US008242305B2
`
`(12) United States Patent
`Batra et a].
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 8,242,305 B2
`Aug. 14, 2012
`
`(54) PROCESS TO PREPARE TREPROSTINIL,
`THE ACTIVE INGREDIENT IN REMODULIN
`
`2008/0280986 A1
`2009/0036465 A1
`2009/0163738 A1
`
`11/2008 Wade et a1.
`2/2009 Roscigno et al.
`6/2009 Batra et a1.
`
`(75) Inventors: Hitesh Batra, Hemdon, 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 (U S)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 567 days.
`
`(21) Appl.N0.: 12/334,731
`
`(22) Filed:
`
`Dec. 15, 2008
`
`(65)
`
`Prior Publication Data
`
`US 2009/0163738 A1
`
`Jun. 25, 2009
`
`Related US. Application Data
`
`(60) Provisional application No. 61/014,232, ?led on Dec.
`17, 2007.
`
`(51) Int. Cl.
`(2006.01)
`C07C 62/00
`(2006.01)
`C07C 65/00
`(52) US. Cl. ..................................................... .. 562/466
`(58) Field of Classi?cation Search ................... .. None
`See application ?le for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`4,306,075 A 12/1981 Aristoff
`4,424,376 A
`1/1984 Moniot et a1.
`4,463,183 A
`7/1984 Haslanger
`4,486,598 A 12/1984 Aristoff
`4,544,764 A 10/1985 Aristoff
`4,668,814 A
`5/1987 Aristoff
`4,683,330 A
`7/1987 Aristoff
`5,153,222 A 10/1992 Tadepalli et a1.
`6,054,486 A
`4/2000 Crow et al.
`6,441,245 B1
`8/2002 Moriarty et al.
`6,521,212 B1
`2/2003 Cloutier et al.
`6,528,688 B2
`3/2003 Moriarty et al.
`6,700,025 B2
`3/2004 Moriarty et al.
`6,756,033 B2
`6/2004 Cloutier et al.
`6,765,117 B2
`7/2004 Moriarty et al.
`6,803,386 B2 10/2004 Shorr et a1.
`6,809,223 B2 10/2004 Moriarty et al.
`7,199,157 B2
`4/2007 Wade et a1.
`7,384,978 B2
`6/2008 Phares et al.
`7,417,070 B2
`8/2008 Phares et al.
`2002/0173672 A1* 11/2002 Moriarty et al. ............ .. 558/357
`2004/0176645 A1
`9/2004 Moriarty et al.
`2005/0085540 A1* 4/2005 Phares et al. ................ .. 514/530
`2005/0101608 A1
`5/2005 Santel
`2005/0165111 A1
`7/2005 Wade et a1.
`2005/0282901 A1 12/2005 Phares et al.
`2005/0282903 A1 12/2005 Wade et a1.
`2007/0078095 A1
`4/2007 Phares et al.
`2007/0078182 A1
`4/2007 Phares et al.
`2008/0200449 A1
`8/2008 Olschewski et al.
`2008/0249167 A1 10/2008 Phares et al.
`
`FOREIGN PATENT DOCUMENTS
`2 710 726 A1
`1/2012
`CA
`101891596 A 11/2010
`CN
`101891715 A 11/2010
`CN
`0 004 335 A2 10/1979
`EP
`0 087 237 B1
`5/1986
`EP
`0 175 450 B1
`3/1989
`EP
`0159 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
`W0
`W0 03/070163 A2
`8/2003
`W0
`W0 WO 2005/007081 A2
`1/2005
`W0 WO 2007/134292 A2 11/2007
`W0 WO 2008/100977 A2
`8/2008
`W0 WO 2009/117095 A1
`9/2009
`W0 WO 2012/009816 A1
`1/2012
`OTHER PUBLICATIONS
`
`“Crystallization and Precipitation” in Ullmann’s Encyclopedia of
`Industrial Chemistry, Copyright © 2002 by Wiley-VCH Verlag
`GmbH & Co. KGaA , pp. 1-51.*
`Moriarty et al., “The Intramolecular Asymmetric Pauson-Khand
`Cyclization as a Novel and General Stereoselective Route to
`Benzindene Prostacyclins: Synthesis of UT-15 (Treprostinil),” J.
`Org. Chem. 2004, 69, 1890-1902.
`Sorbera et al. “UT-15. Treatment of Pulmonary Hypertension Treat
`ment of Peripheral Vascular Disease,” Drug of the Future, 2001,
`26(4), 364-374.
`International Search Report andWritten Opinion mailed Jun. 2, 2009
`in corresponding PCT/US2008/013686, 14 pages.
`Alexander et al., “The Synthesis of Benzindene Prostacyclin Analogs
`as Potential Antiulcer Agents,” Prostaglandins, 1986, 32(5):647-653.
`Aristoff et al., “Total Synthesis of a Novel Antiulcer Agent via a
`Modi?cation of the Intramolecular Wadsworth-Emons-Wittig Reac
`tion,” J. Am. Chem. Soc., 1985, 107:7967-7974.
`Aristoff et al., “Synthesis and Structure-Activity Relationship of
`Novel Stable Prostacyclin Analogs,” Advances in Prostaglandin,
`Thromboxane, and Leukotriene Research, Samuelsson et 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.
`Batra et al., “Crystallization Process Development for a Stable
`Polymorph of Treprostinil Diethanolarnine (UT-15C) by Seeding,”
`Organic Process Research & Development, 2009, 13:242-249.
`Belch et al., “Randomized, Double-Blind, Placebo-Controlled Study
`Evaluating the Ef?cacy 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
`Polymorphs 0n 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.
`
`(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 embodiment provides for
`an improved process to convert benzindene triol to treprosti
`nil via salts of treprostinil and to purify treprostinil.
`28 Claims, No Drawings
`
`1
`
`UT Ex. 2007
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`

`
`US 8,242,305 B2
`Page 2
`
`OTHER PUBLICATIONS
`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.
`Hardinger et al., “Triply-Convergent Syntheses of Two Homochiral
`Arene-Fused Prostacyclin Analogs Related to U68,215,” Bioorga
`nic & Medicinal Chemistry Letters, 1991, l(l):79-82.
`Hicks et al., “A Practical Titanium-Catalyzed Synthesis of Bicyclic
`Cyclopentenones and Allylic Amines,” J. Org. Chem., 1996,
`61:2713-2718.
`Jeong et 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, (R1C2R2)C02(CO)6,
`with Norbomene and its Derivatives,” J. Chem. Soc., J .C.S. Perkin I.,
`1973, 977-981.
`Mathre et al., “A Practical Enantioselective Synthesis of 0t,0t-Diaryl
`2-pyrrolidinemethanol. Preparation and Chemistry of the Corre
`sponding Oxazaborolidines,” J. Org. Chem., 1991, 56:751-762.
`Mulzer et 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, l7(9):9ll-9l8.
`Pagenkopf, Brian L., “Substrate and Reagent Control of
`Diastereo selectivity in Transition Metal -Mediated Process: Develop
`
`ment of a Catalytic Photo Promoted Pauson-Khand Reaction,” Diss.
`Abstr. Int., 57(12):7535, 1977, Abstract.
`Pagenkopf et al., “Photochemical Promotion of the Intramolecular
`Pauson-Khand Reaction. A New Experimental Protocol for Cobalt
`Catalyzed [2 + 2 + l] Cycloadditions,” J. Am. Chem. Soc., 1996,
`118:2285-2286.
`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
`l l 19.
`Shambayati et al., “N-Oxide Promjoted Pauson-Khand Cyclizations
`at Room Temperature,” Tetrahedron Letters, 1990, 31(37):5289
`5292.
`Snell et a1 ., “Investigating the Effect of Impurities on Macromolecule
`Crystal Growth in Microgravity,” Crystal Growth & Design, 2001,
`1(2):151-158.
`Takano et 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.
`Zhang et al., “A Nickel(0)-Catalyzed Process for the Transformation
`of Enynes to Bicyclic Cyclopentenones,” J. Org. Chem., 1996,
`61:4498-4499.
`
`* cited by examiner
`
`2
`
`UT Ex. 2007
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`

`
`US 8,242,305 B2
`
`1
`PROCESS TO PREPARE TREPROSTINIL,
`THE ACTIVE INGREDIENT IN REMODULIN
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application claims priority from U.S. Provisional
`Patent Application 61/014,232, ?led Dec. 17, 2007, the entire
`contents of which are incorporated herein by reference.
`
`BACKGROUND
`
`The process comprises the following steps:
`(a) alkylating a compound of structure 11 with an alkylating
`agent to produce a compound of formula Ill,
`
`M1 L1
`OH
`
`(111)
`
`Yl—C—C—R7
`||
`||
`M1 L1
`OH
`
`H
`
`H
`
`H
`
`OH
`
`0(CH2)WCN
`
`wherein
`w:1, 2, or 3;
`Y1 is trans-CH:CHi, cis-CH:CHi, iCHZ
`(CH2)mi, or 4CECi; m is 1, 2, or 3;
`R7 is
`(1) 4CPH2P4CH3, wherein p is an integer from 1 to 5,
`inclusive,
`(2) phenoxy optionally substituted by one, two or three
`chloro, ?uoro, tri?uoromethyl, (C l-C3) alkyl, or (C 1-C3)
`alkoxy, with the proviso that not more than two sub stitu
`ents are other than alkyl, 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 sub stituted on the aromatic ring by one, two or three
`chloro, ?uoro, tri?uoromethyl, (Cl-C3)alkyl, or (C 1-C3)
`alkoxy, with the proviso that not more than two sub stitu
`ents are other than alkyl,
`
`wherein 4C(Ll)-R7 taken together is
`(1) (C4-C7)cycloalkyl optionally substituted by 1 to 3 (C1
`Cualkyl;
`(2) 2-(2-furyl)ethyl,
`(3) 2-(3 -thienyl)ethoxy, or
`(4) 3 -thienyloxymethyl;
`M1 is 0t-OH:[3-R5 or (x-Rsz?-OH or 0t-OR1:[3-R5 or (x-RS:
`[3-OR2, wherein R5 is hydrogen or methyl, R2 is an alco
`hol protecting group, and
`L1 is 0t-R3 : [3-R4, 0t-R4: [3-R3, or a mixture of0t-R3: [3-R4 and
`0t-R4: [3-R3, wherein R3 and R4 are hydrogen, methyl, or
`?uoro, being the same or different, with the proviso that
`one of R3 and R4 is ?uoro only when the other is hydro
`gen or ?uoro.
`
`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
`pounds possessing activities such as platelet aggregation inhi
`bition, gastric secretion reduction, lesion inhibition, and
`bronchodilation.
`Trepro stinil, the active ingredient in Remodulin®, was ?rst
`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.
`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. U.S. 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 ?led Feb. 8, 2008, discloses tre
`pro stinil treatment of pulmonary ?brosis. 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 ?led
`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 ?led Feb. 8, 2008 discloses treatment of asthma
`with treprostinil. U.S. Pat. Nos. 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 prostacyclin analogs.
`Because Treprostinil, and other prostacyclin derivatives
`are of great importance from a medicinal point of view, a need
`exists for an ef?cient process to synthesize these compounds
`on a large scale suitable for commercial production.
`
`20
`
`25
`
`30
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`
`40
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`55
`
`60
`
`SUMMARY
`
`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.
`
`65
`
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`US 8,242,305 B2
`
`3
`(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 IS
`
`(1:)
`
`(IVS)
`
`(d) reacting the salt from step (c) with an acid to form the
`compound of formula I.
`The present invention provides in another embodiment a
`process for the preparation of a compound of formula IV.
`
`(1V)
`
`20
`
`25
`
`30
`
`35
`
`The process comprises the following steps:
`(a) alkylating a compound of structureV with an alkylating
`agent to produce a compound of formula VI,
`
`40
`
`(V)
`
`45
`
`50
`
`(VI)
`
`55
`
`60
`
`O k CN
`
`(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
`
`65
`
`(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 de?ned 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 speci?ed,
`“a” or “an” means one or more.
`C 1_3-alkyl is a straight or branched alkyl group containing
`1-3 carbon atoms. Exemplary alkyl groups include methyl,
`ethyl, n-propyl, and isopropyl.
`C1_3-alkoxy is a straight or branched alkoxy group contain
`ing 1-3 carbon atoms. Exemplary alkoxy groups include
`methoxy, ethoxy, propoxy, and isopropoxy.
`C4_7-cycloalkyl is an optionally substituted monocyclic,
`bicyclic or tricyclic alkyl group containing between 4-7 car
`bon atoms. Exemplary cycloalkyl groups include but not lim
`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
`compounds which possess stability suf?cient to allow manu
`facture and which maintains the integrity of the compound for
`a suf?cient 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 as biohydrolyzable amides, biohydrolyZ
`able esters, biohydrolyzable carbamates, biohydrolyzable
`carbonates, biohydrolyzable ureides, and biohydrolyzable
`phosphate analogues (e.g., monophosphate, diphosphate or
`triphosphate).
`As used herein, “hydrate” is a form of a 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 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
`pharmaceutically acceptable, as de?ned above, and which
`possess the desired pharmacological activity. Such salts
`
`4
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`US 8,242,305 B2
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`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, tri?uoroacetic 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.
`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
`ceptate, gluconate, glutamate, glycollylarsanilate, hexa?uo
`rophosphate, hexylresorcinate, hydrabamine, hydrobromide,
`hydrochloride, hydroxynaphthoate, iodide, isothionate, lac
`tate, lactobionate, laurate, malate, maleate, mandelate, mesy
`late, methylbromide, methylnitrate, methylsulfate, mucate,
`nap sylate, nitrate, N-methylglucamine ammonium salt, 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 provides for a process for producing
`treprostinil and other pro stacyclin 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 puri?cation by column chromatography is eliminated,
`thus the required amount of ?ammable solvents and waste
`generated are greatly reduced. Furthermore, the salt forma
`tion is a much easier operation than column chromatography.
`Moreover, it was found that the product of the 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 pharmaceutically acceptable salt thereof.
`
`20
`
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`
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`
`50
`
`55
`
`(1)
`
`The process comprises the following steps:
`(a) alkylating a compound of formula II with an alkylating
`agent to produce a compound of formula III,
`
`65
`
`(11)
`
`(111)
`
`M1 L1
`OH
`
`Yl—C—C—R7
`||
`||
`M1 L1
`OH
`
`H
`
`H
`
`H
`
`OH
`
`O(CH2)WCN
`
`wherein
`w:l, 2, or 3;
`Y1 is trans-CH:CHi, cis-CHICHi, iCHZ
`(CH2)M*, 01‘ 4CEC*; m is l, 2, or 3;
`R7 is
`(1) 4CPH2P4CH3, wherein p is an integer from 1 to 5,
`inclusive,
`(2) phenoxy optionally substituted by one, two or three
`chloro, ?uoro, tri?uoromethyl, (C 1-C3) alkyl, or (C 1-C3)
`alkoxy, with the proviso that not more than two substituents
`are other than alkyl, 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, ?uoro, tri?uoromethyl, (Cl-C3)alkyl, or (C 1-C3)
`alkoxy, with the proviso that not more than two sub stitu
`ents are other than alkyl,
`
`wherein 4C(Ll)-R7 taken together is
`(l) (C4-C7)cycloalkyl optionally substituted by l to 3 (C1
`Cualkyl;
`(2) 2-(2-furyl)ethyl,
`(3) 2-(3 -thienyl)ethoxy, or
`(4) 3 -thienyloxymethyl;
`M1 is x-OH:[3-R5 or (x-Rsz?-OH or 0t-OR1:[3-R5 or (x-RS:
`B-ORz, wherein R5 is hydrogen or methyl, R2 is an alco
`hol protecting group, and
`L1 is 0t-R3 : [3-R4, (x-R4: [3-R3, or a mixture ofa-R3: [3-R4 and
`(x-R4: [3-R3, wherein R3 and R4 are hydrogen, methyl, or
`?uoro, being the same or different, with the proviso that
`one of R3 and R4 is ?uoro only when the other is hydro
`gen or ?uoro.
`(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
`
`5
`
`UT Ex. 2007
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`

`
`US 8,242,305 B2
`
`(1V)
`
`(d) reacting the salt from step (c) With an acid to form the
`compound of formula I.
`In one embodiment, the compound of formula I is at least
`90.0%, 95.0%, 99.0%.
`The compound of 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 Us. Pat. No. 6,441,
`245.
`
`Whereinn is 0, 1,2, or3.
`The compound of formula II can be prepared alternatively
`from a compound of formula XIII, Which is a cyclization
`product of a compound of formula XII as described in Us.
`Pat. No. 6,700,025.
`
`O z: m_ P:
`
`m E
`
`OBn
`
`O k COOH
`
`The process comprises
`(a) alkylating a compound of structureV With an alkylating
`agent such as ClCHZCN to produce a compound of formula
`VI,
`
`(V)
`
`(V1)
`
`O kCN
`
`(b) hydrolyZing the product of step (a) With a base such as
`KOH,
`(c) contacting the product of step (b) With a base B such as
`diethanolamine to for a salt of the following structure, and
`
`H0
`
`O
`k
`COOe
`
`(TIHACHZCHZOH);
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`One embodiment of the present invention is a process for
`the preparation of a compound having formula IV, or a
`hydrate, solvate, or pharmaceutically acceptable salt thereof.
`
`(d) reacting the salt from step (b) With an acid such as HCl
`65 to form the compound of formula IV.
`In one embodiment, the purity of compound of formula IV
`is at least 90.0%, 95.0%, 99.0%, 99.5%.
`
`6
`
`UT Ex. 2007
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`

`
`US 8,242,305 B2
`
`10
`bromide (36 g). The reaction mixture was stirred vigorously
`at room temperature (23120 C.) for 16-72 h. The progress of
`the reaction was monitored by TLC. (methanol/CH2C12; 1:9
`and developed by 10% ethanolic solution of PMA). After
`completion of reaction, the reaction mixture was ?ltered with/
`without Celite pad. The ?lter cake was washed with acetone
`(10 L). The ?ltrate 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 further puri?cation.
`
`Example 2
`
`Hydrolysis of BenZindene Nitrile
`
`In one embodiment, the process further comprises a step of
`isolating the salt of formula IVS.
`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” means thin layer chromatography.
`“HPLC” means high performance liquid chromatography.
`“PMA” means phosphomolybdic acid.
`“AUC” means area under curve.
`In view of the foregoing considerations, and speci?c
`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 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.
`
`EXAMPLES
`
`Example 1
`
`Alkylation of BenZindene Triol
`
`KZCO3, Bu4NBr
`Acetone, RT
`
`O kCN
`
`Name
`
`MW
`
`Amount
`
`Mol.
`
`Eq.
`
`Benzindene Triol
`KZCO3 (powder)
`CICHZCN
`Bu4NBr
`Acetone
`
`332.48
`138.20
`75.50
`322.37
`i
`
`1250 g
`1296 g
`567 g
`36 g
`29 L
`
`3.76
`9.38
`7.51
`0.11
`i
`
`1.00
`2.50
`2.0
`0.03
`i
`
`Celite®545
`
`i
`
`115 g
`
`i
`
`i
`
`55
`
`60
`
`A 50-L, three-neck, round-bottom ?ask equipped with a
`mechanical stirrer and a thermocouple was charged with ben
`Zindene triol (1250 g), acetone (19 L) and K2CO3 (powdered)
`(1296 g), chloroacetonitrile (567 g), tetrabutylammonium
`
`65
`
`Name
`
`MW
`
`Amount
`
`Mol.
`
`Eq.
`
`Benzindene Nitrile
`KOH
`Methanol
`
`371.52
`56.11
`i
`
`1397 g*
`844 g
`12 L
`
`1.0
`3.76
`4.0
`15.04
`i 4
`
`Water
`
`4
`
`4.25 L
`
`i 4
`
`*Note:
`This weight is based on 100% yield from the previous step. This is not isolated yield.
`
`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 benZindene nitrile in
`methanol (12 L) and a solution of KOH (844 g of KOH
`dissolved in 4 .25 L of water). The reaction mixture was stirred
`and heated to re?ux (temperature 72.20 C.). The progress of
`the reaction was monitored by TLC (for TLC purpose, 1-2 mL
`of reaction mixture was acidi?ed with 3M HCl to pH 1-2 and
`extracted with ethyl acetate. The ethyl acetate extract was
`used for TLC; Eluent: methanol/CH2C12; 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 with a solution of hydrochloric acid (3 M, 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.
`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 aqueous layer, ethyl acetate (22 L)
`was added and the pH of reaction mixture was adjusted to 1-2
`
`7
`
`UT Ex. 2007
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`

`
`US 8,242,305 B2
`
`11
`by adding 3M HCl (1.7 L) with stirring. The organic layer was
`separated and the aqueous layer was extracted with ethyl
`acetate (2><11 L). The combined organic layers were washed
`with water (3x10 L) and followed by washing with a solution
`of NaHCO3 (30 g of NaHCO3 dissolved in 12 L of water). The
`organic layer was further washed with saturated solution of
`NaCl (3372 g of NaCl dissolved in water (12 L)) and dried
`over anhydrous NaZSO4 (950-1000 g), once ?ltered.
`The ?ltrate was transferred into a 72-L reactor equipped
`with mechanical stirrer, a condenser, and a thermocouple. To
`the solution of treprostinil in reactor was added activated
`carbon (110-130 g). The suspension was heated to re?ux
`(temperature 68-700 C.) for at least one hour. For ?ltration, a
`pad of Celite® 545 (300-600 g) was prepared in sintered glass
`funnel using ethyl acetate. The hot suspension was ?ltered
`through the pad of Celite® 545. The Celite® 545 was washed
`with ethyl acetate until no compound was seen on TLC of the
`washings.
`The ?ltrate (pale-yellow) was reduced to volume of 35-40
`L by evaporation in vacuo at 50-55° C. for direct use in next
`step.
`
`Example 3
`
`Conversion of Treprostinil to Treprostinil
`Diethanolamine Salt (1:1)
`
`(I) EtOH, EtOAc
`(ll) Heptane Slurry
`
`-continued
`
`Ethanol
`
`Ethyl acetate
`
`Treprostinil Diethanolamine
`Salt (seed)
`
`i
`
`4
`
`i
`
`5.1 L
`
`i i
`
`35 L** i i
`
`12 g
`
`i i
`
`*Note:
`This weight is based on 100% yield from benzindene triol. It is not isolated yield. The
`treprostinil was carried from previous step in ethyl acetate solution and used as such for this
`step.
`
`The total volume ofethyl acetate should be in range 35-36 L (it should be 7 times the volume
`of ethanol used). Approximately 35 L of ethyl acetate was carried over from previous step
`and additional 1.0 L ofethyl acetate was used for rinsing the ?ask.
`
`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 diethanolamine (435 g). While stirring, the reac
`tion mixture was heated to 60-750 C., for 0.5-1.0 h to obtain
`a clear solution. The clear solution was cooled to 5515° 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 for 1 h. The suspension was cooled to 20120 C. overnight
`(over a period of 16-24 h). The treprostinil diethanolamine
`salt was collected by ?ltration using Aurora ?lter equipped
`with ?lter cloth, and the solid was washed with ethyl acetate
`(2x8 L). The treprostinil diethanolamine salt was transferred
`to a HDPE/ glass container for air-drying in hood, followed by
`drying in a vacuum oven at 5015° C. under high vacuum.
`At this stage, if melting point of the treprostinil diethano
`lamine salt is more than 104° C., it was considered polymorph
`B. There is no need of recrystallization. If it is less than 1040
`C., it is recrystallized in EtOH-EtOAc to increase the melting
`point.
`Data on Treprostinil Diethanolamine Salt (1:1)
`
`20
`
`25
`
`30
`
`35
`
`40
`
`Wt. of Treprostinil
`Wt. of
`Batch Benzindene Triol Diethanolamine Salt
`NO-
`(5%)
`(111) (g)
`
`1
`2
`3
`4
`
`45
`
`1250
`1250
`1250
`1236
`
`1640
`1528
`1499
`1572
`
`Yield
`(%)
`
`Melting point
`(° C-)
`
`88.00
`8200*
`80.42**
`85.34
`
`1043-1063
`105.5-107.2
`104.7-106.6
`105-108
`
`*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 was recrystallized, for this reason yield was lower.
`
`Example 4
`
`Heptane Slurry of Treprostinil Diethanolamine Salt
`(1 : 1)
`
`OH
`
`Name
`
`MW
`
`Amount
`
`Mol
`
`Eq
`
`Treprostinil
`Diethanolamine
`
`390.52
`105.14
`
`1464 g*
`435 g
`
`3.75
`4.14
`
`1.0
`1.1
`
`65
`
`Name
`
`Batch No.
`
`Amount
`
`Ratio
`
`Treprostinil
`Diethanolamine Salt
`Heptane
`Treprostinil
`Diethanolamine Salt
`Heptane
`
`1
`
`i
`2
`
`i
`
`3168 g
`
`37.5 L
`3071 g
`
`36.0 L
`
`1
`
`12
`1
`
`12
`
`8
`
`UT Ex. 2007
`SteadyMed v. United Therapeutics
`IPR2016-00006
`
`

`
`US 8,242,305 B2
`
`13
`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 of trepro stinil diethanolamine
`salt in heptane (35-40 L). The suspension was heated to
`70-800 C. for 16-24 h. The suspension was cooled to 22120 C.
`over a period of 1-2 h. The salt was collected by ?ltration
`using Aurora ?lter. The cake was washed with heptane (15-30
`L) and the material was dried in Aurora ?lter for 1 h. The salt
`was transferred to trays for air-drying overnight in hood until
`a constant weight of treprostinil diethanolamine salt was 10
`obtained. The material was dried in oven under high vacuum
`for 2-4 h at 50-55° C.
`Analyt1cal Data on and Treprostrnrl D1ethanolam1ne Salt
`
`.
`
`.
`
`.
`
`.
`
`.
`
`14
`-continued
`
`OH
`
`COOH
`
`(
`
`111
`
`)
`
`Test
`
`Batchl
`
`Batch 2
`
`Conforms
`I
`I
`IR I
`<0'1 4’ W/W
`Resldu? on Ignition (ROI)
`0.1% w/w
`Water content
`1050-1065" c.
`Melting point
`+3460
`Speci?c rotation M25589
`Organic volatile impurities
`
`COHEOHHS
`<0'1 4’ W/W
`0.0% w/w
`1045-10550 c.
`+350
`
`Ethan“
`Ethyl acetate
`H
`eptane
`HPLC (Assay)
`Diethanolamine
`
`NOt d?tw?d
`Not detected
`o
`<0.05 A) w/w
`100I4%
`Positive
`
`NOt d?tw?d
`<0.05% w/w
`o
`<0.05 A) w/w
`993%
`Positive
`
`Example 5
`
`_
`_
`_
`_
`_
`Conversron of Treprostrnrl D1ethanola