HK1222401B - Synthesis of a macrocyclic hcv ns3 inhibiting tripeptide - Google Patents

Description

Macrocyclic HCV NS3 inhibits the synthesis of tripeptides

Background Art

This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application Serial No. 61/920,446, filed on December 23, 2013, the entirety of which is incorporated herein by reference.

The present disclosure relates generally to the field of organic synthesis methods and synthetic intermediates thereof for preparing Flaviviridae virus inhibitor compounds.

Hepatitis C virus (HCV), a member of the genus Hepacivirus in the family Flaviviridae, is the leading cause of chronic liver disease in the world (Boyer, N. et al., J Hepatol. 2000, 32, 98-112). Therefore, a major focus of current antiviral research is devoted to the development of improved methods for treating chronic HCV infection in humans (Ciesek, S., von Hahn T. and Manns, MP., Clin. Liver Dis., 2011, 15, 597-609; Soriano, V. et al., J. Antimicrob. Chemother., 2011, 66, 1573-1686; Brody, H., Nature Outlook, 2011, 474, S1-S7; Gordon, C.P. et al., J. Med. Chem. 2005, 48, 1-20; Maradpour, D. et al., Nat. Rev. Micro. 2007, 5, 453-463).

Virological cure of chronic HCV infected patients is difficult to achieve, and this is because the huge daily viral production and the high spontaneous mutation of HCV in chronic infected patients (Neumann etc., Science 1998,282,103-7; Fukimoto etc., Hepatology, 1996,24,1351-4; Domingo etc., Gene 1985,40,1-8; Martell etc., J.Virol.1992,66,3225-9).HCV treatment is further complicated by the fact that HCV is genetically diversified and expressed as several different genotypes and multiple hypotypes.For example, HCV is currently classified into six major genotypes (named 1-6), many hypotypes (named a, b, c etc.) and about 100 different strains (numbered 1,2,3 etc.).

Worldwide, HCV is primarily distributed in the United States, Europe, Australia, and East Asia (Japan, Taiwan, Thailand, and China) as genotypes 1, 2, and 3. Genotype 4 is primarily found in the Middle East, Egypt, and Central Africa, while genotypes 5 and 6 are primarily found in South Africa and Southeast Asia, respectively (Simmonds, P. et al., J Virol. 84:4597-4610, 2010).

There is still a need to develop effective treatments for HCV infection. Suitable compounds for treating HCV infection are disclosed in U.S. Publication No. 2014-0017198, filed on July 2, 2013, entitled "Inhibitors of hepatitis C virus," which include compounds of Formula I:

Summary of the Invention

Improved methods for preparing compounds of Formula I are presented herein, which offer several advantages over known syntheses. Specifically, Route I disclosed herein utilizes a ring-closing metathesis step at a different location than previously disclosed pathways. This results in several advantages over disclosed syntheses, such as higher efficiency and higher overall yield. Additionally, Route II and III provide novel synthetic routes to compounds of Formula I.

In one embodiment, the present disclosure provides a method for preparing a compound of Formula I or a cocrystal or salt thereof, wherein the compound of Formula I is named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropyl[18,19][1,10,3,6]dioxadiazaaromaticnonadecacyclo[11,12-b]quinoxaline-8-carboxamide:

In another embodiment, the present disclosure provides a process for preparing a compound of Formula V, or a co-crystal or salt thereof:

comprising contacting a compound of formula III, or a co-crystal or salt thereof, with a compound of formula IV under O-arylation conditions to provide a compound of formula V, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group, PG is a protecting group and R ¹ is a leaving group.

In another embodiment, the present disclosure provides a process for preparing a compound of Formula VI or a co-crystal or salt thereof:

comprising subjecting a compound of formula V, or a co-crystal or salt thereof, to N-deprotection conditions to provide a compound of formula VI, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group.

In another embodiment, the present disclosure provides a process for preparing a compound of Formula VIII or a co-crystal or salt thereof:

comprising contacting a compound of formula VI, or a co-crystal or salt thereof, with a compound of formula VII, or a co-crystal or salt thereof, under amide coupling conditions to provide a compound of formula VIII, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group.

In another embodiment, the present disclosure provides a process for preparing a compound of formula IX, or a co-crystal or salt thereof:

comprising performing a ring-closing metathesis of a compound of formula VIII, or a co-crystal or salt thereof, to provide a compound of formula IX, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group.

In another embodiment, the present disclosure provides a method for preparing a compound of Formula I (named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropyl[18,19][1,10,3,6]dioxadiazaaromaticnonadecacyclo[11,12-b]quinoxaline-8-carboxamide) or a cocrystal or salt thereof:

include:

a) contacting a compound of formula III, or a co-crystal or salt thereof, with a compound of formula IV under O-arylation conditions to provide a compound of formula V, or a co-crystal or salt thereof:

b) subjecting the compound of formula V, or a co-crystal or salt thereof, to N-deprotection conditions to provide a compound of formula VI, or a co-crystal or salt thereof:

c) contacting a compound of formula VI, or a co-crystal or salt thereof, with a compound of formula VII, or a co-crystal or salt thereof, under amide coupling conditions to provide a compound of formula VIII, or a co-crystal or salt thereof:

d) performing a ring-closing metathesis of the compound of formula VIII, or a co-crystal or salt thereof, to provide a compound of formula IX, or a co-crystal or salt thereof:

e) hydrogenating the compound of formula IX or a co-crystal or salt thereof in the presence of a catalyst to provide a compound of formula X or a co-crystal or salt thereof:

f) hydrolyzing the compound of formula X, or a co-crystal or salt thereof, to provide a compound of formula XI, or a co-crystal or salt thereof:

g) contacting a compound of formula XI, or a co-crystal or salt thereof, with a compound of formula XII, or a co-crystal or salt thereof, under amide coupling conditions to provide a compound of formula I, or a co-crystal or pharmaceutically acceptable salt thereof:

wherein R is a C _1-6 alkyl group, PG is a protecting group and R ¹ is a leaving group.

In another embodiment, the present disclosure provides a process for preparing a compound of Formula XVIII or a co-crystal or salt thereof:

comprising hydrolyzing a compound of formula VIII, or a co-crystal or salt thereof, to provide a compound of formula XVIII, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group.

In another embodiment, the present disclosure provides a process for preparing a compound of formula XIX, or a co-crystal or salt thereof:

This involves performing a ring-closing metathesis of a compound of formula XVIII, or a cocrystal or salt thereof, in the presence of a catalyst to provide a compound of formula XIX.

In another embodiment, the present disclosure provides a process for preparing a compound of formula XI or a co-crystal or salt thereof:

comprising hydrogenating a compound of formula XIX, or a co-crystal or salt thereof, in the presence of a catalyst to provide a compound of formula XI, or a co-crystal or salt thereof:

In another embodiment, the present disclosure provides a method for preparing a compound of Formula I (named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropyl[18,19][1,10,3,6]dioxadiazaaromaticnonadecacyclo[11,12-b]quinoxaline-8-carboxamide) or a cocrystal or pharmaceutically acceptable salt thereof:

include:

a) contacting a compound of formula III, or a co-crystal or salt thereof, with a compound of formula IV under O-arylation conditions to provide a compound of formula V, or a co-crystal or salt thereof:

b) subjecting the compound of formula V, or a co-crystal or salt thereof, to N-deprotection conditions to provide a compound of formula VI, or a co-crystal or salt thereof:

c) contacting a compound of formula VI, or a co-crystal or salt thereof, with a compound of formula VII, or a co-crystal or salt thereof, under amide coupling conditions to provide a compound of formula VIII, or a co-crystal or salt thereof:

d) hydrolyzing the compound of formula VIII or a co-crystal or salt thereof to provide a compound of formula XVIII or a co-crystal or salt thereof:

e) performing a ring-closing metathesis of the compound of formula XVIII or a co-crystal or salt thereof in the presence of a catalyst to provide a compound of formula XIX or a co-crystal or salt thereof:

f) hydrogenating the compound of formula XIX in the presence of a catalyst to provide a compound of formula XI or a co-crystal or salt thereof:

g) contacting a compound of formula XI, or a co-crystal or salt thereof, with a compound of formula XII, or a co-crystal or salt thereof, under amide coupling conditions to provide a compound of formula I, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group, PG is a protecting group and R ¹ is a leaving group.

In another embodiment, the present disclosure provides a process for preparing a compound of formula XV or a co-crystal or salt thereof:

comprising contacting a compound of formula XIII, or a co-crystal or salt thereof, with a compound of formula XIV, or a co-crystal or salt thereof, under cross-metathesis conditions to provide a compound of formula XV, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group.

In another embodiment, the present disclosure provides a process for preparing a compound of Formula XVI or a co-crystal or salt thereof:

comprising hydrogenating a compound of formula XV, or a co-crystal or salt thereof, in the presence of a catalyst to provide a compound of formula XVI, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group.

In another embodiment, the present disclosure provides a process for preparing a compound of Formula XVII, or a co-crystal or salt thereof:

comprising subjecting a compound of Formula XVI, or a co-crystal or salt thereof, to N-deprotection conditions to provide a compound of Formula XVII, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group.

In another embodiment, the present disclosure provides a process for preparing a compound of formula X, or a co-crystal or salt thereof:

This comprises contacting a compound of formula XVII with an amide coupling agent under lactamization conditions to provide a compound of formula X, or a cocrystal or salt thereof, wherein R is C _1-6 alkyl.

In another embodiment, the present disclosure provides a method for preparing a compound of Formula I (named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropyl[18,19][1,10,3,6]dioxadiazaaromaticnonadecacyclo[11,12-b]quinoxaline-8-carboxamide) or a cocrystal or salt thereof:

include:

a) contacting a compound of formula XIII, or a co-crystal or salt thereof, with a compound of formula XIV, or a co-crystal or salt thereof, under cross-metathesis conditions to provide a compound of formula XV, or a co-crystal or salt thereof:

b) hydrogenating the compound of formula XV or a co-crystal or salt thereof in the presence of a catalyst to provide a compound of formula XVI or a co-crystal or salt thereof:

c) subjecting the compound of formula XVI, or a co-crystal or salt thereof, to N-deprotection conditions to provide the compound of formula XVII, or a co-crystal or salt thereof:

d) contacting the compound of formula XVII with an amide coupling agent under lactamization conditions to provide a compound of formula X, or a co-crystal or salt thereof:

e) hydrolyzing the compound of formula X, or a co-crystal or salt thereof, to provide a compound of formula XI, or a co-crystal or salt thereof:

f) contacting a compound of formula XI, or a co-crystal or salt thereof, with a compound of formula XII, or a co-crystal or salt thereof, under amide coupling conditions to provide a compound of formula I, or a co-crystal or salt thereof:

R is a C _1-6 alkyl group and PG is a protecting group.

In another embodiment, the present disclosure provides a method for preparing a compound of formula V-v or a co-crystal or salt thereof:

include:

a) hydrolyzing a compound of formula A-b or a co-crystal or salt thereof to provide a compound of formula A-c or a co-crystal or salt thereof:

b) contacting the compound of formula A-c, or a co-crystal or salt thereof, with dicyclohexylamine to provide a compound of formula A-g, or a co-crystal or salt thereof:

c) contacting A-g, or a co-crystal or salt thereof, with cinchonidine to provide a compound of formula A-h, or a co-crystal or salt thereof:

d) subjecting A-h or a co-crystal or salt thereof to a Curtius rearrangement in the presence of tert-butanol to provide a compound of formula A-i or a co-crystal or salt thereof:

e) hydrolysis of A-i or a co-crystal or salt thereof to provide V-v or a co-crystal or salt thereof.

In another embodiment, the present disclosure provides a compound of formula IV, or a cocrystal or salt thereof:

Wherein ^R1 is a leaving group.

In another embodiment, the present disclosure provides a compound of Formula V, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group.

In another embodiment, the present disclosure provides a compound of Formula VI, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group.

In another embodiment, the present disclosure provides a compound of Formula VII, or a cocrystal or salt thereof:

In another embodiment, the present disclosure provides a compound of Formula VIII, or a cocrystal or salt thereof:

wherein R is a C _1-6 alkyl group.

In another embodiment, the present disclosure provides a compound of Formula XIII, or a cocrystal or salt thereof:

In another embodiment, the present disclosure provides a compound of Formula XIV, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group.

In another embodiment, the present disclosure provides a compound of Formula XV, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group.

In another embodiment, the present disclosure provides a compound of Formula XVI, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group.

In another embodiment, the present disclosure provides a compound of Formula XVII, or a cocrystal or salt thereof:

wherein R is a C _1-6 alkyl group.

In another embodiment, the present disclosure provides a compound of Formula XVIII, or a cocrystal or salt thereof:

In another embodiment, the present disclosure provides a compound of Formula XIX, or a co-crystal or salt thereof:

In another embodiment, the present disclosure provides a compound of formula IV-d, or a cocrystal or salt thereof:

In another embodiment, the present disclosure provides a compound of formula M3, or a co-crystal or salt thereof:

In another embodiment, the present disclosure provides a compound of formula IV-a, or a cocrystal or salt thereof:

In another embodiment, the present disclosure provides a compound of formula IV-b, or a cocrystal or salt thereof:

In another embodiment, the present disclosure provides a compound of formula IV-c or a cocrystal or salt thereof:

More specific implementations are described below.

DETAILED DESCRIPTION

definition

As used in this specification, the following words and phrases are generally intended to have the meanings given below, unless the context in which they are used indicates otherwise.

As used herein, the term "alkyl" refers to a straight or branched saturated hydrocarbon having the number of carbon atoms shown. For example, (C1-C8)alkyl means including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, and neohexyl. In a particular embodiment, the alkyl group has 1 to 20 carbon atoms. The alkyl group can be unsubstituted or optionally substituted with one or more substituents described herein in full.

The term "substituted alkyl" refers to:

1) an alkyl group as defined above having 1, 2, 3, 4, or 5 substituents (in some embodiments, 1, 2, or 3 substituents) selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkyloxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxylalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-cycloalkyl, -SO-heterocyclyl, -SO- _aryl , -SO-heteroaryl, _-SO2 -alkyl, -SO2-cycloalkyl, _-SO2 -heterocyclyl, _-SO2 -aryl, and _-SO2 -heteroaryl. Unless otherwise limited by the definition, all substituents may be optionally further substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxyl, carboxylalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, _CF3 , amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl and -S(O) _nRa , wherein ^Ra is alkyl, aryl or heteroaryl and n is ⁰ , 1 or 2; or

2) an alkyl group as defined above interrupted by 1-10 atoms (e.g., 1, 2, 3, 4, or 5 atoms) independently selected from oxygen, sulfur, and NRa, wherein Ra is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl. All substituents may optionally be further substituted by alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, _CF3 , amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O) _nRa ^, wherein ^Ra is alkyl, aryl, or heteroaryl and n is 0, 1, or 2; or

3) Alkyl groups as defined above having 1, 2, 3, 4 or 5 substituents as defined above and further interrupted by 1-10 atoms (eg, 1, 2, 3, 4 or 5 atoms) as defined below.

As used herein, the term "interrupted by" means that a carbon atom of a group (eg, an alkyl group) is replaced by a heteroatom.

The term "alkylene" refers to a diradical having a branched or unbranched saturated hydrocarbon chain of 1 to 20 carbon atoms (e.g., 1 to 10 carbon atoms or 1, 2, 3, ₄ , 5, or ₆ carbon atoms). The term is exemplified by groups such as methylene ( _-CH2- ), ethylene ( _-CH2CH2- ), propylene isomers (e.g., _-CH2CH2CH2- and -CH( _CH3 ) _CH2- ) _, and the like.

The term "aralkyl" refers to an aryl group covalently linked to an alkylene group, wherein aryl and alkylene are as defined herein. "Optionally substituted aralkyl" refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group. Such aralkyl groups are exemplified by benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.

The term "aralkyloxy" refers to an -O-aralkyl group. "Optionally substituted aralkyloxy" refers to an optionally substituted aralkyl group covalently linked to an optionally substituted alkylene group. Examples of such aralkyl groups include benzyloxy, phenylethoxy, and the like.

The term "alkenyl" refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having 2 to 20 carbon atoms (in some embodiments, 2 to 10 carbon atoms, for example, 2 to 6 carbon atoms) and having 1 to 6 carbon-carbon double bonds (for example, 1, 2, or 3 carbon-carbon double bonds). In some embodiments, the alkenyl group includes ethenyl (or vinyl, i.e., -CH=CH ₂ ), 1-propenyl (or allyl, i.e., -CH ₂ CH=CH ₂ ), isopropenyl (-C(CH ₃ )=CH ₂ ), and the like.

The term "lower alkenyl" refers to an alkenyl group as defined above having 2 to 6 carbon atoms.

The term "substituted alkenyl" refers to an alkenyl group as defined above having from 1 to 5 substituents (in some embodiments, 1, 2, or 3 substituents) as defined above for a substituted alkyl group.

In some embodiments, the term "alkynyl" refers to a monoradical of an unsaturated hydrocarbon having 2-20 carbon atoms (in some embodiments, 2-10 carbon atoms, for example, 2-6 carbon atoms) and 1-6 carbon-carbon triple bonds (for example, 1, 2, or 3 carbon-carbon triple bonds). In some embodiments, alkynyl includes ethynyl (-C≡CH), propargyl (or propynyl, i.e., -C≡CCH ₃ ), and the like.

The term "substituted alkynyl" refers to an alkynyl group as defined above having from 1 to 5 substituents (in some embodiments, 1, 2, or 3 substituents) as defined above for a substituted alkyl group.

The term "hydroxy" or "hydroxyl" refers to an -OH group.

The term "alkoxy" refers to an -O-R group, where R is alkyl, or -Y-Z, where Y is alkylene and Z is alkenyl or alkynyl, where alkyl, alkenyl, and alkynyl are as defined herein. In some embodiments, the alkoxy group is alkyl-O- and includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, 1,2-dimethylbutoxy, and the like.

The term "cycloalkyl" refers to a cyclic alkyl group having 3 to 20 carbon atoms and having a single cyclic ring or multiple fused rings. Such cycloalkyl groups include, for example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, etc., or polycyclic structures such as adamantyl and bicyclo[2.2.1]heptyl, or cyclic alkyl groups fused to aryl groups (e.g., indanyl, etc.), provided that the point of attachment is through the cyclic alkyl group.

The term "cycloalkenyl" refers to a cyclic alkyl group of 3-20 carbon atoms having a single cyclic ring or multiple fused rings and having at least one double bond and, in some embodiments, 1-2 double bonds.

The terms "substituted cycloalkyl" and "substituted cycloalkenyl" refer to cycloalkyl or cycloalkenyl groups having 1, 2, 3, 4, or 5 substituents (in some embodiments, 1, 2, or 3 substituents) selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxylalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-cycloalkyl, -SO-heterocyclyl, -SO-aryl, -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -cycloalkyl, _-SO2 -heterocyclyl, -SO ₂ -aryl, and -SO ₂ -heteroaryl. The term "substituted cycloalkyl" also includes cycloalkyl groups in which one or more of the ring carbon atoms of the cycloalkyl group has an oxo group bonded thereto. Unless otherwise limited by the definition, all substituents may be optionally further substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF ₃ , amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O) _n ^Ra , wherein ^Ra is alkyl, aryl, or heteroaryl and n is 0, 1, or 2.

The term "cycloalkoxy" refers to an -O-cycloalkyl group.

The term "cycloalkenyloxy" refers to an -O-cycloalkenyl group.

The term "aryl" refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl) or multiple fused (condensed) rings (e.g., naphthyl, fluorenyl, and anthracenyl). In some embodiments, aryl includes phenyl, fluorenyl, naphthyl, anthracenyl, etc.

Unless otherwise limited by definition to aryl substituents, such aryl groups may be optionally substituted with 1, 2, 3, 4, or 5 substituents (in some embodiments, 1, 2, or 3 substituents) selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkyloxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxylalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-cycloalkyl, -SO-heterocyclyl, -SO-aryl, -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -cycloalkyl, _-SO2 -heterocyclyl, -SO ₂ -aryl and -SO ₂ -heteroaryl. Unless otherwise limited by the definition, all substituents may be optionally further substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxyl, carboxylalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF ₃ , amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl and -S(O) _n ^Ra , wherein ^Ra is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "aryloxy" refers to an -O-aryl group wherein aryl is as defined above and includes optionally substituted aryl groups also as defined above. The term "arylthio" refers to an R-S- group wherein R is as defined for aryl.

The term "arylene" refers herein to a diradical formed by formally removing a hydrogen atom from an aryl group to become a divalent "aryl" group as defined above.

The term "heterocyclyl," "heterocycle," or "heterocyclic" refers to a monoradical saturated group having 1 to 40 carbon atoms and 1 to 10 heteroatoms (in some embodiments, 1 to 4 heteroatoms) selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring, having a single ring or multiple fused rings. In some embodiments, the "heterocyclyl," "heterocycle," or "heterocyclic" group is attached to the rest of the molecule through one of the heteroatoms within the ring.

Unless otherwise limited by definition to heterocyclic substituents, such heterocyclic groups may be optionally substituted with 1-5 substituents (in some embodiments, 1, 2, or 3 substituents) selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkyloxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxylalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, SO-alkyl, -SO-cycloalkyl, -SO-heterocyclyl, -SO-aryl, -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -cycloalkyl, _-SO2 -heterocyclyl, _-SO2 -aryl and -SO ₂ -heteroaryl. Unless otherwise limited by the definition, all substituents may be optionally further substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxyl, carboxylalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF ₃ , amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(O) _n ^Ra , wherein ^Ra is alkyl, aryl or heteroaryl and n is 0, 1 or 2. Examples of heterocyclyl include tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.

The term "heterocyclyloxy" refers to an -O-heterocyclyl group.

The term "heteroaryl" refers to a group containing a single ring or multiple rings containing 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur within at least one ring. The term "heteroaryl" is a general term for the terms "aromatic heteroaryl" and "partially saturated heteroaryl." The term "aromatic heteroaryl" refers to a heteroaryl group in which at least one ring is aromatic, regardless of the point of attachment. Examples of aromatic heteroaryl groups include pyrrole, thiophene, pyridine, quinoline, and pteridine. The term "partially saturated heteroaryl" refers to a heteroaryl group having one or more double bonds in the aromatic ring of the saturated base aromatic heteroaryl group, which is structurally equivalent to the base aromatic heteroaryl group. Examples of partially saturated heteroaryl groups include dihydropyrrole, dihydropyridine, chroman, 2-oxo-1,2-dihydropyridin-4-yl, and the like.

Unless otherwise limited by definition to heteroaryl substituents, such heteroaryl groups may be optionally substituted with 1-5 substituents (in some embodiments, 1, 2, or 3 substituents) selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkyloxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxylalkyl, arylthio, heteroarylthio, heterocyclylthio, sulfhydryl, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-cycloalkyl, -SO-heterocyclyl, -SO-aryl, -SO-heteroaryl, _-SO2 -alkyl, _-SO2 -cycloalkyl, _-SO2 -heterocyclyl, _-SO2 -aryl and -SO ₂ -heteroaryl. Unless otherwise limited by a definition, all substituents may be optionally further substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxyl, carboxylalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF ₃ , amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(O) _n ^Ra , wherein ^Ra is alkyl, aryl, or heteroaryl and n is 0, 1, or 2. Such heteroaryl groups may have a single ring (e.g., pyridyl or furanyl) or multiple fused rings (e.g., indolizinyl, benzothiazole, or benzothiophenyl). Examples of nitrogen heterocyclic and heteroaryl groups include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, and the like, as well as N-alkoxy-nitrogen heteroaryl compounds.

The term "heteroaryloxy" refers to an -O-heteroaryl group.

The term "amino" refers to a _-NH2 group.

The term "substituted amino" refers to a -NRR group, wherein each R is independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, provided that two Rs are not simultaneously hydrogen or a -YZ group, wherein Y is an optionally substituted alkylene group and Z is an alkenyl, cycloalkenyl, or alkynyl group. Unless otherwise limited by the definition, all substituents may be further optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxyl, carboxylalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF ₃ , amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -S(O) _n ^Ra , wherein ^Ra is alkyl, aryl, or heteroaryl and n is 0, 1, or 2.

The term "alkylamine" refers to R- _NH2 , where R is an optionally substituted alkyl group.

The term "dialkylamine" refers to R-NHR, where each R is independently an optionally substituted alkyl group.

The term "trialkylamine" refers to _NR3 , wherein each R is independently an optionally substituted alkyl group.

The term "cyano" refers to a -CN group.

The term "azido" refers to a group.

The term "keto" or "oxo" refers to a =0 group.

The term "carboxy" refers to a -C(O)-OH group.

The term "ester" or "carboxylate" refers to a -C(O)OR group where R is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, which may be optionally further substituted with alkyl, alkoxy, halogen, _CF3 , amino, substituted amino, cyano or -S(O) _nRa where ^Ra is alkyl, aryl or heteroaryl and n is 0, ¹ or 2.

The term "acyl" refers to a -C(O)R group, where R is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.

The term "carboxyalkyl" refers to a -C(O)O-alkyl or -C(O)O-cycloalkyl group (wherein alkyl and cycloalkyl are as defined herein) and may be optionally further substituted with alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, _CF3 , amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(O) _nRa , where ^Ra is alkyl, aryl or heteroaryl and n is 0, ¹ or 2.

The term "aminocarbonyl" refers to a -C(O)NRR group, wherein each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, or wherein two Rs are joined to form a heterocyclyl (e.g., morpholinyl). Unless otherwise limited by the definition, all substituents may be optionally further substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, _CF3 , amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(O) _nRa , wherein ^Ra is alkyl, aryl, or heteroaryl and n is ⁰ , 1, or 2.

The term "acyloxy" refers to -OC(O)-alkyl, -OC(O)-cycloalkyl, -OC(O)-aryl, -OC(O)-heteroaryl, and -OC(O)-heterocyclyl groups. Unless otherwise limited by the definition, all substituents may be optionally further substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, carboxyl, carboxylalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, _CF3 , amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(O) _nRa , wherein ^Ra is alkyl, aryl, or heteroaryl and n is 0, 1, or 2 ^.

The term "amido" refers to a -NRC(O)R group, wherein each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl. All substituents may be optionally further substituted with alkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, _CF3 , amino, substituted amino, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(O) _nRa , wherein ^Ra is alkyl, aryl, or heteroaryl and n is 0, 1, or 2 ^.

The term "alkoxycarbonylamino" refers to a -N( ^Rc )C(O)OR group where R is optionally substituted alkyl and ^Rc is hydrogen or optionally substituted alkyl.

The term "aminocarbonylamino" refers to a ^-NRdC (O)NRR group where ^Rd is hydrogen or optionally substituted alkyl and each R is independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl. Unless otherwise limited by the definitions, all substituents may be optionally further substituted with 1, 2 or 3 substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxylalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocycloxy, hydroxyamino, alkoxyamino, nitro, SO-alkyl, -SO-cycloalkyl, -SO-heterocyclyl, -SO-aryl, -SO-heteroaryl, _-SO₂ -alkyl, _-SO₂ -cycloalkyl, _-SO₂ -heterocyclyl, _-SO₂ -aryl and _-SO₂ -heteroaryl.

The term "mercapto" refers to a -SH group.

The term "thiocarbonyl" refers to a =S group.

The term "alkylthio" refers to an -S-alkyl group.

The term "substituted alkylthio" refers to an -S-substituted alkyl group.

The term "heterocyclylthio" refers to the -S-heterocyclyl group.

The term "arylthio" refers to an -S-aryl group.

The term "heteroarylthio" refers to an -S-heteroaryl group wherein heteroaryl is as defined above including optionally substituted heteroaryl groups also as defined above.

The term "sulfoxide" refers to a -S(O)R group, where R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. "Substituted sulfoxide" refers to a -S(O)R group, where R is substituted alkyl, substituted cycloalkyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl as defined herein.

The term "sulfone" refers to a -S(O) _2R group, where R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. "Substituted sulfone" refers to a -S(O) _2R group, where R is substituted alkyl, substituted cycloalkyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl as defined herein.

The term "aminosulfonyl" refers to a -S(O) _2NRR group, where each R is independently selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl. Unless otherwise limited by the definitions, all substituents may be optionally further substituted with 1, 2 or 3 substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, cycloalkenyloxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxylalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocycloxy, hydroxyamino, alkoxyamino, nitro, SO-alkyl, -SO-cycloalkyl, -SO-heterocyclyl, -SO-aryl, -SO-heteroaryl, _-SO₂ -alkyl, _-SO₂ -cycloalkyl, _-SO₂ -heterocyclyl, _-SO₂ -aryl and _-SO₂ -heteroaryl.

The term "hydroxyamino" refers to a -NHOH group.

The term "alkoxyamino" refers to a -NHOR group where R is optionally substituted alkyl.

The term "halogen" or "halo" refers to fluoro, bromo, chloro and iodo.

The term "triflate" refers to a trifluoromethanesulfonate group ( _-OSO2 - _CF3 ).

"Optional" or "optionally" means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

"Substituted" groups include embodiments in which a monoradical substituent is bound to a single atom of the substituted group (e.g., to form a branch), and also include embodiments in which a substituent can be a bridged diradical bound to two adjacent atoms of the substituted group, thereby forming a fused ring on the substituted group.

In the case where a given group (part) is described herein as being connected to a second group and the site of attachment is unclear, the given group can be connected to any available site of the second group at any available site of the given group. For example, an "alkyl-substituted phenyl" (wherein the site of attachment is unclear) can have any available site of the alkyl connected to any available site of the phenyl. In this regard, an "available site" is a group site at which the hydrogen of the group can be replaced by a substituent.

It should be understood that in all of the substituted groups defined above, polymers obtained by limiting a substituent to a further substituent (e.g., a substituted aryl having a substituted aryl as a substituent which itself is substituted with a substituted aryl, etc.) are not intended to be encompassed. Nor is an unlimited number of substituents, whether the substituents are the same or different. In these cases, the maximum number of such substituents is 3. Thus, each of the above definitions is limited by, for example, limiting substituted aryl to -substituted aryl-(substituted aryl)-substituted aryl.

Compounds with a given formula (e.g., compounds of Formula I) are intended to encompass salts (e.g., pharmaceutically acceptable salts), esters, isomers, tautomers, solvates, isotopes, hydrates, cocrystals, co-formers and/or prodrugs of the compounds of the present disclosure and these compounds. In addition, the compounds of the present disclosure may have one or more asymmetric centers and may be produced as racemic mixtures or as single enantiomers or diastereomers. The number of stereoisomers present in any given compound of a given formula depends on the number of asymmetric centers present (there are 2n possible stereoisomers when n is the number of asymmetric centers). Single stereoisomers can be obtained by splitting the racemic or non-racemic mixture of intermediates at some appropriate stages of the synthesis or by splitting the compound by conventional means. Single stereoisomers (including single enantiomers and diastereomers) and racemic and non-racemic mixtures of stereoisomers are included in the scope of the present disclosure, all of which are intended to be depicted by the structure of this specification, unless otherwise indicated.

"Isomers" are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers.

"Stereoisomers" are isomers that contain chiral atoms with the same connectivity but differ only in the way the atoms are arranged in space. The term "stereoisomer" as used herein includes "enantiomers" and "diastereomers."

"Enantiomers" are pairs of stereoisomers that are non-superimposable mirror images of each other and do not contain a plane of symmetry. A 1:1 mixture of a pair of stereoisomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate.

"Diastereomers" are stereoisomers that have at least two chiral atoms and may contain a plane of symmetry, but which are not mirror images of each other in the absence of a plane of symmetry.

Absolute stereochemistry is assigned according to the Cahn Ingold Prelog R S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be designated by R or S. Resolved compounds whose absolute configuration is unknown are designated (+) or (-) according to the direction (dextrorotatory or levorotatory) in which they rotate the plane of polarized light at the wavelength of the sodium D line.

If there is a conflict between a depicted structure and the name given to that structure, the depicted structure controls. Additionally, if the stereochemistry of a structure or portion of a structure is not indicated by, for example, bold, wedge-shaped, or dashed lines, that structure or portion of a structure is to be interpreted as encompassing all stereoisomers thereof.

The term "solvate" refers to a complex formed by combining a compound of Formula I or any other formula disclosed herein with a solvent. As used herein, the term "solvate" includes hydrates (ie, solvates wherein the solvent is water).

The term "hydrate" refers to a complex formed by the combination of a compound of Formula I or any formula disclosed herein and water.

The term "co-crystal" refers to a crystalline material formed by combining a compound of Formula I or any formula disclosed herein with one or more co-crystal formers (i.e., molecules, ions, or atoms). In certain instances, a co-crystal may have improved properties compared to the parent form (i.e., free molecule, zwitterion, etc.) or salt of the parent compound. The improved properties may be increased solubility, increased solubility, increased bioavailability, increased dose response, reduced hygroscopicity, crystalline forms of normally amorphous compounds, crystalline forms of compounds that are difficult or non-saltable, reduced form diversity, more desirable morphologies, and the like. Methods for preparing and characterizing co-crystals are known to those skilled in the art.

The term "coformer" or "co-crystal former" refers to a non-ionic association of a compound of Formula I or any formula disclosed herein with one or more molecules, ions or atoms. Exemplary coformers are inorganic or organic bases and/or acids.

Any formula or structure provided herein, including Formula I disclosed herein or any formula, is also intended to represent the unlabeled form and isotope-labeled form of compound. Isotope-labeled compound has the structure described by the formula provided herein, except that one or more atoms are replaced by the atom with the atomic weight or mass number of selection. The example of the isotope that can be incorporated into the compound of the present disclosure includes the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to ² H (deuterium, D), ³ H (tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I. Various isotope-labeled compounds of the present disclosure, for example, wherein incorporate radioactive isotopes such as ³ H, ¹³ C and ¹⁴ C those compounds. Such isotopically labeled compounds are useful in metabolism studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution analysis, or in radiation therapy of patients.

The present disclosure also includes compounds of Formula I or any formula disclosed herein, wherein 1 to "n" hydrogen atoms attached to the carbon atom are replaced by deuterium, where n is the number of hydrogen atoms in the molecule. Such compounds exhibit increased metabolic resistance and are therefore useful for increasing the half-life of any compound of Formula I when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12): 524-527(1984). Such compounds are synthesized by means known in the art, for example, by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

Deuterium-labeled or substituted therapeutic compounds of the present disclosure can have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium can provide certain therapeutic advantages caused by higher metabolic stability, for example, extended in vivo half-life or reduced dosage requirements. ¹⁸ F-labeled compounds can be used for PET or SPECT studies. Isotope-labeled compounds of the present disclosure and prodrugs thereof can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents to carry out the processes disclosed in the scheme or in the following description of the embodiments and preparations. In addition, substitution with heavier isotopes, particularly deuterium (i.e., ² H or D), can provide certain therapeutic advantages caused by higher metabolic stability, for example, extended in vivo half-life or reduced dosage requirements or improvements in therapeutic index. It should be understood that deuterium in this case is considered to be a substituent in the compound of Formula I or any formula disclosed herein.

The concentration of such heavier isotopes (particularly deuterium) can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," that position is understood to be hydrogen having its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

In many cases, the compounds of the present disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

The salt of compound disclosed herein can be base addition salt or acid addition salt according to the reactivity of the functional group present on specific compound.Base addition salt can be derived from inorganic or organic base.Salt derived from inorganic base includes, for example only, sodium, potassium, lithium, ammonium, calcium and magnesium salt.Salt derived from organic base includes, but is not limited to primary, secondary and tertiary amine (such as alkylamine, dialkylamine, trialkylamine, substituted alkylamine, di(substituted alkyl) amine, tri(substituted alkyl) amine, alkenylamine, dienylamine, trialnylamine, substituted alkenylamine, di(substituted alkenyl) amine, tri(substituted alkenyl) amine, cycloalkylamine, di(cycloalkyl) amine, tri(cycloalkyl) amine, substituted cycloalkylamine, disubstituted cycloalkylamine, trisubstituted cycloalkylamine, cycloalkenylamine, di(cycloalkenyl) amine The present invention also includes salts of amines (e.g., cycloalkenylamines, tri(cycloalkenyl)amines, substituted cycloalkenylamines, disubstituted cycloalkenylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines) wherein at least two substituents on the amine are different and are selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclyl, and the like. Also included are amines wherein two or three substituents together with the amino nitrogen form a heterocyclyl or heteroaryl group. Amines have the general structure N( ^R30 )( ^R31 )( ^R32 ), wherein two of the three substituents on the nitrogen of a monosubstituted amine ( ^R30 , ^R31 , and ^R32 ) are hydrogen, one of the three substituents on the nitrogen of a disubstituted amine ( ^R30 , ^R31 , and ^R32 ) is hydrogen, and none of the three substituents on the nitrogen of a trisubstituted amine ( ^R30 , ^R31 , and ^R32 ) are hydrogen. ^R30 , ^R31 , and ^R32 are selected from a variety of substituents such as hydrogen, optionally substituted alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, and the like. The above-mentioned amines refer to compounds in which any one, two, or three substituents on the nitrogen are as listed in the name. For example, the term "cycloalkenylamine" refers to cycloalkenyl- _NH2 , where "cycloalkenyl" is as defined herein. The term "diheteroarylamine" refers to NH(heteroaryl) ₂ , wherein "heteroaryl" is as defined herein, and the like.

Specific examples of suitable amines include, for example, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hepatocyanine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purine, piperazine, morpholine, N-ethylpiperidine, and the like.

Acid addition salts can be derived from inorganic or organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

Any salt disclosed herein may optionally be pharmaceutically acceptable. The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. See P. Heinrich Stahl and Camille G. Wermuth (Eds.) Pharmaceutical Salts: Properties, Selection, and Use (International Union of Pure and Applied Chemistry), Wiley-VCH; 2nd Revised Edition (May 16, 2011). Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases.

Pharmaceutically acceptable base addition salts may be salts prepared from inorganic and organic bases and pharmaceutically acceptable acid addition salts may be salts prepared from inorganic and organic acids.

The term "leaving group" refers to an atom or group of atoms that is removed as a stable species in a chemical reaction along with its bond electrons. Non-limiting examples of leaving groups include halogen, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-triisopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy, benzenesulfonyloxy, (4-methoxy-benzene)sulfonyloxy, etc.

The term "O-arylation reaction conditions" refers to the reaction conditions under which the -O-R' moiety is installed on a _suitable aromatic substrate. As disclosed herein, "O-arylation reaction conditions" typically include a base. Non-limiting examples of bases include sodium carbonate ( _Na2CO3 ) and potassium carbonate ( _K2CO3 ), potassium tert- _butoxide (KOtBu), lithium tert-butoxide (LiOtBu), magnesium tert-butoxide (Mg(OtBu) ₂ ), sodium tert-butoxide (NaOtBu), sodium hydride (NaH), potassium hexamethyldisilizide (KHMDS), potassium phosphate ( _K3PO4 ), potassium hydroxide ₍ KOH), lithium hydroxide (LiOH), and organic bases such as 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the like.

The term "protecting group" refers to a compound portion that shields or changes the properties of a functional group or the properties of the compound as a whole. The chemical substructure of a protecting group varies widely. One function of a protecting group is to serve as an intermediate in the synthesis of a parent drug substance. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See "Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991). Protecting groups are often used to shield the reactivity of specific functional groups to facilitate the efficiency of desired chemical reactions, for example, to form and destroy chemical bonds in an orderly and planned manner. The protection of the functional groups of a compound changes other physical properties other than the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity) and other properties that can be measured by common analytical tools. The chemically protected intermediate itself can be biologically active or inactive. Non-limiting examples of protecting groups for amines include tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), etc.

The term "N-deprotection conditions" refers to reaction conditions in which a protecting group is removed from an amine. Non-limiting examples of protecting groups for amines include tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), and the like. N-deprotection conditions for Boc include the use of acids such as HCl, methanesulfonic acid, p-toluenesulfonic acid, and the like. N-deprotection conditions for Cbz include hydrogenation using hydrogen and a catalyst such as Pd, and the like. N-deprotection conditions for Fmoc include the use of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), piperidine, and the like.

The term "amide coupling conditions" refers to reaction conditions in which an amine and a carboxylic acid are coupled using a coupling reagent in the presence of a base to form an amide. Non-limiting examples of coupling reagents include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) with hydroxybenzotriazole monohydrate (HOBt), O-(7-azabenzotriazol-1-yl)-N,N,N,N'-tetramethyluronium hexafluorophosphate (HATU), 1-hydroxy-7-azabenzotriazole, and the like. Non-limiting examples of bases include N-methylmorpholine, pyridine, morpholine, imidazole, and the like.

The term "ring-closing metathesis" refers to reaction conditions in which two olefins in the same molecule react in the presence of a catalyst to produce a cycloalkane and a volatile olefin.

The term "Courtius rearrangement" refers to a reaction in which a carboxylic acid (R-COOH) is converted to an amine (RNH ₂ ) by first reacting the carboxylic acid with diphenylphosphoryl azide to provide an acyl azide (RCON ₃ ), which then rearranges to form an isocyanate (RNCO), the hydrolysis of which in the presence of an alcohol (e.g., tert-butanol) provides a boc-protected amine (R-NHBoc).

The term "cross-metathesis conditions" refers to reaction conditions in which two olefins in separate molecules react in the presence of a catalyst to produce a cycloalkane and a volatile olefin.

Non-limiting examples of catalysts for "ring-closing metathesis" and "cross-metathesis conditions" include Zhan 1B, ruthenium-based Grubbs, Grubbs-Hoveyda, saturated and unsaturated imidazole and phosphine-based catalysts, and platinum-based catalysts and variations thereof. A representative, non-exhaustive list is shown below, where Cy is cyclohexyl, Me is methyl, Ph is phenyl, and iPr is isopropyl.

In addition, the abbreviations used herein have the following corresponding meanings:

method

As generally described above, the present disclosure, in some embodiments, provides methods for preparing compounds of Formula I. In another embodiment, the present disclosure provides methods for preparing intermediates of compounds of Formula I. The methods can also be applied to synthesize stereoisomers or mixtures of stereoisomers of compounds of Formula I.

Pathway I

In one embodiment, the present disclosure provides a method for preparing a compound of Formula I, or a stereoisomer, mixture of stereoisomers, cocrystal, or pharmaceutically acceptable salt thereof, wherein the compound of Formula I is named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropyl[18,19][1,10,3,6]dioxadiazaaromaticnonadecacyclo[11,12-b]quinoxaline-8-carboxamide:

In another embodiment, the present disclosure provides a method for preparing a compound of Formula I, or a cocrystal or salt thereof, wherein the compound of Formula I is named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropyl[18,19][1,10,3,6]dioxadiazaaromaticnonadecacyclo[11,12-b]quinoxaline-8-carboxamide:

include:

a) contacting a compound of formula III, or a co-crystal or salt thereof, with a compound of formula IV under O-arylation conditions to provide a compound of formula V, or a co-crystal or salt thereof:

b) subjecting the compound of formula V, or a co-crystal or salt thereof, to N-deprotection conditions to provide a compound of formula VI, or a co-crystal or salt thereof:

c) contacting a compound of formula VI, or a co-crystal or salt thereof, with a compound of formula VII, or a co-crystal or salt thereof, under amide coupling conditions to provide a compound of formula VIII, or a co-crystal or salt thereof:

d) performing a ring-closing metathesis of the compound of formula VIII, or a co-crystal or salt thereof, to provide a compound of formula IX, or a co-crystal or salt thereof:

e) hydrogenating the compound of formula IX or a co-crystal or salt thereof in the presence of a catalyst to provide a compound of formula X or a co-crystal or salt thereof:

f) hydrolyzing the compound of formula X, or a co-crystal or salt thereof, to provide a compound of formula XI, or a co-crystal or salt thereof:

g) contacting a compound of formula XI, or a co-crystal or salt thereof, with a compound of formula XII, or a co-crystal or salt thereof, under amide coupling conditions to provide a compound of formula I, or a co-crystal or pharmaceutically acceptable salt thereof:

wherein R is a C _1-6 alkyl group, PG is a protecting group and R ¹ is a leaving group.

The O-arylation conditions of step a) include a base. Non-limiting examples of _the base include sodium carbonate ( _Na2CO3 ) and potassium carbonate ( _{K2CO3 )} , potassium tert-butoxide (KOtBu), cesium carbonate ( _Cs2CO3 ) _, lithium _tert -butoxide (LiOtBu), magnesium tert-butoxide (Mg(OtBu) ₂ ), sodium tert-butoxide (NaOtBu), sodium hydride (NaH), potassium hexamethyldisilazide (KHMDS), potassium phosphate ( _K3PO4 ), potassium hydroxide (KOH), lithium hydroxide (LiOH), and organic bases such as DABCO, DBU, etc. In one embodiment, the base is cesium _carbonate ( _Cs2CO3 ).

Non-limiting examples of leaving groups include halo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-triisopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy, benzenesulfonyloxy, (4-methoxy-benzene)sulfonyloxy.

The O-arylation conditions of step a) also include a solvent. Non-limiting examples of solvents include N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile (MeCN), acetone; aprotic solvents with small amounts of added water ( _H2O ), ethers such as tetrahydrofuran (THF) and 1,4-dioxane, toluene (in the presence of a phase transfer catalyst), and the like. In one embodiment, the solvent is N,N-dimethylacetamide (DMAc). In another embodiment, the O-arylation conditions of step a) include a temperature of about 100-110°C.

A variety of protecting groups, PG, can be used in compounds of Formula III. Non-limiting examples of protecting groups for amines include tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), and the like. In one embodiment, PG is Boc. The N-deprotection conditions of step b) refer to conditions in which the protecting group PG is removed. In one embodiment, PG is Boc and the N-deprotection conditions include an acid such as HCl, methanesulfonic acid, toluenesulfonic acid, and the like. In one embodiment, the acid is p-toluenesulfonic acid.

The N-deprotection conditions of step b) further include a solvent. Non-limiting examples of solvents include methyltetrahydrofuran, MTBE, dioxane, isopropyl acetate, and combinations thereof. In one embodiment, the solvent is a mixture of methyltetrahydrofuran and MTBE. In another embodiment, the N-deprotection conditions of step b) include a temperature of about 50-55°C.

The amide coupling conditions of step c) include coupling reagents in the presence of a base. Non-limiting examples of coupling reagents include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole, O-(7-azabenzotriazole-1-yl)-N,N,N,N'-tetramethyluronium hexafluorophosphate (HATU) and the like. Non-limiting examples of bases include N-methylmorpholine, pyridine, morpholine, triethylamine, N,N-diisopropylethylamine, imidazole and the like. In one embodiment, the coupling conditions of step c) include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and hydroxybenzotriazole using N-methylmorpholine. The amide coupling conditions of step c) include solvents. Non-limiting examples of solvents include dimethylacetamide, acetonitrile, N,N-dimethylformamide and the like. In one embodiment, the solvent is N,N-dimethylformamide. In another embodiment, the amide coupling conditions of step c) comprise a temperature of about 0-20°C.

The ring-closing metathesis of step d) comprises a catalyst. Non-limiting examples of catalysts for "ring-closing metathesis" include Zhan 1B, ruthenium-based Grubbs, Grubbs-Hoveyda, saturated and unsaturated imidazole and phosphine-based catalysts, and platinum-based catalysts and variants thereof. A representative, non-exhaustive list is shown below, where Cy is cyclohexyl, Me is methyl, Ph is phenyl, and iPr is isopropyl.

In one embodiment, the ring-closing metathesis of step d) comprises catalyst Zhan 1B.

The ring-closing metathesis of step d) further comprises a solvent. Non-limiting examples of solvents include dichloromethane, 1,2-dichloroethane, chlorobenzene, hexafluorobenzene, benzene, toluene, THF, methyl tert-butyl ether, cyclopentyl methyl ether, ethyl acetate, methanol, isopropanol, n-heptane, dimethyl carbonate, dimethylformamide, acetonitrile, and the like. In one embodiment, the solvent is toluene. In another embodiment, the ring-closing metathesis of step d) comprises a temperature of about 40-110° C. In another embodiment, the temperature is about 105-110° C.

The ring-closing metathesis of step d) optionally includes a promoter. Non-limiting examples of promoters include acetic acid, benzoquinones, CuI, CsCl, Ti(Oi-Pr) ₄ , microwave irradiation, ethylene, and the like.

The hydrogenation conditions of step e) include hydrogen in the presence of a catalyst. Non-limiting examples of catalysts include platinum, palladium, ruthenium, nickel, and other metals on carbon, alumina, silica, and other heterogeneous supports; metal nanoparticles; hindered Lewis acid-base pairs such as hydrogen [4-[bis(2,4,6-trimethylphenyl)phosphino]-2,3,5,6-tetrafluorophenyl] hydrogen bis(2,3,4,5,6-pentafluorophenyl) borate; homogeneous metal catalysts such as chlorotris(triphenylphosphine)rhodium(I) or (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I) hexafluorophosphate, etc. In one embodiment, the catalyst is platinum on carbon.

The hydrogenation conditions in step e) further include a solvent. Non-limiting examples of solvents include water, protic solvents such as methanol, ethanol, or acetic acid; aprotic solvents such as dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, isopropyl acetate, acetonitrile, toluene, dichloromethane, or acetone; and combinations thereof. In one embodiment, the solvent is isopropyl acetate. In another embodiment, the hydrogenation conditions in step e) include a temperature of about 20-150°C. In another embodiment, the temperature is about 20-25°C.

The hydrogenation conditions of step e) include hydrogen gas or a formates such as ammonium formate or formic acid as the hydrogen source.

The hydrolysis conditions of step f) include acid hydrolysis or alkaline hydrolysis. Non-limiting examples of acids used for acid hydrolysis include protic acids such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid or solid-supported acids; Lewis acids such as boron trifluoride, metal salts, metal complexes or hydrogen bond donors, etc. Non-limiting examples of bases used for alkaline hydrolysis include carbonates such as lithium, sodium and cesium carbonates, metal hydrides such as sodium hydride and potassium hydride; alkoxides such as sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide or tetraalkylammonium alkoxides; hydroxides such as sodium hydroxide, potassium hydroxide, tin hydroxide or tetraalkylammonium hydroxide; amine bases such as 1,8-diazabicycloundec-7-ene, etc. In one embodiment, the hydrolysis of step f) includes a base. In another embodiment, the base is lithium hydroxide.

The hydrolysis conditions of step f) further include a solvent. Non-limiting examples of solvents include polar protic solvents (including water, alcohols such as methanol, ethanol, IPA, tert-butyl alcohol, neopentyl alcohol, glycols, and combinations thereof with water), polar aprotic solvents (including dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, 1,4-dioxane, and combinations thereof with water), ionic liquids such as 3-methylimidazole hexafluorophosphate, and the like. In one embodiment, the solvent is a mixture of isopropyl alcohol and water.

The amide coupling conditions of step g) include a coupling agent in the presence of a base and are similar to those described in step c). In one embodiment, the coupling agent is O-(7-azabenzotriazole-1-yl)-N,N,N,N'-tetramethyluronium hexafluorophosphate (HATU). In another embodiment, the base is N,N-diisopropylethylamine. In another embodiment, the solvent is DMF.

In one embodiment, R is C _1-6 alkyl. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

In one embodiment, R ¹ is selected from halo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-triisopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy, benzenesulfonyloxy, (4-methoxy-benzene)sulfonyloxy. In another embodiment, R ¹ is halo. In another embodiment, R ¹ is chloro.

In another embodiment, the present disclosure provides a process for preparing a compound of formula V or a stereoisomer, mixture of stereoisomers, cocrystal, or salt thereof:

comprising contacting a compound of formula III, or a co-crystal or salt thereof, with a compound of formula IV under O-arylation conditions to provide a compound of formula V, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group, PG is a protecting group and R ¹ is a leaving group.

In another embodiment, the present disclosure provides a process for preparing a compound of formula VI or a co-crystal or salt thereof:

comprising subjecting a compound of formula V, or a co-crystal or salt thereof, to N-deprotection conditions to provide a compound of formula VI, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group.

In another embodiment, the present disclosure provides a process for preparing a compound of Formula VIII or a co-crystal or salt thereof:

comprising contacting a compound of formula VI, or a co-crystal or salt thereof, with a compound of formula VII, or a co-crystal or salt thereof, under amide coupling conditions to provide a compound of formula VIII, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group.

In another embodiment, the present disclosure provides a process for preparing a compound of formula IX, or a co-crystal or salt thereof:

comprising performing a ring-closing metathesis of a compound of formula VIII, or a co-crystal or salt thereof, to provide a compound of formula IX, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group.

Pathway II

In another embodiment, the present disclosure provides a method for preparing a compound of Formula I, or a cocrystal or pharmaceutically acceptable salt thereof, wherein the compound of Formula I is named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropyl[18,19][1,10,3,6]dioxadiazaaromaticnonadecacyclo[11,12-b]quinoxaline-8-carboxamide:

include:

a) contacting a compound of formula III, or a co-crystal or salt thereof, with a compound of formula IV under O-arylation conditions to provide a compound of formula V, or a co-crystal or salt thereof:

b) subjecting the compound of formula V, or a co-crystal or salt thereof, to N-deprotection conditions to provide a compound of formula VI, or a co-crystal or salt thereof:

c) contacting a compound of formula VI, or a co-crystal or salt thereof, with a compound of formula VII, or a co-crystal or salt thereof, under amide coupling conditions to provide a compound of formula VIII, or a co-crystal or salt thereof:

d) hydrolyzing the compound of formula VIII or a co-crystal or salt thereof to provide a compound of formula XVIII or a co-crystal or salt thereof:

e) performing a ring-closing metathesis of the compound of formula XVIII or a co-crystal or salt thereof in the presence of a catalyst to provide a compound of formula XIX or a co-crystal or salt thereof:

f) hydrogenating the compound of formula XIX in the presence of a catalyst to provide a compound of formula XI or a co-crystal or salt thereof:

g) contacting a compound of formula XI, or a co-crystal or salt thereof, with a compound of formula XII, or a co-crystal or salt thereof, under amide coupling conditions to provide a compound of formula I, or a co-crystal or pharmaceutically acceptable salt thereof:

wherein R is a C _1-6 alkyl group, PG is a protecting group and R ¹ is a leaving group.

In Pathway II, there is a variation in the order of assembly where the compound of formula VIII is first hydrolyzed to provide the compound of formula XVIII, which then undergoes ring-closing metathesis to provide the compound of formula XIX, which is hydrogenated to provide the compound of formula XI.

In one embodiment, R is C _1-6 alkyl. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

In one embodiment, R ¹ is selected from halo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy, (2,4,6-triisopropyl-benzene)-sulfonyloxy, (2,4,6-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy, benzenesulfonyloxy, (4-methoxy-benzene)sulfonyloxy. In another embodiment, R ¹ is halo. In another embodiment, R ¹ is chloro.

In another embodiment, the present disclosure provides a process for preparing a compound of Formula XVIII or a co-crystal or salt thereof:

comprising hydrolyzing a compound of formula VIII, or a co-crystal or salt thereof, to provide a compound of formula XVIII, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group.

In another embodiment, the present disclosure provides a process for preparing a compound of formula XIX, or a co-crystal or salt thereof:

This involves performing a ring-closing metathesis of a compound of formula XVIII, or a cocrystal or salt thereof, in the presence of a catalyst to provide a compound of formula XIX.

In another embodiment, the present disclosure provides a process for preparing a compound of formula XI or a co-crystal or salt thereof:

comprising hydrogenating a compound of formula XIX, or a co-crystal or salt thereof, in the presence of a catalyst to provide a compound of formula XI, or a co-crystal or salt thereof:

Pathway III

In another embodiment, the present disclosure provides a method for preparing a compound of Formula I, or a cocrystal or pharmaceutically acceptable salt thereof, wherein the compound of Formula I is named (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropyl[18,19][1,10,3,6]dioxadiazaaromaticnonadecacyclo[11,12-b]quinoxaline-8-carboxamide:

include:

a) contacting a compound of formula XIII, or a co-crystal or salt thereof, with a compound of formula XIV, or a co-crystal or salt thereof, under cross-metathesis conditions to provide a compound of formula XV, or a co-crystal or salt thereof:

b) hydrogenating the compound of formula XV or a co-crystal or salt thereof in the presence of a catalyst to provide a compound of formula XVI or a co-crystal or salt thereof:

c) subjecting the compound of formula XVI, or a co-crystal or salt thereof, to N-deprotection conditions to provide the compound of formula XVII, or a co-crystal or salt thereof:

d) contacting the compound of formula XVII with an amide coupling agent under lactamization conditions to provide a compound of formula X, or a co-crystal or salt thereof:

e) hydrolyzing the compound of formula X, or a co-crystal or salt thereof, to provide a compound of formula XI, or a co-crystal or salt thereof:

f) contacting a compound of formula XI, or a co-crystal or salt thereof, with a compound of formula XII, or a co-crystal or salt thereof, under amide coupling conditions to provide a compound of formula I, or a co-crystal or pharmaceutically acceptable salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group.

The cross-metathesis conditions include a catalyst and a solvent. In one embodiment, the catalyst is Zhan B. In another embodiment, the solvent is toluene. In another embodiment, the cross-metathesis conditions include a temperature of about 90-100°C.

The hydrogenation conditions of step b) include a catalyst and a solvent. In one embodiment, the catalyst is platinum on carbon. In another embodiment, the solvent is isopropyl acetate.

The N-deprotection conditions of step c) include an acid and a solvent. In one embodiment, PG is Boc. In another embodiment, the acid is HCl. In another embodiment, the solvent is dioxane.

The lactamization conditions of step d) include a coupling reagent in the presence of a base and a solvent. In one embodiment, the coupling reagent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and hydroxybenzotriazole monohydrate (HOBt). In another embodiment, the base is triethylamine. In another embodiment, the solvent is N,N-dimethylformamide (DMF).

In one embodiment, R is C _1-6 alkyl. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

In another embodiment, the present disclosure provides a process for preparing a compound of formula XV or a co-crystal or salt thereof:

comprising contacting a compound of formula XIII, or a co-crystal or salt thereof, with a compound of formula XIV, or a co-crystal or salt thereof, under cross-metathesis conditions to provide a compound of formula XV, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group.

In another embodiment, the present disclosure provides a process for preparing a compound of Formula XVI or a co-crystal or salt thereof:

comprising hydrogenating a compound of formula XV, or a co-crystal or salt thereof, in the presence of a catalyst to provide a compound of formula XVI, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group.

In another embodiment, the present disclosure provides a process for preparing a compound of Formula XVII, or a co-crystal or salt thereof:

comprising subjecting a compound of Formula XVI, or a co-crystal or salt thereof, to N-deprotection conditions to provide a compound of Formula XVII, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group.

In another embodiment, the present disclosure provides a process for preparing a compound of formula X, or a co-crystal or salt thereof:

This comprises contacting a compound of formula XVII with an amide coupling agent under lactamization conditions to provide a compound of formula X, or a co-crystal or salt thereof, wherein R is C _1-6 alkyl.

Compound

In another embodiment, the present disclosure provides a compound of formula IV, or a cocrystal or salt thereof:

wherein R ¹ is a leaving group. In one embodiment, R ¹ is selected from halo, -O-(tosyl), -O-(trifluoromethanesulfonyl), -O-(4-nitrophenyl), and -B(OY) ₂ , wherein each Y group is independently H or C _1-4 alkyl, or the two Y groups together with the atoms to which they are attached form a 5- or 6-membered ring. In another embodiment, R ¹ is halo. In another embodiment, R ¹ is chloro.

In another embodiment, R ¹ is NH ₂ .

In another embodiment, the present disclosure provides a compound of Formula V, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group. In one embodiment, PG is selected from Boc, Cbz, and Fmoc. In another embodiment, PG is Boc. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

In another embodiment, the present disclosure provides a compound of Formula VI, or a co-crystal or salt thereof:

wherein R is C _1-6 alkyl. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

In another embodiment, the present disclosure provides a compound of Formula VII, or a cocrystal or salt thereof:

In another embodiment, the present disclosure provides a compound of Formula VIII, or a cocrystal or salt thereof:

wherein R is C _1-6 alkyl. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

In another embodiment, the present disclosure provides a compound of Formula XIII, or a cocrystal or salt thereof:

In another embodiment, the present disclosure provides a compound of Formula XIV, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group. In one embodiment, PG is selected from Boc, Cbz, and Fmoc. In another embodiment, PG is Boc. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

In another embodiment, the present disclosure provides a compound of Formula XV, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group. In one embodiment, PG is selected from Boc, Cbz, and Fmoc. In another embodiment, PG is Boc. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

In another embodiment, the present disclosure provides a compound of Formula XVI, or a co-crystal or salt thereof:

wherein R is a C _1-6 alkyl group and PG is a protecting group. In one embodiment, PG is selected from Boc, Cbz, and Fmoc. In another embodiment, PG is Boc. In another embodiment, R is methyl. In another embodiment, R is tert-butyl.

In another embodiment, the present disclosure provides a compound of Formula XVII, or a cocrystal or salt thereof:

wherein R is C _1-6 alkyl. In one embodiment, R is methyl. In another embodiment, R is tert-butyl.

In another embodiment, the present disclosure provides a compound of Formula XVIII, or a cocrystal or salt thereof:

In another embodiment, the present disclosure provides a compound of Formula XIX, or a co-crystal or salt thereof:

The intermediates in the synthesis of Formula I can be used in the next step with or without purification. Conventional purification methods include recrystallization, chromatography (e.g., adsorption, ion exchange, and HPLC), and the like.

In some embodiments, purification methods may include one or more intermediates in the synthesis of Formula I and/or chiral resolution of Formula I. Non-limiting examples of such methods include crystallization, chiral resolution agents, and/or chiral chromatography. For example, in some embodiments, the compound of Formula I can be further purified by crystallization with a cinchonine alkaloid.

Example

The compounds of the present disclosure can be prepared using the methods disclosed herein and conventional modifications thereof as will be apparent on the basis disclosed herein, as well as methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can be used. The synthesis of the compounds described herein can be accomplished as described in the following examples. If available, reagents can be purchased from, for example, Sigma Aldrich or other suppliers. Unless otherwise noted, the starting materials for the following reactions can be obtained from commercial sources.

Example 1. Synthesis of (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methano-cyclopropyl[18,19][1,10,3,6]dioxadiazaaromaticnonadecacyclo[11,12-b]quinoxaline-8-carboxamide (I) via Route I

The compound of formula I is synthesized via Route I as shown below:

Synthesis of intermediates for compounds of formula I

A. Synthesis of (2S,3S,4R)-3-ethyl-4-hydroxypyrrolidine-2-carboxylic acid methyl ester tosylate (II)

The order of reduction of the double bond and ketone is reversed, forming new intermediates, B (R = tert-butyl) and C (R = tert-butyl). The tert-butyl ester was used in U.S. Publication No. 2014-0017198 to prepare D; however, it was directly converted to the methyl ester tosylate and crystallized to remove diastereomeric impurities without chromatography. Single crystal X-ray data were obtained for the tosylate salt II.

Step 1: Synthesis of A

I. Enamine formation to A

DMF-DMA (125.3 g, 2.0 eq.) and DCM (300 mL) were combined in a reaction vessel and heated to 45°C. In a separate container, commercially available (S)-4-oxopyrrolidone-1,2-dicarboxylic acid di-tert-butyl ester (150 g) was dissolved in DCM (300 mL) under _N₂ . This solution was added to the reaction vessel containing the DMF-DMA solution over approximately 3 hours. Upon completion of the reaction, the solution was cooled to approximately room temperature. 5% LiCl (750 mL) was added to the reactor and the mixture was stirred. The layers were separated and the aqueous layer was removed. The organic layer was washed with water (750 mL) and dried _{over Na₂SO₄} , and the mixture was filtered.

The filtrate was concentrated to 200 mL and loaded with heptane (600 mL) to obtain a turbid solution. The mixture was further concentrated to remove residual DCM. Additional heptane (600 mL) was added and the mixture was heated to approximately 50-60° C. and aged for approximately 1 h to obtain a slurry. The slurry was cooled to approximately 15° C. over approximately 4 hours before aging overnight (18 h) at approximately 15° C. Intermediate A (R=tert-butyl) was isolated by vacuum filtration and washed with 2× heptane. The resulting solid was dried at approximately 45° C. to obtain A (R=tert-butyl). ¹ H NMR (400 MHz, CDCl ₃ ) (mixture of E/Z isomers): δ 7.4 (s, 1H), 5.2-5.3 (s, 1H), 3.8 (d, 2H) 3.2 (broad s, 6H), 1.5 (s, 9H), 1.4 (s, 9H). UPLC/MS M+1=341 amu.

Alternatively, the above disclosed reagents and reaction conditions can be used. For example, alternative solvents such as other polar aprotic solvents (e.g., dimethylformamide, methyl tert-butyl ether and isopropyl acetate) or non-polar solvents (e.g., toluene, cyclohexane, heptane) can be used. The reaction can also be carried out in the absence of a solvent or a mixture of the above solvents. In addition, a temperature of about 25 to about 50°C can be used. Alternatively, a crystallization solvent system (e.g., DCM: heptane, toluene: heptane, cyclohexane: heptane and cyclohexane) can be used.

Step 2: Synthesis of B (R = tert-butyl)

I. Methylation of A (R = tert-butyl) to B (R = tert-butyl):

To the reaction vessel was added A (151 g, 0.44 mol, 1.0 equiv). The vessel was evacuated, purged with nitrogen, and the substrate was dissolved in MeTHF (450 mL, 3 vol). The reaction mixture was cooled to an internal temperature of approximately -12°C and treated dropwise with methylmagnesium bromide (155 mL of a 3.0 M solution in diethyl ether, 0.55 mol, 1.25 equiv) over approximately 1 h. Upon completion of the reaction (approximately 2 h), the reaction was reverse quenched by adding it to cold saturated aqueous ammonium chloride solution (400 mL). If emulsification was observed, more aqueous ammonium chloride solution or 2 M HCl was added. The aqueous layer was extracted with toluene (1 x 200 mL). The organic layers were combined, washed with 1 M HCl (150 mL), then washed with brine (150 mL), and concentrated in vacuo to provide B. ¹ H NMR (400MHz, CDCl ₃ ): δ6.90-6.92(1H,m), 5.08-5.16(1H,m), 3.94-4.00(2H,m), 2.02-2.04(3H,m), 1.44-1.49(18H,m).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other nucleophiles such as methylmagnesium reagent, methyllithium, methyllithium-lithium chloride, methylcopper oxide, and other methylmetal reagents may be used. Additionally, alternative solvents such as other polar or nonpolar aprotic solvents may also be used.

Step 3: Synthesis of C(R＝tert-butyl)

I. Hydrogenation of B (R = tert-butyl) to C (R = tert-butyl):

Enone B (R = tert-butyl) (32.0 g, 0.10 mol) was dissolved in toluene (3 vol) under an _N atmosphere. Pd/C (1.1 g, 0.5 mol%) was then added and the reaction was flushed with _N , followed by _H , and stirred vigorously under 1 atm of _H at room temperature. After the reaction was complete, celite (0.1 S, 13.2 g) was added and the mixture was stirred for 5 minutes. The heterogeneous mixture was filtered through celite and washed with additional toluene (0.5-1 vol) and concentrated to dryness to provide C. ¹ H NMR (400MHz, CD ₃ OD): δ4.68(dd,J＝36.9,9.3Hz,1H),3.99–3.75(m,2H),2.63(tdd,J＝13.7,9.2,4.6Hz,1H),1.8 9(dt,J＝13.8,6.7Hz,1H),1.46(s,9H),1.43(s,9H),1.30–1.16(m,1H),1.07(t,J＝7.4Hz,3H).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other heterogeneous metal catalysts may be used, such as platinum, palladium, ruthenium, nickel, and other metals on carbon, alumina, silica, and other heterogeneous supports, or metal nanoparticles. Additionally, Lewis pairs such as hydrogen [4-[bis(2,4,6-trimethylphenyl)phosphino]-2,3,5,6-tetrafluorophenyl] hydrogen bis(2,3,4,5,6-pentafluorophenyl) borate or homogeneous metal catalysts such as chlorotris(triphenylphosphine)rhodium(I) or (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I) hexafluorophosphate may also be used. Other solvents (e.g., water, protic solvents such as methanol, ethanol, or acetic acid), aprotic solvents (e.g., dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, dichloromethane, or acetone), or combinations thereof may be used. Furthermore, the temperature may be in the range of about -20°C to about 150°C. Additionally, optional hydrogen gas may be used over a range of pressures or formates such as ammonium formate or formic acid may be used. Alternatively, imide reducing conditions may be used.

Step 4: Synthesis of D(R＝tert-butyl)

I. Reduction of C (R = tert-butyl) to provide D (R = tert-butyl)

ZnCl ₂ (27.3 g, 200 mmol, 2 equiv) and CPME (7 vol relative to C, 220 mL) were combined and the heterogeneous mixture was warmed to an internal temperature of about 95° C. and stirred at this temperature for about 1.5 hours. The resulting slurry was cooled to about 25° C., NaBH ₄ (7.56 g, 200 mmol, 2 equiv) was added, and the mixture was stirred overnight (~18 hours).

The slurry was cooled to approximately 0°C, and a solution of C(R=tert-butyl) (-100 mmol) in toluene (3 vol total) was slowly added while maintaining the temperature at approximately below +3°C. After the addition, the mixture was stirred at approximately 0°C until the starting material was completely consumed. The reaction was quenched by adding it back into a solution of citric acid (2.5 equiv, 48 g) in ice water (200 mL). The layers were separated and the organic layer was washed with brine (60 mL, 2 vol), dried over _MgSO4 (0.05S, 1.5 g) and filtered. The crude organic solution was concentrated, diluted with 2 volumes of hexane and filtered through silica gel, eluting with 1:1 acetone:hexane. Concentration in vacuo provided the compound of formula D(R=tert-butyl).

¹ H NMR (400MHz, CDCl ₃ ): δ4.30(dd,J＝26.4,8.4Hz,1H),4.24–4.14(m,1H),3.89(ddd,J＝14.6,10.6,7.5Hz,1H),3.15(ddd,J＝17.7,10.6,7 .1Hz,1H),2.20–2.05(m,2H),1.70–1.59(m,1H),1.48(s,9H),1.44(s,9H),1.35-1.23(m,1H),1.07(t,J＝7.4Hz,3H).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other reducing agents such as borohydrides (e.g., sodium borohydride, lithium borohydride, or calcium borohydride), acyloxyborohydrides (e.g., sodium acetoxyborohydride or lithium trifluoroacetoxyborohydride), borane or borane complexes, hydrogen, aluminum hydride reagents (e.g., lithium aluminum hydride or diisobutylaluminum hydride), diborane, diazene, sodium cyanoborohydride, 9-BBN, tributyltin hydride, silanes (e.g., triethylsilane), aluminum isopropoxides in combination with isopropyl alcohol may be used. In addition, alternative catalysts or promoters may be used, such as Lewis or Bronsted acids or combinations of the two; bases; heterogeneous metal catalysts (e.g., platinum, palladium, ruthenium, nickel, and other metals on carbon, alumina, silica, and other heterogeneous supports); metal nanoparticles; hindered Lewis acid-base pairs (e.g., hydrogen [4-[bis(2,4,6-trimethylphenyl)phosphino]-2,3,5,6-tetrafluorophenyl] hydrogen bis(2,3,4,5,6-pentafluorophenyl) borate); homogeneous metal catalysts (e.g., such as chlorotris(triphenylphosphine)rhodium(I) or (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I) hexafluorophosphate). In addition, other solvents such as water, protic solvents (e.g., methanol, ethanol, or acetic acid), aprotic solvents (e.g., dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, dichloromethane, or acetone), and combinations thereof may be used.

Synthesis of compounds of formula II (R=CH ₃ )

Deprotection of D (R = tert-butyl) and transesterification to give II (R = CH ₃ ):

D(R＝tBu) (5.55 g, 17.6 mmol) and methanol (55.5 mL) were mixed in a reaction vessel. p-Toluenesulfonic acid (10.7 g, 3.2 eq.) was added to the solution and the mixture was stirred at room temperature for approximately 1 hour. The mixture was then heated to approximately 60°C. The reaction was stirred until the reaction was complete. The reaction mixture was concentrated to approximately 4 volumes and cooled to approximately 45°C. MTBE (4 volumes) was slowly added, followed by II seed crystals (0.05%). The mixture was then aged for approximately 30 minutes. Additional MTBE (5 volumes) was added over approximately 90 minutes, and the resulting mixture was stirred overnight.

The mixture was filtered and washed with 2 volumes of MTBE. The resulting wet cake was dried under vacuum at approximately 40°C to afford Compound II (R=CH ₃ ) as a tosylate salt. ¹ H NMR (400 MHz, MeOD) δ 7.7 (d, 2H), 7.2 (d, 2H), 4.7 (d, 1H), 4.3 (m, 1H), 3.8 (s, 3H), 3.6 (m, 1H), 3.2 (m, 1H), 2.4 (m, 1H), 2.3 (s, 3H), 1.3 (m, 2H), 1.0 (t, 3H). LC/MS M+1 = 174.1.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, methanol may be used with a co-solvent of MTBE, toluene, or other non-alcoholic solvents, and temperatures in the range of about 0-60° C. may be used. Additionally, alternative crystallization solvent systems may include methanol:MTBE, ethanol:MTBE, or acetone:MTBE. Furthermore, alternative salts (e.g., HCl, HBr, methanesulfonate, bromobenzenesulfonate, trifluoromethanesulfonate, benzenesulfonate) may be used.

B. Synthesis of 3-chloro-2-(1,1-difluorobut-3-en-1-yl)-6-methoxyquinoxaline (IV)

Compound IV was synthesized by two different routes as described below.

Pathway I

Compound IV contains one more methylene group than the analog used in U.S. Publication No. 2014-0017198 and therefore requires different starting materials. Ethyl trifluoropyruvate is converted to intermediate G in three steps. Intermediate G is telescoped through to a 4:1 regioisomer mixture of J and K. In U.S. Publication No. 2014-0017198, nitro and amino-anisole are used to form the ring in a two-step process that first reacts the amine and then reduces the nitro group to allow cyclization. Two regioisomers are formed. In this approach, the starting material is changed to a diamino analog and a similar mixture is obtained. The mixture is chlorinated and the desired isomer IV is purified by conventional methods.

Step 1: Synthesis of G

I. Synthesis of an intermediate of formula G from ethyl trifluoropyruvate:

a. Allylation of ethyl trifluoropyruvate to provide E:

The reaction vessel was charged with ethyl trifluoropyruvate (86 g, 0.5056 mol, 1.0 equiv) and dichloromethane (260 mL). Allyl alcohol (31 g, 0.5337 mol, 1.1 equiv) was added dropwise over approximately 30 minutes while maintaining the reaction temperature below approximately 27°C. The reaction was cooled to approximately 5°C and pyridine (123 mL, 1.52 mol, 3.0 equiv) was added over approximately 50 minutes, maintaining the reaction temperature below approximately 8°C. Thionyl chloride (90 g, 0.76 mol, 1.5 equiv) was then added over approximately 90 minutes while maintaining the reaction temperature below approximately 12°C. The reaction was stirred at 5-10°C for approximately 30 minutes, then warmed to approximately 22°C over approximately 30 minutes and maintained at approximately 22°C until the reaction was deemed complete. The reaction mixture was poured into 860 mL of chilled (approximately 8°C) water and the phases separated. The aqueous phase was back-extracted with 200 mL of dichloromethane. The combined dichloromethane phases were washed sequentially with water (860 mL), 5 wt% NaHCO ₃ solution (2 x 250 mL) and a final water wash (250 mL) and dried over Na ₂ SO _4. After removal of the solvent, the crude product E was isolated and used directly in the next step. ¹ H NMR (300 MHz, CDCl ₃ ): δ 5.92 (m, 1 H), 5.38 (dq, J = 14.1, 1.4 Hz, 1 H), 5.27 (dq, J = 10.3, 1.2 Hz, 1 H), 4.40 (d, J = 7.1 Hz, 2 H), 4.34 (m, 2 H), 1.30 (t, J = 7.1 Hz, 3 H).

II. Zn-mediated elimination of ClF from E to provide F, followed by Claisen to provide G:

A reaction vessel was charged with zinc powder (324 g, 4.95 mol, 2.0 equiv), CuI (6 g, 0.032 mmol, 0.013 equiv), and N,N-dimethylformamide (DMF) (3.0 L). The mixture was stirred vigorously as _Me3SiCl (309 mL, 2.43 mmol, 1.0 equiv) was added dropwise via an addition funnel over approximately 10 minutes, maintaining the reaction temperature at approximately <25°C. The reaction was stirred at approximately 25°C for approximately 30 minutes. The reaction was then cooled to 0-5°C over 20 minutes, and a solution of Compound E (600 g, 2.43 mol, 1.0 equiv) in DMF (3.0 L) was slowly added over approximately 60 minutes, maintaining the reaction temperature at approximately <10°C. The reaction was stirred at 5-10°C for approximately 30 minutes, warmed to approximately 22°C over approximately 30 minutes, and then maintained at approximately 22°C until the reaction was deemed complete by ^19F NMR (typically 1-2 hours).

Claisen rearrangement of III.F to provide G

The reaction mixture was filtered and washed with ethyl acetate (2 x 3 L). Water (1.5 L) was added to the organic phase and the layers separated. The organic layer was washed with two portions of water (2 x 1.5 L). The organic solution was concentrated to yield crude F. This was dissolved in 3.0 L (5 volumes) of toluene and heated to approximately 80° C. until the reaction was deemed complete (typically 1-3 h). The reaction was cooled to approximately 22° C. and the solvent removed by rotary evaporation to yield crude product G (~70 wt%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 5.90 (m, 1 H), 5.28 (m, 2H), 4.40 (q, J=7.1 Hz, 2H), 2.83 (dt, J=18.5, 7.0 Hz, 2H), 1.32 (t, J=7.0 Hz, 3H); ¹⁹ F NMR (CDCl ₃ ) δ -112.8 (t).

Alternatively reagents and reaction conditions to those disclosed above can also be used. For example, other amine bases (for example, 4-dimethylaminopyridine, imidazoles or triethylamine) can be used. In addition, optional allylating agents (for example, allyl chloride, allyl bromide), halogenating agents (for example, thionyl bromide), olefinating agents (for example, magnesium) or zinc activators (for example, methanesulfonic acid, hydrochloric acid, diisobutylaluminum hydride, diethylaluminum chloride) can be used. In addition, other solvents (for example, methylene dichloride, benzene, toluene, methyl tert-butyl ether, tetrahydrofuran or 2-methyltetrahydrofuran) can be used.

Step 2: Synthesis of H

Synthesis of I.H from G

A reaction flask was charged with G (26.2 g, 136.6 mmol, 1.0 equiv) and THF (236 mL, 9 vol.). Water (52 mL, 2 vol.) was added, followed by LiOH.H ₂ O (14.9 g, 354.5 mmol, 2.6 equiv.), maintaining the reaction temperature below approximately 33°C. The reaction was maintained at approximately 22°C for approximately 3 hours, then quenched with 250 mL of 1 M HCl. The pH was then adjusted to 3 by the addition of concentrated HCl (20 mL). The phases were separated, and the aqueous phase was back-extracted with methyl tert-butyl ether (260 mL). The layers were separated, and NaCl (52 grams) was added to the aqueous phase, which was extracted with MTBE (2 x 130 mL) and then EtOAc (50 mL). All organic phases were combined and dried over Na ₂ SO ₄ , filtered, concentrated, and dried under vacuum to obtain H. ¹ H-NMR (400MHz, DMSO-d ₆ ) δ13.2(br s,1H),6.92(br s,2H),5.83-5.70(m,1H),5.20-5.13(m,2H),2.83-2.65(m,2H). ¹⁹ F-NMR (DMSO-d ₆ ) δ-88.20 (t, J = 20.8 Hz).

Alternatively reagents and reaction conditions of those disclosed above and reaction conditions can also be used. For example, other alkalis can be used, such as potassium hydroxide/sodium hydroxide, potassium tert-butoxide or sodium trimethylsilanol/potassium. In addition, optional catalysts (for example, tetrabutylammonium chloride) can be used. In addition, other solvents can be used, such as methyl-tert-butyl ether/water, 2-methyltetrahydrofuran/water, tetrahydrofuran/water, methyl-tert-butyl ether/water/heptane.

Step 3: Synthesis of J

I. Condensation followed by cyclization to provide J from H:

The reaction vessel was charged with the diamine (6.06 g, 28.7 mmol, 1.0 equiv) and ethanol (130 mL). Triethylamine (8.8 mL, 63.1 mol, 2.2 equiv) was added over approximately 5 minutes, maintaining the reaction temperature at approximately <25°C. The reaction was stirred for approximately 10 minutes to provide a solution. Acetic acid (16.4 mL, 287 mmol, 10 equiv) was added, followed by a solution of H in ethanol (40 mL) (5.75 g, 31.6 mmol, 1.1 equiv) and the reaction was maintained at approximately 22°C until the reaction was complete. The reaction mixture was solvent-exchanged into approximately 80 mL of dichloromethane and washed sequentially with 0.1 N HCl (60 mL), saturated _NaHCO₃ solution (60 mL), and a final brine wash (60 mL). The organic layer was dried _{over Na₂SO₄} and filtered. After removal of the solvent, a crude mixture of J/K was obtained. The crude mixture was dissolved in dichloromethane, washed twice with 0.1N HCl, once with water, and once with brine, then dried over sodium sulfate, filtered, and concentrated to afford J/K. ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.82 (d, J = 9.0 Hz, 1H), 7.38 (m, 1H), 6.97 (dd, J = 9.0, 3.0 Hz, 1H), 6.82 (d, J = 3.0 Hz, 1H), 5.88 (m, 1H), 5.22 (m, 2H), 3.91 (s, 3H), 3.28 (td, J = 12.0, 3.0 Hz, 2H). ¹⁹ F NMR (282.2 MHz, CDCl ₃ ): δ -100.3 ppm (J) and -100.8 ppm (K). LCMS: m/z = 266.93.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, when R = NH ₂ , other bases (e.g., potassium hydroxide/sodium hydroxide, potassium tert-butoxide, sodium/potassium trimethylsilanol) may be used. Other additives and alternative solvents (e.g., ethanol, ethanol/isopropyl acetate, or toluene) may be used.

Additionally, when R = _NO2 , alternative reagents and reaction conditions to those disclosed above may also be used. For example, iron, BHT, and AcOH may be used in combination with ethanol as a solvent and a temperature in the range of about 60°C to about 70°C.

Step 4: Synthesis of IV

Chlorination of I.J to provide a compound of formula IV:

The reaction vessel was charged with J (7.4 g, 27.79 mmol, 1.0 equiv) and DMF (148 mL). Phosphorus oxychloride (POCl ₃ ) (4.2 mL, 44.47 mmol, 1.6 equiv) was added over approximately 3 minutes, maintaining the reaction temperature below approximately 30°C. The reaction was heated to approximately 75°C until completion. The reaction mixture was slowly poured into 150 mL of water while maintaining the temperature below approximately 25°C. Methyl-tert-butyl ether (MTBE) (75 mL) was added and the phases separated. The aqueous phase was stripped with 4 x 75 mL of MTBE. The combined MTBE phases were washed sequentially with saturated NaHCO ₃ solution (200 mL) and saturated NaCl solution (150 mL) and dried over Na ₂ SO _4. After removal of the solvent, the crude product IV was isolated. The crude material was suspended in hexanes (4.3 volumes), heated to dissolve, and slowly cooled to approximately 20°C, resulting in the formation of a slurry of the desired regioisomer IV, which was subsequently isolated by filtration and dried. ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.02 (d, J = 9.0 Hz, 1H), 7.48 (dd, J = 9.0, 3.0 Hz, 1H), 7.34 (d, J = 3.0 Hz, 1H), 5.97 (m, 1H), 5.31 (m, 2H), 4.0 (s, 3H), 3.35 (td, J = 12.0, 3.0 Hz, 2H). ¹⁹ F NMR (282.2 MHz, CDCl ₃ ): δ -96.3 ppm (IV) and -97.1 ppm (regioisomer). LCMS: m/z = 285.27.

Alternatively reagents and reaction conditions to those disclosed above can also be used. For example, other chlorinating agents (e.g., trichloroisocyanuric acid, chlorine, 1,3-dichloro-5,5-dimethylhydantoin, N-chlorosuccinimide, thionyl chloride/DMF, oxalyl chloride/DMF) can be used. In addition, other solvents such as acetonitrile or acetic acid and hydrocarbon solvents (e.g., toluene or heptane), ether (e.g., methyl-tert-butyl ether or THF) or chlorinated solvents (e.g., dichloromethane or chloroform) can be used. Other amine additives (e.g., DABCO, triethylamine or N-methylmorpholine) or phase transfer catalysts (e.g., benzyltrimethylammonium chloride) can be used. In addition, a temperature in the range of about 20°C to about 80°C can be used.

Pathway II

Compounds G and H were synthesized as described in Route I above.

Step 1: Synthesis of IV-b

I. Synthesis of IV-b from H

In a reaction vessel, triphenylphosphine (235.2 g, 896.3 mmol) was dissolved in tetrachloride (300 mL) at ambient temperature. The solution was cooled to below approximately 5°C, followed by the addition of triethylamine (73 mL, 523.7 mmol) and H (41.8 g active material, 295.4 mmol). Aniline (32 mL, 351.2 mmol) was then slowly added over approximately 30 minutes. The mixture was stirred at below approximately 5°C for approximately 1 hour and allowed to warm to ambient temperature. The solution was then heated to 50-55°C, at which point the reaction became exothermic. The reaction temperature rapidly rose to approximately 92°C without heating, accompanied by vigorous reflux and gas evolution. The temperature was cooled to approximately 75°C, and the mixture was stirred for approximately ten hours. Heptane (700 mL) was added to the reaction mixture, which was then concentrated to remove approximately 700 mL of filtrate. The heptane (700 mL) of the second portion was added, and the mixture was heated to about 100° C. reflux for about 30 minutes, then cooled to about 20° C. The mixture was stirred at about 20° C. for about 30 minutes, then filtered. The filter cake was mixed with another heptane (700 mL), heated to reflux for about 30 minutes, cooled to about 20° C. and stirred for about 30 minutes. The mixture was filtered, and two filtrates were combined and concentrated to provide refined IV-b. Crude IV-b was directly used in the next step without further processing. ¹ H NMR (300Hz, CDCl ₃ ): δ7.37–7.45(m,2H), δ7.25(tt,J＝7.8,0.9Hz,1H), δ6.98(dd,J＝8.7,1.2Hz,2H), δ5.82 –5.96(m,1H), δ5.35(d,J＝8.4Hz,1H), δ5.30(s,1H), δ3.07(tdt,J＝15.9,7.2,1.2Hz,2H); ¹³ C NMR (75Hz, CDCl ₃ ): δ144.8,139.7(t,J＝36.7Hz), 129.0,127.7(t,J＝5.8Hz), 126.4,124.2(t,J＝282.8Hz), 121.7,120.2,39.5(t,J＝24.0Hz).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases (e.g., diisopropylethylamine (DIPEA), pyridine, tributylamine, DBU, N-methylmorpholine (NMM)) may be used. Additionally, optional halogenating agents (e.g., N-chlorosuccinimide, chloride (g), chloramine-T) may be used. Additionally, other solvents (e.g., dichloromethane, chloroform, chlorobenzene) may be used.

II. Synthesis of IV-b from G

a. Synthesis of IV-a from G

In a reaction vessel, G (10.0 g, 60.9 mmol) was dissolved in aniline (50 mL, 548.7 mmol) at ambient temperature. The solution was heated to reflux at about 150° C. under nitrogen for about 24 hours. The mixture was cooled to below about 5° C. and then diluted with MTBE (100 mL). The pH was then adjusted to acidic by adding about 100 mL of 6N aqueous HCl at below about 5° C. The mixture was allowed to warm to the maximum ambient temperature, settle, and separate. The aqueous phase was extracted with MTBE (2×100 mL). The organic phases were combined and washed sequentially with 1N aqueous HCl and 5% aqueous NaHCO ₃ . The organic phase was filtered through a pad of Na ₂ SO ₄ and concentrated to provide crude IV-a. ¹ HNMR (300Hz, CDCl ₃ ): δ7.95(bs,1H), δ7.57(d,J＝7.5Hz,1H), δ7.37(tt,J＝8.7,2.4Hz,1H), δ7.19(tt,J＝7.8, 1.2Hz, 1H), δ5.72–5.86 (m, 1H), δ5.27–5.35 (m, 2H), δ2.96 (tdt, J = 17.1, 7.5, 1.2Hz, 2H); ¹³ C NMR (75Hz, CDCl ₃ ): δ 161.6 (t, J = 28.7 Hz), 135.9, 129.2, 127.0 (t, J = 5.7 Hz), 125.6, 122.2, 120.2, 117.1 (t, J = 254.3 Hz), 38.4 (t, J = 24.0 Hz); MP: 48.0° C.; GCMS m/z (relative intensity): 211 (100, M ⁺ ).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other solvents (toluene, xylenes, chlorobenzene, acetonitrile) may be used.

b. Synthesis of IV-b from IV-a

IV-a (6.1 g, 28.0 mmol) was dissolved in DCM (60 mL) in a reaction vessel at ambient temperature. Phosphorus pentachloride (10.8 g, 51.9 mmol) was added in one portion. The mixture was stirred at ambient temperature for about 16 hours. The reaction mixture was quenched by slowly transferring the mixture into a 40% aqueous K ₃ PO ₄ solution while maintaining the temperature below about 20° C. The pH of the aqueous phase was adjusted to about 7.5 by adding additional 40% aqueous K ₃ PO ₄ solution. The phases were separated, and the aqueous phase was extracted with DCM (60 mL). The combined organic phases were filtered through a pad of Na ₂ SO ₄ and concentrated to provide crude IV-b. ¹ H NMR (300Hz, CDCl ₃ ): δ7.37–7.45(m,2H), δ7.25(tt,J＝7.8,0.9Hz,1H), δ6.98(dd,J＝8.7,1.2Hz,2H), δ5.82 –5.96(m,1H), δ5.35(d,J＝8.4Hz,1H), δ5.30(s,1H), δ3.07(tdt,J＝15.9,7.2,1.2Hz,2H); ¹³ C NMR (75Hz, CDCl ₃ ): δ144.8,139.7(t,J＝36.7Hz), 129.0,127.7(t,J＝5.8Hz), 126.4,124.2(t,J＝282.8Hz), 121.7,120.2,39.5(t,J＝24.0Hz).

Alternatively, reagents and reaction conditions other than those disclosed above may be used. For example, other bases (e.g., sodium hydroxide, potassium hydroxide, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate) may be used. Additionally, optional halogenating agents (e.g., N-chlorosuccinimide, chloride (g), chloramine-T, phosphorus oxychloride, thionyl chloride) may be used. Additionally, other solvents (e.g., methylene chloride, chloroform, chlorobenzene, toluene, acetonitrile) may be used.

Step 2: Synthesis of IV-c from IV-b

In a reaction vessel, IV-b (29.5 g active material or 32 g crude material, 128.2 mmol) was dissolved in acetonitrile (500 mL), followed by the addition of potassium cyanide (8.5 g, 130.5 mmol). The mixture was degassed with nitrogen vacuum and stirred at ambient temperature for about 16 hours. The mixture was concentrated in vacuo to completely remove the acetonitrile and then suspended in toluene (500 mL). A 5% aqueous solution of NaHCO ₃ (250 mL) was added to dissolve the inorganic salts. The mixture was settled and separated. The aqueous phase was extracted with toluene (250 mL). The organic phases were combined, filtered through a pad of Na ₂ SO ₄ and concentrated to provide crude IV-c. ¹ H NMR (300Hz, CDCl ₃ ): δ7.49(tt,J＝7.2,1.8Hz,2H), δ7.41(tt,J＝7.2,1.2Hz,1H), δ7.26(dt,J＝7.2,1.8Hz,2H), δ5.7 9–5.92(m,1H), δ5.37(dd,J＝5.1,1.2Hz,1H), δ5.32(s,1H), δ3.07(tdt,J＝16.5,7.2,1.2Hz,2H); ¹³ C NMR (75Hz, CDCl ₃ ): δ 146.0, 135.7 (t, J = 35.5 Hz), 129.5, 127.0 (t, J = 4.7), 122.4, 120.9, 120.2, 117.3 (t, J = 245.0 Hz), 108.9, 38.8 (t, J = 24.1 Hz); GCMS m/z (relative intensity): 220 (70, M ⁺ ).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases (e.g., sodium hydroxide, potassium hydroxide, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate) may be used. Additionally, optional cyaniding agents (e.g., trimethylsilyl cyanide, sodium cyanide, potassium ferricyanide, lithium cyanide) may be used. Additionally, other solvents (e.g., dichloromethane, chloroform, chlorobenzene, toluene) may be used.

Step 3: Synthesis of IV-d from IV-c

In a reaction vessel, methoxy-o-phenylenediamine and toluene (41 mL) were mixed at ambient temperature, followed by the addition of acetic acid (14.2 mL, 248 mmol). The black solution was degassed with nitrogen under vacuum. A prepared solution of IV-c (4.89 g active material or 6.4 g crude material, 22.2 mmol) in toluene (11 mL) was slowly added to the solution over approximately three hours at approximately 20°C, while maintaining the temperature at approximately 20°C. The resulting mixture was then heated to approximately 30°C for approximately 64 hours. The reaction mixture was cooled to below approximately 20°C, and EtOAc (40 mL) was added, followed by the pH being adjusted to approximately 9–9.5 with approximately 76.5 mL of 3N aqueous NaOH. The mixture was filtered through celite (5 g), allowed to settle, and the phases separated. The separated aqueous phase was extracted with EtOAc (80 mL). The two organic phases were combined, and activated carbon (5 g) was added. The mixture was stirred at ambient temperature for approximately 16 hours and filtered through celite (5 g). The filtrate was concentrated in vacuo to completely remove the solvent, and IPA (20 mL) was added. The mixture was heated at about 40°C to dissolve the crude solid. The solution was heated to reflux for about 30 minutes and then cooled to about 20°C. IV-d seed crystals (5 mg) were added to induce crystallization. The suspension was stirred at about 20°C for about 1 hour. Water (30 mL) was added in a buffered manner over about five hours while maintaining the temperature at about 20°C. The resulting suspension was stirred at about 20°C for more than about 10 hours, then filtered and washed with 33% IPA/ _H2O (15 mL). The filter cake was dried to provide IV-d. ¹ H NMR (300Hz, CDCl ₃ ): δ7.77(d,J＝8.7Hz,1H), δ7.09(dd,J＝9.6,3.0Hz,1H), δ6.98(d,J＝3.0Hz,1H), δ5.93 –6.07(m,1H), δ5.25–5.37(m,4H), δ3.92(s,3H), δ3.32(tdt,J=17.4,6.9,1.2Hz,2H); ¹³ C NMR (75Hz, CDCl ₃ ): δ 162.3, 149.9, 144.1, 134.5 (t, J = 30.9 Hz), 131.6, 130.4, 128.9 (t, J = 4.6 Hz), 122.6 (t, J = 238.2 Hz), 120.9, 118.2, 104.0, 55.7, 39.4 (t, J = 24.1 Hz); MP: 102.4° C.; LCMS m/z (relative intensity) 265.70 (100, M ⁺ ).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other solvents (e.g., dichloromethane, chloroform, chlorobenzene, toluene, acetonitrile) and temperatures in the range of 10-80°C may be used.

Step 4: Synthesis of IV from IV-d

In a reaction vessel, IV-d (5.0 g, 18.8 mmol) was dissolved in 100 mL of DCM at ambient temperature. The solution was cooled to below approximately 5°C, followed by the addition of 1 M _BCl₃ (19 mL, 19 mmol) in DCM over a buffered period of approximately 15 minutes. t- _BuNO₂ (9 mL) was then added slowly over approximately two hours while maintaining the temperature below approximately 5°C. The mixture was allowed to warm to ambient temperature and stirred for approximately 12 hours. Upon completion of the reaction, the mixture was concentrated in vacuo to remove the solvent and then dissolved in EtOAc (100 mL). The solution was cooled to below approximately 5°C, followed by the slow addition of 5% _aqueous NaHCO₃. The resulting mixture was allowed to warm to ambient temperature, settled, and separated. The aqueous phase was extracted with EtOAc (2 x 100 mL). Activated carbon (2.0 g) was added to the combined organic phases, and the mixture was stirred for approximately 16 hours, then filtered through celite (5 g). The filtrate was concentrated in vacuo to completely remove the solvent, and IPA (25 mL) was added. The mixture was heated to reflux for about 30 minutes and then slowly cooled. IV seed crystals (5 mg) were added at 35-40°C to induce crystallization. The mixture was cooled to about 20°C and stirred for about two hours. Water (10 mL) was slowly added over about two hours. The mixture was stirred for about 1 hour and then cooled to below about 5°C. The mixture was stirred at below about 5°C for about 1 hour, then filtered and washed with 50% IPA/ _H2O (15 mL). The filter cake was dried to provide IV. ¹ H NMR (400Hz, CDCl ₃ ): δ8.00(d,J＝9.2Hz,1H), δ7.45(dd,J＝9.6,2.8Hz,1H), δ7.32(d,J＝2.8Hz,1H), δ5.91 –6.01(m,1H), δ5.23–5.34(m,2H), δ3.98(s,3H), δ3.32(tdt,J＝16.8,7.2,1.2Hz,2H); ¹³ C NMR (400Hz, CDCl ₃ ): δ 162.8, 144.7, 143.9, 142.9 (t, J = 29.7 Hz), 134.9, 130.4, 128.6 (t, J = 4.6 Hz), 124.3, 122.4, 120.0 (t, J = 241.8 Hz), 105.5, 56.0, 40.2 (t, J = 24.5 Hz); MP: 82.8° C.; LCMS m/z (relative intensity): 284.69 (100, M ⁺ ).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases (e.g., sodium hydroxide, potassium hydroxide, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate) may be used. In addition, other solvents (e.g., dichloromethane, chloroform, chlorobenzene, toluene, acetonitrile) may be used.

C. Synthesis of (S)-2-((((1R,2R)-2-allylcyclopropyloxy)carbonyl)amino)-3,3-dimethylbutyric acid (S)-1-phenylethyl-1-amine salt (VII)

Compound VII was synthesized by two different routes as described below.

Pathway I

The compound of formula VII is obtained from 5-bromo-pent-1-ene by Kulinkovich cyclopropanation, acylation, and enzymatic resolution. Cyclopropyl alcohol and then cyclopropyl acetate are distilled, but this is not required. Acid extraction is used to remove any remaining acetylated material. The final product is isolated as the S-1-phenylethylamine salt, which increases the diastereoisomers and overall purity of the product. Recrystallization can be used to further increase the purity of the product. Other salts are also possible.

Step 1: Synthesis of (1R,2R)-2-allylcyclopropan-1-ol (M1)

Kulinkovich reaction, acetylation and enzymatic resolution:

I. Kulinkovich reaction with ethyl formate and 5-bromo-1-pentene

Magnesium turnings (2.45 equivalents) and MeTHF (8 volumes) were added to the reaction vessel. The flask was then sparged with nitrogen, and 5-bromo-1-pentene (2.4 equivalents) was added to the addition funnel. The mixture was heated to approximately 60°C and 0.05 volumes of 5-bromo-1-pentene were added dropwise to the mixture to initiate the reaction. Once the reaction began, the remainder of the 5-bromo-1-pentene was slowly added to the flask over approximately 3 hours. After addition, the reaction was allowed to stir at approximately 60°C for approximately 1 hour, after which Grignard L was cooled to room temperature. Titanium isopropoxide (0.5 equivalent) in ethyl formate (1.0 equivalent) and MeTHF (2 volumes) was added to a separate flask under nitrogen. The mixture was cooled to approximately 0°C, and Grignard L was slowly added to the flask over 3 hours. Upon completion of the addition, the reaction mixture was allowed to warm to room temperature and the reaction stirred for approximately 12 hours. The mixture was then cooled to approximately 0°C and 4M sulfuric acid (10 volumes) was slowly added. The slurry was stirred for 30 minutes, after which the salt dissolved. The mixture was then polish filtered. The biphasic mixture was separated and the organic layer was then washed twice with 10 wt.% sodium bicarbonate (10 volumes) and once with water (10 volumes). The organic layer was concentrated under reduced pressure at approximately 0°C to afford crude 2-allylcyclopentanol M. ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.53-5.43 (m, 1H), 4.76-4.70 (m, 1H), 4.65-4.59 (m, 1H), 2.90-2.86 (m, 1H), 1.75 (br s, 1H), 1.65-1.51 (m, 2H), 0.69-0.59 (m, 1H), 0.40-0.35 (m, 1H), 0.05-0.01 (m, 1H).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other aprotic solvents (e.g., tetrahydrofuran or diethyl ether) may be used. Additionally, other titanium catalysts, such as titanium (IV) alkoxides (e.g., MeTi(OiPr) ₃ , MeTi(OtBu) ₃ , ClTi(OiPr) ₃ , ClTi(OtBu) ₃ , or Ti(OtBu) ₄ ) may be used. Furthermore, temperatures in the range of about −20° C. to about 100° C. may be used.

II. Acetylation of 2-allylcyclopentanol (+/-)-M:

2-allylcyclopentanol M (1 equivalent) in MeTHF (10 times of volume) is added to the reaction vessel. The container is purged with nitrogen, and the solution is subsequently cooled to 0 ° C. Triethylamine (3.0 equivalents) is then slowly added to the solution over approximately 30 minutes. The mixture is allowed to stir for approximately 30 minutes, after which acetyl chloride (2.5 equivalents) is added, maintaining the internal temperature below approximately 20 ° C. The reaction is then allowed to stir at approximately 21 ° C for at least 12 hours. After the prescribed time, water (6 times of volume) is slowly loaded into the reactor and phase separated. The organic layer is then washed with 2M hydrochloric acid (6 times of volume), 10wt.% sodium bicarbonate (6 times of volume) and subsequently with brine (6 times of volume). The organic layer is concentrated under reduced pressure at approximately 0 ° C to obtain crude racemic 2-allylcyclopropyl acetate N. ¹ H NMR (400MHz, CDCl ₃ ): δ5.85-5.73(m,1H),5.10-5.04(m,1H),5.00-4.97(m,1H),3.85-3.82(m,1H),2.13-2.07(m, 1H),1.99(s,3H),2.01-1.89(m,1H),1.14-1.03(m,1H),0.87-0.76(m,1H),0.64-0.57(m,1H).

Alternative reagents and reaction conditions to those disclosed above can also be used. For example, other acetylating agents such as acetic anhydride can be used. In addition, other acyl groups can be used for enzymatic resolution, such as alkyl homologues (e.g., C1-C10) or aromatic groups (e.g., benzoic acid, substituted benzoic acids or naphthoic acids). In addition, other amine bases (e.g., N, N'-diisopropylethylamine, pyridine or piperidine), metal hydrides (e.g., sodium hydride and potassium hydride), alkoxides (e.g., sodium tert-butoxide, lithium tert-butoxide or potassium tert-butoxide) can be used. Other halogenated solvents (e.g., dichloromethane or dichloroethane) can be used, and combinations of these with 2-methyltetrahydrofuran or tetrahydrofuran. In addition, other temperature ranges between about -20°C and about 80°C can be used.

III. Enzymatic Resolution of 2-Allylcyclopentanol

The reaction vessel was loaded with 2-allylcyclopropyl acetate N in MeTHF (2 volumes) and MTBE phosphate buffer (10 volumes). The MTBE phosphate buffer was prepared by first dissolving dipotassium hydrogen phosphate (283 g) and potassium dihydrogen phosphate (104.8 g) in water (1.6 L). MTBE (800 mL) was added to the solution and the biphasic mixture was stirred at about 21° C. for about 1 hour. The organic layer was then separated and used as the MTBE phosphate buffer. The reaction mixture was then cooled to about 0° C. and loaded with solid-supported Novozyme 435 (1.7 wt.%). The reaction was allowed to stir at about 0° C. for about 6 hours, after which the mixture was filtered. The filtrate was then concentrated under reduced pressure at about 0° C. to afford racemic (1S,2S)-2-allylcyclopropan-1-ol in a 10:1-15:1 mixture of primarily (1R,2R)-2-allylcyclopropan-1-ol M1 and as a mixture of the corresponding residual acylated starting material. The crude mixture was carried forward as is.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, ether solvents (e.g., tetrahydrofuran (THF), methyltetrahydrofuran (MeTHF), diethyl ether (Et ₂ O), or 1,4-dioxane), water-miscible solvents (e.g., methanol, ethanol, and isopropanol), or other organic solvents (e.g., acetone or acetonitrile) may be used. Additionally, other deacylating ligases may be used. Furthermore, temperatures ranging from about −20° C. to about 20° C. may be used.

Step 2: Synthesis of VII

I. Coupling to obtain VII

A solution of alcohol M1 in MTBE and MeTHF (containing 14g of the desired alcohol) is loaded into the reactor. DMF (140mL) and N,N'-disuccinimidyl carbonate (DSC) (47.5g, 1.3eq) are loaded into the reactor to obtain a thin slurry. Pyridine (11.3g, 1eq) is loaded and the reaction mixture is heated to about 45°C. Upon completion of the reaction, the reaction mixture is cooled to about 0°C and quenched with water (196mL). The reaction mixture is stirred for at least 30 minutes. Succinimide O can optionally be separated by extraction with ethyl acetate, the organic layer is washed and the solvent is removed by distillation, or it can be directly used in subsequent steps without purification. ¹ HNMR (400MHz, CDCl ₃ ): δ5.83-5.74(m,1H),5.12-4.99(m,2H),4.13-3.99(m,1H),2.81(s,4H),2 .13-1.92(m,2H),1.39-1.30(m,1H),1.11-1.04(m,1H),0.73-0.68(m,1H).

Continuing with crude succinate intermediate O, tert-leucine (23.4 g, 1.25 eq) and K ₃ PO ₄ (84.8 g, 2.8 eq.) were loaded into the reactor. The resulting mixture was warmed to room temperature and the resulting solution was stirred for approximately 18 h. Upon completion of the reaction, the mixture was diluted with MTBE (210 mL) and the pH was adjusted to pH 3 with 6 M HCl (~180 mL). The layers were separated and the organic layer was adjusted to pH>10 with 2.5 M NaOH (~70 mL). The aqueous layer was removed and the organic layer was washed with 0.5 M NaOH (100 mL). The combined alkaline aqueous layer was re-adjusted to pH<3 with 6 M HCl (~50 mL) and washed twice with MTBE (100 mL x 2).

The combined organic layers were solvent exchanged with MTBE (107 mL). In a separate container, S(-)1-phenylethylamine (10.9 g, 1 eq.) was dissolved in MTBE (32.7 mL). The amine solution was slowly added to the solution containing the succinimide intermediate. A small amount of VII (S)-1-phenylethyl-1-amine salt (0.055 g, 0.5%) was added, followed by the remaining amine solution. The slurry was aged overnight to obtain a thick slurry. The resulting slurry was filtered and washed with MTBE (50 mL). The solid material was dried in a vacuum oven until a constant weight was reached, thereby obtaining VII as the (S)-1-phenylethyl-1-amine salt. NMR of the free acid: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.4 (m, 5H), 6.3 (broad s, 3H), 5.8 (m, 1H), 5.3 (d, 1H), 5.1 (d, 1H), 4.2 (q, 1H), 3.8 (d, 1H), 3.7 (m, 1H), 2.1 (m, 1H), 1.9 (m, 1H), 1.5 (d, 3H), 1.1 (m, 1H), 0.9 (d, 9H), 0.8 (m, 1H), 0.5 (q, 1H). ¹³ C-NMR (CDCl ₃ ) δ 173.1, 157.0, 115.7, 63.3, 53.9, 36.2, 34.9, 33.7, 27.1, 17.3, 11.7.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, polar aprotic solvents (e.g., dimethylacetamide) and temperatures in the range of about 25° C. to about 65° C. may be used. Additionally, alternative crystallization solvent systems (e.g., acetonitrile) may be used.

Pathway II

Pathway II shown above differs from Pathway I in the formation of intermediate M3 and its conversion to M1. The synthesis of M3 and its conversion to VII are discussed below.

Synthesis of M3 from M2

The reaction vessel was charged with alcohol M2 (100.0 g, 1019.0 mmol, alcohol M2 was provided as a solution in MTBE along with acetate impurity N1 from the previous enzymatic resolution step. The actual amount of solution loaded was calculated by determining the wt% of the enzymatic resolution solution and then adjusting the loading to ensure that 100.0 g of alcohol was present in the charge). Dichloromethane (300 mL) and triethylamine (134.0 g, 1324.6 mmol) were added. The reaction was cooled to an internal temperature of approximately 0°C. In a separate flask, 3,5-dinitrobenzoyl chloride (305.4 g, 1324.6 mmol) was dissolved in dichloromethane (300 mL). The dinitrobenzoyl chloride stream was then added to the alcohol stream over approximately 15 minutes, maintaining the internal temperature below approximately 5°C. The combined mixture was aged for approximately 4 hours. The reaction mixture was allowed to warm to room temperature and then water (600 mL) was added and the phases were stirred vigorously to ensure good mixing of the phases. The mixture was allowed to settle, and the bottom phase was separated and washed twice with additional water (600mL). Silica gel (200g) was loaded to the final organic phase, and the slurries were allowed to age at room temperature for about 30 minutes. The slurries were filtered and the silica gel cake was washed with 20vol% isopropyl alcohol in heptane (the amount of the washing solution was determined by eluting with 4x silica gel pad volume). The filtrate and washings merged were concentrated to a volume of about 200mL by rotary evaporation. Isopropyl alcohol (600mL) was loaded into the concentrated stream and distilled to a volume of about 200mL by rotary evaporation. This process was repeated until ^1H NMR observed less than 5% dichloromethane compared with isopropyl alcohol. Heptane was then loaded into the reaction mixture to reach a final volume of about 500mL. The mixture was then heated to an internal temperature of about 45°C. Then crystallization was carried out using 0.5wt% (500mg) of ester M3 seed crystals. The reaction was then cooled to about 0°C through about 5h and aged at this temperature for at least about 12h. The resulting slurry was filtered and the filter cake was washed with hepatane (100 mL). The isolated solid material was then dried under vacuum at approximately 21° C. to provide M3. ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.22-9.21 (m, 1H), 9.11-9.10 (m, 2H), 5.95-5.85 (m, 1H), 5.17-5.05 (m, 2H), 4.27-4.24 (m, 1H), 2.22-2.07 (m, 2H), 1.41-1.33 (m, 1H), 1.14-1.09 (m, 1H), 0.85-0.80 (m, 1H); HRMS calc`d C ₁₃ H ₁₃ N ₂ O ₆ [M+H] ⁺ : 293.0774 Found: 293.0777.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases (e.g., diisopropylethylamine, N-methylmorpholine) and other solvents (e.g., chloroform, tetrahydrofuran, MTBE, 2-methyltetrahydrofuran, cyclopentyl methyl ether) may be used.

M3 is hydrolyzed to M1

M3 (100.0 g, 342.2 mmol) was loaded into the reaction vessel and dissolved in tetrahydrofuran (300 mL). Sodium hydroxide (300 mL of 1.0 M aqueous solution) was loaded thereto and the resulting mixture was stirred at room temperature for about 1 h. Toluene (200 mL) was loaded into the reaction, followed by HCl (120 mL of 1.0 M aqueous solution). The phases of the resulting two-phase mixture were separated and the organic phase was washed with sodium bicarbonate (120 mL of a 5 wt% aqueous solution). The phases were separated again and the organic layer was washed twice with water (200 mL). The final organic phase was washed with brine (200 mL of a 10 wt% aqueous solution), dried with MgSO ₄ and then filtered. The final alcohol M1 solution was used in subsequent steps without further purification.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases (e.g., potassium hydroxide, tetrabutylammonium hydroxide) and other solvents (e.g., 2-methyltetrahydrofuran, MTBE, toluene) may be used.

Synthesis of O from M1

The reaction vessel was loaded with a toluene solution of alcohol M1 (the amount of solution loaded was determined by using ¹ H NMR to obtain the wt% of the alcohol in the solution and then loading the amount required to obtain 28.0 g, 285.3 mmol of alcohol M1 in the reaction). Pyridine (29.3 g, 370.9 mmol) was loaded therein, followed by N, N′-disuccinimidyl carbonate (116.9 g, 456.5 mmol). The resulting heterogeneous reaction mixture was heated to 45° C. and stirred at this temperature for 4 h. The reaction was then cooled to room temperature and water (170 mL) was added. The mixture was stirred at room temperature for 30 min and then phase separated. The final toluene solution was used in the subsequent step without further purification. In this way, O (52.9 g, determined by ¹ H NMR wt% analysis, 221.3 mmol, 77.6%) was synthesized.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases (e.g., diisopropylamine, triethylamine, diisopropylethylamine) and other solvents (e.g., xylenes, chlorobenzene, MTBE) may be used. Furthermore, temperatures in the range of about 0°C to about 110°C may be used.

Synthesis of VII from O

The reaction vessel was charged with a toluene solution of carbonate O (the amount of solution charged was determined by using ¹ H NMR to obtain the wt% carbonate in the solution and then charging the amount required to have 9.9 g, 41.4 mmol, of carbonate O in the reaction). Additional toluene was charged to the reaction to bring the final reaction volume to 60 mL. Diisopropylethylamine (10.7 g, 82.8 mmol) and L-tert-leucine (6.0 g, 45.52 mmol) were charged to this solution. The reaction mixture was heated to approximately 45°C and stirred at this temperature for approximately 6 hours. The reaction was then cooled to room temperature and charged with hydrochloric acid (60 mL of a 3N aqueous solution). The two-phase mixture was stirred at room temperature for approximately 30 minutes and then phase separated. The organic-rich stream was then concentrated to approximately 20 mL by rotary evaporation and 80 mL of acetonitrile was subsequently added. The stream was concentrated to 20 mL and then further acetonitrile was added until the amount of toluene was approximately <5% v/v. The final stream was adjusted to a volume of 80 mL using acetonitrile and heated to approximately 50°C. The mixture was then heated to approximately 50°C and loaded with (S)-phenylethylamine (6.0 g, 49.7 mmol as a solution in 30 mL of acetonitrile at 50°C). The reaction mixture was seeded with 0.5 wt% crystals of VII (0.05 g) and the dilute slurry was aged at 50°C for 1 hour. The mixture was then cooled to room temperature over approximately 3 hours and the resulting slurry was aged for at least approximately 12 hours. The solid material was collected by filtration and the filter cake was washed with approximately 20 mL of acetonitrile. The final wet cake was dried in a vacuum oven at approximately 40°C to provide VII.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases (e.g., potassium carbonate, sodium carbonate, potassium phosphate) and other solvents (e.g., dimethylformamide, dimethylacetamide) may be used. Furthermore, other salt-forming amines (e.g., (R)-phenylethylamine, D-phenylalaninol, (1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, (S)-(+)-2-phenylglycinol) may be used.

D. Synthesis of (1R,2R)-1-amino-2-(difluoromethyl)-N-((1-methylcyclopropyl)sulfonyl)cyclopropane-1-carboxamide hydrochloride (XII)

The existing process pathway shown above is disclosed in U.S. Publication No. 2014-0017198. The pathway shown below proceeds through a common known intermediate V-v. The intermediate V-v is synthesized using two alternative schemes. In the first scheme, racemic A-b is selectively hydrolyzed to racemic (±)-A-c, with a cis/trans diastereomer ratio of approximately 10:1. This monoacid undergoes classical resolution with a chiral amine to form chiral A-c as a salt. Recrystallization can be performed to enhance enantiomeric excess. The carboxylic acid is then converted to an amide A-d and separated. In the telescoping step, the amide undergoes a Hoffman rearrangement, hydrolyzed to an amine, and the amine is protected with Boc and hydrolyzed with a methyl ester to form the desired amino acid, V-v. V-v is then converted to XII as shown in the above scheme.

Intermediate V-v is used in the first alternative for the synthesis of XII

Synthesis of (1S,2R)-2-(difluoromethyl)-1-(isopropoxycarbonyl)cyclopropane-1-carboxylic acid (A-c)

Synthesis of (1S,2R)-2-(difluoromethyl)-1-(isopropoxycarbonyl)cyclopropane-1-carboxylic acid (B)

Step 1: Synthesis of intermediate Z

A reactor was charged with difluoroacetaldehyde ethyl hemiacetal Y (100 g, 0.79 mole), cyclopentyl methyl ether (CPME, 500 mL, 5 mL/g), and diisopropyl malonate (150 mL, 1 eq.). To the resulting solution, maintained at approximately 20°C, was added triethylamine ( _Et₃N , 100 mL, 1 mL/g). The mixture was warmed to approximately 35°C and stirred for approximately 20 hours. Upon completion of the reaction, a small sample was taken from this CPME solution of alcohol Z and washed _with 1 M aq. _KH₂PO₄ until the pH dropped to ~7, followed by a brine wash. The organic layer was dried over _MgSO₄ and concentrated to dryness in vacuo. The residue was purified by column chromatography on silica gel using a gradient of 0% to 25% MTBE in hexane to provide a clean sample of alcohol Z. ¹ H NMR (300MHz, CDCl ₃ ): δ1.275-1.30(m,12H),3.63(d,J＝4.5Hz,1H),3.95(d,J＝7.8Hz,1H),4.32-4.45(m,1H),5.06-5.20(m,2H)and 5.93(dt,J=55.4Hz and 4.2Hz). ¹⁹ F NMR (282MHz, CDCl ₃ ): δ-129.0 (m). LCMS: (m/z) 291.1(M+Na), 269.1(M+H).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other ether solvents (e.g., THF, MeTHF, or MTBE) may be used. Additionally, temperatures in the range of about 0°C to about 60°C may be used. Additionally, other organic amines (e.g., DIPEA) and malonate analogs (e.g., methyl esters, ethyl esters, benzyl esters, and various other esters) may be used.

Step 2: Synthesis of intermediate A-a from Z:

The CPME solution of alcohol Z was cooled to approximately 20°C, followed by the addition of acetic anhydride ( _Ac₂O , 200 mL, 2 mL/g) and 4-(dimethylamino)pyridine (DMAP, 4.83 g, 0.05 eq.), which resulted in an exotherm reaching a maximum of approximately 50°C. The resulting solution was stirred at approximately 20°C for approximately 20 hours. Upon completion of the reaction, 1M aq. _K₂HPO₄ (1.0 L, 10 mL/g) was _added , resulting in an exotherm. After 15 minutes, the layers were separated. The CPME layer was washed with 1M aq. _{K₂HPO₄ (} 500 mL, 5 mL/g), _a 1:1 mixture of 1M aq _{. K₂HPO₄} and 1M aq. _KH₂PO₄ (100 mL), and brine (500 mL, 5 mL/g). CPME (500 mL, 5 mL/g) was added to the CPME solution and the volume was reduced to ~400 mL (4 mL/g) by vacuum distillation. A small sample was taken from this CPME solution of alkene Aa and the solution was concentrated to dryness in vacuo. The residue was purified by column chromatography on silica gel using a 0% to 15% MTBE in hexanes gradient to provide a clean sample of alkene Aa. ^1H NMR (300 MHz, CDCl ₃ ): δ 1.25-1.29 (m, 12H), 5.06-5.21 (m, 2H), 6.50 (dt, J=54.6 Hz and 5.72 Hz) and 6.67-6.75 (m, 1H). ^19F NMR (282 MHz, CDCl ₃ ): δ -114.4 (m). GCMS: (m/z) 251 (M+H).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other ethereal solvents (e.g., THF, MeTHF, or MTBE) or non-ethereal solvents (e.g., toluene) may be used. Additionally, strong organic bases (e.g., DBU) may be used. Additionally, other activated groups (e.g., trifluoromethanesulfonic anhydride, methanesulfonyl chloride, or toluenesulfonyl chloride) and temperatures in the range of about 0°C to about 60°C may be used.

Step 3: Synthesis of A-b from A-a:

The reactor was charged with trimethylsulfoxide iodide ( _Me₃SOI , 200 g, 1.15 eq.), potassium tert-butoxide (KOtBu, 97.5 g, 1.0 eq.), and dimethylsulfoxide (DMSO, 500 mL, 5 mL/g). The resulting suspension was stirred at approximately 25°C for approximately 4 hours, after which a clear solution formed. To this DMSO solution, a solution of olefin C in CPME was slowly added at a rate that did not exceed approximately 55°C. The resulting suspension was stirred at approximately 25°C overnight. The temperature was lowered to approximately 20°C, followed by the addition _of 1 M aq. _H₂SO₄ (1.0 L, 10 mL/g), which resulted in an exotherm. After 15 minutes, the layers were separated. To the organic layer were added CPME (400 mL, 4 mL/g) and 10% aq _{. K₂CO₃} (500 mL, 5 mL/g). The layers were separated. The organic layer was washed with water (250 mL, 2.5 mL/g), followed by the addition of CPME (200 mL, 2 mL/g) and the volume reduced to ~500 mL (~5 mL/g) by vacuum distillation. Charcoal (5.0 g, 0.05 g/g) was added to the resulting suspension. The resulting suspension was filtered through celite and then washed with CPME (200 mL, 2 mL/g). A small sample was taken from the CPME solution of cyclopropane Ab and concentrated to dryness in vacuo and analyzed. The residue was purified by column chromatography on silica gel using a gradient of 0%-15% MTBE in hexane to provide a clean sample of cyclopropane Ab. ¹ H NMR (300MHz, CDCl ₃ ): δ1.24-1.30(m,12H), 1.46-1.51(m,1H), 1.69-1.74(m,1H), 2.26-2.40(m,1H), 5.01-5.14(m,2H) and 5.68(dt,J=56.0Hz and 5.1Hz). ¹⁹ F NMR (282MHz, CDCl ₃ ): δ-114.1 (m). GCMS: (m/z)223(M+H). LCMS: (m/z)287.1(M+Na), 265.1(M+H).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, mixtures of DMSO with other aprotic solvents (e.g., THF, MeTHF, or MTBE) and temperatures in the range of about 0° C. to about 60° C. may be used. In addition, strong bases such as NaH may be used.

Step 4: Synthesis of intermediate A-c from A-b:

Synthesis of (1S,2R)-2-(difluoromethyl)-1-(isopropoxycarbonyl)cyclopropane-1-carboxylic acid (A-c)

A solution of cyclopropane Ab in CPME was diluted with isopropyl alcohol (IPA, 800 mL) and the volume was reduced to ~400 mL by vacuum distillation. The resulting solution was cooled to approximately -3°C, followed by the addition of 35% aqueous tetraethylammonium hydroxide ( _Et₄NOH , 266 mL, 0.80 eq.) at a rate such that the temperature did not exceed approximately 0°C. The reaction mixture was stirred overnight. 1M aq. HCl (200 mL) was slowly added at a rate such that the temperature did not exceed approximately 5°C, followed by the addition of water (400 mL). The temperature was raised to approximately 15°C, and CPME (200 mL) was added. The layers were separated. The pH of the aqueous layer was checked and confirmed to be ~6.5. The CPME layer _was extracted with 0.5M aq. _K₂CO₃ (100 mL). The two aqueous layers were combined, followed by the addition _of concentrated _H₂SO₄ (20 mL), which lowered the pH to ~2. CPME (400 mL) was then added, and the layers were separated. The CPME was extracted twice with 0.5M aq _{. K₂CO₃} . The two aqueous layers were combined and acidified to pH ~2 with H ₂ SO ₄ (20 mL). CPME (500 mL) was then added. The layers were separated. The CPME layer was washed with water (250 mL) and then CPME (400 mL) was added. The volume was reduced to ~500 mL by vacuum distillation. Activated carbon (5.0 g) was now added and the resulting suspension was filtered through celite and then washed with CPME (100 mL). The volume was again reduced to ~500 mL by vacuum distillation. A small sample was taken from this CPME solution of half ester/acid (±)-Ac and the CPA salt was formed. Solid material was obtained by filtration. The solid material was suspended in CPME and 1M aq. NaOH. After all the solid material had dissolved, the layers were separated. The aqueous layer was acidified to pH ~2 with concentrated H ₂ SO ₄ and the half ester/acid (±)-Ac was extracted into CPME. The solution was concentrated to dryness in vacuo to provide a clean sample of half ester/acid (±)-Ac. ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.31 (d, J = 6.3 Hz, 5H), 1.91-1.98 (m, 2H), 2.52-2.59 (m, 1H), 5.15-5.24 (m, 2H) and 5.80 (dt, J = 55.7 Hz and 6.3 Hz). ¹⁹ F NMR (282 MHz, CDCl ₃ ): δ -111.9 (m). LCMS: (m/z) 443.0 (2M-H), 220.9 (MH).

To a solution of the half-ester/acid (±)-Ac in CPME was added (R)-(+)-1-(4-methylphenyl)ethanamine (62.5 mL, 0.55 eq.), resulting in an exotherm. Next, seed crystals of Ac (100 mg) in heptane (20 mL) were added, followed by heptane (500 mL, 5 ml/g). After the suspension thickened, the temperature rose to approximately 50°C. After stirring overnight, the temperature was lowered to approximately 25°C over approximately 5 hours. The temperature was then lowered to 0-5°C and maintained at this temperature for approximately 1 hour. The solid material was collected by filtration and washed with 33% CPME in heptane (250 mL, 2.5 mL/g). The solid material was dried in a vacuum oven at approximately 40°C to constant weight to provide the salt of the half-ester/acid Ac. This material was suspended in CPME (500 mL, 10 mL/g) and heated to approximately 70°C, at which point a clear solution was obtained. The solution was cooled to approximately 65°C, and seed crystals were then added. The resulting suspension was cooled to about 50° C. over about 3 hours. The resulting thick suspension was kept at about 50° C. overnight. The temperature was lowered to about 30° C. over about 4 hours, then lowered to 0° C.-5° C. and maintained at that temperature for about 1 hour. The solid material was obtained by filtration and then washed with 50% CPME in heptane (100 mL). The solid material was dried in a vacuum oven at about 40° C. to constant weight to provide the salt of the half ester/acid Ac. ¹ H NMR (300MHz, DMSO-d ₆ ): δ1.08-1.17(m,7H),1.44(d,J＝6.3Hz,3H),1.86-1.90(m,1H),2.30(s,3H),4.23-4.30(m,1H), 4.81-4.89 (m, 1H), 5.70 (dt, J = 56.3Hz and 6.0Hz, 1H), 7.20 (d, J = 7.5Hz, 2H) and 7.35 (d, J = 7.5Hz, 2H). ¹⁹ F NMR (282MHz, DMSO-d ₆ ): δ-111.4 (m).

The two mother liquors were combined and extracted twice _with 0.5 M aq. _K₂CO₃ (500 mL). The two aqueous layers were combined and acidified to pH ~ ₂ with _H₂SO₄ (30 mL, 0.3 mL/g) at a rate such that the temperature did not exceed approximately 30°C. CPME (500 mL) was then added and the layers separated. The CPME layer was washed with water (250 mL). CPME (600 mL) was then added and the volume was reduced to ~500 mL by vacuum distillation. Charcoal (5.0 g) was then added and the resulting suspension was filtered through celite, followed by rinsing with CPME (100 mL). The volume of the filtrate was reduced to ~500 mL by vacuum distillation. (S)-(-)-1-(4-methylphenyl)ethanamine (51 mL, 0.45 eq.) was then added, resulting in an exotherm. Seed crystals (100 mg) were added to the resulting solution, followed by heptane (500 mL). After about 1 hour, the resulting suspension was heated to about 60° C. After about 1.5 hours, the temperature was lowered over about 1 hour to about 50° C. The resulting suspension was maintained at about 50° C. overnight.

The temperature was reduced to about 25°C over about 5 hours. The temperature was further reduced to about 0°C-about 5°C and maintained at this temperature for about 1 hour. The solid material was collected by filtration and washed with 33% CPME in heptane (200mL). The solid material was dried to constant weight in a vacuum oven at about 40°C to provide a salt of half ester/acid Ac. The material was suspended in CPME (500mL) and heated to about 75°C, at which point a clear solution was obtained. The solution was cooled to about 65°C, followed by the addition of seed crystals. The resulting suspension was cooled to about 50°C over about 5 hours. The resulting thick suspension was maintained at about 50°C overnight. The temperature was then reduced to about 30°C over about 4 hours, followed by the temperature being reduced to 0°C-5°C and maintained at this temperature for about 1 hour. The solid material was obtained by filtration and then washed with 50% CPME in heptane (110mL). The solid material was dried to constant weight in a vacuum oven at about 40°C to provide a salt of half ester/acid Ac. ¹ HNMR (300MHz, DMSO-d ₆ ): δ1.08-1.17(m,7H),1.44(d,J＝6.3Hz,3H),1.86-1.90(m,1H),2.30(s,3H),4.23-4.30(m,1H), 4.81-4.89 (m, 1H), 5.70 (dt, J = 56.3Hz and 6.0Hz, 1H), 7.20 (d, J = 7.5Hz, 2H) and 7.35 (d, J = 7.5Hz, 2H). ¹⁹ F NMR (282MHz, DMSO-d ₆ ): δ-111.4 (m).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other alcohol solvents that match the residual ester may be used. Additionally, other soluble hydroxides in IPA (e.g., KOH) and additional phase transfer catalysts (e.g., tetrabutylammonium hydroxide) may be used. Furthermore, other chiral amines (which produce crystalline salts of the appropriate product stereoisomer) and temperatures in the range of about -20°C to about 60°C may be used.

Synthesis of V-v from A-c

Synthesis of A-d from A-c

The salt of the half-ester/acid Ac (35 g, 97.9 mmol) was suspended in CPME (105 mL) and 1 M aq. HCl (105 mL). The resulting suspension was stirred until all solid material dissolved. The layers were separated, and the CPME layer was washed with 1 M aq. HCl (35 mL) and brine (70 mL), then dried _{over Na₂SO₄} and concentrated in vacuo. 1,1'-Carbonyldiimidazole (CDI, 19.9 g, 1.25 eq.) was slowly added to the resulting solution at a rate that controlled off-gassing. The reaction mixture was stirred for 1 hour, during which time a precipitate formed. 28% aqueous ammonium hydroxide ( _NH₄OH , 35 mL, 2.86 eq.) was then added. The reaction mixture was stirred overnight. The next morning, the layers were separated, and the CPME layer was washed with 0.5 M aq _{. H₂SO₄} (105 mL), 0.5 M aq _{. K₂CO₃} (105 mL), and brine (70 mL), respectively. The CPME solution was dried over MgSO ₄ and concentrated to dryness in vacuo to afford the crude amide Ad. GCMS: 221 (M+).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, ethereal solvents (e.g., THF, MeTHF, or MTBE) and temperatures in the range of about 0°C to about 60°C may be used. In addition, other ammonia sources (e.g., liquid ammonia) may be used. In addition, other activating agents, such as any peptide coupling agent (e.g., T3P) or chlorinating agents (e.g., thionyl chloride) may be used.

Synthesis of A-e from A-d

The crude amide Ad was dissolved in methanol (MeOH, 262 mL, 7.5 mL/g) and trichloroisocyanuric acid (TCCA, 8.65 g, 0.38 eq.) was added, followed by the slow addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 35 mL, 2.4 eq.) at a rate such that the temperature did not exceed 40°C. After approximately 1 hour, the temperature was raised to approximately 65°C and the reaction mixture was maintained at this temperature for 20 hours. The MeOH was then removed by vacuum distillation. The residue was diluted with isopropyl acetate (IPAC, 175 mL) and 1M aq. KH ₂ PO ₄ (175 mL). After vigorous stirring for 15 minutes, the solid material was removed by filtration through celite and then washed with IPAC (35 mL). The layers of the filtrate were separated. The IPAC layer was washed with brine (70 mL, 2 mL/g), then dried over MgSO ₄ and concentrated to dryness in vacuo to provide the carbamate Ae. GCMS: 223 (M+).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, mixtures of other methanol with aprotic solvents (e.g., THF, MeTHF, or MTBE) and temperatures in the range of about 0° C. to about 60° C. may be used. In addition, other halogenated solvents (e.g., chlorine, bromine, NBS, or NCS) and strongly hindered organic bases (e.g., DIPEA) may be used.

Synthesis of A-f from A-e:

The residue containing crude carbamate Ae was dissolved in isopropyl acetate (70 mL), followed by the addition of di-tert-butyl dicarbonate (Boc ₂ O, 21.4 g, 1.0 eq.) and DMAP (598 mg, 0.05 eq.). The reaction mixture was stirred for approximately 20 hours. The reaction mixture was concentrated to dryness in vacuo to provide biscarbamate Af. GCMS: 257 (M-tBu), 223 (M-Boc).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, aprotic solvents (e.g., THF, MeTHF, MTBE, or toluene) and temperatures in the range of about 0° C. to about 60° C. may be used. Additionally, hindered organic bases (e.g., DIPEA) may be used.

Synthesis of V-v from A-f

The residue containing the biscarbamate Af was dissolved in IPA (100 mL, 2.5 mL/g), followed by the addition of 2M aq. KOH (100 mL). After stirring overnight, 2M aq. HCl (100 mL) and subsequently CPME (100 mL) were added. The layers were separated. The CPME layer was extracted twice with 1M aq. NaOH (35 mL). The two aqueous layers were combined, followed by the addition of IPA (70 mL) and 1M aq. HCl (70 mL). After stirring overnight, the resulting suspension was filtered and the solid material (racemic Vv) was washed with 50% aq. IPA (35 mL). The filtrate was extracted with IPAC (100 mL). The IPAC layer was dried over Na ₂ SO ₄ and concentrated to dryness in vacuo. The residue was dissolved in heptane and concentrated to dryness in vacuo. The residue was dissolved in THF (25 mL) and 1 M aq. NaOH (25 mL), followed by the addition of Boc ₂ O (21.4 g, 1.0 eq.). The reaction mixture was stirred overnight. The next morning, IPAC (25 mL) and water (25 mL) were added. The layers were separated. The IPAC layer was extracted with 0.5 M aq. _{K 2} CO ₃ (12.5 mL). The two aqueous layers were combined and IPAC (25 mL) was added, followed by acidification to pH ~2 with 1 M aq. HCl. The layers were separated. The IPAC layer was washed with water (25 mL). The IPAC layer was then dried over Na ₂ SO ₄ and concentrated to dryness in vacuo. The residue was dissolved in IPAC (10 mL) and hexane (200 mL) was slowly added. The resulting suspension was stirred for several hours. The solid material was collected by filtration, washed with hexane and dried in a vacuum oven at approximately 40° C. to provide Vv (6.8 g).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other alcohol solvents (e.g., methanol or ethanol) and temperatures in the range of about 0° C. to about 60° C. may be used. Additionally, other hydroxide sources (e.g., LiOH or tetrabutylammonium hydroxide) may be used.

In the second alternative, racemic A-b is selectively hydrolyzed to racemic (±)-A-c. This monoacid (±)-A-c forms salt A-g with dicyclohexylamine. This salt is then free-based and subjected to classical resolution by conversion to cinchonidine salt A-h. Curtius rearrangement of A-h followed by hydrolysis provides intermediate V-v, which is then converted to XII as shown in the above scheme.

Second Alternative for the Synthesis of Intermediates V-v of XII

A-b is hydrolyzed to (±)-A-c

Isopropyl alcohol (250 mL) was added to the solution of Ab, and the solution was cooled to between about -15 and -10°C. Tetraethylammonium hydroxide (35 wt% in H ₂ O, 365.2 g, 0.88 mole, 2.2 equiv) was added over at least about two hours, maintaining the temperature below about -10°C. The mixture was stirred between about -15 and -10°C for about 12 hours until the reaction was complete, and toluene (250 mL) and water (200 mL) were added, maintaining the temperature below about 0°C. The mixture was stirred at about -5 to 0°C for about 15 minutes, and then warmed to about 20°C to about 25°C. The mixture was stirred at about 20°C to about 25°C for about 15 minutes, and the phases were allowed to separate for 30 minutes.

The aqueous layer was transferred to a second reactor and toluene (150 mL) was added. This mixture was stirred at about 20°C to about 25°C for about 15 minutes and the phases were allowed to separate for about 30 minutes. The phases were separated and toluene (400 mL) was added to the aqueous layer. The mixture was cooled to about 10°C and 50% aq. H ₂ SO ₄ (ca. 20 mL) was added, maintaining the temperature below about 15°C until a pH of about 2-3 was reached. This mixture was stirred at about 10°C for about 15 minutes and the phases were allowed to separate for about 30 minutes. The organic layer was analyzed and the volume was reduced from 550 mL to 80 mL by vacuum distillation at about 40°C to about 45°C to provide Ac.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other bases (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, tetrabutylammonium hydroxide, tetramethylammonium hydroxide, tetrapropylammonium hydroxide, dipotassium hydrogen phosphate, potassium carbonate, sodium carbonate) may be used. Additionally, other solvents (e.g., cyclopentyl methyl ether, methyl tert-butyl ether, dichloromethane, chloroform, chlorobenzene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methanol, ethanol, tert-butanol) may be used. Furthermore, temperatures in the range of about -15°C to about -10°C may be used.

Synthesis of A-g from (±)-A-c

Toluene (54 mL) was added to the above toluene solution. Dicyclohexylamine (26.2 g, 140 mmol, 0.36 equiv) was then added, maintaining the temperature below about 40°C. The mixture was heated to 75°C until dissolution was achieved. The mixture was cooled to about 65°C to allow crystallization, then stirred at about 65°C for about 30 minutes, and then cooled to about 0°C over three hours. The slurry was stirred at about 0°C for about two hours and then filtered. The filter cake was washed three times with 10:1 heptane:toluene (20 mL), and the solid material was dried under vacuum at about 40°C to provide Ag. ^1H NMR (400 MHz, CDCl ₃ ): δ 1.18-1.26 (m, 12H), 1.28-1.33 (m, 1H), 1.39-1.48 (m, 5H), 1.65 (d, J=8 Hz, 2H), 1.79 (d, J=12 Hz, 4H), 1.99 (d, J=11.6 Hz, 4H), 2.1-2.2 (m, 1H), 2.95 (tt, J=8 Hz and 3.6, 2H), 5.03 (septet, J=6 Hz, 1H), 5.63 (td, J=56.4 and 5.6, 1H). ^19F NMR (376 MHz, CDCl ₃ ): δ -113 (ddd, J=2326 Hz, 285 Hz and 8.3 Hz).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other solvents (e.g., dichloromethane, chloroform, chlorobenzene, methyl tert-butyl ether, cyclopentyl methyl ether, 2-methyltetrahydrofuran, hexane, cyclohexane) may be used.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other solvents (e.g., dichloromethane, chloroform, chlorobenzene, MTBE, cyclopentyl methyl ether, 2-methyltetrahydrofuran, hexane, cyclohexane) may be used.

Synthesis of A-h from A-g

Solid Ag (444.8 g, 1.10 mol) was loaded into a 5-L reactor under _N₂ . Methyl isobutyl ketone (MIBK, 2200 _L ) was added, followed by 1 M _H₃PO₄ (2200 mL), and the layers were stirred for approximately 15 minutes and separated. The organic layer was washed with water (1 L). The reaction contents were concentrated by distillation of ~500 mL of solvent (including _H₂O ). The solution was filtered through celite.

Cinchonidine (304.5 g, 1.03 moles, 1.0 equiv.) was added to a reactor along with MIBK (2500 ml). To this suspension was added a solution of (±)-A-c in 2000 ml of MIBK. The reaction mixture was heated to approximately 50°C. A-h (534 mg, 0.1 wt%) was added as a seed, and the mixture was then subjected to the following temperature program: approximately 50°C for approximately 1 hr, heated to approximately 60°C over approximately 30 minutes, aged at approximately 60°C for approximately 3 hours, cooled to approximately 58°C over approximately 4 hours, cooled to approximately 50°C over approximately 4 hours, cooled to approximately 40°C over approximately 2 hours, cooled to approximately 20°C over approximately 2 hours, and held at approximately 20°C for approximately 2 hours. The slurry was filtered. The filter cake was washed with MIBK (400 ml). The material was dried in a vacuum oven.

The resulting solid material was added to a 5-L reactor under _N₂ , followed by MIBK (1438 mL, 7 V) and methanol (144 mL, 0.7 V). The resulting slurry was heated to approximately 60°C to obtain a solution, which was then seeded with 0.1 wt% Ah. The light suspension was maintained at approximately 60°C for approximately three hours, then parabolicly cooled to approximately 20°C and maintained at approximately 20°C for approximately five hours. Next, MIBK (200 mL, 1 V) was added, and the slurry was vacuum distilled to approximately 6.5-7 V to remove MeOH. Once the MeOH content was below 0.5%, the slurry was cooled to approximately 5°C over approximately 2.5 hours and maintained at approximately 5°C for approximately 1 hour. The slurry was filtered, and the filter cake was washed three times with MIBK (150 mL, 0.7 V). The material was dried in a vacuum oven to provide Ah. ¹ H NMR (400MHz, CDCl ₃ ): δ1.24(t,J＝6Hz,7H),1.41-1.45(m,1H),1.52(t,J＝5.6Hz,1H),1.70-1.80(m,1H), 2.02(m,1H),2.10(m,1H),2.20-2.30(m,1H),2.60(bs,1H),3.03(td,J＝13.6Hz and 4.4Hz 1H), 3.10-3.16 (m, 1H), 3.33 (dt, J = 10.4 Hz and 3.2 Hz, 2H), 4.30 (m, 1H), 4.98-5.00 (m, 1H), 5.08 (septet, J = 6.4 Hz, 1H), 5.48-5.55 (m, 1H), 5.69 (td, J = 56.8 Hz and 5.2 Hz, 1H), 6.26 (s, 1H), 7.46 (t, J = 8 Hz, 1H), 7.63 (t, J = 8 Hz, 1H), 7.69 (d, 4.4 Hz, 1H), 7.92 (d, 8.4 Hz, 1H), 8.03 (d, J = 8 Hz, 1H), 8.86 (d, J = 4.4 Hz, 1H). ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ-113 (ddd, J=2435 Hz, 286 Hz and 7.1 Hz).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other acids (e.g., sulfuric acid) may be used and other solvents (e.g., isopropyl acetate, MTBE) may be used.

Curtis rearrangement of A-h to give A-i

A reaction vessel was charged with Ah (200 g, 387 mmol) and 15% aq _{. H₃PO₄} (800 mL, 4 mL/g). MTBE (400 mL, 2 mL/g) was added to the resulting suspension, and an exotherm from approximately 22°C to approximately 25°C was observed. Within approximately 5 minutes, all solid material dissolved. After approximately 15 minutes, stirring was stopped, and the layers were allowed to separate for approximately 10 minutes. The bottom layer (~880 mL; pH ~2.5; aq. layer 1) was removed. Stirring was resumed, and water (400 mL, 2 mL/g) was added. After approximately 15 minutes, stirring was stopped, and the layers were allowed to separate for approximately 10 minutes. The bottom layer (~400 mL; pH ~2.5; aq. layer 2) was removed. Stirring was resumed, and toluene (400 mL, 2 mL/g) was added. The volume was reduced to 300 mL under vacuum (1.5 mL/g; 40 Torr, jacket temperature approximately 50° C. -575 mL distillate; Distillate 1). The KF was checked and deemed acceptable (32 ppm; <100 ppm).

A reaction vessel was charged with DMAP (94.5 g, 774 mmol, 2 equiv.) and toluene (300 mL, 1.5 mL/g), followed by the addition of DPPA (125 mL, 581 mmol, 1.5 eq.). The resulting suspension was heated to approximately 85°C. The hazy product in the toluene solution was polish filtered into the hot DMAP/DPPA suspension at a rate to maintain the temperature between approximately 80°C and approximately 100°C. This was then rinsed with toluene (100 mL, 0.5 mL/g). Upon completion of the addition, the reaction contents were cooled to approximately 80°C to approximately 83°C. t-BuOH (65.5 mL, 774 mmol, 2 equiv.) was added. The reaction mixture was aged at approximately 75°C to approximately 80°C for approximately 6 hours. The reaction mixture was cooled to approximately 20°C, followed by the addition of water (400 mL, 2 mL/g), which resulted in an exotherm reaching a maximum of approximately 23°C. Stirring was discontinued after approximately 15 minutes, and the layers were allowed to separate for approximately 15 minutes. Remove the bottom layer (~600 mL, pH ~9; aq. layer 3). Resume stirring and add water (200 mL, 1 mL/g). After approximately 10 minutes, stop stirring and allow the layers to settle for approximately 10 minutes. Remove the bottom layer (~200 mL, pH ~9; aq. layer 4). Resume stirring and reduce the volume to 300 mL (1.5 mL/g) by distillation. Cool the resulting solution to approximately 20°C.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other acids (e.g., sulfuric acid) and other bases (e.g., diisopropylethylamine, triethylamine) may be used. Furthermore, temperatures in the range of about 70°C to 100°C may be used.

A-i is hydrolyzed to V-v

The reaction vessel was charged with MeOH (300 mL, 1.5 mL/g) and powdered KOH (43.4 g, 774 mmol, 2 equiv). After the exotherm subsided, the resulting cloudy solution was added to a two-liter reactor, which resulted in an exotherm to approximately 40° C. The reaction was deemed complete after approximately 3 hours.

At this point, 15% aq. _H₃PO₄ (600 mL, 3 mL/g) was _added , resulting in an exotherm reaching a maximum of approximately 32°C and a pH of approximately 2.5. After approximately 10 minutes, the resulting suspension was filtered and then washed with MTBE (200 mL, 1 mL/g). The filtrate was stirred for approximately five minutes, after which stirring was stopped. The layers were allowed to separate for approximately five minutes. The bottom layer (~900 mL, pH ~2.5; aq. layer 5) was removed. Stirring was resumed and water (200 mL, 1 mL/g) was added. After approximately five minutes, stirring was stopped and the layers were allowed to separate for approximately 5 minutes. The bottom layer (~250 mL, pH ~2.5; aq. layer 6) was removed. Stirring was resumed and toluene (400 mL, 2 mL/g) was added. The volume was reduced to 300 mL (1.5 mL/g) by distillation. The resulting solution was stirred at approximately 20°C and formed a suspension within approximately 1 hour. After approximately 3 hours, heptane (300 mL, 1.5 mL/g) was slowly added over approximately 30 minutes. The resulting suspension was stirred overnight and then cooled to approximately 5°C. A solid was obtained by filtration. The mother liquor was used for washing and the wash was added to the filter cake. After the filter cake was pulled dry, a wash of 40% toluene in heptane (100 mL, 0.5 mL/g) was added to the filter cake, which was then passed through the filter cake. The solid was dried in a vacuum oven at approximately 40°C to provide Vv. ^1H NMR (400 MHz, _CD3OD ): δ 1.43 (s, 10H), 1.64-1.80 (m, 1H), 1.89-2.00 (m, 1H), 5.87 (td, J = 53.6 Hz and 7.2 Hz, 1H). ^19F NMR (376 MHz, _CDCl3 ): δ -113 (m).

Route I: Assembly steps for obtaining the compound of formula I

A. Synthesis of compound of formula III (R=CH ₃ )

I. Free base and Boc-protection of II (R=CH ₃ ) to provide III (R=CH ₃ ):

II (10.1g, 29.3mmol, 1.00 equivalent) was mixed with dichloromethane (40mL) and the mixture was stirred at about 20-about 25°C. Triethylamine (8.36g, 82.6mmol, 3.00 equivalent) was added dropwise via a syringe, maintaining the reaction temperature at about 20°C-about 25°C. 4-dimethylaminopyridine (360mg, 2.95mmol, 0.1 equivalent) was added to the resulting solution, followed by a solution of di-tert-butyl dicarbonate (6.52g, 29.9mmol, 1.02 equivalent) in dichloromethane (40mL), while maintaining the reaction temperature at about 20°C-about 25°C. The mixture was stirred for about 2-4 hours and monitored for completion. Upon completion of the reaction, 100mL of 1.0N HCl was added dropwise while maintaining the reaction temperature below about 30°C. The biphasic mixture was stirred vigorously for about 15 minutes before allowing the layers to separate. The bottom organic layer was separated and washed sequentially with 5% wt/wt aqueous sodium bicarbonate solution (100 mL) and water (100 mL). The organic phase was concentrated under reduced pressure and dried in vacuo to provide III (R=CH ₃ ). ¹ H NMR (300 MHz, CD ₃ OD): δ 4.41 (d, J=6.0 Hz, 1H), 4.01-4.07 (m, 1H), 3.65-3.79 (m, 4H), 3.05-3.15 (m, 1H), 2.10-2.20 (m, 1H), 1.50-1.60 (m, 1H), 1.39-1.45 (app d, 9H), 1.10-1.20 (m, 2H), 0.99-1.08 (m, 3H). ¹³ C NMR (75MHz, CDCl ₃ ): δ 12.3, 21.3, 28.2, 50.5, 50.6, 51.4, 52.2, 61.8, 71.9, 80.2, 154.2, 171.9.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, an amine base (e.g., diisopropylethylamine or sodium hexamethyldisilazide), a carbonate (e.g., potassium carbonate or cesium carbonate), a bicarbonate (e.g., sodium bicarbonate), or an inorganic/organic hydroxide (e.g., sodium hydroxide or tetramethylammonium hydroxide) may be used. In addition, other Boc-delivery agents (e.g., BOC-ON═C(CN)Ph, BOC-ONH ₂ , 1,2,2,2-tetrachloroethyl tert-butyl carbonate, or 1-(tert-butoxycarbonyl)benzotriazole) and accelerators (e.g., imidazole or ultrasound) may be used. In addition, other organic solvents (toluene, acetonitrile or acetone), water, polar aprotics (e.g., N,N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO) or combinations of these with water), alcohols (e.g., methanol or ethanol), ethers (e.g., tetrahydrofuran, dioxane or methyl tert-butyl ether) or esters (e.g., ethyl acetate) may be used.

B. Synthesis of Compound V (R=CH ₃ )

II.IV reacts with the _SNAr of III(R=CH ₃ ) to form V(R=CH ₃ )

Under a nitrogen atmosphere, a reactor containing III (R = CH ₃ ) (1.00 equiv) in N,N-dimethylacetamide (6 volumes) was charged with IV (1.00 equiv) and cesium carbonate (1.20 equiv). The heterogeneous reaction was heated to about 100-110° C. with stirring. Upon completion of the reaction, the reaction mixture was then cooled to about 20° C. and charged with MTBE (10 volumes). The resulting mixture was washed twice with water (6 volumes), and the MTBE solvent was exchanged with isopropanol (6 volumes) by vacuum distillation. The solution was then heated to about 60° C. and water (3 volumes) was added over a buffered period of about 1.5 hours. Once the addition was complete, the mixture was held at about 60° C. for about 30 minutes. A small amount of V (R = CH ₃ ) (1-2 wt/wt %) was then added, after which the temperature was slowly cooled to room temperature over about 3 hours. The contents were then aged for at least about 12 hours, after which the slurry was filtered on a suitable filter. The wet cake was washed with 2:1 isopropanol/water (3.5 volumes), then washed twice with water (3.5 volumes) and dried in an oven under vacuum at approximately 40-45° C. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.93-7.90 (m, 1H), 7.25-7.22 (m, 1H), 7.20-7.16 (m, 1H), 5.95-5.85 (m, 1H), 5.44-5.38 (m, 1H), 5.25-5.21 (m, 2H), 4.54-4.52 (m, 1H), 4.47-4.40 (m, 1H), 3.97 (s, 3H) ,3.77(s,3H),3.43-3.39(m,1H),3.27-3.17(m,2H),2.79-2.68(m,1H),1.64-1.55( m,1H),1.44-1.43(m,9H),1.44-1.32(m,1H),1.10-1.06(m,3H).LCMS(M+1):521.97.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other inorganic bases (e.g., _sodium carbonate ( _Na2CO3 ), potassium carbonate ( _K2CO3 ), potassium tert- _butoxide (KOtBu), lithium tert-butoxide (LiOtBu), magnesium tert-butoxide (Mg(OtBu) ₂ ), sodium tert-butoxide (NaOtBu), sodium hydride (NaH), potassium hexamethyldisilazide (KHMDS), potassium phosphate ( _K3PO4 ), potassium hydroxide ( _KOH ), or lithium hydroxide (LiOH)) or organic bases (e.g., DABCO or DBU) may be used. Alternatively, an aprotic solvent (e.g., N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), acetonitrile (MeCN), or acetone) may be used in the presence of a phase transfer catalyst, an aprotic solvent with a small amount of water, an ether (e.g., tetrahydrofuran (THF) or 1,4-dioxane), or toluene. Furthermore, other additives (e.g., tetra-n-butylammonium bromide (TBAB), tetra-n-butylammonium iodide (TBAI), tetra-n-butylammonium chloride (TBACl), sodium iodide (NaI), or tetra-n-butylphosphonium bromide (TBPB)) and a temperature in the range of about 20° C. to about 120° C. may be used.

C. Synthesis of the tosylate salt of the compound of formula VI (R=CH ₃ )

Boc deprotection of IV (R=CH ₃ ) to provide VI (R=CH ₃ )

V(R=CH ₃ ) (50.0 g, 95.9 mmol, 1.00 equiv) was mixed with methyltetrahydrofuran (150 mL, 3.0 volumes) and the mixture was stirred at about 15-25° C., preferably about 20° C. p-Toluenesulfonic acid (45.6 g, 240 mmol, 2.50 equiv) in methyltetrahydrofuran (100 mL, 2.0 volumes) was added to the reaction mixture. Once the acid addition was complete, the contents were heated to about 50-60° C. and the reaction contents were stirred for about 3-5 hours. Upon completion of the reaction, MTBE (100 mL, 2 volumes) was slowly added to the slurry. The contents were then cooled to about 15-25° C., and the slurry was filtered and washed with a mixture of methyltetrahydrofuran (105 mL, 2.1 volumes) and MTBE (45 mL, 0.9 volumes). The solid material was dried in a vacuum oven at about 35-45° C. ¹ H NMR (400MHz, CDCl ₃ )δ10.33(s,1H),9.58(s,1H),7.92(d,J＝9.2Hz,1H),7.72(d,J＝8.1Hz,2H),7.31–7.21(m,1H),7.11(t,J＝5.7Hz, 3H),5.97–5.77(m,1H),5.49(t,J＝7.1Hz,1H),5.19(dd,J＝27.6,13.7Hz,2H),4.73(dd,J＝12.1,5.7Hz,1H),4.49 (dd,J＝11.8,6.4Hz,1H),3.93(d,J＝9.1Hz,3H),3.77(s,3H),3.60(dd,J＝13.2,3.5Hz,1H),3.17(td,J＝16.8,7.0 Hz, 2H), 2.84 (dd, J = 14.1, 6.9 Hz, 1H), 2.30 (s, 3H), 1.67–1.34 (m, 2H), 1.05 (t, J = 7.4Hz, 3H). LC/MS: M/Z = 422.2.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other acids (e.g., hydrochloric acid or methanesulfonic acid) may be used. Additionally, other organic solvents (e.g., isopropyl acetate) may be used.

D. Synthesis of compound of formula VIII (R=CH ₃ )

I. Salt break of VII to provide VII free acid

VII (33.0 g, 87.6 mmol, 1.0 equiv) was mixed with MTBE (198 mL, 6.0 volumes) and the resulting suspension was stirred. A solution of concentrated hydrochloric acid (33 mL, 1.0 volume) and water (165 mL, 5.0 volumes) was added to the suspension at a rate that maintained a reaction temperature of approximately 15-25°C. As the acid was added, the suspension became a biphasic solution. The resulting reaction mixture was stirred at approximately 15-25°C for approximately 1 hour. Stirring was stopped and the layers were separated for approximately 15 minutes, after which the aqueous layer was removed. Water (330 mL, 10 volumes) was added to the organic layer and stirred at approximately 15-25°C for approximately 15 minutes. Stirring was stopped and the layers were separated for approximately 15 minutes, after which the aqueous layer was removed. Water (330 mL, 10 volumes) was added to the organic layer and stirred at approximately 15-25°C for approximately 15 minutes. Stirring was stopped and the layers were separated for approximately 15 minutes, after which the aqueous layer was removed. A 10 wt.% sodium chloride solution in water (300 mL, 9 volumes) was added to the organic layer, and the mixture was stirred at approximately 15-25°C for approximately 15 minutes. Stirring was stopped and the layers were allowed to separate for approximately 15 minutes, after which the aqueous layer was removed. The resulting organic layer was then concentrated to a minimum volume and diluted with dimethylformamide (297 mL, 9 volumes). The final solution was removed and polish filtered.

Alternative reagents and reaction conditions to those disclosed above can also be used. For example, other acids (for example, sulfuric acid or phosphoric acid) can be used. In addition, other organic solvents (for example, methyl-THF or ethyl acetate) can be used.

II. Amide coupling of VI (R=CH ₃ ) and VII (free acid) to provide VIII (R=CH ₃ )

VII (free acid) (40.0 g; 67.4 mmol; 0.77 eq.), EDC·HCl (16.8 g, 87.6 mmol, 1.0 eq.), and HOBt monohydrate (13.4 g, 87.6 mmol, 1.0 eq.) were combined in a reaction vessel. The previously prepared VII (free acid) was added to the solid material in a DMF solution, rinsed with DMF (39.6 mL, 1.2 vol), and stirred to form a solution. The reaction mixture was cooled to approximately 0-10°C, after which NMM (19.3 mL, 175 mmol, 2.0 eq.) was added. The contents were stirred at approximately 0-10°C for no less than approximately 1 hour. The reaction mixture was then heated to approximately 15-25°C and stirred until the reaction was determined to be complete by LC analysis. Upon completion of the reaction, toluene (429 mL, 13 volumes) was added to the reactor and the temperature was adjusted to approximately -5 to 5°C. Water (198 mL, 6 volumes) was slowly added to maintain the reaction temperature between about 0 and 25°C. After the water addition was complete, the contents were adjusted to about 15-25°C. Stirring was stopped and the contents were allowed to settle for no less than 15 minutes, after which the aqueous layer was removed. A solution of potassium carbonate (20.6 g, 149 mmol, 1.7 equivalents) in water (181 mL, 5.5 volumes) was added to the organic phase and the resulting solution was allowed to stir for about 15 minutes, after which stirring was stopped and the contents were allowed to settle for about 15 minutes. The alkaline aqueous layer was removed. Water (181 mL, 5.5 volumes) was added to the organic phase and stirred for about 15 minutes, after which stirring was stopped and the contents were allowed to settle for about 15 minutes. The alkaline aqueous layer was removed. The organic phase was again distributed between water (181 mL 5.5 volumes) and stirred for about 15 minutes, after which stirring was stopped and the contents were allowed to settle for about 15 minutes. The alkaline aqueous layer was removed. A solution of sodium chloride (20.5 g; 350 mmol 4.00 equivalents) in water (181 mL; 5.5 volumes) was added to the organic layer and stirred for approximately 15 minutes, after which stirring was stopped and the contents were allowed to settle for approximately 15 minutes. The basic aqueous layer was removed. The organic layer was concentrated to a minimum stirring volume, removed, and polish filtered.

¹ H NMR(400MHz, CDCl3)δ8.01(d,J＝9.1Hz,1H),7.19-7.34(m,3H),6.09–5.78(m,2H),5.55–5.21(m,3H),5.06(dd,J＝32.9,13.4Hz,2 H),4.92(d,J＝8.5Hz,1H),4.59(dd,J＝10.7,6.3Hz,1H),4.35(d,J＝9.7Hz,1H),4.11–3.92(s,3H),3.95–3.87(m,1H),3.85(d,J＝2 8.1Hz,3H),3.78–3.70(m,1H),3.37–3.17(m,2H),2.81–2.69(m,1H),2.18–2.06(m,1H),1.95(d,J＝7.4Hz,1H),1.63(dd,J＝14.4, 7.3Hz, 1H), 1.48 (dd, J = 14.4, 7.2Hz, 1H), 1.17 (t, J = 7.4Hz, 3H), 1.12 (s, 9H), 0.84 (s, 1H), 0.54 (d, J = 6.4Hz, 1H). LC/MS: m/z = 659.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other coupling agents (e.g., 1-hydroxy-7-azabenzotriazole) and bases (e.g., pyridine, morpholine, or imidazole) may be used. Additionally, other organic solvents (e.g., dimethylacetamide or acetonitrile) may be used.

E. Synthesis of compound of formula IX (R=CH ₃ )

Ring-closing metathesis of VIII (R=CH ₃ ) to provide IX (R=CH ₃ ):

VIII (R = CH ₃ ) (33 g, 14.3 wt.% solution in toluene, 7.1 mmol, 1.00 eq) and toluene (27 mL) were mixed and the mixture was stirred and heated to reflux (110° C.) and maintained at reflux temperature for about 3-5 hours. Separately, toluene (20 mL) was charged to the reaction vessel and vigorously degassed. Zhan 1B catalyst (173 mg, 0.24 mmol, 0.033 eq) was charged and the mixture was stirred at about 20-25° C. for about 60 minutes to obtain a homogeneous solution. The toluene solution of the Zhan catalyst was added to the refluxing toluene solution of VIII (R = CH ₃ ) over about 2 hours, maintaining the reaction temperature at about 111° C. Upon completion of the reaction, the reaction was cooled to about 20° C. and 9.4 grams (2S) of silica gel were charged. The slurry was vigorously stirred for about 4 hours and then filtered. The reactor and filter were washed with isopropyl acetate (2 x 32 mL) and the filtrate was concentrated to 50% volume (approximately 11 volumes). To this solution was added 2.4 g of activated carbon (0.5S). The slurry was stirred vigorously for about 4 hours and then filtered. The reactor and filter were washed with isopropyl acetate (2 x 16 mL) and the filtrate was solvent exchanged to 5 volumes of isopropyl acetate and used directly in the next step. ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.95 (d, J = 6.0 Hz, 1H), 7.26 (m, 1H), 7.12 (m, 1H), 5.89 (m, 1H), 5.69 (m, 2H), 5.22 (d, J = 9.0 Hz, 1H), 4.77 (d, J = 6.0 Hz, 1H), 4.40 (d, J = 9.0 Hz, 1H), 4.29 (d, J = 6.0 Hz, 1H), 4.02-3.95 (m, 1H), 3 .96(s,3H),3.85(m,1H),3.73(s,3H),3.21(s,2H),2.90-2.70(m,1H),2.49(d,J＝12.0Hz,1H),1 .41(m,2H),1.25-1.18(m,4H),1.06(s,9H),1.00-0.93(m,2H),0.50(m,1H).LCMS: m/z=631.02.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other ruthenium-based Grubbs, Grubbs-Hoveyda, saturated and unsaturated imidazole and phosphine-based catalysts and platinum-based catalysts and variations thereof may be used (see below for a representative, non-exhaustive list wherein Cy is cyclohexyl, Me is methyl, Ph is phenyl and iPr is isopropyl).

In addition, other promoters (e.g., acetic acid, benzoquinones, CuI, CsCl, or Ti(Oi-Pr) ₄ ), ethylene, or promoting conditions (e.g., microwave irradiation) may be used. Furthermore, temperatures in the range of about 40° C. to 110° C. may be used. Other solvents may be used, such as halogenated (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, or hexafluorobenzene), organic (e.g., benzene, THF, methyl-tert-butyl ether, cyclopentyl methyl ether, ethyl acetate, n-heptane, dimethyl carbonate, dimethylformamide, acetonitrile), or alcohols (e.g., methanol, isopropanol).

F. Synthesis of compound of formula X (R=CH ₃ )

Hydrogenation of IX (R = CH ₃ ) to provide X (R = CH ₃ ):

5 volumes of IX (R = CH ₃ ) and Pt / C (5 wt % relative to IX (R = CH ₃ )) in isopropyl acetate (IPAc) are loaded into a reaction vessel. The reactor is inertized with N ₂ , then evacuated and filled with H ₂ to 5 psig. The mixture is vigorously stirred under 5 psig H ₂ at room temperature for about 12-24 hours. After the reaction is complete, celite (5 wt %) is added, and the mixture is filtered to remove solid matter, washing with additional IPAc. The IPAc solution is treated with 6 volumes of 5% aqueous N-acetylcysteine at about 50° C. with vigorous stirring under N ₂ overnight. After cooling to room temperature, the aqueous layer is removed and the organic layer is washed with 6 volumes of 5-10% aqueous NaHCO ₃ and 6 volumes of 10% aqueous NaCl. Celite (0.5S) is added, the mixture is stirred for about 5 minutes, and the solid matter is then removed by filtration. The solution of X (R = CH ₃ ) is carried on without further purification.

¹ H NMR (400MHz, CDCl ₃ )δ7.97(d,J＝9.2Hz,1H),7.26(dd,J＝9.2,2.7Hz,1H),7.09(d,J＝2.7Hz,1H),5.88(d,J＝3.9Hz,1H),5.29(d,J＝ 9.9Hz,1H),4.74(d,J＝7.2Hz,1H),4.38–4.25(m,2H),4.13–4.07(m,1H),3.94(s,3H),3.78–3.76(m,1H),3.71 (s,3H)2.63(appdd,J＝15.0,7.5Hz,1H),2.54–2.32(m,1H),2.02–1.98(m,1H),1.84–1.63(m,4H),1.53–1.33( m,3H),1.30–1.10(m,4H),1.07(s,9H),0.95–0.80(m,2H),0.77–0.64(m,1H),0.46(dd,J＝12.9,6.3Hz,1H).19F NMR (376MHz, CDCl3) δ-102.43 (ddd, J=250.4, 25.4, 8.6Hz), -103.47 (ddd, J=250.4, 28.7, 11.3Hz).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other catalysts such as heterogeneous metal catalysts (e.g., platinum, palladium, ruthenium, or nickel), metals on carbon, alumina, silica, and other heterogeneous supports, metal nanoparticles, hindered Lewis acid-base pairs (e.g., hydrogen [4-[bis(2,4,6-trimethylphenyl)phosphino]-2,3,5,6-tetrafluorophenyl] hydrogen bis(2,3,4,5,6-pentafluorophenyl) borate), homogeneous metal catalysts (e.g., chlorotris(triphenylphosphine)rhodium(I) or (1,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I) hexafluorophosphate) may be used. In addition, water, protic solvents (e.g., methanol, ethanol, or acetic acid), aprotic solvents (e.g., dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, dichloromethane, or acetone), or combinations thereof may be used. Additionally, hydrogen gas or formates (eg, ammonium formate or formic acid) within a range of pressures may be used. Additionally, imides and temperatures within a range of about -20°C to about 150°C may be used.

G. Synthesis of compounds of formula XI (R=H) from X (R=CH ₃ )

II. Hydrolysis of X to provide XI:

To a solution of X (R = CH ₃ ) in IPA (7 volumes) was added an aqueous solution of LiOH (1 M, 2.3 eq) at approximately 30°C under N ₂ over approximately 5-10 minutes. The reaction mixture was warmed to an internal temperature of approximately 40°C and stirred. After cooling to room temperature, MTBE (8 volumes) was added. The resulting mixture was acidified to pH 3 with 1M HCl. The aqueous layer was removed, and the organic layer was washed twice with 10% aqueous NaCl. Celite (0.1S) was added, and the resulting slurry was filtered and washed with additional MTBE. The MTBE was removed by vacuum distillation, and the resulting solid material was dissolved in 5 volumes of ethanol and 5 volumes of heptane at approximately 60-65°C. The solution was then cooled to approximately 45-50°C and seeded with a slurry of XI in ethanol/heptane (0.005S). After stirring at approximately 45°C for approximately 6 hours, the slurry was cooled to approximately 15°C over approximately 10 hours. An additional 5 volumes of heptane were added over approximately 1 hour. XI was isolated by vacuum filtration and washed with 5 volumes of 1:9 EtOH:heptane. The resulting solid was dried in a vacuum oven at approximately 40°C to constant weight. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.95 (d, J = 9.2 Hz, 1H), 7.24 (dd, J = 9.2, 2.6 Hz, 1H), 7.07 (d, J = 2.6 Hz, 1H), 5.87 (d, J = 3.5 Hz, 1H), 5.47 (d, J = 9.9 Hz, 1H), 4.72 (d, J = 7.2 Hz, 1H), 4.33 (d, J = 12.2 Hz, 1H) ),4.32(d,J＝9.9Hz,1H),4.04(dd,J＝11.9,4.0Hz,1H),3.93(s,3H),3.7(m,1H),2.6 4(m,1H),2.43(m,1H),1.99(m,1H),1.8-1.3(m,6H),1.25-1.15(m,3H),1.0(m,1H). ¹³ C NMR (75MHz, CDCl ₃ ): δ 172.63, 171.64, 162.06, 157.49, 153.37, 142.42, 139.12 (dd, J _CF = 30.6, 25.8Hz), 133.06, 130.44, 120.1 (t, J _CF =245Hz),119.93,105.31,77.45,61.66,59.49,55.74,54.98,51.92,46.52,36.42(t,J _CF =25.0),34.91,30.35,27.74,26.19,21.53,19.99,18.34,12.06,11.33.

Alternative reagents and reaction conditions to those disclosed above can also be used. For example, carbonate (for example, lithium, sodium or cesium carbonate), metal hydride (for example, sodium hydride or potassium hydride), alkoxide (for example, sodium methoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-butoxide or tetraalkylammonium alkoxide), hydroxide (for example, sodium hydroxide, potassium hydroxide, tin hydroxide or tetraalkylammonium hydroxide) or amine base (for example, DBU) can be used. In addition, protonic acid (for example, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid or solid-supported acid), Lewis acid (for example, boron trifluoride), metal salt, metal complex or hydrogen bond donor can be used. In addition, polar protic solvents including water, alcohols (e.g., methanol, ethanol, isopropanol, tert-butanol, neopentyl alcohol, glycols, and combinations of these with water), polar aprotic solvents (e.g., dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, 1,4-dioxane, or combinations of these with water), or ionic liquids (e.g., 3-methylimidazolium hexafluorophosphate) may be used.

H. Synthesis of compounds of formula I from X(R=CH ₃ )

The synthesis of compounds of formula I from X is similar to that described in US Publication No. 2014-0017198. X (R=CH ₃ ) is hydrolyzed to form XI (R=H), which is coupled with XII to form I.

Alternative pathway using tert-butyl esters on proline

An alternative approach employing a tert-butyl ester of the proline moiety is as used in US Publication No. 2014-0017198, but with a new RCM pathway homolog of the proline and cyclopropyl-leucine moieties. The tert-butyl group can be removed by acid treatment after the hydrogenation stage.

Synthesis of Formula VI Compound (R = tert-Bu), (2S,3S,4R)-4-((3-(1,1-difluorobut-3-en-1-yl)-7-methoxyquinoxalin-2-yl)oxy)-3-ethylpyrrolidine-2-carboxylic acid tert-butyl ester

I. Boc deprotection of V (R = tert-Bu) to provide VI (R = tert-Bu)

V (R = tert-Bu) (0.88 g, 1.56 mmol, 1.0 eq.), t-BuOAc (9.5 mL, 11 vols.), and CH ₂ Cl ₂ (2.4 mL, 2.7 vols.) were charged to a round-bottom flask equipped with a magnetic stir bar. Methanesulfonic acid (0.51 mL, 7.8 mmol, 5.0 eq.) was added, and the reaction mixture was stirred overnight at approximately 20° C. for approximately two hours. The reaction solution was then poured into 60 mL of a 1:1 saturated NaHCO ₃ /EtOAc mixture, and the organic layer was separated. The aqueous layer was then back-extracted with EtOAc, and the combined organic layers were washed sequentially with saturated NaHCO ₃ and brine, then dried over magnesium sulfate, filtered, and concentrated to afford VI (R = tert-Bu). LCMS: m/z = 464.4.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other acids such as mineral acids (e.g., hydrochloric acid) or organic acids (e.g., p-toluenesulfonic acid) may be used. Additionally, other organic solvents (e.g., isopropyl acetate, methyl tert-butyl ether, or 2-methyltetrahydrofuran) and temperatures in the range of about 50° C. to about 60° C. may be used.

Synthesis of Formula VIII Compound (R = tert-Bu), (2S,3S,4R)-1-((S)-2-((((1R,2R)-2-allylcyclopropyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-4-((3-(1,1-difluorobut-3-en-1-yl)-7-methoxyquinoxalin-2-yl)oxy)-3-ethylpyrrolidine-2-carboxylic acid tert-butyl ester

I. Amide coupling of VI (R = tert-Bu) and VII to provide VIII (R = tert-Bu)

VI (R = tert-Bu) (4.12 g, 8.9 mmol, 1.0 eq.), VII (2.72 g, 10.7 mmol, 1.2 eq.), and acetonitrile (120 mL, 29 vols.) were added to a flask. HATU (4.4 g, 11.6 mmol, 1.3 eq.) was then added, followed by DIPEA (6.2 mL, 35.6 mmol 4 eq.). The reaction mixture was stirred at approximately 20°C overnight. The reaction mixture was then concentrated and purified by silica gel flash column chromatography (elution gradient: 0% to 18% to 25% ethyl acetate in hexanes) to obtain VIII. LCMS: m/z = 701.1.

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other coupling reagents (e.g., ethyl-3-(3-dimethylaminopropyl)carbodiimide or hydroxybenzotriazole monohydrate) may be used. Additionally, other bases (e.g., pyridine, morpholine, imidazole, or N-methylmorpholine) and organic solvents (e.g., dimethylacetamide or N,N-dimethylformamide) may be used.

Synthesis of the compound of formula IX (R=tert-Bu)(33R,34S,35S,91R,92R,5S)-5-(tert-butyl)-34-ethyl-14,14-difluoro-17-methoxy-4,7-dioxo-2,8-dioxa-6-aza-1(2,3)-quinoxalino-3(3,1)-pyrrolidine-9(1,2)-cyclopropanecyclotetradecaphan-11-ene-35-carboxylic acid tert-butyl ester

I. Ring-closing metathesis of VIII (R = tert-Bu) to provide IX (R = tert-Bu)

Zhan 1B catalyst (26 mg, 0.036 mmol, 0.025 equiv.) was charged to the flask. The flask was evacuated and backfilled with nitrogen three times. Nitrogen-sparged toluene (25 mL) was added and the mixture was stirred and heated to reflux (about 110°C). A solution of compound VIII (R = tert-Bu) in 5 mL of toluene (1.0 g, 1.4 mmol, 1.00 equiv.) was added over 30 minutes, maintaining the reaction temperature at about 110°C. Upon completion of the reaction, the reaction mixture was cooled to about 20°C and purified by flash column chromatography (54 g silica gel, 20% ethyl acetate in hexanes as eluent) to yield IX (R = tert-Bu). ^1H NMR (300 MHz, CDCl ₃ ): δ7.95(d,J＝6.0Hz,1H),7.26(m,1H),7.12(m,1H),5.89(m,1H),5.69(m,2H),5.27(d,J＝ 9.0Hz,1H),4.62(d,J＝6.0Hz,1H),4.35(d,J＝9.0Hz,1H),4.29(d,J＝6.0Hz,1H),4.02-3.95 (m,1H),3.96(s,3H),3.88(m,1H),3.21(s,2H),2.90-2.70(m,1H),2.49(d,J＝12.0Hz,1H), 1.48(m,9H),1.41(m,2H),1.25-1.18(m,4H),1.06(s,9H),1.00-0.93(m,2H),0.50(m,1H). ¹⁹ F NMR (282.2MHz, CDCl ₃ ): δ-101.0ppm (m).

Alternative reagents and reaction conditions to those disclosed above may also be used. For example, other ruthenium-based Grubbs, Grubbs-Hoveyda, saturated and unsaturated imidazole and phosphine-based catalysts and platinum-based catalysts and variations thereof may be used (see below for a representative, non-exhaustive list wherein Cy is cyclohexyl, Me is methyl, Ph is phenyl and iPr is isopropyl).

Alternatively, other promoters (e.g., acetic acid, benzoquinones, CuI, CsCl, or Ti(O-i-Pr)) or promoting conditions (e.g., microwave irradiation or ethylene) may be used. Furthermore, temperatures in the range of about 40°C to 110°C may be used. Other solvents such as halogenated (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, or hexafluorobenzene), organic (e.g., benzene, THF, methyl tert-butyl ether, cyclopentyl methyl ether, ethyl acetate, n-heptane, dimethyl carbonate, dimethylformamide, or acetonitrile) or alcohols (e.g., methanol, isopropanol) may be used.

Example 2. Synthesis of (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropyl[18,19][1,10,3,6]dioxadiazaaromaticnonadecacyclo[11,12-b]quinoxaline-8-carboxamide (I) via Route II

a. Hydrolysis, ring-closing metathesis and hydrogenation:

Route II differs from Route I of Example 1 in the order of assembly. The compound of formula VIII is first hydrolyzed to provide the compound of formula XVIII and then subjected to ring-closing metathesis to provide the compound of formula XIX, which upon hydrogenation produces the compound of formula XI. The reaction conditions for hydrolysis, ring-closing metathesis, and hydrogenation are similar to those disclosed in Route I. The compound of formula XI is converted to the compound of formula I as described above in Example 1.

Example 3. Synthesis of (1aR,5S,8S,9S,10R,22aR)-5-tert-butyl-N-[(1R,2R)-2-(difluoromethyl)-1-{[(1-methylcyclopropyl)sulfonyl]carbamoyl}cyclopropyl]-9-ethyl-18,18-difluoro-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropyl[18,19][1,10,3,6]dioxadiazaaromaticnonadecacyclo[11,12-b]quinoxaline-8-carboxamide (I) via Route III

The compound of formula I is synthesized via route III as shown below:

Synthesis of A.XV

Compounds XIV (R=CH ₃ ) (180 mg, 0.35 mmol, 1 equiv) and XIII (180 mg, 0.67 mmol, 1.9 equiv) were dissolved in 15 volumes of degassed toluene (2.7 mL). The system was inertized under nitrogen and loaded with Zhan 1B catalyst (53 mg, 0.073 mmol, 0.20 equiv). The mixture was warmed to about 95° C. and stirred for about 45 minutes. The reaction was cooled to about 20° C. and purified by silica gel chromatography to provide intermediate XV (R=CH ₃ ). LCMS (M+1): 749 m/z. ¹ H NMR (400 MHz, CDCl ₃ ): δ7.98-7.90(m,1H),7.28-7.14(m,2H),6.30-5.95(m,1H),5.58-5.19( m,3H),4.56(dd,1H,J＝36.8,8.5Hz),4.46-4.24(m,1H),4.22-4.01(m,3H) ,3.95(s,3H),3.85-3.67(m,5H),3.40-3.27(m,1H),2.50-1.98(m,4H),1 .65-1.55(m,1H),1.43-1.41(m,9H),1.1-0.7(m,11H),0.57-0.40(m,2H).

B. Hydrogenation of intermediate XV (R=CH ₃ ) and hydrolysis of XVI (R=CH ₃ ):

A mixture of Intermediate XV (R = CH ₃ ) (117 mg, 0.156 mmol) and Pt / C (13 mg, 5 wt %) in 14 volumes of IPAc (1.6 mL) was stirred at room temperature under 5 psig H ₂ for 20 hours. The mixture was filtered through celite, concentrated in vacuo and purified by silica gel chromatography to produce ~75 mg of Intermediate XVI (64% yield). Intermediate XVI was dissolved in 1 mL of CH ₂ Cl ₂ and mixed with 0.5 mL of 4M HCl in dioxane at room temperature. After about 40 minutes, the mixture was concentrated to produce Intermediate XVII, which was carried forward without further purification.

C. Lactamization of (S)-2-((((1S,2S)-2-(5-(3-(((3R,4S,5S)-4-ethyl-5-(methoxycarbonyl)pyrrolidin-3-yl)oxy)-6-methoxyquinoxalin-2-yl)-5,5-difluoropentyl)cyclopropyloxy)carbonyl)amino)-3,3-dimethylbutyric acid hydrochloride (XVII (R=CH ₃ )) to form X (R=CH ₃ ):

To a solution of XVII (20 mg, 0.029 mmol, 1 equiv) in 100 V DMF (2 mL) at rt was added HOBt (39.3 mg, 0.29 mmol, 10 equiv) followed by EDC (56 mg, 0.29 mmol, 10 equiv). The mixture was stirred for 5 minutes, at which time triethylamine (0.1 mL, 0.72 mmol, 25 equiv) was added. After 4.5 hours, the mixture was diluted with MTBE, washed twice with saturated aqueous _NH₄Cl solution and twice with saturated aqueous _NaHCO₃ solution, dried over _MgSO₄ , filtered, and concentrated in vacuo. The crude product thus obtained was diluted to 25 mL in a volumetric flask. UPLC analysis indicated the presence of X( _R═CH₃ ) (10.6 mg, 59% assay yield).

However, alternative reagents and reaction conditions to those disclosed above may also be used. For example, other coupling reagents (e.g., carbodiimidazole, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, benzotriazole-1-yl-oxytripyrrolidinium hexafluorophosphate, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate or 2,4,6-trichlorobenzoyl chloride) may be used. In addition, other bases such as amines (e.g., diisopropylethylamine, pyridine or sodium hexamethyldisilazane), carbonates (e.g., potassium carbonate or cesium carbonate), bicarbonates (e.g., sodium bicarbonate) or inorganic/organic hydroxides (e.g., sodium hydroxide or tetramethylammonium hydroxide) may be used. Other promoters (e.g., 4-dimethylaminopyridine or 1-hydroxy-7-azabenzotriazole) may be used. In addition, other solvents such as water, polar aprotic solvents (e.g., N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) (or combinations of these with water), organic solvents (e.g., toluene, acetonitrile or acetone), alcohols (e.g., methanol or ethanol), ethers (e.g., tetrahydrofuran, dioxane or methyl tert-butyl ether), esters (e.g., ethyl acetate) or chlorinated solvents (e.g., dichloromethane) may be used.

The compound of formula X is converted to the compound of formula I as described in Example 1 above.

Claims (3)

1. A method for preparing a compound of formula V or its eutectic or salt: This includes contacting a compound of formula III or its eutectic or salt with a compound of formula IV under O-arylation conditions to provide a compound of formula V or its eutectic or salt: Where R is a _C1-6 alkyl group, PG is a protecting group, and ^R1 is a leaving group. 2. A method for preparing a compound of formula I or a eutectic or pharmaceutically acceptable salt thereof: include: a) Contacting a compound of formula III, or its eutectic or salt, with a compound of formula IV under O-arylation conditions to provide a compound of formula V, or its eutectic or salt. b) Subjecting a compound of formula V, or its eutectic or salt, to N-deprotection conditions to provide a compound of formula VI, or its eutectic or salt: c) Contacting a compound of formula VI or its eutectic or salt with a compound of formula VII or its eutectic or salt under amide coupling conditions to provide a compound of formula VIII or its eutectic or salt: d) Perform cyclic metathesis of a compound of formula VIII or its eutectic or salt to provide a compound of formula IX or its eutectic or salt; e) Hydrogenating a compound of formula IX or its eutectic or salt in the presence of a catalyst to provide a compound of formula X or its eutectic or salt: f) Hydrolyze a compound of formula X or its eutectic or salt to provide a compound of formula XI or its eutectic or salt: g) Contacting a compound of formula XI or its eutectic or salt with a compound of formula XII or its eutectic or salt under amide coupling conditions to provide a compound of formula I or its eutectic or pharmaceutically acceptable salt: Where R is a _C1-6 alkyl group, PG is a protecting group and ^R1 is a leaving group. 3. A method for preparing a compound of formula I or a eutectic or pharmaceutically acceptable salt thereof: include: a) Contacting a compound of formula III or its eutectic or salt with a compound of formula IV under O-arylation conditions to provide a compound of formula V or its eutectic or salt: b) Contacting a compound of formula V, or its eutectic or salt, with an acid under N-deprotection conditions to provide a compound of formula VI, or its eutectic or salt: c) Contacting a compound of formula VI or its eutectic or salt with a compound of formula VII or its eutectic or salt under amide coupling conditions to provide a compound of formula VIII or its eutectic or salt: d) Hydrolyzing a compound of formula VIII or its eutectic or salt to provide a compound of formula XVIII or its eutectic or salt: e) To perform ring-closure metathesis of a compound of formula XVIII or its eutectic or salt in the presence of a catalyst to provide a compound of formula XIX or its eutectic or salt: f) Hydrogenating a compound of formula XIX in the presence of a catalyst to provide a compound of formula XI or its eutectic or salt: g) Contacting a compound of formula XI or its eutectic or salt with a compound of formula XII or its eutectic or salt under amide coupling conditions to provide a compound of formula I or its eutectic or pharmaceutically acceptable salt: Where R is a _C1-6 alkyl group, PG is a protecting group, and ^R1 is a leaving group.