap Eclipse Tribrid or Thermo Fisher Scientific Orbitrap Fusion Tribrid mass spectrometer by electrospray ionization. All the measured masses were within 5 ppm of their corresponding exact mass.

[0740] HPLC purity was determined via chromatography with a Waters X-Select Charged Surface Hybrid (CSH) C18, 2.5 micron, 4.6 mm x 150 mm analyzed at 250 nm. The method used for analysis was a 35 minute method with 5 to 95% MeCN in water with 0.05% TFA additive.

[0741]

[0742] Method 1 - Synthesis of camlipixant

[0743] Stage 1 - Acylation

[0744] TIPSCI (1 eq), NMM (1 eq), THF (5 vol) then LDA (1.2 eq), -78°C eth l diethox acetate (1 1 e )

[0745] 3,5-difluorobenzoic acid (40 g, 1 eq) was charged to a 1 L reactor containing THF (200 mL, 5 vol). TIPSCI (54.1 mL, 1 eq) was added to the reactor. N-methylmorpholine (27.8 mL, 1 eq) was added dropwise to the reactor over 10 minutes at 20°C. The reaction mixture was stirred for 1 hour at 20°C and then filtered. Separately, in a 2L reactor LDA (2M, 152 mL, 1 .2 eq) was cooled to -78°C. The filtrate from the first reaction was added dropwise to the precooled solution of LDA while maintaining the internal temperature below -70°C. After completion of addition, the reaction was allowed to stir at -78°C for 15 minutes. Then ethyl diethoxyacetate (49.8 mL, 1.1 eq) was added while maintaining the internal temperature below -70°C. The reaction was allowed to stir at -78°C for 15 minutes. Upon completion of reaction, isopropanol (40 mL, 1 vol) was charged while maintaining the internal temperature below -70°C. Then 4M HCI (160 mL, 4 vol) was charged to the reactor via addition funnel while maintaining the internal temperature below -40°C. CPME (200 mL, 5 vol) was charged to the reactor and the reaction mixture was allowed to raise to 20°C. The phases were separated and the organic layer was distilled down to 5 vol. The solution was heated to 50°C and then imidazole (17.2 g, 1 eq) was charged. The reaction mixture was cooled to 20°C over 1 hour and then heptane (100 mL, 2.5 vol) over 3 hours. The reaction was filtered and the cake was washed with 1 :1 CP ME (heptane (200 mL, 5 vol) and then heptane (200 mL, 5 vol). The filter cake was dried in a 25 °C vacuum oven (56.5 g, 63% yield).1H-NMR (DMSO-d6, 501 MHz): 5 (ppm) 7.86 - 7.94 (m, 1 H), 7.63 (s, 2H), 7.13 (d, J=1.1 Hz, 2H), 5.25 (s, 1 H), 3.56 - 3.69 (m, 4H), 1.10 (t, J=7.0 Hz, 6H).13C-NMR (DMSO-d6, 126 MHz): 5 (ppm) 193.1 (s), 164.9 (t, J=3 Hz), 158.8 (dd, J=252, 8 Hz), 138.0 (br t, J=9 Hz), 135.0 (s), 121.3 (s), 118.4 (t, J=21 Hz), 112.6 (br s), 100.8 (s), 62.8 (s), 15.0 (s). HRMS (ESI) m / z: [M+H]- calc’d for C13H14F2O5 287.0736; found 287.0748. Rt 0.53 min.

[0746] Stage 2 - Amidation

[0747] The imidazole salt (50 g, 1 eq) was dissolved in DMSO (200 mL, 4 vol) in a 1 L reactor. CDI (29.6 g, 1 .3 eq) was added portionwise to the reactor. The reaction was left to stir for 1 hour at 20°C. Methylamine hydrochloride (13.3 g, 1 .4 eq) was added to the reactor and the reaction was left to stir for 1 hour at 20°C. Water (100 mL, 2 vol) was charged to the reactor over 3 hours. Additional water (200 m L, 4 vol) was charged to the reactor over 1 hour. The product was isolated via filtration. The filter cake was washed twice with a DMSO:water mixture (2:3, 200 mL, 4 vol) then twice with a water wash (200 mL, 4 vol) and then dried under vacuum at 40 °C (29.7 g, 70% yield).1H-NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.66 - 8.79 (m, 1 H), 7.60 - 7.65 (m, 2H), 5.25 (s, 1 H), 3.56 - 3.68 (m, 4H), 2.80 (d, J=4.6 Hz, 3H), 1.10 (t, J=7.0 Hz, 6H).13C-NMR (DMSO-d6, 126MHz): 5 (ppm) 193.0 (s), 163.4 (t, J=2 Hz), 158.9 (dd, J=252, 8 Hz), 139.4 (t, J=9 Hz), 117.5 (t, J=21 Hz), 110.8 - 111.1 (m), 100.8 (s), 62.8 (s), 26.4 (s), 15.0 (s). HRMS (ESI) m / z: [M+H]+calc’d for C14H17F2NO4 302.1198; found 302.1199. Rt 1.03 min.

[0748] Alternative Formation of Stage 2 product

[0749] To an inert reactor was charged 2,2,6, 6-tetram ethylpiperidine (TMP) (13.4 g, 16.1 mL,

[0750] 2.5 equiv.) and THF (42 mL, 7 vol). The reaction mixture was then cooled to -78 °C and N- butyllithium (37.9 mL, 2.5 M in hexanes, 2.5 equiv.) was charged dropwise, maintaining internal temperature less than -60 °C. To a second inerted reactor was charged 3,5- difluorobenzoic acid (6 g, 1 equiv.), TMEDA (11.4 mL, 2 equiv.) and THF (42 mL, 7 vol). This reaction was also cooled to -78 °C. This reaction mixture was transferred via cannula to the LiTMP reaction mixture, while keeping the internal temperature less than -60 °C. To a third, inerted reactor, ethyl 2,2-diethoxyacetate (7.13 mL, 1.05 equiv.) was dissolved in THF (6 mL, 1 vol). This solution was then added to the aryllithium solution, maintaining an internal temperature less than -70 °C. Upon completion, the reaction mixture was warmed to 0°C and quenched with aqueous HCI (76 mL, 6 M, 12 equiv.) slowly while keeping the internal temperature less than 10 °C. The layers were separated, the organic layer was concentrated to dryness. The residue was dissolved in DM SO (24 mL, 4 vol) and to the reactor was charged imidazole (1.29 g, 0.5 equiv.) and carbonyldiimidazole (9.85 g, 1.6 equiv.). Methylamine hydrochloride (5.12 g, 2 equiv.) was then charged to the reactor. After the reaction was complete, water (24 mL, 6 vol) was charged over 4 hours. The solid was isolated by filtration and washed with water (16 mL, 4 vol) and dried in the vacuum (3.28 g, 28% yield). 1 H-NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.66 - 8.79 (m, 1 H), 7.60 - 7.65 (m, 2H), 5.25 (s, 1 H), 3.56 - 3.68 (m, 4H), 2.80 (d, J=4.6 Hz, 3H), 1.10 (t, J=7.0 Hz, 6H). 13C-NMR (DMSO-d6, 126MHz): 5 (ppm) 193.0 (s), 163.4 (t, J=2 Hz), 158.9 (dd, J=252, 8 Hz), 139.4 (t, J=9 Hz), 117.5 (t, J=21 Hz), 110.8 - 111.1 (m), 100.8 (s), 62.8 (s), 26.4 (s), 15.0 (s). HRMS (ESI) m / z: [M+H]+ calc’d for C14H17F2NO4 302.1198; found 302.1199. Rt 1.03 min.

[0751] Stage 3 - Imidazole Adduct Formation

[0752] To a 100 mL reactor was added acetal (30 g, 1 eq) and then added formic acid (60 mL, 2 vol) at 25°C. The resulting solution was heated to 65°C and stirred for 18 hours until complete consumption of acetal starting material. The reaction mixture was cooled to 25 °C. In a second reactor at 25°C, Meldrum’s acid (14.4 g, 1 eq) and imidazole (11.2 g, 1.65 eq) were dissolved in TH F (240 m L, 8 vol). The form ic acid solution was added to the TH F solution as quickly as possibly while maintaining internal temperature below 35 °C. After completion of addition, the reaction was stirred at 25°C for 20 hours. The product was isolated via filtration. The filter cake was washed three times with THF (90 mL, 3 vol) and then dried under vacuum at 40 °C (29.7 g, 70% yield).1H-NMR (Acetic acid-d4, 600 MHz): 5 (ppm) 8.87 - 8.96 (m, 1 H), 7.66 - 7.71 (m, 1 H), 7.57 - 7.58 (m, 2H), 7.55 - 7.56 (m , 1 H), 6.74 (s, 1 H), 2.99 (s, 3H), 1 .40 (s, 6H).13C-NMR (Acetic acid-d4, 151 MHz): 5 (ppm) 191.7 (s), 170.1 (s), 168.1 (s), 166.8 (s), 162.3 (dd, J=257, 6 Hz), 141.0 (t, J=9 Hz), 137.2 (s), 124.3 (s), 120.7 (s), 118.9 (t, J=17 Hz), 113.0 - 113.2 (m), 105.4 (s), 75.0 (s), 68.1 (s), 28.3 (s), 26.9 (s). HRMS (ESI) m / z: [M+H]+calc’d for C19H17F2N3O6 422.1158; found 422.1166. Rt 0.32 min.

[0753] Stage 4 - Cyclization

[0754] To a 500 mL reactor was added the imidazole adduct (40 g, 1 eq) and 2-amino-4- methylpyridine (14.7 g, 1.5 eq). MeCN (150 mL, 3.75 vol) and AcOH (50 mL, 1.25 vol) were added to the reactor and the mixture was sparged with nitrogen for 15 minutes while stirring. The reaction mixture was heated to 82°C for20 hours. Upon completion, the reaction mixture is cooled to 20°C over 10 hours. The reaction was aged for 24 hours then filtered. The filter cake was rinsed three times with MeCN (100 mL, 2 vol). The filter cake was dried under vacuum at 50 °C (26.4 g, 75% yield).1H-N MR (DMSO-d6, 501 MHz): 5 (ppm) 12.64 (dt, J=6.3, 4.5 Hz, 1 H), 8.70 (q, J=4.4 Hz, 1 H), 8.31 (d, J=7.0 Hz, 1 H), 7.63 - 7.70 (m, 2H), 7.40 (s, 1 H), 6.86 (dd, J=7.0, 1.5 Hz, 1 H), 3.90 (s, 2H), 2.83 (d, J=4.4 Hz, 3H), 2.40 (s, 3H).13C-NMR (DMSO-d6, 126MHz): 5 (ppm) 170.8 (s), 164.4 (t, J=2 Hz), 160.3 (dd, J=249, 7 Hz), 145.3 (s), 137.3 (t, J=9 Hz), 135.9 (s), 131.1 (s), 125.2 (s), 118.1 (s), 115.4 (s), 115.1 (s), 114.6 (t, J=20 Hz), 111.1 (dd, J=22 Hz), 29.7 (s), 26.9 (s), 21.2 (s). HRMS (ESI) m / z: [M+H]+calc’d for C18H15F2N3O3 360.1154; found 360.1158. Rt 0.50 min.

[0755] Stage 5 - Ylide Formation (a)

[0756] To a solution of carboxylic acid (4.00 g, 1 eq) in THF (20 mL, 5 vol) was added 1 ,1’- carbonyldiimidazole (2.99 g, 1.85 eq). The reaction mixture was stirred at 20°C until conversion to the acyl imidazole was deemed complete by HPLC. In a separate reactor, potassium tert-pentoxide (13.7 mL, 2.8 eq, 2M in THF) was added to trimethylsulfoxonium chloride (4.02 g, 3.2 eq) at 20°C. The mixture was heated to 45°C for 1 h then cooled to 0°C. The solution of activated ylide was then added to the activated acid and the mixture was stirred at 0°C until deemed complete by HPLC. Aqueous citric acid solution (20% w / w, 6 mL, 1 .5 vol) was added and the mixture warmed to 20°C. Water (26 mL, 6.5 vol) was charged and THF was removed via distillation. The resulting slurry is filtered to collect the solids. The reactor is rinsed with water (12 mL, 3 vol) and this rinse is used to wash the wet cake. The wet cake is wash once more with water (12 mL, 3 vol) then dried under vacuum at 40-60 °C to provide the ylide (3.4 g, 76% yield).1H-NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.69 (q, J=4.3 Hz, 1 H), 8.25 (d, J=7.0 Hz, 1 H), 7.60 - 7.70 (m , 2H), 7.36 (s, 1 H), 6.82 (dd, J=7.0, 1 .5 Hz), 4.65 (s, 1 H), 3.61 (s, 2H), 3.36 (s, 6H), 2.82 (d, J=4.6 Hz, 3H), 2.38 (s, 3H).13C-NMR (DMSO-d6 ,126 MHz): 5 (ppm) 182.8 (s), 164.0 (t, J=2 Hz), 159.9 (dd, J=249, 7 Hz), 144.7 (s), 136.7 (t, J=9 Hz), 135.1 (s), 130.4 (s), 124.7 (s), 119.8 (s), 114.9 (s), 114.7 (t, J=20 Hz), 114.5 (s), 110.6 (dd, J=27, 6 Hz), 72.5 (s), 40.3 (s), 35.0 (s), 26.4 (s), 20.8 (s). HRMS (ESI) m / z: [M+H]+calc’d for C21 H21 F2N3O3S 434.1344; found 434.1352. Rt 0.49 min.

[0757] Stage 5 - Ylide Formation (b)

[0758] To a solution of carboxylic acid (6.00 g, 1 eq) in DMSO (18 mL, 3 vol) was added 1 ,1’- carbonyldiimidazole (3.19 g, 1.25 eq). The reaction mixture was stirred at 20°C until conversion to the acyl imidazole was deemed complete by HPLC. In a separate reactor, THF (18 mL, 3 vol), potassium tert-butoxide (2.21 g, 1.25 eq), and trimethylsulfoxonium chloride (3.04 g, 1 .5 eq) were charged at 20°C. The solution of activated ylide was then cooled to 10°C and the acyl imidazole solution was transferred to the pre-cooled ylide slurry. Upon completion by HPLC, the THF was removed via distillation. Water (24 mL, 4 vol) was charged. The resulting slurry is filtered to collect the solids. The reactor is rinsed with water (12 mL, 3 vol) and this rinse is used to wash the wet cake. The wet cake is wash once more with water (12 mL, 3 vol) then dried under vacuum at 40-60 °C to provide the ylide (5.92 g, 83% yield).1H- NM R (DMSO-d6, 501 M Hz): 5 (ppm) 8.69 (q, J=4.3 Hz, 1 H), 8.25 (d, J=7.0 Hz, 1 H), 7.60 - 7.70 (m, 2H), 7.36 (s, 1 H), 6.82 (dd, J=7.0, 1 .5 Hz), 4.65 (s, 1 H), 3.61 (s, 2H), 3.36 (s, 6H), 2.82 (d, J=4.6 Hz, 3H), 2.38 (s, 3H).13C-NMR (DMSO-d6 ,126 MHz): 5 (ppm) 182.8 (s), 164.0 (t, J=2 Hz), 159.9 (dd, J=249, 7 Hz), 144.7 (s), 136.7 (t, J=9 Hz), 135.1 (s), 130.4 (s), 124.7 (s), 119.8 (s), 114.9 (s), 114.7 (t, J=20 Hz), 114.5 (s), 110.6 (dd, J=27, 6 Hz), 72.5 (s), 40.3 (s), 35.0 (s), 26.4 (s), 20.8 (s). HRMS (ESI) m / z: [M+H]+calc’d for C21H21F2N3O3S 434.1344; found 434.1352. Rt 0.49 min. Stage 6 - Chlorination Alkylation of Ylide (a)

[0759] To a 100 mL reactor was added ylide (5 g, 1 eq) and lithium chloride (750 mg, 1.6 eq). N,N- dim ethylacetamide (15 mL, 3 vol) was added to the reactor and the mixture was stirred at 25°C. MsOH (1.44 mL, 2 eq) was added in a single portion and the mixture was stirred at 25 °C for 4.5 hours. Upon completion, the mixture was cooled to -10 °C and 2,2- dimethoxyethanamine (4.15 mL, 4 eq) was added over 1 hour. The reaction was aged for 20 hours. Upon completion, methyl chloroform ate (1.7 mL, 2 eq) was added over 30 minutes. The reaction was warmed to 20 °C. The pH was adjusted to 7 with 5 M aqueous NaOH (5.53 mL, 2.5 eq). Water (53 mL, 9.7 vol) was added dropwise over 2 hours. The mixture was aged for 24 hours then filtered. The filter cake was rinsed once with 3:1 water: DMA (5 mL, 1 vol) and twice with water (5 mL, 1 vol). The filtercake was dried under vacuum at 35 °C (3.106 g, 54% yield).1H NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.32 - 8.48 (m, 1 H), 8.08 (d, J=6.9 Hz, 1 H), 7.57 - 7.67 (m, 2H), 7.36 (s, 1 H), 6.82 (dd, J=7.0, 1.2 Hz, 1 H), 4.37 (t, J=5.1 Hz, 1 H), 4.19 (s, 2H), 4.08 (s, 2H), 3.54 (brs, 3H), 3.27 (brd, J=5.2 Hz, 2H), 3.25 (s, 6H), 2.85 (d, J=4.6 Hz, 3H), 2.41 (s, 3H).13C-NMR (DMSO-d6, 126 MHz): 5 (ppm) 200.5 (s), 163.6 (s), 159.5 (dd, J=249, 7 Hz), 155.7 (s), 144.7 (s), 136.6 (t, J=9 Hz), 134.8 (s), 131.0 (s), 123.7 (s), 116.4 (s), 114.7 (s), 114.1 (s), 113.8 (t, J=20 Hz), 109.6 - 110.4 (m), 102.5 (s), 56.3 (s), 53.4 (s), 51.9 (s), 49.3 (s), 33.8 (s), 25.8 (s), 20.1 (s). HRMS (ESI) m / z: [M+H]+calc’d for C25H28F2N4O6 519.2049; found 519.2049. Rt 1.01 min.

[0760] Stage 6 - Chlorination Alkylation of Ylide (b)

[0761] To a 50 mL reactor was added ylide (3.5 g, 1 eq) and lithium chloride (510 mg, 1.5 eq). N,N- dim ethylacetamide (7 mL, 2 vol) was added to the reactor and the mixture was stirred at 25°C. MsOH (1 .44 mL, 2 eq) was added in a single portion and the mixture was stirred at 25 °C for 4.5 hours. Upon completion, the mixture was cooled to 10 °C. Triethylamine (1.67 g, 2 equiv) and 2,2-dimethoxyethanamine (1.74 g, 2 eq) was added over 1 hour. The reaction was aged for 20 hours. Upon completion, methyl chloroformate (1.7 mL, 2 eq) was added over 30 minutes. The reaction was warmed to 20 °C. Water (7 mL, 2 vol) was charged and the pH was adjusted to 10 with 10 M aqueous NaOH (2.82 mL, 3.5 eq). The mixture heated to 45 °C was seeded with 0.1 wt % product and held for 8 hours. The mixture was cooled to 20 °C and then held for an additional 16 hrs and then filtered. The filter cake was rinsed once with 3:1 water: DM Ac (5 mL, 1 vol) and twice with water (5 mL, 1 vol). The filter cake was dried under vacuum at 35 °C (2.37 g, 57% yield).1H NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.32 - 8.48 (m, 1 H), 8.08 (d, J=6.9 Hz, 1 H), 7.57 - 7.67 (m, 2H), 7.36 (s, 1 H), 6.82 (dd, J=7.0, 1.2 Hz, 1 H), 4.37 (t, J=5.1 Hz, 1 H), 4.19 (s, 2H), 4.08 (s, 2H), 3.54 (br s, 3H), 3.27 (br d, J=5.2 Hz, 2H), 3.25 (s, 6H), 2.85 (d, J=4.6 Hz, 3H), 2.41 (s, 3H).13C-NMR (DMSO-d6, 126 MHz): 5 (ppm) 200.5 (s), 163.6 (s), 159.5 (dd, J=249, 7 Hz), 155.7 (s), 144.7 (s), 136.6 (t, J=9 Hz), 134.8 (s), 131.0 (s), 123.7 (s), 116.4 (s), 114.7 (s), 114.1 (s), 113.8 (t, J=20 Hz), 109.6 - 110.4 (m), 102.5 (s), 56.3 (s), 53.4 (s), 51.9 (s), 49.3 (s), 33.8 (s), 25.8 (s), 20.1 (s). HRMS (ESI) m / z: [M+H]+calc’d for C25H28F2N4O6 519.2049; found 519.2049. Rt 1 .01 min.

[0762] Stage 7 - Noyori Hydrogenation

[0763] To a 40 mL vial was added ketone (1 g, 1 eq) and RuCI-(S,S)-TsDENEB (52.7 mg, 0.05 eq). THF (7 mL, 7 vol) was added and mixture was allowed to stir for 5 minutes. To the vial was added 5:2 HCO2H:NEt3 azeotrope (1.35 mL, 2 eq), and reaction was stirred overnight at 25°C. After stirring for 18 hours, a nitrogen line was placed in the reaction vial to purge CO2 and the mixture was aged for 20 hours then filtered. The filter cake was rinsed with THF (2 mL, 2 vol), then 3:7 THF:water (2 mL, 2 vol), THF (1 mL, 1 vol). Filter cake was transferred to an 8 mL vial and allowed to dry under vacuum at 35°C (523 mg, 61 % yield, 84% ee).1H NMR (DMSO- d6, 501 MHz): 5 (ppm) 8.45 - 8.55 (m, 1 H), 8.39 (d, J=7.2 Hz, 1 H), 7.59 - 7.67 (m, 2H), 7.32 (s, 1 H), 6.80 (dd, 7=7.0, 1 .7 Hz, 1 H), 4.84 (d, J=5.7 Hz, 1 H), 4.34 (t, J=5.2 Hz, 1 H), 3.79 - 3.91 (m, 1 H), 3.49 (br s, 3H), 3.27 (dd, 7=14.4, 5.0 Hz, 1 H), 3.22 - 3.24 (m, 3H), 3.21 (s, 3H), 3.14 - 3.19 (m, 1 H), 3.13 - 3.18 (m, 1 H), 3.04 - 3.09 (m, 1 H), 2.87 - 2.91 (m, 2H), 2.85 (d, 7=4.6 Hz, 3H), 2.39 (d, 7=0.6 Hz, 3H).13C NMR (DMSO-d6, 126 MHz): 5 (ppm) 163.6 (s), 159.7 (dd, 7=248, 7 Hz), 155.8 (s), 144.4 (s), 136.6 (t, 7=9 Hz), 134.3 (s), 130.1 (s), 124.2 (s), 120.9 (s), 114.6 (s), 114.4 - 114.9 (m), 113.9 (s), 110.0 (s), 102.5 (s), 68.5 (s), 53.6 (s), 53.2 (s), 53.1 (s), 51.7 (s), 49.2 (s), 28.5 (s), 25.9 (s), 20.2 (s). HRMS (ESI) m / z: [M+H]+calc’d for C25H30F2N4O6 521 .2206; found 521 .2206. Rt 0.96 min.

[0764] Stage 8 - Camlipixant (a)

[0765] To a solution of the chiral alcohol (150 mg, 1 eq) in MeCN (0.450 mL, 10 vol) at 25°C was added MsOH (0.075 mL, 4 eq). The reaction was allowed to stir at 25°C for 10 minutes. To this solution was added TMDS (0.20 mL, 4 eq) and the reaction was heated at 50°C for 18 hours. Upon completion, the reaction mixture was cooled to 25°C and concentrated to dryness. The residue was purified by flash chromatography using a gradient from 10-100% of a 3:1 mix of EtOAc / EtOH in hexanes over 15 min (0.048 g, 36% yield, 72% ee).1H NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.70 (q, J=4.4 Hz, 1 H), 8.43 (d, J=7.2 Hz, 1 H), 7.63 - 7.67 (m, 2H), 7.34 - 7.37 (m, 1 H), 6.84 (dd, J=7.2, 1.7 Hz, 1 H), 3.69 - 3.79 (m, 1 H), 3.62 - 3.67 (m, 1 H), 3.59 - 3.65 (m, 1 H), 3.55 (s, 3H), 3.41 - 3.51 (m, 1 H), 3.22 (td, J=11 .8, 2.8 Hz, 1 H), 2.98 - 3.09 (m, 2H), 2.82 (d, J=4.4 Hz, 3H), 2.74 - 2.82 (m, 1 H), 2.45 - 2.55 (m, 1 H), 2.35 - 2.40 (m, 3H).13C NMR (DMSO-d6, 126MHz): 5 (ppm) 164.0 (s), 159.9 (dd, J=248, 7 Hz), 154.9 (s), 144.7 (s), 136.9 (t, J=9 Hz), 135.1 (s), 130.8 (s), 124.6 (s), 119.5 (s), 115.0 (s), 114.7 - 115.0 (m), 114.6 (s), 110.3 - 110.7 (m), 73.7 (br s), 65.7 (s), 52.4 (s), 47.3 (br s), 42.9 (br s), 26.4 (s), 26.4 (s), 20.7 (s). HRMS (ESI) m / z: [M+H]+calc’d forC23H24F2N4O4459.1838; found 459.1839. Achiral: Rt 0.67 min. Chiral: Daicel Chiralpak AD-H, 4.6x250 mm, 5.0 pm. Rt 18.25 min.

[0766] Stage 8 - Camlipixant (b)

[0767] To a solution of the chiral alcohol (7 g, 1 eq) in MeCN (14 mL, 2 vol) at25°C was added MsOH (5.09 mL, 6 eq) dropwise. The reaction was allowed to stir at 25°C for 10 minutes. To this solution was added TMDS (4.62 mL, 2 eq) and the reaction was heated at 60°C for 18 hours. Upon completion, the reaction mixture was cooled to 25°C and water (14 ml, 2 vol) and heptane (21 mL, 3 vol) were added. The layers were separated and the aqueous layer was distilled to remove the MeCN. 2-Propanol (21 mL, 3 vol) and aq. 50 wt % NaOH (4.12 mL, 6 equiv) were added and the bottom aqueous layer is removed. The 2-propanol layer was heated to 50°C. Water (42 mL, 6 vol) was charged and the mixture was slowly cooled to 25°C. The slurry is filtered and washed with 2:1 water:2-propanol (14 mL, 2 vol) and 3:1 water:2- propanol (2x 14 mL, 2x 2 vol). The filter cakewas dried under vacuum (5.09 g, 85% yield, 84% ee).1H NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.70 (q, J=4.4 Hz, 1 H), 8.43 (d, J=7.2 Hz, 1 H), 7.63 - 7.67 (m, 2H), 7.34 - 7.37 (m, 1 H), 6.84 (dd, J=7.2, 1 .7 Hz, 1 H), 3.69 - 3.79 (m, 1 H), 3.62 - 3.67 (m, 1 H), 3.59 - 3.65 (m, 1 H), 3.55 (s, 3H), 3.41 - 3.51 (m, 1 H), 3.22 (td, J=11.8, 2.8 Hz, 1 H), 2.98 - 3.09 (m, 2H), 2.82 (d, J=4.4 Hz, 3H), 2.74 - 2.82 (m, 1 H), 2.45 - 2.55 (m, 1 H), 2.35 - 2.40 (m, 3H).13C NMR (DMSO-d6, 126MHz): 5 (ppm) 164.0 (s), 159.9 (dd, J=248, 7 Hz), 154.9 (s), 144.7 (s), 136.9 (t, J=9 Hz), 135.1 (s), 130.8 (s), 124.6 (s), 119.5 (s), 115.0 (s), 114.7 - 115.0 (m), 114.6 (s), 110.3 - 110.7 (m), 73.7 (br s), 65.7 (s), 52.4 (s), 47.3 (br s), 42.9 (br s), 26.4 (s), 26.4 (s), 20.7 (s). HRMS (ESI) m / z: [M+H]+calc’d for C23H24F2N4O4459.1838; found 459.1839. Achiral: Rt 0.67 min. Chiral: Daicel Chiralpak AD-H, 4.6x250 mm, 5.0 pm. Rt 18.25 min.

[0768] As an impurity found within the isolation of camlipixant, a compound having the following structure was also observed in an amount of 0.01 to 0.5% area as measured by HPLC,

[0769] HRMS (ESI) m / z: [M+H]+calc’d for C46H45F4N8O8 913.3291 ; found 913.3291. Rt 31.72 min.

[0770] As an impurity found within the isolation of camlipixant, a compound having the following structure was also observed in an amount of 0.01 to 1.0% area as measured by HPLC, HRMS (ESI) m / z: [M+H]+calc’d for C23H24F2N3O5 460.1678; found 460.1678. Rt 32.31 min.

[0771] Stage 9 - Camlipixant API

[0772] Camlipixant from Stage 8 (5.5 g, 1 equiv) was added to F / MeOH (30 mL, 1 : 8.8 v:v, 5.45 vol) and heated to 50°C until dissolution. H2O (24 mL, 4.36 vol) was then charged over 4 hours. Micronized camlipixant was charged as seed (55.5 mg, 1 wt %) and the slurry was held for 3.5 hours. The slurry was cooled to 25°C over 5.0 hours and then H2O (27 mL, 4.9 vol) was added over 4 hours. The slurry was held for 2 hours and then filtered. The cake was washed with 2:1 FLCLMeOH (7.2 mL, 1.3 vol) and dried via blowdown. The cake was dried in a vacuum oven at 50°C to give camlipixant API (4.92 g, 89% yield).1H NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.70 (q, J=4.4 Hz, 1 H), 8.43 (d, J=7.2 Hz, 1 H), 7.63 - 7.67 (m, 2H), 7.34 - 7.37 (m, 1 H), 6.84 (dd, J=7.2, 1.7 Hz, 1 H), 3.69 - 3.79 (m, 1 H), 3.62 - 3.67 (m, 1 H), 3.59 - 3.65 (m, 1 H), 3.55 (s, 3H), 3.41 - 3.51 (m, 1 H), 3.22 (td, J=11.8, 2.8 Hz, 1 H), 2.98 - 3.09 (m, 2H), 2.82 (d, J=4.4 Hz, 3H), 2.74 - 2.82 (m, 1 H), 2.45 - 2.55 (m, 1 H), 2.35 - 2.40 (m, 3H).13C NMR (DMSO-d6, 126MHz): 5 (ppm) 164.0 (s), 159.9 (dd, J=248, 7 Hz), 154.9 (s), 144.7 (s), 136.9 (t, J=9 Hz), 135.1 (s), 130.8 (s), 124.6 (s), 119.5 (s), 115.0 (s), 114.7 - 115.0 (m), 114.6 (s), 110.3 - 110.7 (m), 73.7 (br s), 65.7 (s), 52.4 (s), 47.3 (br s), 42.9 (br s), 26.4 (s), 26.4 (s), 20.7 (s). HRMS (ESI) m / z: [M+H]+calc’d for C23H24F2N4O4459.1838; found 459.1839.

[0773] Following recrystallization as set out above, the amount of a compound having the following structure was also observed in an amount of 0.01 to 0.1 % area as measured by HPLC,

[0774] API is intended to refer to drug substance that is suitable for formulation into tablets for use in patients.

[0775] Method 2 - Synthesis of camlipixant

[0776] Stage 1 - Amidation

[0777] 3,5-difluorobenzoic acid (80 g, 1 equiv) was charged to a 1 L reactor containing acetonitrile (320 mL, 4 vol). This was stirred at 40 °C to give a homogeneous solution. CDI was added (111.1 g, 1.3 equiv) portion-wise to the reactor and stirred at 40 °C for at least 30 minutes. M ethanamine hydrochloride was added (54.7 g, 1.6 equiv) portion-wise to the reactor and stirring continued until the reaction was determined to be complete by HPLC. Water (160 mL, 2 vol) was charged to the 40 °C reaction solution and the solution concentrated under reduced pressure until 2 vol of acetonitrile was removed. Water (800 mL, 10 vol) was slowly added to the slurry and then aged for 1 hour. The product was isolated via filtration and the filter cake was washed with 9:1 wateracetonitrile (240 mL, 3 vol) then with water (240 mL, 3 vol). The filter cake was dried in a 55 °C vacuum oven to yield the product (74.1 g, 85.6% yield).

[0778] 1H-NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.54 - 8.70 (m, 1 H), 7.49 - 7.55 (m, 2H), 7.45 (tt, J=9.1 , 2.4 Hz, 1 H), 2.79 (d, J=4.6 Hz, 3H).13C-NMR (DMSO-d6, 126 MHz): 5 (ppm) 164.0 (br s), 162.2 (dd, J=247, 13 Hz), 138.0 (s), 110.2 - 110.7 (m), 106.6 (t, J=26 Hz), 26.3 (s). HRMS (ESI) m / z: [M+H]+calc’d for C8H7F2NO 172.0568; found 172.0568. Rt 0.71 min.

[0779] Stage 2 - Acylation

[0780] TMEDA (11.8 g, 2.9 equiv) and LDA (2M, 50.8 mL, 2.9 equiv) were charged to a dry, nitrogen purged reactor at ambient temperature. This solution was cooled to -75 °C before a THF solution (60 mL, 10 vol) of 3,5-difluoro-N-methylbenzamide (6 g, 1 equiv) was added at a rate that kept the reaction temperature below -65 °C. After aging for 1 hour at -70 °C neat ethyl 2,2-diethoxyacetate (8.0 g, 1 .3 equiv) was charged at a rate such that the reaction temperature did not rise above -65 °C. This was aged until the reaction was determined to be complete by HPLC. The reaction was quenched at -70 °C with an acetic acid (10.1 mL, 5 equiv) and water (10 mL) mixture then allowed the reaction solution to warm to ambient temperature. Additional water (50 mL) and THF (60 mL, 10 vol) was added to the reactor and transfered to a separatory funnel. The aqueous layer was drawn off and organic layer washed with citric acid (2M, 105 mL, 6 equiv) followed by a 10% saturated brine solution (120 mL, 20 vol). The organic layer was dried over MgSC , filtered and concentrated to dryness. The residue was dissolved in warm toluene (60 mL, 10 vol) then allowed to cool to ambient temperature with stirring. After some crystallization occurred, methylcyclohexane (90 mL, 15 vol) was slowly added then this slurry was aged for 1 hour. The product was isolated via filtration. The filter cake was washed twice with a toluene:methylcyclohexane mixture (2:3, 60 mL, 10 vol) then dried under vacuum at 40 °C to afford the desired product (6.2 g, 58% yield).

[0781] 1H-NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.66 - 8.79 (m, 1 H), 7.60 - 7.65 (m, 2H), 5.25 (s, 1 H), 3.56 - 3.68 (m, 4H), 2.80 (d, J=4.6 Hz, 3H), 1.10 (t, J=7.0 Hz, 6H).13C-NMR (DMSO-d6, 126MHz): 5 (ppm) 193.0 (s), 163.4 (t, J=2 Hz), 158.9 (dd, J=252, 8 Hz), 139.4 (t, J=9 Hz), 117.5 (t, J=21 Hz), 110.8 - 111.1 (m), 100.8 (s), 62.8 (s), 26.4 (s), 15.0 (s). HRMS (ESI) m / z: [M+H]+calc’d for C14H17F2NO4 302.1198; found 302.1199. Rt 1 .03 min.

[0782] Stage 3 - Deprotection and Three Component Coupling

[0783] To a reactor was added the above acetal (8 g, 1 equiv) and then added formic acid (24 mL, 3 vol). The resulting solution was heated to 95 °C and stirred for ~3 hours until complete consumption of acetal starting material. The reaction mixture was cooled to 25 °C and then concentrated to a foam. Then toluene (120 mL, 15 vol) was added to the foam and concentrated to remove formic acid and this was repeated twice more. The residue was dissolved in dimethylacetamide (23 mL, 3.5 vol) followed by addition of 2-amino-4- m ethylpyridine (4.62 g, 1 .6 equiv) and Meldrum’s acid (3.84 g, 1 equiv). The resulting solution was stirred at 65 °C for 3 hours to afford a dark suspension. The suspension was then stirred at 95 °C for6 hours and subsequently cooled to 25 °C. Acetonitrile (75 mL, 10 vol) was added and the resulting suspension was stirred at 25 °C for 16 hours before filtering to collect the product. The wetcake of product was washed three times with acetonitrile (25 mL, 3 vol) before drying in the vaccum oven at 75 °C for 6 h to afford the desired product (5.57 g, 54.2% yield over three steps).

[0784] 1H-NMR (DMSO-d6, 501 MHz): 5 (ppm) 12.64 (dt, J=6.3, 4.5 Hz, 1 H), 8.70 (q, J=4.4 Hz, 1 H), 8.31 (d, J=7.0 Hz, 1 H), 7.63 - 7.70 (m, 2H), 7.40 (s, 1 H), 6.86 (dd, J=7.0, 1 .5 Hz, 1 H), 3.90 (s, 2H), 2.83 (d, J=4.4 Hz, 3H), 2.40 (s, 3H).13C-NMR (DMSO-d6, 126MHz): 5 (ppm) 170.8 (s), 164.4 (t, J=2 Hz), 160.3 (dd, J=249, 7 Hz), 145.3 (s), 137.3 (t, J=9 Hz), 135.9 (s), 131.1 (s), 125.2 (s), 118.1 (s), 115.4 (s), 115.1 (s), 114.6 (t, J=20 Hz), 111.1 (dd, J=22 Hz), 29.7 (s), 26.9 (s), 21 .2 (s). H RMS (ESI) m / z: [M+ H]+calc’d forCisH^NsOs 360.1154; found 360.1158. Rt 0.50 min. Stage 4 - Ylide Formation

[0785] To a solution of the above carboxylic acid (7.5 g, 1 equiv) in THF (75 mL, 10 vol) was added 1 ,1’-carbonyldiimidazole (5.33 g, 1.75 equiv). The reaction mixture was stirred at ambient temperature until conversion to the acyl imidazole is deemed complete by HPLC.

[0786] In a separate reactor, potassium tert-butoxide (33.8 mL, 1.8 equiv, 1.0 M in THF) was added to trimethylsulfoxonium chloride (4.9 g, 2.0 equiv) in THF (75 mL, 10 vol) at ambient temperature. The mixture was heated to 45 °C for 1 h then cooled to 0 °C. The solution of acyl imidazole was then added and the mixture stirred at 0 °C until deemed complete by HPLC. Water (60 mL, 8 vol) was added and the mixture was concentrated. The resulting slurry was filtered to collect the solids. The reactor was rinsed with water (22.5 mL, 3 vol) and this rinse used to wash the wet cake. The wet cake was washed once more with water (22.5 mL, 3 vol) then dried under vacuum at 40-60 °C to provide the desired ylide (5.45 g, 67% yield).

[0787] 1H-NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.69 (q, J=4.3 Hz, 1 H), 8.25 (d, J=7.0 Hz, 1 H), 7.60 - 7.70 (m, 2H), 7.36 (s, 1 H), 6.82 (dd, J=7.0, 1.5 Hz), 4.65 (s, 1 H), 3.61 (s, 2H), 3.36 (s, 6H), 2.82 (d, J=4.6 Hz, 3H), 2.38 (s, 3H).13C-NMR (DMSO-d6 ,126 MHz): 5 (ppm) 182.8 (s), 164.0 (t, J=2 Hz), 159.9 (dd, J=249, 7 Hz), 144.7 (s), 136.7 (t, J=9 Hz), 135.1 (s), 130.4 (s), 124.7 (s), 119.8 (s), 114.9 (s), 114.7 (t, J=20 Hz), 114.5 (s), 110.6 (dd, J=27, 6 Hz), 72.5 (s), 40.3 (s), 35.0 (s), 26.4 (s), 20.8 (s). HRMS (ESI) m / z: [M+H]+calc’d for C2iH2iF2N3O3S 434.1344; found 434.1352. Rt 0.49 min.

[0788] Stage 5 - Chlorination of Ylide

[0789] To the ylide (0.917 g, 1.692 mmol, 1 equiv) in MeTHF (9.17 mL, 0.185 M, 10 Vol) in a reactor was added HCI in EtOH (4.062 mL, 1.25 M, 5.077 mmol, 3 equiv). The reaction mixture was heated to 50°C until full conversion as monitored by HPLC. The reaction mixture was basified with saturated aqueous NaHCO3, the layers were separated, and the organic layer was washed with saturated aqueous NaCI solution. The organic layer was concentrated down to dryness. The residue was dissolved in 5% MeOH / DCM and chromatographed 0-10% MeOH / DCM to give a pale yellow solid (0.46 g, 69% yield).

[0790] 1H NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.69 (q, J=4.4 Hz, 1 H), 8.21 (d, J=7.2 Hz, 1 H), 7.60 - 7.69 (m, 2H), 7.39 - 7.43 (m, 1 H), 6.86 (dd, J=7.0, 1 .5 Hz, 1 H), 4.68 (s, 2H), 4.24 (s, 2H), 2.82 (d, J=4.4 Hz, 3H), 2.38 - 2.41 (m, 3H).13C-NMR (DMSO-d6, 126 MHz): 5 (ppm) 197.2 (s), 163.9 (s), 159.8 (dd, J=249, 7 Hz), 144.9 (s), 136.7 (t, J=9 Hz), 135.6 - 136.1 (m), 130.7 - 131.0 (m), 124.7 (s), 116.9 (s), 114.9 (s), 114.8 (s), 113.6 - 114.2 (m), 110.4 - 111.0 (m), 48.7 (s), 34.4 (s), 26.4 (s), 20.8 (s). HRMS (ESI) m / z: [M+H]+calc’d forCi9Hi6CIF2N3O2 392.0971 ; found 392.0967. Rt 0.66 min.

[0791] Stage 6 - Noyori Hydrogenation

[0792] To a solution of chloroketone (620 mg, 0.051 mmol, 1 equiv) in THF (6.2 mL, 10 vol) was added (S.S)-Ts-DENEB RuCI (0.056 g, 0.085 mmol, 0.054 equiv) and HCO2H:EfeN complex (5:2) (4.319 mL, 10.286 mmol, 6.5 equiv) and the mixture became a homogeneous solution. The vial was capped and a needle was driven through the septum to allow CO2 to escape and stirred overnight at ambient temperature. Upon completion by HPLC, the reaction mixture was quenched with 15 mL 10% aq. NaHCOs to give a biphasic mixture. The layers were separated and the aqueous phase was extracted 3x 5 mL 2-MeTHF. The combined organic phases were washed 1x 5 mL 10% aq. NaCI. The organic phase was dried over MgSC and the desiccant was removed via vacuum filtration. The organic phase was concentrated to give a red-brown solid (0.573 g, 92% recovery).

[0793] 1H NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.70 (q, J=4.3 Hz, 1 H), 8.42 (d, J=7.0 Hz, 1 H), 7.60 - 7.67 (m, J=8.3 Hz, 2H), 7.33 - 7.36 (m, 1 H), 6.83 (dd, J=7.1 , 1.6 Hz, 1 H), 5.43 (br s, 1 H), 3.79 - 3.86 (m, 1 H), 3.44 (dd, J=10.9, 5.3 Hz, 1 H), 3.39 (dd, J=10.9, 5.3 Hz, 1 H), 3.10 (dd, J=15.3, 4.4 Hz, 1 H), 3.00 (dd, J=15.3, 7.7 Hz, 1 H), 2.82 (d, J=4.6 Hz, 3H), 2.36 - 2.39 (m, 3H).13C NMR (DMSO-d6, 126 MHz): 5 (ppm) 163.9 (s), 160.0 (dd, J=248, 7 Hz), 144.8 (s), 136.8 (t, J=9 Hz), 135.0 (s), 130.6 (s), 124.7 (s), 120.4 (s), 114.9 (s), 114.9 (t, J=20 Hz), 114.3 (s), 110.2 - 110.7 (m), 69.7 (s), 48.5 (s), 27.6 (s), 26.4 (s), 20.7 (s). HRMS (ESI) m / z: [M+H]+calc’d for C19H18CIF2N3O2 394.1128; found 394.1117. Rt 1 .46 min. Stage 7 - Epoxidation

[0794] To a solution of 4-[3-(3-chloro-2-hydroxypropyl)-7-methylimidazo[1 ,2-a]pyridin-2-yl]-3,5- difluoro-N-methylbenzamide (0.364 g, 0.828 mmol, 1 equiv) in CH2CI2 (3.64 mL, 10 vol) was added tetrabutylammonium bromide (0.013 g, 0.041 mmol, 0.05 equiv) and KOH (0.06 g, 1.076 mmol, 1.3 equiv). The reaction was stirred at ambient temperature until complete by HPLC. Reaction diluted with 1 mL water. The phases were separated and the organic layer was dried with Na2SO4 and concentrated to give a pale yellow solid (0.257 g, 87% isolated yield).

[0795] 1H NMR (DMS0-d6, 501 MHz): 5 (ppm) 8.70 (br q, J=4.4 Hz, 1 H), 8.41 (d, J=7.2 Hz, 1 H), 7.64 - 7.68 (m, 2H), 7.37 (s, 1 H), 6.86 (dd, J=7.0, 1 .5 Hz, 1 H), 3.26 (dd, J= 14.9, 2.8 Hz), 3.05 - 3.07 (m, 1 H), 3.01 - 3.05 (m, 1 H), 2.82 (d, J=4.6 Hz, 3H), 2.63 - 2.66 (m, 1 H), 2.39 - 2.42 (m, 1 H), 2.37 - 2.39 (m, 3H).13C NMR (DMSO-d6, 126 MHz): 5 (ppm) 164.0 (s), 159.9 (dd, J=249, 7 Hz), 144.9 (s), 136.8 - 137.1 (m), 135.4 (s), 130.6 (s), 124.5 (s), 119.4 (s), 115.0 (s), 114.8 (s), 114.5 (s), 110.6 (br d, J=27 Hz), 50.2 (s), 45.6 (s), 26.4 (s), 25.9 (s), 20.8 (s). HRMS (ESI) m / z: [M+H]+calc’d for C19H17F2N3O2 358.1361 ; found 358.1366. Rt 0.59 min.

[0796] Stage 8 - Morpholine Synthesis

[0797] To a solution of 2-aminoethyl hydrogen sulfate (0.148 g, 1.049 mmol, 1.5 equiv) in toluene (0.5 mL, 2 vol) and EtOH (0.5 mL, 2 vol) was added DBU (0.151 mL, 1.014 mmol, 1.45 equiv) and heated to 65°C for at least 1 hr. To this solution was added 3,5-difluoro-N-methyl-4-[7- methyl-3-(oxiran-2-ylmethyl)imidazo[1 ,2-a]pyridin-2-yl]benzamide (0.25 g, 0.7 mmol, 1 equiv) with additional toluene (2.5 mL, 10 Vol). The reaction continued to heat at 65°C overnight. Upon completion, the reaction mixture was concentrated to dryness and then redissolved in EtOH (12.5 mL, 50 vol). To this solution was added NaOH (0.42 g, 10.494 mmol, 15 equiv) and heated to 70°C. The reaction mixture was cooled to ambient temperature and concentrated to dryness. The residue was dissolved in 20 m L of CH2CI2 and then washed with 5 mL water. The layers were separated and the organic layer was washed with 5 mL sat. aq. NaCI solution. The organic layer was separated and dried over Na2SO4. Concentrated the organic layer and dissolved in minimal CH2CI2 and chromatographed using 50% Heptane in 3:1 EtOAc:EtOH -> 100% 3:1 EtOAc:EtOH to get a pale brown solid (0.027 g, 10% yield).

[0798] 1H NMR (DMS0-d6, 600 MHz): 6 (ppm) 8.74 (q, J=4.3 Hz, 1 H), 8.38 (d, J=7.1 Hz, 1 H), 7.63 - 7.69 (m, 2H), 7.35 (s, 1 H), 6.83 (dd, J=7.1 , 1 .5 Hz, 1 H), 3.60 (dd, J=11 .5, 2.5 Hz, 1 H), 3.49 - 3.56 (m, 2H), 3.26 - 3.32 (m, 1 H), 3.00 (dd, J= 15.6, 7.6 Hz, 1 H), 2.92 (dd, J=15.6, 4.9 Hz, 1 H), 2.82 (d, J=4.5 Hz, 3H), 2.68 (d, J=12.4 Hz, 1 H), 2.65 (d, J= 12.7 Hz, 1 H), 2.56 (td, J=11 .9, 3.2 Hz, 1 H), 2.38 (s, 3H), 2.29 - 2.34 (m, 1 H).13C NMR (DMSO-d6, 151 MHz): 5 (ppm) 163.9 (s),

[0799] 159.9 (dd, J=248, 7 Hz), 144.7 (s), 136.8 (t, J=8 Hz), 135.0 (s), 130.5 (s), 124.5 (s), 120.0 (s),

[0800] 114.9 (s), 114.8 (t, J=20 Hz), 114.5 (s), 110.3 - 110.7 (m), 74.5 (s), 66.3 (s), 49.2 (s), 44.3 (s),

[0801] 26.9 (s), 26.4 (s), 20.7 (s). HRMS (ESI) m / z: [M+H]+ calc’d for C21H22F2N4O2401.1783; found 401.1792. Rt 0.39 min.

[0802] Stage 9 - Camlipixant

[0803] To a solution of 3,5-difluoro-N-methyl-4-[7-methyl-3-(morpholin-2-ylmethyl)imidazo[1 ,2- a]pyridin-2-yl]benzamide (0.027 g, 0.067 mmol, 1 equiv) in acetone (0.108 mL, 4 vol) and water (0.108 mL, 4 vol) was added NEta (0.019 mL, 0.135 mmol, 2 equiv) and methyl chloroformate (0.006 mL, 0.081 mmol, 1.2 equiv). The reason was stirred at ambient temperature until complete by HPLC. The reaction mixture was diluted with 1 mL acetone and chromatographed using 50% heptane in 3:1 EtOAc:EtOH to 100% 3:1 EtOAc:EtOH to give an off white residue (0.009 g, 29% yield).

[0804] 1H NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.70 (q, J=4.4 Hz, 1 H), 8.43 (d, J=7.2 Hz, 1 H), 7.63 - 7.67 (m, 2H), 7.34 - 7.37 (m, 1 H), 6.84 (dd, J=7.2, 1 .7 Hz, 1 H), 3.69 - 3.79 (m, 1 H), 3.62 - 3.67 (m, 1 H), 3.59 - 3.65 (m, 1 H), 3.55 (s, 3H), 3.41 - 3.51 (m, 1 H), 3.22 (td, J=11.8, 2.8 Hz, 1 H), 2.98 - 3.09 (m, 2H), 2.82 (d, J=4.4 Hz, 3H), 2.74 - 2.82 (m, 1 H), 2.45 - 2.55 (m, 1 H), 2.35 - 2.40 (m, 3H).13C NMR (DMSO-d6, 126MHz): 5 (ppm) 164.0 (s), 159.9 (dd, J=248, 7 Hz), 154.9 (s), 144.7 (s), 136.9 (t, J=9 Hz), 135.1 (s), 130.8 (s), 124.6 (s), 119.5 (s), 115.0 (s), 114.7 - 115.0 (m), 114.6 (s), 110.3 - 110.7 (m), 73.7 (br s), 65.7 (s), 52.4 (s), 47.3 (br s), 42.9 (br s), 26.4 (s), 26.4 (s), 20.7 (s). HRMS (ESI) m / z: [M+H]+calc’d for C23H24F2N4O4459.1838; found 459.1839. Achiral: Rt 0.67 min. Chiral: Daicel Chiralpak AD-H, 4.6x250 mm, 5.0 pm. Rt 18.25 min.

[0805] Method 3 - Synthesis of camlipixant

[0806] Bromide Stage 1 - Acylation

[0807] LDA (1 2 e uiv)

[0808] 1-bromo-3,5-difluorobenzene (11.933 mL, 103.632 mmol, 1 equiv) was dissolved in THF (140 mL, 7 vol). The mixture was cooled to -78 °C. Lithium diisopropylamide (62.179 mL, 2 M, 124.358 mmol, 1.2 equiv) was added dropwise via syringe. Ethyl 2,2-diethoxyacetate (19.466 mL, 108.813 mmol, 1.05 equiv) was added neat. Upon completion by HPLC, the reaction was quenched slowly with acetic acid (29.779 mL, 518.159 mmol, 5 equiv) in an equal volume of water (29.779 mL), then warmed to ambient temperature. Ethyl acetate (35 mL) and 2 M aq. citric acid (310.895 mL, 621.791 mmol, 6 equiv) were added and the phases were separated. The organic layer was washed with 10% aq. NaCI (35 mL). The organic layer was dried over anhydrous MgSC , filtered, and concentrated under reduced pressure. The crude oil was purified by silica gel chromatography (0 to 20% ethyl acetate / hexanes) to afford the product as a clear oil (18.924 g, 57%).

[0809] 1H NMR (DMSO-d6, 501 MHz): 5 (ppm) 7.58 (d, J=7.5 Hz, 2H), 5.19 (s, 1 H), 3.50 - 3.70 (m, 4H), 1.10 (t, J=7.2 Hz, 6H).13C NMR (DMSO-d6, 126 MHz): 5 (ppm) 192.2 (t, J=2 Hz), 159.2 (dd, J=255, 9 Hz), 125.1 (t, J=12 Hz), 115.8 - 116.2 (m), 115.0 (t, J=21 Hz), 100.8 (s), 62.7 (s), 14.8 (s). HRMS (ESI) m / z: [M+H]+calc’d for Ci2Hi3BrF2O3323.0088; found 323.0085. Rt 1.46 min.

[0810] Bromide Stage 2 - Three Component Cyclization 1-(4-bromo-2,6-difluorophenyl)-2,2-diethoxyethanone (23.6 g, 73.035 mmol, 1 equiv) was dissolved in formic acid (70.8 mL, 3 vol) and stirred at 95 °C . Upon completion by HPLC, solvent was removed in vacuo. The resulting oil was re-dissolved in ethyl acetate (100 mL), then washed with sat. aq. NaHCOs (100 mL). The organic layer was washed with water (100 mL), dried over anhydrous MgSO4, and filtered. Solvent was removed in vacuo. The resulting oil was dissolved in N,N-dimethylacetamide (82.6 mL, 0.884 M, 3.5 Vol). 2-amino-4- m ethylpyridine (7.898 g, 73.035 mmol, 1 equiv) and meldrum's acid (10.526 g, 73.035 mmol, 1 equiv) were added and the reaction was stirred at 95 °C. Upon completion, the reaction was cooled to room temperature and acetonitrile (236 mL, 10 Vol) was added dropwise. The mixture was filtered and the cake was dried in vacuo affording a white solid (6.833 g, 25%).

[0811] 1H NMR (DMSO-d6, 501 MHz): 5 (ppm) 11.79 - 13.83 (m, 1 H), 8.28 (d, J=7.0 Hz, 1 H), 7.61 (d, J=7.0 Hz, 2H), 7.37 (d, J=0.8 Hz, 1 H), 6.83 (dd, J=7.0, 1.5 Hz, 1 H), 3.85 (s, 2H), 2.38 (s, 3H).13C NMR (DMSO-d6, 126MHz): 5 (ppm) 170.4 (s), 160.1 (dd, J=252, 8 Hz), 144.7 (s), 135.3 (s), 130.3 (s), 124.7 (s), 121 .6 (t, J=13 Hz), 117.8 (s), 115.3 - 116.3 (m), 114.9 (s), 114.5 (s), 111.5 (t, J=20 Hz), 29.4 (s), 20.8 (s). HRMS (ESI) m / z: [M+H]+calc’d for Ci6HnBrF2N2O2381.0044; found 381.0040. Rt 0.69 min.

[0812] Bromide Stage 3 - Ylide Formation

[0813] Trim ethyl(oxo)-A6-sulf any Hum chloride (4.184 g, 32.531 mmol, 2 equiv) was dissolved in dry THF (62 mL, 10 vol). Potassium tert-butoxide in THF (29.278 mL, 1 M, 29.278 mmol, 1.8 equiv) was added dropwise over 10 minutes and the reaction was stirred at 45 °C. After 90 minutes, the reaction was cooled to 0 °C. In a separate vessel, [2-(4-bromo-2,6- difluorophenyl)-7-methylimidazo[1 ,2-a]pyridin-3-yl]acetic acid (6.2 g, 16.265 mmol, 1 equiv) was dissolved in dry THF (62 mL, 10 vol). Carbonyldiimidazole (4.879 g, 30.091 mmol, 1.85 equiv) was added in 2 x 2.44 g portions over 5 minutes. Upon complete consumption of the carboxylic acid by HPLC, this mixturewas added dropwise to the ylide solution at 0 °C, rinsing with THF (2 x 5 mL). Upon completion by HPLC, the mixturewas warmed to room temperature and quenched with water (31 mL, 5 Vol). Ethyl acetate (31 mL, 5 Vol) was added and the phases were separated. The organic layer was washed with 10% aqueous NaCI (2 x 31 mL, 2 x 5 Vol), dried over anhydrous MgSO4, and filtered. Solvent was removed in vacuo. The resulting solid was slurried in tert-butylmethyl ether (62 mL, 10 Vol) and filtered. The cake was re-slurried in tert-butylmethyl ether and filtered (2 x 31 mL, 2 x 5Vol). The cake was dried in vacuo to afford the product as a white solid (3.667 g, 50%).

[0814] 1H NMR (DMS0-d6, 501 MHz): 5 (ppm) 8.25 (d, J=7.0 Hz, 1 H), 7.60 (d, J=6.9 Hz, 2H), 7.35 (s, 1 H), 6.81 (dd, J=7.1 , 1.6 Hz, 1 H), 4.65 (s, 1 H), 3.59 (s, 2H), 3.36 (s, 6H), 2.37 (s, 3H).13C NMR (DMSO-d6, 126 MHz): 5 (ppm) 182.8 (s), 160.2 (dd, J=252, 8 Hz), 144.6 (s), 135.0 (s), 130.1 (s), 124.6 (s), 121.5 (t, J=13 Hz), 119.7 (s), 115.7 (br d, J=29 Hz), 114.9 (s), 114.4 (s), 111.9 (t, J=20 Hz), 72.5 (s), 40.3 (s), 35.0 (s), 20.8 (s). HRMS (ESI) m / z: [M+H]+calc’d for Ci9Hi7BrF2N2O2S 455.0234; found 455.0228. Rt 0.64 min.

[0815] Bromide Stage 4 - Chlorination of Ylide

[0816] {3-[2-(4-bromo-2,6-difluorophenyl)-7-methylimidazo[1 ,2-a]pyridin-3-yl]-2- oxopropylidene}dimethyl-A6-sulfanone (3 g, 6.589 mmol, 1 equiv) was dissolved in THF (30 mL, 10 vol). HCI in EtOH (15.813 mL, 1.25 M, 19.766 mmol, 3 equiv) was added and the reaction was stirred at 50 °C. Upon completion by HPLC, the reaction was cooled to room temperature and quenched with sat. aq. NaHCOs (30 mL, 10 vol). Ethyl acetate (30 mL, 10 vol) was added and the phases were separated. The organics were washed with saturated NaCI (30 mL), dried over anhydrous MgSC , and filtered. Solvent was removed in vacuo, then tert-butylmethyl ether (30 mL, 10 Vol) was added. The resulting slurry was filtered and the cake was washed with tert-butylmethyl ether (2 x 15 mL, 2 x 5 Vol). The cake was dried in vacuo to afford the product as a white solid (1 .223 g, 45%).

[0817] 1H NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.19 (d, J=7.0 Hz, 1 H), 7.56 - 7.64 (m, 2H), 7.39 (br s, 1 H), 6.84 (dd, J=7.1 , 1.6 Hz, 1 H), 4.69 (s, 2H), 4.22 (s, 2H), 2.38 (d, J=0.6 Hz, 3H).13C NMR (DMSO-d6, 126 MHz): 5 (ppm) 197.2 (s), 160.1 (dd, J=252, 8 Hz), 144.9 (s), 135.6 (s), 130.8 (s), 124.6 (s), 121.6 (t, J=13 Hz), 116.7 (s), 115.7 - 116.0 (m), 115.0 (s), 114.6 (s), 111.3 (t, J=20 Hz), 48.7 (s), 34.4 (s), 20.7 (s). HRMS (ESI) m / z: [M+H]+calc’d forCi7Hi2BrCIF2N2O 412.9862; found 412.9859. Rt 0.87 min.

[0818] Bromide Stage 5 - Noyori Hydrogenation

[0819] In an inert atmosphere glovebox, 1-[2-(4-bromo-2,6-difluorophenyl)-7-methylimidazo[1 ,2- a]pyridin-3-yl]-3-chloropropan-2-one (600 mg, 1.451 mmol, 1 equiv) and (S,S)-Ts-DENEB RuCI (48.576 mg, 0.078 mmol, 0.054 equiv) were dissolved in THF (6.48 mL, 0.224 M, 10.8 Vol). 5:2 HCO2H:NEt3 (3.959 mL, 9.428 mmol, 6.5 equiv) was added and the reaction was stirred at room temperature. Upon completion by HPLC, the reaction was removed from the glovebox and the pH was adjusted to 9 with sat. aq. NaHCOs. The layers were separated, and the aqueous phase was washed with MeTHF (3 x 10 mL). The combined organics were washed with sat. aq. NaCI (10 mL), dried over anhydrous MgSC , and filtered. Solvent was removed in vacuo. Dichloromethane (1 mL) was added and the resulting slurry was filtered. The mother liquor was concentrated in vacuo. The dark residue was purified by silica gel chromatography (O to 10% methanol / ethyl acetate) to afford the product as a white solid (219.3 mg, 36%, 88% ee).

[0820] 1H NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.40 (d, J=7.0 Hz, 1 H), 7.55 - 7.69 (m, 2H), 7.29 - 7.38 (m, 1 H), 6.82 (dd, J=7.2, 1.7 Hz, 1 H), 5.41 (d, J=5.4 Hz, 1 H), 3.75 - 3.88 (m, 1 H), 3.46 (dd, J=10.9, 5.2 Hz, 1 H), 3.40 (dd, J=10.7, 5.4 Hz, 1 H), 3.08 (dd, J=15.3, 4.4 Hz, 1 H), 2.98 (dd, J=15.3, 7.6 Hz, 1 H), 2.37 (d, J=0.6 Hz, 3H).13C NMR (DMSO-d6, 126 MHz): 5 (ppm) 160.3 (dd, J=251 , 8 Hz), 144.8 (s), 135.0 (s), 130.3 (s), 124.7 (s), 121.6 (t, J=13 Hz), 120.3 (s), 115.5 - 115.8 (m), 114.9 (s), 114.3 (s), 112.1 (t, J=20 Hz), 69.7 (s), 48.6 (s), 27.6 (s), 20.7 (s). HRMS (ESI) m / z: [M+H]+calc’d for Ci7Hi4BrCIF2N2O 415.0018; found 415.0015. Rt 0.85 min.

[0821] Bromide Stage 6 - Epoxidation

[0822] (S)-1-(2-(4-bromo-2,6-difluorophenyl)-7-methylimidazo[1 ,2-a]pyridin-3-yl)-3-chloropropan-2- ol, (219.3 mg, 0.528 mmol, 1 equiv), KOH (38.481 mg, 0.686 mmol, 1.3 equiv), and tetrabutylammonium bromide (8.504 mg, 0.026 mmol, 0.05 equiv) were suspended in CH2CI2 (2.19 mL, 10 vol). Upon completion by HPLC, the reaction was washed with water (2 x 2.2 mL, 2 x 10 vol). The organic phase was dried over anhydrous MgSC , filtered, and solvent was removed in vacuo. The residue was purified by silica gel chromatography (0 to 20% methanol / dichlorom ethane) to afford the product as a white solid (157.7 mg, 79%, 93.2% ee).

[0823] 1H NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.40 (d, J=7.0 Hz, 1 H), 7.60 - 7.65 (m, 2H), 7.35 - 7.38 (m, 1 H), 6.86 (dd, J=7.0, 1.7 Hz, 1 H), 3.25 (dd, J=15.5, 3.4 Hz, 1 H), 3.03 - 3.08 (m, 1 H), 2.97 - 3.03 (m, 1 H), 2.65 (dd, J=5.0, 4.0 Hz, 1 H), 2.40 (dd, J=5.0, 2.6 Hz, 1 H), 2.38 (s, 3H).13C NMR (DMSO-d6, 126 MHz): 5 (ppm) 160.2 (dd, J=251 , 8 Hz), 144.8 (s), 135.4 (s), 130.3 (s), 124.5 (s), 121.8 (t, J=13 Hz), 119.3 (s), 115.5 - 116.0 (m), 115.0 (s), 114.7 (s), 111.7 (t, J=20 Hz), 50.2 (s), 45.5 (s), 25.8 (s), 20.7 (s). HRMS (ESI) m / z: [M+H]+calc’d Ci7Hi3BrF2N2O 379.0252; found 379.0249. Rt 1.62 min.

[0824] Bromide Stage 7 - Morpholine Synthesis

[0825] 2-Aminoethyl hydrogen sulfate (88.071 mg, 0.624 mmol, 1.5 equiv) was dissolved in ethanol (1.577 mL, 10 vol). DBU (86.927 pL, 0.582 mmol, 1.4 equiv) was added and the mixture was stirred at 65 °C for two hours. Upon cooling to room temperature, the mixture was added to (S)-2-(4-bromo-2,6-difluorophenyl)-7-methyl-3-(oxiran-2-ylmethyl)imidazo[1 ,2-a]pyridine (157.7 mg, 0.416 mmol, 1 equiv). EtOH (1.577 mL, 10 vol) was added, followed by freshly ground sodium hydroxide (83.194 mg, 2.08 mmol, 5 equiv). The reaction was stirred at 65°C. Upon completion by HPLC, the mixture was cooled to room temperature and added dropwise to 2M aq. citric acid (1.456 mL, 2.912 mmol, 7 equiv). Water (3 mL) and dichloromethane (3 mL) were added. The pH was adjusted to 4 with 2 M aqueous citric acid. The layers were separated and the organic layer was discarded. Dichloromethane (3 mL) was added to the aqueous phase and the pH was adjusted to 6 with sat. aq. NaHCOs. The layers were separated. The organic layer was dried over anhydrous MgSC and filtered. Ethyl acetate (2 mL) was added and the volume was reduced to 1 mL in vacuo. The resulting slurry was filtered and washed with ethyl acetate (3 x 1 mL). Solvent was removed from the liquor in vacuo and the crude white solid was used for the next step without further purification (30.3 mg, 17%).

[0826] 1H NMR (DMSO-d6, 501 MHz): 5 (ppm) 8.36 (d, J=7.0 Hz, 1 H), 7.59 - 7.64 (m, 2H), 7.32 - 7.34 (m, 1 H), 6.82 (dd, J=7.0, 1.7 Hz, 1 H), 3.54 - 3.58 (m, 1 H), 3.39 - 3.46 (m, 2H), 3.23 (td, J=11.1 , 3.1 Hz, 1 H), 2.94 (dd, J=15.5, 7.5 Hz, 1 H), 2.86 (dd, J=15.5, 5.0 Hz, 1 H), 2.54 - 2.59 (m, 1 H), 2.49 - 2.56 (m, 2H), 2.37 (d, J=0.9 Hz, 3H), 2.22 (dd, J=12.0, 10.0 Hz, 1 H).13C NMR (DMSO-d6, 126 MHz): 5 (ppm) 160.2 (dd, J=251 , 8 Hz), 144.6 (s), 134.9 (s), 130.1 (s), 124.5 (s), 121.6 (t, J=13 Hz), 120.2 (s), 115.5 - 115.8 (m, J=29 Hz), 114.9 (s), 114.5 (s), 112.1 (s), 75.3 (s), 67.3 (s), 50.2 (s), 45.0 (s), 27.0 (s), 20.7 (s). HRMS (ESI) m / z: [M+H]+calc’d Ci9Hi8BrF2N3O 422.0674; found 422.0693. Rt 0.54 min.

[0827] Bromide Stage 8 - Methyl ester installation

[0828] (S)-2-((2-(4-bromo-2,6-difluorophenyl)-7-methylimidazo[1 ,2-a]pyridin-3-yl)methyl)morpholine (30.3 mg, 0.072 mmol, 1 equiv) was dissolved in acetone (60.6 pL, 2 vol) and water (90.9 pL, 3 vol). NEts (30.1 pL, 0.216 mmol, 3 equiv) was added. Methyl chloroformate (6.692 pL, 0.086 mmol, 1.2 equiv) was added and the reaction was stirred at ambient temperature. Upon completion by HPLC, the mixture was purified by silica gel chromatography (0 to 70% ethyl acetate / hexanes) to afford the product (11.1 mg, 32%).

[0829] 1H NMR (DMSO-d6, 600MHz, 80°C): 6 (ppm) 8.37 (d, J=7.1 Hz, 1 H), 7.50 - 7.54 (m, 2H), 7.32 (s, 1 H), 6.81 (dd, J=7.2, 0.8 Hz, 1 H), 3.70 - 3.74 (m, 1 H), 3.66 - 3.70 (m, 1 H), 3.63 - 3.67 (m, 1 H), 3.58 (s, 3H), 3.47 - 3.53 (m, 1 H), 3.26 (td, J=11.6, 2.6 Hz, 1 H), 3.02 (d, J=6.0 Hz, 2H), 2.83 (td, J=12.4, 3.3 Hz, 1 H), 2.56 (dd, J=12.8, 10.6 Hz, 1 H), 2.39 (s, 3H).13C NMR (DMSO- d6, 151 MHz, 80°C): 5 (ppm) 159.9 (dd, J=252, 8 Hz), 154.6 (s), 144.4 (s), 134.5 (s), 130.3 (s), 124.0 (s), 119.1 (s), 115.0 - 115.3 (m), 73.4 (s), 65.3 (s), 51.8 (s), 47.1 (s), 42.7 (s), 26.2 (s), 20.2 (s). HRMS (ESI) m / z: [M+H]+calc’d C2iH2oBrF2N303480.0728; found 480.0725. Rt 1.13 min.

Claims

CLAIMS1 . A process for the preparation of a compound of Formula (A),whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (15) to a compound of FormulawhereinR7is independently selected from C1-3 alkyl; andX1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and X1may be the same or different.

2. A process according to claim 1 , wherein said conversion comprises contacting a compound of Formula (15) with a suitable acid, followed by a suitable reducing agent.

3. A process according to claim 2, wherein the suitable acid is selected from the group consisting of a sulfonic acid, sulfuric acid, trimethylsilyl trifluoromethanesulfonate, triflic acid, boron trifluoride etherate, hydrogen chloride, hydrogen bromide, and trifluoroacetic acid.

4. A process according to claim 2 or claim 3, wherein the suitable acid is methanesulfonic acid.

5. A process according to any one of claims 2 to 4, wherein the suitable reducing agent is tetramethyldisiloxane (TMDS), hydrogen, polymethylhydrogen siloxane, or triethylsilane.

6. A process according to claim 5, wherein the suitable reducing agent is tetramethyldisiloxane (TMDS).

7. A process according to any one of the preceding claims, further com prising contacting a compound of Formula (14)with a suitable reducing agent to provide a compound of Formula (15).

8. A process according to claim 7, wherein the reducing agent is a chiral reducing agent.

9. A process according to claim 8, wherein the chiral reducing agent is a ketoreductase enzyme in the presence of a cofactor or wherein the chiral reducing agent comprises a ruthenium-based catalyst and a suitable source of hydrogen.

10. A process according to claim 9, wherein the cofactor is NADP+.

11. A process according to claim 9, wherein the chiral reducing agent is a ruthenium -based catalyst and a suitable source of hydrogen.

12. A process according to claim 11 , wherein the suitable source of hydrogen is formic acid and a suitable amine, wherein the suitable amine is a tertiary amine, optionally selected from the group consisting of triethylamine, N-m ethyl dicyclohexylamine, N- methyl morpholine, N,N-dim ethylaminoethanol, TMEDA, (-)-sparteine and isopropylamine.

13. A process according to any one of the preceding claims, wherein R7is methyl.

14. A process according to any one of the preceding claims, further com prising contacting a compound of Formula (V)with a compound of Formulfollowed by an agent selected from methyl chloroform ate, dimethyl carbonate and dimethyl dicarbonate to provide a compound of Formula (14), optionally in the presence of a suitable base, wherein LG is a suitable leaving group.

15. A process according to claim 14, wherein LG is selected from the group consisting of halo, tosylate, mesylate and triflate.

16. A process according to claim 15, wherein LG is halo.

17. A process according to claim 16, wherein LG is chloro.

18. A process according to any one of claims 14 to 17, wherein R7is methyl.

19. A process according to any one of claims 14 to 18, wherein the agent is methyl chloroform ate.

20. A process according to any one of the preceding claims, further com prising contacting a compound of Formula (VI)with a hydrogen halide, to provide a compound of Formula (V).

21. A process according to claim 20, wherein the hydrogen halide is hydrochloric acid.

22. A process according to claim 21 , wherein the hydrochloric acid is prepared by a combination of lithium chloride and methanesulfonic acid.

23. A process according to any one of the preceding claims, further comprising contacting a compound of Formula (VII)with a trimethylsulfoxonium halide in the presence of a coupling reagent and a suitable base, to provide a compound of Formula (VI).

24. A process according to claim 23, wherein the trimethylsulfoxonium halide is trim ethylsulf oxonium chloride.

25. A process according to claim 23 or 24, wherein the coupling reagent is oxalyl chloride, thionyl chloride, DCC, HATU, EDC, or CDI.

26. A process according to claim 25, wherein the coupling reagent is CDI.

27. A process according to any one of claims 23 to 26, wherein the suitable base is potassium tert-butoxide, sodium hydride, lithium bis(trimethylsilyl)am ide or a guanidine-based base.

28. A process according to claim 27, wherein the suitable base is potassium tert-butoxide.

29. A process according to any one of the preceding claims, further com prising contacting a compound of Formula (with a compound of Formula (VIII)in the presence of a suitable acid, to provide a compound of Formula (VII), wherein Y is a suitable amine group bound through nitrogen or a suitable trialkylphosphine group bound though phosphorus.

30. A process according to claim 29, wherein Y is imidazolyl, in particular N-linked imidazolyl.31 . A process according to claim 29 or 30, wherein the suitable acid is formic acid or acetic acid, in particular acetic acid.

32. A process according to any one of the preceding claims, further com prising contacting a compound of Formula (IX)with a compound of Formula (X)in the presence of a suitable nitrogen- or trialky Iphosphorous-containing nucleophile, to provide a compound of Formula (13).

33. A process according to claim 32, wherein the suitable nucleophile is a nitrogencontaining nucleophile, in particular imidazole.

34. A process according to any one of the preceding claims, further com prising contacting a compound of Formula (XI)with a suitable acid, to provide a compound of Formula (X), wherein R' is C1-3 alkyl.

35. A process according to claim 34, wherein the suitable acid is selected from the group consisting of hydrochloric acid, methanesulfonic acid, acetic acid or formic acid, or a combination thereof.

36. A process according to claim 35, wherein the suitable acid is a combination of methanesulfonic acid and formic acid.

37. A process for the preparation of a compound of Formula (A),whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (14) to a compound of FormulawhereinR7is C1-3 alkyl; andX1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and X1may be the same or different.

38. A process for the preparation of a compound of Formula (A),whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (V)to a compound of Formula (14)whereinR7is C1-3 alkyl; andX1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and X1may be the same or different.

39. A process for the preparation of a compound of Formula (A),whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (VI)to a compound of Formula (V)wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and X1may be the same or different; and LG is a suitable leaving group.

40. A process for the preparation of a compound of Formula (A),whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (VII)to a compound of Formula (VI)wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband - SO2NRaRb, where X and X1may be the same or different.41 . A process for the preparation of a compound of Formula (A),whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (13)wherein Y is a suitable amine group bound through nitrogen or a suitable trialkylphosphine group bound though phosphorus to a compound of Formula (VII)wherein X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and X1may be the same or different.

42. A process for the preparation of a compound of Formula (A),whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of Formula (VII)to a compound of Formula (13)whereinY is a suitable amine group bound through nitrogen or a suitable trialkylphosphine group bound though phosphorus; andX1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb, where X and X1may be the same or different.

43. A process for the preparation of a compound of Formula (A),whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;X is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; the process comprising conversion of a compound of44. A process according to any one of the preceding claims, wherein the compound of Formula (A) is camlipixant.

45. A compound of Formula (VI)whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

46. A compound of Formula (VII)whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

47. A compound of Formula (V)whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb;Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl; and LG is a suitable leaving group.

48. A compound of Formula (V-l)whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

49. A compound of Formula (14)whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;R7is C1-3 alkyl;X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

50. A compound of Formula (14-1)whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

51. A compound of Formula (15)whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

52. A compound of Formula (15-1)whereinR1and R2are independently selected from hydrogen, halo and C1-3 alkyl;R3, R4, R5and R6are independently selected from hydrogen, halo and C1-3 alkyl;X1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

53. A compound of Formula (13)whereinY is a suitable amine group bound through nitrogen or a suitable trialkylphosphine group bound though phosphorus; andX1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; andRaand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

54. A compound of Formula (13-1)whereinX1is selected from halo, -C(O)NRaRb, -C(O)ORa, -NRaC(O)Rband -SO2NRaRb; and Raand Rbare independently selected from hydrogen, C1-3 alkyl and C3-6 cycloalkyl.

55. A process or compound according to any one of the preceding claims, wherein R1is methyl, R2is hydrogen, R3and R4are fluoro, and R5and R6are hydrogen.

56. A process or compound according to any one of the preceding claims, wherein X and / or X1is -C(O)NHCH3.

57. A compound having one of the following structures

Images