Case 1:16-cv-01221-LPS Document 53 Filed 05/23/18 Page 1 of 70 PageID #: 387
`
`
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`
`Plaintiffs,
`
`Defendants.
`
`
`
`
`
`
`C.A. No. 16-1221 (LPS)
`CONSOLIDATED
`
`BAYER HEALTHCARE LLC and BAYER
`HEALTHCARE PHARMACEUTICALS
`INC.,
`
`
`
`
`
`TEVA PHARMACEUTICALS USA, INC.,
`et al.,
`
`
`
`
`
`
`
`
`
`
`
`v.
`
`
`
`APPENDIX TO JOINT CLAIM CONSTRUCTION CHART
`
`SHAW KELLER LLP
`John W. Shaw (#3362)
`Karen E. Keller (#4489)
`David M. Fry (#5486)
`1105 North Market Street
`12th Floor
`Wilmington, DE 19801
`(302) 298-0701
`jshaw@shawkeller.com
`kkeller@shawkeller.com
`dfry@shawkeller.com
`
`Attorneys for Defendant Teva Pharmaceuticals
`USA, Inc.
`
`MORRIS JAMES LLP
`Kenneth L. Dorsney (#3726)
`500 Delaware Avenue, Suite 1500
`Wilmington, DE 19801-1494
`(302) 888-6855
`kdorsney@morrisjames.com
`
`Attorneys for Defendants Apotex Inc. and
`Apotex Corp.
`
`
`MORRIS, NICHOLS, ARSHT & TUNNELL LLP
`Jack B. Blumenfeld (#1014)
`Derek J. Fahnestock (#4705)
`Anthony D. Raucci (#5948)
`1201 North Market Street
`P.O. Box 1347
`Wilmington, DE 19899
`(302) 658-9200
`jblumenfeld@mnat.com
`dfahnestock@mnat.com
`araucci@mnat.com
`
`Attorneys for Plaintiffs Bayer HealthCare LLC
`and Bayer HealthCare Pharmaceuticals Inc.
`
`
`
`May 23, 2018
`
`
`
`
`

`

`Case 1:16-cv-01221-LPS Document 53 Filed 05/23/18 Page 2 of 70 PageID #: 388
`
`
`
`TABLE OF CONTENTS
`
`
`Tab A
`Tab B
`Tab C
`
`U.S. Patent No. 9,458,107
`U.S. Patent No. 8,680,124
`Excerpt of File History of U.S. Patent No. 8,680,124 – Originally Filed
`Specification and Claims
`
`
`
`
`
`

`

`Case 1:16-cv-01221-LPS Document 53 Filed 05/23/18 Page 3 of 70 PageID #: 389
`Case 1:16-cv—01221-LPS Document 53 Filed 05/23/18 Page 3 of 70 PageID #: 389
`
`TAB A
`
`TAB A
`
`

`

`Case 1:16-cv-01221-LPS Document 53 Filed 05/23/18 Page 4 of 70 PageID #: 390
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US009458107B2
`
`c12) United States Patent
`Stiehl et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,458,107 B2
`Oct. 4, 2016
`
`(54) PROCESS FOR THE PREPARATION OF
`4-{ 4-[( {[ 4
`CHLOR0-3-(TRIFLUOROMETHYL)(cid:173)
`PHENYL ]AMINO }CARBONYL)AMIN0]-
`3-FLUORPHENOXY-N-ETHYLPYRIDIE(cid:173)
`CARBOXAMIDE, ITS SALTS AND
`MONOHYDRATE
`
`(71) Applicant: Bayer HealthCare LLC, Whippany, NJ
`(US)
`
`(72)
`
`Inventors: Juergen Stiehl, Sprockhiivel (DE);
`Werner Heilmann, Wuppertal (DE);
`Michael Liigers, Wuppertal (DE);
`Joachim Rehse, Leichlingen (DE);
`Michael Gottfried, Wuppertal (DE);
`Saskia Wichmann, Berlin (DE)
`
`(73) Assignee: BAYER INTELLECTUAL
`PROPERTY GMBH (DE)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 14/252,850
`
`(22) Filed:
`
`Apr. 15, 2014
`
`(65)
`
`Prior Publication Data
`
`US 2014/0221661 Al
`
`Aug. 7, 2014
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 13/640,959, filed as
`application No. PCT/EP2011/055508 onApr. 8, 2011,
`now Pat. No. 8,748,622.
`
`(30)
`
`Foreign Application Priority Data
`
`Apr. 15, 2010
`
`(EP) ..................................... 10004022
`
`(51)
`
`(2006.01)
`(2006.01)
`
`Int. Cl.
`C07D 213163
`C07D 213181
`(52) U.S. Cl.
`CPC ................................... C07D 213181 (2013.01)
`( 58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`6,187,799 Bl
`7,235,576 Bl
`7,329,670 Bl
`7,351,834 Bl
`7,371,763 B2
`7,517,880 B2
`7,528,255 B2
`7,557,129 B2
`7,678,811 B2
`7,838,524 B2
`7 ,838,541 B2
`
`2/2001 Wood et al.
`6/2007 Riedl et al.
`2/2008 Dumas et al.
`4/2008 Riedl et al.
`5/2008 Dumas et al.
`412009 Miller et al.
`512009 Riedl et al.
`712009 Scott et al.
`3/2010 Dumas et al.
`11/2010 Lee et al.
`11/2010 Dumas et al.
`
`7,897,623 B2
`8,071,616 B2
`8,076,488 B2
`8,101,773 B2
`8,110,587 B2
`8,124,630 B2
`8,124,782 B2
`8,207,166 B2
`8,242,147 B2
`8,618,141 B2
`8,637,553 B2
`8,680,124 B2
`8,748,622 B2
`8,796,250 B2
`8,841,330 B2
`8,877,933 B2
`9,181,188 B2
`2003/0181442 Al
`2003/0232765 Al
`2005/0038080 Al
`2005/0059703 Al
`2006/0058358 Al
`2007/0020704 Al
`2008/0153823 Al
`2008/0227828 Al
`2008/0242707 Al
`2008/0262236 Al
`2008/0269265 Al
`2009/0093526 Al
`2009/0192127 Al
`2009/0215833 Al
`2009/0215835 Al
`2010/0144749 Al
`2010/0173953 Al
`2010/0173954 Al
`2011/0257035 Al
`
`3/2011 Riedl et al.
`12/2011 Dumas et al.
`12/2011 Dumas et al.
`1/2012 Smith et al.
`2/2012 Dumas et al.
`2/2012 Riedl et al.
`2/2012 Logers et al.
`6/2012 Lee et al.
`8/2012 Dumas et al.
`12/2013 Dumas et al.
`1/2014 Boyer et al.
`3/2014 Wilhelm et al.
`612014 Stiehl et al.
`8/2014 Wilhelm et al.
`912014 Riedl et al.
`11/2014 Grunenberg et al.
`11/2015 Dumas et al.
`9/2003 Riedl et al.
`12/2003 Carter et al.
`212005 Boyer et al.
`3/2005 Wilhelm et al.
`3/2006 Dumas et al.
`1/2007 Wilhelm et al.
`6/2008 Riedl et al.
`9/2008 Dumas et al.
`10/2008 Schuckler et al.
`10/2008 Logers et al.
`10/2008 Miller et al.
`412009 Miller et al.
`712009 Scheuring et al.
`8/2009 Grunenberg et al.
`8/2009 Wilhelm
`6/2010 Wilhelm
`712010 Grunenberg et al.
`712010 Wilhelm et al.
`10/2011 Pena
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`
`00 42012
`712000
`2005 009961
`212005
`(Continued)
`
`OTHER PUBLICATIONS
`
`Bankston, D. et al., "A scaleable synthesis of BAY 43-9006: A
`Potent Raf Kinase Inhibitor for the Treatment of Cancer," Organic
`Process Research & Development, 2002, vol. 6, pp. 777-781.
`(Continued)
`
`Primary Examiner - Heidi Reese
`(74) Attorney, Agent, or Firm - Millen, White, Zelano &
`Branigan, P.C.
`
`(57)
`
`ABSTRACT
`
`The present invention relates to a process for preparing
`4-( 4-[ ( {[ 4-chloro-3-( trifluoromethy I )-pheny I]
`amino }carbony !)amino ]-3-fluorophenoxy )-N-methy lpyri(cid:173)
`dine-2-carboxamide, its salts and monohydrate.
`
`30 Claims, No Drawings
`
`

`

`Case 1:16-cv-01221-LPS Document 53 Filed 05/23/18 Page 5 of 70 PageID #: 391
`
`US 9,458,107 B2
`Page 2
`
`(56)
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
`
`U.S. PATENT DOCUMENTS
`
`2012/0040925 Al
`2012/0136157 Al
`2012/0142741 Al
`2012/0142742 Al
`2013/0116492 Al
`2013/0131122 Al
`2013/0183268 Al
`2013/0261120 Al
`2014/0065212 Al
`2014/0235678 Al
`2014/0296301 Al
`2014/0036210 Al
`2014/0329866 Al
`2015/0018393 Al
`2016/0015697 Al
`
`212012 Carter et al.
`512012 Dumas et al.
`612012 Schueckler
`612012 Riedl et al.
`512013 Goldman et al.
`512013 Boyer et al.
`7/2013 Christensen et al.
`10/2013 Puhl er
`3/2014 Skrabs et al.
`8/2014 Bottger
`10/2014 Bottger
`11/2014 Carter et al.
`11/2014 Riedl et al.
`1/2015 Wilhelm et al.
`1/2016 Dumas et al.
`
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`WO 2005009961 A2 *
`2006 034796
`2008 043446
`2008/055629 Al
`2008/089388 A2
`2008/089389 A2
`2010/130779 A2
`
`212005
`412006
`4/2008
`5/2008
`7/2008
`7/2008
`1112010
`
`OTHER PUBLICATIONS
`
`International Search Report for PCT/EP2011/055508, Date of the
`actual completion of the international search: Jun. 14, 2011, Date of
`mailing of the international search report: Jun. 21, 2011.
`Streitwieser, A. et al., Introduction to Organic Chemistry, New York,
`Macmillan 1992, pp. 736-737.
`* cited by examiner
`
`

`

`Case 1:16-cv-01221-LPS Document 53 Filed 05/23/18 Page 6 of 70 PageID #: 392
`
`US 9,458,107 B2
`
`1
`PROCESS FOR THE PREPARATION OF
`4-{ 4-[( {[ 4
`CHLOR0-3-(TRIFLUOROMETHYL)(cid:173)
`PHENYL ]AMINO }CARBONYL)AMIN0]-3-
`FLUORPHENOXY-N-ETHYLPYRIDIE(cid:173)
`CARBOXAMIDE, ITS SALTS AND
`MONOHYDRATE
`
`The present invention relates to a process for preparing
`4-{ 4-[( {[ 4-chloro-3-(trifluoromethyl)-phenyl]
`amino }carbony 1 )amino ]-3-fluorophenoxy }-N-methylpyri(cid:173)
`dine-2-carboxamide, its salts and monohydrate.
`4-{ 4-[ ( {[ 4-chloro-3-( trifluoromethy 1 )phenyl]
`amino }carbony 1 )amino ]-3-fluorophenoxy} )-N-methy lpyri(cid:173)
`dine-2-carboxamide is mentioned in WO 05/009961 and
`corresponds to the compound of the formula (I):
`
`10
`
`15
`
`(I)
`
`2
`-continued
`
`Cl~
`UNCO
`
`The monohydrate of the compound of formula (I) is
`mentioned in WO 08/043,446. Furthermore salts of the
`compound of formula (I) such as its hydrochloride, mesylate
`and phenylsulfonate are mentioned in WO 05/009961 and
`can be formed by treating the compound of the formula (I)
`with the corresponding acid. The compound of formula (I)
`is described for treating hyper-proliferative disorders such as
`cancers, tumors, lymphomas, sarcomas and leukemias.
`WO 05/009961 describes a process for preparing the
`compound of the formula (I), which is illustrated in the
`following scheme:
`
`In the first step 4-amino-3-fluorophenol was treated with
`potassium tert-butoxide and 4-chloro-N-methyl-2-pyridin(cid:173)
`ecarboxamide was added in N,N-dimethylacetamide to form
`4-( 4-amino-3-fluorophenoxy )pyridine-2-carboxylic
`acid
`methylamide which after extraction was finally treated with
`30 4-chloro-3-(trifluoromethyl)phenyl isocyanate in toluene to
`form 4{ 4-[3-( 4-chloro-3-trifluoromethylphenyl)-ureido ]-3-
`fluorophenoxy }-pyridine-2-carboxylic acid methylamide
`which is the compound of formula (I).
`While the processes disclosed by the prior art are per se
`35 effective for preparing the compound of the formula (I), its
`monohydrate, hydrochloride, mesylate and phenylsulfonate,
`factors such as purity, product yields, process efficiency,
`safety and economy are very significant for an industrial
`scale process of a pharmaceutical product.
`It is an object of the present invention to provide a process
`for preparing the compound of the formula (I), its salts and
`monohydrate in industrial scale (kilogram to metric tons
`range) which satisfies the criteria which apply in production
`and provides improvements in purity, environmental com-
`45 patibility, industrial employability, safety aspects and vol(cid:173)
`ume yield. Especially purity and safety aspects are to be
`considered for the preparation of pharmaceuticals. This
`object is achieved by the present invention.
`The inventive preparation of the compound of the formula
`(I) is shown in the following scheme:
`
`40
`
`-
`
`!
`
`(III)
`
`

`

`Case 1:16-cv-01221-LPS Document 53 Filed 05/23/18 Page 7 of 70 PageID #: 393
`
`US 9,458,107 B2
`
`3
`
`-continued
`
`4
`
`(IV)
`
`Cl~
`
`UNCO
`
`(V)
`
`~
`
`0
`
`ou~~~Jlo~~/H;
`
`F
`
`(I)
`
`Preparation of the Compound of the Formula (I), its Mono(cid:173)
`hydrate or Salts:
`The present invention comprises a process for preparing
`of the compound of the formula (I)
`
`(I)
`
`Cl~ O qO~N/CH3,
`UN)lN I# ~h H
`
`40
`
`H
`
`H
`
`F
`
`its salt or monohydrate by treating the compound of the
`formula (IV)
`
`(IV)
`
`which is 4-( 4-amino-3-fluorophenoxy )-N-methylpyridine-
`2-carboxamide with the compound of formula (V)
`
`which is 4-chloro-3-trifluoromethyl-phenyl isocyanate in a
`30 reaction mixture and thereafter the solved compound of the
`formula (I) is treated with an acid to form a salt of the
`compound of the formula (I) which precipitates from the
`solution containing the solved compound of the formula (I),
`optionally the salt of the compound of the formula (I) is then
`35 treated with an aqueous basic solution to precipitate the
`monohydrate of the compound of the formula (I), and
`optionally the monohydrate is dried under reduced pressure
`until the compound of the formula (I) is formed.
`The salt of the compound of the formula (I) can be
`prepared by treating the compound of the formula (IV) with
`the compound of formula (V) in a reaction mixture and
`thereafter the solved compound of the formula (I) is treated
`with an acid to form the salt of the compound of the formula
`45 (I) which precipitates from the solution containing the
`solved compound of the formula (I).
`The monohydrate of the compound of the formula (I) can
`be prepared by treating the compound of the formula (IV)
`with the compound of formula (V) in a reaction mixture and
`50 thereafter the solved compound of the formula (I) is treated
`with an acid to form a salt of the compound of the formula
`(I) which precipitates from the solution containing the
`solved compound of the formula (I), the salt of the com(cid:173)
`pound of the formula (I) is then treated with an aqueous
`55 basic solution to precipitate the monohydrate of the com(cid:173)
`pound of the formula (I), preferably at a temperature of from
`35° C. to 45° C., most preferably from 38° C. to 42° C.
`The compound of the formula (I) can be prepared by
`treating the compound of the formula (IV) with the com(cid:173)
`pound of formula (V) in a reaction mixture and thereafter the
`solved compound of the formula (I) is treated with an acid
`to form a salt of the compound of the formula (I) which
`precipitates from the solution containing the solved com(cid:173)
`pound of the formula (I), the salt of the compound of the
`65 formula (I) is then treated with an aqueous basic solution to
`precipitate the monohydrate of the compound of the formula
`(I) and the monohydrate is dried under reduced pressure
`
`(V) 60
`
`Cl~
`
`UNCO
`
`

`

`Case 1:16-cv-01221-LPS Document 53 Filed 05/23/18 Page 8 of 70 PageID #: 394
`
`US 9,458,107 B2
`
`5
`until the compound of the formula (I) is formed, preferably
`at a temperature of 85° C. to 120° C., and preferably at a
`pressure of below 30 mbar.
`According to the processes described above the solution
`containing the solved compound of the formula (I) and what
`from the salt of the compound of the formula (I) precipitates
`can be preferably the reaction mixture or can be a separate
`solution containing the compound of the formula (I). The
`separate solution can be prepared after isolation of the
`compound of the formula (I) from the reaction mixture for 10
`example by standard work-up procedures as described for
`example in WO 05/009961 and solving the compound of the
`formula (I) in an suitable organic solvent.
`In a preferred embodiment of the process for preparing of 15
`the compound of the formula (I), its monohydrate or salt as
`described above the acid is generated in situ in the solution
`containing the solved compound of the formula (I) by
`adding to the reaction mixture a protic substance and an acid
`precursor.
`In a more preferred embodiment of the process for
`preparing of the compound of the formula (I), its monohy(cid:173)
`drate or salt the acid is generated in situ in the reaction
`mixture after the compound of the formula (I) is formed by
`adding to the reaction mixture an alcohol and an acid
`precursor.
`In a most preferred embodiment of the process for pre(cid:173)
`paring of the compound of the formula (I), its monohydrate
`or salt the acid is generated in situ in the reaction mixture
`after the compound of the formula (I) is formed by adding
`to the reaction mixture an alcohol and an acylchloride,
`preferably acetylchloride.
`In the process for preparing of the compound of the
`formula (I), its monohydrate or salt the reaction of the
`compound of the formula (IV) with the compound of the
`formula (V) is effected in an suitable organic solvent, for
`example in tetrahydrofuran, at a temperature above 15° C.
`and below 70° C., preferably at a temperature of from 15°
`C. to 60° C., more preferably from 15° C. to 50° C., most
`preferably at room temperature. Preference is given to
`initially charging the compound of the formula (IV) in a
`suitable organic solvent, for example in tetrahydrofuran, and
`admixing within 30 to 300 minutes, preferably within 60 to
`150 minutes, most preferably within 80 to 100 minutes the
`compound of the formula (V), preferably dissolved or sus(cid:173)
`pended in a suitable organic solvent, for example toluene,
`which can be different to the first suitable organic solvent.
`After formation of the compound of the formula (I) an acid
`is added to the reaction mixture. Preferably the acid is
`generated in situ in the reaction mixture by adding a protic 50
`substance for example water and/or an alcohol, preferably an
`alcohol, and an acid precursor, preferably an acylchloride,
`within for example 5 to 60 minutes, preferably within 10 to
`30 minutes, in order to generate the corresponding acid in
`situ. Preferably the protic substance is added first. The salt
`of the compound of the formula (I) can be isolated by
`precipitation.
`In order to prepare the monohydrate of the compound of
`the formula (I) the salt of the compound of the formula (I)
`is further treated with an aqueous basic solution, preferably 60
`with a mixture of an organic solvent and an aqueous basic
`solution. The monohydrate of the compound of the formula
`(I) can be isolated by precipitation, preferably at a tempera(cid:173)
`ture of from 35° C. to 45° C., most preferably from 38° C.
`to 42° C.
`In order to prepare the compound of the formula (I) the
`monohydrate of the compound of the formula (I) is dried
`
`6
`preferably at a temperature of 85° C. to 120° C. and under
`reduced pressure, more preferably at a pressure of below 30
`mbar.
`Suitable acids in the process for preparing of the com(cid:173)
`pound of the formula (I), its monohydrate or salt include but
`are not limited to mineral acids, carboxylic acids and sul(cid:173)
`fonic acids, for example hydrochloric acid, hydrobromic
`acid, sulfuric acid, phosphoric acid, methanesulfonic acid,
`trifluoromethanesulfonic acid, ethanesulfonic acid, toluene(cid:173)
`sulfonic acid, benzenesulfonic acid, naphthalenedisulfonic
`acid, acetic acid, propionic acid, lactic acid, tartaric acid,
`malic acid, citric acid, fumaric acid, maleic acid and benzoic
`acid. Preference is given to hydrochloric acid, hydrobromic
`acid, sulfuric acid, phosphoric acid, methanesulfonic acid,
`trifluoromethanesulfonic acid, ethanesulfonic acid, toluene-
`sulfonic acid, benzenesulfonic acid and naphthalenedisulfo(cid:173)
`nic acid, more preferably to hydrochloric acid, benzenesul(cid:173)
`fonic acid, toluenesulfonic acid or methanesulfonic acid,
`20 most preferably to hydrochloric acid.
`Salts of the compound of the formula (I) which are
`pharmaceutically acceptable salts include but are not limited
`to acid addition salts of mineral acids, carboxylic acids and
`sulfonic acids, for example salts of hydrochloric acid, hyd-
`25 robromic acid, sulfuric acid, phosphoric acid, methanesul(cid:173)
`fonic acid, trifluoromethanesulfonic acid, ethanesulfonic
`acid, toluenesulfonic acid, benzenesulfonic acid, naphtha(cid:173)
`lenedisulfonic acid, acetic acid, propionic acid, lactic acid,
`tartaric acid, malic acid, citric acid, fumaric acid, maleic
`30 acid and benzoic acid. Preference is given to salts of
`hydrochloric acid, hydrobromic acid, sulfuric acid, phos(cid:173)
`phoric acid, methanesulfonic acid, trifluoromethanesulfonic
`acid, ethanesulfonic acid, toluenesulfonic acid, benzenesul(cid:173)
`fonic acid and naphthalenedisulfonic acid, more preferably
`35 to salts of hydrochloric acid, benzenesulfonic acid, toluene(cid:173)
`sulfonic acid or methanesulfonic acid, most preferably to the
`hydrochloric acid salt.
`According to the present invention alcohols are organic
`substances carrying at least one hydroxyl group. Alcohols
`40 include but are not limited to methanol, ethanol, n-propanol,
`isopropanol, n-butanol, sec-butanol, isobutanol, n-pentanol,
`glycerol or a mixture thereof. Preferably methanol, ethanol
`and isopropanol are used as alcohols in the present process.
`In order to prepare the acid in situ suitable acid precursors
`45 include but are not limited to organic acid halogenides,
`preferably acylhalegonides such as acylchlorides and acyl(cid:173)
`bromides, more preferably acetylchloride, a cetylbromide,
`propionylchloride or propionylbromide, most preferably
`acetylchloride.
`Preference is given to a process described above wherein
`the acid is prepared in situ without water.
`Suitable organic solvents in the process for preparing of
`the compound of the formula (I), its monohydrate or salt
`include but are not limited to tetrahydrofuran, toluene, ethyl
`55 acetate, dioxane, methyl tert-butyl ether, dimethoxyethane,
`dimethy lsulfoxide, dimethy lformamide, 1-methy 1-2-pyrroli(cid:173)
`dinone or mixtures of the mentioned solvents. More pref(cid:173)
`erably tetrahydrofuran, toluene and mixtures thereof are
`used.
`Suitable aqueous basic solutions in the process for pre-
`paring of the monohydrate of the compound of the formula
`(I) include but are not limited to aqueous solutions of alkali
`metal hydroxides, alkali earth metal hydroxides, alkali metal
`alkoxides, alkali earth metal alkoxides, organic amines and
`65 ammonia, preferably sodium hydroxide and potassium
`hydroxide, more preferably an aqueous solution of sodium
`hydroxide. The aqueous basic solution can be mixed with an
`
`

`

`Case 1:16-cv-01221-LPS Document 53 Filed 05/23/18 Page 9 of 70 PageID #: 395
`
`US 9,458,107 B2
`
`7
`organic solvent such as acetone, ethyl acetate, tetrahydro(cid:173)
`furan, preferably with acetone.
`According to the present process potential side products,
`in particular anilinic side products such as the starting
`compounds 4-amino-3-fluorophenol and the compound of 5
`the formula (IV) can be separated very effectively form the
`salt of the compound of the formula (I), preferably the
`hydrochloric acid salt, because the salts of the anilinic side
`products, in particular the salts of the compound of the
`formula (IV), preferably the hydrochloric acid salt of the 10
`compound of the formula (IV), do not precipitate under the
`conditions according to the present process and remain in
`the filtrate. Furthermore in the case when the acid is gen(cid:173)
`erated in situ by using acylhalogenides the corresponding 15
`acylated derivatives of the anilinic side products, in particu-
`lar of the compound of the formula (IV), can be separated
`easily from the salt of the compound of the formula (I),
`preferably the hydrochloric acid salt, because the acylated
`derivatives do not precipitate under the conditions according 20
`to the present process and remain in the filtrate. Therefore
`the compound of the formula (I), its salts and its monohy(cid:173)
`drate can be prepared in a very high purity.
`Another embodiment of the present invention is the
`compound of formula (I), its monohydrate or salt in a very 25
`high purity containing or contaminated with one or more
`anilinic substances each in an amount of equal or less than
`0.05%, that means from 0.0001 % to a maximum of 0.05%,
`preferably each in an amount of equal or less than 0.025%,
`that means from 0.0001 % to a maximum of 0.025%, most 30
`preferably each in an amount of equal or less than 0.01 %,
`that means from 0.0001 % to a maximum of0.01 % by weight
`based on the amount of the compound of the formula (I). In
`other words the another embodiment is a mixture of the 35
`compound of formula (I), its monohydrate or salt with one
`or more anilinic substances each anilinic substance in an
`amount of equal or less than 0.05%, that means from
`0.0001 % to a maximum of 0.05%, preferably each in an
`amount of equal or less than 0.025%, that means from 40
`0.0001 % to a maximum of 0.025%, most preferably each in
`an amount of equal or less than 0.01 %, that means from
`0.0001 % to a maximum of 0.01 % by weight based on the
`amount of the compound of the formula (I)
`Anilinic substances
`include but are not limited to 45
`4-amino-3-fluorophenol, 4-chloro-3-trifluoromethy !aniline,
`4-( 4-amino-3-fluorophenoxy )pyridine-2-carboxy lie
`acid
`methylamide which is the compound of the formula (IV).
`Preference is given to the compound of formula (I), its
`monohydrate or salt containing or contaminated with 50
`4-amino-3-fluorophenol and/ or 4-( 4-amino-3-fluorophe(cid:173)
`noxy )pyridine-2-carboxylic acid methylamide each in an
`amount of equal or less than 0.05%, that means from
`0.0001 % to a maximum of 0.05%, preferably each in an
`amount of equal or less than 0.025%, that means from 55
`0.0001 % to a maximum of 0.025%, most preferably each in
`an amount of equal or less than 0.01 %, that means from
`0.0001 % to a maximum of 0.01 % by weight based on the
`amount of the compound of the formula (I). In other words
`preference is given to a mixture of the compound of formula 60
`(I), its monohydrate or salt with 4-amino-3-fluorophenol
`and/or 4-( 4-amino-3-fluorophenoxy )pyridine-2-carboxylic
`acid methylamide each anilinic substance in an amount of
`equal or less than 0.05%, that means from 0.0001 % to a
`maximum of 0.05%, preferably each in an amount of equal 65
`or less than 0.025%, that means from 0.0001 % to a maxi(cid:173)
`mum of0.025%, most preferably each in an amount of equal
`
`8
`or less than 0.01 %, that means from 0.0001 % to a maximum
`of 0.01 % by weight based on the amount of the compound
`of the formula (I).
`Preparation of the Compound of the Formula (IV):
`The present invention likewise comprises a process for
`preparing the compound of the formula (IV) by reacting the
`compound of the formula (III)
`
`(III)
`
`wherein R 1 and R2 are independently selected from the
`group consisting of hydrogen, methyl, ethyl, n-propyl,
`iso-propyl, n-butyl,
`iso-butyl, sec-butyl, tert-butyl,
`n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl,
`2-hexyl and 3-hexyl, or
`R 1 and R 2 are joined and, taken together with the carbon
`atom to which they are attached, form a 4- to 7-mem(cid:173)
`bered cycloalkyl ring,
`with the compound of the formula (II)
`
`(II)
`
`which is 4-chloro-N-methyl-2-pyridinecarboxamide in the
`presence of a base, followed by adding an acid to deliver the
`compound of the formula (IV).
`In a preferred embodiment of the process for preparing of
`the compound of the formula (IV) the compound of the
`formula (III) is used in a solution of a suitable organic
`solvent and is formed by reacting 4-amino-3-fluorophenol
`with the compound of the formula (VI)
`
`(VI)
`
`wherein R 1 and R2 are independently selected from the
`group consisting of hydrogen, methyl, ethyl, n-propyl,
`iso-propyl, n-butyl,
`iso-butyl, sec-butyl, tert-butyl,
`n-pentyl, 2-pentyl, 3-pentyl, neopentyl, n-hexyl,
`2-hexyl and 3-hexyl, or
`R 1 and R 2 are joined and, taken together with the carbon
`atom to which they are attached, form a 4- to 7-mem(cid:173)
`bered cycloalkyl ring.
`In a further preferred embodiment of the process for
`preparing of the compound of the formula (IV) the com(cid:173)
`pound of the formula (II) is used in a solution of a suitable
`organic solvent which solution is prepared by neutralization
`the hydrochloric acid salt of the compound of the formula
`(II) with a base, preferably with sodium hydroxide, more
`preferably with an aqueous solution of sodium hydroxide.
`
`

`

`Case 1:16-cv-01221-LPS Document 53 Filed 05/23/18 Page 10 of 70 PageID #: 396
`
`US 9,458,107 B2
`
`10
`in a suitable organic solvent, preferably in toluene, and is
`neutralized by adding an aqueous solution of a base, pref(cid:173)
`erably an aqueous solution of sodium hydroxide. After
`separation of the phases the organic phase is optionally
`concentrated under reduced pressure and a suitable organic
`solvent, preferably l-methyl-2-pyrrolidinone, is added to
`prepare a solution which can be used directly for the
`preparation of the compound of the formula (IV) as
`described above.
`Suitable organic solvents in the process for preparing of
`4-chloro-N-methyl-2-pyridinecarboxamide include but are
`not limited to tetrahydrofuran, toluene, ethyl acetate, diox(cid:173)
`ane, methyl tert-butyl ether, dimethoxyethane, dimethylsul(cid:173)
`foxide, dimethylformamide,
`l-methyl-2-pyrrolidinone or
`mixtures of the mentioned solvents. More preferably tetra(cid:173)
`hydrofuran, toluene and mixtures thereof are used.
`According to the present invention alcohols are organic
`substances carrying at least one hydroxyl group. Alcohols
`include but are not limited to methanol, ethanol, n-propanol,
`isopropanol, n-butanol, sec-butanol, isobutanol, n-pentanol,
`glycerol or a mixture thereof. Preferably methanol, ethanol,
`isopropanol are used as alcohols in the present process.
`In order to prepare the acid in situ suitable precursors
`25 include but are not limited to organic acid halogenides,
`preferably acylhalegonides such as acylchlorides and acyl(cid:173)
`bromides, more preferably acetylchloride, acteylbromide,
`propionylchloride or propionylbromide, most preferably
`acetylchloride.
`Preference is given to an in situ preparation of the acid
`without water.
`Alternatively the compound of formula (II) and its hydro(cid:173)
`chloric acid salt can be prepared as described in WO
`05/009961 or
`in Bankston et al.
`(Organic Process
`35 Research & Development, 2002, 6, 777-781).
`The compound of the formula (V) which is 4-chloro-3-
`trifluoromethyl-phenylisocyanate can be prepared as
`described in WO 00/42012.
`
`9
`In the process for preparing of the compound of the
`formula (IV) 4-amino-3-fluorophenol reacts with the com(cid:173)
`pound of formula (VI) at a temperature of from 20° C. up to
`reflux temperature, preferably from 50° C. up to reflux
`temperature, most preferably at the reflux temperature of the 5
`compound of formula (VI) which can be used in excess and
`as solvent. Optionally a further different solvent can be
`added such as toluene, ethyl acetate, cyclohexane or a
`mixture thereof. The volatile reaction components can be
`removed by azeotropic distillation optionally under reduced 10
`pressure. The formed compound of the formula (III) can be
`used in a solution of a suitable organic solvent, preferably in
`a solution of l-methyl-2-pyrrolidinone, and is treated with
`4-chloro-N-methyl-2-pyridinecarboxamide, preferably used
`in a solution with a suitable organic solvent, more preferably 15
`in a solution of l-methyl-2-pyrrolidinone, in the presence of
`a base. The reaction mixture is heated to a temperature of
`from 50° C. up to 150° C., preferably from 80° C. up to 120°
`C. After 1 to 5 h, preferably 2 to 4 h, the temperature is
`adjusted to from 50° C. up to 90° C., preferably from 70° C. 20
`up to 90° C., and an acid, preferably acetic acid in water, is
`added. After cooling, preferably to a temperature of from 0°
`C. to 10° C. and optionally seeding with crystals of the
`compound of the formula (IV), the compound of the formula
`(IV) can be isolated by precipitation.
`Preference is given to a compound of the formula (VI)
`wherein R 1 and R2 are independently selected from methyl,
`ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or
`R 1 and R2 are joined and, taken together with the carbon
`atom to which they are attached, form a 4- to 7-membered 30
`cycloalkyl ring. More preferably the compound of the for(cid:173)
`mula (VI) is selected from the group consisting of 4-methyl-
`2-pentanone, 3-methyl-2-butanone, 2-butanone, 2-pen(cid:173)
`tanone,
`4-heptanone,
`2,4-dimethyl-3-pentanone
`and
`cyclohexanone.
`Suitable organic solvents in the process for preparing of
`the compound of the formula (IV) include but are not limited
`to l-methyl-2-pyrrolidinone, dimethylformamide, N,N-dim(cid:173)
`ethylacetamide, dimethyl sulfoxide, sulfolane or mixtures of
`the solvents mentioned. Preferably l-methyl-2-pyrrolidi- 40
`none and/or dimethylformamide are used.
`In the process for preparing of the compound of the
`formula (IV) suitable bases are alkali metal hydroxides and
`alkali metal alkoxides. Preference is given to potassium
`tert-butoxide. Potassium tert-butoxide is preferably used in
`a solution, more preferably in a tetrahydrofuran solution.
`In order to provide a highly purified version of the
`compound of the formula (II) it is solved in a suitable
`organic solvent, treated with an acid which is generated in
`situ by adding a protic substance and an acid precursor,
`precipitated as a salt of the compound of the formula (II),
`preferably the hydrochloric acid salt of the compound of the
`formula (II), and neutralized by adding an aqueous solution
`of a base.
`For that purpose the starting compound 4-chloro-N(cid:173)
`methyl-2-pyridinecarboxamide
`is solved in a suitable
`organic solvent, preferably in toluene, and is treated with an
`acid which is generated in situ by adding a protic substance,
`for example water and/or an alcohol, preferably an alcohol,
`and an acid precursor, preferably an acylchloride, for 60
`example within 5 to 60 minutes, preferably within 10 to 30
`minutes, in order to generate the corresponding acid in situ.
`Preferably the protic substance is added first. The salt of
`4-chloro-N-methyl-2-pyridinecarboxamide, preferably the
`hydrochloric acid salt of 4-chloro-N-methyl-2-pyridinecar- 65
`boxamide, can be isolated by precipitation. Such purified
`salt of 4-chloro-N-methyl-2-pyridinecarboxamide is solved
`
`45
`
`50
`
`55
`
`ABBREVIATIONS
`
`DCI direct chemical ionization (in MS)
`DMF dimethylformamide
`DMSO dimethyl sulfoxide
`EI electro