(12) United States Patent
`US 8,497,393 B2
`(10) Patent N0.:
`Batra et al.
`
`(45) Date of Patent: Jul. 30, 2013
`
`USOO8497393B2
`
`(54) PROCESS TO PREPARE TREPROSTINIL,
`THE ACTIVE INGREDIENT IN
`REMODULIN®
`
`(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 (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 US. 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.
`C07C 62/00
`C07C 65/00
`
`(2006.01)
`(2006.01)
`
`(52) US. Cl.
`USPC .......................................................... 562/466
`
`(58) Field of Classification Search
`None
`
`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 B1
`6,521,212 B1
`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
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`7,999,007 B2
`2002/0173672 A1
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`2007/0078095 A1
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`12/2011 Batra et a1.
`1/2012 Wade et a1.
`1/2012 Rothblatt et a1.
`
`CA
`CN
`CN
`EP
`EP
`EP
`EP
`EP
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`
`FOREIGN PATENT DOCUMENTS
`2 710 726 A1
`1/2012
`101891596 A
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`101891715 A
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`10/1979
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`5/1986
`0 175 450 B1
`3/1989
`0159 784 B1
`6/1989
`0 496 548 A1
`7/1992
`WO 98/39337 A1
`9/1998
`WO 99/21830 A1
`5/1999
`W0 03/070163 A2
`8/2003
`WO 2005/007081 A2
`1/2005
`WO 2007/134292 A2
`11/2007
`WO 2008/100977 A2
`8/2008
`WO 2009/117095 A1
`9/2009
`WO 2012/009816 A1
`1/2012
`
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`Aristoff et a1., “Synthesis of Benzopyran Prostaglandins, Potent
`Stable Prostacyclin Analogs, Via an Intramolecular Mistunobu Reac-
`tion,” Tetrahedron Letters, 1984, 25(36):3955-3958.
`Aristoff et a1., “Total Synthesis of a Novel Antiulcer Agent via a
`Modification of the Intramolecular Wadsworth-Emons-Wittig Reac-
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`Batra et a1., “Crystallization Process Development for a Stable
`Polymorph 0f Treprostinil Diethanolamine (UT-15C) by Seeding,”
`Organic Process Research & Development, 2009, 13:242-249.
`
`(Continued)
`
`Primary Examiner 7 Yevegeny Valenrod
`(74) Attorney, Agent, or Firm 7 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.
`
`22 Claims, No Drawings
`
`Liquidia - Exhibit 1004 - Page 1
`
`Liquidia - Exhibit 1004 - Page 1
`
`

`

`US 8,497,393 B2
`
`Page 2
`
`OTHER PUBLICATIONS
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`Hardinger et al., “Triply-Convergent Syntheses of Two Homochiral
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`Acetylenehexacarbonyl-dicobalt Complexes,
`(R1C2R2)C02(CO)6,
`with Norbornene and its Derivatives,” J. Chem. Soc., J.C.S. Perkin I.,
`1973, 977-981.
`Mathre et al., “A Practical Enantioselective Synthesis of ot,ot-Diaryl-
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`sponding Oxazaborolidines,” J. Org. Chem., 1991, 56:751-762.
`Moriarty et al., “The Intramolecular Asymmetric Pauson-Khand
`Cyclization as a Novel and General Stereoselective Route to
`Benzindene Prostacyclins: Synthesis of UT-15 (Treprostinil),” J.
`Org. Chem. 2004, 69, 1890-1902.
`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, 17(9):911-918.
`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,
`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.
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`41(24):5855-5860.
`Schore, Neil E., “Transition-Metal-Mediated Cycloaddition Reac-
`tions ofAlkynes in Organic Synthesis,” Chem. Rev., 1988, 88: 1081-
`1 1 19.
`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.
`Sorbera et al. “UT-15. Treatment of Pulmonary Hypertension Treat-
`ment of Peripheral Vascular Disease,” Drug of the Future, 2001,
`26(4), 364-374.
`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.
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`Alkoxide Directed Lithiation,” J. Org. Chem., 1989, 54:3730-3732.
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`Oxazaborolidine-Catalyzed Enantioselective Reduction ofKetones,”
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`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 OL-Lithionitriles to Benzynes,” J. Am. Chem.
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`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 INGREDIENT IN
`REMODULIN®
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a Continuation of US. application Ser.
`No. 12/334,731, filed Dec. 15, 2008, which claims priority
`from US. Provisional Patent Application 61/014,232, filed
`Dec. 17, 2007, the entire contents of which are incorporated
`herein by reference.
`
`BACKGROUND
`
`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 first
`described in US. 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, US. 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.
`US. 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. US. 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. US. patent application
`publication No. 2005/0165111 discloses treprostinil treat-
`ment of ischemic lesions. US. Pat. No. 7,199,157 discloses
`that treprostinil treatment improves kidney functions. US.
`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-
`pro stinil treatment ofpulmonary fibrosis. US. Pat. No. 6,054,
`486 discloses treatment of peripheral vascular disease with
`treprostinil. US. 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. US. application Ser. No.
`12/028,471 filed Feb. 8, 2008 discloses treatment of asthma
`with treprostinil. US. Pat. No. 7,417,070, 7,384,978 and US.
`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 ofgreat importance from a medicinal point ofview, a need
`exists for an efficient process to synthesize these compounds
`on a large scale suitable for commercial production.
`
`SUMMARY
`
`The present invention provides in one embodiment a pro-
`cess for the preparation of a compound of formula I, hydrate,
`solvate, prodrug, or pharrnaceutically acceptable salt thereof.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`(1)
`
`H
`
`Yl—C—C—R7
`||
`||
`M1
`L1
`OH
`
`H
`O(CH2)WCOOH
`
`The process comprises the following steps:
`(a) alkylating a compound of structure 11 with an alkylating
`agent to produce a compound of formula 111,
`
`(H)
`
`(111)
`
`Yl—C—C—R7
`||
`||
`M1
`L1
`OH
`
`Yl—C—C—R7
`||
`||
`M1
`L1
`OH
`
`H
`
`H
`
`H
`
`H
`
`OH
`
`O(CH2)WCN
`
`iCHZ
`
`wherein
`w:1, 2, or 3;
`Y1
`is
`trans-CH:CH7, cis-CH:CH7,
`(CH2)mis 01‘ *CEcig In 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, fluoro, trifluoromethyl, (C1-C3) alkyl, or (C1-
`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, fluoro, trifluoromethyl, (C 1-C3)alkyl, or
`(C1-C3)alkoxy, with the proviso that not more than
`two substituents are other than alkyl,
`(4) cis-CH:CH7CH27CH3,
`(5) 7(CH2)27CH(OH)%H3, or
`(6) 4(CH2)34CH:C(CH3)2;
`wherein 7C(L1)7R7 taken together is
`(1) (C4-C7)cycloalkyl optionally substituted by 1 to 3
`(Cr'C5)alkyl§
`(2) 2-(2-furyl)ethyl,
`(3) 2-(3-thienyl)ethoxy, or
`(4) 3-thienyloxymethyl;
`M1 is ot-OHzfi-R5 or ot-Rszfi-OH or ot-ORlzfi-R5 or
`ot-R5 :B-ORZ, wherein R5 is hydrogen or methyl, R2 is
`an alcohol protecting group, and
`L1 is ot-R3:[3-R4, ot-R4:[3-R3, or a mixture of ot-R3:[3-R4
`and ot-R4:[3-R3, wherein R3 and R4 are hydrogen,
`methyl, or fluoro, being the same or different, with the
`
`Liquidia - Exhibit 1004 - Page 3
`
`Liquidia - Exhibit 1004 - Page 3
`
`

`

`US 8,497,393 B2
`
`4
`
`(1V5)
`
`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 IS
`
`H
`
`Yl—C—C—R7
`||
`||
`M1
`L1
`
`(1:)
`
`5
`
`10
`
`OH (D
`
`H
`e
`0(CH2)wCOO
`
`HB
`
`15
`
`(d) reacting the salt from step (b) with an acid to form the
`compound of formula IV.
`
`DETAILED DESCRIPTION
`
`(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 20
`process for the preparation of a compound of formula IV.
`
`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,
`25 carriers, or steps may be present. Unless otherwise specified,
`“a” or “an” means one or more.
`
`30
`
`C1_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-
`35 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
`40 compounds which possess stability sufficient to allow manu-
`facture and which maintains the integrity ofthe compound for
`a sufficient period of time to be useful for the purposes
`detailed herein.
`
`As used herein, the term “prodrug” means a 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. Examples of prodrugs include, but are not
`limited to, derivatives of a compound that 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).
`As used herein, “hydrate” is a form of a compound wherein
`55 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-
`
`60
`
`65
`
`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 defined above, and which
`possess the desired pharmacological activity. Such salts
`
`Liquidia - Exhibit 1004 - Page 4
`
`(1V)
`
` O
`
`k
`
`COOH
`
`The process comprises the following steps:
`(a) alkylating a compound ofstructureV with an alkylating
`agent to produce a compound of formula VI,
`
`(V)
`
`(V1)
`
`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
`
`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.
`
`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, hexafluo-
`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 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 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 pharmaceutically acceptable salt thereof.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`(1)
`
`Yl—C—C—R7
`||
`||
`M1
`L1
`OH
`
`H
`
`H
`
`O(CH2)WCOOH
`
`The process comprises the following steps:
`(a) alkylating a compound of formula II with an alkylating
`agent to produce a compound of formula III,
`
`60
`
`65
`
`(11)
`
`(111)
`
`L1
`
`M1
`OH
`
`Yl—fi—fi—R
`M1
`L1
`OH
`
`H
`
`H
`
`H
`
`OH
`
`O(CH2)WCN
`
`wherein
`
`w:l, 2, or 3;
`
`Y1 is trans-CH:CH7, cis-CH:CH7, 4CH2(CH2)
`m7, or 4CEC7; m is l, 2, or 3;
`
`R7 is
`
`(l) 4CPH2P4CH3, wherein p 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
`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, fluoro, trifluoromethyl, (C 1-C3)alkyl, or
`(C1-C3) alkoxy, with the proviso that not more than
`two substituents are other than alkyl,
`
`(4) cis-CH:CH7CH27CH3,
`
`(5) 7(CH2)27CH(OH)%H3, or
`
`(6) i(CH2)3iCH:C(CH3)2§
`wherein 7C(L1)-R7 taken together is
`
`(l) (C4-C7)cycloalkyl optionally substituted by l to 3
`(C1-C5)a1ky1;
`(2) 2-(2-furyl)ethyl,
`
`(3) 2-(3-thienyl)ethoxy, or
`
`(4) 3-thienyloxymethyl;
`
`M1 is ot-OH:[3-R5 or ot-Rszfi-OH or ot-ORlzfi-R5 or
`ot-R5 :B-ORZ, wherein R5 is hydrogen or methyl, R2 is
`an alcohol protecting group, and
`
`L1 is ot-R3:[3-R4, ot-R4:[3-R3, or a mixture of ot-R3:[3-R4
`and ot-R4:[3-R3, wherein R3 and R4 are hydrogen,
`methyl, or fluoro, being the same or different, with the
`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 15
`
`Liquidia - Exhibit 1004 - Page 5
`
`Liquidia - Exhibit 1004 - Page 5
`
`

`

`US 8,497,393 B2
`
`(1:)
`
`(1V)
`
` 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
`
`
`
`.quIOH
`
`
`
`@ NH2(CH2CHZOH)2
`
`(d) reacting the salt from step (b) with an acid such as HCl
`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%.
`
`Liquidia - Exhibit 1004 - Page 6
`
`Yl—C—C—R7
`||
`||
`M1
`L1
`OH
`
`HB
`
`H
`
`H
`
`O(CH2)WCOOO
`
`(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.
`
`(X)
`
`(X1)
`
`0Rl
`
`\
`
`\
`
`Yl—C—C—R7
`||
`||
`M1
`L1
`
`0(CHZ),.CH3
`
`
`
`O(CH2),,CH3
`
`Whereinn 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
`product of a compound of formula XII as described in US.
`Pat. No. 6,700,025.
`
`(X11)
`
`(XIII)
`
`0Rl
`
`C\\C
`
`\
`
`\Yl—C—C—R7
`II
`II
`M1
`L1
`
`Yl—C—C—R7
`II
`II
`M1
`L1
`OH
`
`H
`
`H
`
`OBn
`
`OBn
`
`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.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`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 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 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 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
`
`
`
`C1
`k
`
`KZCO3, BU4NBr—>
`Acetone, RT
`HO
`
`
`
`Name
`
`MW
`
`Amount
`
`Benzindene Triol
`K2CO3 (powder)
`C1CH2CN
`Bu4NBr
`Acetone
`Celite ® 545
`
`332.48
`138.20
`75.50
`322.37
`7
`7
`
`1250 g
`1296 g
`567 g
`36 g
`29 L
`115 g
`
`Mol.
`
`3.76
`9.38
`7.51
`0.11
`7
`7
`
`Eq.
`
`1.00
`2.50
`2.0
`0.03
`7
`7
`
`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 K2CO3 (powdered)
`(1296 g), chloroacetonitrile (567 g), tetrabutylammonium
`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/CH2C12; 1:9
`and developed by 10% ethanolic solution of PMA). After
`completion ofreaction, the reaction mixture was filtered with/
`without Celite pad. The filter cake was washed with acetone
`(10 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 further purification.
`
`Example 2
`
`Hydrolysis of Benzindene Nitrile
`
`5
`
`10
`
`15
`
`20
`
`25
`
`
`
`50
`
`55
`
`60
`
`65
`
`Name
`
`Benzindene Nitrile
`KOH
`Methanol
`Water
`
`MW
`
`Amount
`
`371.52
`56.11
`7
`7
`
`1397 g*
`844g
`12 L
`4.25 L
`
`Mol.
`
`3.76
`15.04
`7
`7
`
`Eq.
`
`1.0
`4.0
`7
`7
`
`*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 ofwater). The reaction mixture was stirred
`and heated to reflux (temperature 72.20 C.). The progress of
`
`Liquidia - Exhibit 1004 - Page 7
`
`Liquidia - Exhibit 1004 - Page 7
`
`

`

`11
`
`US 8,497,393 B2
`
`12
`-continued
`
` H
`
`O
`
`4 e
`
`COO HzN
`
`9/
`
`OH
`
`OH
`
`Name
`
`MW Amount
`
`Mol
`
`Eq
`
`the reaction was monitored by TLC (for TLC purpose, 1-2 mL
`of reaction mixture was acidified 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 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.
`
`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 ofreaction mixture was adjusted to 1-2
`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
`ofNaHCO3 (30 g ofNaHCO3 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 NaZSO4 (950-1000 g), once filtered.
`The filtrate 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 reflux
`(temperature 68-700 C.) for at least one hour. For filtration, a
`pad ofCelite® 545 (300-600 g) was prepared in sintered glass
`funnel using ethyl acetate. The hot suspension was filtered
`through the pad of Celite®545. The Celite® 545 was washed
`with ethyl acetate until no compound was seen on TLC ofthe
`washings.
`The filtrate (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—>
`(H) Heptane Slurry
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`390.52
`105.14
`7
`7
`7
`
`1464 g*
`435 g
`5.1 L
`35 L**
`12 g
`
`3.75
`4.14
`7
`7
`7
`
`1.0
`1.1
`7
`7
`7
`
`Treprostinil
`Diethanolamine
`Ethanol
`Ethyl acetate
`Treprostinil Diethanolamine
`Salt (seed)
`*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.
`**Note:
`The total volume of ethyl acetate should be in range of 35-36 L (it should be 7 times the
`volume ofethanol used). Approximately35 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 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 filtration using Aurora filter equipped
`with filter 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
`
`Batch
`No.
`1
`2
`
`Wt. of
`Benzindene Triol
`(g)
`1250
`1250
`
`Wt. of Treprostinil
`Diethanolamine
`Salt (1:1) (g)
`1640
`1528
`
`Yield
`(%)
`88.00
`8200*
`
`Melting
`point
`(O C.)
`1043-1063
`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
`(° C.)
`
`1250
`1236
`
`1499
`1572
`
`8042’”
`85.34
`
`1047-1066
`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 was recrystallized, for this reason yield was lower.
`
`Example 4
`
`Heptane Slum of Treprostinil Diethanolamine Salt 1:1
`Name
`Batch No.
`Amount
`
`Ratio
`
`Treprostinil
`Diethanolamine Salt
`Heptane