US 8,497,393 B2
`(10) Patent No.:
`a2) United States Patent
`Batraet al.
`(45) Date of Patent:
`Jul. 30, 2013
`
`
`US008497393B2
`
`(75)
`
`(54) PROCESS TO PREPARE TREPROSTINIL,
`THE ACTIVE INGREDIENTIN
`REMODULIN®
`.
`Inventors: Hitesh Batra, Herndon, VA (US);
`Sudersan M. Tuladhar, Silver Spring,
`MD (US); Raju Penmasta, Herndon, VA
`.
`*
`(US); David A. Walsh, Palmyra, VA
`(US)
`
`(73) Assignee: United Therapeutics Corporation,
`Silver Spring, MD (US)
`:
`:
`:
`:
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`:
`(*) Notice:
`
`(21) Appl. No.: 13/548,446
`14.
`Filed:
`
`Jul. 13, 2012
`
`(22)
`
`2004/0176645 Al
`2005/0085540 Al
`2005/0101608 Al
`2005/0165111 Al
`2005/0282901 Al
`2005/0282903 Al
`2007/0078095 Al
`2007/0078182 Al
`2008/0200449 Al
`2008/0249167 Al
`2008/0280986 Al
`2009/0036465 Al
`2009/0124697 Al
`2009/0163738 Al
`2009/0281189 Al
`2010/0076083 Al
`3010/0282622 Al
`201 1/0092599 Al
`2011/0118213 AL
`2011/0144204 Al
`2011/0224236 Al
`2011/0319641 Al
`2012/0004307 Al
`2012/0010159 Al
`
`9/2004 Moriartyetal.
`4/2005 Pharesetal.
`5/2005 Santel
`7/2005 Wadeetal.
`12/2005 Pharesetal.
`12/2005 Wadeetal.
`4/2007 Pharesetal.
`4/2007 Pharesetal.
`8/2008 Olschewskietal.
`10/2008 Phareset al.
`11/2008 Wadeet al.
`2/2009 Roscignoet al.
`5/2009 Cloutieretal.
`6/2009 Batraet al.
`11/2009 Walsh
`3/2010 Olschewski
`11/2010 Phares 1
`4/2011 Wadeetal.
`5/2011 Phareset al.
`6/2011 Jeffs et al.
`9/2011 Rothblatt et al.
`12/2011 Batra et al.
`1/2012 Wadeetal.
`1/2012 Rothblatt et al.
`
`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.
`°
`
`FOREIGN PATENT DOCUMENTS
`Prior Publication Data
`(65)
`US 2012/0283470 Al—Nov. 8, 2012 CA 2710726 Al 1/2012
`
`
`
`CN
`101891596 A
`11/2010
`CN
`101891715 A
`11/2010
`EP
`9 004 335 A2
`10/1979
`EP
`0 087 237 Bl
`5/1986
`EP
`0 175 450 BL
`3/1989
`EP
`0159784 Bl
`6/1989
`EP
`0 496 548 Al
`7/1992
`WO
`WO98/39337 Al
`9/1998
`wo
`WO 99/21830 Al
`5/1999
`WO
`WO 03/070163 A2
`8/2003
`WO
`WO 2005/007081 A2
`1/2005
`WO
`WO 2007/134292 A2
`11/2007
`WO
`WO 2008/100977 A2_
`_—8/2008
`WO
`WO 2009/117095 Al
`9/2009
`WO
`WO 2012/009816 Al
`1/2012
`OTHER PUBLICATIONS
`
`51
`(51)
`
`Cl
`Int.
`Cl.
`Int.
`CO7C 62/00
`CO07C 65/00
`(52) US.CL.
`USPC ciccecccccccesetsccesenteceecesseecensssaeecestsseeeeeees 562/466
`
`(2006.01)
`(2006.01)
`
`(58) Wield of Classification Search
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,306,075 A
`4,424,376 A
`4,463,183 A
`4,486,598 A
`4,544,764 A
`4,668,814 A
`4,683,330 A
`5,039,814 A
`5,153,222 A
`6,054,486 A
`6,441,245 Bl
`6,521,212 Bl
`6,528,688 B2
`6,700,025 B2
`6,756,033 B2
`6,765,117 B2
`6,803,386 B2
`6,809,223 B2
`6,933,385 B2
`7,199,157 B2
`7,384,978 B2
`7,417,070 B2
`7,999,007 B2
`2002/0173672 Al
`
`12/1981 Aristoff
`1/1984 Moniotetal.
`7/1984 Haslanger
`12/1984 Aristoff
`10/1985 Aristoff
`5/1987 Aristoff
`7/1987 Aristoff
`8/1991 Shuman etal.
`10/1992 Tadepalli et al.
`4/2000 Crowetal.
`8/2002 Moriarty et al.
`2/2003 Cloutieret al.
`3/2003 Moriarty etal.
`3/2004 Moriarty etal.
`6/2004 Cloutieret al.
`7/2004 Moriarty etal.
`10/2004 Shorr et al.
`10/2004 Moriarty etal.
`8/2005 Westermannetal.
`4/2007 Wadeetal.
`6/2008 Phareset al.
`8/2008 Phareset al.
`8/2011 Jeffs et al.
`11/2002 Moriarty etal.
`
`Alexanderetal., “The SynthesisofBenzindene ProstacyclinAnalogs
`
`as Potential Antiulcer Agents,” Prostaglandins, 1986, 32(5):647-653.
`Aristoff et al., “Synthesis and Structure-Activity Relationship of
`Novel Stable Prostacyclin Analogs,” Advances in Prostaglandin,
`Thromboxane, and Leukotriene Research, Samuelssonet al., .Eds.,
`1983, 11:267-274.
`Aristoff et al., “Synthesis of Benzopyran Prostaglandins, Potent
`Stable Prostacyclin Analogs, Via an Intramolecular Mistunobu Reac-
`tion,” Tetrahedron Letters, 1984, 25(36):3955-3958.
`Aristoff et al., “Total Synthesis of a Novel Antiulcer Agent via a
`Modification of the Intramolecular Wadsworth-Emons-Wittig Reac-
`tion,” J. Am. Chem. Soc., 1985, 107:7967-7974.
`Batra et al., “Crystallization Process Development for a Stable
`Polymorph of Treprostinil Diethanolamine (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
`
`(57)
`
`ABSTRACT
`
`This present invention relates to an improved process to pre-
`pare prostacyclin derivatives. One embodimentprovides for
`an improved process to convert benzindenetriol to treprosti-
`nil via salts of treprostinil and to purify treprostinil.
`
`22 Claims, No Drawings
`
`Liquidia - Exhibit 1004 - Page 1
`
`Liquidia - Exhibit 1004 - Page 1
`
`

`

`US 8,497,393 B2
`
`Page 2
`
`OTHER PUBLICATIONS
`Belch etal., “Randomized, Double-Blind, Placebo-Controlled Study
`Evaluating the Efficacy and Safety of AS-013, a Prostaglandin E1
`Prodrug,
`in Patients with Intermittent Claudication,” Circulation,
`May 6, 1997, 95(9):2298-2302.
`Chemburkar et al., “Dealing with the Impact of Ritonavir
`Polymorphson the Late Stages of Bulk Drug Process Development,”
`Organic Process Research & Development, 2000, 4:413-417.
`Chung et al., “Promoters for the (Alkyne)hexacarbonyldicobalt-
`Based Cyclopentenone Synthesis,” Organometallics, 1993, 12:220-
`223.
`Clark et al., “High-Performance Liquid Chromatographic Method
`for Determining the Enantiomeric Purity of a Benzindene
`Prostaglandin by a Diastereomeric Separation,” Journal of Chroma-
`tography, 1987, 408:275-283.
`Hardingeret al., “Triply-Convergent Syntheses of Two Homochiral
`Arene-Fused Prostacyclin Analogs Related to U68,215,” Bioorganic
`& Medicinal Chemistry Letters, 1991, 1(1):79-82.
`Hickset al., “A Practical Titanium-Catalyzed Synthesis of Bicyclic
`Cyclopentenones and Allylic Amines,” J. Org. Chem., 1996,
`61:2713-2718.
`Jeonget al., “Catalytic Version of the Intramolecular Pauson-Khand
`Reaction,” J. Am. Chem. Soc., 1994, 116:3159-3160.
`Khand et al., “Organocobalt Complexes. Part
`II. Reaction of
`Acetylenehexacarbonyl-dicobalt Complexes,
`(R'C,R7)Co(CO),,
`with Norborneneandits Derivatives,” J. Chem. Soc., J.C.S. Perkin I.,
`1973, 977-981.
`Mathreet al., “A Practical Enantioselective Synthesis of a,a-Diaryl-
`2-pyrrolidinemethanol. Preparation and Chemistry of the Corre-
`sponding Oxazaborolidines,” J. Org. Chem., 1991, 56:75 1-762.
`Moriarty et al., “The Intramolecular Asymmetric Pauson-Khand
`Cyclization as a Novel and General Stereoselective Route to
`Benzindene Prostacyclins: Synthesis of UT-15 (Treprostinil),” 7
`Org. Chem. 2004, 69, 1890-1902.
`Mulzeret al., “Asymmetric Synthesis of Carbacyclin Precursors by
`Pauson-Khand Cyclization,” Liebigs Ann. Chem., 1988, 891-897.
`Nelson, Norman A., “Prostaglandin Nomenclature,” J. Med, Chem.,
`Sep. 1974, 17(9):911-918.
`Pagenkopfet 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,
`118:2285-2286.
`
`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.
`Paulson, Peter L., “The Khand Reaction,” Tetrahedron, 1985,
`41(24):5855-5860.
`Schore, Neil E., “Transition-Metal-Mediated Cycloaddition Reac-
`tions ofAlkynes in Organic Synthesis,” Chem. Rev., 1988, 88:1081-
`1119.
`Shambayati et al., “N-Oxide Promjoted Pauson-Khand Cyclizations
`at Room Temperature,” Tetrahedron Letters, 1990, 31(37):5289-
`5292.
`Snell et al., “Investigating the Effect of Impurities on Macromolecule
`Crystal Growth in Microgravity,” Crystal Growth & Design, 2001,
`1(2): 151-158.
`Sorberaet al. “UT-15. Treatment of Pulmonary Hypertension Treat-
`ment of Peripheral Vascular Disease,” Drug of the Future, 2001,
`26(4), 364-374.
`Takanoet al., “Enantiodivergent 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.
`Zhanget al., “A Nickel(0)-Catalyzed Process for the Transformation
`of Enynes to Bicyclic Cyclopentenones,” J. Org. Chem., 1996,
`61:4498-4499.
`U.S. Appl. No. 13/409,685, filed Mar. 1, 2012, Sharma, Vijay.
`Cominset al., “Ortho Metalation Directed by a-Amino Alkoxides,”
`J. Org. Chem., 1984, 49:1078-1083.
`Cominset al., “Ortho Substitution of M-Anisaldehyde via a-Amino
`Alkoxide Directed Lithiation,” J. Org. Chem., 1989, 54:3730-3732.
`Corey etal. “Novel Electronic Effects of Remote 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.
`1,2,3-
`Pansegrau et al.,
`“The Oxazoline-Benzyne Route to
`Trisubstituted Benzenes. Tandem Addition of Organolithiums,
`Organocuprates, and c-Lithionitriles to Benzynes,” J. Am. Chem.
`Soc., 1988, 110:7178-7184.
`Rowley et al., “Application of the Pauson-Khandreaction to the
`synthesis of pentalenic acid,’ Journal of Organometallic Chemistry,
`1991, 413:C5-C9.
`
`Liquidia - Exhibit 1004 - Page 2
`
`Liquidia - Exhibit 1004 - Page 2
`
`

`

`US 8,497,393 B2
`
`1
`PROCESS TO PREPARE TREPROSTINIL,
`THE ACTIVE INGREDIENTIN
`REMODULIN®
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a Continuation of U.S. application Ser.
`No. 12/334,731, filed Dec. 15, 2008, which claims priority
`from U.S. Provisional Patent Application 61/014,232, filed
`Dec. 17, 2007, the entire contents of which are incorporated
`herein by reference.
`
`BACKGROUND
`
`@
`
`H
`O(CH),,COOH
`
`The process comprises the following steps:
`(a) alkylating a compoundofstructure I] with an alkylating
`agent to produce a compoundof formulaIII,
`
`Ly
`
`M,
`OH
`
`H
`
`OH
`
`HO Xie —C— Ry
`ll
`Il
`M Ly
`OH
`
`H
`
`O(CH»)yCN
`
`qd)
`
`arp
`
`-—CH,
`
`The present invention relates to a process for producing
`prostacyclin derivatives and novel intermediate compounds
`useful in the process.
`Prostacyclin derivatives are useful pharmaceutical com-
`poundspossessing activities such as platelet aggregation inhi-
`bition, gastric secretion reduction,
`lesion inhibition, and
`bronchedilation.
`Treprostinil, the active ingredient in Remodulin®,wasfirst
`described in U.S. Pat. No. 4,306,075. Treprostinil, and other
`prostacyclin derivatives have been prepared as described in
`Moriarty, et al in. Org. Chem. 2004, 69, 1890-1902, Drug of
`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.
`USS. Pat. No. 5,153,222 describes use of treprostinil for
`treatment of pulmonary hypertension. Treprostinil
`is
`approved for the intravenous as well as subcutaneousroute,
`the latter avoiding septic events associated with continuous
`wherein
`intravenous catheters. U.S. Pat. Nos. 6,521,212 and 6,756,
`w=1, 2, or 3;
`033 describe administration of treprostinil by inhalation for
`cis-CH—CH—,
`Y,
`is
`trans-CH—CH—,
`treatment of pulmonary hypertension, peripheral vascular
`disease and other diseases and conditions. U.S. Pat. No.
`(CH,),,—, or —C==C—, m is 1, 2, or 3;
`R, is
`6,803,386 discloses administration of treprostinil for treating
`cancer such aslung,liver, brain, pancreatic, kidney, prostate,
`(1) —C,H,,—CHs3, wherein p is an integer from1to 5,
`breast, colon and head-neck cancer. U.S. patent application
`inclusive,
`40
`publication No. 2005/0165111 discloses treprostinil treat-
`(2) phenoxy optionally substituted by one, two orthree
`mentof ischemic lesions. U.S. Pat. No. 7,199,157 discloses
`chloro, fluoro, trifluoromethyl, (C,-C,;) alkyl, or (C,-
`that treprostinil treatment improves kidney functions. U.S.
`C,)alkoxy, with the proviso that not more than two
`patent application publication No. 2005/0282903 discloses
`substituents are other than alkyl, with the proviso that
`treprostinil treatment of neuropathic foot ulcers. U.S. appli-
`R, is phenoxyor substituted phenoxy, only when R,
`cation Ser. No. 12/028,471 filed Feb. 8, 2008, discloses tre-
`and R, are hydrogen or methyl, being the same or
`prostinil treatment ofpulmonary fibrosis. U.S. Pat. No. 6,054,
`different,
`486 discloses treatment of peripheral vascular disease with
`treprostinil. U.S. patent application Ser. No. 11/873,645 filed
`(3) phenyl, benzyl, phenylethy], or phenylpropy] option-
`Oct. 17, 2007 discloses combination therapies comprising
`ally substituted on the aromatic ring by one, two or
`treprostinil. U.S. publication No. 2008/0200449 discloses
`three chloro, fluoro, trifluoromethyl, (C, -C, Jalkyl, or
`delivery of treprostinil using a metered dose inhaler. U.S.
`(C,-C,)alkoxy, with the proviso that not more than
`publication No. 2008/0280986 discloses treatment of inter-
`twosubstituents are other than alkyl,
`stitial lung disease withtreprostinil. U.S. application Ser. No.
`(4) cis-CH—CH—CH,—CH,,
`12/028,471 filed Feb. 8, 2008 discloses treatment of asthma
`(5) —(CH,),—CH(OH)—CH,, or
`with treprostinil. U.S. Pat. No. 7,417,070, 7,384,978 and U.S.
`(6) (CH,);—CH=C(CH,),;
`publication Nos. 2007/0078095, 2005/0282901, and 2008/
`wherein —C(L,)—R,taken togetheris
`0249167 describe oral formulations of treprostinil and other
`(1) (C,-C,)cycloalkyl] optionally substituted by 1 to 3
`prostacyclin analogs.
`(C,-Cs)alkyl;
`Because Treprostinil, and other prostacyclin derivatives
`(2) 2-(2-furylethyl,
`are ofgreat importance from a medicinalpointofview, a need
`(3) 2-3-thienyl)ethoxy, or
`exists for an efficient process to synthesize these compounds
`(4) 3-thienyloxymethy];
`onalarge scale suitable for commercial production.
`M,
`is a-OH:6-R; or a-R;:8-OH or a-OR,:B-R; or
`a-R,;:B-OR,, wherein R, is hydrogen or methyl, R, is
`an alcohol protecting group, and
`L, is a-R3:B-Ry, a-R,:B-R;, or a mixture of a-R;:6-Ry,
`and a-R,:B-R3, wherein R; and R, are hydrogen,
`methyl, or fluoro, being the same ordifferent, with the
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`SUMMARY
`
`The present invention provides in one embodimenta pro-
`cess for the preparation of a compoundofformula I, hydrate,
`solvate, prodrug, or pharmaceutically acceptablesalt thereof.
`
`Liquidia - Exhibit 1004 - Page 3
`
`Liquidia - Exhibit 1004 - Page 3
`
`

`

`3
`proviso that one of R, and R, is fluoro only when the
`other is hydrogen or fluoro.
`(b) hydrolyzing the product of step (a) with a base,
`(c) contacting the productof step (b) with a baseBto fora
`salt of formulaI,
`5
`
`US 8,497,393 B2
`
`4
`
`(IV,)
`
`ds)
`
`H©
`
`O(CH2)wCOO
`
`(d) reacting the salt from step (c) with an acid to form the
`compoundof formula I.
`The present invention provides in another embodiment a 2
`process for the preparation of a compoundof formulaIV.
`
`ss
`
`(d) reacting the salt from step (b) with an acid to form the
`compoundof formula IV.
`
`DETAILED DESCRIPTION
`
`2
`
`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 substances, additives,
`25 Carriers, or steps may be present. Unless otherwise specified,
`“a” or “an” means one or more.
`
`(IV)
`
`C,_;-alkyl is a straight or branched alkyl group containing
`1-3 carbon atoms. Exemplary alkyl groups include methyl,
`ethyl, n-propyl, and isopropyl.
`30.=C,_,-alkoxy is a straight or branched alkoxy group contain-
`ing 1-3 carbon atoms. Exemplary alkoxy groups include
`methoxy, ethoxy, propoxy, and isopropoxy.
`C,_,-cycloalkyl is an optionally substituted monocyclic,
`
` 0
`
`L
`
`COOH
`
`The process comprises the followingsteps:
`(a) alkylating a compoundofstructure V with an alkylating
`agent to produce a compoundof formula VI,
`
`(Vv)
`
`(VT)
`
`O
`
`LL
`
`CN
`
`descriptionbeing useful in preparing a pharmaceutical 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
`65
`(b) hydrolyzing the product of step (a) with a base,
`
`(c) contacting the productof step (b) with a baseBto fora pharmaceutically acceptable, as defined above, and which
`salt of formula IV,, and
`possess the desired pharmacological activity. Such salts
`
`bicyclic or tricyclic alkyl group containing between 4-7 car-
`
`35 bon atoms. Exemplary cycloalkyl groups include butnotlim-
`ited to cyclobutyl, cyclopentyl, 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
`40 compounds whichpossess stability sufficient to allow manu-
`facture and which maintainsthe integrity ofthe compoundfor
`a sufficient period of time to be useful for the purposes
`detailed herein.
`
`Asusedherein, the term “prodrug” meansa derivative of a
`45 compound that can hydrolyze, oxidize, or otherwise react
`under biological conditions (in vitro or in vivo) to provide an
`active compound. Examplesof prodrugsinclude, but are not
`limited to, derivatives of a compoundthat include biohydro-
`lyzable groups such as biohydrolyzable amides, biohydrolyz-
`50 able esters, biohydrolyzable carbamates, biohydrolyzable
`carbonates, biohydrolyzable ureides, and biohydrolyzable
`phosphate analogues (e.g., monophosphate, diphosphate or
`triphosphate).
`Asusedherein,“hydrate”is a form of acompound wherein
`55 water molecules are combined in a certain ratio as an integral
`part of the structure complex of the compound.
`Asused 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
`
`60
`
`Liquidia - Exhibit 1004 - Page 4
`
`Liquidia - Exhibit 1004 - Page 4
`
`

`

`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, succinic 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, ethanolamine, diethanolamine, N-methylglucamine,
`choline and the like. Included in the invention are pharma-
`ceutically acceptable salts or compounds of any of the for-
`mulae herein.
`
`qd)
`
`ain
`
`M ly
`OH
`
`H
`
`OH
`
`H nn
`M ly
`OH
`
`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 edetate,
`camsylate, carbonate, chloride, citrate, clavulariate, dihydro-
`chloride, edetate, edisylate, estolate, esylate, fumarate, glu-
`Y, is trans-CH—CH—, cis-CH—CH—, —CH,(CH,)
`ceptate, gluconate, glutamate, glycollylarsanilate, hexafluo-
`m—, of —C==C—; mis 1, 2, or 3;
`rophosphate, hexylresorcinate, hydrabamine, hydrobromide,
`hydrochloride, hydroxynaphthoate, iodide, isothionate, lac-
`R,is
`tate, lactobionate, laurate, malate, maleate, mandelate, mesy-
`(1) —C,H2,—CHs, wherein p is an integer from1to 5,
`late, methylbromide, methylnitrate, methylsulfate, mucate,
`inclusive,
`30
`napsylate, nitrate, N-methylglucamine ammoniumsalt, 3-hy-
`droxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-
`methene-bis-2-hydroxy-3-naphthoate, einbonate), pantoth-
`enate, phosphate/diphosphate, picrate, polygalacturonate,
`propionate, p-toluenesulfonate, salicylate, stearate, subac-
`etate, succinate, sulfate, sulfosalicylate, suramate, tannate,
`tartrate, teoclate, tosylate, triethiodide, and valerate salts.
`The present invention providesfor 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 forma-
`tion is a mucheasier operation than column chromatography.
`Moreover, it was foundthat the productofthe 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 embodimentof the present invention is a process for
`the preparation of a compound of formula I, or a hydrate,
`solvate, prodrug, or pharmaceutically acceptablesalt thereof.
`
`Yi-C—C—R,
`lI
`M ly
`OH
`
`a
`
`H
`
`O(CH),,COOH
`
`55
`
`@
`
`60
`
`The process comprises the following steps:
`(a) alkylating a compoundof formula II with an alkylating
`agent to produce a compoundof formulaIII,
`
`Liquidia - Exhibit 1004 - Page 5
`
`20
`
`25
`
`35
`
`40
`
`45
`
`50
`
`O(CH),CN
`
`wherein
`
`w=1, 2, or 3;
`
`(2) phenoxy optionally substituted by one, two orthree
`chloro, fluoro, trifluoromethyl, (C,-C,;) alkyl, or (C,-
`C,)alkoxy, with the proviso that not more than two
`substituents are other than alkyl, with the proviso that
`R, is phenoxyor substituted phenoxy, only when R,
`and R, are hydrogen or methyl, being the same or
`different,
`
`(3) phenyl, benzyl, phenylethy], or phenylpropy] option-
`ally substituted on the aromatic ring by one, two or
`three chloro, fluoro, trifluoromethyl, (C,-C, alkyl, or
`(C,-C,) alkoxy, with the proviso that not more than
`twosubstituents are other than alkyl,
`(4) cis-CH—CH—CH,—CH,,
`(5) —(CH,).—CH(OH)—CH,, or
`(6) (CH,);—CH—C(CH3),;
`wherein —C(L,)-R, taken together is
`(1) (C,-C,)cycloalkyl optionally substituted by 1 to 3
`(C,-Cs)alkyl;
`(2) 2-(2-furylethyl,
`
`(3) 2-(3-thienyl)ethoxy, or
`(4) 3-thienyloxymethy];
`M,
`is a-OH:6-R; or a-R;:8-OH or a-OR,:B-R; or
`a-R,;:B-OR,, wherein R, is hydrogen or methyl, R, is
`an alcohol protecting group, and
`L, is a-R;:B-R,, a-R,:B-R;, or a mixture of a-R,:6-R,
`and a-R,:B-R3, wherein R; and R, are hydrogen,
`methyl, or fluoro, being the same ordifferent, with the
`proviso that one of R, and R,is fluoro only when the
`other is hydrogen or fluoro.
`b) hydrolyzing the productof step (a) with a base,
`(c) contacting the productof step (b) with a base B to fora
`salt of formula I,
`
`Liquidia - Exhibit 1004 - Page 5
`
`

`

`US 8,497,393 B2
`
`(Is)
`
`H
`
`Y;—C—C—R,
`M ly
`OH
`
`HB
`
`H
`O(CHy),COO®
`
`dv) 0
`
`(d) reacting the salt from step (c) with an acid to form the
`compoundof formula I.
`In one embodiment, the compound of formulaIis at least
`90.0%, 95.0%, 99.0%.
`The process comprises
`(a) alkylating a compoundofstructure V with an alkylating
`agent such as CICH,CN to produce a compound of
`formula VI,
`
`LCOOH
`
`The compoundof formula II can be 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.
`
`40
`Whereinnis 0, 1, 2, or 3.
`
`OR,
`
`(&)
`
`N
`
`_
`
`Y;—C—C—R,
`ll
`ll
`M,
`Ly
`
`O(CH)),CH3
`
`(xT)
`
`O(CH),CH3
`
`20
`
`25
`
`30
`
`35
`
`The compoundof formula II can be preparedalternatively
`from a compound of formula XIII, which is a cyclization
`product of a compound of formula XII as described in U.S.
`Pat. No. 6,700,025.
`
`(XID
`
`cx)
`
`OR
`
`Ne
`SS
`
`Sy,—c—c—R,
`ll
`ll
`M,
`Ly;
`
`Xi-C—C—R,
`lll
`M,
`Ly;
`OH
`
`wo
`
`H
`
`OBn
`
`OBn
`
`One embodimentof the present invention is a process for
`the preparation of a compound having formula IV, or a
`hydrate, solvate, or pharmaceutically acceptablesalt thereof.
`
`45
`
`50
`
`55
`
`60
`
`65
`
`(V)
`(v1) 0
`
`LCN
`
`(b) hydrolyzing the product of step (a) with a base such as
`KOH,
`(c) contacting the productof step (b) with a base B such as
`diethanolamineto for a salt of the following structure,
`and
`
`HO
`
`“unOH
`
`
`
`® NH>(CH)CH>0H)2
`
`(d) reacting the salt from step (b) with an acid such as HCl
`to form the compoundof formula IV.
`In one embodiment, the purity of compoundof formula IV
`is at least 90.0%, 95.0%, 99.0%, 99.5%.
`
`Liquidia - Exhibit 1004 - Page 6
`
`Liquidia - Exhibit 1004 - Page 6
`
`

`

`US 8,497,393 B2
`
`9
`In one embodiment, the process further comprises a step of
`isolating the salt of formula IV,.
`In one embodiment,the base 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” meansthin layer chromatography.
`“HPLC” means high performanceliquid chromatography.
`“PMA”means phosphomolybdic acid.
`“AUC” meansarea under curve.
`
`10
`A 50-L, three-neck, round-bottom flask equipped with a
`mechanicalstirrer and a thermocouple wascharged with ben-
`zindenetriol (1250 g), acetone (19 L) and K,,CO,(powdered)
`(1296 g), chloroacetonitrile (567 g), tetrabutylammonium
`> bromide (36 g). The reaction mixture wasstirred vigorously
`at room temperature (23+2° C.) for 16-72 h. The progress of
`the reaction was monitored by TLC. (methanol/CH,Cl,; 1:9
`and developed by 10% ethanolic solution of PMA). After
`completion ofreaction, the reaction mixture wasfiltered with/
`without Celite pad. The filter cake was washed with acetone
`(10 L). Thefiltrate was concentrated in vacuo at 50-55° C. to
`give a light-brown, viscous liquid benzindene nitrile. The
`crude benzindenenitrile was used as such in the next step
`without further purification.
`
`In view of the foregoing considerations, and specific
`examples below, those whoare 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 described 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.
`
`20
`
`Example 2
`
`Hydrolysis of BenzindeneNitrile
`
`EXAMPLES
`
`Example 1
`
`Alkylation of Benzindene Triol
`
`
`HO oO
`
`K,CO3, BusNBrOe
`Acetone, RT
`
`CN
`
`Ln
`
`Name
`
`MW
`
`Amount
`
`Benzindene Triol
`K,CO3 (powder)
`CICH,CN
`Bu,NBr
`Acetone
`Celite ® 545
`
`332.48
`138.20
`75.50
`322.37
`—
`—_—
`
`1250¢
`1296g
`567g
`36g
`29L
`115g
`
`Mol.
`
`3.76
`9.38
`751
`0.11
`—
`—_—
`
`Eq.
`
`1.00
`2.50
`2.0
`0.03
`
`25
`
`50
`
`35
`
`Name
`
`Benzindene Nitrile
`KOH
`Methanol
`Water
`
`MW
`
`Amount
`
`371.52
`56.11
`—_—
`—
`
`1397 g*
`844g
`12L
`4.25 L
`
`Mol.
`
`3.76
`15.04
`—_—
`—
`
`Eq.
`
`1.0
`4.0
`—_—
`—
`
`*Note:
`
`60 This weight is based on 100% yield from the previousstep. This is not isolated yield.
`
`A 50-L, cylindrical reactor equipped with a heating/cool-
`ing system, a mechanicalstirrer, a condenser, and a thermo-
`couple was charged with a solution of benzindenenitrile in
`65 methanol (12 L) and a solution of KOH (844 g of KOH
`dissolved in 4.25 L ofwater). The reaction mixture wasstirred
`and heated to reflux (temperature 72.2° C.). The progress of
`
`Liquidia - Exhibit 1004 - Page 7
`
`Liquidia - Exhibit 1004 - Page 7
`
`

`

`12
`-continued
`
` H
`
`Oo
`
`OH
`
`( e
`
`coo HN
`
`oo
`
`US 8,497,393 B2
`
`11
`the reaction was monitored by TLC (for TLC purpose, 1-2 mL
`of reaction mixture wasacidified with 3M HClto pH 1-2 and
`extracted with ethyl acetate. The ethyl acetate extract was
`used for TLC; Eluent: methanol/CH,ClL,; 1:9, and developed
`by 10% ethanolic solution of PMA). After completion of the
`reaction (~5 h), the reaction mixture was cooled to -5 to 10°
`C. and quenched witha solution ofhydrochloric acid (3M,3.1
`L) while stirring. The reaction mixture was concentrated in
`vacuo at 50-55° C. to obtain approximately 12-14 L of con-
`densate. The condensate was discarded.
`
`
`
`Name MW~~Amount Mol Eq
`
`
`
`OH
`
`The aqueous layer was diluted with water (7-8 L) and
`extracted with ethyl acetate (2x6 L) to remove impurities
`soluble in ethyl acetate. To aqueouslayer, ethyl acetate (22 L)
`was added and the pH ofreaction mixture was adjustedto 1-2
`by adding 3M HCI (1.7 L) withstirring. The organic layer was
`separated and the aqueous layer was extracted with ethyl
`acetate (2x11 L). The combined organic layers were washed
`with water (3x10 L) and followed by washing with a solution
`20
`ofNaHCO,(30 g ofNaHCO,dissolved in 12 L ofwater). The
`
`organic layer was further washed with saturated solution of
`NaCl (3372 g of NaCl dissolved in water (12 L)) and dried
`over anhydrous Na,SO, (950-1000 g), once filtered.
`Thefiltrate was transferred into a 72-L reactor equipped
`with mechanicalstirrer, a condenser, and a thermocouple. To
`the solution of treprostinil in reactor was added activated
`carbon (110-130 g). The suspension was heated to reflux
`(temperature 68-70° C.) for at least one hour.Forfiltration, a
`pad ofCelite® 545 (300-600 g) was preparedin sintered glass
`funnel using ethyl acetate. The hot suspension wasfiltered
`through the pad of Celite®545. The Celite® 545 was washed
`with ethyl acetate until no compound was seen on TLC ofthe
`washings.
`Thefiltrate (pale-yellow) was reduced to volume of 35-40
`L by evaporation in vacuo at 50-55° C. for direct use in next
`step.
`
`25
`
`30
`
`35
`
`Example 3
`
`Conversion of Treprostinil to Treprostinil
`Diethanolamine Salt (1:1)
`
`
`
`COOH
`
`(I) EtOH, EtOAc
`dD Heptane Slurry
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`390.52
`105.14
`—_—
`—
`—
`
`1464 g*
`435¢
`5.1L
`35 L**
`12¢g
`
`3.75
`4.14
`—_—
`—
`—
`
`1.0
`1.1
`—_—
`—
`—
`
`Treprostinil
`Diethanolamine
`Ethanol
`Ethyl!acetate
`Treprostinil Diethanolamine
`Salt (seed)
`*Note:
`This weight is based on 100% yield from benzindenetriol. It is not isolated yield. The
`treprostinil was carried from previousstep in ethy! acetate solution and used as suchforthis
`step.
`**Note:
`The total volume of ethyl acetate should be in range of 35-36 L (it should be 7 times the
`volumeofethanol used). Approximately 35 L ofethyl! acetate was carried over from previous
`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 mechanicalstirrer, 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 diethanolamine (435 g). Whilestirring, 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 oftreprostinil
`diethanolaminesalt (~12 g) was addedto the clear solution.
`The suspension of polymorph B wasstirred at this tempera-
`ture for 1 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 with ethyl acetate
`(2x8 L). The treprostinil diethanolaminesalt was transferred
`toa HDPE/glass containerforair-drying in hood, followed by
`drying in a vacuum oven at 50+5° C. under high vacuum.
`Atthis stage, if melting point of the treprostinil diethano-
`laminesalt is more than 104° C., it was considered polymorph
`B. There is no need ofrecrystallization.If it is less than 104°
`C., itis recrystallized in EtCOH-EtOActo increase the melting
`point.
`
`Data on Treprostinil Diethanolamine Salt
`
`(1:1
`
`Batch
`No.
`1
`2
`
`Wt. of
`Benzindene Triol
`(g)
`1250
`1250
`
`Wt. of Treprostinil
`Diethanolamine
`Salt (1:1) (g)
`1640
`1528
`
`Yield
`(%)
`88.00
`82.00*
`
`Melting
`point
`CC)
` 104.3-106.3
` 105.5-107.2
`
`Liquidia - Exhibit 1004 - Page 8
`
`Liquidia - Exhibit 1004 - Page 8
`
`

`

`US 8,497,393 B2
`
`13
`-continued
`
`14
`Example 5
`
`Conversion of Treprostinil Diethanolamine Salt (1:1)
`to Treprostinil
`
`Data on Treprostinil Diethanolamine Salt (1:1)
`
`Wt. of
`Benzindene Triol
`(g)
`
`Wt. of Treprostinil
`Diethanolamine
`Salt (1:1) (g)
`
`Yield
`(%)
`
`Melting
`point
`CC)
`
`1250
`1236
`
`1499
`1572
`
`80.42**
`85.34
`
`104.7-106.6
`105-108
`
`Batch
`No.
`
`3
`4
`
`*Note:
`In this batch, approximately 1200 mL ofethyl acetate solution oftreprostinil before carbon
`treatment was removed for R&D carbon treatment experiments.
`**Note:
`This batch wasrecrystallized, for this reason yield was lower.
`
`Example 4
`
`Heptane Slurry of Treprostinil Diethanolamine Salt
`Name
`Batch No.
`Amount
`
`(1:1
`
`Ratio
`
`Treprostinil
`Diethanolamine Salt
`Heptane
`Treprostinil
`Diethanolamine Salt
`Heptane
`
`1
`
`—
`2
`
`—
`
`3168 g
`
`37.5L
`3071 g
`
`36.0 L
`
`1
`
`12
`1
`
`12
`
`A 50-L, cylindrical reactor equipped with a heating/cool-
`ing system, a mechanical stirrer, a condenser, and a thermo-
`couple was charged with slurry oftreprostinil diethanolamine
`salt in heptane (35-40 L). The suspension was heated to
`70-80° C. for 16-24 h. The suspension wascooled to 22+#2°C.
`over a