I IIIII IIIIIIII Ill lllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111
`US009416109B2
`
`c12) United States Patent
`Moniz et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 9,416,109 B2
`Aug. 16, 2016
`
`(54) METHODS AND COMPOUNDS USEFUL IN
`THE SYNTHESIS OF OREXIN-2 RECEPTOR
`ANTAGONISTS
`
`(71) Applicant: Eisai R&D Management Co., Ltd.,
`Tokyo (JP)
`
`(58) Field of Classification Search
`CPC .... C07D 239/34; C07C 69/16; C07C 309/66;
`C07C 309/73; C07C 401/12; C07C 303/28;
`C07C 29/147; C07C 2101/02; C12P 7/22
`USPC ............................................................ 549/75
`See application file for complete search history.
`
`(72)
`
`Inventors: George Anthony Moniz, Cambridge,
`MA (US); Annie Zhu Wilcoxen, North
`Reading, MA (US); Farid Benayoud,
`North Andover, MA (US); Jaemoon Lee,
`Andover, MA (US); Huiming Zhang,
`Andover, MA (US); Taro Terauchi,
`Tsukuba (JP); Ayumi Takemura,
`Tsukuba (JP); Yu Yoshida, Tsukuba (JP);
`Toshiaki Tanaka, Tsukuba (JP); Keiichi
`Sorimachi, Tsukuba (JP); Yoshimitsu
`Naoe, Tsukuba (JP); Yuji Kazuta,
`Tsukuba (JP)
`
`(73) Assignee: Eisai R&D Management Co., Ltd.,
`Tokyo (JP)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`(21) Appl. No.:
`
`14/379,063
`
`(22) PCT Filed:
`
`Feb.14,2013
`
`(86) PCT No.:
`
`PCT /US2013/026204
`
`§ 371 (c)(l),
`(2) Date:
`
`Aug.15,2014
`
`(87) PCT Pub. No.: W02013/123240
`
`PCT Pub. Date: Aug. 22, 2013
`
`(65)
`
`Prior Publication Data
`
`US 2015/0025237 Al
`
`Jan.22,2015
`
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 61/600,109, filed on Feb.
`17, 2012.
`
`(51)
`
`(52)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`C07D 239/34
`C07C 69/16
`C07C 309/66
`C12P 7122
`C07C 309/73
`C07D 401/12
`C07C 303/28
`C07C 291147
`U.S. Cl.
`CPC ............ C07D 239/34 (2013.01); C07C 291147
`(2013.01); C07C 69/16 (2013.01); C07C
`303/28 (2013.01); C07C 309/66 (2013.01);
`C07C 309/73 (2013.01); C07D 401/12
`(2013.01); C12P 7122 (2013.01); C07C 2101/02
`(2013.01)
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,849,954 A * 12/1998 Carpino et al.
`8,268,848 B2
`9/2012 Terauchi et al.
`2012/0095031 Al*
`4/2012 Terauchi et al.
`
`................... 568/8
`
`.............. 514/269
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`WO
`WO
`
`WO 2008/057575 A2
`WO 2008/150364 Al
`WO 2010/032200 Al
`WO 2010/063662 Al
`
`5/2008
`12/2008
`3/2010
`6/2010
`
`OTHER PUBLICATIONS
`
`Aldrich Chemfiles 2007 7(2), Peptide Synthesis, copyright Sigma
`Aldrich Co., p. 1-20.*
`International Search Report and Written Opinion, PCT/US2013/
`026204, mailed Apr. 25, 2013.
`Valgimigli Let al. The effect of ring nitrogen atoms on the homolytic
`reactivity of phenolic compounds: understanding the radical-scav(cid:173)
`enging ability 5-pyrimidinols. Chem Eur J. Oct. 17, 2003; 9(20):
`4997-5010.
`Yamaguchi Ket al. Construction of a cis-cyclopropane via reductive
`radical decarboxylation. Enantioselective synthesis of cis- and trans(cid:173)
`l-arylpiperazyl-2-phenylcyclopropanes
`designed
`as
`antidoparninergic agents. J Org Chem. Jun. 11, 2003; 68(24): 9255-
`9262.
`Response to Office Action, Chinese Patent Application No.
`201380009575.3, Oct. 15, 2015.
`Response to Office Action, Singapore Patent Application No.
`l 1201403216U, Oct. 27, 2015.
`Office Action, Israeli Application No. 232949; Nov. 2, 2015.
`Banfi L et al. On the optimization of pig pancreatic lipase catalyzed
`monoacetylation of prochiral diols. Tetrahedron Asymmetry. 1995;
`6(6): 1345-1356.
`Oger C et al. Lipase-Catalyzed Regioselective Monoacetylation of
`Unsymmetrical 1,5-Primary Diols. Journal of Organic Chemistry.
`2010; 75: 1892-1897.
`Office Action, Singapore Patent Application No. 11201403216U,
`mailed May 27, 2015.
`Office Action, Chinese Patent Application No. 201380009575.3,
`mailed Jun. 1, 2015.
`
`(Continued)
`
`Primary Examiner - Samantha Shterengarts
`Assistant Examiner - Matt Mauro
`(74) Attorney, Agent, or Firm - Myers Bigel & Sibley, P.A.
`
`(57)
`
`ABSTRACT
`
`The present disclosure provides compounds and methods that
`are useful for the preparation of compounds useful as
`orexin-2 receptor antagonists.
`
`32 Claims, No Drawings
`
`Page 1 of 33
`
`EISAI EXHIBIT 1006
`
`

`

`US 9,416,109 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`Response to Office Action, Israeli Application No. 23 2949 (Hebrew)
`(3 pages), filed Mar. 20, 2016, and English translation thereof (3
`pages); Annex A ( 1 page); Annex B ( 1 page); Annex C ( 1 page);
`Claims (13 pages); specification (69 pages).
`
`Patent Office of the People's Republic of China; Notification to Go
`Through Formalities of Registration, Notification to Grant Patent
`Right for Invention, Chinese Patent Application No. 2013 80009 57 5.
`3, issued May 24, 2016 (2 pages) and English translation (3 pages).
`
`* cited by examiner
`
`Page 2 of 33
`
`

`

`US 9,416,109 B2
`
`1
`METHODS AND COMPOUNDS USEFUL IN
`THE SYNTHESIS OF OREXIN-2 RECEPTOR
`ANTAGONISTS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`2
`SUMMARY
`
`Provided herein are compounds and methods that are use(cid:173)
`ful for the preparation of compounds useful as orexin-2 recep-
`tor antagonists.
`Provided is a process for making a compound of Formula I,
`
`5
`
`This application claims the benefit of U.S. Provisional
`Patent Application No. 61/600,109, filed Feb. 17, 2012,
`which is incorporated by reference herein in its entirety.
`
`10
`
`FIELD OF THE INVENTION
`
`HO~OH
`
`The present invention relates to compounds and methods
`that are useful for the preparation of compounds useful as
`orexin-2 receptor antagonists.
`
`BACKGROUND OF THE INVENTION
`
`wherein Ar is an aryl such as phenyl, which aryl may be
`15 unsubstituted, or substituted 1-3 times, for example, with
`substituents independently selected from the group consist(cid:173)
`ing of: halo, C 1 _6alkyl, C 1_6alkoxy, and haloC 1 _6alkyl,
`the method comprising one or more of the steps of:
`i) providing a composition comprising a compound of
`Formula II:
`
`20
`
`II
`
`Compound A 50
`
`~
`F~',,A. ,,_O
`I
`NO
`)LN U,
`
`Me
`
`\
`
`HN
`
`Me
`
`N
`
`I ~
`
`60
`
`Ila
`
`There is thus a need for synthetic methods and intermedi(cid:173)
`ates useful in the preparation of Compound A and related 65
`compounds. It is, therefore, an object of the present applica(cid:173)
`tion to provide such synthetic methods and intermediates.
`
`In some embodiments, the compound of Formula II has an
`enantiomeric excess ( ee) of the Formula Ila stereoisomerofat
`least 75, 80, 85, 90, 95, 98, 99%, or greater.
`
`Orexin receptors are G-protein coupled receptors found
`predominately in the brain. Their endogenous ligands,
`orexin-A and orexin-B, are expressed by neurons localized in
`the hypothalamus. Orexin-A is a 33 amino acid peptide;
`orexin-B consists of 28 amino acids. (Sakurai T. et al., Cell, 25
`1998, 92, 573-585). There are two subtypes of orexin recep(cid:173)
`tors, OX 1 and OX2 ; OX 1 binds orexin-A preferentially, while
`OX2 binds both orexin-A and -B. Orexins stimulate food
`consumption in rats, and it has been suggested that orexin
`signaling could play a role in a central feedback mechanism 30
`for regulating feeding behavior (Sakurai et al., supra). It has
`also been observed that orexins control wake-sleep condi(cid:173)
`tions (Chemelli R. M. eta!., Cell, 1999, 98, 437-451). Orexins
`may also play roles in brain changes associated with opioid
`and nicotine dependence (S. L. Borglandet al., Neuron, 2006, 35
`49, 598-601; C. J. Winrow et al., Neuropharmacology, 2010,
`58, 185-194), and ethanol dependence (J. R. Shoblock et al.,
`Psychopharmacology, 2011, 215, 191-203). Orexins have
`additionally been suggested to play a role in some stress
`reactions (T. Ida et al., Biochem. Biophys. Res. Commun., 40
`2000, 270, 318-323).
`Compounds such as (1R,2S)-2-(((2,4-dimethylpyrimidin-
`5-yl)oxy)methyl)-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-
`yl)cyclopropanecarboxamide (Compound A, below) have
`been found to be potent orexin receptor antagonists, and may
`be useful in the treatment of sleep disorders such as insonmia,
`as well as for other therapeutic uses.
`
`wherein Ar is as given above, and an organic solvent,
`wherein said composition is at a temperature of from -30 to
`40° C., or from -30 to 30° C., or from -30 to 10° C., or from
`-10 to 0° C., or from -10 to -5° C.; and
`ii) adding to said composition a hydride reducing agent,
`wherein said agent reduces said compound of Formula II into
`said compound of Formula I,
`to thereby make said compound of Formula I.
`In some embodiments, Ar is phenyl, which phenyl may be
`unsubstituted, or substituted 1-3 times with a halo indepen(cid:173)
`dently selected from the group consisting of: chloro, fluoro,
`bromo, and iodo.
`In some embodiments, the organic solvent is an aromatic
`hydrocarbon solvent, an aliphatic hydrocarbon solvent, a
`halogenated hydrocarbon solvent or an ether solvent.
`In some embodiments, the process may further include the
`step of mixing ( e.g., by stirring) the composition after said
`adding step for a time of 12 to 24 hours.
`In some embodiments, the process may further include the
`step of quenching the reduction by adding to said composi(cid:173)
`tion a mild aqueous acid (e.g., citric acid, EDTA or tartaric
`acid).
`In some embodiments, the compound of Formula II has the
`55 absolute stereochemistry of Formula Ila:
`
`45
`
`Page 3 of 33
`
`

`

`3
`In some embodiments, the compound of Formula II or
`Formula Ila is the compound:
`
`4
`Also provided is a process for making a compound of
`Formula III:
`
`US 9,416,109 B2
`
`F
`
`III
`
`10
`
`In some embodiments, the compound of Formula I has the 15
`absolute stereochemistry of Formula Ia:
`
`Ar,,,,, .. D
`
`HO~OH .
`
`la
`
`20
`
`HO~OA c
`
`wherein Ar is aryl such as phenyl, which aryl may be
`unsubstituted, or substituted 1-3 times, for example with sub(cid:173)
`stituents independently selected from the group consisting of:
`halo, C 1 _6alkyl, C 1_6alkoxy, and haloC 1 _6alkyl,
`comprising reacting a mixture of:
`i) a compound of Formula Ia:
`
`la
`
`In some embodiments, the compound of Formula I has an
`enantiomeric excess (ee) of the Formula Ia stereoisomer of at 25
`least 75, 80, 85, 90, 95, 98, 99%, or greater.
`In some embodiments, the compound of Formula I or For(cid:173)
`mula Ia is:
`
`wherein Ar is as given above,
`ii) vinyl acetate,
`iii) a lipase, and
`iv) an organic solvent
`for a time of from 5 to 36 hours, or from 7 to 18 hours,
`to thereby make the compound of Formula III.
`In some embodiments, Ar is phenyl, which phenyl may be
`30 unsubstituted, or substituted 1-3 times with a halo indepen(cid:173)
`dently selected from the group consisting of: chloro, fluoro,
`bromo, and iodo.
`In some embodiments, the organic solvent is tetrahydrofu(cid:173)
`ran, 2-methyltetrahydrofuran, an ether solvent, acetone, or
`35 acetonitrile.
`In some embodiments, the lipase is a Candida Antarctica
`lipase, for example, a Candida Antarctica B lipase, which
`may be coupled to solid support such as an acrylic resin.
`In some embodiments, the process may further include the
`40 step of filtering the mixture after said reacting to produce a
`filtrate, and may further include concentrating the filtrate to
`produce a concentrated filtrate. In some embodiments, the
`process may further include the step of washing the concen(cid:173)
`trated filtrate with water or water comprising a salt ( e.g., a
`45 solution of 15-20% NaCl in water).
`Also provided is a compound of Formula IV:
`
`Also provided is compound of Formula III:
`
`HO~OA c
`
`III
`
`wherein Ar is an aryl such as phenyl, which aryl may be
`unsubstituted, or substituted 1-3 times, for example with sub(cid:173)
`stituents independently chosen from the group consisting of: 50
`halo, C 1 _6alkyl, C 1_6alkoxy, and haloC 1 _6alkyl.
`In some embodiments, Ar is phenyl, which phenyl may be
`unsubstituted, or substituted 1-3 times with a halo indepen(cid:173)
`dently selected from the group consisting of: chloro, fluoro,
`bromo, and iodo.
`In some embodiments, the compound is:
`
`55
`
`R1~0A c
`
`IV
`
`F 6 ),,,,,, .. D
`
`OAc.
`
`HO~
`
`60
`
`wherein:
`Ar is an aryl such as phenyl, which aryl may be unsubsti(cid:173)
`tuted, or substituted 1-3 times, for example with substituents
`independently selected from the group consisting of: halo,
`C 1_6alkyl, C 1_6alkoxy, and haloC 1 _6alkyl; and
`R 1 is a leaving group.
`In some embodiments, Ar is phenyl, which phenyl may be
`unsubstituted, or substituted 1-3 times with a halo indepen(cid:173)
`dently selected from the group consisting of: chloro, fluoro,
`bromo, and iodo.
`In some embodiments, the leaving group is a sulfonate
`65 ester leaving group selected from the group consisting of:
`mesylate, tosylate, nosylate, benzene sulfonate, and brosy(cid:173)
`late.
`
`Page 4 of 33
`
`

`

`5
`In some embodiments, the compound is:
`
`6
`In some embodiments, the compound of Formula III is:
`
`US 9,416,109 B2
`
`OF
`
`),,,,, •.. / \
`
`OAc.
`
`HO~
`
`10
`
`In some embodiments, the compound of Formula IV has
`the absolute stereochemistry of Formula IVa:
`
`!Va
`
`15
`
`In some embodiments, the compound of Formula IV has
`the absolute stereochemistry of Formula IVa:
`
`20
`
`!Va
`
`In some embodiments, the compound ofF ormula IV has an
`enantiomeric excess (ee) of the Formula IVa stereoisomer of
`at least 75, 80, 85, 90, 95, 98, 99%, or greater.
`Further provided is a process for making a compound of
`Formula IV:
`
`25
`
`30
`
`R 1~ 0A c
`
`IV 35
`
`wherein Ar is an aryl such as phenyl, which aryl may be 40
`unsubstituted, or substituted 1-3 times, for example with sub(cid:173)
`stituents independently selected from the group consisting of:
`halo, C 1 _6alkyl, C 1_6alkoxy, and haloC 1 _6alkyl; and
`R1 is a sulfonate ester leaving group,
`said process comprising reacting a compound of Formula III: 45
`
`HO~OA c
`
`III
`
`50
`
`wherein Ar is as given above,
`with a compound selected from the group consisting of: tosyl
`chloride, mesyl chloride, nosy! chloride, toluenesulfonyl 55
`chloride, toluenesulfonic anhydride and methanesulfonic
`anhydride, wherein said reacting is carried out in an organic
`solvent in the presence of a base,
`to thereby make said compound of Formula IV.
`In some embodiments, Ar is phenyl, which phenyl may be 60
`unsubstituted, or substituted 1-3 times with a halo indepen(cid:173)
`dently selected from the group consisting of: chloro, fluoro,
`bromo, and iodo.
`In some embodiments, the reacting is carried out for a time
`of from 10 minutes to 2 hours.
`In some embodiments, the base is an organic amine or
`potassium carbonate.
`
`65
`
`In some embodiments, the compound of Formula IV has an
`enantiomeric excess (ee) of the Formula IVa stereoisomer of
`at least 75, 80, 85, 90, 95, 98, 99%, or greater.
`Also provided is a process for making a compound of
`Formula\!,
`
`V
`
`wherein Ar is an aryl such as phenyl, which aryl may be
`unsubstituted, or substituted 1-3 times, for example with sub(cid:173)
`stituents independently selected from the group consisting of:
`halo, C 1 _6alkyl, C 1_6alkoxy, and haloC 1 _6alkyl; and
`R2 and R3 are each independently selected from the group
`alkyl,
`consisting of: hydrogen, C 1_6alkyl, haloC 1_6
`C 1_6alkoxy, and hydroxyC 1 _6alkyl,
`comprising the steps of:
`a) stirring a mixture of:
`i) a compound of Formula IV:
`
`R1~0A c
`
`wherein Ar is as given above; and
`R 1 is a leaving group,
`ii) a substituted pyrimidine of Formula VI:
`
`IV
`
`VI
`
`wherein R2 and R3 are as given above;
`iii) a base; and
`iv) an organic solvent,
`at a temperature of from 65-70° C., for 1 to 12 hours; and then
`b) reacting the mixture with an aqueous base for a time of
`from 2 to 20 hours,
`to thereby make said compound of Formula V.
`
`Page 5 of 33
`
`

`

`US 9,416,109 B2
`
`8
`Also provided is a process for making a compound of
`Formula B:
`
`B
`
`7
`In some embodiments, Ar is phenyl, which phenyl may be
`unsubstituted, or substituted 1-3 times with a halo indepen(cid:173)
`dently selected from the group consisting of: chloro, fluoro,
`bromo, and iodo.
`In some embodiments, R2 and R3 are each independently
`selected from the group consisting of: hydrogen and
`cl-6alkyl.
`In some embodiments, the compound of Formula IV has
`the absolute stereochemistry of Formula IVa:
`
`5
`
`10
`
`!Va
`
`In some embodiments, the compound ofF ormula IV has an
`enantiomeric excess (ee) of the Formula IVa stereoisomer of
`at least 75, 80, 85, 90, 95, 98, 99%, or greater.
`Further provided is a process for making a compound of
`Formula VI:
`
`15
`
`20
`
`wherein:
`R2 and R3 are each independently selected from the group
`consisting of: hydrogen and C 1 _6 alkyl; and
`R4 is C 1_6 alkyl,
`comprising mixing:
`i) a compound of Formula A:
`
`A
`
`25
`
`VI
`
`wherein R2 and R3 are each independently selected from
`the group consisting of: hydrogen and C 1_6 alkyl,
`comprising the step of heating a mixture of:
`i) a compound of Formula B:
`
`B
`
`wherein:
`R2 and R3 are as given above; and
`R4 is C 1 _6 alkyl,
`ii) an alkoxide or hydroxide salt,
`iii) a thiol, and
`iv) an organic solvent,
`to thereby make said compound of Formula VI.
`In some embodiments, the heating is to a temperature of
`from 50° C. to 140° C. In some embodiments, heating com(cid:173)
`prises boiling or refluxing the mixture.
`In some embodiments, the heating is carried out in a time of
`from 5 to 50 hours.
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`wherein R4 is as given above,
`ii) trimethylaluminum,
`iii) a palladium catalyst, and
`iv) an organic solvent,
`to thereby make said compound of Formula B.
`In some embodiments, the mixing step is carried out for a
`time of from 12 to 48 hours.
`In some embodiments, the mixing step is carried out at a
`temperature of from 20° C. to 110° C.
`In some embodiments, the process further includes a step
`of quenching the reaction, e.g., with water comprising a base
`( e.g., a hydroxide such as sodium hydroxide).
`In some embodiments, the process further includes a step
`of treating said compound of Formula B with a solution
`comprising hydrogen chloride and a solvent such as an alco(cid:173)
`hol (e.g., isopropyl alcohol) to obtain said compound of For(cid:173)
`mula B as a hydrochloride salt. In some embodiments this is
`done after a quenching step.
`Further provided is a process for making a compound of
`Formula B:
`
`B
`
`wherein:
`R2 and R3 are each independently selected from the group
`consisting of: hydrogen and C 1 _6 alkyl; and
`R4 is C 1_6 alkyl,
`
`Page 6 of 33
`
`

`

`9
`
`comprising mixing:
`i) a compound of Formula A:
`
`US 9,416,109 B2
`
`10
`
`comprising the steps of:
`a) oxidizing a compound of Formula V:
`
`V
`
`A 5
`
`10
`
`15
`
`wherein Ar, R2 and R3 are as given above,
`with a first oxidizing agent, to form an aldehyde of Formula
`20 VIII:
`
`25
`
`VIII
`
`wherein R4 is as given above,
`ii) a nickel catalyst (e.g., Ni(acac)2, Ni(PPh3 ) 2Cl2, or Ni(d(cid:173)
`ppp )Cl2),
`iii) an alkylmagnesium halide, and
`iv) an organic solvent,
`to thereby make said compound of Formula B.
`In some embodiments, the mixing is carried out for a time
`of from 6 to 36 hours.
`In some embodiments, the mixing is carried out at a tem(cid:173)
`perature of from 10° C. to 30° C.
`In some embodiments, the process further includes a step
`of quenching the reaction, e.g., with water comprising an acid 30
`(e.g., citric acid). In some embodiments, the process further
`includes a step of adding ammonium hydroxide after the
`quenching step.
`In some embodiments, the process further includes react(cid:173)
`ing the compound of Formula B with a solution comprising 35
`hydrogen chloride and a solvent such as an alcohol (e.g.,
`isopropyl alcohol) to obtain the compound of Formula Bas a
`hydrochloride salt.
`Also provided is a process for making a compound of 40
`Formula VII:
`
`wherein Ar, R2 and R3 are as given above; and then
`b) oxidizing the aldehyde of Formula VIII with a second
`oxidizing agent, to thereby make said compound of Formula
`VII.
`In some embodiments, Ar is phenyl, which phenyl may be
`unsubstituted, or substituted 1-3 times with a halo indepen-
`45 dently selected from the group consisting of: chloro, fluoro,
`bromo, and iodo.
`In some embodiments, R2 and R3 are each independently
`selected from the group consisting of: hydrogen and
`50 cl-6alkyl.
`In some embodiments, the first oxidizing agent is sodium
`hypochlorite.
`In some embodiments, oxidizing of step a) is catalyzed
`with an effective amount of 2,2,6,6-tetramethylpiperidine
`1-oxyl (TEMPO).
`In some embodiments, the second oxidizing agent is
`sodium chlorite.
`In some embodiments, the first oxidizing agent and the
`60 second oxidizing agent are the same. In some embodiments,
`the first oxidizing agent and the second oxidizing agent are
`different.
`In some embodiments, the oxidizing of step a) and/or step
`65 b) is carried out in an organic solvent ( e.g., dichloromethane,
`tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetoni(cid:173)
`trile, or ethyl acetate).
`
`55
`
`VII
`
`wherein Ar is an aryl such as phenyl, which aryl may be
`unsubstituted, or substituted 1-3 times, for example with sub(cid:173)
`stituents independently selected from the group consisting of:
`halo, C 1 _6 alkyl, C 1_6 alkoxy, and haloC 1 _6 alkyl; and
`R2 and R3 are each independently selected from the group
`consisting of: hydrogen, C 1 _6 alkyl, haloC 1_6 alkyl, C 1 _6
`alkoxy, and hydroxyC 1 _6 alkyl,
`
`Page 7 of 33
`
`

`

`US 9,416,109 B2
`
`11
`Further provided is a process for preparing a compound of
`Formula VII:
`
`VII
`
`12
`
`wherein:
`Ar is an aryl such as phenyl, which aryl may be unsubsti(cid:173)
`tuted, or substituted 1-3 times, for example with substituents
`independently selected from the group consisting of: halo,
`5 C 1_6alkyl, C 1_6alkoxy, and haloC 1 _6alkyl;
`R2 and R3 are each independently selected from the group
`cons1stmg of: hydrogen, C 1_6alkyl, haloC 1_6 alkyl,
`C 1_6alkoxy, and hydroxyC 1 _6alkyl; and
`Ar' is a pyridine group:
`
`10
`
`wherein Ar is an aryl such as phenyl, which aryl may be
`unsubstituted, or substituted 1-3 times, for example with sub- 15
`stituents independently selected from the group consisting of:
`halo, C 1 _6alkyl, C 1_6alkoxy, and haloC 1 _6alkyl; and
`R2 and R3 are each independently selected from the group
`cons1stmg of: hydrogen, C 1 _6alkyl, haloC 1_6 alkyl,
`C 1 _6alkoxy, and hydroxyC1 _6alkyl,
`comprising: oxidizing a compound of Formula V:
`
`20
`
`Rs
`
`V
`
`25
`
`wherein:
`R4 is selected from the group consisting of: hydrogen, halo,
`C 1_6alkyl, C1 _6alkoxy, and (C 1_6alkoxy)C 1_6alkyl;
`Rs is selected from the group consisting of: hydrogen, halo,
`C 1_6alkyl, and haloC 1 _6alkyl; and
`R6 is selected from the group consisting of: hydrogen, halo,
`C 1_6alkyl, haloC 1 _6alkyl, C 1 _6alkoxy, (C 1 _6alkoxy)C 1_
`6alkyl, and cyano;
`30 comprising the step ofreacting a compound of Formula VII:
`
`35
`
`wherein Ar, R2 and R3 are as given above,
`with sodium hypochlorite and sodium chlorite,
`to thereby make said compound of Formula VII.
`In some embodiments, Ar is phenyl, which phenyl may be
`unsubstituted, or substituted 1-3 times with a halo indepen- 40
`dently selected from the group consisting of: chloro, fluoro,
`bromo, and iodo.
`In some embodiments, R2 and R3 are each independently
`selected from the group consisting of: hydrogen and
`cl-6alkyl.
`the oxidizing with sodium
`In some embodiments,
`hypochlorite and sodium chlorite is carried out simulta(cid:173)
`neously.
`In some embodiments, the oxidizing is catalyzed with an
`effective amount of 2,2,6,6-tetramethylpiperidine 1-oxyl 50
`(TEMPO).
`Also provided is a process for making a compound of
`Formula IX:
`
`wherein Ar, R2 and R3 are as given above,
`45 with a compound of Formula X:
`
`VII
`
`X
`
`55
`
`IX
`
`60
`
`65
`
`wherein R4 , Rs, and R6 are as given above,
`said reacting carried out in an organic solvent in the presence
`of an organic amine and an amide coupling agent,
`to thereby make said compound of Formula IX.
`In some embodiments, Ar is phenyl, which phenyl may be
`unsubstituted, or substituted 1-3 times with a halo indepen(cid:173)
`dently selected from the group consisting of: chloro, fluoro,
`bromo, and iodo.
`In some embodiments, R2 and R3 are each independently
`selected from the group consisting of: hydrogen and
`cl-6alkyl.
`
`Page 8 of 33
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`US 9,416,109 B2
`
`13
`DETAILED DESCRIPTION
`
`All U.S. Patent references are hereby incorporated by ref(cid:173)
`erence herein to the extent they are consistent with the present
`descriptions.
`
`A. DEFINITIONS
`
`Compounds of this invention include those described gen(cid:173)
`erally above, and are further illustrated by the embodiments,
`sub-embodiments, and species disclosed herein. As used
`herein, the following definitions shall apply unless otherwise
`indicated.
`As described herein, compounds of the invention may
`optionally be substituted with one or more substituents, such
`as are illustrated generally above, or as exemplified by par(cid:173)
`ticular classes, subclasses, and species of the invention. In
`general, the term "substituted" refers to the replacement of
`hydrogen in a given structure with a specified substituent.
`Unless otherwise indicated, a substituted group may have a 20
`substituent at each substitutable position of the group, and
`when more than one position in any given structure may be
`substituted with more than one substituent selected from a
`specified group, the substituent may be either the same or
`different at every position. Combinations of substituents
`envisioned by this invention are preferably those that result in
`the formation of stable or chemically feasible compounds.
`"Isomers" refer to compounds having the same number
`and kind of atoms and hence the same molecular weight, but
`differing with respect to the arrangement or configuration of
`the atoms.
`"Stereoisomers" refer to isomers that differ only in the
`arrangement of the atoms in space.
`"Absolute stereochemistry" refers to the specific spatial
`arrangement of atoms or groups in a chemical compound 35
`about an asymmetric atom. For example, a carbon atom is
`asymmetric if it is attached to four different types of atoms or
`groups of atoms.
`"Diastereoisomers" refer to stereoisomers that are not mir(cid:173)
`ror images of each other.
`"Enantiomers" refers to stereoisomers that are non-super(cid:173)
`imposable mirror images of one another.
`Enantiomers include "enantiomerically pure" isomers that
`comprise substantially a single enantiomer, for example,
`greater than or equal to 90%, 92%, 95%, 98%, or 99%, or
`equal to 100% of a single enantiomer.
`"Enantiomerically pure" as used herein means a com(cid:173)
`pound, or composition of a compound, that comprises sub(cid:173)
`stantially a single enantiomer, for example, greater than or
`equal to 90%, 92%, 95%, 98%, or 99%, or equal to 100% of
`a single enantiomer.
`"Stereomerically pure" as used herein means a compound
`or composition thereof that comprises one stereoisomer of a
`compound and is substantially free of other stereoisomers of
`that compound. For example, a stereomerically pure compo- 55
`sition of a compound having one chiral center will be sub(cid:173)
`stantially free of the opposite enantiomer of the compound. A
`stereomerically pure composition of a compound having two
`chiral centers will be substantially free of diastereomers, and
`substantially free of the enantiomer, of the compound. A
`typical stereomerically pure compound comprises greater
`than about 80% by weight of one stereoisomer of the com(cid:173)
`pound and less than about 20% by weight of other stereoiso(cid:173)
`mers of the compound, more preferably greater than about
`90% by weight of one stereoisomer of the compound and less
`than about 10% by weight of the other stereoisomers of the
`compound, even more preferably greater than about 95% by
`
`14
`weight of one stereoisomer of the compound and less than
`about 5% by weight of the other stereoisomers of the com(cid:173)
`pound, and most preferably greater than about 97% by weight
`of one stereoisomer of the compound and less than about 3%
`5 by weight of the other stereoisomers of the compound. See,
`e.g., U.S. Pat. No. 7,189,715.
`"R" and "S" as terms describing isomers are descriptors of
`the stereochemical configuration at an asymmetrically sub(cid:173)
`stituted carbon atom. The designation of an asymmetrically
`10 substituted carbon atom as "R" or "S" is done by application
`of the Cahn-Ingold-Prelog priority rules, as are well known to
`those skilled in the art, and described in the International
`Union of Pure and Applied Chemistry (IUPAC) Rules for the
`Nomenclature of Organic Chemistry. Section E, Stereochem-
`15 istry.
`"Enantiomeric excess" ( ee) of an enantiomer, when
`expressed as a percentage, is [(the mole fraction of the major
`enantiomer) minus (the mole fraction of the minor enanti(cid:173)
`omer)]xlOO.
`"Stable" as used herein refers to compounds that are not
`substantially altered when subjected to conditions to allow for
`their production, detection, and preferably their recovery,
`purification, and use for one or more of the purposes disclosed
`herein. In some embodiments, a stable compound or chemi-
`25 cally feasible compound is one that is not substantially altered
`when kept at a temperature of 40° C. or less, in the absence of
`moisture or other chemically reactive conditions, for at least
`a week.
`"Refluxing" as used herein refers to a technique in which
`30 vapors from a boiling liquid are condensed and returned to the
`mixture from which it came, typically by boiling the liquid in
`a vessel attached to a condenser.
`"Concentrating" as used herein refers to reducing the vol(cid:173)
`ume of solvent in a composition or mixture.
`A "filtrate" is the liquid produced after filtering thereof;
`filtering typically includes the removal of a suspension of
`solid from the liquid.
`An "organic" compound as used herein is a compound that
`contains carbon. Similarly, an "organic solvent" is a com-
`40 pound containing carbon that is useful as a solvent. Examples
`of organic solvents include, but are not limited to, acid amides
`such as N,N-dimethylformamide and N,N-dimethylaceta(cid:173)
`mide; alcohols such as ethanol, methanol, isopropanol, amyl
`alcohol, ethylene glycol, propylene glycol, 1-butanol, butyl
`45 carbitol acetate and glycerin; aliphatic hydrocarbons such as
`hexane and octane; aromatic hydrocarbons such as toluene,
`xylenes and benzene; ketones such as acetone, methyl ethyl
`ketone and cyclohexanone; halogenated hydrocarbons such
`as methylene chloride, chlorobenzene and chloroform; esters
`50 such as ethyl acetate, amyl acetate and butyl acetate; ethers
`such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-diox(cid:173)
`ane, tert-butyl methyl ether, diethyl ether and ethylene glycol
`dimethyl ether; nitriles such as acetonitrile; and sulfoxides
`such as dimethylsulfoxide.
`An "inorganic" compound is a compound not containing
`carbon.
`A "hydrocarbon" is an organic compound consisting of
`carbon and hydrogen atoms. Examples of hydrocarbons use(cid:173)
`ful as "hydrocarbon solvents" include, but are not limited to,
`60 an "aromatic hydrocarbon solvent" such as benzene, toluene,
`xylenes, etc., and an "aliphatic hydrocarbon solvent" such as
`pentane, hexane, heptane, etc.
`An "amine", "organic amine", "amine base" or "organic
`amine base" as used herein refers to an organic compound
`65 having a basic nitrogen atom (R-NR'R"), and may be a
`primary (R-NH2 ), secondary (R-NHR') or tertiary
`(R-NR'R") amine. R, R' and R" may be independently
`
`Page 9 of 33
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`US 9,416,109 B2
`
`15
`selected from the group consisting of alkyl ( e.g., cycloalkyl),
`aryl and heteroaryl, which groups may be optionally substi(cid:173)
`tuted, or Rand R', Rand R" and/or R' and R", when present,
`may also combine to form cyclic or heteroalicyclic ring. The
`term heteroalicyclic as used herein refers to mono-, bi- or 5
`tricyclic ring or ring systems having one or more heteroatoms
`(for example, oxygen, nitrogen or sulfur) inat least one of the
`rings. The ring system may be a "saturated ring", which
`means that the ring does not contain any alkene or alkyne
`moieties, or it may also be an "unsaturated ring" which means 10
`that it contains at least one alkene or alkyne moiety provided
`that the ring system is not aromatic. The cyclic or heteroali(cid:173)
`cyclic group may be unsubstituted or substituted as defined
`herein.
`In some embodiments the amine is aromatic. Examples of
`aromatic amines include, but are not limited to, pyridine,
`pyrimidine, quinoline, isoquinolines, purine, pyrrole, imida(cid:173)
`zole, and indole. The aromatic amines may be substituted or
`unsubstituted.
`The term "optionally substituted" is used interchangeably
`with