USOO9593066B2
`
`(12) United States Patent
`Batra et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,593,066 B2
`*Mar. 14, 2017
`
`(54)
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`(71)
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`(72)
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`(73)
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`(*)
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`PROCESS TO PREPARE TREPROSTINIL,
`THE ACTIVE INGREDIENT IN
`REMODULINGR)
`
`Applicant: United Therapeutics Corporation,
`Silver Spring, MD (US)
`
`Inventors: Hitesh Batra, Herndon, VA (US);
`Sudersan M. Tuladhar, Silver Spring,
`MD (US); Raju Penmasta, Herndon,
`VA (US); David A. Walsh, Palmyra,
`VA (US)
`Assignee: United Therapeutics Corporation,
`Silver Spring, MD (US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`This patent is Subject to a terminal dis
`claimer.
`
`Notice:
`
`Appl. No.: 14/849,981
`Filed:
`Sep. 10, 2015
`
`Prior Publication Data
`US 2015/0376106 A1
`Dec. 31, 2015
`
`Related U.S. Application Data
`Division of application No. 13/933,623, filed on Jul.
`2, 2013, now Pat. No. 9,156,786, which is a
`continuation of application No. 13/548,446, filed on
`Jul. 13, 2012, now Pat. No. 8,497,393, which is a
`continuation of application No. 12/334,731, filed on
`Dec. 15, 2008, now Pat. No. 8,242,305.
`
`Provisional application No. 61/014,232, filed on Dec.
`17, 2007.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. C.
`C07C 59/72
`C07C 5 L/08
`CD7C5L/4I
`CD7C 23/08
`CD7C 405/00
`AOIN 37/10
`CO7C 39/12
`CO7C 39/17
`CO7C 59/60
`U.S. C.
`CPC .............. C07C 59/72 (2013.01); C07C 51/08
`(2013.01); C07C 51/41 (2013.01); C07C
`51/412 (2013.01); C07C 213/08 (2013.01);
`C07C 405/0075 (2013.01); A0IN 37/10
`(2013.01); C07C39/12 (2013.01); C07C39/17
`(2013.01); C07C 59/60 (2013.01)
`Field of Classification Search
`CPC ......... C07C 59/72; C07C 51/08; C07C 51/41;
`C07C 51/412; C07C 213/08; C07C
`405/OO75
`See application file for complete search history.
`
`(56)
`
`References Cited
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`CN
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`(Continued)
`
`OTHER PUBLICATIONS
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`(Continued)
`
`Primary Examiner — Yevegeny Valenrod
`(74) Attorney, Agent, or Firm — Foley & Lardner LLP
`
`ABSTRACT
`(57)
`This present invention relates to an improved process to
`prepare prostacyclin derivatives. One embodiment provides
`for an improved process to convert benzindene triol to
`treprostinil via salts of treprostinil and to purify treprostinil.
`
`10 Claims, No Drawings
`
`Liquidia - Exhibit 1001 - Page 1
`
`

`

`US 9,593,066 B2
`Page 2
`
`(56)
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`
`Liquidia - Exhibit 1001 - Page 2
`
`

`

`US 9,593,066 B2
`Page 3
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`
`Liquidia - Exhibit 1001 - Page 3
`
`

`

`US 9,593,066 B2
`
`1.
`PROCESS TO PREPARE TREPROSTINIL,
`THE ACTIVE INGREDIENT IN
`REMODULINGR)
`
`2
`need exists for an efficient process to synthesize these
`compounds on a large scale Suitable for commercial pro
`duction.
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a Divisional of U.S. application Ser.
`No. 13/933,623, filed Jul. 2, 2013, which is a Continuation
`of U.S. application Ser. No. 13/548,446, filed Jul. 13, 2012,
`which is a Continuation of U.S. application Ser. No. 12/334,
`731, filed Dec. 15, 2008, which claims priority from U.S.
`Provisional Patent Application 61/014,232, filed Dec. 17,
`2007, the entire contents of which are incorporated herein by
`reference.
`
`10
`
`15
`
`BACKGROUND
`
`SUMMARY
`
`The present invention provides in one embodiment a
`process for the preparation of a compound of formula I,
`hydrate, Solvate, prodrug, or pharmaceutically acceptable
`salt thereof.
`
`H Y-C-C-R
`
`(I)
`
`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
`inhibition, gastric secretion reduction, lesion inhibition, and
`bronchodilation.
`Treprostinil, the active ingredient in Remodulin(R), was
`first described in U.S. Pat. No. 4,306,075. Treprostinil, and
`other prostacyclin derivatives have been prepared as
`described in Moriarty, et al in J. 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 treat
`ing cancer Such as lung, liver, brain, pancreatic, kidney,
`prostate, breast, colon and head-neck cancer. U.S. patent
`application publication No. 2005/0165111 discloses trepro
`stinil treatment of ischemic lesions. U.S. Pat. No. 7,199,157
`discloses that treprostinil treatment improves kidney func
`tions. U.S. patent application publication No. 2005/0282903
`discloses treprostinil treatment of neuropathic foot ulcers.
`U.S. application Ser. No. 12/028,471 filed Feb. 8, 2008,
`discloses treprostinil treatment of pulmonary fibrosis. U.S.
`Pat. No. 6,054,486 discloses treatment of peripheral vascular
`disease with treprostinil. U.S. patent application Ser. No.
`11/873,645 filed Oct. 17, 2007 discloses combination thera
`pies 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 interstitial lung disease with treprostinil. U.S.
`application Ser. No. 12/028,471 filed 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 formula
`tions of treprostinil and other prostacyclin analogs.
`Because Treprostinil, and other prostacyclin derivatives
`are of great importance from a medicinal point of view, a
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`The process comprises the following steps:
`(a) alkylating a compound of structure II with an alky
`lating agent to produce a compound of formula III,
`
`(II)
`
`(III)
`
`H Y-C-C-R
`||
`||
`M. L.
`OH
`
`H
`
`OH
`
`H Y- i -R
`M. L.
`OH
`
`H
`
`O(CH2)CN
`
`wherein
`w=1, 2, or 3:
`Y is trans-CH=CH-, cis-CH=CH , —CH(CH)
`, or —C=C-; m is 1, 2, or 3;
`R, 1 S
`(1) —CH, CH, wherein p is an integer from 1 to 5.
`inclusive,
`(2) phenoxy optionally substituted by one, two or three
`chloro, fluoro, trifluoromethyl, (C-C)alkyl, or (C-
`C.)alkoxy, with the proviso that not more than two
`substituents are other than alkyl, with the proviso that
`R, is phenoxy or Substituted phenoxy, only when R.
`and R 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-C)alkyl, or
`(C-C)alkoxy, with the proviso that not more than two
`substituents are other than alkyl,
`(4) cis-CH=CH-CH CH,
`(5) —(CH) CH(OH)—CH, or
`(6) —(CH) CH=C(CH):
`
`Liquidia - Exhibit 1001 - Page 4
`
`

`

`US 9,593,066 B2
`
`3
`wherein —C(L)-R taken together is
`(1) (C-C2)cycloalkyl optionally substituted by 1 to 3
`(C-Cs)alkyl;
`(2) 2-(2-furyl)ethyl,
`(3) 2-(3-thienyl)ethoxy, or
`(4) 3-thienyloxymethyl;
`M is C.-OH: B-Rs or C.-Rs: B-OH or C-OR: B-Rs or C-Rs:
`B-OR, wherein Rs is hydrogen or methyl, R is an
`alcohol protecting group, and
`L is C.-R:f3-Ra, O-Ra:f3-Rs, or a mixture of C-R. B-Ra
`and C-R. 3-Rs, wherein R and R are hydrogen,
`methyl, or fluoro, being the same or different, with the
`proviso that one of R and R is fluoro only when the
`other is hydrogen or fluoro.
`(b) hydrolyzing the product of step (a) with a base,
`(c) contacting the product of step (b) with a base B to for
`a salt of formula I
`
`10
`
`15
`
`4
`-continued
`
`HO
`
`(VI)
`
`
`
`O N 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 IV, and
`
`H Y-C-C-R
`||
`||
`M. L.
`OH
`
`H
`()(CH), COO
`
`G
`HB
`
`
`
`(Is)
`
`25
`
`30
`
`(IV)
`
`(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.
`
`
`
`(IV)
`
`The process comprises the following steps:
`(a) alkylating a compound of structure V with an alky
`lating agent to produce a compound of formula VI,
`
`
`
`(V)
`
`35
`
`(d) reacting the salt from step (b) with an acid to form the
`compound of formula IV.
`
`DETAILED DESCRIPTION
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`The various terms used, separately and in combinations,
`in the processes herein described are defined below.
`The expression "comprising means “including but not
`limited to.” Thus, other non-mentioned Substances, addi
`tives, carriers, or steps may be present. Unless otherwise
`specified, “a” or “an” means one or more.
`C-alkyl is a straight or branched alkyl group containing
`1-3 carbon atoms. Exemplary alkyl groups include methyl,
`ethyl, n-propyl, and isopropyl.
`C-alkoxy is a straight or branched alkoxy group con
`taining 1-3 carbon atoms. Exemplary alkoxy groups include
`methoxy, ethoxy, propoxy, and isopropoxy.
`C-7-cycloalkyl is an optionally Substituted monocyclic,
`bicyclic or tricyclic alkyl group containing between 4-7
`carbon atoms. Exemplary cycloalkyl groups include but not
`limited to cyclobutyl, cyclopentyl, cyclohexyl, and cyclo
`heptyl.
`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 Sufficient to allow
`manufacture and which maintains the integrity of the com
`pound 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 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
`
`Liquidia - Exhibit 1001 - Page 5
`
`

`

`5
`limited to, derivatives of a compound that include biohy
`drolyzable groups such as biohydrolyzable amides, biohy
`drolyzable esters, biohydrolyzable carbamates, biohydrolyz
`able
`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
`integral 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 bio
`15
`logically nor otherwise undesirable and includes being use
`ful 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
`include acid addition salts formed with organic and inor
`ganic acids, Such as hydrogen chloride, hydrogen bromide,
`hydrogen iodide, Sulfuric acid, phosphoric acid, acetic acid,
`glycolic acid, maleic acid, malonic acid, oxalic acid, meth
`anesulfonic 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
`formulae 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
`compound. 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-dis
`ulfonate), benzenesulfonate, benzonate, bicarbonate, bisul
`fate, bitartrate, borate, bromide, butyrate, calcium, calcium
`edetate, camsylate, carbonate, chloride, citrate, clavulariate,
`dihydrochloride, edetate, edisylate, estolate, esylate, fumar
`ate, gluceptate, gluconate, glutamate, glycolylarsanilate,
`hexafluorophosphate, hexylresorcinate, hydrabamine, hyd
`45
`robromide, hydrochloride, hydroxynaphthoate, iodide, iso
`thionate, lactate, lactobionate, laurate, malate, maleate, man
`delate,
`mesylate,
`methylbromide,
`methylnitrate,
`methylsulfate, mucate, napsylate, nitrate, N-methylglu
`camine ammonium salt, 3-hydroxy-2-naphthoate, oleate,
`oxalate, palmitate, pamoate (1.1-methene-bis-2-hydroxy-3-
`naphthoate, einbonate), pantothenate, phosphate/diphos
`phate, picrate, polygalacturonate, propionate, p-toluenesul
`fonate, Salicylate, Stearate, Subacetate. Succinate, Sulfate,
`Sulfosalicylate, Suramate, tannate, tartrate, teoclate, tosylate,
`triethiodide, and Valerate salts.
`The present invention provides for a process for produc
`ing treprostinil and other prostacyclin derivatives and novel
`intermediate 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 chromatogra
`phy. Moreover, it was found that the product of the process
`according to the present invention has higher purity. There
`
`25
`
`30
`
`35
`
`40
`
`50
`
`55
`
`60
`
`65
`
`US 9,593,066 B2
`
`10
`
`6
`fore the present invention provides for a process that is more
`economical, 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.
`
`(I)
`
`H ---
`M1 Li
`OH
`
`H
`O(CH2)COOH
`
`The process comprises the following steps:
`(a) alkylating a compound of formula II with an alkylating
`agent to produce a compound of formula III,
`
`(II)
`
`(III)
`
`H Y-C-C-R
`||
`||
`M1 Li
`OH
`
`H
`
`OH
`
`H Y-C-C-R
`||
`||
`M. L.
`OH
`
`H
`
`O(CH2)CN
`
`wherein
`w=1, 2, or 3:
`Y is trans-CH=CH-, cis-CH=CH , —CH2(CH)
`, or —C=C-; m is 1, 2, or 3:
`R, is
`(1) —CH2—CHs, wherein p is an integer from 1 to 5.
`inclusive,
`(2) phenoxy optionally substituted by one, two or three
`chloro, fluoro, trifluoromethyl, (C-C)alkyl, or (C-
`C.)alkoxy, with the proviso that not more than two
`substituents are other than alkyl, with the proviso that
`R, is phenoxy or substituted phenoxy, only when R.
`and R 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-C)alkyl, or
`(C-C)alkoxy, with the proviso that not more than two
`substituents are other than alkyl,
`(4) cis-CH=CH-CH CH,
`(5) —(CH) CH(OH)—CH, or
`(6) —(CH) CH=C(CH):
`wherein —C(L)-R taken together is
`(1) (C-C7)cycloalkyl optionally substituted by 1 to 3
`(C-Cs)alkyl;
`
`Liquidia - Exhibit 1001 - Page 6
`
`

`

`US 9,593,066 B2
`
`7
`
`(2) 2-(2-furyl)ethyl,
`(3) 2-(3-thienyl)ethoxy, or
`(4) 3-thienyloxymethyl;
`M is C.-OH: B-Rs or C.-Rs: B-OH or C-OR: B-Rs or C-Rs: 5
`B-OR, wherein Rs is hydrogen or methyl, R is an
`alcohol protecting group, and
`L is C.-R.3-R. C.-Ra: B-Rs, or a mixture of C-R. B-Ra
`and C-Ra:f3-Rs, wherein R and Ra are hydrogen,
`methyl, or fluoro, being the same or different, with the
`proviso that one of R and R is fluoro only when the
`other is hydrogen or fluoro.
`(b) hydrolyzing the product of step (a) with a base,
`(c) contacting the product of step (b) with a base B to for 15
`a salt of formula I
`
`10
`
`8
`
`OR
`
`OB
`
`Y-C-C-R
`N ||
`||
`M. L.
`
`H Y-C-C-R7
`||
`||
`M. L.
`OH
`
`H
`
`OB
`
`(XII)
`
`(XIII)
`
`Y---R;
`||
`||
`M. L.
`OH
`
`(Is) 20
`
`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.
`
`H
`()(CH),COO
`
`H
`
`25
`
`(d) reacting the Salt from step (c) with an acid to form the 30
`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
`compound of formula XI, which is a cyclization product of
`a compound of formula X as described in U.S. Pat. No.
`6,441,245.
`
`(IV)
`
`O ls
`
`COOH
`
`The process comprises
`(a) alkylating a compound of structure V with an alky
`lating agent Such as CICH2CN to produce a compound of
`formula VI,
`
`40
`
`(X)
`
`(V)
`
`(VI)
`
`OR
`
`O(CH2)CH3
`
`OR
`
`H
`
`O(CH2)CH
`
`n
`Y-C-C-R
`N ||
`||
`M. L.
`
`45
`
`
`
`Y-C-C-R
`||
`||
`M. L.
`
`50
`
`(XI)
`
`
`
`60
`
`Wherein n 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 65
`product of a compound of formula XII as described in U.S.
`Pat. No. 6,700,025.
`
`Liquidia - Exhibit 1001 - Page 7
`
`

`

`US 9,593,066 B2
`
`9
`(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
`
`HO
`
`NH, CHCH-OH),
`
`10
`-continued
`
`HO
`
`
`
`l
`
`CN
`
`5
`
`10
`
`15
`
`2O
`
`Name
`
`MW Amount
`
`Mol.
`
`BenZindene Triol
`K2CO3 (powder)
`CICHCN
`BuNBr
`Acetone
`Celite (R545
`
`332.48
`138.20
`75.50
`322.37
`
`3.76
`9.38
`7.51
`O.11
`
`1250 g
`1296 g
`567 g
`36 g
`29 L
`115 g
`
`Eq.
`
`1.00
`2.50
`2.0
`O.O3
`
`30
`
`A 50-L, three-neck, round-bottom flask equipped with a
`25 mechanical stirrer and a thermocouple was charged with
`benzindene triol (1250 g), acetone (19 L) and KCO
`(powdered) (1296 g), chloroacetonitrile (567 g), tetrabuty
`lammonium 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/CH.Cl; 1:9 and developed by 10% ethanolic
`solution of PMA). After completion of reaction, the reaction
`mixture was filtered with/without Celite pad. The filter cake
`was washed with acetone (10 L). The filtrate was concen
`trated 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.
`
`35
`
`(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%.
`In one embodiment, the process further comprises a step
`of isolating the salt of formula IV.
`In one e