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`Case 3:l4—cv—05499—PGS—LHG Document 42-2 Filed 07/07/15 Page 1 of 99 Page|D: 587
`
`
`
`EXHIBIT 1
`EXHIBIT 1
`
`
`
`

`
`Case 3:14-cv-05499-PGS-LHG Document 42-2 Filed 07/07/15 Page 2 of 99 PageID: 588
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`Case 3:14—cv—O5499—PGS—LHG Document 42-2 Filed 07/07/15 Page 3 of 99 Page|D:
`Case 3:14-cv-05499-PGS-LHG Document 42-2 Filed 07/07/15 Page 3 of 99 PageID: 589
`
`
`
`(12) United States Patent
`Batra et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,497,393 B2
`Jul. 30, 2013
`
`US00849"/393B2
`
`(54) PROCESS T0 PREPARE TREPROSTINIL,
`THE ACTIVE INGREDIENT IN
`REMODULIN®
`
`(75)
`
`Inventors: Hitesh Batra, Herndon, VA (US);
`Sudersan M. Tuladhar, Silver Spring,
`MD (US); Raju Penmasta, Herndon, VA
`NS); David A. Walsh, Palmyra, VA
`(US)
`
`(73) Assignee: United Therapeutics Corporation,
`Silver Spring, MD (US)
`
`( "' ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S,C. 154(b) by 0 days.
`
`(21) Appl.No.: 13/548,446
`
`(22)
`
`Filed:
`
`Jul. 13, 2012
`
`(65)
`
`Prior Publication Data
`US 2012/0283470 A1
`Nov. 8, 2012
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 12/334,731, filed on
`Dec. 15, 2008, now Pat. No. 8,242,305.
`
`(60) Provisional application No. 61/014,232, filed on Dec.
`17, 2007.
`
`(51)
`
`Int. Cl.
`(2006.01)
`C07C 62/00
`(2006.01)
`C07C 65/00
`(52) U.S. C1.
`562/466
`USPC
`(58) Field of Classlfication Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
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`4,306,075 A
`12/1981 Aristofl‘
`4,424,376 A
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`2002/0173672 A1
`11/2002 Moriarty et a1.
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`2005/0165111 A1
`2005/0282901 A1
`2005/0282903 A1
`2007/0078095 A1
`2007/0078182 A1
`2008/0200449 A1
`2008/0249167 A1
`2008/0280986 A1
`2009/0036465 A1
`2009/0124697 A1
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`2011/0092599 A1
`2011/0118213 Al
`2011/0144204 A1
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`9/2004 Moriarty et al.
`4/2005 Phares et a1.
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`11/2008 Wade etal.
`2/2009 Roscigno etal.
`5/2009 Cloutieret al.
`6/2009 Batraet a1.
`11/2009 Walsh
`3/2010 Olschewski
`11/2010 Phares
`4/2011 Wadeetal.
`5/2011 Pliaresetal.
`6/2011 Jeffsetal.
`9/2011 Rotliblattetal,
`12/2011 Batraetal.
`1/2012 Wadeetal.
`1/2012 Rothblattetal.
`
`FOREIGN PATENT DOCUMENTS
`2 710 726 A1
`1/2012
`CA
`101891596 A
`ll/2010
`CN
`101891715 A
`ll/2010
`CN
`0 004 335 A2
`10/1979
`EP
`0 087 237 B1
`5/1986
`FTP
`0175 450 B1
`3/1989
`EP
`0 159 784 B1
`6/1989
`EP
`0 496 548 A1
`7/1992
`EP
`WO 98/39337 A1
`9/1998
`W0
`WO 99/21830 A1
`5/1999
`WO
`W0 03/070163 A2
`8/2003
`W0
`VVO W0 2005/007081 A2
`1/2005
`W0 W0 2007/134292 A2
`11/2007
`W0 W0 2008/1 00977 A2
`8/2008
`W0 W0 2009/1 17095 A1
`9/2009
`W0
`WO 2012/009816 A1
`1/2012
`OTHER PUBLICATIONS
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`Alexander et al., “The Synthesis ofBenzindene Prostacyc1i.nAna1ogs
`as Potential An1iulcerAgents," Prostaglandins, 1986, 32(5):647-653.
`Aristoff et :11., “Synthesis and Structure-Activity Relationship of
`Novel Stable Prostacyclin Analogs," Advances in Prosmglandjn,
`Thromboxane, and Leulcotricnc Research, Samuelsson et al., .Eds.,
`1983, 11:267-274.
`Aristofi” et :11, “Synthesis of Benzopyran Prostaglandins, Potent
`Stable Prostacyclin Analogs, Via an Intrarnolecular Mistunobu Reic-
`tion,” Tetrahedron Letters, 1984, 25(36):3955-3958.
`Aristofl’ et 211., “Total Synthesis 01' a Novel Antiulccr Agent via a
`Modification ofthe I_ntrarnolecu1a.r Wadsworth-Enions-V1/lttig Reac-
`tion,” J. Am. Chem, Soc., 1985, 107:7967-7974.
`Batra et a1., “Crystallization Process Development for a Stable
`Polymorph of Treprostinil Dietlianolarnine (UT-15C) by Seeding,”
`Organic Process Research & Development, 2009. 13:242-249.
`
`(Continued)
`
`Primary Examiner — Yevegeny Valenrod
`(74) Attorney, Agent, or Firm — Foley & Lardner LLP
`
`ABSTRAC '1'
`(57)
`This present invention relates to an improved process to pre-
`pare prostacyclin derivatives. One embodiment provides for
`an improved process to convert benzindene 1:riol to treprosti-
`nil via salts of treprostinil and to purify treprostinil.
`
`22 Claims, No Drawings
`
`Copy provided by USPTO from the PIRS Image Database on 03/24/2015
`
`
`
`UTC_REM_||_000003354
`
`

`
`US 8,497,393 B2
`Page 2
`
`OTHER PUBLICATIONS
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`Clark et al., “High-Performance Liquid Chromatographic Method
`for Determining the Enantiomeric Purity of a Benzindene
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`Hardinger et al., “Triply-Convergent Syntheses of Two I-[omochiral
`Arene-Fused Prostacyclin Analogs Related to U68,215,” Bioorganic
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`Cyclopentenones and Allylic Amines,” J. Org. Chem., 1996,
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`Reaction,” J. Am. Chem. Soc., 1994, 11623159-3160.
`Khand et al., “Organocobalt Complexes. Part 11. Reaction of
`Acetylenehexacarbonyl-dicohalt Complexes,
`(R1C2R2)Co2(C0)5,
`WithNorbomene and its Derivatives,” J. Chem. Soc., J.C.S. Perkin I.,
`1973, 977-981.
`Mathre et al., “A Practical Enantioselective Synthesis of 0t,ot-Diary1-
`2-pyrrolidinernethanol. Preparation and Chemistry of the Corre-
`sponding Oxazaborolidines,” J. Org. Chem., 1991, 56:751-762.
`Moriarty et al., “The Intrarnolecular Asymmetric Pauson-Khand
`Cyclization as a Novel and General Stereoselective Route to
`Benzindene Prostacyclinst Synthesis of UT-15 (Treprostinil)," .Z
`Org. Chem. 2004, 69, 1890-1902.
`Mulzer et al., “Asymmetric Synthesis of Carbacyclin Precursors by
`Pauson-Khand Cyclizarion,” Liebigs Ann. Chem., 1988, 891-897.
`Nelson, Norman A., “Pro staglandin Nomenclature," J. Med, Chem.,
`Sep. 1974, 17(9):9l1-918.
`Pagenkopf et al., “Photochemical Promotion of the Intramolecular
`Pauson-Khand Reaction. A New Experimental Protocol for Cobalt-
`Catalyzed [2 +2+2+1] Cycloadditions,” J. Am. Chem. Soc., 1996,
`1153:2285-2286.
`
`and Reagent Control of
`“Substrate
`Pagenkopf, Brian L.,
`Diastereoselectivity in Transition Metal-Mediated Process: Develop-
`ment of a Catalytic Photo Promoted Pauson-Khand Reaction,” Diss.
`Abstr. Int., 57(12):7535, 1977, Abstract.
`Paul son, Peter L., “The Khand Reaction,” Tetrahedron, 1985,
`41(24):5855-5860.
`Schore, Neil E., “Transition-Metal-Mediated Cyctoaddition Reac-
`tions ofAlkynes in Organic Synthesis,” Chem. Rev., 1988, 88: 1081-
`1 119.
`Shambayati et al., “N-Oxide Promj oted Pauson-Khand Cyclizations
`at Room Temperature,” Tetrahedron Letters, 1990, 31(37):5289-
`5292.
`Snell et al ., “Investigating the Effect ofImpurities on Macromolecule
`Crystal Growth in Microgravity,” Crystal Growth & Design, 2001,
`1(2):l51-158.
`Sorbera et al. “UT-15. Treatment of Pulmonary Hypertension Treat-
`ment of Peripheral Vascular Disease,” Drug of the Future, 2001,
`26(4), 364-374.
`Talcano et al., “Ena.ntiodivergent Synthesis of Both Enantiomers of
`Sulcatol and Matsutake Alcohol from (R)-Epichlorohydrin,” Chem-
`istry Letters, 1987, 2017-2020.
`Viedma, Cristobal, “Selective Chiral Symmetry Breaking during
`Crystallization: Parity Violation of Cryptochiral Environment in
`Control?” Crystal Growth & Design, 2007, 7(3):553—556.
`Zhang et al., “A Nicke1(0)-Catalyzed Process for the Transformation
`of Enyncs to Bicyclic Cyclopentenones,” J. Org. Chem., 1996,
`61:4-198-4499.
`U.S. Appl. No. 13/409,685, filed Mar. 1, 2012, Sharrna, Vijay.
`Comins et al., “Ortho Metalation Directed by oi.-Amino Al.koxidcs,”
`J. Org. Che1n., 1984, 49:1078-1083.
`Comins et al., "Ortho Substitution ofM-Anisaldehyde via ot-Amino
`Alkoxide Directed Lithiation,” J. Org. Chem., 1989, 54:3730-3732.
`Corey et al. “Novel Electronic Effects ofRemote Substituents on the
`Oxazaborolidine-Catalyzed Enantioselective Reduction ofKetones,"
`Tetrahedron Letters, 1995, 36(50):9153-9156.
`Greene et al., “Protecting Groups,” Protective Groups in Organic
`Synthesis, 2d Ed., 1991, p. 1-11.
`Pansegrau er al., “The Oxazoline-Benzyne Route to 1,2,3-
`Trisubstituted Benzenes. Tandem Addition of Organolithiums,
`Organocuprates. and or-Lithionitriles to Benzynes," J. Am. Chem.
`Soc., 1988, ll0:7178-7184.
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`synthesis ofpentalenic acid,” Journal of Organometallic Chemistry,
`1991, 4l3:C5—C9.
`
` t 1
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`US 8,497,393 B2
`
`1
`PROCESS T0 PREPARE TREPROSTINIL,
`THE ACTIVE INGREDIENT IN
`REMODULIN®
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`,
`
`This application is a Continuation ofU.S. application Ser.
`No. 12/334,731, filed Dec. 15, 2008, which claims priority
`from U.S. Provisional Patent Application 61/014,232, filed 10
`Dec. 17, 2007, the entire contents of which are incorporated
`herein by reference
`
`BACKGROUND
`
`2
`
`H
`
`Y:—l9i-fi—“v
`M’
`L*
`OH
`
`(1)
`
`H
`O(CH2),.,COOI-I
`
`,
`,
`V ,
`lhe process comprises the following steps:
`(a) alkylating a compound of structure 11 withan alkylating
`agent to produce a compound of formula III,
`
`
`
`30
`
`35
`
`40
`
`45
`
`The present invention relates to a process for producing 15
`prostacyclin derivatives and novel intermediate compounds
`usefiil in the process.
`'
`Prostacyclin derivatives are useful pharmaceutical com-
`pounds possessing activities such as platelet aggregation inhi-
`bition, gastric secretion reduction,
`lesion inhibition, and 20
`bronchodilation.
`Treprostinil, the active ingredient in Remodulin®, was first
`described in US. Pat. No. 4,306,075. Treprostinil, and other
`prostacyclin derivatives have been prepared as described in
`Moriarty, eta1in.l. Org. Chem. 2004, 69, 1890-1902,Drugof 25
`the Future, 2001, 26(4), 364-374, U.S. Pat. Nos. 6,441,245,
`6,528,688, 6,765,117 and 6,809,223. Their teachings are
`incorporated by reference to show how to practice the
`embodiments of the present invention.
`U.S. Pat. No. 5,153,222 describes use of treprostinil for
`treatment of pulmonary hypertension. Treprostinil
`is
`approved for the intravenous as well as subcutaneous route,
`the latter avoiding septic events associated with continuous
`intravenous catheters. U.S. Pat. Nos. 6,521,212 and 6,756,
`033 describe administration of treprostinil by inhalation for
`treatment of pulmonary hypertension, peripheral vascular
`disease and other diseases and conditions. US. Pat. No.
`6,803,386 discloses administration of treprostinil for treating
`cancer such as lung, liver, brain, pancreatic, kidney, prostate,
`breast, colon and head-neck cancer. U.S. patent application
`publication No. 2005/0165111 discloses treprostinil treat-
`ment of ischemic lesions. U.S. Pat. No. 7,199,157 discloses
`that treprostinil treatment improves kidney functions. U.S.
`patent application publication No. 2005/0282903 discloses
`treprostinil treatment of neuropathic foot ulcers. U.S. appli-
`cation Ser. No. 12/028,471 filed Feb. 8, 2008, discloses tre-
`prostinil treatment ofpulmonary fibrosis. U.S. Pat. No. 6,054,
`486 discloses treatment of peripheral vascular disease with
`treprostinil. U.S. patent application Ser. No. 1 1/873,645 filed
`Oct. 17, 2007 discloses combination therapies comprising
`treprostinil. U.S. publication No. 2008/0200449 discloses
`delivery of treprostinil using a metered dose inhaler. U.S.
`publication No. 2008/0280986 discloses treatment of inter-
`stitial lung disease with treprostinil. U.S. application Ser. No.
`12/028,471 filed Feb. 8, 2008 discloses treatment of asthma
`withtrep1'ostini1.U.S. Pat. No, 7,417,070, 7,384,978 and U.S.
`publication Nos. 2007/0078095, 2005/0282901, and 2008/
`0249167 describe oral formulations of treprostinil and other
`pro stacyclin analogs.
`Because Treprostinil, and other prostacyclin derivatives
`are ofgreat importance fi‘om arnedicinal point ofview, a need
`exists for an efficient process to synthesize these compounds
`on a large scale suitable for corrnnereial production.
`SUMMARY
`
`55
`
`60
`
`The present invention provides in one embodiment a pro-
`cess for the preparation of a compound of formula I, hydrate,
`solvate, prodrug, or pharmaceutically acceptable salt thereof.
`
`
`
`([1)
`
`(111)
`
`Y1_C_‘C"'R7
`IUI
`ILI
`1
`OH
`
`1
`
`Y _C__C_R
`'
`7
`
`L,
`
`M,
`OH
`
`H
`
`H
`
`H
`
`0H
`
`O(C1I2)wCN
`
`H
`
`wherein
`w=1, 2, or 3;
`Y,
`is
`trans-CH:CH——, cis-CH:CH—, —CII,
`(CI1,),,,——, or —~C=C~', m is 1, 2, or 3;
`R7 is
`(1) —C,,I'I2p——CH3, whereinp is an integer from 1 to 5,
`inclusive,
`(2) phenoxy optionally substituted by one, two or three
`chloro, fluoro, trifluoromethyl, (C1-C3) alkyl, or (C1-
`C3)alkoxy, with the proviso that not more than two
`sub stituents are other than all<yl, with the proviso that
`R7 is phenoxy or substituted phenoxy, only when R3
`and R4 are hydrogen or methyl, being the same or
`different,
`(3) phenyl, benzyl, phenylethyl, or phenylpropyl option-
`ally substituted on the aromatic ring by one, two or
`three chloro, fluoro, trifluoromethyl, (C1-C_,_)alkyl, or
`(C,-C3)alkoxy, with the proviso that not more than
`two substituents are other than alkyl,
`(4) cis-CI-l:~CH—CH,—CH,,
`(5) ——(CH2)2—CH(OH)—CH3, or
`(5) ’(CH2)3—‘CH:*C(CH3)2§
`wherein —C(L,)—R7 taken together is
`(1) (C4—C7)cycloalkyl optionally substituted by 1 to 3
`(C i'C5)a1kY1S
`(2) 2-[2-fiiryl)ethyl,
`(3) 2-(3-thienyl)ethoxy, or
`(4) 3-thicnyloxymethyl;
`M,
`is or-OI-I:[3-R5 or or-R5213-OH or ot—OR,:[3-R5 or
`or-R5 : [3 -OR,, wherein R5 is hydrogen or methyl, R2 is
`an alcohol protecting group, and
`L1 is on-R3:[3-R4, 0.-R428-R3, or a mixture of (1-R3:|3-R4
`and or-R4: [3-R3, wherein R3 and R4 are hydrogen,
`methyl, or fluoro, being the same or different, with the
`
`
`Copy provided by USPTO from the PIRS Image Database on 03/24/2015
`
`
`
`11 UTC_REM_||_000003356
`
`
`

`
`in.
`
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`
`
`
`US 8,497,393 B2
`
`3
`proviso that one of R3 and R4 is fluoro only when the
`other is hydrogen or fluoro.
`(b) hydrolyzing the product of step (a) with a base,
`(c) Contacting the product of step (b) with a base B to for a
`salt of formula ls
`
`(L)
`
`H Y“ii"l_“’
`M,
`L,
`OH
`
`H
`
`o(cH2),,coo9
`
`(3
`H
`
`(d) reacting the salt from step (c) with an acid to fonn the
`compound of formula I.
`The present invention provides in another embodiment a
`process for the preparation of a compound of formula IV.
`
`H
`
`20
`
`(IV)
`
`25
`
` O
`
`K
`
`COOH
`
`The process comprises the following steps:
`(a) alkylating a compound of structureV with an alkylating
`agent to produce a compound of formula VI,
`
`(V)
`
`(VI)
`
`
`
`
`(b) hydrolyzing the product of step (a) with a base,
`(c) contacting the product of step (b) with a base B to for a
`salt of formula IVS, and
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`(IV; A
`
`
`
`K 9COO
`
`(d) reacting the salt from step (b) with an acid to form the
`compound of formula IV.
`
`DETAILED DESCRIPTION
`
`The various terms used, separately and in combinations, in
`the processes herein described are defined below.
`The expression “comprising” means “including but not
`limited to.”Thus, other non-mentioned sub stances, additives,
`carriers, or steps may be present. Unless otherwise specified,
`“a” or “an” means one or more.
`
`CH-alkyl is a straight or branched alkyl group containing
`1-3 carbon atoms. Exemplary alkyl groups include methyl,
`ethyl, r1-propyl, and isopropyl.
`C1_3-alkoxy is a straight or branched alkoxy group contain-
`ing 1-3 carbon atoms. Exemplary aikoxy groups include
`methoxy, ethoxy, propoxy, and isopropoxy.
`C4,-cycloalkyl is an optionally substituted monocyclic,
`bicyclic or tricyclic alkyl group containing between 4-7 car-
`bon atoms. Exemplary cycloallcyl groups include but not lim-
`ited to cyelobutyl, eyclopentyl, cyclohexyl, and cycloheptyl.
`Combinations of substituents and variables envisioned by
`this invention are only those that result in the formation of
`stable compounds. The term “stable”, as used herein, refers to
`compounds which possess stability sufficient to allow manu-
`facture and which maintains the integrity ofthe compound for
`a sullicient period of time to be useful for the purposes
`detailed herein.
`As used herein, the term “prodrug” means a derivative of a
`compound that can hydrolyze, oxidize, or otherwise react
`under biological conditions (in vitro or in vivo) to provide an
`active compound. Examples of prodrugs include, but are not
`limited to, derivatives of a compound that include biohydro-
`lyzable groups such asbiohydrolyzable amides, biohydrolyz-
`able esters, biohydrolyzable carbamates, biohydrolymble
`carbonates, biohydrolyzable ureides, and biohydrolyzable
`phosphate analogues (e.g., monopho sphate, djpho sphate or
`triphosphate).
`As used herein, “hydrate” is a form ofa compound wherein
`water molecules are combined in a certain ratio as an integral
`part of the structure complex of the compound.
`As used herein, “solvate” is a form of a compound where
`solvent molecules are combined in a certain ratio as an inte-
`gral part of the structure complex of the compound.
`“Pharmaceutically acceptable” means
`in the present
`description being useful in preparing a pltarmaceutical com-
`position that is generally safe, non-toxic and neither biologi-
`cally nor otherwise undesirable and includes being useful for
`veterinary use as well as human pharmaceutical use.
`“Pharmaceutically acceptable salts” mean salts which are
`pharmaceutieally acceptable, as defined above, and which
`possess the desired pharmacological activity. Such salts
`
`
`
`Copy provided by USPTO from the PIRS Image Database on 03/24/2015
`
`
`
`UTC:§EM_||_T)T)0003357
`
`
`

`
`
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`US 8,497,393 B2
`
`5
`include acid addition salts formed with organic and inorganic
`acids, such as hydrogen chloride, hydrogen bromide, hydro-
`gen iodide, sulfuric acid, phosphoric acid, acetic acid, gly-
`colic acid, maleic acid, malonic acid, oxalic acid, methane-
`sulfonic acid, trifluoroacetic acid, fumaric acid, suecinic acid,
`tartaric acid, citric acid, benzoic acid, ascorbic acid and the
`like. Base addition salts may be formed with organic and
`inorganic bases, such as sodium, ammonia, potassium, cal-
`cium, ethanolarnine, diethanolamine, N-methylglucamine,
`choline and the like. Included in the invention are pharrna-
`ceutically acceptable salts or compounds of any of the for-
`mulae herein.
`
`Depending on its structure, the phrase “pharmaceutically
`acceptable salt,” as used herein, refers to a pharmaceutically
`acceptable organic or inorganic acid or base salt of a com-
`pound. Representative pharmaceutically acceptable salts
`include, e.g., alkali metal salts, alkali earth salts, ammonium
`salts, water-soluble and water-insoluble salts, such as the
`acetate,
`amsonate
`(4,4—diaminostilbene-2,2-disulfonate),
`benzenesulfonate, benzonate, bicarbonate, bisulfate, bitar-
`trate, borate, bromide, butyrate, calcium, calcium edetatc,
`camsylate, carbonate, chloride, citrate, clavulariate, dihydro-
`chloride, edetate, edisylate, estolate, esylate, fumaratc, glu-
`ceptate, gluconate, glutamate, glycollylarsanilate, hexafluo-
`rophosphate, hexylresorcinate, hydrabamine, hydrobromidc,
`hydrochloride, hydroxynaphthoate, iodide, isothjonate, lac-
`tate, lactobionate, laurate, malate, maleate, rnandelate, mesy-
`late, methylbromide, methylnitrate, methylsulfate, mucate,
`nap sylate, nitrate, N-mcthylglucainine ammonium salt, 3-hy-
`droxy-2-naphthoate, oleate, oxalate, paliuitate, painoate (1,1-
`methene-bis-2-hydroxy-3-naphthoate, einbonate), pantoth—
`enate, phosphate/diphosphate, pierate, polygalacturonate,
`propionatc, p-toluenesulfonate, salicylate, stearate, subac-
`etate, succinate, sulfate, sulfosalieylate, suramate, tannate,
`tartrate, teoclate, tosylate, triethiodide, and Valerate salts.
`The present invention provides for a process for producing
`treprostinil and other prostacyclin derivatives and novel inter-
`mediate compounds useful
`in the process. The process
`according to the present invention provides advantages on
`large-scale synthesis over the existing method. For example,
`the purification by column chromatography is eliminated,
`thus the required amount of flammable solvents and waste
`generated are greatly reduced. Furthermore, the salt fonna-
`tion is a much easier operation than column chromatography.
`Moreover, it was found that the product ofthe process accord-
`ing to the present invention has higher purity. Therefore the
`present invention provides for a process that is more economi-
`cal, safer, faster, greener, easier to operate, and provides
`higher purity.
`One embodiment of the present invention is a process for
`the preparation of a compound of formula I, or a hydrate,
`solvate, prodrug, or pharrnaeeutiically acceptable salt thereof.
`
`Y1—C—C—R7
`
`II IIM, L,
`on
`
`(D
`
`H
`
`H
`
`O(CH2),,,COOH
`
`The process comprises the following steps:
`(a) alkylating a compound of formula ll with an alkylating
`agent to produce a compound of formula III,
`
`10
`
`15
`
`20
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`
`Y1-C—C—R-r
`
`
`II IIM, L,
`OH
`
`v,—c—c—R-,
`II
`II
`M1
`L1
`OH
`
`H
`
`H
`
`H
`
`H
`
`OH
`
`O(CH2),,,CN
`
`(H)
`
`(111)
`
`wherein
`
`w=l,2,or3;
`
`Y, is trans—CH=CH , cis-CH:CH—, ——CH2(CH2)
`m—, or -—CEC—; m is 1, 2, or 3;
`R7 is
`
`(l) —C,,H3P~CH3, whereinp is an integer from 1 to 5,
`inclusive,
`
`(2) phenoxy optionally substituted by one, two or three
`chloro, fluoro, trifiuoromethyl, (C1-C3) alkyl, or (C ,-
`C3)alkoxy, with the proviso that not more than two
`substituents are other than alkyl, with the proviso that
`R, is phenoxy or substituted phenoxy, only when R3
`and R4 are hydrogen or methyl, being the same or
`different,
`
`(3) phcnyl, benzyl, phenylethyl, or phenylpropyl option-
`ally substituted on the aromatic ring by one, two or
`three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or
`(C1-C3) alkoxy, with the proviso that not more than
`two substituents are other than alkyl,
`(4) cis-cH=cH—CH,—CH,,
`(5) 4CIl2)2—CH(Om4H3, or
`(5) —(CH2)3—CH=C(CH3)23
`wherein ~C(L L)-R7 taken together is
`(1) (C4-C7)cycloalkyl optionally substituted by 1 to 3
`(C 1-C5)a1kyl;
`(2) 2-[2-furyl)ethyl,
`(3) 2—(3-thienyl)ethoxy, or
`(4) 3-thienyloxymethyl;
`M,
`is ct-OH:[5-R5 or ot-R5:B—OH or or-OR,:[3-R5 or
`Ol-R5t[5-UR2, wherein R5 is hydrogen or methyl, R2 is
`an alcohol protecting group, and
`
`L1 is or-R3:[3-R4, or-R4: [3-R3, or a mixture of 0.-R3:[5-R4
`and ot-R4:B-R3, wherein R3 and R4 are hydrogen,
`methyl, or fluoro, being the same or different, with the
`proviso that one ofR, and R4 is fluoro only when the
`other is hydrogen or fluoro.
`
`b) hydrolyzing the product of step (a) with a base,
`(C) contacting the product of step (b) with ahase B to for a
`salt of formula I,
`
`
`
`Lll
`
`t1
`
`
`Copy provided by USPTO from the PIRS Image Database on 03/24/2015
`
`UTC_REM_||_000003358
`
`
`

`
`Case 3:14-cv-05499-PGS-LHG Document 42-2 Filed 07/07/15 Page 8 of 99 PageID: 594
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`
`{
`
`
`
`7
`
`8
`
`US 8,497,393 B2
`
`
`
`23
`.3
`at
`H}.
`K3
`‘»»
`
`1
`3::
`“:3
`
`ji;
`
`at
`Fl
`‘it,
`
`I
`1
`:1
`%
`E
`
`fit
`1%‘ll‘
`1
`
`‘E
`E
`,l
`l
`
`(Iv)
`
`(V)
`
`(vr)
`
`
`
`O
`K
`
`COOH
`
`The process comprises
`(a)a1ky1afing 5‘ Compound Ofstmcmrevwith an alkylafing
`agent Such as C1CH2CN to Produce 3 compound 0f
`fommla V1:
`
`7
`
`H
`
`H
`
`Y,—c—c—R7
`ill
`ll
`1
`~1
`OH
`HBE
`
`O(CHZ)wCOOe
`
`05>
`
`5
`
`10
`
`(d) reacting the salt from step (C) with an acid to form the
`oompound of formula 1.
`In one embodiment, the compound of formula I is at least 15
`90.0%, 95.0%, 99.0%.
`The compound of formula H can he prepared from a com-
`pound of formula XI, which is a cyclization product of a
`compound of formula X as described in U.S. Pat. No. 6,441,
`245.
`
`20
`
`OK,
`
`0(CH2)..CHs
`
`C\\C\
`\
`
`Y]—C—C—Rw
`II
`II
`M1
`L1
`
`(X)
`
`25
`
`30
`
`(X1)
`
`
`
`O(CH;),,CH3
`
`35
`
`'
`
`_
`.
`Wheremn is 0, 1, 2, or 3.
`The compound of formula II can be prepared alternatively
`from a compound of formula XIII, which is a cyclization
`ggidlgcot %f,7a0:)0(r)gI5mund of fommla X11 as dfiscnbed in US" 45
`'
`'
`’
`’
`'
`
`40
`
`OR]
`
`OBI!
`
`\
`
`C \
`~\\.C
`\ ‘“‘fi‘il“‘7
`M1
`L1
`
`Y1—C—-C—R7
`II
`II
`l\/11 L.
`
`OH
`
`H
`
`H
`
`(XII,
`’
`
`(X111)
`
`50
`
`55
`
`60
`
`0
`K
`
`C);
`
`(b) hydrolyzing the product ofstep (a) with a base such as
`KOH,
`(C) contacting the product of step (b) with a base B such as
`dietlranolamine to for a salt of the following structure,
`and
`
`
`
`H0
`
`....u
`
`'OH
`
`®NH2<CH2CHz0H>2
`
`
`0
`K
`
`C009
`
`OB.u
`One embodiment of the present invention is a process for 55
`
`(d) reacting the salt from step (b) with an acid such as HCl
`to form the compound of formula IV.
`
`hydrate, solvate, or pharmaceutically acceptable salt thereof.
`
`the preparation of a compound having formula IV, or a
`
`is at least 90.0%, 95.0%, 99.0%, 99.5%.
`
`Inoneembodiment,thepurityofcompoundofformulaIV
`
`>
`
`K
`E
`
`.
`,
`«
`
`‘
`i
`}
`i
`
`F
`
` Copy provided by USPTO trom the PIRS Image Database pn 03/24/2015
`
`1l
`
`UTC_REM_||_000003359
`
`
`

`
`
`Case 3:14-cv-05499-PGS-LHG Document 42-2 Filed 07/07/15 Page 9 of 99 PageID: 595
`595
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`
`US 8,497,393 B2
`
`10
`A 50-L, three-neck, round-bottom flask equipped with a
`mechanical stirrer and a thermocouple was charged with ben-
`zindene triol (1250 g), acetone (19 L) and KZCO3 (powdered)
`(1296 g), chloroacetonitrile (567 g), tetrabutylammoniurn
`bromide (36 g). The reaction mixture was stirred vigorously
`at room temperature (23:2“ C.) for 16-72 h. The progress of
`the reaction was monitored by TLC. (methanol/CH2Cl2; l :9
`and developed by 10% cthanolic solution of PMA). After
`completion ofreaction, the reactionmixture was filtered with/
`without Celite pad. The filter cake was Washed with acetone
`(1 0 L). The filtrate was concentrated in Vacuo at 50-55° C. to
`give a light-brown, Viscous liquid benzindene nitrile. The
`crude benzindene nitrile was used as such in the next step
`without fiirther purification.
`
`Example 2 ’
`
`Hydrolysis of Benzindene Nitrilc
`
`5
`
`10
`
`15
`
`20
`
`25
`
`
`
`KOH,
`MeOH
`
`I-[20,
`Reflux
`
`
`
`
`
`
`
`
`
`
`MW Amount Mol.Name liq.
`Benzindene Nitrilc
`371.52
`1397 g*
`3.76
`1.0
`KOH
`56.11
`844 g
`15.04
`4.0
`Methanol
`—
`12 I,
`—
`-—
`Water
`—
`4.25 L
`—
`—
`
`*Note:
`This weight is Jascd on 100% yield from the previous step. This is not isolated yield.
`
`A 50-L, cylindrical reactor equipped with a heating/coo1-
`ing system, a mechanical stirrer, a condenser, and a thermo-
`couple was charged with a solution of benzindene nitrile in
`methanol (12 L) and a solution of KOH (844 g of KOII
`dis solved in4.25 L ofwater). The reaction mixture was stirred
`and heated to reflux (temperature 72.2° C.). The progress of
`
`40
`
`45
`
`55
`
`60
`
`65
`
`1.00
`3 .76
`1250 g
`332.48
`Benzindene Triol
`2.50
`9.38
`1296 g
`138.20
`KQCOQ (powder)
`2.0
`7.51
`S 67 g
`75.50
`CICHZCN
`0.03
`0.11
`36 g
`322.37
`Bu,,N'Br
`—
`—~
`29 L
`—
`Acetone
`
`
`
`
`— 115 g -—Celile ® 545 —
`
`
`
`Copy provided by USPTO from the PIRS Image Database on 03/24/2015
`
`UTC_REM_||_000003360
`
`
`9
`In one embodiment, the process further comprises a step of
`isolating the salt of formula 1V5.
`In one embodiment, thebase B in step (c) may be ammonia,
`N-methylglucamine, procaine,
`tromethanine, magnesium,
`L—lysine, L-arginine, or triethanolamine.
`The following abbreviations are used in the description
`and/or appended claims, and they have the following mean-
`ings:
`“MW” means molecular weight.
`“Eq.” means equivalent.
`“TLC” means thin layer chromatography.
`“HPLC” means high performance liquid chromatography.
`“PMA” means phosphornolyhdic acid.
`“AUC” means area under curve.
`In View of the foregoing considerations, and specific
`examples below, those who are skilled in the art will appre-
`ciate that how to select necessary reagents and solvents in
`practicing the present invention.
`The invention will now be dcscribed in reference to the
`following Examples. These examples are not to be regarded
`as limiting the scope of the present invention, but shall only
`serve in an illustrative manner.
`
`EXAMPLES
`
`Example 1
`
`Alkylation of Benzindcnc Triol
`
`
`
`C1
`K
`
`-——-————>
`K2003, l3u4Nl3r
`
`Acetone, Kl‘HO
`
`
`
`OKCN
`
`
`
`Name
`
`MW
`
`Amount
`
`Mol.
`
`Eq.
`
`

`
`
`
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`US 8,497,393 B2
`
`12
`-continued
`
`
`
`Name
`
`MW Amount
`
`Mol
`
`Eq
`
`6/
`4 e
`COO HZN
`
`01'-l
`
`390.52
`105.14
`—
`
`1.0
`3.75
`1464 g"
`Trcprostinil
`1.1
`4.14
`435 g
`Dietlmuolarnine
`-
`-—
`5.1 L
`Ethanol
`—-
`—
`35 L**
`Ethyl acetate
`—-
`—
`12 g
`—
`Trep1'osti:n.il Dietlianolamiric
`Salt (seed) _?_?_:
`‘Note:
`This weight is based on 100% yield from benzindene l1l0l. It is not isolated yield. The
`treprostinil was carried from previous step in ethyl acetate solution and used as such forthis
`step.
`*"Note:
`The total volume of ethyl acetate should be in range of 35-36 L (it should be 7 times die
`volume ofethanol used). Approximately 35 L ofethyl acetate was carried over frornprevious
`step and additional 1.0 L of ethyl acetate was used for rinsing the flask.
`
`A 50-L, cylindrical reactor equipped with a heating/cool-
`ing system, a mechanical stirrer, a condenser, and a thermo-
`couple was charged with a solution of treprostinil in ethyl
`acetate (35-40 L from the previous step), anhydrous ethanol
`(5.1 L) and diethanolarnine (435 g). While stirring, the reac-
`tion mixture was heated to 60-75° C., for 0.5-1.0 h to obtain
`a clear solution. The clear solution was cooled to 55:5‘’ C. At
`this temperature, the seed of polymorph B of treprostinil
`diethanolamine salt (~12 g) was added to the clear solution.
`The suspension of polymorph B was stirred at this tempera-
`ture f()I'l h. The suspension was cooled to 20:2" C. overnight
`(over a period of 16-24 h). The treprostinil diethanolamine
`salt was collected by filtration using Aurora filter equipped
`with filter cloth, and the solid was washed wi‘d1 ethyl acetate
`(2><8 L). The trepro stinil diethanolarnine salt was transferred
`to a HDPE/glass container for air-drying in hood, followed by
`drying in a vacuum oven at 50:5” C. under high vacuum.
`At this stage, if melting point of the trcprostinil diethano-
`lamine salt is morethan104° C., it was considered polymorph
`B. There is no need of recrystallization. If it is less than 104°
`C., it is recrystallized in Et()1-1-1-jtL)Ac to increase the melting
`point.
`
`11
`the reaction was monitored by TLC (for TLC purpo se, 1-2 mL
`ofreaction mixture was acidified with 3M 1-1C1 to pH 1-2 and
`extracted with ethyl acetate. The ethyl acetate extract was
`used for TLC; Eluent: methanol/CH2Cl2; 1:9, and developed
`by 10% ethanolic