Case 3:14-cv-05499-PGS-LHG Document 41-5 Filed 07/07/15 Page 1 of 19 PageID: 403
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`Exhibit 2
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`Case 3:14-cv-05499-PGS-LHG Document 41-5 Filed 07/07/15 Page 2 of 19 PageID: 404
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`Case 3:14-cv-05499-PGS-LHG Document 41-5 Filed 07/07/15 Page 3 of 19 PageID: 405
`405
`Case 3:14-cv-05499-PGS-LHG Document 41-5 Filed 07/07/15 Page 3 of 19 Page|D:
`
`(12) United States Patent
`Batra et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,497,393 B2
`Jul. 30, 2013
`
`US008497393B2
`
`(54) PROCESS T0 PREPARE TREPROSTINIL,
`THE ACTIVE INGREDIENT IN
`REMODULIN®
`
`(75)
`
`Inventors: Hitesh Batra, Hcrndon, 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, M) (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.N0.: 13/548,446
`
`(22) Filed:
`
`Jul. 13, 2012
`
`(65)
`
`Prior Publication Data
`US 2012/0283470 Al
`Nov. 8, 2012
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 12/334,731, filed on
`Dec. 15, 2008, now Pat, No. 8,242,305.
`
`(60) Provisional application No. 61/014,232, filed on Dec.
`17, 2007.
`
`(51)
`
`(2006.01)
`(2006.01)
`
`
`Int. Cl.
`co7c 62/00
`C07C 65/00
`(52) U.S. C1.
`..................... .. 562/466
`USPC
`(58) Field of Classrficatron Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
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`2 710 726 A1
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`CA
`101891596 A
`ll/2010
`CN
`101891715 A
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`10/1979
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`0 087 237 B1
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`11/2007
`W0 W0 2008/100977 A2
`8/2008
`W0 W0 2009/ 1 17095 A1
`9/2009
`W0
`WO 2012/009816 Al
`1/2012
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`Polymorpli of Treprostinil Dietlianolamine (UT-15C) by Seeding,”
`Organic Process Research & Development, 2009. 13 :242-249.
`
`(Continued)
`
`Primary Examiner — Yevegeny Valenrod
`(74) Attorney, Agent, or firm — Foley & Lardner LLP
`
`ABSTRACT
`(57)
`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 trepr0sti-
`1111 via salts of treprostinil and to purify treprostinil.
`
`22 Claims, No Drawings
`
`
`
`Copy provided by USPTO from the PIRS Image Database on 03/24/2015
`
`UTC_REM_||_000003354
`
`

`
` Case 3:14—cv—O5499—PGS—LHG Document 41-5 Filed 07/07/15 Page 4 of 19 Page|D:
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`Case 3:14-cv-05499-PGS-LHG Document 41-5 Filed 07/07/15 Page 4 of 19 PageID: 406
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`Page 2
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`OTHER PUBLICATIONS
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`Acetylenehexacarbonyl-dicobalt Complexes,
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`1973, 977-981.
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`Moriarty et al., “The Intraniolecular Asymmetric Pauson-Khand
`Cyclization as a Novel and General Stereoselective Route to
`Benzindene Pro stacyclins: Synthesis of UT-15 (Trepro stinil)," 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.
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`ment of Peripheral Vascular Disease,” Drug of the Future, 2001.
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`
`
`
`P UTC_REM_||_00000335
`
`
`Copy provided by USPTO from the PIRS Image Database on 03/24/2015
`
`

`
`
`Case 3:14-cv-05499-PGS-LHG Document 41-5 Filed 07/07/15 Page 5 of 19 Page|D: 407 ii
`Case 3:14-cv-05499-PGS-LHG Document 41-5 Filed 07/07/15 Page 5 of 19 PageID: 407
`
`
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`US 8,497,393 B2
`
`PROCESS T0 PREPARE TREPROSTINIL,
`THE ACTIVE INGREDIENT IN
`REMODULIN®
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`5
`
`This application is a Continuation of U.S. application Ser.
`No. 12/334,731, filed Dec. 15, 2008, which claims priority
`from U.S. Provisional Patent Application 61/014,232, filed 10
`Dec. 17, 2007, the entire contents of which are incorporated
`herein by Ieferencg
`
`BACKGROUND
`The present invention relates to a process for producing 15
`prosta
`clin derivatives and novel intermediate com ounds
`usefiilc'iii the process.
`P
`i
`Prostacyclin derivatives are useful pharmaceutical com-
`pounds possessing activities such as platelet aggregation inhi-
`bition, gastric secretion reduction,
`lesion inhibition, and 20
`bronchodilation.
`Treprostinil, the active ingredient inRemodulin®, was first
`described in U.S. Pat. No. 4,306,075. Treprostini], and other
`prostacyclin derivatives have been prepared as described in
`Moriarty, et al inJ. Org. Chem. 2004, 69, 1890-1902, Drug of 25
`the Future, 2001, 26(4), 364-374, U.S. Pat. Nos. 6,441,245,
`6,528,688, 6,765,117 and 6,809,223. Their teachings are
`incorporated by reference to show how to practice the
`embodiments of the present invention.
`U.S. Pat. No. 5,153,222 describes use of treprostinil for
`treatment of pulmonary hypertension. Treprostini]
`is 30
`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 oftreprostinjl by inhalation for
`treatment of pulmonary hypertension, peripheral vascular 35
`disease and other diseases and conditions. U.S. Pat. No.
`6,803,386 discloses administration oftreprostinil for treating
`cancer such as lung, liver, brain, pancreatic, kidney, prostate,
`breast, colon and head-neck cancer. U.S. patent application
`ptiblicatioii No, 2005/0165111 discloses treprostinil treat- 40
`s::t;‘.§.:::‘sn::i::::.‘i;:;.E::§:iZ;;9%.ti;:;:?%i:f
`.
`.
`.
`.
`.
`patent application publication No. 2005/0282903 discloses
`treprostinil treatment of neuropathic foot ulcers. U.S. appli-
`cation Ser. No. 12/028,471 filed Feb. 8, 2008, discloses tre-
`prostinil treatment ofpulmonary fibrosis. U.S. Pat. No. 6,054,
`486 discloses treatment of peripheral vascular disease with
`treprostinil. U.S. patent application Ser. No. 1 1/873,645 liled
`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. 50
`,
`_
`,
`_
`.
`publication No. 200870280986.discloses treatrnent of inter-
`stitial lung disease with treprostinil. U.S. application Ser. No.
`12/028,471 filed Feb. 8, 2008 discloses treatment of asthma
`withtreprostinil. U.S. Pat. No. 7,417,070, 7,384,978 and U.S.
`publication Nos. 2007/0078095, 2005/0282901, and 2008/ 55
`0249167 describe oral formulations oftreprostinil and other
`p1~(§tacyc1inana1c,gs,
`1
`d th
`1
`d
`are ofgreatimportancefiomamedicinalpointofView,aneed
`ecause Treprostini , an 0 er prostacyc in erivatives
`exists for an efficient process to synthesize these compounds 60
`on a large scale suitable for commercial production.
`
`45
`
`SUMMARY
`
`The present invention provides in one embodiment a pro-
`cess for the preparation ofa compound of formula I, hydrate,
`solvate, prodrug, or phaimaceutically acceptable salt thereof.
`
`05
`
`;
`
`l [
`
`3
`
`2
`
`H
`
`(1)
`
`Y1-l9i—fi—Rv
`M1
`L‘
`OH
`
`H
`O(CH2),.,CO0H
`
`_
`_
`_ ,
`llie process comprises the following steps:
`(a) alkylating a compound of structure Il withan alkylatiiig
`agent to produce a compound of formula III,
`
`(II)
`
`(111)
`
`Y1_C_'C"'R7
`IUI
`|L|
`I
`I
`OH
`
`Y _C__C_R
`1
`7
`M1
`L,
`OH
`
`H
`
`II
`
`H
`
`H
`
`0H
`
`O(C1iz)wCN
`
`.
`11
`W erem
`_
`,
`W:1’.2= or 33
`°15‘CH:CH—a ‘CI12
`Y1
`15 T”‘115'C'H:CH“‘a
`(CH2)m'*a OT -'CECm§ In 15 1, 2, 01‘ 3;
`R7 is
`(1) —C,,H,P——CH3, wherein p is an integer from 1 to 5,
`jnchlsivej
`(2) phenoxy optionally substituted by one, two or three
`;gi°w=<C-Cs>
`3)alkoxy, with the proviso that not more than two
`b .
`th
`11
`IL 1
`filth
`.
`h
`5“ Ftltuents are 0 ert an a V ’ W1
`e pmvlmt at
`R7 is phenoxy or substituted phenoxy, only when R3
`and R4 are hydrogen or methyl, being the same or
`different,
`(3) phenyl, benzyl, phenylethyl, or phenylpropyl option-
`ally substituted on the aromatic ring by one, two or
`three chloro, fluoro, trifluoromethyl, (C1-C3)a1kyl, or
`(C C )a1kOX
`-th th
`-
`—
`y, W]
`e proviso that not more than
`twlo Susbsfiments are other than alkyl
`(4\
`. CH_CH CH
`CH
`’
`) ms‘
`”' — 2:C 3’
`(5? *7 (CH2)2—CH(0H)
`H2= 0’
`_
`(6) ~§CHz)3~CH=C(CHs)z;
`Wham“ —C(Li)—R7 taken mgefllel‘ 15
`(1)(éC4‘;C),.;1c1y;iloalkyl optionally substituted by 1 to 3
`(2) 2-(2-fiJr,V1)ethy1,
`1-
`is
`;
`(3) 2-(3411-l€13Y1)€Th0Xy,
`(4) 3-thicnyloxymethyl;
`M,
`is or-OI-l:[3-R5 or 0.-R528-OH or (1-OR1:[5-R5 or
`or-R :[3-OR2, whereinR is hydrogen or methyl, R is
`an aicohol protecting griiup, and
`2
`L1 is on-R3:[3—R4, on-R413-R3, or a mixture of or-R3: [3-R4
`and 0.-R4:[3-R3, wherein R3 and R4 are hydrogen,
`methyl, or fluoro, being the same or different, with the
`
`OI
`
`
`
` Copy provided by USPTO from the PIRS Image Database on 03/24/2015
`UTC_RE—|\/|_||_000003356
`
`
`

`
`Case 3:14-cv-05499-PGS-LHG Document 41-5 Filed 07/07/15 Page 6 of 19 PageID: 408
`
` Case 3:14—cv—O5499—PGS—LHG Document 41-5 Filed 07/07/15 Page 6 of 19 Page|D:
`
`US 8,497,393 B2
`
`3
`proviso that one of R3 and R4 is fluoro only when the
`other is hydrogen or fluoro.
`(b) hydrolyzing the product of step (a) with a base,
`(C) Contacting the product of step (b) with a base B to for a
`salt of formula Is
`
`as)
`
`H
`
`Y,—c——c ——R7
`H
`H
`M] M
`OH
`
`H
`9
`O(CH2)wCO0
`
`I};
`
`(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.
`
`10
`
`15
`
`20
`
`(IV)
`
`25
`
` O
`
`K
`
`COOH
`
`The process comprises the following steps:
`(a) alkylating a compound of structureV with an alkylating
`agent to produce a compound offormula VI,
`
`(V)
`
`(VI)
`
`
` O
`
`KCN
`
`(b) hydrolyzing the product of step (a) with a base,
`(c) contacting the product of step (b) with a base B to for a
`salt of formula IVS, and
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`(IVS) A
`
`
`
`(d) reacting the salt from step (b) with an acid to form the
`compound of formula IV.
`
`DETAILED DESCRIPTION
`
`The various terms used, separately and in combinations, in
`the processes herein described are defined below.
`The expression “comprising” means “including but not
`limited to.” Thus, other non-mentioned sub stances, additives,
`carriers, or steps may be present. Unless otherwise specified,
`“a” or “an" means one or more.
`
`C,,3—alkyl is a straight or branched alkyl group containing
`1-3 carbon atoms. Exemplary alkyl groups include methyl,
`ethyl, i1-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.
`CM-eycloalltyl is an optionally substituted rnonocyclic,
`bieyelic or tricyclic alkyl group containing between 4-7 car-
`bon atoms. Exemplary cycloallcyl 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 suflicicnt to allow manu-
`facture and which maintains the integrity ofthe compound for
`a su [Ileient 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 ofprodrugs 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 urcidcs, and biohydrolyzable
`phosphate analogues (e.g., monopho sphate, dipho sphate or
`triphosphate).
`As used herein, “hydrate” is a form ofa compound wherein
`water molecules are combined in a certain ratio as an integral
`part of the structure complex of the compound.
`As used herein, “solvate” is a form of a compound where
`solvent molecules are combined in a certain ratio as an inte-
`gral part of‘ the structure complex of the compound.
`“Pharmaceutically acceptable” means
`in the present
`description being useful in preparing a pharmaceutical com-
`position that is gcnerally 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
`
`Copy provided by USPTO from the PIHS Image Database on 03/24/2015
`
`I EE
`
`:
`
`
`
`,5‘
`§
`J
`
`1I
`
`UTC_REM_||_000003357
`
`
`

`
`
`
`5
`include acid addition salts fonnedwithorganic 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. Ease addition salts may be formed with organic and
`inorganic bases, such as sodium, ammonia, potassium, cal-
`cium, ethanolamine, diethanolamine, N—metl1ylglucamine,
`choline and the like. Included in the invention are pharrna-
`ceutically acceptable salts or compounds of any of the for-
`mulae herein.
`
`Depending on its structure, the phrase “pharmaceutically
`acceptable salt,” as used herein, refers to a pharmaceutically
`acceptable organic or inorganic acid or base salt of a com-
`pound. Representative pharmaceutically acceptable salts
`include, e.g., alkali metal salts, alkali earth salts, ammonium
`salts, water-soluble and water-insoluble salts, such as the
`acetate,
`amsonate
`(4,4-diaminostilbene-2,2-disulfonate),
`benzenesulfonate, benzonate, bicarbonate, bisulfate, bitar-
`trate, boratc, 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, hydrobromidc,
`hydrochloride, hydroxynaphthoate, iodide, isothionate, lac-
`tate, laetobionate, laurate, rnalate, maleate, mandclate, mesy—
`late, niethylbromide, methylnitrate, methylsulfate, mucate,
`nap sylate, nitrate, N-mcthylglucamine ammonium salt, 3-hy-
`droxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1, l -
`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 prostacyclin derivatives and novel inter-
`mediate compounds useful
`in the process. The process
`according to the present invention provides advantages on
`large-scale synthesis over the existing method. For example,
`the purification by column chromatography is eliminated,
`thus the required amount of flammable solvents and waste
`generated are greatly reduced. Furthermore, the salt forma-
`tion is a 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
`
`30
`
`35
`
`45
`
`50
`
`55
`
`(1)
`
`Y,—c—c—R,
`
`II IIM, L,
`on
`
`H
`
`ll
`
`0(CH2]wCOOH
`
`The process comprises the following steps:
`(a) alkylating a compound of formula 11 with an alkylating
`agent to produce a compound of formula III,
`
`60
`
`65
`
`(13)
`
`H
`
`Y,—C—C—R7
`
`
`|| IIM, L,
`on
`
`H
`
`H
`
`H
`
`OH
`
`O(CH2),,,CN
`
`(111)
`
`"“i‘i""’
`lVl1
`L]
`()1-1
`
`wherein
`
`w=1,2,or3;
`
`Y, is trans-CH=CI-I —, cis-CH:CH—, ~—CH2(CH2)
`m—, or -—CEC—; m is 1, 2, or 3;
`R7 is
`
`(1) —CPH2,,~CH3, wherein p is an integer from 1 to 5,
`inclusive,
`
`(2) phenoxy optionally substituted by one, two or three
`chloro, fluoro, trifiuoromethyl, (C1-C3) alkyl, or (C_-
`C3)alkoXy, with the proviso that not more than two
`substituents are other than alkyl, with the proviso that
`R, is phenoxy or substituted phenoxy, only when R3
`and R4 are hydrogen or methyl, being the same or
`different,
`
`(3) phenyl, benzyl, phenylethyl, or phenylpropyl option-
`ally substituted on the aromatic ring by one, two or
`three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or
`(C1-C3) alkoxy, with the proviso that not more than
`two substituents are other than alkyl,
`
`(4) cis-CH=CH—CH2—CH3,
`(5) —{CH2)2—CH(OH)—CH3, or
`(6) —(CH2)3—CHi(CH3)29
`wherein ~C(L,)-R7 taken together is
`(1) (C4-C7)cycloalkyl optionally substituted by 1 to 3
`(C1'C5)a]-kyli
`(2) 2-(2-furyl)cthyl,
`(3) 2-(3-thienyl)ethoxy, or
`(4) 3-thienyloxymcthyl;
`M,
`is on-OH:[3-R5 or ot-R5:I3—OH or or-OR,:[3-R5 or
`ot-R515-OR2, wherein R5 is hydrogen or methyl, R2 is
`an alcohol protecting group, and
`
`L, is or-R3:[3-R4, or-R415-R3, or a mixture ofo.-R3:[5-R4
`and or-R4:[3-R3, wherein R3 and Rs, 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 I,
`
`Case 3:14-cv-05499-PGS-LHG Document 41-5 Filed 07/07/15 Page 7 of 19 PageID: 409
`
`US 8,497,393 B2
`
` Case 3:14—cv—O5499—PGS—LHG Document 41-5 Filed 07/07/15 Page 7 of 19 Page|D:
`
`
`Copy provided by USPTO from the PIRS Image Database on 03/24/2015
`
`
`
`

`
`Case 3:14-cv-05499-PGS-LHG Document 41-5 Filed 07/07/15 Page 8 of 19 PageID: 410
`Case 3:14—cv—O5499—PGS—LHG Document 41-5 Filed 07/07/15 Page 8 of 19 Page|D:
`
`=
`
`
`
`>
`g
`
`I
`
`E
`
`;
`
`.
`3
`
`.
`V.
`
`1
`~
`
`‘
`i
`}
`i
`
`‘
`
`
`
`1
`
`ll
`
`ml»
`
`‘
`
`,5
`3»
`
`1
`)3:
`‘;
`“:3
`3:
`
`Cl}
`»r:‘
`‘I
`‘I
`
`I
`1
`:1
`%
`3
`
`.
`la
`1;,
`ii‘
`‘ Iit
`
`E
`
`“
`
`7
`
`8
`
`US 8,497,393 B2
`
`H
`
`H
`
`Y,—o—c—k7
`II
`||
`
`OH
`HBG)
`
`O(CH2)wCOOe
`
`10
`
`(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 15
`90.0%, 95.0%, 99.0%.
`The compound Offormula H can be prepared Rom ,1 CUm_
`pound of formula XI, which is a cyclization product of a
`compound offormula X as described in US. Pat. No. 6,441,
`245.
`
`20
`
`(1.)
`
`(IV)
`
`
`
`O
`K
`
`CUOH
`
`The process comprises
`(a) alkylating a compound ofstructureVwithan alkylating
`agent Such as C1CH2CN to Produce 3 Comlmund of
`formula VI:
`
`OR,
`
`(X)
`
`25
`
`c\\C\
`\
`
`Y,—C—C—R7
`ll
`ll
`M1
`1-1
`
`0(CH2)nCH3
`
`30
`
`(X1)
`
`0
`
`(V)
`
`(VI)
`
`OR‘
`
`Y1——C——C-——P.7
`II
`II
`M1
`L1
`(J
`
`35
`
`
`
`O(CH;),,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
`Ilzgidlhlcot %f7aOg06gI5mund of formula X11 as desmbed 111 US‘ 45
`'
`'
`’
`5
`'
`
`40
`
`011,
`
`OBI]
`
`C\
`\C\
`\ ““fi‘fi‘R7
`M1
`L1
`
`Y1—-C——C—R-7
`II
`II
`M1 L,
`
`OH
`
`H
`
`H
`
`(XIIW
`‘
`’
`
`(XIII)
`
`50
`
`55
`
`60
`
`0
`K
`
`CN
`
`(b) hydrolyzing the product of step (a) with a base such as
`KOH,
`(c) contacting the product ofstep (b) with a base B such as
`diethanolamine to for a salt of the following structure,
`and
`
`HO
`
`
`
`......
`
`'0”
`
`@NH2(CH2CHz0H)z
`
`
`0
`K
`
`cooe
`
`01311
`One embodiment of the present invention is a process for 65
`
`P
`b with an acid such as HC1
`d reacting the salt from ste
`to form the compound of formula IV
`
`hydrate, solvate, or pharmaceutically acceptable salt thereof.
`
`the preparation of a compound having formula IV, or a
`
`is at least 90.0%, 95.0%, 99.0%, 99.5%.
`
`Inoneembodiment,thepurityofcompoundofformulaIV
`
`
`
` Copy provided by USPTO from the PIRS Image Database on 93/24/2015
`UTC_REM_||_0000033£J39
`
`
`

`
`
`Case 3:14-cv-05499-PGS-LHG Document 41-5 Filed 07/07/15 Page 9 of 19 PageID: 411
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`
`411
`
`US 8,497,393 B2
`
`10
`A 50-L, three-neck, round—bottom flask equipped with a
`mechanical stirrer and a thermocouple was charged with ben-
`zindene triol (1250 g), acetone (19 L) and KZCO3 (powdered)
`(1296 g), chloroacetonitrile (567 g), tetrabutylamrnonium
`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/CHEC112; 1:9
`and developed by 10% ethanolic solution of PMA). After
`completion ofreaction, the reactionmixture 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
`
`
`
`KOH.
`MeOH
`
`I-[20,
`Reflux
`
`
`
`MW
`
`Amount
`
`Mel.
`
`Eq.
`
`Name
`
`3.76
`1397 g*
`3 71.52
`Benzindene Nitrllc
`15.04
`844 g
`56.11
`KOH
`—
`12 L
`—
`Methanol
`Water
`—
`4.25 L
`——
`
`*Not::
`This weight is based on 100% yield from the previous step. This is not isolated yield.
`
`1.0
`4.0
`~
`
`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
`dis solved in4.25 L ofwater). The reaction mixture was stirred
`and heated to reflux (temperature 722° C.). The progress of
`
`40
`
`45
`
`55
`
`60
`
`65
`
`9
`In one embodiment, the process further comprises a step of
`isolating the salt of formula 1V5.
`In one embodiment, the base B in step (c) may be ammonia,
`N—methy1glucamine_. 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 Benzindcnc Triol
`
`
`
`C1
`K
`
`———-————>
`K2003, BmNBr
`
`Acetone, RTHO
`
`
`
`O K
`
`CN
`
`
`
`MW
`
`Amount
`
`Mol.
`
`Eq.
`
`Name
`
`1.00
`3.76
`1250 g
`332.48
`Benzindene Triol
`2.50
`9.38
`1296 g
`138.20
`K2CO; (powder)
`2.0
`7.51
`5 67 g
`75.50
`CICHZCN
`0.03
`0.11
`36 g
`322.37
`Bu,,NBr
`—
`—
`29 L
`—
`Acetone
`
`
`
`
`— 115 g 4Celite ® 545 —
`
`
`
`Copy provided by USPTO from the PIRS Image Database on 03/24/2015
`
`
`
`UTC_REM_II_000003360
`
`
`

`
`
`
`Case 3:14-cv-05499-PGS-LHG Document 41-5 Filed 07/07/15 Page 10 of 19 PageID: 412
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`
`US 8,497,393 B2
`
`11
`the reaction was monitored by TLC (for TLC purpo se, 1-2 mL
`ofreaction mixture was acidified with 3M I-1C1 to pH 1-2 and
`extracted with ethyl acetate. The ethyl acetate extract was
`used for TLC; Eluent: methanol/CH2Cl2; 1:9, and developed
`by 10% ethanolic solution ofPMA). After completion of the
`readion (~5 h), the reaction mixture was cooled to -5 to 10°
`C. and quenchedwith a solution ofhydrochloric acid (3M, 3 .1
`L) while stirring. The reaction mixture was concentrated in
`vacuo at 50-55° C. to obtain approximately 12-1 4 L of con-
`densate. The condensate was discarded.
`
`The aqueous layer was diluted with water (7-8 L) and
`extracted with cthyl acetate (2><6 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 (3><10 L) and followed by washing with a solution
`ofNaHCO3 (30 g ofNaHCO3 dissolved in 12 Lofwater). The
`organic layer Was further washed with saturated solution of
`NaCl (3372 g of NaCl dissolved in water (12 L)) and dried
`over anhydrous Na2SO4 (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 68-70° 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 (palc—ycl1ow) 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)
`
`
`
`-—:——-4»
`(I) EtOH, EtOAc
`(ll) Heptane Slurry
`
`
`
`
`
`
`
`
`
`
`
`
`12
`-continued
`
`
`
`OH
`
`
` Name _\/[W Amount Mol Eq
`
`
`
`
`Treprostinll
`390.52
`1464 g"
`3.75
`1.0
`Dicthanolarnine
`105.14