Boric acid derivatives and their synthesis

Abstract

Disclosed herein are antimicrobial compound compositions, pharmaceutical compositions, uses thereof, and methods of making them. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents, e.g., β-lactamase inhibitors (BLIs).

Description

[0001] background

[0002] Incorporation by reference into any priority application

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 571,149, filed on October 11, 2017, entitled Boronic Acid Derivatives and Syntheses Thereof, the disclosure of which is incorporated herein by reference in its entirety.

[0004] Statement Regarding Federally Funded Research and Development

[0005] This invention was made with government support under Grant No. HHSO100201600026C awarded by the Department of Health and Human Services. The government has certain rights in this invention.

[0006] field

[0007] The present invention relates to the fields of chemistry and medicine. More specifically, the present invention relates to boric acid antimicrobial compounds, compositions, their preparation and their use as therapeutic agents.

[0008] Related technical description

[0009] Over the past half century, antibiotics have been an effective tool for treating infectious diseases. From the development of antibiotic therapy to the late 1980s, bacterial infections were almost completely controlled in developed countries. However, due to the pressure of antibiotic use, multiple resistance mechanisms have become common and threaten the clinical utility of antimicrobial therapy. The increase in antibiotic-resistant strains has been particularly common in major hospitals and nursing centers. The consequences of the increase in resistant strains include higher morbidity and mortality, longer patient hospitalizations, and increased treatment costs.

[0010] Various bacteria have evolved β-lactam deactivating enzymes, i.e. β-lactamases that counteract the efficacy of various β-lactam antibiotics. β-lactamases can be divided into 4 categories based on their amino acid sequences, i.e., Ambler class A, B, C, and D. Enzymes in classes A, C, and D include active site serine β-lactamases, and the less frequently encountered class B enzymes are Zn-dependent. These enzymes catalyze the chemical degradation of β-lactam antibiotics, rendering them inactive. Some β-lactamases can be transferred within and between various bacterial strains and species. The rapid spread of bacterial resistance and the evolution of multi-resistant strains have severely limited the availability of β-lactam treatment options.

[0011] The increase in class D β-lactamase-expressing bacterial strains, such as Acinetobacter baumannii, is an emerging multidrug-resistant threat. A. baumannii strains express class A, C, and D β-lactamases. Class D β-lactamases, such as the OXA family, are resistant to carbapenem-destroying β-lactam antibiotics (e.g., imipenem, Merck's The active carbapenem component of the cephalosporin class is particularly effective (Montefour, K. et al., Crit. Care Nurse 2008, 28, 15; Perez, F. et al., Expert Rev. Anti Infect. Ther. 2008, 6, 269; Bou, G.; Martinez-Beltran, J., Antimicrob. Agents Chemother. 2000, 40, 428. 2006, 50, 2280; Bou, G. et al., J. Antimicrob. Agents Chemother. 2000, 44, 1556). This poses an urgent threat to the effective use of this class of drugs for the treatment and prevention of bacterial infections. In fact, the number of classified serine-based β-lactamases has surged from less than 10 in the 1970s to more than 300 variants. These problems have prompted the development of five "generations" of cephalosporins. When initially introduced into clinical practice, extended-spectrum cephalosporins resisted hydrolysis by the prevalent class A β-lactamases, TEM-1 and SHV-1. However, the development of resistant strains due to the evolution of single amino acid substitutions in TEM-1 and SHV-1 has led to the emergence of an extended-spectrum β-lactamase (ESBL) phenotype.

[0012] Recently, new types of β-lactamases have evolved that hydrolyze carbapenem antimicrobials (including imipenem, biapenem, doripenem, meropenem and ertapenem, as well as other β-lactam antibiotics). These carbapenemases belong to molecular classes A, B and D. Class A carbapenemases of the KPC type are primarily found in Klebsiella pneumoniae, but are now also reported in other Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. KPC carbapenemases were first described in North Carolina in 1996, but have since spread widely in the United States. They have been particularly problematic in the New York City area, where several reports of spread and patient morbidity within major hospitals have been reported. These enzymes have also recently been reported in France, Greece, Sweden, the United Kingdom, and an outbreak has recently been reported in Germany. Treatment of resistant strains with carbapenems may result in a poor prognosis.

[0013] Zinc-dependent class B metallo-β-lactamases are mainly represented by VIM, IMP and NDM types. IMP-producing and VIM-producing Klebsiella pneumoniae were first observed in Japan in the 1990s and southern Europe in 2001, respectively. IMP-positive strains remain frequent in Japan, and they have also caused hospital outbreaks in China and Australia. However, the spread of IMP-producing Enterobacteriaceae in the rest of the world seems to be slightly limited. VIM-producing Enterobacteriaceae can be frequently isolated in Mediterranean countries, reaching infection proportions in Greece. The isolation of VIM-producing strains remains low in Northern Europe and the United States. In contrast, the characteristics of NDM-producing Klebsiella pneumoniae isolates are that they spread rapidly from their center (Indian subcontinent) to Western Europe, North America, Australia and the Far East. Moreover, the NDM gene has spread to many species besides Klebsiella pneumoniae.

[0014] The plasmid-expressed class D carbapenemases belong to the OXA-48 type. OXA-48-producing Klebsiella pneumoniae were first detected in Turkey in 2001. The Middle East and North Africa remain the main centers of infection. However, recent isolations of OXA-48-producing organisms in India, Senegal, and Argentina suggest the potential for global expansion. The isolation of OXA-48 in bacteria other than Klebsiella pneumoniae emphasizes the potential for spread of OXA-48.

[0015] Treatment with carbapenems of strains producing any of these carbapenemases may result in a poor prognosis.

[0016] Another mechanism of β-lactamase-mediated resistance to carbapenems involves a combination of permeability or efflux mechanisms combined with overproduction of β-lactamases. An example is that loss of porins combined with overproduction of ampC β-lactamases leads to resistance to imipenem in Pseudomonas aeruginosa. Overexpression of efflux pumps combined with overproduction of ampC β-lactamases can also lead to resistance to carbapenems such as meropenem.

[0017] Therefore, there is a need for efficient methods to synthesize β-lactamase inhibitors (BLIs). Summary of the invention

[0018] One embodiment relates to a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0019]

[0020] The method comprises the following steps: The compound of formula (A-III) is reacted with a boronating agent to form an organic boron intermediate; the organic boron intermediate is converted into and hydrolyzing a compound of formula (A-III) to form a compound of formula (I), wherein R 1 is a carboxylic acid protecting group. 1 It is C 1-6 alkyl.

[0021] Some embodiments relate to methods of preparing a compound of formula (A-III) or a pharmaceutically acceptable salt thereof,

[0022]

[0023] The method comprises the following steps:

[0024] AI The compound is reacted with a boronating agent to form an organoboron intermediate;

[0025] converting the organoboron intermediate into a compound of formula (A-III);

[0026] in:

[0027] R 1 It is a carboxylic acid protecting group.

[0028] Some embodiments relate to the preparation of formula (I) A method for preparing a compound of formula (A-II) or a pharmaceutically acceptable salt thereof, the method comprising the following steps: The compound of formula (A-III) is converted into and hydrolyzing the compound of formula (A-III) to form a compound of formula (I).

[0029] Some embodiments relate to methods of preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0030]

[0031] The method comprises the following steps: The compound and one or more chiral auxiliary agents are combined to form a chiral complex, and the chiral complex is reacted with a cyclopropylating agent to form a compound of formula (III): and hydrolyzing the compound of formula (A-III) to form a compound of formula (I).

[0032] In some embodiments, converting the organoboron intermediate comprises reacting the organoboron intermediate with a cyclopropanating agent.

[0033] In some embodiments, conversion of the organoboron intermediate comprises combining the organoboron intermediate and one or more chiral auxiliaries to form a chiral complex, and reacting the chiral complex with a cyclopropanating agent.

[0034] Some embodiments relate to a method of preparing a compound of formula (A-II), comprising the step of reacting a compound of formula (AI) with a boronating agent to form a compound of formula (A-II).

[0035] Some embodiments relate to the preparation of formula (AI) The method comprises the following steps: making a compound of formula (AV) The compound of formula (A-VI) is reacted with an alkylating agent to form a compound of formula (A-VI), (A-VI); and converting a compound of formula (A-VI) into a compound of formula (AI). Some embodiments relate to a method for preparing a compound of formula (AI), the method comprising the steps of: converting a compound of formula (AV) The compound of formula (A-VI') is reacted with an alkylating agent to form and converting a compound of formula (A-VI') into a compound of formula (AI), wherein R 1 It is a carboxylic acid protecting group.

[0036] Some embodiments relate to methods of preparing compounds of formula (A-I'),

[0037]

[0038] The method comprises the following steps:

[0039] AV The compound of formula (A-VI') is reacted with an alkylating agent to form a compound of formula (A-VI'),

[0040]

[0041] converting a compound of formula (A-VI') into a compound of formula (AI), and

[0042] Hydrolyzing a compound of formula (AI) to form a compound of formula (A-I'),

[0043] in:

[0044] R 1 is a carboxylic acid protecting group. 1 It is C 1-6 alkyl.

[0045] In some embodiments, the hydrolysis of the compound of formula (A-III) is performed using a base. In some embodiments, the base is NaOH.

[0046] Some embodiments relate to the preparation of formula (A-IV) A method for preparing a compound comprising hydrolyzing the compound with a base to form a compound of formula (A-IV).

[0047] In some embodiments, the In some embodiments, the hydrolysis step is performed at about 145° C. In some embodiments, the base is NaOH.

[0048] Some embodiments involve having A compound of the structure wherein R 1 is a carboxylic acid protecting group. Some embodiments relate to The structure of the compound.

[0049] Some embodiments involve having A compound of the structure wherein R 1 is a carboxylic acid protecting group. Some embodiments relate to The structure of the compound.

[0050] Some embodiments involve having A compound of the structure wherein R 1 is a carboxylic acid protecting group. Some embodiments relate to The structure of the compound.

[0051] Some embodiments involve having A compound of the structure wherein R 1 is a carboxylic acid protecting group, and each R 3 is an optionally substituted C 1-6 Alkyl, or two R 3 together are optionally substituted C 2-4 The alkylene chain and together with the intervening atoms form an optionally substituted 5- to 7-membered heterocyclyl ring.

[0052] Some embodiments involve having The structure of the compound.

[0053] Some embodiments involve having A compound of the structure wherein R 1 It is a carboxylic acid protecting group.

[0054] Some embodiments involve having or The structure of the compound.

[0055] Some embodiments involve having or The structure of the compound.

[0056] Some embodiments involve having or The structure of the compound.

[0057] Some embodiments involve having or The structure of the compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 is a graph showing the reaction yields of the boration step using various catalyst compositions. DETAILED DESCRIPTION

[0060] Compound A and its pharmaceutically acceptable salts are described in International Application PCT / US2017 / 039787, which is incorporated herein by reference in its entirety. Compound A is a β-lactamase inhibitor that is effective in treating bacterial infections when used in combination with β-lactam antibiotics.

[0061]

[0062] The synthesis of compounds of formula (I) (including compound A and its pharmaceutically acceptable salts (e.g., sodium salt)) and the reaction intermediates involved in the preparation are described in some embodiments. The synthesis methods described herein can achieve high yields and high enantioselectivities, which lead to easy separation and high purity of the target enantiomers (e.g., compound A and its pharmaceutically acceptable salts). The preparation methods described herein can achieve high yields and high enantiomeric excess (ee) of compounds of formula (I) (e.g., compound A). The reaction reagents used in the preparation methods can produce compounds of formula (I) in a cost-effective manner, and are advantageous for use in large-scale synthesis.

[0063] Some embodiments relate to a method for preparing a compound of formula (I) (Compound A) or a pharmaceutically acceptable salt thereof,

[0064]

[0065] The method comprises the following steps:

[0066] AI The compound is reacted with a boronating agent to form an organoboron intermediate;

[0067] Convert the organoboron intermediate into formula (A-III) Compounds of

[0068] hydrolyzing a compound of formula (A-III) to form a compound of formula (I),

[0069] in:

[0070] R 1It is a carboxylic acid protecting group.

[0071] Some embodiments relate to a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the steps of:

[0072] Formula (A-II) The compound of formula (A-III) is converted into Compounds of

[0073] hydrolyzing a compound of formula (A-III) to form a compound of formula (I),

[0074] in:

[0075] R 1 is a carboxylic acid protecting group, and

[0076] R a is OH or optionally substituted -OC 1-6 alkyl.

[0077] In some embodiments, the method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof further comprises the following steps:

[0078] Formula (A-II) The compound and one or more chiral auxiliary agents are combined to form a compound having formula (A-II'): The chiral complex of

[0079] The chiral complex is reacted with a cyclopropylating agent to form a compound of formula (III) Compounds of

[0080] hydrolyzing a compound of formula (A-III) to form a compound of formula (I),

[0081] in:

[0082] R 1 is a carboxylic acid protecting group,

[0083] R a is OH or optionally substituted -OC 1-6 Alkyl, and

[0084] R c and R d Together with any intervening atoms, form an optionally substituted 4- to 7-membered heterocyclyl ring.

[0085] Some embodiments relate to a method of preparing a compound of formula (A-II), comprising the steps of reacting a compound of formula (AI) with a boronating agent to form a compound of formula (A-II).

[0086] Some embodiments relate to a method for preparing a compound of formula (A-III), the method comprising the steps of:

[0087] Formula (A-II) and one or more chiral auxiliaries to form a chiral complex, and

[0088] The chiral complex is reacted with a cyclopropylating agent to form a compound of formula (III) Compounds of

[0089] in:

[0090] R 1 is a carboxylic acid protecting group, and

[0091] R a is OH or optionally substituted -OC 1-6 alkyl.

[0092] Some embodiments relate to methods of preparing compounds of formula (A-I'),

[0093]

[0094] The method comprises the following steps:

[0095] AV The compound of formula (A-VI') is reacted with an alkylating agent to form a compound of formula (A-VI'),

[0096]

[0097] converting a compound of formula (A-VI') into a compound of formula (AI), and

[0098] Reducing and hydrolyzing a compound of formula (AI) to form a compound of formula (A-I'),

[0099] Where R 1 It is a carboxylic acid protecting group.

[0100] For compounds of Formula (I), Formula (AI), Formula (A-II), Formula (A-II′), Formula (A-III), Formula (A-IV), Formula (AV), Formula (A-VI), and Formula (A-VII′), R 1 is a carboxylic acid protecting group. 1 is an optionally substituted C 1-6 Alkyl, optionally substituted C 3-7 cyclocarbocyclic group, optionally substituted 3- to 10-membered heterocyclic group, optionally substituted C 6-10 aryl, or an optionally substituted 5- to 10-membered heteroaryl. 1 It is C1-6 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is an optionally substituted C 1-6 alkyl.

[0101] The borating agent can be any borating agent suitable for introducing a boron atom into a furan ring. In some embodiments, the borating agent is (R 2 O)2B-B(OR 2 )2, where each R 2 are independently H, optionally substituted C 1-6 Alkyl, or two R 2 together are optionally substituted C 2-4 In some embodiments, the borating agent is selected from B2(Pin)2 (bis(pinacolato)diboron), B2(Cat)2 (bis(catechol)diboron) and B2neop2 (bis(neopentylethylene glycol)diboron). In some embodiments, the borating agent is B2(Pin)2.

[0102] In some embodiments, R 3 is an optionally substituted C 1-6 Alkyl, or two R 3 together are optionally substituted C 2-4 In some embodiments, each R is an alkylene chain and together with the intervening atoms form an optionally substituted 5- to 7-membered heterocyclyl ring. 3 is independently optionally substituted C 1-6 Alkyl, or two R 3 together are optionally substituted C 2-3 In some embodiments, R 3 It is C 1-6 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 is optionally replaced by one or more C 1-4 Alkyl substituted C 1-6 In some embodiments, two R 3 Together with the intervening atoms, they can form an optionally substituted 5- to 6-membered heterocyclyl ring. 3Together with the intervening atoms, they may form an optionally substituted 5- to 6-membered heterocyclyl ring, and the two R 3 Form C 2-3 Alkylene chain. In some embodiments, the optionally substituted 5- to 6-membered heterocyclyl ring contains one or more oxygen atoms.

[0103] In some embodiments, R a is OH. In some embodiments, R a is optionally substituted -OC 1-6 In some embodiments, R a In some embodiments, R a It is O-ethyl.

[0104] In some embodiments, R c and R d and any intervening atoms to form an optionally substituted 4- to 7-membered heterocyclyl ring. c and R d With any intervening atoms, an optionally substituted oxazaborolidine is formed. c and R d Together with any intervening atoms, an optionally substituted 4- to 7-membered heterocyclyl ring containing one or more O, S, N, or B atoms is formed. c and R d With any intervening atoms, an optionally substituted 4- to 7-membered heterocyclyl ring containing B, N, and O atoms is formed. In some embodiments, the heterocyclyl ring is optionally selected from C 1-4 Alkyl, C 6-10 Aryl, OH and -OC 1-4 In some embodiments, the heterocyclyl ring is optionally selected from C 1-4 Alkyl, C 6-10 Aryl, OH, oxo, COOH, and -OC 1-4 In some embodiments, the heterocyclyl ring is optionally selected from C 1-4 Alkyl and C 6-10 The aryl group is substituted with one or more substituents.

[0105] In some embodiments, the compound of formula (AI) is

[0106] In some embodiments, the compound of formula (A-II) is

[0107] In some embodiments, the compound of formula (A-III) is

[0108] In some embodiments, the compound of formula (I) is

[0109] In some embodiments, the alkylating agent is CH(OR 3 )2CH2X, and X is halogen. In some embodiments, the alkylating agent is CH(OEt)2CH2Br. In some embodiments, X is Cl. In some embodiments, X is Br.

[0110] In some embodiments, for the preparation of compounds of Formula (AI) and Formula (A-I'), the alkylating agent is R 4 OOCCH2X, where R 4 is an optionally substituted C 1-6 In some embodiments, the alkylating agent is MeOOCCH2Cl. In some embodiments, R 4 It is C 1-6 In some embodiments, R 4 In some embodiments, X is Cl. In some embodiments, X is Br.

[0111] In some embodiments, the method for preparing a compound of formula (AI) or formula (A-I') further comprises protecting a compound of formula (A-IV) to form a compound of formula (AV).

[0112] In some embodiments, the compound of formula (A-IV) is

[0113] In some embodiments, the compound of formula (AV) is

[0114] In some embodiments, the compound of formula (A-VI) is

[0115] In some embodiments, the method for preparing the compound of formula (A-I') further comprises Converted to formula (A-IV) of compounds.

[0116] In some embodiments, the compound of formula (A-VI') is

[0117] In some embodiments, converting the compound of formula (A-VI') to the compound of formula (AI) further comprises converting the compound of formula (A-VI') to the compound of formula (A-VII') The compound of formula (A-VII') is then reduced and dehydrated to form the compound of formula (AI).

[0118] In some embodiments, the compound of formula (A-VII') is

[0119] In some embodiments, the reaction of the compound of formula (AI) and the boronating agent is carried out in the presence of a first catalyst. In some embodiments, the first catalyst comprises one or more Ni catalyst precursors and one or more ligands. In some embodiments, the first catalyst is formed by combining a nickel catalyst precursor and one or more ligands. In some embodiments, the first catalyst is formed by combining a nickel catalyst precursor and one or more ligands in an organic solvent (e.g., toluene, xylene, or THF).

[0120] In some embodiments, the Ni catalyst precursor is selected from NiCl2, Ni(Acac)2, Ni(COD)2, NiCl2(PPh3)2, NiCl2(PCy2Ph)2, NiCl2(PPh2CH2CH2PPh2), NiCl2(1,3-bis(diphenylphosphino)propane) and NiCl2(1,3-bis(diphenylphosphino)ethane). In some embodiments, the Ni catalyst precursor is NiCl2 or Ni(Acac)2. In some embodiments, the Ni catalyst precursor is NiCl2.

[0121] In some embodiments, the ligand is monodentate or bidentate. In some embodiments, the ligand is selected from aliphatic, aromatic, NHC ligands, phosphites, phosphoramidites and amines. In some embodiments, the ligand is selected from NHC ligands, phosphine, phosphites, phosphoramidites, amines, alcohols, amino alcohols and combinations thereof. In some embodiments, the ligand is an amine optionally substituted with aryl, alkyl and / or heteroaryl. In some embodiments, the ligand is an NHC ligand. In some embodiments, the ligand is a phosphine. In some embodiments, the ligand is a phosphite. In some embodiments, the ligand is a phosphoramidite. In some embodiments, the ligand is an amine. In some embodiments, the ligand is an alcohol. In some embodiments, the ligand is an amino alcohol.In some embodiments, the ligand or catalyst is selected from bis(di-cyclopentylphosphonium)ethyltetrafluoroborate, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 2,2'-bis(dicyclohexylphosphino)-1,1'-biphenyl, 1,2-bis((di-tert-butylphosphino)methyl)benzene, 1,3-bis(1-adamantyl)imidazolium, 1,3-di-tert-butylimidazolium, 1,3-bis(2,6-diisopropyl-phenyl)-4,5-dihydroimidazol-2-ylidene, 1,3-bis(2,6-diisopropylphenyl)-1H-imidazol-3-ylidene, P(octyl)3, Dppf, DiPrf, dcype, JosiPhos 9-1、(S,S,R,R)-TangPhos、(S,S,R,R)-DuanPhos、DavePhos、P(tBu)3、XantPhos、(tBu)XantPhos、(R)-SegPhos、(R)-DM-SegPhos、(R)-MeOBIPHEP、(R,S)-BinaPhos、Binaphane、Phosphoramidite、(S)-SegphosRu(Oac)2、trans-PdCl2(Pcy3)2、[Rh(S,S)EtDuPhos(COD)]Otf、(S)-XylylPhanePhos、(R)-C3-TunePhos、(R)-DTBM-Garphos、(R)-DMM-Garphos、(R,R,R)-Xyl-SKP、Sulfo-XantPhos、Ta niaPhos, SPANPhos, tri(4-methoxyphenyl)phosphine, tri(2,6-dimethoxyphenyl)phosphine, trioctylphosphine, bis(dicyclohexylphosphino)methane), DCYPE, 1,3-bis(dicyclohexylphosphino)propane, 1,2-bis(diphenylphosphino)ethane, (R,R)-Dipamp, bis(dicyclohexylphosphinophenyl)ether, DPEPhos, bis(2-diphenylphosphinoethyl)phenylphosphine, 1,1,1-tris(2-diphenylphosphinoethyl)phenylphosphine, (diphenylphosphinomethyl)ethane, DPPF, 1,1′-diphenylphosphino-bis(dicyclohexylphosphine), DTBPF, DiPrF, 1-diphenylphosphino-1′-(di-butylphosphino)ferrocene, HiersoPhos, iPr(NHC), SIMes, IMes and (1,3-bis[bis(o-methoxyphenyl)phosphino]propane. In some embodiments, the ligand is P(octyl)3, diPrf or dcype.

[0122] In some embodiments, the ligand is selected from bis(di-cyclopentylphosphonium)ethyltetrafluoroborate, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 2,2'-bis(dicyclohexylphosphino)-1,1'-biphenyl, 1,2-bis((di-tert-butylphosphino)methyl)benzene, 1,3-bis(1-adamantyl)imidazolium, 1,3-di-tert-butylimidazolium, 1,3-bis(2,6-diisopropyl-phenyl)-4,5-dihydroimidazol-2-ylidene, 1,3-bis(2,6-diisopropylphenyl)-1H-imidazol-3-ylidene, P(octyl)3, Dppf, DiPrf, dcype, JosiPhos 9-1, (S,S,R,R)-TangPhos, (S,S,R,R)-DuanPhos, DavePhos, P(tBu)3, XantPhos, (tBu)XantPhos, (R)-SegPhos, (R)-DM-SegPhos, (R)-MeOBIPHEP, (R,S)-BinaPhos, Binaphane, phosphoramidite, (S)-XylylPhanePhos, (R)-C3-TunePhos, (R)-DTBM-Garphos, (R)-DMM-Garphos, (R,R,R)-Xyl-SKP, thio-XantPhos, TaniaPhos, SPANPhos, tri(4-methoxyphenyl)phosphine, tri( 2,6-dimethoxyphenyl)phosphine, trioctylphosphine, bis(dicyclohexylphosphino)methane), DCYPE, 1,3-bis(dicyclohexylphosphino)propane, 1,2-bis(diphenylphosphino)ethane, (R,R)-Dipamp, bis(dicyclohexylphosphinophenyl)ether, DPEpHos, bis(2-diphenylphosphinoethyl)phenylphosphine, 1,1,1-tris(diphenylphosphinomethyl)ethane, DPPF, 1,1′-diphenylphosphino-bis(dicyclohexylphosphine), DTBPF, DiPrF, 1-diphenylphosphino-1′-(di-butylphosphino)ferrocene, HiersoPhos, iPr(NHC), SIMes, IMes and (1,3-bis[bis(o-methoxyphenyl)phosphino]propane. In some embodiments, the ligand is P(octyl)3, diPrf or dcype.

[0123] In some embodiments, the amount of Ni catalyst precursor is about 5mol% to about 25mol% of the compound of formula (AI). In some embodiments, the amount of Ni catalyst precursor is about 5mol%, 10mol%, 15mol%, 20mol%, 25mol%, 30mol%, 40mol%, 50mol% of the compound of formula (AI). In some embodiments, the amount of Ni catalyst precursor is greater than about 1mol%, 5mol%, 10mol%, 15mol%, 20mol%, 25mol%, 30mol%, 40mol%, 50mol% of the compound of formula (AI). In some embodiments, the amount of Ni catalyst precursor is less than about 5mol%, 10mol%, 15mol%, 20mol%, 25mol%, 30mol%, 40mol%, 50mol% of the compound of formula (AI). In some embodiments, the amount of Ni catalyst precursor is from about 1 mol% to about 20 mol%, from about 1 mol% to about 30 mol%, from about 5 mol% to about 20 mol%, from about 5 mol% to 30 mol%, from about 5 mol% to about 40 mol%, from about 5 mol% to about 50 mol% of the compound of formula (AI).

[0124] The ratio of ligand to Ni catalyst precursor can depend on the type of precursor and ligand used. In some embodiments, the ratio of ligand to Ni catalyst precursor can be about 0.5 to about 5. In some embodiments, the ratio of ligand to Ni catalyst precursor can be about 0.5, 1, 1.5, 2, 2.5 or 5. In some embodiments, the ratio of ligand to Ni catalyst precursor can be about 0.1 to 10, 0.5 to 5, 0.5 to 3, 0.5 to 2.5, 1 to 2, 1 to 3, 1 to 4, 1 to 5 or 1 to 2.5. In some embodiments, the ratio of ligand to Ni catalyst precursor can be greater than about 0.1, 0.5, 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, 6 or 10. In some embodiments, the ratio of ligand to Ni catalyst precursor can be less than 0.5, 1, 1.25, 1.5, 1.75, 2, 3, 4, 5, 6, 10 or 20.

[0125] In some embodiments, the reaction of the compound of formula (AI) and the boronating agent is carried out in the presence of a base system. In some embodiments, the base system includes one or more inorganic bases. In some embodiments, the base system includes K2CO3, Cs2CO3, Li2CO3 or any combination thereof.

[0126] In some embodiments, the base system comprises a mixture of K2CO3 and Cs2CO3, wherein the molar ratio of K2CO3 to Cs2CO3 is about 5: 1 to 15: 1. In some embodiments, the base system comprises a mixture of K2CO3 and Cs2CO3, wherein the molar ratio of K2CO3 to Cs2CO3 is about 9:1.

[0127] In some embodiments, the reaction of the compound of formula (AI) and the boronating agent is carried out using a catalyst system including NiCl2 and P(octyl)3 in the presence of K2CO3 and Cs2CO3, wherein the molar ratio of K2CO3 to Cs2CO3 is 9:1.

[0128] In some embodiments, the method further comprises combining a nickel precursor and a ligand to prepare a first catalyst. In some embodiments, one or more organic solvents are used to prepare the first catalyst. In some embodiments, the reaction of the compound of formula (AI) and the boronating agent is carried out in an organic solvent. In some embodiments, the organic solvent is selected from THF, CH2Cl2, chlorobenzene, AcOEt and toluene. In some embodiments, the organic solvent is toluene or THF.

[0129] In some embodiments, the reaction of the compound of formula (AI) and the borating agent is carried out at a temperature of about 70° C. to 100° C. In some embodiments, the reaction of the compound of formula (AI) and the borating agent is carried out at a temperature of about 90° C.

[0130] In some embodiments, a cyclopropyl group is introduced by reacting an organoboron intermediate (e.g., a compound of formula (A-II)) with a carbene or with diazomethane in the presence of a second catalyst. In some embodiments, a cyclopropyl group is introduced by reacting an organoboron intermediate (e.g., a compound of formula (A-II)) with diazomethane. In some embodiments, the cyclopropyl group is introduced into an organoboron intermediate (e.g., a compound of formula (A-II)) in the presence of a second catalyst. In some embodiments, a cyclopropyl group is introduced by reacting an organoboron intermediate (e.g., a compound of formula (A-II)) with a Simmons Smith reagent. In some embodiments, a cyclopropyl group is introduced using diazomethane.

[0131] In some embodiments, the second catalyst is a metal catalyst. In some embodiments, the second catalyst includes a Pd catalyst, a Cu catalyst, a Zn catalyst, a Fe catalyst, a Mn catalyst, a Rh catalyst or a combination thereof. In some embodiments, the second catalyst is a Pd catalyst. In some embodiments, the Pd catalyst is a Pd (II) catalyst. In some embodiments, the Pd catalyst is Pd (OAc) 2. In some embodiments, the Cu catalyst is a Cu (I) catalyst. In some embodiments, the Cu catalyst is Cu (OTf), Cu (OtBu) or CuCl / NaBArF.

[0132] In some embodiments, the reaction of the organoboron intermediate (e.g., a compound of formula (A-II)) with a borating agent is carried out in the presence of one or more chiral auxiliary agents. In some embodiments, the chiral auxiliary agent is combined with the organoboron intermediate to form a chiral complex. In some embodiments, the chiral complex has a structure of formula (A-II'). In some embodiments, the chiral complex can be reacted with a cyclopropylating agent to form a compound of formula (A-III).

[0133] In some embodiments, the chiral auxiliary is selected from monohydric alcohols, diols, amino alcohols, diamines, and hydroxy acids and esters. In some embodiments, the chiral auxiliary is selected from (R)-(+)-1-phenylethanol, L-menthol, (-)-camphenol, (4S,5S)-2,2-dimethyl-α,α,α',α'-tetraphenyldioxolane-4,5-dimethanol, (R)-(+)-1,1'-bis(2-naphthol), (R)-(-)-2-phenylglycinol, (R)-(-)-2-amino-1-phenylethanol, (S,S)-(-)-2-amino-1,2-diphenylethanol, (R)-(-)-2-pyrrolidinemethanol, (R)-(+)-α,α,-diphenyl-2-pyrrolidinemethanol, (1R,2S)-(-)-ephedrine, (1R,2R)- (+)-1,2-diphenylethylenediamine, (1R,2R)-(-)-N-p-toluenesulfonyl-1,2,-diphenylethylenediamine, L-(+)-lactic acid, (R)-(-)-mandelic acid, (-)-methyl L-lactate, L-(+)-tartaric acid, L-(+)-dimethyl tartarate, (1S,2S)-(+)-pseudoephedrine, (1R,2S)-(-)-norephedrine, (1R,2S)-(-)-N-methylephedrine, (S)-2-(pyrrolidin-2-yl)propan-2-ol, N-methyl-D-glucamine, (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, quinine and hydroquinine. In some embodiments, the chiral auxiliary is ephedrine or an ephedrine derivative. In some embodiments, the chiral auxiliary agent is selected from (1S,2S)-(+)-pseudoephedrine, (1R,2S)-(-)-norephedrine, (1R,2S)-(-)-N-methylephedrine, and combinations thereof. In some embodiments, the chiral auxiliary agent is (1S,2S)-(+)-pseudoephedrine.

[0134] In some embodiments, the compound of formula (A-III) can be prepared with an enantiomeric excess of greater than about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 99%. In some embodiments, the compound of formula (A-III) can be prepared with an enantiomeric excess of less than about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 99%. In some embodiments, the compound of formula (A-III) can be prepared with an enantiomeric excess of about 30% to 60%, about 30% to 80%, about 30% to 90%, 40% to 60%, about 40% to 80%, about 340% to 90%, about 50% to 90%, about 30% to 99%, about 40% to 99%, or about 50% to 99%. In some embodiments, the synthesis of compounds of Formula (A-III) (e.g., Compound 3) can be achieved with an enantiomeric excess of greater than about 50%, about 60%, about 70%, about 80%, about 90%, or about 95%.

[0135] Scheme A below summarizes the synthetic routes for compounds of formula (I) described herein. 1 is a carboxylic acid protecting group. The reaction product of step 2 can be subjected to an enantiomeric purification step to produce a compound of formula (A-III) with high purity. Purification can be performed using chromatography or crystallization.

[0136] Plan A

[0137]

[0138] In Scheme A, step 1 reaction can be carried out in the presence of a first catalyst. The first catalyst can be prepared by combining a metal catalyst precursor and one or more ligands. In some embodiments, the first catalyst can be prepared by combining a Ni catalyst precursor and one or more ligands. In some embodiments, the first catalyst can be a Ru or Ni catalyst. The ligand used in the reaction of step 1 can be a phosphine ligand, such as P(octyl)3, diPrf or dcype. Step 2 reaction can be carried out in the presence of a second catalyst. In some embodiments, the second catalyst includes a metal catalyst and one or more chiral auxiliary agents. In some embodiments, the second catalyst includes a Pd catalyst and one or more chiral auxiliary agents, such as ephedrine or an ephedrine derivative (e.g., (1S, 2S)-(+)-pseudoephedrine). The reaction product of step 2 can also be purified to produce a compound of formula (A-III) with high purity. Purification can be achieved by chromatography, crystallization, and other purification methods suitable for separating enantiomers.

[0139] Compound A and its salts (eg, sodium salt) can be prepared using Scheme B shown below. The cyclopropylating agent can be CH2N2, Pd(OAc)2 (with or without a chiral auxiliary) or Et2Zn, CH2I2 and DME.

[0140] Plan B

[0141]

[0142] The enantioselective cyclopropanation of 2 can directly produce the desired target compound with good stereocontrol. The cyclopropanation reagent used here can include diazomethane with a metal catalyst and one or more chiral auxiliary agents. Some chiral auxiliary agents such as ephedrine or ephedrine derivatives (e.g., (1S, 2S)-(+)-pseudoephedrine) can lead to high enantioselectivity in the cyclopropanation step.

[0143] Plan C

[0144]

[0145] The borylation step can form an organoboron intermediate that can be used later in a cyclopropanation reaction. Scheme C shows a non-limiting example of a boronate intermediate and subsequent reaction prior to performing the cyclopropanation step. In some embodiments, the organoboron intermediate 2 (R a is OH or optionally substituted -OC 1-6 alkyl) can be combined with one or more chiral auxiliaries to form a chiral complex 2'(R c and R d With any intervening atoms to form an optionally substituted 4- to 7-membered heterocyclyl ring). In some embodiments, the chiral complex can be subjected to a cyclopropanation step to form a compound of formula (A-III) with high enantioselectivity.

[0146] In some embodiments, the cyclopropanation reaction can be carried out in parallel equipment when possible. The original reaction products can be analyzed (e.g., by 1 H-NMR) and analysis of compound 3 (e.g., chiral HPLC) to monitor the results.

[0147] Some embodiments relate to the synthesis of compound A-II (e.g., compound 2). In some embodiments, oxaborin, such as compound 2, can be prepared by inserting boron into the C2-O bond of benzofuran using a Ni catalyst. In some embodiments, the reaction described in JACS, 2016, 15315 and Yorimitsu et al. (both of which are incorporated by reference as a whole) can be used to prepare oxaborin, such as compound 2. In some embodiments, compound 2 can be prepared from benzofuran derivative 1, as shown in Scheme D.

[0148] Solution D: Boration

[0149]

[0150] In some embodiments, as described in Scheme D, the reaction with a catalyst produced in situ by Ni(COD)2 and iPr-NHC or dcype at 10% catalyst loading can have a yield of 40% to 50%. In some embodiments, the reaction can be carried out in a glove box. In some embodiments, the reaction can be carried out outside the glove box. In some embodiments, Cs2CO3 used in large excess can be replaced by a 9:1 mixture of K2CO3 / Cs2CO3. In some embodiments, Ni(Acac)2 and NiCl2 can also be used as Ni catalyst precursors. In some embodiments, by using Ni(Acac)2 and dcype to maintain a water content as low as possible (dried CsCO3, anhydrous solvent, etc.), the reaction can achieve a high yield (>90%). In some embodiments, a 9:1 mixture of K2CO3 / Cs2CO3 can achieve a yield higher than 80% (e.g., a conversion rate of 85% after 24 hours).

[0151] In some embodiments, the cleavage and further functionalization (arylation, alkylation, borylation) of the CO bond in the aryl ether can be achieved with a variety of metal catalysts, including but not limited to Ni (as described in JACS, 1979, 2246 and JACS, 2016, 6711; JACS, 2017, 10347, which are incorporated by reference as a whole), Ru (as described in Ang Chem Int Ed, 2015, 9293, which is incorporated herein by reference as a whole) and Rh (as described in JACS, 2015, 1593, which is incorporated by reference as a whole). In all cases, a series of ligands selected from monodentate / bident phosphines or N-heterocyclic carbenes can be used. Additives can also be used to improve yields, as described in Org Lett 2013, 6298, which are incorporated by reference as a whole. In some embodiments, applicable catalysts and ligands can include Ni, Ru, Rh catalysts and other commercially available ligands / catalysts. In some embodiments, the applicable catalyst and ligand may be Ni.

[0152] In some embodiments, relatively cheap catalysts and ligands with high turnover numbers, low-cost alkalis and other reagents that are easily available can be used in the reactions described herein. For example, when compared with other metal catalysts, NiCl is a cheap catalyst, and when compared with other ligands, trioctylphosphine is a low-cost ligand. NiCl and trioctylphosphine can be used in the borylation reaction described herein in combination to achieve high yields.

[0153] In some embodiments, the catalyst used to convert compound 1 to compound 2 (Scheme D) can achieve a yield of at least 90%.

[0154] In some embodiments, the reaction can have a yield of at least 50% for the desired compound 2.

[0155] In some embodiments, suitable catalysts may include the ligands or catalysts shown in Table 1. Exemplary metal precursors for preparing the catalysts for the reaction are listed in the table below.

[0156] Table 1. Ni metal precursors used for borylation reactions.

[0157]

[0158] Table 2a and Table 2b list some examples of ligands, including phosphines (monodentate or bidentate, aliphatic or aromatic), NHC ligands, phosphites, phosphoramidites, amines (see below examples of phosphines related to dcpE and NHC).

[0159] Table 2a. Examples of ligands used in borylation reactions

[0160]

[0161] Table 2b. Examples of ligands used in borylation reactions

[0162]

[0163] Except part / catalyst, some reaction parameters are also important, comprise alkali, solvent, temperature and additive.In some embodiments, reaction can be carried out in the organic solvent selected from toluene, THF, dioxane and any combination thereof.In some embodiments, reaction can use halogenide, Lewis acid (activation benzofuran is to carry out CO bond cracking), organic base.In some embodiments, reaction can use Cs2CO3.

[0164] In some embodiments, the reactions described herein can achieve 90% isolated yields. In some embodiments, the reactions described herein can have yields greater than 80% with about 1 mol% catalyst (or as low a catalyst loading as possible).

[0165] Some embodiments involve having or The structure of the compound.

[0166] Some embodiments involve having or The structure of the compound.

[0167] In some embodiments, the pharmaceutically acceptable salt is selected from an alkali metal salt or an ammonium salt. In one embodiment, the pharmaceutically acceptable salt is a sodium salt.

[0168] When the compounds disclosed herein have at least one chiral center, they can exist as individual enantiomers and diastereomers or as mixtures of such isomers (including racemates). Separation of individual isomers or selective synthesis of individual isomers is achieved by applying a variety of methods known to practitioners in the art. Unless otherwise noted, all such isomers and mixtures thereof are included in the scope of compounds disclosed herein. In addition, compounds disclosed herein may exist in one or more crystalline forms or amorphous forms. Unless otherwise noted, all such forms (including any polymorphic forms) are included in the scope of compounds disclosed herein. In addition, some compounds disclosed herein can form solvates (i.e., hydrates) with water or form solvates with common organic solvents. Unless otherwise noted, such solvates are included in the scope of compounds disclosed herein.

[0169] The skilled artisan will recognize that some of the structures described herein may be resonance forms or tautomers of compounds that may be clearly represented by other chemical structures, even kinetically; the skilled artisan will recognize that such structures may represent only a very small sample of such compounds. Although such resonance forms or tautomers are not represented herein, such compounds are considered to be within the scope of the described structures.

[0170] definition

[0171] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present disclosure belongs. All patents, applications, published applications, and other publications are incorporated herein by reference in their entirety. Where multiple definitions exist for a term in this article, the definitions in this section shall prevail unless otherwise stated.

[0172] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effects and properties of a compound and is not biologically or otherwise undesirable for use in medicine. In many cases, due to the presence of an amino group and / or a carboxyl group or a group similar thereto, the compounds disclosed herein are capable of forming acid salts and / or basic salts. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be obtained include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be obtained include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Pharmaceutically acceptable base addition salts can also be formed with inorganic bases and organic bases. Inorganic bases from which salts can be obtained include, for example, bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; ammonium, potassium, sodium, calcium, and magnesium salts are particularly preferred. In some embodiments, treatment of the compounds disclosed herein with an inorganic base results in the loss of an unstable hydrogen in the compound to yield a compound containing, for example, Li + 、Na + , K + Mg 2+ and Ca 2+ The salt form of inorganic cations such as . Organic bases from which salts can be obtained include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, Johnston et al., published September 11, 1987, which is incorporated herein by reference in its entirety.

[0173] As used herein, “Ca To C b " or "C a-b ” (where “a” and “b” are integers) refers to the number of carbon atoms in the specified group. That is, the group can contain from “a” to “b” (including a and b) carbon atoms. Thus, for example, “C1 to C4 alkyl” or “C 1-4 "Alkyl" groups refer to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, (CH3)2CHCH2- and (CH3)3C-.

[0174] The term "halogen" or "halo" as used herein means any of the radiostable atoms in column 7 of the periodic table, such as fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine.

[0175] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., does not contain double or triple bonds). The alkyl group can have 1 to 20 carbon atoms (whenever it appears in this article, a numerical range such as "1 to 20" refers to each integer in the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also covers the term "alkyl" in which no numerical range is specified). The alkyl group can also be a medium-sized alkyl group having 1 to 9 carbon atoms. The alkyl group can also be a low alkyl group having 1 to 4 carbon atoms. The alkyl group can be designated as "C 1-4 alkyl" or similar designation. By way of example only, "C 1-4 "Alkyl" means that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Typical alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.

[0176] As used herein, "alkoxy" refers to a group of the formula -OR, wherein R is an alkyl group as defined above, for example "C 1-9 "Alkoxy" includes, but is not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, etc.

[0177] As used herein, "alkylthio" refers to the formula -SR, wherein R is an alkyl group as defined above, for example "C 1-9"Alkylthio" and the like, including but not limited to methylthio, ethylthio, n-propylthio, 1-methylethylthio (isopropylthio), n-butylthio, isobutylthio, sec-butylthio, tert-butylthio and the like.

[0178] As used herein, "alkenyl" refers to a straight or branched hydrocarbon chain containing one or more double bonds. An alkenyl group can have from 2 to 20 carbon atoms, however, this definition also encompasses the term "alkenyl" where an unspecified numerical range is present. An alkenyl group can also be a medium-sized alkenyl group having from 2 to 9 carbon atoms. An alkenyl group can also be a lower alkenyl group having from 2 to 4 carbon atoms. An alkenyl group can be designated as "C 2-4 By way of example only, "C 2-4 “Alkenyl” means that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2-dienyl and buta-1,2-dien-4-yl. Typical alkenyl groups include, but are by no means limited to, ethenyl, propenyl, butenyl, pentenyl and hexenyl, and the like.

[0179] As used herein, "alkynyl" refers to a straight or branched hydrocarbon chain containing one or more triple bonds. Alkynyl groups can have from 2 to 20 carbon atoms, however, this definition also encompasses the term "alkynyl" where an unspecified numerical range is present. Alkynyl groups can also be medium-sized alkynyl groups having from 2 to 9 carbon atoms. Alkynyl groups can also be low-sized alkynyl groups having from 2 to 4 carbon atoms. Alkynyl groups can be designated as "C 2-4 "alkynyl" or similar designation. By way of example only, "C 2-4 "Alkynyl" means that there are two to four carbon atoms in the alkynyl chain, that is, the alkynyl chain is selected from ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl and 2-butynyl. Typical alkynyl groups include, but are by no means limited to, ethynyl, propynyl, butynyl, pentynyl and hexynyl, etc.

[0180] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms (i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur) in the backbone of the chain. A heteroalkyl group can have from 1 to 20 carbon atoms, however, this definition also encompasses the term "heteroalkyl" where an unspecified numerical range is present. A heteroalkyl group can also be a medium-sized heteroalkyl group having from 1 to 9 carbon atoms. A heteroalkyl group can also be a low-sized heteroalkyl group having from 1 to 4 carbon atoms. A heteroalkyl group can be designated as "C 1-4"heteroalkyl" or similar designation. A heteroalkyl group may contain one or more heteroatoms. By way of example only, "C 1-4 "Heteroalkyl" means having from one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.

[0181] As used herein, "alkylene" means a fully saturated branched or straight chain diradical chemical group containing only carbon and hydrogen, which is attached to the rest of the molecule via two points of attachment (i.e., alkanediyl). Alkylene groups can have from 1 to 20 carbon atoms, however, this definition also encompasses the term alkylene where an unspecified numerical range is present. Alkylene groups can also be medium-sized alkylene groups having from 1 to 9 carbon atoms. Alkylene groups can also be lower alkylene groups having from 1 to 4 carbon atoms. Alkylene groups can be designated as "C 1-4 "alkylene" or similar designation. By way of example only, "C 1-4 "Alkylene" means having from one to four carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from methylene, ethylene, ethane-1,1-diyl, propylene, propylene-1,1-diyl, propylene-2,2-diyl, 1-methyl-ethylene, butylene, butane-1,1-diyl, butane-2,2-diyl, 2-methyl-propylene-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene and 1-ethyl-ethylene.

[0182] As used herein, "alkenylene" means a straight or branched diradical chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond, which is connected to the rest of the molecule via two points of attachment. An alkenylene group can have from 2 to 20 carbon atoms, however, this definition also encompasses the term alkenylene where there is no specified numerical range. An alkenylene group can also be a medium-sized alkenylene group having from 2 to 9 carbon atoms. An alkenylene group can also be a low-sized alkenylene group having from 2 to 4 carbon atoms. An alkenylene group can be designated as "C 2-4 "C 2-4The term "alkenylene" means that there are two to four carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from vinylene, ethylene-1,1-diyl, propenylene, propen-1,1-diyl, prop-2-ene-1,1-diyl, 1-methylvinylene, but-1-enyl, but-2-enyl, but-1,3-dienyl, butene-1,1-diyl, but-1,3-diene-1,1-diyl, but-2- ... -1,1-diyl, but-3-ene-1,1-diyl, 1-methyl-prop-2-ene-1,1-diyl, 2-methyl-prop-2-ene-1,1-diyl, 1-ethyl-vinylidene, 1,2-dimethyl-vinylidene, 1-methyl-propenylidene, 2-methyl-propenylidene, 3-methyl-propenylidene, 2-methyl-propenylidene, and 2,2-dimethyl-ethylene-1,1-diyl.

[0183] The term "aromatic" refers to a ring or ring system having a conjugated π electron system and includes carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of atoms) groups, provided that the entire ring system is aromatic.

[0184] As used herein, "aryl" refers to an aromatic ring or ring system containing only carbon in the ring backbone (i.e., two or more fused rings that share two adjacent carbon atoms). When aryl is a ring system, each ring in the system is aromatic. Aryl groups can have from 6 to 18 carbon atoms, although this definition also encompasses the term "aryl" where no numerical range is specified. In some embodiments, aryl groups have from 6 to 10 carbon atoms. Aryl groups can be designated as "C 6-10 Aryl", "C6 or C 10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.

[0185] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, wherein R is an aryl group as defined above, for example, "C 6-10 Aryloxy" or "C 6-10 "Arylthio" and the like, including but not limited to phenoxy.

[0186] "Aralkyl" or "arylalkyl" is an aryl group attached as a substituent through an alkylene group, such as "C 7-14 "Aralkyl" and the like, including but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C 1-4 alkylene group).

[0187] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms) containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen and sulfur) in the ring backbone. When heteroaryl is a ring system, each ring in the system is aromatic. The heteroaryl group can have 5 to 18 ring members (i.e., the number of atoms constituting the ring backbone, including carbon atoms and heteroatoms), but the present definition also encompasses the term "heteroaryl" in which an unspecified numerical range exists. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group can be designated as "5- to 7-membered heteroaryl", "5- to 10-membered heteroaryl" or similar designations. Examples of heteroaryl rings include, but are not limited to, furanyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothiophenyl.

[0188] "Heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group as a substituent attached via an alkylene group. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furanylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., C 1-4 alkylene group).

[0189] As used herein, "carbocyclyl" means a non-aromatic ring or ring system containing only carbon atoms in the main chain of the ring system. When a carbocyclyl is a ring system, two or more rings are joined together in a fused, bridged or spiro-connected manner. The carbocyclyl can have any degree of saturation, provided that at least one ring in the ring system is non-aromatic. Therefore, carbocyclyl includes cycloalkyl, cycloalkenyl and cycloalkynyl. A carbocyclyl group can have 3 to 20 carbon atoms, however, this definition also encompasses the term "carbocyclyl" where an unspecified numerical range exists. A carbocyclyl group can also be a medium-sized carbocyclyl group having 3 to 10 carbon atoms. A carbocyclyl group can also be a carbocyclyl group having 3 to 6 carbon atoms. A carbocyclyl group can be designated as "C 3-6 Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicyclo[2.2.2]octanyl, adamantyl, and spiro[4.4]nonyl.

[0190] "(Carbocyclyl)alkyl" is a carbocyclyl group attached as a substituent via an alkylene group, for example "C 4-10"(Carbocyclyl)alkyl" and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl and the like. In some cases, the alkylene group is a lower alkylene group.

[0191] As used herein, "cycloalkyl" means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0192] As used herein, "cycloalkenyl" means a carbocyclic ring or ring system having at least one double bond, wherein none of the rings in the ring system is aromatic. An example is cyclohexenyl.

[0193] As used herein, "heterocyclyl" means a non-aromatic ring or ring system containing at least one heteroatom in the ring backbone. The heterocyclyl group can be joined together in a fused, bridged or spirally connected manner. The heterocyclyl group can have any degree of saturation, provided that at least one ring in the ring system is non-aromatic. The heteroatom can be present in a non-aromatic ring or an aromatic ring in the ring system. The heterocyclyl group can have 3 to 20 ring members (i.e., the number of atoms constituting the ring backbone, including carbon atoms and heteroatoms), but this definition also covers the term "heterocyclyl" in which an unspecified numerical range exists. The heterocyclyl group can also be a medium-sized heterocyclyl with 3 to 10 ring members. The heterocyclyl group can also be a heterocyclyl with 3 to 6 ring members. The heteroatoms in the ring can include O, N, B or S. The heterocyclyl group can be designated as "3- to 6-membered heterocyclyl" or similar designation. In preferred six-membered monocyclic heterocyclic groups, heteroatoms are selected from one to three of O, N, B or S, and in preferred five-membered monocyclic heterocyclic groups, heteroatoms are selected from one or two heteroatoms of O, N, B or S. In monocyclic heterocyclic groups containing 4, 5, 6, 7 or 8 atoms, heteroatoms are selected from one to three of O, N, B or S, and in preferred five- or six-membered monocyclic heterocyclic groups, heteroatoms are selected from one or two heteroatoms of O, N, B or S. Examples of heterocyclyl rings include, but are not limited to, dioxaborolane, nitroborolane, azaborolane, oxaborolane, oxazoborolane, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathianyl 1,4-oxathiolanyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinone, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiomorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl and tetrahydroquinoline.

[0194] "(Heterocyclyl)alkyl" is a heterocyclyl group attached as a substituent via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0195] As used herein, "acyl" refers to -C(=O)R, wherein R is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl. Non-limiting examples include formyl, acetyl, propionyl, benzoyl, and acryloyl.

[0196] An "O-carboxyl" group refers to a "-OC(=O)R" group, wherein R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0197] A "C-carboxyl" group refers to a "-C(=O)OR" group, wherein R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl. Non-limiting examples include carboxyl (ie, -C(=O)OH).

[0198] A "cyano" group refers to a "-CN" group.

[0199] A "cyanato" group refers to a "-OCN" group.

[0200] An "isocyanato" group refers to a "-NCO" group.

[0201] "Thiocyanato" refers to a "-SCN" group.

[0202] An "isothiocyanato" group refers to a "-NCS" group.

[0203] A "sulfinyl" group refers to a "-S(=O)R" group, wherein R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0204] A "sulfonyl" group refers to a "-SO2R" group, wherein R is selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0205] The "S-sulfonamido" group refers to the "-SO2NR A R B " group, wherein, as defined herein, R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0206] An "N-sulfonamido" group refers to an "-N(R A )SO2R B " group, wherein, as defined herein, R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0207] An "O-carbamoyl" group refers to a "-OC(=O)NR A R B " group, wherein, as defined herein, R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0208] An "N-carbamoyl" group refers to an "-N(R A )C(=O)OR B " group, wherein, as defined herein, R A and R B are each independently selected from hydrogen, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0209] An "O-thiocarbamoyl" group refers to an "-OC(=S)NR A R B " group, wherein, as defined herein, R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0210] An "N-thiocarbamoyl" group refers to an "-N(R A )C(=S)OR B " group, wherein, as defined herein, R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0211] A "C-amido" group refers to a "-C(=O)NR A R B " group, wherein, as defined herein, R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0212] An "N-amido" group refers to an "-N(R A )C(=O)R B " group, wherein, as defined herein, R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl.

[0213] An "amino" group refers to an "-NR A R B " group, wherein, as defined herein, R A and R B are each independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Carbocyclic group, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl. Non-limiting examples include free amino (ie, -NH2).

[0214] An "aminoalkyl" group refers to an amino group attached through an alkylene group.

[0215] An "alkoxyalkyl" group refers to an alkoxy group attached through an alkylene group, for example, "C 2-8 "Alkoxyalkyl" and the like.

[0216] As used herein, the substituted group is derived from an unsubstituted parent group in which one or more hydrogen atoms are exchanged with another atom or group. Unless otherwise indicated, when a group is considered to be "substituted", it means that the group is substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halogen, C1-C6 substituted), 3- to 10-membered heterocyclyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 3- to 10-membered heterocyclyl-C1-C6-alkyl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), aryl (C1-C6) alkyl (optionally substituted with halogen, C1-C6 C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy substituted), 5- to 10-membered heteroaryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), 5- to 10-membered heteroaryl (optionally substituted with halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl and C1-C6 haloalkoxy), halogen, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy (C1-C6) alkyl (i.e., ether ), aryloxy, thiol (mercapto), halo (C1-C6) alkyl (e.g., -CF3), halo (C1-C6) alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino (C1-C6) alkyl, nitro, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonylamino, N-sulfonylamino, C-carboxyl, O-carboxyl, acyl, cyano, isocyano, thiocyano, isothiocyano, sulfinyl, sulfonyl, and oxo (=O). Unless otherwise indicated, whenever a group is described as "optionally substituted", the group may be substituted by the above substituents.

[0217] It is understood that certain radical naming conventions may include monoradicals or diradicals, depending on the context. For example, when a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a diradical. For example, substituents identified as alkyl groups that require two points of attachment include diradicals, such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-, etc. Other radical naming conventions clearly indicate that the radical is a diradical, such as "alkylene" or "alkenylene".

[0218] When two R groups are considered to form a ring (e.g., a carbocyclyl, heterocyclyl, aryl or heteroaryl ring) "together with the atoms to which they are attached", it is meant that the collective unit of the atoms and the two R groups is the ring. When mentioned individually, the ring is no longer further limited by the definitions of the individual R groups. For example, when the following substructure is present:

[0219]

[0220] And R 1 ' and R 2 ' is defined as being selected from hydrogen and alkyl, or R 1 ' and R 2 ' together with the nitrogen to which they are attached form a heteroaryl group, which means that R 1 ' and R 2 ' may be selected from hydrogen or alkyl, or alternatively, the substructure has the structure:

[0221]

[0222] wherein Ring A is a heteroaryl ring containing said nitrogen.

[0223] Similarly, when two "adjacent" R groups are said to form a ring "together with the atoms to which they are attached," it is meant that the collective unit of the atoms, the intervening bond, and the two R groups is the ring. For example, when the following substructure is present:

[0224]

[0225] And R 1 ' and R 2 ' is defined as being selected from hydrogen and alkyl, or R 1 ' and R 2 ' together with the atoms to which they are attached form an aryl or carbocyclic group, which means that R 1 ' and R 2 ' may be selected from hydrogen or alkyl, or alternatively, the substructure has the structure:

[0226]

[0227] wherein A is an aryl ring or a carbocyclic group containing the double bond.

[0228] Whenever a substituent is described as a diradical (i.e., having two points of attachment to the rest of the molecule), it is understood that the substituent may be attached in any orientation unless otherwise specified. Thus, for example, a substituent described as -AE- or -AE- The substituents of include those oriented so that A is attached at the leftmost attachment point of the molecule, as well as those in which A is attached at the rightmost attachment point of the molecule.

[0229] Protecting Group

[0230] In some cases, it may be necessary to selectively carry out a chemical reaction at one reactive site in a multifunctional compound. One such method for achieving such selectivity is to temporarily block one or more reactive sites in a multifunctional compound with a protecting group. Such methods are generally referred to as "protecting" functional groups. Many protecting groups are known in the art. See, for example, Greene et al., Protective Groups in Organic Synthesis, Third Edition (John Wiley & Sons, Inc. 1999), which is incorporated herein by reference in its entirety; Wutz et al., Greene's Protective Groups in Organic Synthesis, Fourth Edition (John Wiley & Sons, Inc. 2007), which is incorporated herein by reference in its entirety. When more than one reactive site in a multifunctional compound needs to be protected, or when preparing a compound that will have more than one protected functional group, it is important to use an orthogonal protecting group. If the protecting group is easy to selectively remove, the protecting group is orthogonal.

[0231] In some embodiments, it may be desirable to protect one or more functional groups to prevent them from interfering in a desired reaction. For example, it may be desirable to protect one or more functional groups, such as amine, carboxylic acid and / or hydroxyl groups.

[0232] Suitable protecting groups for carboxylic acids include: esters, such as enzymatically cleavable esters, including heptyl, 2-N-(morpholinyl)ethyl, choline, (methoxyethoxy)ethyl, methoxyethyl; alkyl esters, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, neopentyl, hexyl, heptyl, nonyl, decyl and configurational isomers thereof; substituted methyl esters, such as 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, pivaloyloxymethyl, phenylacetoxymethyl, triisopropylsilylmethyl, cyanomethyl, acetol, benzoyl (phe 2-substituted ethyl esters, such as 2,2,2-trichloroethyl, 2-haloethyl, ω-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfinyl)ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2'-pyridyl)ethyl, 2-(p-methoxyphenyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, 2-(4-acetyl)ethyl, 2-(4-hydroxyphenyl ... phenyl, 2,6-dimethylphenyl, 2,6-diisopropylphenyl, 2,6-di-tert-butyl-4-methylphenyl, 2,6-di-tert-butyl-4-methoxyphenyl, p-(methylthio)phenyl, pentafluorophenyl, benzyl, 2,6-di-tert-butyl-4-methoxyphenyl ... substituted benzyl esters, for example triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzocycloheptyl, 1-pyrenylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, 4-azidomethoxybenzyl, 4-{N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino}benzyl, piperonyl, 4-picolyl, polymer-supported p-benzyl;Silyl esters, such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, isopropyldimethylsilyl, phenyldimethylsilyl, di-tert-butylmethylsilyl, triisopropylsilyl; activated esters, such as thiol esters; oxazoles; 2-alkyl-1,3-oxazolines; 4-alkyl-5-oxo-1,3-oxazolidines; 2,2-bistrifluoromethyl-4-alkyl-5-oxo-1,3-oxazolidines; 5-alkyl-4-oxo-1,3-dioxolanes; dioxanones; orthoesters; pentaaminocobalt(III) complexes; and stannyl esters , such as triethylstannyl and tri-n-butylstannyl; amides such as N,N-dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroaniline, N-7-nitroindolyl, N-8-nitro-1,2,3,4-tetrahydroquinolinyl, 2-(2-aminophenyl)acetaldehyde dimethyl acetalamide and polymer-supported p-benzenesulfonamide; hydrazides such as N-phenyl, N,N'-diisopropyl; and tetraalkylammonium salts such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, pentyl, neopentyl, hexyl, heptyl, nonyl, decyl and configurational isomers thereof. ;

[0233] Example

[0234] Example 1

[0235] Synthesis of Ethyl 6-Fluorobenzofuran-7-carboxylate

[0236] Benzofuran 1 is an intermediate for the preparation of compound A and is synthesized in 3 steps as shown in Scheme 1A. Slow Fisher esterification (2-3 days) of 6-fluoro-salicylic acid (1a) with methanesulfonic acid in ethanol affords 1b in excellent yield. The phenol group is then alkylated with bromoacetaldehyde diethyl acetal in the presence of t-BuOK in DMF at 100 °C to afford the benzofuran precursor 1c in quantitative yield. Ring closure is then achieved with Amberlyst 15 (sulfonic acid resin) in dichloroethane at 90 °C to afford the desired benzofuran 1 in an overall yield of 40-45%.

[0237] Option 1A

[0238]

[0239] Synthesis of 6-fluoro-salicylic acid ethyl ester 1b:

[0240] Methanesulfonic acid (20.8mL, 0.32mol) is added to a solution of hydroxy acid 1a (50g, 0.32mol) in EtOH (350mL) at room temperature. The clear light orange solution is heated to reflux. After reflux for 3 days, HPLC shows 93.5% conversion. EtOH (200mL) is distilled out and replaced with fresh EtOH (200mL). After an additional 24 hours at 90°C, HPLC shows 96.1% conversion. The pH of the cooled reaction mixture is raised to 7.0 with 4N NaOH (80mL), and most of EtOH is removed under vacuum. The residual heterogeneous two-phase mixture is absorbed in ethyl acetate (250mL) and water (100mL). Separate layer, and the organic phase is washed with water (100mL), then concentrated to dryness, azeotropic with heptane (100mL) and dried under high vacuum, to obtain 54.9g of compound 1b (93% yield). The product is used without purification.

[0241] Benzofuran precursor 1c:

[0242] Solid t-BuOK (43.5 g, 0.39 mol) was added to a solution of phenol 1b (54.9 g, 0.3 mol) in DMF (220 mL) at room temperature (24°C to 61°C exotherm). Once the temperature began to decrease, an alkylating agent (50 mL, 0.33 mol, 1.1 eq.) was added and the reaction mixture was heated at 100°C. After stirring at 100°C for 24 hours, HPLC showed that about 7.5% of the starting material remained. More alkylating agent (5 mL, 30 mmol, 0.1 eq.) was added. After additional stirring at 100°C for 24 hours, HPLC showed that only 2.4% of the starting material remained. The cooled black reaction mixture was quenched with water (250 mL) and diluted with MTBE (250 mL). The layers were separated and the organic phase was washed with water (2×250 mL). The MTBE solution was passed through a silica gel plug (9 g) and the plug was rinsed with MTBE (2×20 mL). The combined filtrates were concentrated under reduced pressure to give a black oil, 91 g, 101% yield.

[0243] Synthesis of benzofuran 1:

[0244] Amberlyst 15 (A15) resin (1.78 g, 20 wt%) was added to a solution of diethyl acetal 1c (8.9 g, 30 mmol) in dichloroethane (89 mL) at room temperature. The reaction mixture was heated at 90 ° C. After 3 days at 90 ° C, HPLC showed only 2.5% of the starting material. The reaction mixture was cooled to room temperature. The resin was filtered out and rinsed with dichloroethane. The filtrate was concentrated to dryness. The black oil was purified on silica gel by column chromatography using a gradient of 0% to 30% ethyl acetate in hexane to obtain a light orange oil, 3.049 g, 49% yield.

[0245] Example 2

[0246] Benzofuran 1f' was synthesized in 6 steps with only 2 isolations as shown in Scheme 1B. Sodium hydroxide-mediated fluoride displacement of 2,6-difluorobenzoic acid was carried out in excellent yield at 145 °C in water, and crude 6-fluorosalicylic acid 1b' was converted to the ethyl ester 1c' at reflux with methanesulfonic acid in ethanol. The phenol was then partially alkylated in a 2-step one-pot procedure by tBuOK-mediated reaction of potassium phenol with methyl chloroacetate followed by in situ selective saponification of the methyl ester to afford phenoxyacetic acid 1d' in 75% overall yield over 3 steps after crystallization from water. The carboxylic acid was derivatized to the acid chloride with oxalyl chloride and catalytic DMF, and ring closure was achieved by treatment with 2 equivalents of aluminum chloride to afford the benzofuranone 1e'. Compound 1e' was then converted to benzofuran 1 in a 2-step one-pot procedure by first reducing the ketone with sodium borohydride and acetic acid in THF, followed by in situ dehydration of the intermediate hydroxy-dihydrobenzofuran with HCl. The final compound was then obtained by saponification of the ethyl ester with NaOH in water and THF, followed by crystallization from water to afford 6-fluorobenzofuran-7-carboxylic acid 1f' with a yield of 70% over the last 3 steps and an overall yield of 53% from 2,6-difluorobenzoic acid.

[0247] Option 1B

[0248]

[0249] Step 1: Synthesis of 6-fluoro-salicylic acid 1b'. Solid NaOH (70.8 g, 1.77 mol, 7 equiv) was added in portions at 90°C to a suspension of 2,6-difluorobenzoic acid (40 g, 0.25 mol) in water (160 mL) in a Teflon flask, and the solution was heated at 145°C. After stirring at 140°C for 3 days, the conversion was 100% by HPLC, and 4% dimer was present. The reaction mixture was cooled to room temperature and diluted with a mixture of 9 / 1 MTBE / ethanol (200 mL). The two-phase mixture was cooled to 2.2°C. Concentrated HCl was added, keeping the temperature <20°C until pH 1.8 (150 mL). The organic layer was separated from the milky white aqueous layer, washed with 0.01N HCl (120 mL) and concentrated to dryness to give a pink solid, 37.7 g, 95.4% yield, 99.83% purity.

[0250] Step 2: Synthesis of 6-fluorosalicylic acid ethyl ester 1c'. Methanesulfonic acid (18.7 mL, 288 mmol, 0.6 eq) was added to a solution of crude fluorosalicylic acid 1b' (75 g, 480 mmol, 99.7% purity) in anhydrous EtOH (375 mL) at room temperature. The clear light amber solution was heated at 95°C. After 8 hours at reflux, half of the solvent was removed by distillation and replaced with anhydrous EtOH. After reflux for 3 days, the conversion rate was 93% by HPLC. Half of the EtOH was removed by distillation and replaced with the same amount of anhydrous EtOH. After reflux for an additional 24 hours, the conversion rate was 96% by HPLC. The clear light amber solution was cooled to 0°C. The pH was rinsed to about 7.0 with 4N NaOH (actual pH 7.15; 78 mL), and most of the EtOH was removed under vacuum. The remaining heterogeneous two-phase mixture was taken up in heptane (225 mL) and water (75 mL). The layers were separated and the organic layer was washed with water (150 mL), concentrated to dryness, azeotroped with heptane (2×75 mL) to remove water and residual EtOH, and dried in vacuo to give 79.2 g, 93% yield, 99.48% purity.

[0251] Step 3: Synthesis of 2-(2-ethoxycarbonyl-3-fluorophenoxy)acetic acid 1d'. Solid tBuOK (25.6 g, 228 mmol) was added to a solution of crude phenol (40 g, 217 mmol, 99.56% purity) in DMF (160 mL) at room temperature (exothermic to 55°C). After stirring at room temperature for 2 hours, a slightly heterogeneous mixture was obtained. Methyl chloroacetate (22 mL, 330 mmol) was added in one portion at room temperature (slow exothermic from 22°C to 38.2°C in 10 minutes). After stirring at room temperature for 18 hours, HPLC showed 4.1% of starting material remaining and 0.5% of Claisen condensation byproduct. The heterogeneous reaction mixture was cooled to -4°C and water (40 mL, Note 2) was added. The reaction mixture was cooled to -15°C and 2NNaOH (131 mL, 262 mmol) was added, keeping the temperature <-10°C. After the saponification of the methyl ester was complete (0.9% Claisen condensation byproduct), the reaction mixture was diluted with MTBE (80 mL) and the pH of the biphasic mixture was lowered to 6.0 with 6N HCl (5 mL). The layers were separated (the aqueous layer was retained) and the aqueous layer was extracted with MTBE (80 mL, the aqueous layer was retained). MTBE (120 mL) was added to the aqueous layer and the pH was lowered to 2.0 with 6N HCl. The layers were separated (the organic layer was retained) and the aqueous layer was extracted with MTBE (2×80 mL, Note 5). The combined organic extracts of the pH 2 aqueous layer were washed with water (2×80 mL) and most of the MTBE was removed under vacuum. Water (160 mL) was added and the biphasic mixture was heated at 60° C. in a light vacuum to remove the remaining MTBE (crude product purity = 96.35%). The mixture was cooled and seed crystals (5 mg) were added at 30° C. The product began to crystallize within a few minutes. After stirring overnight at room temperature, the solid was collected by filtration and rinsed with water (2 x 60 mL) then heptane (2 x 60 mL), air dried and then vacuum dried to give a white powder 44.2 g, 84% yield, 99.79% purity.

[0252] Step 4: Synthesis of 6-fluoro-3-oxo-benzofuran-7-carboxylic acid ethyl ester 1e'. Oxalyl chloride (6.3 mL, 73 mmol) was added to a solution of phenoxyacetic acid 1d' (14.8 g, 61 mmol, purity 99.5%) in dichloromethane (75 mL) containing DMF (0.08 mL) at room temperature (gas evolution). After stirring at room temperature for 3 hours, <1% of the starting material was measured by HPLC. The clear amber reaction mixture was concentrated to dryness and azeotroped with dichloromethane (2×30 mL). The brown oil was absorbed in dichloromethane (30 mL) and added to a suspension of aluminum chloride (16.3 g, 122 mmol) in dichloromethane (45 mL) at 0°C, keeping the temperature <10°C to obtain a clear amber solution. The reaction mixture was warmed to room temperature. After stirring at room temperature for 1 hour, the reaction mixture was heated to reflux. After stirring at reflux for 1 hour, HPLC showed <1% of the starting material. The reaction mixture was cooled to 0° C. and poured into water (75 mL) at 0° C., maintaining the temperature <10° C. The layers were separated and the organic layer was washed with brine (2×45 mL) and then concentrated to dryness to give a yellow oil that crystallized on standing, 13.47 g, 98% yield, 91.6% purity.

[0253] Step 5: Synthesis of ethyl 6-fluorobenzofuran-7-carboxylate 1. An aqueous solution of 3M NaBH4 was prepared by dissolving NaBH4 (2.27 g) in 0.01 N NaOH (20 mL) to give a turbid solution at pH 11.3. The pH of the solution was raised to 12 with a few drops of 4N NaOH. An aliquot of this solution was added to a solution of benzofuranone 5 (13 g, 58 mmol, 91.6% purity) and AcOH (1.3 mL, 23 mmol, Note 1) in THF (52 mL) at 0°C (note gas evolution), keeping the temperature <5°C and checking for complete conversion regularly by HPLC. A total of 16.5 mL was added (Note 2). 6N HCl (19 mL, 116 mmol) was added at 0°C (almost no gas evolution); a two-phase mixture was obtained, which was heated at 60°C. After stirring at 60°C for 2 hours, HPLC showed no intermediate alcohol remaining. The two-phase reaction mixture was cooled to room temperature and diluted with heptane (25 mL) and water. The aqueous layer was back extracted with 1 / 1 THF / heptane (25 mL). The combined organic extracts were sequentially washed with water (40 mL), 1N NaOH (40 mL, injection) and water (2×40 mL) and then concentrated to dryness to obtain an amber oil, 9.24 g, 77% yield, 97.55% purity.

[0254] Synthesis of 6-fluorobenzofuran-7-carboxylic acid 1f'. 4N NaOH (40mL, 160mmol) is added to a solution of ethyl ester (16.62g, 80mmol, 95.66% purity) in THF (40mL) at room temperature. The two-phase red reaction mixture is heated at 60°C. After 90 minutes at 60°C, HPLC shows complete conversion. The cooled clear red reaction mixture is extracted with MTBE (40mL) to remove residual organic matter. The water layer is concentrated under reduced pressure to remove THF. The solution is filtered through diatomaceous earth polishing, and the pad and flask are rinsed with water (20mL in total). The pH of the filtrate is reduced to 2 in 1 hour with 3N HCl. After stirring at room temperature overnight, the solid is collected by filtration and rinsed with water (2×30mL), air-dried, and then dried under high vacuum to obtain a cream-colored powder 13.4g, 93% yield, 99.16% purity.

[0255] Example 3. Synthesis of Compound A

[0256] Compound A is a preclinical β-lactamase inhibitor. An overview of the synthetic route is shown in Scheme 2 below. The reaction described in Step 1 can include an economical catalyst / ligand combination. Enantioselectivity can be introduced by the reaction of Step 2, and separation of enantiomers can be achieved, thereby eliminating the need for chromatography.

[0257] Solution 2

[0258]

[0259] A heterogeneous mixture of benzofuran 1 (3.90 g, 19 mmol), diboron reagent (7.14 g, 28 mmol), oven-dried and powdered cesium carbonate (18.31 g, 56 mmol), dcype ligand (1.58 g, 4 mmol) and Ni(acac)2 (0.96 g, 4 mmol) in toluene (39 mL) was degassed in an oven-dried flask (slight blackening of the reaction mixture could be observed). The reaction mixture was heated at 90°C. After heating at 90°C for 6 hours, HPLC showed 69% conversion. After 28 hours at 90°C, HPLC showed 98.7% conversion. The reaction mixture was cooled to 0°C. Water (39 mL) was added and 6N HCl was added until pH 2. After stirring at 0°C for 2 hours, the solid (pinacol hexahydrate) was filtered out and rinsed with toluene. The filtrate was layered, and the organic matter was washed twice with water and then concentrated to dryness. The residue was subjected to flash chromatography on silica gel (220 g, 0% to 8% MeOH in dichloromethane) to afford 4.37 g of product containing 24 mol% pinacol material (90% corrected yield).

[0260] A solution of sodium periodate (1.39g, 7mmol) in water (16mL) is added to a solution of the chromatographically separated product in dioxane (8mL) at room temperature. After stirring at room temperature for 4 hours, TLC (9 / 1CH2Cl2 / MeOH) shows that pinacol is not left. The yellow heterogeneous reaction mixture is diluted with water and ethyl acetate. Separating layer, and organic matter is washed with water containing 20% ​​saline, and then concentrated to dryness. Make the residue undergo column chromatography (120g, 0% to 8% MeOH in dichloromethane) on silica gel, to obtain 3.24g of compound 2 (106% yield). The product crystallized in a flask within 2 days.

[0261] Solution 3

[0262]

[0263] Neat diethylzinc (1.42 g, 11.5 mmol) was added to a solution of DME (1.2 mL, 1.04 mmol) in dichloromethane (3 mL) at -10 °C. A solution of methylene iodide (6.17 g, 23.1 mmol) in dichloromethane (2 mL) was added slowly (25 min), keeping the temperature at -12 °C to -9 °C, to give a clear, colorless solution. After stirring at -10 °C for 10 min, a solution of vinyl borate compound 2 (0.68 g, 2.88 mmol) in dichloromethane (3 mL) was added slowly (10 min), keeping the temperature below -7 °C. The cooling bath was removed, and the clear yellow solution was allowed to warm to room temperature. Precipitation was observed at 19 °C, and HPLC showed a 58% conversion. After stirring at room temperature for 3 hours, a clear solution was obtained. After 5.5 hours at room temperature, a heterogeneous mixture was obtained; HPLC showed an 88% conversion. The heterogeneous yellow reaction mixture was stirred at room temperature over the weekend; HPLC showed 96% conversion. The reaction mixture was quenched with 1M aqueous phosphoric acid and diluted with dichloromethane. The layers were separated, and the organic matter was washed with water and then concentrated to dryness. The crude product was subjected to flash chromatography on silica gel (80 g, 0% to 15% MeOH in dichloromethane) to obtain 692 mg of compound rac-3 (96% yield).

[0264] Separation of isomers of compound rac-3

[0265] Separation of the isomers of Compound 3 was achieved using a RegisPack 250 mm x 4.6 mm id, 5 micron column with a hexane-EtOH-MeOH-TFA gradient.

[0266] Solution 4

[0267]

[0268] 25%NaOH (2.3mL) is added to the solution of ethyl ester 3 (760mg) in dioxane (2.3mL) at room temperature. The reaction mixture is stirred at room temperature for 3 days, and then HPLC shows that there is no remaining starting material. The pH of the clear orange solution is reduced to 8.0 with 6N HCl. The solution is extracted with MTBE to remove organic matter. The water layer is concentrated to dryness to remove dioxane. The residue is absorbed in water (5mL) and filtered through a syringe filter. The clear orange filtrate is concentrated to dryness. The residue is absorbed in water (2mL) and dioxane (12mL) is added. Two-phase heterogeneous mixture is obtained. After stirring at room temperature overnight, the solid is collected by filtration and rinsed with acetone, air-dried, and then dried under high vacuum to obtain compound A, 452mg (52% yield) as an off-white powder. The two-phase filtrate is left standing at room temperature over the weekend. Observe and collect solid, then rinse and dry with dioxane to obtain 275mg of the second batch of products (32% yield).

[0269] Example 4

[0270] In a 2.5 mL vial equipped with a magnetic stirrer, NiCl2 (0.24 mmol; 31.10 mg) and P(octyl)3 (0.56 mmol; 207.56 mg) were added and dissolved in THF (1.5 mL). The vial was capped and stirred at 90°C for 1 hour.

[0271] Solution 5

[0272]

[0273] In a 5 mL vial equipped with a magnetic stirrer, K2CO3 (447.6 mg) and Cs2CO3 (117.2 mg) (3.6 mmol base 9 / 1 ratio) were added. B2(Pin)2 (1.84 mmol; 467.25 mg) was then added. The catalyst solution was added to the mixture, followed by more THF (4.5 mL). Finally, the substrate (1.2 mmol; 250 mg) was added and the vial was capped. The reaction was stirred at 90°C overnight (approximately 20 hours).

[0274] Et2O (4mL) was added to the reaction mixture, followed by H2O (4mL), and 6N HCl was added until pH=1 (about 1.2mL). The mixture was stirred at 0°C for 30 minutes. The organic phase was then extracted, dried over sodium sulfate, filtered and the solvent was removed in vacuo. The sample was subjected to HPLC analysis (MeCN and a small amount of toluene as solvent). The procedure using NiCl2 / P (octyl)3 at 20mol% catalyst loading had a desired product of up to 96 area %, while 87 area % of the desired product was obtained at 10mol%, with the catalyst solution being added slowly over time.

[0275] NiCl2 and P(octyl)3 used to form the catalyst in this reaction have the advantage of lower cost while still maintaining high conversion and yield (at 20 mol%).

[0276] Example 5

[0277] 11 Ni catalysts were tested using the following 3 Ni precursors (NiCl2, Ni(Acac)2, Ni(COD)2) and 3 bisphosphines (dppf, diPrf and dcype). In all cases, 1.5 equivalents of B2(Pin)2 and 3 equivalents of Cs2(CO)3 were used relative to the substrate at S / C=5 (i.e., 20 mol% of the catalyst). The reaction was carried out at 90°C for 17 to 20 hours.

[0278]

[0279] All Ni precursors and ligands were handled in an N2 glove box under an inert atmosphere. All catalysts were preformed by stirring the Ni precursors in the presence of the ligands at 90°C for 1 hour. It was also observed that B2(Pin)2 and Cs2(CO3) are quite hygroscopic and should also be better handled under an inert atmosphere.

[0280] Catalyst preparation: In a N2 glove box, Ni precursor (0.06 mmol), ligand (0.08 mmol) and Cs2(CO)3 (50 mg, 0.15 mmol) were placed in a 2.5 mL vial equipped with a magnetic stirrer. Toluene (0.75 mL) was added, the vial was capped, and stirred at 90°C for 1 hour.

[0281] Reaction procedure: In a N2 glove box, B2(Pin)2 (0.46 mmol; 116.8 mg) and Cs2(CO3) (0.9 mmol; 293.2 mg) were added to a 2.5 mL vial equipped with a magnetic stirrer. The catalyst solution and toluene (0.75 mL) were then added, and finally the benzofuran substrate (0.3 mmol; 62.4 mg) was added. The vial was capped and stirred at 90°C for 17 to 23 hours.

[0282] Reaction post-treatment (outside the glove box): distilled water (1 mL) was added to the crude reaction. The solution was cooled to 0°C and 6N HCl (about 300 μL) was added until the pH reached 1. The solution was stirred for 40 minutes (a white solid formed in the aqueous phase). Et2O (2 mL) was added to the vial and the organic phase was extracted and dried with Na2SO4. The organic phase was filtered and the solvent was removed in vacuo.

[0283] The results of the catalyst testing are reported in Table 3 as area %.

[0284] Table 3. Test results of three ligands

[0285]

[0286] Good yields were achieved with NiCl2 as Ni catalyst precursor and dppf as ligand (entry 1). Good conversions were obtained with NiCl2 for diPrf (entries 4, 5, 6 in Table 3). The HPLC chromatogram was relatively clean with only 1 major other peak at 10.179. Similar results were obtained for dcype (entries 7 to 11 in Table 3), but using Ni(Acac)2 as Ni source - the only difference being that higher amounts of vinyl-phenol were observed in this case. The results were reproduced (entries 7-8 in Table 3). For NiCl2 / diPrf: 96% area product. For Ni(Acac)2 / dcype: 92% area product, 1% area yield of vinylphenol assay (quantitative HPLC; separation). For NiCl2 / diPrf and Ni(Acac)2 / dcype: Both catalysts NiCl2 / diPrf and Ni(Acac)2 / dcype were tested again on a larger scale (factor x 4) and at a slightly lower S / C (15 mol% instead of 20 mol%) with the goal of determining the yield via quantitative HPLC and isolation of the desired product.

[0287] Catalyst preparation: In a N2 glove box, Ni precursor (0.18 mmol, 15 mol%), ligand (diPrf or dcype) (0.21 mmol, 1.17 equivalents / Ni) were placed in a vial equipped with a magnetic stirrer. Toluene (3 mL) was added, and the vial was capped and stirred at 90°C for 1 hour.

[0288] Reaction procedure: In a N2 glove box, B2(Pin)2 (1.84 mmol; 467 mg) and Cs2(CO3) (3.6 mmol; 1173 mg) were added to a vial equipped with a magnetic stirrer. The catalyst solution and 3 mL of toluene were then added. Finally, benzofuran substrate (1.2 mmol; 250 mg) was added. The vial was capped and stirred at 90°C for 17 to 23 hours.

[0289] Reaction workup (outside the glove box): The reaction mixture was transferred to a 25 mL vial and diluted with Et2O (3 mL). H2O (3 mL) was added and 6N HCl was added until pH = 1 (about 1.2 mL). The mixture was stirred at 0°C for 30 minutes. The organic phase was extracted, dried over sodium sulfate, filtered and the solvent was removed in vacuo. The sample was subjected to HPLC analysis (MeCN + a small amount of toluene as solvent).

[0290] Separation via column chromatography: The crude sample was purified by silica gel column chromatography using DCM:MeOH (0% to 7%).

[0291] The results of the catalyst testing are reported in area % in Table 4 below.

[0292] Table 4. Test results of two ligands

[0293]

[0294] For both reactions, the HPLC chromatograms were relatively clean. In the case of NiCl2 / diPrf, a small amount of vinyl-phenol was observed (peak at 11.63 min). It was also present with Ni(Acac)2 / dcype and some diboronate. The amount of the desired product 2 obtained after workup was determined by quantitative HPLC (using a calibration curve), with a yield of 75% (HPLC=78% area) for NiCl2 / diPrf.

[0295] The material produced in NiCl2 / diPrf was separated via column chromatography (SiO2, DCM:MeOH as eluent) to give 302 mg of a thick light yellow oil, a higher mass (283 mg) than the expected 100% yield. 1H NMR showed the presence of a large amount of pinacol / pinacol compounds in addition to the expected product. A second workup was performed, consisting of dissolving the sample in a mixture of Et2O / pentane, then adding 1M HCl and stirring at 0°C for 90 minutes. After separation of the organic phase, 274 mg of a thick light yellow oil were obtained. 1 H NMR showed that a significant amount of pinacol / pinacol compounds were removed, but not completely. The same work-up was repeated once more (longer stirring: 18 h) to give 223 mg of a very thick light-colored oil. 1 H NMR showed that most of the pinacol / pinacol compound was removed, but some hydrolysis of the ester occurred (about 20%). An overall isolated yield of 78% was obtained, which was consistent with the HPLC measurement.

[0296] Although the HPLC chromatogram of the material after standard acidic workup and column showed only one peak at the expected retention time of compound 2, the 1H NMR spectrum of the same material seemed to indicate the presence of two compounds: compound 2 and a possible pinacol adduct of compound 2 (either closed or open ring).

[0297]

[0298] The reaction was carried out with benzofuran substrate (0.3 mmol; 62.4 mg) under 10 mol% Ni catalyst.

[0299] Table 5. Test results of various solvents used in Ni catalyst system

[0300]

[0301]

[0302] *SM (starting material); P (product - compound 2); by-product - vinyl phenol

[0303] For Ni(Acac)2 / dcype, toluene (010) and THF (06) gave similar results - not far behind EtOAc (09). In the case of NiCl2 / diPrf, toluene (05) outperformed THF (01) / AcOEt (04).

[0304] Example 6

[0305] In a N2 glove box, Ni precursor (respectively 0.015mmol; 0.03mmol or 0.06mmol, 5mol%; 10mol% and 20mol%) and ligand (0.0175mmol; 0.035mmol and 0.07mmol, 1.17 equivalents / Ni) were placed in a vial equipped with a magnetic stirrer. Toluene (0.75mL) was added and the vial was capped. The vial was taken out of the glove box and placed in a reactor. Under N2 (3bar), the vial was stirred at 90°C for 1 hour.

[0306] Reaction procedure: In a N2 glove box, Cs2CO3 (0.9mmol; 293mg) and B2(Pin)2 (0.46mmol; 117mg) were added to a vial equipped with a magnetic stirrer. The catalyst solution and 0.75mL of toluene were then added. Finally, benzofuran substrate (0.3mmol; 62.5mg) was added. The vial was capped and removed from the glove box. The vial was placed in an A96 reactor and kept under a flow of N2 (3 bar). The vial was stirred at 90°C for 17 hours.

[0307] Reaction workup (outside the glove box): Et2O (1 mL) was added to the reaction mixture. H2O (1 mL) was added and 6N HCl was added until pH = 1 (about 0.3 mL). The mixture was stirred at 0°C for 30 minutes. The organic phase was then extracted, dried over sodium sulfate, filtered and the solvent removed in vacuo. The sample was subjected to HPLC analysis (MeCN and a small amount of toluene as solvent).

[0308] Stirring rate: Two catalysts Ni(acac)2 / dcype and NiCl2 / diPrf were tested in parallel reactors at different catalyst loadings (5 mol%, 10 mol% and 20 mol%). Although both reactor units used the same vial and magnetic stirrer, the bar block system allowed stirring speeds up to 1000 rpm (750 rpm was used), while in A96 the maximum stirring speed was 300 rpm.

[0309] Background reaction: In addition, uncoordinated nickel salt at 10 mol% loading was also tested as a blank reaction.

[0310] Ligands with various Ni precursors: Three Ni precursors (NiCl2, Ni(acac)2, and Ni(COD)2) were combined with ligands (four bidentate phosphines and one monodentate phosphine) and tested at 5 mol% catalyst loading.

[0311]

[0312] Reaction conditions: Ni (5 mol%, 10 mol%, 20 mol%); ligand (1.2 eq / Ni); compound 1 (0.3 mmol); Cs2CO3 (3 eq / compound 1); B2Pin2 (1.5 eq / compound 1); toluene (1.5 mL); 90°C, 18 hours. The catalyst loading of the unliganded catalyst was 10 mol%, and the catalyst loading of the ligand was 5 mol%.

[0313] Table 6. Test results of various Ni precursor and ligand combinations

[0314]

[0315]

[0316] *SM (starting material); P (product - compound 2); by-product - vinyl phenol

[0317] For both catalysts (Ni(acac)2 / dcype and NiCl2 / diPrf), the conversion did not vary linearly with catalyst loading, indicating rapid catalyst deactivation (entries 1 to 3; entries 5 to 7). A small amount of product was obtained with unliganded Ni(acac)2 at 10 mol%, however, it was much less than the product in the presence of the ligand: no ligand: 9%; Dcype: 36%.

[0318] Among the bidentate ligands tested, the Ni(COD)2 / (S,S,R,R)-TangPhos system gave a conversion comparable to the one in the Ni(acac)2 / dcype system at 5 mol% loading - confirming that electron-rich bulky phosphines are good ligands for this transformation.

[0319] Example 7

[0320] Several ligands were combined with nickel precursors Ni(acac)2 and Ni(COD)2 (see Table 7). In addition, mixed phosphine-phosphites and monodentate phosphoramidites were also included. Three complexes based on other metals (Ru, Pd, Rh) were also tested. All 18 reactions were performed under standard conditions at 5 mol% catalyst loading.

[0321]

[0322]

[0323] Table 7. Summary of test results based on HPLC analysis

[0324]

[0325] *Area calculated as the sum of two overlapping peaks; *SM (starting material); P (product - compound 2); by-product - vinylphenol.

[0326] The dcype or diPrf systems produced good results. Combinations of bulky electron-rich phosphines such as SegPhos, DM-SegPhos, and MeOBIPHEP with Ni(COD)2 (entries LS62 and LS66) or Ni(acac)2 (LS64) gave benzoxaborin products 1 with better conversions than the trans-rotated ligands.

[0327] Example 8

[0328] A large set of electron-rich ligands shown below were tested in combination with Ni(acac)2 and Ni(COD)2 in a rod block (ie, under more efficient stirring). The reactions were performed using the conditions described in Example 5.

[0329]

[0330] Table 8. Summary of test results based on HPLC analysis

[0331]

[0332]

[0333] *Area calculated as the sum of two overlapping peaks; SM-starting material; P-product compound 2.

[0334] Among all the ligands tested, the electron-rich (R)-DMM-GarPhos in combination with Ni(COD)2 (LS82) gave compound 2 with 67% area in the clean chromatogram.

[0335] Additional tests were performed using DiPrf and dcype at lower catalyst loadings. The same procedure as described in Example 5, with a total of 3 equivalents of base / substrate in two different solvents: THF for Ni(Acac)2 / dcype and toluene for NiCl2 / diPrf. The reaction was performed with benzofuran substrate (0.3 mmol; 62.4 mg) at 10 mol% Ni catalyst.

[0336] Table 9. Analysis of reactions using various base combinations

[0337]

[0338] *SM (starting material); P (product - compound 2); by-product - vinyl phenol and peak at 8.1 min.

[0339] For NiCl2 / diPrf in toluene, the combination of Li2CO3 / Cs2CO3 (9:1) gave 42 area % of the desired product (compared to 75 area % for Cs2CO3). For Ni(Acac)2 / dcype in THF, several base / base combinations gave conversions very similar to those obtained with Cs2CO3, with small amounts of byproducts: K2CO3 / Cs2CO3 (9:1) (O19); Li2CO3 (O16); K2CO3 (O18).

[0340] Example 9

[0341] The activities of the three catalysts dcype, diPrf and (R)-DMM-Garphos are summarized in Table 10.

[0342] Table 10. Summary of the activities of dcype, DiPrf and (R)-DMM-Garphos

[0343]

[0344] *SM (starting material); P (product - compound 2); by-product - vinyl phenol

[0345] The Ni(COD)2 and Ni(acac)2 precursors were combined with three ligands: thio-XantPhos, a more electron-rich variant of the XantPhos ligand, the bulky and electron-rich Taniaphos, and the trans-rotated ligand SPANPhos (shown below).

[0346]

[0347] In a N2 glove box, Ni precursor (0.015mmol, 5mol%) and ligand (0.0175mmol, 1.17 equivalents / Ni) were placed in a vial equipped with a magnetic stirrer. Toluene (0.75mL) was added and the vial was capped. The vial was placed in a rod block and stirred at 90°C for 1 hour.

[0348] In a N2 glove box, Cs2CO3 (0.9 mmol; 293 mg) and B2(Pin)2 (0.46 mmol; 117 mg) were added to a vial equipped with a magnetic stirrer. The catalyst solution and 0.75 mL of toluene were then added. Finally, the benzofuran substrate (1.2 mmol; 250 mg) was added. The vial was capped and placed in a rod block. The vial was stirred at 90°C for 17 hours.

[0349] Reaction post-treatment (outside the glove box): Et2O (1 mL) was added to the reaction mixture. H2O (1 mL) was added and 6N HCl was added until pH=1 (about 0.3 mL). The mixture was stirred at 0°C for 30 minutes. Then, the organic phase was extracted, dried over sodium sulfate, filtered and the solvent was removed in vacuo. The sample was subjected to HPLC analysis (MeCN and a small amount of toluene as solvent). The results are summarized in Table 11. The reaction using Ni(COD)2 / TaniaPhos produced compound 2 in good yield.

[0350] Table 11. Analysis of test results

[0351]

[0352] *SM (starting material); P (product - compound 2); by-product - vinyl phenol

[0353] Example 10

[0354] Studies using PPh3 have also been conducted in the presence of Zn powder and iodide. Zn powder and halide additives have been used for self-coupling and cross-coupling reactions of aryl halides in the presence of Ni / PPh3 systems. Zn acts as a reducing agent, while the halide stabilizes the Ni via the formation of a pentacoordinated nickelate intermediate. 0 , as described in ChemRev 2011, 111(3): 1346-1416, which is incorporated herein by reference. Two additives (Zn, Bu4NI) were tested with two Ni precursors in two different solvents.

[0355] NiCl2(PPh3)3 was selected as the metal precursor because it is known that 0 In the presence of Ni(PPh3)3, Ni(PPh3)3 is an active catalyst for the activation of CO and CX bonds. Excess PPh3 is also added because PPh3 can be separated from Ni due to spatial constraints. 0 Complex dissociation. Under similar reaction conditions, the combination of NiCl2 as metal precursor and PPh3 as stabilizing ligand was also studied (see table below).

[0356] Reaction procedure: In a N2 glove box, Bu4NI (0.45mmol; 166mg); B2(Pin)2 (0.46mmol; 117mg) and zinc (0.9mmol; 59mg) were added to a vial equipped with a magnetic stirrer. NiCl2(PPh3)3 (0.03mmol; 20mg) or NiCl2 (0.03mmol; 4mg) and PPh3 (0.0; 0.06; 0.12 or 0.18mmol) were added to the reaction. Finally, solvent (1.5mL) and benzofuran substrate (0.3mmol; 250mg) were added. The vial was capped and placed in a rod block. The vial was stirred at 90°C for 17 hours. The results are compiled in the following table (area % of product).

[0357] Table 12. Improvement of test results based on HPLC analysis

[0358]

[0359] *SM (starting material); P (product - compound 2); by-product - vinyl phenol

[0360] In Zn / I - Two catalysts, dppf and P(tBu)3, were tested in the presence of NiCl2 / dppf and NiCl2 / P(tBu)3. - A similar set of reactions. In some reactions K2CO3 is also added.

[0361] Reaction procedure: In a N2 glove box, Bu4NI (0.45mmol; 166mg); K2CO3 (0.9mmol; 124mg); B2(Pin)2 (0.46mmol; 117mg) and zinc (0.9mmol; 59mg) were added to a vial equipped with a magnetic stirrer. NiCl2(dppf) (0.03mmol; 20mg) or NiCl2 (0.03mmol; 4mg) and PPh3 / P(tBu)3 (0.0; 0.06; 0.12 or 0.18mmol) were added to the reaction. Finally, solvent (1.5mL) and benzofuran substrate (0.3mmol; 250mg) were added. The vial was capped and placed in a rod block. The vial was stirred at 90°C for 17 hours. The results are compiled in Table 13 (area % of product).

[0362] Table 13. Summary of test results based on HPLC analysis

[0363]

[0364] *SM (starting material); P (product - compound 2); by-product - vinyl phenol

[0365] In THF, when all additives (I - A large amount of product (32%) was obtained with NiCl2(dppf) catalyst when 3 equivalents of CsCO3 in toluene were used. NiCl2 / dppf was tested before 20 mol% to give 43% area product.

[0366] Embodiment 11

[0367] All reactions were performed on 3 rod blocks placed inside a glove box. Up to 30 reactions could be performed with this setup at a stirring speed of 750 rpm.

[0368] Catalyst preparation: In a N2 glove box, Ni precursor (0.015mmol, 5mol%) and ligand (0.0175mmol, 1.17 equivalents / Ni) were placed in a vial equipped with a magnetic stirrer. Toluene (0.75mL) was added and the vial was capped. The vial was placed in a rod block and stirred at 90°C for 1 hour.

[0369] Reaction procedure: In a N2 glove box, Cs2CO3 (0.9 mmol; 293 mg) and B2(Pin)2 (0.46 mmol; 117 mg) were added to a vial equipped with a magnetic stirrer. The catalyst solution and 0.75 mL of toluene were then added. Finally, benzofuran substrate (0.3 mmol; 62 mg) was added. The vial was capped and placed in a rod block. The vial was stirred at 90°C for 17 hours.

[0370] Reaction workup (outside the glove box): Et2O (1 mL) was added to the reaction mixture. H2O (1 mL) was added and 6N HCl was added until pH = 1 (about 0.3 mL). The mixture was stirred at 0°C for 30 minutes. The organic phase was then extracted, dried over sodium sulfate, filtered and the solvent removed in vacuo. The sample was subjected to HPLC analysis (MeCN and a small amount of toluene as solvent).

[0371] Catalyst efficiency can depend on the phosphine ligand and the nickel precursor. Under standard reaction conditions (1.5 equivalents of B2Pin2, 3 equivalents of Cs2CO3, toluene, 90°C), new phosphines related to those phosphines that provide high activity were studied in combination with available nickel precursors. All reactions were performed using a 5mol% catalyst loading in order to clearly distinguish the differences in activity. Four nickel precursors NiCl2 shown below were used in the reaction; Ni(acac)2; Ni(COD)2 and NiCl2(PPh3)2 and 18 ligands.

[0372]

[0373]

[0374]

[0375] Reaction conditions: Ni salt (5 mol%); ligand (1.17 eq / Ni); compound 1 (0.3 mmol); Cs2CO3 (3 eq / compound 1); B2Pin2 (1.5 eq / compound 1); toluene (1.5 mL); 90°C, 20 hours. Ligand loading: monodentate ligand: 10 mol% (2.3 eq / Ni); bidentate ligand: 5 mol% (1.17 eq / Ni). The test results are summarized in Tables 14a to 14d and Figure 1 In. SM (starting material); P (product - compound 2); by-product - vinyl phenol.

[0376] Table 14a. Test results of NiCl2 precursor (in area %).

[0377]

[0378]

[0379] Table 14b. Test results of Ni(acac)2 precursor (in area %).

[0380]

[0381] Table 14c. Test results of Ni(COD)2 precursor (in area %).

[0382]

[0383]

[0384] Table 14d. Test results of NiCl2(PPh3)2 precursor (in area %).

[0385]

[0386] Among the monodentate phosphines (L1 to L3): L2 appears to be active with all Ni precursors, giving yields of 20 to 30 area % P. L5 (dcype) also provided good yields when used in combination with Ni(Acac)2. L6 (dcypp) with a 3-carbon bridge also showed good activity with NiCl2(PPh3)2. L9 (forming an 8-membered chelate with the metal or acting as a tridentate ligand) also achieved good yields in combination with Ni(COD)2.

[0387] Among the ferrocene-based ligands (L13 to L18), both dcypf and diPrpf (L16) showed good activities.

[0388] Example 12

[0389] N-heterocyclic carbenes were tested in this study. The four nickel precursors studied in module 2 (NiCl2; Ni(acac)2; Ni(COD)2 and NiCl2(PPh3)2) were combined with the three carbene ligands shown below under standard reaction conditions (1.5 eq. of B2Pin2, 3 eq. of Cs2CO3, toluene, 90°C). All reactions were performed using a 5 mol% catalyst loading in order to clearly distinguish differences in activity.

[0390]

[0391] All reactions were performed on a 3 rod block placed inside a glove box. Up to 30 reactions could be performed with this setup at a stirring speed of 750 rpm.

[0392] Catalyst preparation: In a N2 glove box, Ni precursor (0.015mmol, 5mol%) and ligand (0.0175mmol, 1.17 equivalents / Ni) were placed in a vial equipped with a magnetic stirrer. Toluene (0.75mL) was added and the vial was capped. The vial was placed in a rod block and stirred at 90°C for 1 hour. For L21 in the table below, Cs2CO3 (1.2 equivalents / L) was added to deprotonate the carbene.

[0393] Reaction procedure: In a N2 glove box, Cs2CO3 (0.9 mmol; 293 mg) and B2(Pin)2 (0.46 mmol; 117 mg) were added to a vial equipped with a magnetic stirrer. The catalyst solution and 0.75 mL of toluene were then added. Finally, benzofuran substrate (0.3 mmol; 62 mg) was added. The vial was capped and placed in a rod block. The vial was stirred at 90°C for 17 hours.

[0394] Reaction workup (outside the glove box): Et2O (1 mL) was added to the reaction mixture. H2O (1 mL) was added and 6N HCl was added until pH = 1 (about 0.3 mL). The mixture was stirred at 0°C for 30 minutes. The organic phase was then extracted, dried over sodium sulfate, filtered and the solvent removed in vacuo. The sample was subjected to HPLC analysis (MeCN and a small amount of toluene as solvent).

[0395] Reaction conditions: Ni salt (5 mol%); ligand (1.17 equivalents / Ni); compound 1 (0.3 mmol); Cs2CO3 (3 equivalents / 1); B2Pin2 (1.5 equivalents / 1); toluene (1.5 mL); 90°C, 20 hours. The reaction results (in area %) are shown in the table below.

[0396] Table 15. Summary of reaction results

[0397]

[0398] Example 13

[0399] Three ligands: L3, L13 and L14 (structures shown below) were combined with NiCl2 as a Ni precursor and subjected to borylation reaction under standard conditions (1.5 equivalents of B2Pin2, 3 equivalents of Cs2CO3, toluene) using different catalyst loadings and temperatures.

[0400]

[0401] The reaction conditions at 90°C included: Ni salt (5 mol%; 10 mol% and 20 mol%); ligand (1.17 eq / Ni); compound 1 (0.3 mmol); Cs2CO3 (3 eq / 1); B2Pin2 (1.5 eq / 1); toluene (1.5 mL); 20 hours. The reaction results at 90°C are shown in Table 16. The reaction conditions at 100°C included: Ni salt (2.5 mol%; 5 mol% and 10 mol%); ligand (1.17 eq / Ni); compound 1 (0.3 mmol); Cs2CO3 (3 eq / 1); B2Pin2 (1.5 eq / 1); toluene (1.5 mL); 20 hours. The reaction results at 100°C are shown in Table 20. Ligand loading: monodentate ligand (L3): (2.3 equivalents / Ni); bidentate ligands (L13, L14): (1.17 equivalents / Ni).

[0402] Table 16. Reaction results at 90°C (in area %)

[0403] Ligand Catalyst loading (mol%) Area % (SM) Area%(P) Area % (vinylphenol) L3 5 57 40 3 L3 10 39 58 1 L3 20 12 83 L13 5 51 38 L13 10 43 45 1 L13 20 25 55 L14 5 23 71 3 L14 10 20 80 L14 20 >99

[0404] *SM (starting material); P (product - compound 2); by-product - vinyl phenol

[0405] Table 17. Reaction results at 100°C (in area %)

[0406] Ligand Catalyst loading (mol%) Area % (SM) Area%(P) Area % (vinylphenol) L3 2.5 96 1 L3 5 93 1 2 L3 10 68 26 1 L13 2.5 75 5 3 L13 5 74 5 1 L13 10 59 15 L14 2.5 90 6 L14 5 47 46 L14 10 10 87

[0407] *SM (starting material); P (product - compound 2); by-product - vinyl phenol Example 14

[0408] All reactions were performed on 3 rod blocks placed inside a glove box. Up to 30 reactions could be performed with this setup at a stirring speed of 750 rpm.

[0409] In a N2 glove box, Ni precursor (0.015mmol, 5mol%) and ligand (0.0175mmol, 1.17 equivalents / Ni) were placed in a vial equipped with a magnetic stirrer. Toluene (0.75mL) was added and the vial was capped. The vial was placed in a rod block and stirred at 90°C for 1 hour.

[0410] Reaction procedure: In a N2 glove box, Cs2CO3 (0.9 mmol; 293 mg) and B2(Pin)2 (0.46 mmol; 117 mg) were added to a vial equipped with a magnetic stirrer. The catalyst solution and 0.75 mL of toluene were then added. Finally, benzofuran substrate (0.3 mmol; 62 mg) was added. The vial was capped and placed in a rod block. The vial was stirred at 90°C for 17 hours.

[0411] Reaction workup (outside the glove box): Et2O (1 mL) was added to the reaction mixture. H2O (1 mL) was added and 6N HCl was added until pH = 1 (about 0.3 mL). The mixture was stirred at 0°C for 30 minutes. The organic phase was then extracted, dried over sodium sulfate, filtered and the solvent removed in vacuo. The sample was subjected to HPLC analysis (MeCN and a small amount of toluene as solvent).

[0412] Three selected ligands: L3 trioctylphosphine, L13 DPPF and L14 1,1′-ferrocenyldiyl-bis(dicyclohexylphosphine) were tested in combination with NiCl2 as a Ni precursor under standard conditions (1.5 equivalents of B2Pin2, 3 equivalents of Cs2CO3) using different catalyst loadings. Two solvents (toluene and its higher boiling analog, p-xylene) were selected for the reaction at two temperatures (90°C and 100°C). To prevent the cap from decomposing at high temperatures, a 10 mL vial was used so that the cap was not in contact with the heating zone of the rod block.

[0413] Reaction conditions: Ni salt (x mol%, see below); ligand (1.17 eq / Ni); compound 1 (0.3 mmol); Cs2CO3 (3 eq / 1); B2Pin2 (1.5 eq / 1); toluene or p-xylene (1.5 mL); 20 hours. For T = 90 ° C, catalyst loading = 5 mol%; 10 mol% and 20 mol%. For T = 100 ° C, catalyst loading = 2.5 mol%; 5 mol% and 10 mol%.

[0414] Ligand to metal ratio: monodentate ligand (L3, P(Oct)3): (2.3 equivalents / Ni). Bidentate ligand (L13 DPPF, L14 DCyPF): (1.17 equivalents / Ni). The reaction results are shown in the table below.

[0415] Table 18. Summary of reaction results (in area %)

[0416]

[0417]

[0418] *SM (starting material); P (product - compound 2); by-product - vinyl phenol

[0419] At 90°C, good reproducibility was achieved at 5 mol% ligand loading for all three catalysts. NiCl2 / L3 (in p-xylene) and NiCl2 / L14 (in toluene) catalysts gave almost complete conversion at 20 mol% at 90°C. When NiCl2 / L13 catalyst was used at 20 mol%, a conversion of 55% was obtained. For L13, the same activity was obtained in both toluene and p-xylene.

[0420] Embodiment 15

[0421] The heating rate and stirring rate in the catalytic reaction were studied. The boronation reaction using 5mol% NiCl2 / L3 catalyst was carried out in a microwave at 100°C, where heating was very fast compared to thermal heating. The boronation reaction of NiCl2 / L3 catalysis was carried out in toluene and p-xylene using 10mol% and 20mol% catalyst loadings at relatively low temperatures (i.e. 80°C). The idea was to test whether a relatively low reaction temperature would limit the deactivation / decomposition of the catalyst. The NiCl2 / L3 catalyst (1.25mmol of compound 1 instead of 0.3mmol) was tested on a larger scale in a Schlenk test tube. In this device, very effective mixing of reagents was achieved via rapid magnetic stirring while gradually increasing the reaction temperature (approximately 30 to 40 minutes, until reaching 90°C, oil bath). Reaction conditions: Ni salt (5 mol%; 10 mol% and 20 mol%); ligand (1.17 or 2.3 equiv / Ni; 10 mol%; 20 mol% or 40 mol%); compound 1 (0.3 mmol); Cs2CO3 (3 equiv / 1); B2Pin2 (1.5 equiv / 1); solvent (1.5 mL); 20 hours.

[0422] Table 19. Summary of reaction results (in area %)

[0423] T / ℃ Solvents Device Ni(mol%) Ligand (mol%) Area % (SM) Area%(P) 100 Toluene MW NiCl2(5%) P(Oct)3(10%) 96 1 80 Toluene Rod block NiCl2(10%) P(Oct)3(20%) 56 33 80 Toluene Rod block NiCl2(20%) P(Oct)3(40%) 58 41 80 p-Xylene Rod block NiCl2(10%) P(Oct)3(20%) 70 30 80 p-Xylene Rod block NiCl2(20%) P(Oct)3(40%) 53 47 90* Toluene Rod block NiCl2(10%) P(Oct)3(20%) 39 58 90* Toluene Schrank NiCl2(10%) P(Oct)3(20%) 38 55

[0424] *SM (starting material); P (product - compound 2)

[0425] When the borylation reaction was carried out in a microwave, the NiCl2 / L3 catalyst showed no activity at all, indicating that the catalyst is thermally unstable when subjected to rapid heating. Product formation at 80°C was lower than that at 90°C. In summary, the decrease in reaction rate could not be compensated by the higher catalyst stability expected at a lower T. Reactions carried out at 90°C in rod blocks and on a larger scale in Schlenk tubes showed very similar conversions (58% vs. 55%).

[0426] Example 16

[0427] Phosphine to metal ratios and dosing catalysts were investigated using several ligands. To investigate the factors causing catalyst deactivation, two additional experiments were performed at 90 °C using p-xylene / toluene as solvent:

[0428] NiCl2 / L3 catalyzed borylation reactions were performed using different molar amounts of phosphine ligands (10 mol%; 20 mol% and 40 mol% ligands in combination with 10 mol% NiCl2) to investigate whether catalyst deactivation may originate from phosphine mismatching of the catalytically active Ni species. Using excess phosphine ligands can be used for Ni-promoted cross-coupling and CO cracking to enhance the life of the catalyst, as described in Chem. Rev. 2011, 111, 1346, which is incorporated herein by reference.

[0429] The NiCl2 / L3 catalyst was dosed in two portions (5 mol% and 5 mol%) to determine whether the rapid deactivation of the catalyst could be due to rapid changes in oxidation state and / or continuous disproportionation of the catalytically active Ni species. This form of deactivation can be seen to be due to the ability of Ni to readily enter many oxidation states (i.e., from Ni(0) to Ni(III)); and its inherent tendency to participate in disproportionation / anti-disproportionation reactions (i.e., disproportionation of NiX2(dppe) in Inorg. Chem. 1991, 30, 2098, which is incorporated herein by reference).

[0430] Reaction conditions: Ni salt (5 mol%; 10 mol% and 20 mol%); ligand (1.17 or 2.3 equiv / Ni; 10 mol%; 20 mol% or 40 mol%); compound 1 (0.3 mmol); Cs2CO3 (3 equiv / 1); B2Pin2 (1.5 equiv / 1); solvent (1.5 mL); 20 hours.

[0431] Reaction conditions (catalyst was prepared in two parts): Ni salt (10 mol%); ligand (2.3 eq / Ni; 20 mol%); compound 1 (0.3 mmol); Cs2CO3 (3 eq / 1); B2Pin2 (1.5 eq / 1); solvent (1.5 mL); 20 hours.

[0432] The catalyst was prepared in toluene (800 μL) and stirred at 90° C. for 1 hour. Half of the solution (400 μL) was added to the reaction mixture and after 2 hours the remaining catalyst (400 μL) was added to the reaction. The results are summarized in the table below.

[0433] Table 20. Summary of study results (in area %):

[0434]

[0435] *SM (starting material); P (product - compound 2)

[0436] The molar amount of phosphine was found to play a key role in catalyzing the borylation. A two-fold reduction in the molar amount of phosphine resulted in lower conversion (26% vs. 40%), while a two-fold increase did not significantly improve the reaction results (42% vs. 40%). These experiments indicate that a 1 / 2 Ni / P(Oct)3 ratio gives good results and that phosphine mismatch may not be the main reason behind catalyst deactivation.

[0437] When the catalyst was dosed in two, a modest increase in reaction conversion (67% vs. 58%) was found, indicating that the lifetime of the NiCl2 / L3 catalyst can be improved via the dosing scheme. By similar behavior to that exhibited by the NiX2(dppe) complex, it is possible that the disproportionation reaction shown below will occur under the reaction conditions, leading to the deactivation of the precatalyst. Diluting the precatalyst may help shift the equilibrium to the left.

[0438]

[0439] The effects of solvent and base were then investigated by testing the NiCl2 / L3-catalyzed borylation of 4 at 90°C using a 10 mol% catalyst loading. The following bases (K2CO3; K2CO3 / Cs2CO3 9 / 1; Cs2CO3 and Li2CO3) were selected with 5 solvents (non-polar solvents: toluene and p-xylene; ethereal solvents: THF and dibutyl ether, and very polar dimethylacetamide (DMA)) for investigation. The reaction conditions included: Ni salt (10 mol%); ligand (2.3 eq / Ni; 20 mol%); compound 1 (0.3 mmol); Cs2CO3 (3 eq / compound 1); B2Pin2 (1.5 eq / compound 1); solvent (1.5 mL); 20 hours. The results are shown in the table below.

[0440] Table 21. Summary of reaction results (in area %):

[0441] Alkali Solvent / T Area % (SM) Area%(P) <![CDATA[K2CO3]]> Toluene 79 16 <![CDATA[K2CO3 / Cs2CO3 9 / 1]]> 32 66 <![CDATA[Cs2CO3]]> 61 39 <![CDATA[Li2CO3]]> 99 1 <![CDATA[K2CO3]]> Xylene 75 22 <![CDATA[K2CO3 / Cs2CO3 9 / 1]]> 50 49 <![CDATA[Cs2CO3]]> 49 51 <![CDATA[Li2CO3]]> 99 1 <![CDATA[K2CO3]]> THF 40 57 <![CDATA[K2CO3 / Cs2CO3 9 / 1]]> 24 74 <![CDATA[Cs2CO3]]> 30 69 <![CDATA[Li2CO3]]> 98 2 <![CDATA[K2CO3]]> DMA 68 28 <![CDATA[K2CO3 / Cs2CO3 9 / 1]]> 67 29 <![CDATA[Cs2CO3]]> 59 37 <![CDATA[Li2CO3]]> 90 2 <![CDATA[K2CO3]]> Dibutyl ether 77 23 <![CDATA[K2CO3 / Cs2CO3 9 / 1]]> 69 29 <![CDATA[Cs2CO3]]> 60 39 <![CDATA[Li2CO3]]> 99 1

[0442] *SM (starting material); P (product - compound 2)

[0443] The highest conversion (74 area %) was obtained with THF as solvent and KCO / CsCO 9 / 1 as base. The mixture of KCO / CsCO 9 / 1 also gave the highest conversion in toluene, while CsCO was the most effective base in p-xylene, DMA and dibutyl ether. The NiCl / L3 catalyst showed higher efficiency in non-polar solvents (toluene and p-xylene) and THF, while significantly lower conversions were obtained in DMA and dibutyl ether.

[0444] Embodiment 17

[0445] The NiCl2 / L3-catalyzed borylation of compound 1 was studied on a larger scale under reaction conditions that yielded the desired product 2 at a higher conversion. Therefore, the borylation of 1 (0.6 mmol) was first tested at 90°C in THF as solvent and K2CO3 / Cs2CO3 9 / 1 as base. The first reaction was carried out in a 10 mL vial in a rod block and a dosing scheme was used in which the catalyst solution (10 mol%) was added to the reaction mixture in five portions (2 mol%) at 1 hour intervals. The second borylation reaction of 1 (1.2 mmol) was carried out in a Schlenk tube under the same conditions (solvent, base, temperature), but the catalyst (20 mol%) was added in a single portion at the beginning of the reaction.

[0446] Reaction conditions (block) included: Ni salt (10 mol%); ligand (2.3 eq / Ni; 20 mol%); compound 1 (0.6 mmol); K2CO3 / Cs2CO3 9 / 1 (3 eq / compound 1); B2Pin2 (1.5 eq / compound 1); THF (3.0 mL); 20 hours. The catalyst was prepared in toluene (1000 μL) and stirred at 90°C for 1 hour. The catalyst solution was added to the reaction mixture in five portions (200 μL each) at 1 hour intervals, and once the addition was complete, the reaction was stirred at 90°C overnight.

[0447] The reaction conditions (Schlenk tube) included: Ni salt (20 mol%); ligand (2.3 eq / Ni; 40 mol%); compound 1 (1.2 mmol); K2CO3 / Cs2CO3 9 / 1 (3 eq / compound 1); B2Pin2 (1.5 eq / compound 1); THF (6.0 mL); 20 hours. The results are shown in the table below.

[0448] Table 22. Summary of reaction results (in area %):

[0449]

[0450] *SM (starting material); P (product - compound 2); by-product - vinyl phenol

[0451] By dosing the catalyst solution, a gradual increase in the conversion of 1 was observed, which resulted in a final 87% area of ​​the desired borocyclohexine 2. No solvent loss occurred when the reaction was carried out in a sealed vial and the catalyst was added via a syringe through a septum. At 10 mol% ligand loading, NiCl2 / P(Oct)3 and K2CO3 / Cs2CO3 9 / 1 produced high yields.

[0452] Embodiment 18

[0453] The study involved the synthesis of compound 3 via enantioselective cyclopropanation of 2 using diazomethane as shown in Scheme 6.

[0454] Scheme 6: Enantioselective cyclopropanation towards 3

[0455]

[0456] First, an analytical method was developed and implemented - allowing separation of the two enantiomers of the starting material and the product using chiral HPLC.

[0457] Reaction of 2 with diazomethane in the presence of Pd(OAc)2 afforded approximately 30% yield. Compound 2 is stable in the presence of CH2N2, but can react with acetic acid (used as a quencher for CH2N2). The diastereoselective cyclopropanation using Pd(OAc)2 as a catalyst was shown to be quantitative when 8 equivalents of CH2N2 were used, so the low yield is most likely due to losses during isolation.

[0458] 18 chiral auxiliaries were studied to form adducts with compound 2 via the B-OH moiety. The chiral auxiliary compounds were selected from 5 different types of chiral compounds: monoalcohols, diols, amino alcohols, diamines, hydroxy acids / esters. After pre-forming the adduct in THF at room temperature, it was exposed to CH2N2 at -15°C in the presence of a catalytic amount of Pd(OAc)2. In the case of 2 chiral auxiliaries (prolinol derivatives and ephedrine), the desired products were obtained with significant enantiomeric excess (ee): 55% and 44%, respectively. 7 amino-alcohol compounds were tested. One compound, pseudoephedrine, gave high selectivity (desired enantiomer 78%). In general, all ephedrine derivatives were active and enantioselective. It was also shown that cyclopropanation at -40°C instead of -15°C resulted in an increase in enantiomeric excess, although at the expense of conversion. The procedure for the enantioselective cyclopropanation of 2 with pseudoephedrine is shown in Scheme 7.

[0459] Solution 7:

[0460]

[0461] A stock solution of oxaborin 2 in anhydrous THF (30 mg / mL, 0.127 mmol) was prepared. Pseudoephedrine (1.1 eq / l) was weighed into a 20 mL glass vial and dissolved in 4 mL of anhydrous THF. 1 mL of the substrate stock solution was added to the solution of the chiral auxiliary and the mixture was stirred at room temperature for 1 hour. A stock solution of Pd(OAc)2 (1 mg / mL, 0.004 mmol) was prepared. A fresh solution of diazomethane in Et2 O was prepared. After reaction with benzoic acid, its concentration was determined by GC (~0.33 M).

[0462] The substrate / pseudoephedrine solution was cooled to -15°C in a salt / ice / water bath. 1 mL of catalyst stock solution (Sub / Cat=28) and 3 mL of diazomethane solution (CH2N2 / Sub=7.8) were added to the reactor vial. The reaction mixture was stirred at -15°C for 30 minutes, and then the temperature was slowly raised to 22°C.

[0463] HPLC samples: To cleave the chiral auxiliary, treat each HPLC sample with excess H2O for at least 10 minutes, then inject: 100 μL reaction mixture; 900 μL heptane / EtOH (100 / 1); 20 μL H2O. Using a combination of a pre-set column and a chiral HPLC column, a method for analyzing substrates and enantiomeric products can be developed. Dissolve the reaction sample in heptane / EtOH (99 / 1) to ~1 mg / mL.

[0464] Embodiment 19

[0465] Using the diazomethane kit from Aldrich (without ground glass connection) Prepare a solution of diazomethane in ether as shown in Scheme 8. A solution of (6.0 g, 28.0 mmol) in diethyl ether (60 mL) was dosed into a warm (65° C.) solution of KOH / water (15 mL, 5.4 M, 81 mmol) and carbitol (17 mL, diethylene glycol monomethyl ether). The diazomethane / ether solution was distilled at 65° C. and collected at -30° C. to -40° C. An additional 10 mL of ether was used to clean the apparatus.

[0466] Solution 8: Preparation of diazomethane

[0467]

[0468] The concentration of diazomethane in ether was determined by analyzing the amount of methyl benzoate formed after esterification of benzoic acid with CH2N2 by GC. 0.5 mL of a solution of diazomethane in ether (-0.33 M) was dissolved in 0.5 mL of a benzoic acid solution (0.8 M) and 10 mL of an acetonitrile solution. The resulting methyl benzoate was quantitatively analyzed by GC.

[0469] Embodiment 20

[0470] A diastereoselective catalyst was used to determine the amount of CH2N2 required for complete conversion and the isolated yield. 50 mg of benzoxaborin (2) (0.212 mmol) was dissolved in 2 mL of anhydrous THF. 5 mg of Pd(OAc)2 (0.022 mmol, S / C=10) was added, and the reaction mixture was cooled to T=-16°C or T=-40°C. Three tests were performed: Test A: A 15 equivalent of CH2N2 (solution (0.335 M) in diethyl ether) was added to the solution at -40°C, and the vial was removed from the cooling bath. Test B: 12 ​​equivalents of CH2N2 were added to the solution at -16°C in 4 portions. Test C: A 15 equivalent of CH2N2 (solution (0.335 M) in diethyl ether) was added to the solution at -40°C in 4 portions.

[0471] 8 equivalents of CH2N2 were added.

[0472] 30 minutes after each addition, the reaction mixture was analyzed by HPLC. AcOH was used as a quencher for Test B, as it does not lead to some decomposition of 2. For Test A: After the addition of CH2N2, the vial was taken out of the cooling bath. When warming to room temperature, a large amount of N2 was produced. Complete conversion was measured by HPLC. For Test B and Test C, the conversion increased with the amount of CH2N2 before reaching 100% conversion. As already mentioned, AcOH was used as a quencher for Test B, except for the last sample with 12.6 equivalents of CH2N2.

[0473] Embodiment 21

[0474] Studies with Pd(OAc)2 were performed to determine the amount of CH2N2 that resulted in complete conversion and the isolated yield.

[0475] 104 mg of benzoxaborin (1) (0.442 mmol) was dissolved in 1 mL of anhydrous THF. 5 mg of Pd(OAc)2 (0.022 mmol, S / C=20) in 1 mL of THF was added and the reaction mixture was cooled to T=-16°C. A 7.6 equivalent portion of CH2N2 (ether solution, 0.281 M, 12 mL) was added. Emission of N2 and formation of solid (PE) were observed. After T was increased to room temperature T overnight, the reaction mixture was analyzed by HPLC, showing complete conversion and an assay yield of 86%.

[0476] In order to isolate the product, the reaction mixture was filtered on a diatomaceous earth filter to remove solids (PE and Pd black). The THF / ether solution was concentrated in vacuo (40°C, 40mbar) to give 132mg of oily residue. 1H-NMR was consistent with the desired product and some THF residues (~13%). In order to further isolate the product, preparative column chromatography was used with heptane / EtOH (4 / 1) as eluent. In preparative column chromatography, the oily residue was further concentrated on a rotary evaporator (40°C, 40 mbar) to remove residual THF. This produced 122mg of a viscous oil with solid tar that was no longer completely dissolved in heptane, ethanol or ether.

[0477] Analysis of the reaction mixture after different reaction times with CH2N2: Same procedure as above except: 4 equivalents of CH2N2 instead of 7.6 equivalents, 4 mL of THF instead of 2 mL. The reaction mixture was sampled after 5 minutes, 10 minutes, 20 minutes, 30 minutes, and 240 minutes. After 5 minutes, HPLC analysis showed 85% conversion, 80% assay yield. No changes were observed thereafter, indicating that the reaction occurred within the first 5 minutes.

[0478] Embodiment 22

[0479] The chiral auxiliary compounds shown in the table below were tested. A stock solution of oxaborin 2 in anhydrous THF (30 mg / mL, 0.127 mmol) was prepared. The chiral auxiliary (1.1 equivalents / 1) was weighed and placed in a 20 mL glass vial. 4 mL of anhydrous THF was added to the chiral auxiliary. 1 mL of the substrate stock solution was added to the chiral auxiliary, and the mixture was stirred at room temperature for 4 hours.

[0480] Prepare a stock solution of Pd(OAc)2 (1 mg / mL, 0.004 mmol). Prepare a fresh solution of diazomethane in Et2O. After reaction with benzoic acid, its concentration was determined by GC (~0.33M). The substrate / chiral auxiliary mixture was cooled to -15°C in a salt / ice / water bath. 1 mL of catalyst stock solution (Sub / Cat=28) and 3 mL of diazomethane solution (CH2N2 / Sub=7.8) were added to the reactor vial. The reaction mixture was stirred at -15°C for 30 minutes, and then the temperature was slowly raised to 22°C.

[0481] Table 23. Chiral auxiliary compounds

[0482]

[0483]

[0484] Prepare a stock solution of oxaborin 2 in anhydrous THF (30 mg / mL, 0.127 mmol). Weigh the chiral auxiliary (1.1 eq / 1) and place in a 20 mL glass vial. Add 4 mL of anhydrous THF to the chiral auxiliary. Add 1 mL of the substrate stock solution to the chiral auxiliary and stir the mixture at room temperature for 4 hours. For acids (A14, A15, and A17), add 1 eq or 2 eq of Et3N. Prepare a stock solution of Pd(OAc)2 (1 mg / mL, 0.004 mmol). A fresh solution of diazomethane in Et2 O was prepared. After reaction with benzoic acid, its concentration was determined by GC (~0.33 M).

[0485] The mixture of substrate / chiral auxiliary was cooled to -15°C in a salt / ice / water bath. 1 mL of catalyst stock solution (Sub / Cat=28) and 3 mL of diazomethane solution (CH2N2 / substrate=7.8) were added to the reactor vial. The reaction mixture was stirred at -15°C for 30 minutes, and then the temperature was slowly increased to 22°C. HPLC samples: To cleave the chiral auxiliary, each HPLC sample was treated with excess H2O and then injected: 100 μL of reaction mixture; 900 μL of heptane / EtOH (100 / 1); 20 μL of H2O.

[0486] The conversion rate and yield of the product were determined via the area of ​​the remaining starting material or the obtained product relative to the expected area, and the results are shown in the following table.

[0487] Table 24. Summary of reaction results

[0488]

[0489] Good conversions were obtained with the chiral auxiliaries. For the three chiral auxiliaries (A4, A10, A11), significant enantiomeric excesses were obtained. In the case of A10 and A11, the chromatograms did not show co-elution. A true enantioselective cyclopropanation was achieved. Both auxiliaries were also injected onto the column and did not co-elute with the product.

[0490] A small sample of the reaction mixture obtained with A11 was further hydrolyzed with 0.1N HCl: 1 mL of 0.1N HCl was added to 1 mL of the reaction mixture concentrated on a rotary evaporator and extracted with 1 mL of EtOAc. The organic phase was dried over Na2SO4. 0.1 mL of this solution was diluted into 0.9 mL of eluent and injected onto HPLC (ee=38%).

[0491] The reaction mixture obtained with A11 was further worked up according to the following procedure: The reaction mixture was concentrated on a rotary evaporator (50 mbar). 5 mL of EtOAc and then 5 mL of 0.1 M HCl were added to give a two-phase mixture containing some solids (polyethylene). The layers were separated and the aqueous phase was washed with 2 mL of EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated on a rotary evaporator (40°C, 20 mbar). 23.5 mg of oil were obtained - equivalent to 27.6 mg if we correct from sampling (expected maximum = 31.7 mg) - estimated yield: 87%.

[0492] Embodiment 22

[0493] Addition of an enantiomerically pure chiral auxiliary to oxaborin leads to the formation of at least 2 diastereomers (boron center = becomes chiral upon coordination bonding to the N lone pair of electrons). The situation is even more complicated for N-monosubstituted amino alcohols (e.g., ephedrine) due to the formation of N-dimers (i.e., 4 diastereomers) (Scheme 9).

[0494] Solution 9:

[0495]

[0496] N,N-dimethylamino alcohol leads to a less stable adduct, while there is not much difference between the unsubstituted adduct and the monomethylated adduct. The trans configuration of the substituent (pseudoephedrine) leads to a stronger N->B bond. Studies on the structure of ephedrine / pseudoephedrine-Ph2BH adducts are described in J. Organomet. Chem. 1997, 544, 175-188, which is incorporated herein by reference.

[0497] Embodiment 23

[0498] A list of chiral auxiliaries tested for enantioselective cyclopropanation includes A6 to A11 in Table 24 and A19 to A25 having the structures of the following chiral auxiliary compounds. Since the enantiomeric excess is calculated according to the following formula: (area (first peak) - area (second peak)) / (area (first peak) + area (second peak))%, a negative ee means that the desired enantiomer is mainly formed. This is the case with A10 (prolinol derivative), while A11 (ephedrine) gives the other enantiomer.

[0499] A10: (R)-(+)-α,α-diphenyl-2-pyrrolidinemethanol 50% conversion, -55% ee

[0500]

[0501] (Correct enantiomer) ephedrine derivative

[0502] A11: ((1R,2S)-(-)-ephedrine (100% conversion, 38% ee (wrong enantiomer)

[0503]

[0504] Chiral amino alcohol ephedrine derivatives: The three ephedrines used for structure-activity relationships are also shown below.

[0505] A19: ((1S,2S)-(+)-pseudoephedrine (trans configuration)

[0506] A20: (1R,2S)-(-)-Norephedrine (cis configuration; primary amine)

[0507] A21: (1R,2S)-(-)-N-methylephedrine (cis configuration; tertiary amine)

[0508] Amino acid derivatives: 1 less hindered prolinol

[0509] A22: (S)-2-(Pyrrolidin-2-yl)propan-2-ol

[0510] Amino alcohols:

[0511] A23: N-methyl-D-glucosamine

[0512] A24: (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol

[0513] A25: Quinine A26: Hydroquinine

[0514] Prepare a stock solution of oxaborin 2 in anhydrous THF (30 mg / mL, 0.127 mmol). Weigh the chiral auxiliary (1.1 eq / 2) and place in a 20 mL glass vial. Add 4 mL of anhydrous THF to the chiral auxiliary. Add 1 mL of the substrate stock solution to the chiral auxiliary and stir the mixture at room temperature for 1 hour. Prepare a stock solution of Pd(OAc)2 (1 mg / mL, 0.004 mmol). Prepare a fresh solution of diazomethane in Et2O. After reaction with benzoic acid, its concentration is determined by GC (~0.33 M). The mixture of substrate / chiral auxiliary is cooled to -15°C in a salt / ice / water bath. 1 mL of catalyst stock solution (Sub / Cat=28) and 3 mL of diazomethane solution (CH2N2 / Sub=7.8) are added to the reactor vial. The reaction mixture is stirred at -15°C for 30 minutes, and then the temperature is slowly increased to 22°C. HPLC samples: To cleave the chiral auxiliary, each HPLC sample is treated with excess H2O and then injected: 100 μL reaction mixture; 900 μL heptane / EtOH (100 / 1); 20 μL H2O.

[0515] The conversion and yield of the product were determined via the area of ​​the remaining starting material or product obtained relative to the expected area.

[0516] Table 25. Summary of reaction results.

[0517] entry# Chiral auxiliary Conversion rate (%) Yield (%) ee(%) 1 A11 99 82 30 2 A11 88 78 43 3 A19 99 82 -78 (correct isomer) 4 A20 73 63 -15 (correct isomer) 5 A21 97 86 -55 (correct isomer) 6 A22 41 37 -4 7 A23 92 11 8 8 A24 25 21 28 9 A25 2 - -

[0518] Entries #1 and #2: A11 (ephedrine) was tested again and gave a slightly lower ee (30% vs. 38%) than the previous time. At the lower temperature, the reaction was not complete, but a slightly higher enantiomeric excess was obtained. Entries #3, #4, #5: All ephedrine analogs gave some enantiomeric enriched product, with the highest enantiomeric excess obtained with pseudoephedrine (78% at full conversion) favoring the desired enantiomer. Note that pseudoephedrine is the only ephedrine derivative in which the Me and Ph substituents are in the trans configuration.

[0519]

[0520] Unlike the related A7, which gave a racemic product, norephedrine (the primary amine) gave some enantiomeric excess. This indicates the importance of having a chiral center at the amine group.

[0521] N-Me-(-)-ephedrine (tertiary amine) is also an effective chiral auxiliary, giving the correct enantiomer with slightly lower ee. Simple addition of a methyl group to (-)-ephedrine triggers the formation of the opposite enantiomer.

Claims

1. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, The method comprises the following steps: Formula (A-II) The compound of formula (A-III) is converted into Compounds of as well as hydrolyzing the compound of formula (A-III) to form the compound of formula (I), in: R 1 is a carboxylic acid protecting group; and R a Is OH or -OC 1-6 Alkyl; and wherein the conversion of the compound of formula (A-II) to the compound of formula (A-III) comprises: combining the compound of formula (A-II) and one or more chiral auxiliary agents to form a chiral complex, wherein the chiral auxiliary agent is selected from (1S, 2S)-(+)-pseudoephedrine, (1R, 2S)-(-)-norephedrine and (1R, 2S)-(-)-N-methylephedrine; and The method further comprises reacting the chiral complex with diazomethane in the presence of Pd(OAc)2.

2. The method of claim 1, comprising: A step of reacting with a boronating agent to form an organoboron intermediate of formula (A-II).

3. The method of claim 2, wherein the boronating agent is (R 2 O)2B-B(OR 2 )2, where each R 2 Independently H, C 1-6 Alkyl, or two R 2 Together is C 2-4 The alkylene chain and the intervening atoms form a 5- to 7-membered heterocyclyl ring.

4. The method of claim 2, wherein the boronating agent is selected from (HO)2B-B(OH)2, B2(Pin)2, B2(Cat)2 and B2neop2.

5. The method of claim 2, wherein the boronating agent is B2(Pin)2.

6. The method of claim 2, wherein the reaction of the compound of formula (AI) and the boronating agent is carried out in the presence of a first catalyst.

7. The method of claim 6, wherein the first catalyst comprises one or more Ni catalyst precursors and one or more ligands.

8. The method of claim 7, wherein the Ni catalyst precursor is selected from the group consisting of NiCl2, Ni(Acac)2, Ni(COD)2, NiCl2(PPh3)2, NiCl2(PCy2Ph)2, NiCl2(PPh2CH2CH2PPh2), NiCl2(1,3-bis(diphenylphosphino)propane) and NiCl2(1,3-bis(diphenylphosphino)ethane).

9. The method of claim 7, wherein the Ni catalyst precursor is NiCl2 or Ni(Acac)2.

10. The method of claim 7, wherein the ligand is monodentate or bidentate.

11. The method of claim 7, wherein the ligand is selected from the group consisting of NHC ligands, phosphines, phosphites, phosphoramidites, amines, alcohols, and combinations thereof.

12. The method of claim 11, wherein the alcohol is an amino alcohol.

13. The method of claim 7, wherein the ligand is selected from bis(di-cyclopentylphosphonium)ethyltetrafluoroborate, 4,5-bis(di-tert-butylphosphino)-9,9-dimethylxanthene, 2,2'-bis(dicyclohexylphosphino)-1,1'-biphenyl, 1,2-bis((di-tert-butylphosphino)methyl)benzene, 1,3-bis(1-adamantyl)imidazolium, 1,3-di-tert-butylimidazolium, 1,3-bis(2,6-diisopropyl-phenyl)-4,5-dihydroimidazole-2-ylidene, 1,3-bis(2,6-diisopropylphenyl)-1H-imidazol-3-ylidene, P(octyl)3, Dppf, dcype, (S,S,R,R)-TangPhos, (S,S,R,R)-DuanPhos, DavePhos, P(tBu)3, inaPhos, Binaphane, phosphoramidite, (S)-SegphosRu(Oac)2, [Rh(S,S)EtDuPhos(COD)]Otf, (S)-XylylPhanePhos, (R)-C3-TunePhos, (R)-DTBM-Garphos, (R)-D MM-Garphos, (R,R,R)-Xyl-SKP, thio-XantPhos, TaniaPhos, SPANPhos, tri(4-methoxyphenyl)phosphine, tri(2,6-dimethoxyphenyl)phosphine, trioctylphosphine, bis(dicyclohexylphosphino)methane), 1,3-bis(dicyclohexylphosphino)propane, 1,2-bis(diphenylphosphino)ethane, (R,R)-Dipamp, bis(dicyclohexylphosphinophenyl)ether, DPEPhos, bis(2-diphenylphosphinoethyl)phenylphosphine, 1,1,1-tris(diphenylphosphinomethyl)ethane, 1,1′-ferrocenediyl-bis(dicyclohexylphosphine), DTBPF, 1-diphenylphosphino-1′-(di-butylphosphino)ferrocene, SIMes, IMes and (1,3-bis[bis(o-methoxyphenyl)phosphino]propane.

14. The method of claim 7, wherein the ligand is P(octyl)3, or dcype.

15. The method of claim 2, wherein the reaction of the compound of formula (AI) and the boronating agent is carried out in the presence of a base system.

16. The method of claim 15, wherein the base system is one or more inorganic bases.

17. The method of claim 15, wherein the base system is K2CO3, Cs2CO3, Li2CO3 or any combination thereof.

18. The method of claim 15, wherein the base system is a mixture of K2CO3 and Cs2CO3, wherein the molar ratio of K2CO3 to Cs2CO3 is 5:1 to 15:

1.

19. The method of claim 2, wherein the reaction of the compound of formula (AI) and the boronating agent is carried out in an organic solvent.

20. The method of claim 19, wherein the organic solvent is toluene, xylene or THF.

21. The method of claim 2, wherein the reaction of the compound of formula (AI) and the boronating agent is carried out at a temperature of 70°C to 100°C.

22. The process of claim 2, wherein said reaction of said compound of formula (AI) and said boronating agent is carried out at a temperature of 90°C.

23. The method of claim 1, wherein the chiral auxiliary is (1S,2S)-(+)-pseudoephedrine.

24. The method of claim 1, further comprising purifying the compound of formula (A-III) prior to the hydrolysis step.

25. The method of claim 24, wherein the purification is performed using chromatography or crystallization.

26. The process of claim 1, wherein the hydrolysis of the compound of formula (A-III) is carried out using a base.

27. The method of claim 26, wherein the base is NaOH.

28. The method of claim 1, wherein R 1 It is C 1-6 alkyl.

29. The method of claim 1, wherein R 1 It is ethyl.

30. The method of claim 1, further comprising purifying the compound of formula (I).

31. The method of claim 2, wherein the compound of formula (AI) is 32. The method of claim 2, wherein the compound of formula (A-II) is 33. The method of claim 1, wherein the compound of formula (A-III) is 34. The method of claim 1, wherein the compound of formula (I) is 35. The method of claim 1, wherein the pharmaceutically acceptable salt of the compound of formula (I) is 36. The method of claim 2, wherein the compound of formula (AI) is prepared by The method comprises the following steps: AV The compound of formula (A-VI) is reacted with an alkylating agent to form a compound of formula (A-VI), Converting the compound of formula (A-VI) into the compound of formula (AI), in: R 1 is a carboxylic acid protecting group; Each R 3 Independently C 1-6 Alkyl, or two R 3 Together is C 2-3 The alkylene group and the intervening atoms form a 5- to 6-membered heterocyclyl ring.

37. The method of claim 36, wherein the alkylating agent is CH(OR 3 )2CH2X, and X is halogen.

38. The method of claim 36, wherein the alkylating agent is CH(OEt)2CH2Br.

39. The method of claim 36, further protecting a compound of formula (A-IV) to form the compound of formula (AV).

40. The method of claim 36, wherein the compound of formula (AV) is 41. The method of claim 36, wherein the compound of formula (A-VI) is 42. The method of claim 36, wherein the compound of formula (AI) is

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