I IIIII IIIIIIII Ill lllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111
`US009828336B2
`
`c12) United States Patent
`Moniz et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 9,828,336 B2
`Nov. 28, 2017
`
`(54) METHODS AND COMPOUNDS USEFUL IN
`THE SYNTHESIS OF OREXIN-2 RECEPTOR
`ANTAGONISTS
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`(71) Applicant: Eisai R&D Management Co., Ltd.,
`Tokyo (JP)
`
`(72)
`
`Inventors: George Anthony Moniz, Cambridge,
`MA (US); Annie Zhu Wilcoxen, North
`Reading, MA (US); Farid Benayoud,
`North Andover, MA (US); Toshiaki
`Tanaka, Tsukuba (JP); Keiichi
`Sorimachi, 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.: 15/158,687
`
`(22) Filed:
`
`May 19, 2016
`
`(65)
`
`Prior Publication Data
`
`US 2016/0318858 Al
`
`Nov. 3, 2016
`
`Related U.S. Application Data
`
`(62) Division of application No. 14/379,063, filed as
`application No. PCT/US2013/026204 on Feb. 14,
`2013, now Pat. No. 9,416,109.
`
`(60)
`
`Provisional application No. 61/600,109, filed on Feb.
`17, 2012.
`
`(51)
`
`(52)
`
`(58)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`C07C 309/73
`C07C 303/44
`C07C 309/66
`C07C 69/16
`C12P 7122
`C07D 401/12
`C07D 239/34
`C07C 303/28
`C07C 291147
`U.S. Cl.
`CPC .......... C07C 309/73 (2013.01); C07C 291147
`(2013.01); C07C 69/16 (2013.01); C07C
`303/28 (2013.01); C07C 303/44 (2013.01);
`C07C 309/66 (2013.01); C07D 239/34
`(2013.01); C07D 401/12 (2013.01); C12P 7122
`(2013.01); C07B 2200/07 (2013.01); C07C
`2601/02 (2017 .05)
`
`Field of Classification Search
`CPC ... C07C 309/73; C07C 303/44; C07C 309/66;
`C07C 69/16; C07C 29/147; C07C 303/28;
`C07C 2101/02; C12P 7/22; C07D 239/34;
`C07D 401/12; C07B 2200/07
`See application file for complete search history.
`
`5,849,954 A
`8,268,848 B2
`9,416,109 B2 *
`2012/0095031 Al
`
`12/ 1998 Carpino et al.
`9/2012 Terauchi et al.
`8/2016 Moniz ................... C07C 309/73
`4/2012 Terauchi et al.
`
`FOREIGN PATENT DOCUMENTS
`
`FR
`FR
`JP
`WO
`WO
`WO
`WO
`
`2302994 Al
`2941454 Al
`A-2010-509334
`WO 2008/057575 A2
`WO 2008/150364 Al
`WO 2010/032200 Al
`WO 2010/063662 Al
`
`10/1976
`7/2010
`3/2010
`5/2008
`12/2008
`3/2010
`6/2010
`
`OTHER PUBLICATIONS
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`Viout, P., "Formation of a cyclopropane ester on a polymer support:
`effect of the macromolecular backbone on the stereoselectivity of
`cyclization." Journal of the Chemical Society, Perkin Transactions
`1 (1984): 1351-1356.*
`United States Patent and Trademark Office, Notice of Allowance,
`U.S. Appl. No. 14/379,063, dated Jan. 21, 2016, 7 pages.
`State of Israel Justice Department Patents Authority, Notification
`before Allowance of Patent Application No. 232949, dated Jun. 22,
`2016 (2 pages) and English translation (2 pages).
`International Search Report and Written Opinion, PCT/US2013/
`026204, dated Apr. 25, 2013.
`Valgimigli L et al. The effect of ring nitrogen atoms on the
`homolytic reactivity of phenolic compounds; understanding the
`radical-scavenging 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-l-arylpiperazyl-2-phenylcyclopropanes
`designed
`as
`antidopaminergic agents. J Org Chem. Jun. 11, 2003; 68(24):
`9255-9262.
`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
`Unsynunetrical 1,5-Primary Diols. Journal of Organic Chemistry.
`2010; 75: 1892-1897.
`Office Action, Singapore Patent Application No. 11201403216U,
`dated May 27, 2015.
`Office Action, Chinese Patent Application No. 201380009575.3,
`dated Jun. 1, 2015.
`Response to Office Action, Chinese Patent Application No.
`201380009575.3, dated Oct. 15, 2015.
`Response to Office Action, Singapore Patent Application No.
`11201403216U, dated Oct. 27, 2015.
`Office Action, Israeli Application No. 232949; dated Nov. 2, 2015.
`Aldrich Chemfiles 2007 7(2), Peptide Synthesis, copyright Sigma
`Aldrich Co., p. 1-20.
`Office Action, U.S. Appl. No. 14/370,063, dated Mar. 11, 2015, 7
`pp.
`
`(Continued)
`
`Primary Examiner - Matt Mauro
`(74) Attorney, Agent, or Firm - Myers Bigel, P.A.
`
`ABSTRACT
`(57)
`The present disclosure provides compounds and methods
`that are useful for the preparation of compounds useful as
`orexin-2 receptor antagonists.
`
`15 Claims, No Drawings
`
`Page 1 of 30
`
`EISAI EXHIBIT 1035
`
`

`

`US 9,828,336 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`Office Action, U.S. Appl. No. 14/370,063, dated Jul. 24, 2015, 16
`pp.
`Response to Office Action, Israeli Application No. 232949
`(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).
`United States Patent and Trademark Office, Notice of Allowance,
`U.S. Appl. No. 14/379,063, dated May 12, 2016, 7 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.201380009575.
`3, dated May 24, 2016 (2 pages) and English translation (3 pages).
`Notice of Allowance, Russian Patent Application No. 2014137 4 70,
`dated Feb. 1, 2017.
`trisubstituted
`synthesis of
`Xu F
`et al. Stereocontrolled
`cyclopropanes: expedient, atom-economical, asymmetric syntheses
`of ( + )-bicifadine and D0V2l947. Organic Letters, 8(17), Jul. 25,
`2006, 3885-3888.
`
`Shuto S et al. Synthesis of conformationally restricted analogs of
`baclofen, a potent GABA(B) receptor agonist, by the introduction of
`a cyclopropane ring. Chemical & Pharmaceutical Bulletin, 47(8),
`1999, 1188-1192.
`Shuto S et al. Synthesis of ( +) and ( - )-milnaciprans and their
`conformationally restricted analogs. Tetrahedron Letters, 37(5),
`1996, 641-644.
`Kazuta Yet al. Synthesis of derivatives of ( 1 S,2R)-l-phenyl-2-[(S)(cid:173)
`l-aminopropy l ]-N,N-diethylcyclopropanecarboxamide
`(PPDC)
`modified at the 1-aromatic moiety as novel NMDA receptor antago(cid:173)
`nists: the aromatic group is essential for the activity. Bioorganic &
`Medicinal Chemistry, 10, 2002, 3829-3848.
`Office Action. Mexican Patent Application No. MX/z/2014/009917,
`dated May 24, 2017.
`Response to Office Action, Mexican Patent Application No. MX/a/
`2014/009917, submitted to the Mexican Institute of Industrial
`Property dated Aug. 14, 201 7.
`European Patent Office Examination Report, EP 13706674.8, dated
`Oct. 6, 2017.
`
`* cited by examiner
`
`Page 2 of 30
`
`

`

`US 9,828,336 B2
`
`1
`METHODS AND COMPOUNDS USEFUL IN
`THE SYNTHESIS OF OREXIN-2 RECEPTOR
`ANTAGONISTS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a divisional of and claims priority to
`U.S. patent application Ser. No. 14/379,063, filed Aug. 15,
`2014, now allowed, which is a 35 U.S.C. §371 national
`phase entry of PCT Application PCT/US2013/026204, filed
`Feb. 14, 2013, and published in English on Aug. 22, 2013,
`as International Publication No. WO 2013/123240, and
`which claims the benefit of U.S. Provisional Patent Appli(cid:173)
`cation No. 61/600,109, filed Feb. 17, 2012, the disclosure of
`each of which is incorporated by reference herein in its 15
`entirety.
`
`10
`
`FIELD OF THE INVENTION
`
`The present invention relates to compounds and methods 20
`that are useful for the preparation of compounds useful as
`orexin-2 receptor antagonists.
`
`BACKGROUND OF THE INVENTION
`
`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,
`1998, 92, 573-585). There are two subtypes of orexin
`receptors, 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 for regulating feeding behavior (Sakurai et al.,
`supra). It has also been observed that orexins control wake(cid:173)
`sleep conditions (Chemelli R. M. et al., Cell, 1999, 98,
`437-451). Orexins may also play roles in brain changes
`associated with opioid and nicotine dependence (S. L.
`Borgland et al., Neuron, 2006, 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 sug(cid:173)
`gested to play a role in some stress reactions (T. Ida et al.,
`Biochem. Biophys. Res. Commun., 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 insom(cid:173)
`nia, as well as for other therapeutic uses.
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`A r/""·Allo
`FMHe ( J N I~
`"Q,
`)-N
`
`Me
`
`Compound A
`
`55
`
`60
`
`65
`
`2
`There is thus a need for synthetic methods and interme(cid:173)
`diates useful in the preparation of Compound A and related
`compounds. It is, therefore, an object of the present appli(cid:173)
`cation to provide such synthetic methods and intermediates.
`
`SUMMARY
`
`Provided herein are compounds and methods that are
`useful for the preparation of compounds useful as orexin-2
`receptor antagonists.
`Provided is a process for making a compound of Formula
`
`I,
`
`HO~OH
`
`wherein Ar is an aryl such as phenyl, which aryl may be
`unsubstituted, 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,
`the method comprising one or more of the steps of:
`i) providing a composition comprising a compound of
`Formula II:
`
`II
`
`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
`composition a mild aqueous acid ( e.g., citric acid, EDTA or
`tartaric acid).
`In some embodiments, the compound of Formula II has
`the absolute stereochemistry of Formula Ila:
`
`Ila
`
`Page 3 of 30
`
`

`

`US 9,828,336 B2
`
`3
`In some embodiments, the compound of Formula II has an
`enantiomeric excess (ee) of the Formula Ila stereoisomer of
`at least 75, 80, 85, 90, 95, 98, 99%, or greater.
`In some embodiments, the compound of Formula II or
`Formula Ila is the compound:
`
`5
`
`4
`Also provided is a process for making a compound of
`Formula III:
`
`III
`
`F
`
`HO~OA c
`
`10
`
`wherein Ar is aryl such as phenyl, which aryl may be
`unsubstituted, 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,
`15 comprising reacting a mixture of:
`i) a compound of Formula Ia:
`
`In some embodiments, the compound of Formula I has the
`absolute stereochemistry of Formula Ia:
`
`Ar,,,,. A
`
`HO~OH .
`
`20
`
`la
`
`la
`
`In some embodiments, the compound of Formula I has an
`enantiomeric excess ( ee) of the Formula Ia stereoisomer of
`at least 75, 80, 85, 90, 95, 98, 99%, or greater.
`In some embodiments, the compound of Formula I or
`Formula Ia is:
`
`F 6 )),,,,,. A
`
`HO~
`
`OH.
`
`25
`
`35
`
`Also provided is compound of Formula III:
`
`HO~OA c
`
`III
`
`45
`
`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,
`30 to thereby make the compound of Formula III.
`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 tetrahydro(cid:173)
`furan, 2-methyltetrahydrofuran, an ether solvent, acetone, or
`acetonitrile.
`In some embodiments, the lipase is a Candida Antarctica
`lipase, for example, a Candida Antarctica B lipase, which
`40 may be coupled to solid support such as an acrylic resin.
`In some embodiments, the process may further include
`the 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 con(cid:173)
`centrated filtrate with water or water comprising a salt ( e.g.,
`a solution of 15-20% NaCl in water).
`Also provided is a compound of Formula IV:
`
`wherein Ar is an aryl such as phenyl, which aryl may be
`unsubstituted, or substituted 1-3 times, for example
`with substituents independently chosen from the group 50
`consisting of: 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, 55
`bromo, and iodo.
`In some embodiments, the compound is:
`
`IV
`
`F 6 )J,,,,,. J'\
`
`HO~
`
`OAc.
`
`60
`
`wherein:
`Ar is an aryl such as phenyl, which aryl may be unsub(cid:173)
`stituted, 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
`65 unsubstituted, or substituted 1-3 times with a halo indepen(cid:173)
`dently selected from the group consisting of: chloro, fluoro,
`bromo, and iodo.
`
`Page 4 of 30
`
`

`

`US 9,828,336 B2
`
`5
`In some embodiments, the leaving group is a sulfonate
`ester leaving group selected from the group consisting of:
`mesylate, tosylate, nosylate, benzene sulfonate, and brosy(cid:173)
`late.
`In some embodiments, the compound is:
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`In some embodiments, the compound of Formula IV has
`the absolute stereochemistry of Formula IVa:
`
`!Va
`
`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.
`Further provided is a process for making a compound of
`Formula IV:
`
`IV 40
`
`wherein Ar is an aryl such as phenyl, which aryl may be 45
`unsubstituted, 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
`R1 is a sulfonate ester leaving group,
`said process comprising reacting a compound of Formula
`III:
`
`50
`
`HO~OA c
`
`III 55
`
`60
`
`wherein Ar is as given above,
`with a compound selected from the group consisting of:
`tosyl chloride, mesyl chloride, nosy! chloride, toluenesulfo(cid:173)
`nyl chloride, toluenesulfonic anhydride and methanesulfo(cid:173)
`nic anhydride, wherein said reacting is carried out in an 65
`organic solvent in the presence of a base,
`to thereby make said compound of Formula IV.
`
`6
`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 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.
`In some embodiments, the compound of Formula III is:
`
`F 6 ),,,,,, .. _D.
`
`OAc.
`
`HO~
`
`In some embodiments, the compound of Formula IV has
`the absolute stereochemistry of Formula IVa:
`
`!Va
`
`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,
`
`V
`
`wherein Ar is an aryl such as phenyl, which aryl may be
`unsubstituted, 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
`R2 and R3 are each independently selected from the group
`consisting of: hydrogen, C 1 _6alkyl, haloC 1 _6 alkyl,
`C 1_6alkoxy, and hydroxyC 1_6alkyl,
`comprising the steps of:
`a) stirring a mixture of:
`i) a compound of Formula IV:
`
`IV
`
`Page 5 of 30
`
`

`

`7
`wherein Ar is as given above; and
`R 1 is a leaving group,
`ii) a substituted pyrimidine of Formula VI:
`
`US 9,828,336 B2
`
`8
`comprising the step of heating a mixture of:
`i) a compound of Formula B:
`
`B
`
`VI
`
`10
`
`15
`
`20
`
`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
`25 comprises boiling or refluxing the mixture.
`In some embodiments, the heating is carried out in a time
`of from 5 to 50 hours.
`Also provided is a process for making a compound of
`Formula B:
`
`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.
`In some embodiments, Ar is phenyl, which phenyl may be
`unsubstituted, or substituted 1-3 times with a halo indepen-
`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 35
`cl-6alkyl.
`In some embodiments, the compound of Formula IV has
`the absolute stereochemistry of Formula IVa:
`
`30
`
`B
`
`40
`
`!Va
`
`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:
`
`45
`
`50
`
`A
`
`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.
`Further provided is a process for making a compound of
`Formula VI:
`
`55
`
`VI
`
`60
`
`wherein R2 and R3 are each independently selected from
`the group consisting of: hydrogen and C 1_6 alkyl,
`
`wherein R4 is as given above,
`ii) trimethylaluminum,
`iii) a palladium catalyst, and
`iv) an organic solvent,
`65 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.
`
`Page 6 of 30
`
`

`

`US 9,828,336 B2
`
`9
`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
`alcohol (e.g., isopropyl alcohol) to obtain said compound of
`Formula B as a hydrochloride salt. In some embodiments 10
`this is done after a quenching step.
`Further provided is a process for making a compound of
`Formula B:
`
`5
`
`15
`
`B
`
`20
`
`25
`
`30
`
`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:
`
`10
`
`VII
`
`wherein Ar is an aryl such as phenyl, which aryl may be
`unsubstituted, 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
`R2 and R3 are each independently selected from the group
`consisting of: hydrogen, C 1 _6alkyl, haloC 1 _6 alkyl,
`C 1_6alkoxy, and hydroxyC 1_6alkyl,
`comprising the steps of:
`a) oxidizing a compound of Formula V:
`
`V
`
`A 35
`
`wherein Ar, R2 and R3 are as given above,
`with a first oxidizing agent, to form an aldehyde of
`Formula VIII:
`
`wherein R4 is as given above,
`ii) a nickel catalyst (e.g., Ni(acac) 2 , Ni(PPh3 ) 2 Cl2 , or
`Ni( dppp )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
`temperature 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 (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
`hydrogen chloride and a solvent such as an alcohol (e.g.,
`isopropyl alcohol) to obtain the compound of Formula B as
`a hydrochloride salt.
`Also provided is a process for making a compound of
`Formula VII:
`
`VIII
`
`40
`
`45
`
`50
`
`wherein Ar, R2 and R3 are as given above; and then
`b) oxidizing the aldehyde of Formula VIII with a second
`oxidizing agent,
`55 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(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 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).
`
`60
`
`65
`
`Page 7 of 30
`
`

`

`US 9,828,336 B2
`
`11
`In some embodiments, the second oxidizing agent is
`sodium chlorite.
`In some embodiments, the first oxidizing agent and the
`second oxidizing agent are the same. In some embodiments,
`the first oxidizing agent and the second oxidizing agent are 5
`different.
`In some embodiments, the oxidizing of step a) and/or step
`b) is carried out in an organic solvent ( e.g., dichloromethane,
`tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetoni-
`trile, or ethyl acetate).
`Further provided is a process for preparing a compound of
`Formula VII:
`
`10
`
`15
`
`VII
`
`20
`
`25
`
`wherein Ar is an aryl such as phenyl, which aryl may be
`unsubstituted, or substituted 1-3 times, for example
`with substituents independently selected from the
`group consisting of: halo, C 1 _6alkyl, C 1_6alkoxy, and 30
`haloC 1 _6alkyl; and
`R2 and R3 are each independently selected from the group
`consisting of: hydrogen, C 1 _6alkyl, haloC1 _6 alkyl,
`C 1_6alkoxy, and hydroxyC 1 _6alkyl,
`comprising: oxidizing a compound of Formula V:
`
`35
`
`V
`
`40
`
`45
`
`50
`
`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(cid:173)
`dently selected from the group consisting of: chloro, fluoro, 55
`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 60
`In some embodiments,
`hypochlorite and sodium chlorite is carried out simultane(cid:173)
`ously.
`In some embodiments, the oxidizing is catalyzed with an
`effective amount of 2,2,6,6-tetramethylpiperidine 1-oxyl
`(TEMPO).
`Also provided is a process for making a compound of
`Formula IX:
`
`65
`
`12
`
`IX
`
`wherein:
`Ar is an aryl such as phenyl, which aryl may be unsub(cid:173)
`stituted, 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;
`R2 and R3 are each independently selected from the group
`consisting of: hydrogen, C 1 _6alkyl, haloC 1 _6 alkyl,
`C 1_6alkoxy, and hydroxyC 1_6alkyl; and
`Ar' is a pyridine group:
`
`Rs
`
`wherein:
`R4 is selected from the group consisting of: hydrogen,
`halo, C 1_6alkyl, C 1_6alkoxy, and (C 1 _6alkoxy)C 1 _6
`alkyl;
`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_6
`alkyl, C1 _6alkoxy,
`(C 1_6alkoxy)C 1_6alkyl, and cyano;
`comprising the step of reacting a compound of Formula
`VII:
`
`VII
`
`X
`
`wherein Ar, R2 and R3 are as given above,
`with a compound of Formula X:
`
`wherein R4 , Rs, and R6 are as given above,
`
`Page 8 of 30
`
`

`

`US 9,828,336 B2
`
`13
`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.
`
`DETAILED DESCRIPTION
`
`All U.S. Patent references are hereby incorporated by
`reference herein to the extent they are consistent with the
`present descriptions.
`
`A. Definitions
`
`Compounds of this invention include those described
`generally above, and are further illustrated by the embodi(cid:173)
`ments, 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
`particular 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
`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 45
`arrangement of atoms or groups in a chemical compound
`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 50
`mirror 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
`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.
`"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 com(cid:173)
`position of a compound having one chiral center will be
`
`5
`
`14
`substantially free of the opposite enantiomer of the com(cid:173)
`pound. 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 stereoi(cid:173)
`somer of the compound and less than about 20% by weight
`of other stereoisomers of the compound, more preferably
`greater than about 90% by weight of one stereoisomer of the
`10 compound and less than about 10% by weight of the other
`stereoisomers of the compound, even more preferably
`greater than about 95% by weight of one stereoisomer of the
`compound and less than about 5% by weight of the other
`stereoisomers of the compound, and most preferably greater
`15 than about 97% by weight of one stereoisomer of the
`compound and less than about 3% 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
`20 of the stereochemical configuration at an asymmetrically
`substituted carbon atom. The designation of an asymmetri(cid:173)
`cally 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
`25 International Union of Pure and Applied Chemistry (IU(cid:173)
`PAC) Rules for the Nomenclature of Organic Chemistry.
`Section E, Stereochemistry.
`"Enantiomeric excess" ( ee) of an enantiomer, when
`expressed as a percentage, is [(the mole fraction of the major
`30 enantiomer) minus (the mole fraction of the minor
`enantiomer)]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,
`35 purification, and use for one or more of the purposes
`disclosed herein. In some embodiments, a stable compound
`or chemically feasible compound is one that is not substan(cid:173)
`tially altered when kept at a temperature of 40° C. or less, in
`the absence of moisture or other chemically reactive condi-
`40 tions, for at least a week.
`"Refluxing" as used herein refers to a technique in which
`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
`volume 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
`compound 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-
`55 dimethylacetamide; alcohols such as ethanol, methanol,
`isopropanol, amyl alcohol, ethylene glycol, propylene gly(cid:173)
`col, 1-butanol, butyl carbitol acetate and glycerin; aliphatic
`hydrocarbons such as hexane and octane; aromatic hydro(cid:173)
`carbons such as toluene, xylenes and benzene; ketones such
`60 as acetone, methyl ethyl ketone and cyclohexanone; halo(cid:173)
`genated hydrocarbons such as methylene chlori