|||||||||||||||||||||||||||l|||||||||||||||||||||||||||||||||||||||||||||||
`115009550716B2
`
`(12) United States Patent
`(10) Patent No.:
`US 9,550,716 32
`Giust et al.
`(45) Date of Patent:
`Jan. 24, 2017
`
`(54) PROCESS FOR 'I‘Rl-IPROS'I‘INII. SALT
`PREPARATION
`
`(25)
`
`Inventors: Walter Giust. Toronto (CA); Fabio
`Souza. Mississauga (CA); Jan
`Oudenes. Aurora (CA): Boris Gorin.
`Uakvillc (CA): Elena Bejan. Brantlord
`(135)
`
`(T3) Assignee: EON LABS, INC.. Princeton. NJ (US)
`
`( ’9‘ ) Notice:
`
`Subject to any disclaimer, the term ol'lhis
`patent
`is extended or adjustm] under 35
`11.3.0. 154(h) by 240 days.
`
`(21) Appl. No.:
`
`13520.37:
`
`(22)
`
`PL'l' I’llcil:
`
`Dec. 22. 2011
`
`PL'l' N11:
`§ 370 (0)0).
`(2). (4) Date:
`
`PC’UCA20111050804
`
`Oct. 8. 2013
`
`PCT Pub. No; “112012108860?
`PL'I Pub. Date: Jul. 5, 2012
`
`Prior Publication Data
`US 201410024856 A1
`Jan. 23. 2014
`
`(80)
`
`(82)
`
`(65)
`
`(30)
`
`Foreign Application Priority Data
`
`
`Dec. 30. 2010
`
`(CA)
`
`27215599
`
`(51)
`
`(52)
`
`(58)
`
`(513)
`
`lnt.(‘.|.
`('0 7(' 51/43
`('0 7(' 51/41
`
` [1.3. (.‘l.
`t‘l’t‘
`
`(2006.01)
`(2006.01)
`
`(“026' 51/412 (2013.01); (.‘t‘!?(.‘ 51/43
`(2013.01)
`
`Field of Classification Search
`None
`Sec application file for complete search history.
`
`References (Tired
`1L8. PA'I‘HN'I‘ IXXTUMl-iN'l‘S
`
`4.300.025 A
`4.486.598 .-\
`4.532.346 .-’\
`5.810.021 A
`5.950.715 A
`(1.132.249 Bl
`(1.441.245 151
`6.700.025 B2
`6.765.112 BE
`6.809.223 HZ
`7.321.388 B2
`2.417.020 152‘:
`2008-0249162 .-\l"’
`200930163238 .-’\1
`2011-0310641 AI
`2012-0192041 Al
`
`12.31981 Aristoii'
`12-"1984 Arisluil‘
`R-"IORS Duprc’?
`0.31008
`i‘avlin
`9.51999 Jonsson c! a].
`2-"2001 Bt'ost et al.
`852002 Moriarty e1 :11.
`312004 Moriarty et :11.
`7.32004 Moriarty c! al.
`1032004 Moriarty c! al.
`5.32008 Zhao et al.
`852008 Phares e1 :41.
`10.52008 Plun'es e1 :11.
`632009 Balm ct al.
`12-201 | Balm cl al.
`832012 Batra ct al
`
`.. 514532
`
`FOREIGN l’A'l'HN'l' 1X)(‘UM]~1N'I‘S
`
`(TA
`CA
`CA
`CA
`CA
`CA
`131’
`W0
`W0
`Wt)
`Wt.)
`
`1201112
`2 302 163 C
`2 R4? 985 A1
`2 698 721 Al
`TTTOTO
`2210220
`1 611 32 BI
`20043092552 A2
`2011151161
`20120119816
`201211886117
`
`3.1986
`5.51999
`5.31999
`3.32000
`125201 1
`1-2012
`12-‘2010
`10-2004
`12"2011
`1.2012
`7.5201 2
`
`OT] IER PUBLICATIONS
`
`Danisherskyct a1...|.Am.1.'l'ten't. Sou. 1117:1421-1423 i_|9b'5)."'1he
`total synthesis of Quinocarcinol Methyl Ester."
`Gould el aL..
`lnLernational Journal of Pharmaceutics 33201-21?
`(1936). "Still selection for basic drugs.”
`Green Ct 211.. "Protective groups in organics synthesis: Protection for
`thcHydroxyl gJ'oup. including 1.2- and .3 diols“. pp. 86-90. (1999).
`Third Edition.
`[Iorila ela1.'I'cIrahcr.1mn 42(11):?)021-3028 {1986). "()nthc selec-
`tivity of deproteetion of benzyl. nipm 94—methoxybenzy11 and
`11mpm (3.4«limethnxyhenvyl‘y protecting groups for hydroxy t‘une-
`lions.”
`Moriarty et a1.. 1019. Chem. 64108904902 (20041. "The Intramo-
`lecular Asymmetric [mttsun-ki‘tzuitl cyclimtin as a novel and general
`slereosclcctivc route to hen/indent: prostncyctins:
`synthesis or
`UT—lS treprostinil."
`Slahl et al.. Handbook on Pharmaceutical salts: Ploperties. selec-
`tion. and 1153.. pp. 214-210. 314. 315 Ftltt1322.t'2002).
`International Preliminary Report on Patentabilty on PCT-C'.—\2011-'
`050451. (ittlcrt Dec. 20. 2012.
`Written Opinion of the Interntniunal Search .-\ul.ltority PCT!
`CA2011r'050443. dated Sort. IS. 2011.
`Office Action, 'I'hirtl Party Submission under 3'? (IR 1.290, Dated
`Mar.2|.m14.pp.1-|.">1.1.'.S.App1.Xo.13-'811.301.
`Ofiicc Action. Third Pany Submission under 3‘." CFR 1.290. Dated
`Mar. 21, 2014, pp. 1-32. 1.5.App1. No. 13-"520,872.
`Ii. .1.. ct £11.. "Synthetic approaches to the 2002 new thugs" Mini
`reviews in Medicinal Chemistry. 2004. 207-233.
`Lukac et al. "The. methoxybenzyl ethers as useful plotecting groups
`for hythoxy eomlmumis: methods 01' tlepmtmztion.” Acta Facultatis
`l’hanrinoeulicae Liniwrsilntis Cotnenianne.
`'l'onius L11. 2005. p.
`31—32.
`Remodulation Injection Package Insert.
`11.8. Appl. No. 618231.115. fileti.1un.3. 2010.
`11.5. Appl. No. 133435.720. filed Mar. '50. 2012.
`11.8..\ppl.1\'n. 133151.465. tiled Jun. 2. 2011.
`11.5. r\ppl. No. 133811.301. filed Aug. 30. 2013.
`11.5. Appl. No. 133811305, filed Mar. 28. 2013.
`(Continued)
`
`Prirttrlr'll Exatrtiner — Sudhakar Katakani
`Assistant Et'rtmt'ner
`Jennifer C Sawyer
`(Ti-‘1} Attume}: Agent, or Firm — Nixon Peabody 1.1.11'
`A BSTR.“ IT
`
`(57}
`Disclosed is a process for preparing a trcprostinil salt. The
`process involves the step of dissolving treprostinil
`in a
`water-miscible organic solvent to form a trcprostinil solu-
`tion. The treprostinil solution is reacted with an aqueous
`basic solution containing an alkali metal cation to limit
`lreprostinil salt. Allowing crystallisation of the treproslinil
`salt to lake plaice. and then collecting the lrcprostinil sail
`formed.
`
`34 Claims. 1 Drawing Sheet
`
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR2017—01621
`
`UNITED THERAPEUTICS, EX. 2082
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`Page ‘1 of 7
`
`

`

`US 9,550,716 82
`Page 2
`
`(56)
`
`References Cited
`
`0'” ||-'.R PI PH] .I(T.N|'I()NS
`
`lJanishcfsky CI al. “The 10ml synthesis or quinnuaruinol methyl
`csler." J. 01' lhc American Chemical Sucjct}:
`I985. vol. 10?.
`MEI—I423.
`UmlltL "Salt selection for basic drugs." Inlcmalional Journal 01‘
`Pharmaceutics. 1986. 33:201—2l?.’[
`Stahl et 31.. Handbook ot'l’hammceulical Salts. 3003. pp. 214—316.
`314. 315 and 321+
`
`" cited by cxalnincr
`T cited by lhird party
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017—01621
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`UNITED THERAPEUTICS, EX. 2082
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`Page 2 of 7
`
`

`

`U.S. Patent
`
`Jan. 24, 2017
`
`US 9,550,716 32
`
`
`
`
`'2..AMHJVDIWA/M/X 3's.
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`I I I
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`
`
`
`13039;Lot:204qu2.SCAN:2.0f40._§3l0.02i1.2(59¢).Cu.{(maszgfififl1:02:1010mg__
`
`'25
`
`
`
`Two-Theta(deg)
`
`.20.
`
`I'
`
`
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`III
`
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`mmauem
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, |PR2017—01621
`
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`Page 3 of 7
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`

`

`US 9,550,716 B2
`
`1
`PROCESS FOR 'I‘REPROS'I‘INII. SALT
`PREPARATIOV
`
`CROSS REFERENCE TO RELATED
`APPI alt I.-’\'l"l( 1N S
`
`This application is a 35 U.S.C. §3Tl National Stage Entry
`Application of International Application No. PC'I't'CA2Ullt'
`050804. filed Dec. 22. 2011. which designates the US... and
`which claims benefit under 35 U.S.C. §119(b) of Canadian
`Patent Application No. 2,72ti.599. filed Dec. 30. 2010. the
`content of the above patent application is hereby expressly
`incorporated herein by reference into the detailed descrip-
`tion hereof in its entirety.
`
`It}
`
`IS
`
`'I'ECI INICAL FIELD
`
`2
`the art for a process Ior The synthesis oftreprostinil sodium.
`including a commercially viable process.
`SUMMARY ()|-'
`'1‘] H". lN\’|-'.N'I'I(1N
`
`In one aspect, the specification relates to a process for
`preparing a treprostinil salt, comprising:
`dissolving treprostinil in a water-miscible organic solvent
`to Form a treprostinil solution;
`reacting tlle trcprostinil solution with an aqueous basic
`solution containing an alkali metal cation to form a
`reaction mixture containing the treprostinil salt:
`allowing crystallization of the treprostinil salt: and
`collecting the treprostinil salt tonned.
`BRIEF DESCRIPTION OF 'I‘Hli- DRAWINGS
`
`This specification relates to a process for treprostinil salt
`preparation.
`
`21}
`
`BACKGROUND
`
`I shows a powder X—ray dilli'action spectrum of
`FIG.
`treprostinil
`sodium obtained according to the reaction
`described herein.
`
`DE'I‘AILHI) DESCRIPTION
`
`Proslacyclin derivatives are uselill pharmaceutical colit—
`pounds possessing pharmacological activities such as plate—
`let aggregation inhibition. gastric secretion reduction, lesion
`inhibition. vasodilation and hronchodilalion. 'l‘rcprostinil is
`a prostacyclin analogue, having the lollowing chemical
`structure:
`
`HOO(‘—\I)
`
`'-
`2.
`
`1—:
`
`s
`
`.-‘
`
`mum”
`CHI...11
`
`Ull
`
`'I'rcprostinil sodium solution is marketed as Remodelintléi-
`and 'I'yvasoR for treatment ol' pulmonary arterial hyperten—
`sion.
`Process for preparation of treprostinil. treprostinil deriva-
`tives and intermediates useful in preparation of treprostinil
`are described in US. Pat. Nos. 4,306,075: 6.700.025: 6,809,
`223 and b.?65.11?. U.S. Pat. No. 4.306.0T5 (col. 40. I.
`41-62) discloses a general procedure for preparation of
`pharmacologically acceptable salts of treprostinil. where
`preparation 01‘ an inorganic salt olilreprostinil can be carried
`out by dissolution of treprostinil
`in water. followed by
`neutralization with appropriate amounts ol‘ corresponding
`inorganic base. However. a commercially viable synthetic
`route for preparation of the sodiunt salt or trepnostinil
`is
`desired.
`Preparation of treprostinil sodium can be difllcult. as the
`salt is soluble in water and ditlicn It to precipitate. while the
`treproslinil acid is only sparingly soluble in water. Salts ol‘
`a compound can be uselul due in part
`to their increased
`stability. bioavailability and solubility in water. Availability
`ot‘treprostinil salt can also help in preparation ot‘a formu—
`lation. including a pharmaceutical formulation.
`'Iberefore. there is a need in the art for a process for the
`preparation ot'a salt 01‘ treprostinil. Moreover. there is a need
`
`9%
`
`ll}
`
`35
`
`40
`
`4 u
`
`it}
`
`55
`
`60
`
`I55
`
`As noted above. the specification relates to a process for
`preparing a Lreprostinil salt, tlte process containing the steps
`ol‘:
`dissolving treprostinil in a water-miscible organic solvent
`to fonn a treprostinil solution;
`roaming the Ireprostinil solution with an aqueous basic
`solution containing an alkali metal cation to form a
`reaction mixture containing the treprostinil salt:
`allowing crystallization of the trcprostinil salt'. and
`collecting the crystals of the treprostinil salt.
`The water-miscible organic solvent used for dissolving
`treprostinil is Itot particularly limited. and can contain one or
`more functional youps, as long as the organic solvent is
`miscible and can form a solution with water. In one etnbodi—
`ment, for example and without limitation. the water-miscible
`organic solvent is a water-miscible ketone solvent. water-
`miscible alcohol or water—miscible ether.
`In one embodiment. for example and without limitation,
`the water—miscible organic solvent
`is a waiter—miscible
`ketone solvent. 'Ihe number of carbon atoms in the water—
`Iniscible ketone solvent is not particularly limited but can be
`any number. as long, as the water-miscible ketone solvent is
`miscible in water. In one embodiment. the water-miscible
`ketone solvent contains from 3 to 8 carbon atoms. In another
`embodiment, for example and without limitation. the water—
`misciblc ketone solvent
`is a hydrocarbon based water-
`miscible ketone solvent. A hydrocarbon based water-mis-
`cible kctone solvent contains a ketonc functional group and
`a hydrocarbon chain having carbon and hydrogen atoms. In
`a further embodiment. for example and without limitation,
`the water—miscible ketone solvent
`is a linear or branched
`alkyl ketone. The number of carbon atoms in the alkyl
`ketone is not particularly limited and contain, for example
`and without limitation. 3 to 6 carbon atoms. In one embodi-
`ment, for example and without limitation. the water-miscible
`solvent is acetone.
`I'anlnplos ot‘ water—miscible ketone solvents for use in
`preparation of lrepmstinil salt can include. for example and
`without limitation, acetone. butanone. 2—penlunoue. 3—pen—
`tanone, methyl isopropyl ketone= Z—Iiettanone= 3—hexanone.
`methyl
`isobutyl ketono (MIIBKJ. ethyl
`isopropyl ketone.
`eyelopentanone. 2-methyl cyclopentanone. 3-methyl cyclo-
`pentanone1 cyclohexanone and others.
`
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR2017—01621
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`

`US 9,550,716 B2
`
`[U
`
`21}
`
`EU
`
`3
`In another embodiment. the water—miscible organic sol—
`vent
`is a water-miscible alcohol. The number of carbon
`atoms in the water—rtiiscihle alcohol is not particularly Iitri—
`iterl hilt can be any number1 as long as the alcohol is miscible
`in water.
`In one embodiment,
`for example and without
`limitation. the water—miscible alcohol contains From 3 to 8
`carbon atoms.
`In another embodiment,
`liir exaliiple anti
`without limitation. the water—miscible alcohol is a hydrocar—
`bon based water—miscible alcohol. A hydrocarbon based
`water-miscible alcohol contains an alcohol functional group
`and a hydrocarbon chain having carbon and hydrogen
`atoms. In a further embodiment. for cxample and without
`limitation. the watersmiscible alcohol is a linear or branched
`alkyl alcohol. The number of carbon atoms in the linear or
`branched hydrocarbon based alcohol
`is not particularly
`limited and contain. for example and without limitation. 3 to
`6 carbon atoms.
`In one embodiment.
`lor exatriple and
`without limitation. the water-miscible alcohol is methanol,
`ethanol, propanol, isopropanol and others.
`Similar to the water—miscible organic ketones solvent and
`water-miscible alcohols noted above. other water-nuscible
`organic solvents can also he used. Examples of other water—
`miscible organic solvents call
`include.
`lor exaritple and
`without limitation. tetrahydroi'urrm, acetonitrile and others.
`In addition. two or more organic solvents can also he used
`so long the organic solvents together are miscible in water.
`The ratio of treprostinil
`to the water—miscible organic
`solvent as described herein is not particularly limited. In one
`embodiment. for example and without limitation. the ratio of
`treproslinil to the water—miscible organic solvent is l g 01'
`treprostinil to from 5 to 50 mL ofthc water-miscible organic
`solvent. In another embodiment the ratio of lreprostinil to
`the water-miscible organic solvent
`is.
`for example and
`without limitation,
`l g ol‘treprostinil to from 15 lo 30 ml.ol'
`the water-miscible organic solvent.
`The aqueous basic solution for reaction with treprostinil
`to form tr'eprostinil salt contains an aqueous solution and a
`base. which can deprotonate carboxylic acid moiety of
`treprostinil. the base in the aqueous basic solution for use in
`the reaction described herein is not particularly limited and
`contains all anion and an alkali metal cation. In one cathodi—
`ment.
`for example and without
`limitation.
`the anion is
`hydroxide. carbonate or bicarbonate union. the alkali metal
`cation tor rise in the reaction described herein can be, for
`example and without limitation. lithium. sodium or potas—
`sium. Appropriate anion and alkali metal cation can be
`determined based on the reaction conditions and the desired
`treproslinil salt. In one embodiment, liir example arid with—
`out limitation. the aqueous basic solution contains sodium
`hydroxide for reaction with treprostinil to form treprostinil
`sodium.
`The concentration of the base in the aqucous basic solu-
`tion for reaction with treprostinil is not particularly limited.
`Suflicient concentration of the aqueous basic solution can be
`u.U:
`used to allow reaction with treprostinil and to allow lbnna— .
`tion of treprostinil salt. In one embodiment. for example and
`without limitation. the base in the aqueous hasic solution has
`a concentration of from about 2 to about 8 molar. In another
`embodiment. for example and without limitation. the base in
`the aqueous basic solution has a concentnttion ol‘Irom about
`5 molar.
`'lhe mole ratio 01' the base in the aqueous basic solution
`to treprostinil in the treprostinil solution is not particularly
`limited. the mole ratio used can be chosen to maximize
`yield. by reaction of the base with treprostinil turd allowing
`crystallization of treprostinil salt. In general. the ratio of the
`base to treprostinil used allows for deprotonation of trepro—
`
`40
`
`4."!
`
`.
`
`60
`
`4
`stinil. In one embodiment. ior example and without Iirriita—
`tion. the mole ratio of base in the basic solution to trepro-
`stitiil iii the treprostinil solution ranges Ii‘otn 1:]
`to 2:1.
`In
`another embodiment.
`the mole ratio of base in the basic
`solution to trepmstinil
`in the treprostinil solution is,
`tor
`example andwitliout limitation, about 1.05:1, 1.111 or I .211.
`The voltinietric ratio ol'tlie water—miscible organic solvent
`to the aqueous basic solution for preparation o l‘ treprostinil
`salt from treprioslinil is not particularly limited. The volu—
`metric ratio can be set to maximize yield and.’or quality of
`treprostinil salt obtained. In one embodiment. for example
`and without limitation. the volumetric ratio of the water-
`miscible organic solvent to the aqueous basic solution is
`from 10:1 to Y0:l. In another embodiment. the volumetric
`ratio 01‘ the water—miscible organic solvent to the aqueous
`basic solution is. for example and without limitation. about
`40:1.
`In one embodiment, the process for preparation oftrepro-
`stinil salt from treprostinil is carried out by warming the
`treprostiiiil solution prior to reaction of the treprostinil
`solution with the aqueous basic solution. The temperature
`the treproslitril solution is wanned is not particularly Iiirtited.
`In one embodiment. iiir example and without lltlllllllltll1,1l1t‘
`treprostinil solution is warmed up to about so" (T. prior to
`reacting it with the aqueous basic solution.
`In another
`embodiment,
`the treprostinil
`solution is warmed,
`for
`example and without limitation. up to about 30° C. prior to
`reacting it with the aqueous basic solution. The temperature
`the treprostinil solution is warmed can include all tempera-
`ture values between those noted above.
`The addition of reactants for performing the reaction of
`treprostinil in the treprostinil solution with the aqueous basic
`solution is not particularly limited. In one embodiment. for
`example and without limitation. the aqueous basic solution
`is added to the treprostinil solution for reaction with trepro-
`stinil.
`The temperature for carrying out the reaction of trepros-
`tinil
`iii
`the treprostinil solution with the aqueous basic
`solution is not particularly limited. In one embodiment. for
`example and without limitation, the reaction of the trepro-
`stitiil solution with the aqueous basic solution is carried out
`at an internal
`temperature below about oil“ t‘. In another
`embodiment. the reaction of the treprostinil solution with the
`aqueous basic solution is carried out at an internal tempera—
`ture. for example and without limitation. below about 30" C.
`The temperature For carrying out the reaction can include all
`values between those noted above.
`The reactitm ol‘treprostinil in the treprostinil solution with
`the aqueous basic solution as described herein can be carried
`out. for example and without limitation. by agitating the
`reaction. The rate 01‘ agitation for carryhig out the reaction
`is not particularly limited. The rate of agitation can be set to
`maximize yield andJ'or quality 01‘ treprostinil salt.
`In one
`embodiment. for example and without limitation. agitation
`is continued even al'ter allowing crystallization ol‘ trepr'os—
`tinil salt. The time period for the agitation is also not
`particularly limited arid can be, for example and without
`limitation. tor at least about 4 hours. In another embodiment,
`the agitation is carried out. tor example and without limi-
`tation. for about
`1 hour.
`The temperature at which the reaction mixture is agitated
`alter allowing crystallization ot'treptostinil still and prior to
`collecting lreprostitiil salt is not particularly limited. In one
`embodiment. for example and without limitation. the reac—
`tion mixture is agitated at room temperature.
`In another embodiment. the reaction mixture is cooled
`prior to collecting tmpmstinil salt. The temperature to which
`
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`US 9,550,716 B2
`
`5
`the reaction mixture is cooled prior to collecting treprostinil
`salt is not particularly limited and can be, for example and
`without lirrlilalion, from i] to 15° (7. In another embodiment.
`the Ienipemture to which the reaction mixture is ctmled prior
`to collecting treprustinil salt
`is. for example rind without
`limitation. 0 lo 5° C. In a timber embodiment, agitation can
`continued during the cooling of the reaction mixture.
`The time period for which the reaction mixture is cooled
`and-”or agitated prior to collecting, the crystals is not particu—
`larly limited. In one embodiment. for example and without
`limitation. the reaction mixture is cooled and agitatcd for
`about 5 hours. In another embodiment. the reaction mixture
`is cooled and agitated. for example and without limitation.
`about 1 hour.
`limited after
`The method of collecting lrteprtostinil salt
`completion oftlrc reaction is not particularly limited. In one
`embodiment, for example and without limitation. treprosli—
`nil salt is collected by vacuum filtration. In another embodi-
`ment. treprostinil salt collected is dried.
`Iii one embodiment.
`the treprostinil sodium can be
`obtained ii'om intermediate 1. as shown in scheme 1. Inter-
`Inediate 1
`is all-tylaled their hydroly'lied to obtain lrepmstioil.
`The reaction product obtained alter alkylatiorl call be. for
`example and without
`limitation, an ester.
`'l‘he treprostinil
`obtained is dissolved in a water—miscibleorganiic solvent and
`reacted with an aqueous basic solution. as described herein,
`to form treproslinil sodium. The treprostinil sodium is
`allowed to crystallize and then collected.
`
`H0
`
`H
`
`‘
`
`._
`
`0:I
`
`(ZN-I
`Intermediate 1
`
`lIUt K '—\I)
`
`Ital kylrdion
`CsH u —"
`3,1 liydmlysrs
`
`so:
`Formsrlon
`
`C311“
`
`511
`
`I:
`
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`
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`
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`Oil
`Trepi‘ostinil
`
`NuUUC —\t)
`
`H.
`
`-.
`
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`
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`
`i
`0"
`Treprostrriil sodium
`
`Fin
`
`6
`is not particu—
`The alkylalion method of intermediate 1
`larly limited and tlillerent methods can he used depending
`upon the synthetic route adopted. In one embodiment. for
`example arid without limitation. intermediate 1 is alkylated
`using a halo—acetate or an acetate having a leaving group at
`the alkyl moiety. In a further embodiment. the halo-acetate
`can be, for example and without limitation. broinoacetate or
`chloroacetate.
`The solvent for the alkylation reaction is not particularly
`limited and can be determined. In one embodiment. for
`example and without
`limitation, the alkylation reaction is
`carried otlt in acetone. In addition. the tilne and temperature
`for carrying ouL the alkylaliou reaction are also not particu—
`larly limited, and can be determined. In one embodiment, for
`example and without limitation, the reaction was carried out
`1211" about Ii'om 5 to 10 hours. In another embodiment. the
`reaction temperature can be, for example and without linii—
`tation. room temperature or from room temperature to about
`50° C. Upon completion.
`the reaction is worked up and
`purified using standard methodology to obtain treprostinil.
`EXAMPLES
`
`5
`
`[U
`
`21}
`
`9%
`
`The following examples are illustrative and non—limiting
`and represent speci lie embodiments of the present invention.
`
`Hi}
`
`40
`
`4."!
`
`u.U:
`
`60
`
`Example 1
`
`'l'rcprostinil Preparation
`
`A nrixture of Intermediate 1 {3.8 g: 11.3 nunoL), methyl
`brornoaectate (2.2 g; 14.1 mlnol.) and potassium carbonate
`(3.1 g: 22.4 Innrol.) in acetone {30 nil.) was retluxed for (1.5
`hours and then cooled to room temperature. The reaction
`mixture was filtered and the cake was washed forward with
`acetone. The filtrate was concentrated and dried under high
`vacuum to give 4.5 *3, ol‘ intermediate 2 (having a methyl
`ester acetate) that was carried forward without purification.
`Methanol-Water mixture (16 Juli] 6 ml.) was added to
`intermediate 2 and potassium hydroxide (0.63 g; 15.8
`mmoI.). The reaction mixture was refluxed for 2 hours then
`cooled to room temperature. Aqueous 2M hydrochloric acid
`(10 ml .1 was added to adjust the p11 to 1-2. The slurry was
`stirred ovcmjght. filtered and washed with a mixture of
`methanolfwater (40 ml... 1:1) and 2x10 ntL water. The solid
`was dried under vacuum to give Treprostinil as a white solid
`(4.0 g; 90%).
`
`Example 2
`
`Treprostinil Sodium Salt Preparation
`
`A 100 ml round bottom flask was charged with Trepros—
`tinil (1.021 g, 2.61 mmol) followed by 25 ml acetone. This
`solution was wanned up to 30“ C'. and added ol‘SM Sodium
`hydroxide (0.61 nil. 3.05 inniol} dropwise while maintaining.
`an internal temperature below 30“ C. The pH of the solution
`was maintained at 8-9. After 15 minutes under agitation. a
`fiber like solid began to crystallize from the reaction mix-
`ture.'l'|1e mixture was stirred for 1 hour at room temperature
`then cooled to (1—5” t‘. and stirred at this temperature for
`another hour. 'lhe solid was Collected by vacuum filtration,
`rinsed with acetone and dried under vacuum ovemight
`to
`yield [1.95 g of a white solid. (purity: 99.67% by l-Il’IITL
`yield: 88%; Sodium content
`(ICP): 6.05% wfw). Powder
`X-ray diffraction spectra of the treprostinil sodium is shown
`in FIG. 'I.
`
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR2017—01621
`
`UNITED THERAPEUTICS, EX. 2082
`
`Page 6 of 7
`
`

`

`US 9,550,716 B2
`
`7
`
`'lhe invention claimed is:
`1. A process for preparing a treproslinil salt. comprising:
`dissolving treprostinil
`in a solvent. wherein the solvent
`consists essentially ofa water—miscible organic solvent.
`to lorrn a treprostinil solution. wherein the water—
`miseiblc organic solvent
`is selected from a water-
`miscible ketone. at water—miscible ether or acetonitrile;
`reacting the treprostinil solution with an aqueous basic
`solution containing an alkali metal cation to form a
`reaction mixture containing the treprostini] salt;
`allowing crystallization of tile treprostinil salt: and
`collecting the treprostinil salt formed.
`2. The process according to claim 1. wherein the water-
`miscible organic solvent
`is a hydrocarbon based water-
`miscible ketone solvent.
`3. The process according to claim 1. wherein the water-
`miscible ketone solvent is a linear or branched alkyl ketone.
`4. The process according to claim 'I, wherein the water—
`miscible ketonc solvent is acetone.
`5. The process according to claim I. wherein the water-
`miscible organic solvent is tetrahydroiilran.
`6. The process according to claim 1. wherein ratio of
`trcprostinil to the water-miscible organic solvent is l g 01'
`treprostinil to front 5 to 100 mL of the water-miscible
`organic solvent.
`7. The process according to claim 1, wherein ratio of
`treprostinil to the water—iniscible organic solvent is l g of
`treprostinil
`to from 15 to 50 ml. of the water—miscible
`organic solvent.
`8. The process according to claim 'I. wherein the aqueous
`basic solution contains hydroxide, carbonate or bicarbonate
`union.
`9. The process according to claim 1. wherein the alkali
`metal cation is lithium, sodium or potassium.
`1“. The process according to claim I, wherein the alkali
`metal cation is sodium.
`11 . The process according to claim 1. wherein the aqueous
`basic solution contains sodium hydroxide.
`12. The process according to claim I. wherein the base in
`the aqueous basic solution has a concentration ofii'om about
`2 to about 8 molar.
`13. The process according to claim I, wherein the base in
`the aqueous basic solution has a concentration 01‘ about 5
`molar.
`14. The process according to claim 1, wherein mole ratio
`of base in the aqueous basic solution to treprostinil ranges
`front 1:1 to 2:1.
`
`15. The process ' ‘cording to claim 1, wherein mole ratio
`of base in the aqueous basic solution Io lreprostinil is about
`1.1:].
`
`It}
`
`21}
`
`31}
`
`40
`
`4."!
`
`8
`16. The process according to claint 1. wherein volumetric
`ratio of the water-miscible organic solvent to the aqueous
`basic solution is from 10:] to 70:1.
`1'7. The process according to claim 1. wherein volumetric
`ratio ol' the water—miscible organic solvent to the aqueous
`basic solution is about 40:1.
`18. The process according to claim 1. wherein the trepro—
`stinil salt is treprostinil sodium.
`19. The process according to claim 1. lilrther comprising
`wamiing the treproslinil solution up to about 60" (i. prior to
`reacting it with the aqueous basic solution.
`20. The process according to claint 1. furtlter comprising
`warming the treprostinil solution up to about 30° C. prior to
`reacting it with the aqueous basic solution.
`2|.'l‘hepmoessacuirtlingtoclaim l,wherein the aqueous
`basic soltaion is added to the lreprostinil solution I'or reac—
`tion therewith.
`22. The process according to claim 1. wherein the reaction
`of the treprostinil solution with the aqueous basic solution is
`utrried out at an internal temperature below about 60° C.
`23. The process according to claim 1. wherein the reaction
`o 1‘ Lhe treprostinil solution with the aqueous basic solution is
`carried out at an internal temperature below about 30° C.
`24. The process according to claim 1, wherein the reaction
`of the treprostinil solution with the aqueous basic solution is
`agitated.
`25. The process according to claim 1. wherein after
`allowing crystallization of trcprostinil salt.
`the reaction
`mixture is agitated for at least about 4 hours.
`26. The process according]
`to claim 1. wherein after
`allowing crystalliyation ol' the lreprostinil salt. tlte reaction
`mixture is agitated for about 1 hour.
`27. The process according to claim 25. wherein the
`agitation is carried out at room tempemtnre.
`28. ‘lhe process according to claim 1.
`l‘urthcr comprising
`cooling the reaction mixture from 0 to 1.")3 C. prior to
`collecting Ihe crystals.
`29. The process according to claint 1. further comprising
`cooling the reaction mixture from U to 5" C. prior to
`collecting the crystals.
`30. The process according to claim 28. further comprising
`agitating the reaction mixture during cooling.
`3 I. The process according to claitn 30. wherein the
`solution is cooled and agitated for about 5 hours.
`32. The process according to claitn 3 I. wherein the
`solution is cooled and ag‘tated for about 1 hour.
`33. The process according to claim 1. wherein the trepro—
`stinil salt is collected by vacuum filtration.
`34. The process according to claim 1, wherein the trepro-
`stitiil salt collected is dried.
`*****
`
`
`
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR2017—01621
`
`UNITED THERAPEUTICS, EX. 2082
`
`Page 7 of 7
`
`