IN THE UNITED STATES PATENTAND TRADEAIARK OFFICE
`
`Atty. Dkt. No. 080618-0629
`
`Applicant:
`
`Hitesh BATRA et al.
`
`Title:
`
`AN IMPROVED PROCESS TO PREPARE
`
`TREPROSTINIL, THE ACTIVE
`INGREDIENT IN REMODULIN®
`
`Appl. No.:
`
`Unassigned
`
`Filing Date:
`
`12/12/2008
`
`Examiner:
`
`Unassigned
`
`Art Unit:
`
`Unassigned
`
`UTILITY PATENT APPLICATION
`TRANSMITTAL
`
`Commissioner for Patents
`P.O. Box 1450
`
`Alexandria, VA 22313-1450
`
`Sir:
`
`Transmitted herewith for filing under 37 C.F.R. § 1.53(b) is the nonprovisional utility
`
`patent application of:
`
`Hitesh BATRA
`
`Sudersan M. TULADHAR
`
`Raju PENMASTA
`David A. WALSH
`
`[X] Applicant claims small entity status under 37 CFR 1.27.
`
`Enclosed are:
`
`[X] Description, Claims, and Abstract (27 pages).
`
`[X ] Application Data Sheet (37 CFR 1.76).
`
`WASH_5143443.1
`
`_1_
`
`SteadyMed - Exhibit 1002 - Page 1
`
`SteadyMed - Exhibit 1002 - Page 1
`
`

`

`Atty. Dkt. No. 080618-0629
`
`The adjustment to the number of sheets for EFS—Web filing follows:
`
`Number of
`Sheets
`27
`
`x
`
`EFS—Web
`Adjustment
`75%
`
`The filing fee is calculated below:
`
`Number of Sheets for EFS—Web
`
`21
`
`Number
`Filed
`
`Included
`in
`Basic Fee
`
`Extra
`
`Rate
`
`Fee
`Totals
`
`$330.00 =
`
`$330.00
`
`Basic Filing
`Fee
`
`Search Fee
`Examination
`Fee
`
`Size Fee
`Total
`Claims:
`
`21
`19
`
`-
`—
`
`100
`20
`
`= 0
`= 0
`
`= 0
`3
`—
`2
`Independent:
`If any Multiple Dependent Claim(s) present:
`Surcharge under 37 CFR 1.16(f) for late filing of
`Executed Declaration and late payment of Basic
`Filing Fee
`
`$540.00
`$220.00
`
`$270.00
`$52.00 =
`
`$220.00 =
`$390.00 =
`$130.00
`
`=
`
`X
`x
`
`x
`+
`+
`
`$540.00
`$220.00
`
`$0.00
`$0.00
`
`$0.00
`$0.00
`$130.00
`
`$1220.00
`$610.00
`$83.00
`$527.00
`$0.00
`
`$527.00
`
`[ X ]
`
`SUBTOTAL: =
`Small Entity Fees Apply (subtract ‘/2 of above): =
`Basic Filing Fee Reduction for Filing via EFS—Web
`TOTAL FILING FEE: =
`+
`=
`Assignment Recordation Fee:
`Processing Fee under 37 CFR 1.17(i) for Late Filing +
`$130.00 _
`of English Translation of Application:
`--
`TOTAL FEE
`=
`
`The required filing fees are not enclosed but will be submitted in response to the
`
`Notice to File Missing Parts of Application.
`
`WASH_5143443.1
`
`_2_
`
`SteadyMed - Exhibit 1002 - Page 2
`
`SteadyMed - Exhibit 1002 - Page 2
`
`

`

`Atty. Dlct. No. 080618-0629
`
`Please direct all correspondence to the undersigned attorney or agent at the address
`
`indicated below.
`
`Respectfully submitted,
`
`Date December 15 2008
`
`FOLEY & LARDNER LLP
`Customer Number: 22428
`Telephone:
`(202) 672-5569
`Facsimile:
`(202) 672-5399
`
`Stephen B. Maebius
`Attorney for Applicant
`Registration No. 35,264
`
`WASH__5143443.1
`
`_3_
`
`SteadyMed - Exhibit 1002 - Page 3
`
`SteadyMed - Exhibit 1002 - Page 3
`
`

`

`AN IMPROVED PROCESS TO PREPARE TREPROSTINIL, THE ACTIVE
`INGREDIENT IN REMODULIN®
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`[0001]
`
`This application claims priority from U.S. Provisional Patent Application
`
`61/014,232, filed December 17, 2007, the entire contents of which are incorporated herein by
`
`reference.
`
`BACKGROUND
`
`[0002]
`
`The present invention relates to a process for producing prostacyclin derivatives
`
`and novel intermediate compounds useful in the process.
`
`[0003]
`
`Prostacyclin derivatives
`
`are useful pharmaceutical
`
`compounds possessing
`
`activities such as platelet aggregation inhibition, gastric secretion reduction, lesion inhibition,
`
`and bronchodilation.
`
`[0004]
`
`Treprostinil, the active ingredient in Remodulin®, was first described in US patent
`
`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, 6,809,223 and 6,756,117 Their
`
`teachings are incorporated by reference to show how to practice the embodiments of the
`
`present invention.
`
`[0005]
`
`U.S. Patent 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. patents
`
`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. patent No. 6,803,386 discloses administration of treprostinil for treating
`
`cancer such as lung, liver, brain, pancreatic, kidney, prostate, breast, colon and head-neck
`
`cancer. U.S. patent application publication No. 2005/0165111 discloses treprostinil treatment
`
`of ischemic lesions. U.S. patent No. 7,199,157 discloses that treprostinil treatment improves
`
`kidney functions. U.S. patent application publication No. 2005/0282903 discloses treprostinil
`
`treatment of neuropathic foot ulcers. U.S. application No. 12/028,471 filed February 8, 2008,
`
`WAS H_51 42948.1
`
`_1_
`
`SteadyMed - Exhibit 1002 - Page 4
`
`SteadyMed - Exhibit 1002 - Page 4
`
`

`

`discloses treprostinil treatment of pulmonary fibrosis. U.S. 6,054,486 discloses treatment of
`
`peripheral vascular disease with treprostinil. U.S. patent application ll/873,645 filed
`
`October 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 interstitial lung disease with treprostinil.
`
`U.S. application No. 12/028,471 filed February 8, 2008 discloscs treatment of asthma with
`
`treprostinil.
`
`U.S. 7,417,070, 7,384,978 and U.S. publication Nos. 2007/0078095,
`
`2005/0282901, and 2008/0249167 describe oral
`
`formulations of treprostinil and other
`
`prostacyclin analogs.
`
`[0006]
`
`Because Treprostinil, and other prostacyclin derivatives are of great importance
`
`from a medicinal point of view, a need exists for an efficient process to synthesize these
`
`compounds on a large scale suitable for commercial production.
`
`SUMMARY
`
`[0007]
`
`The present invention provides in one embodiment a process for the preparation of
`
`a compound of formula I, hydrate, solvatc, prodrug, or pharmaccutically acceptable salt
`
`thereof.
`
`Y1‘fi_fi_R7
`M1 L1
`OH
`
`H
`
`H
`
`O(CH2)WCOOH
`
`(1)
`
`[0008]
`
`The process comprises the following steps:
`
`(a)
`
`alkylating a compound of structure 11 with an alkylating agent to produce a
`
`compound of formula 111,
`
`Y1_fi—fi—R7
`M1 L1
`OH
`
`H
`
`H
`
`OH
`
`Y1‘fi_fi_R7
`M1 L1
`OH
`
`H
`
`H
`
`(11)
`
`O(CH2x~CN
`
`(111)
`
`WAS H_51 42948.1
`
`_ 2 _
`
`SteadyMed - Exhibit 1002 - Page 5
`
`SteadyMed - Exhibit 1002 - Page 5
`
`

`

`wherein
`
`w= 1, 2, or 3;
`
`Y1 is trans—CH=CH—, cis—CH=CH—, —CH2(CH2),,,—, or —CEC—; m is 1, 2, or 3;
`
`R7 is
`
`(l)
`
`(2)
`
`-CpH2p-CH3, wherein p is an integer from 1 to 5, inclusive,
`
`phenoxy optionally substituted by one,
`
`two or three chloro, fluoro,
`
`trifluoromethyl, (C1-C3) alkyl, or (C 1-C3)all<oxy, 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 optionally substituted on
`
`the aromatic ring by one,
`
`two or three chloro, fluoro,
`
`trifluoromethyl,
`
`(C1—C3)all<yl, or
`
`(C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl,
`
`(4)
`
`(5)
`
`(6)
`
`cis-CH=CH-CH2-CH3,
`
`-(CH2);-CH(OH)-CH3, or
`
`'(CH2)3-CH:C(CH3)2;
`
`wherein -C(L1)-R7 taken together is
`
`(1)
`
`(2)
`
`(3)
`
`(4)
`
`(C4-C7)cycloalkyl optionally substituted by 1 to 3 (C1-C5)a1kyl;
`
`2—(2—furyl)ethyl,
`
`2—(3 —thienyl)ethoxy, or
`
`3-thienyloxymethylg
`
`M1 is or-OH:B-R5 or or-R5:[3-OH or or-OR1:[3-R5 or or-R5:[3-OR2, wherein R5 is
`
`hydrogen or methyl, R2 is an alcohol protecting group, and
`
`L1 is oL—R3:B—R4, oL—R4:B—R3, or a mixture of oL—R3:B—R4 and oL—R4:B—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)
`
`(c)
`
`hydrolyzing the product of step (a) with a base,
`
`contacting the product of step (b) with a base B to for a salt of formula 15
`
`WAS H_51 42948.1
`
`SteadyMed - Exhibit 1002 - Page 6
`
`SteadyMed - Exhibit 1002 - Page 6
`
`

`

`H
`
`H
`
`Y1'fi_fi—R7
`M1 L1
`OH
`
`HB®
`
`O(CH2)WCOOe
`
`as)
`
`(d)
`
`reacting the salt from step (c) with an acid to form the compound of formula I.
`
`[0009]
`
`The present
`
`invention provides in another embodiment a process for
`
`the
`
`preparation of a compound of formula IV.
`
` K
`
`COOH
`
`(IV)
`
`[0010]
`
`The process comprises the following steps:
`
`(a)
`
`alkylating a compound of structure V with an alkylating agent to produce a
`
`compound of formula VI,
`
` K
`
`(V)
`
`C“
`
`(V1)
`
`
`
`(b)
`
`(c)
`
`and
`
`hydrolyzing the product of step (a) with a base,
`
`contacting the product of step (b) with a base B to for a salt of formula IVS,
`
`WAS H_51 42948.1
`
`SteadyMed - Exhibit 1002 - Page 7
`
`SteadyMed - Exhibit 1002 - Page 7
`
`

`

`
`
`(IVs)
`
`(d)
`
`reacting the salt
`
`from step (b) with an acid to form the compound of
`
`formula IV.
`
`DETAILED DESCRIPTION
`
`[0011]
`
`The various terms used, separately and in combinations, in the processes herein
`
`described are defined below.
`
`[0012]
`
`The expression “comprising” means “including but not limited to.” Thus, other
`
`non-mentioned substances, additives, carriers, or steps may be present. Unless otherwise
`
`specified, “a” or “an” means one or more.
`
`[0013]
`
`C1_3—all<yl
`
`is a straight or branched alkyl group containing 1-3 carbon atoms.
`
`Exemplary alkyl groups include methyl, ethyl, n-propyl, and isopropyl.
`
`[0014]
`
`C1_3-alkoxy is a straight or branched alkoxy group containing 1-3 carbon atoms.
`
`Exemplary alkoxy groups include methoxy, ethoxy, propoxy, and isopropoxy.
`
`[0015]
`
`C4_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 cycloheptyl.
`
`[0016]
`
`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 compound for a sufficient period of time to be useful for the
`
`purposes detailed herein.
`
`[0017]
`
`As used herein, the term “prodrug” means a derivative of a compound that can
`
`hydrolyze, oxidize, or otherwise react under biological conditions (in. vitro or in vivo) to
`
`provide an active compound.
`
`Examples of prodrugs include, but are not
`
`limited to,
`
`WASH_5142948. 1
`
`_ 5 _
`
`SteadyMed - Exhibit 1002 - Page 8
`
`SteadyMed - Exhibit 1002 - Page 8
`
`

`

`derivatives of a compound that include biohydrolyzable groups such as biohydrolyzable
`
`amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates,
`
`biohydrolyzable ureides, and biohydrolyzable phosphate analogues (e.g., monophosphate,
`
`diphosphate or triphosphate).
`
`[0018]
`
`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.
`
`[0019]
`
`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.
`
`[0020]
`
`“Pharmaceutically acceptable” means in the present description being useful in
`
`preparing a pharmaceutical composition that
`
`is generally safe, non-toxic and neither
`
`biologically nor otherwise undesirable and includes being useful for veterinary use as well as
`
`human pharmaceutical use.
`
`[0021]
`
`“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 inorganic acids, such as hydrogen
`
`chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid,
`
`glycolic acid, maleic acid, malonic acid, oxalic acid, methanesulfonic 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, calcium, ethanolamine, diethanolamine, N-methylglucamine, choline
`
`and the like. Included in the invention are pharmaceutically acceptable salts or compounds of
`
`any of the formulae herein.
`
`[0022]
`
`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 -disulfonate), benzenesulfonate, benzonate,
`
`bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate,
`
`camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,
`
`estolate,
`
`esylate,
`
`fiimarate,
`
`gluceptate,
`
`gluconate,
`
`glutamate,
`
`glycollylarsanilate,
`
`hexafluorophosphate,
`
`hexylresorcinate,
`
`hydrabamine,
`
`hydrobromide,
`
`hydrochloride,
`
`WASH_5142948. 1
`
`_ 6 _
`
`SteadyMed - Exhibit 1002 - Page 9
`
`SteadyMed - Exhibit 1002 - Page 9
`
`

`

`hydroxynaphthoate,
`
`iodide,
`
`isothionate,
`
`lactate,
`
`lactobionate,
`
`laurate, malate, maleate,
`
`mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,
`
`N—methylglucamine ammonium salt, 3—hydroXy—2—naphthoate, oleate, oxalate, palmitate,
`
`pamoate
`
`(1 , 1 —methene—bis—2—hydroxy—3 —naphthoate,
`
`einbonate),
`
`pantothenate,
`
`phosphate/diphosphate, picrate, polygalacturonate, propionate, p—toluenesulfonate, salicylate,
`
`stcaratc, subacctatc, succinatc, sulfatc, sulfosalicylatc, suramatc, tannatc, tartratc, tcoclatc,
`
`tosylate, triethiodide, and valerate salts.
`
`[0023]
`
`The present invention provides for a process for producing 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 formation is a much easier operation than column chromatography.
`
`Moreover, it was found that the product of the process according to the present invention has
`
`higher purity.
`
`Therefore the present
`
`invention provides for a process that
`
`is more
`
`economical, safer, faster, greener, easier to operate, and provides higher purity.
`
`[0024]
`
`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.
`
`Y1"fi—fi—R7
`M1 L1
`OH
`
`H
`
`H
`
`O(CH2)WCOOH
`
`(1)
`
`[0025]
`
`The process comprises the following steps:
`
`(a)
`
`alkylating a compound of formula II with an alkylating agent to produce a
`
`compound of formula III,
`
`WAS H_51 42948.1
`
`SteadyMed - Exhibit 1002 - Page 10
`
`SteadyMed - Exhibit 1002 - Page 10
`
`

`

`Y1‘fi—fi_R7
`M1 L1
`OH
`
`H
`
`H
`
`(11)
`
`O(CH2)wCN
`
`(111)
`
`Y1—fi—fi—R7
`M1 L1
`OH
`
`H
`
`H
`
`OH
`
`wherein
`
`w= l, 2, or 3;
`
`Y1 is trans-CH=CH-, cis-CH=CH-, -CH2(CH2),,,-, or -CEC-; m is l, 2, or 3;
`
`R7 lS
`
`(1)
`
`(2)
`
`—CpH2p—CH3, wherein p is an integer from 1 to 5, inclusive,
`
`phenoxy optionally substituted by one, two or three chloro, fluoro,
`
`trifluoromethyl, (C1-C3) alkyl, or (C1-C3)all<oxy, 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 optionally substituted on
`
`the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)all<yl, or (C1-
`
`C3)alkoXy, with the proviso that not more than two substituents are other than alkyl,
`
`(4)
`
`(5)
`
`(6)
`
`cis—CH=CH—CH2—CH3,
`
`—(CH2)2—CH(OH)—CH3, or
`
`'(CH2)3-CH=C(CH3)2;
`
`wherein -C(L1)-R7 taken together is
`
`(l)
`
`(2)
`
`(3)
`
`(4)
`
`(C4-C7)cycloall<yl optionally substituted by l to 3 (C1-C5)all<yl;
`
`2-(2-furyl)ethyl,
`
`2-(3-thienyl)ethoxy, or
`
`3-thienyloxymethylg
`
`M1 is 0.—OH2|3-R5 or ot—R5:B—OH or ot—OR1:B—R5 or 0.-R52B—OR2, wherein R5 is
`
`hydrogen or methyl, R2 is an alcohol protecting group, and
`
`L1 is ot-R3:B-R4, ot-R4:B-R3, or a mixture of ot-R3:B-R4 and ot-R4:B-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,
`
`WASH_5142948. 1
`
`_ 8 _
`
`SteadyMed - Exhibit 1002 - Page 11
`
`SteadyMed - Exhibit 1002 - Page 11
`
`

`

`(C)
`
`contacting the product of step (b) with a base B to for a salt of formula Is
`
`H
`
`H
`
`Y1'fi—fi—R7
`M1M
`OH
`
`6)
`
`HB
`
`G
`oanbmcoo
`
`G9
`
`(d)
`
`reacting the salt from step (c) with an acid to form the compound of formula I.
`
`[0026]
`
`In one embodiment, the compound of formula I is at least 90.0%, 95.0%, 99.0%.
`
`[0027]
`
`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.
`
`OR1
`
`CR1
`
`Y1-fi—fi—R7
`M1M
`6 o
`
`\ Yrrfi-R7
`M1M
`
`O(CH 2)nCH3
`
`H
`O(CH2)nCH3
`
`(XI)
`
`Wherein n is 0, l, 2, or 3.
`
`[0028]
`
`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
`
`U.S. Pat. No. 6,700,025.
`
`O
`
`R‘
`
`_ _ _
`g Y1 ICE
`Icl: R7
`M1 L1
`
`Y1'$f‘fi‘R7
`.21“
`
`H
`
`OBn
`
`(XII)
`
`OBn
`
`(XIII)
`
`[0029]
`
`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
`
`WAS H_51 42948.1
`
`SteadyMed - Exhibit 1002 - Page 12
`
`SteadyMed - Exhibit 1002 - Page 12
`
`

`

` K
`
`COOH
`
`(IV)
`
`[0030]
`
`The process comprises
`
`(a)
`
`alkylating a compound of structure V with an alkylating agent such as
`
`ClCH2CN to produce a compound of formula VI,
`
` K
`
`(V)
`
`C“
`
`(V1)
`
`
`
`(b)
`
`(c)
`
`hydrolyzing the product of step (a) with a base such as KOH,
`
`contacting the product of step (b) with a base B such as diethanolamine to for
`
`a salt of the following structure, and
`
`HO
`
` ® NH2(CH2CH2OH)2
`
`(d)
`
`reacting the salt from step (b) with an acid such as HCl to form the compound
`
`of formula IV.
`
`[0031]
`
`In one embodiment, the purity of compound of formula IV is at least 90.0%,
`
`95.0%, 99.0%, 99.5%.
`
`WASH_5142948. 1
`
`_ 10 _
`
`SteadyMed - Exhibit 1002 - Page 13
`
`SteadyMed - Exhibit 1002 - Page 13
`
`

`

`[0032]
`
`In one embodiment, the process further comprises a step of isolating the salt of
`
`formula IVS.
`
`[0033]
`
`In one embodiment, the base B in step (c) may be ammonia, N—methylglucamine,
`
`procaine, tromethanine, magnesium, L—lysine, L—arginine, or triethanolamine.
`
`[0034]
`
`The following abbreviations are used in the description and/or appended claims,
`
`and they have the following meanings:
`
`“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.
`
`[0035]
`
`In view of the foregoing considerations, and specific examples below, those who
`
`are skilled in the art will appreciate that how to select necessary reagents and solvents in
`
`practicing the present invention.
`
`[0036]
`
`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.
`
`Example I.
`
`Alkylation of Benzindene Triol
`
`EXAMPLES
`
`
`
`KZCO3, Bu4NBr
`Acetone, RT
`
`WASH_5142948. 1
`
`_ 11 _
`
`SteadyMed - Exhibit 1002 - Page 14
`
`SteadyMed - Exhibit 1002 - Page 14
`
`

`

`Name
`
`Benzindene Triol
`
`K2CO3 (powder)
`CICHZCN
`
`Bu4NBr
`
`1296g
`
`138.20
`.
`
`.
`
`
`
`M01.
`
`3.76
`
`Eq.
`
`1.00
`
`7.51
`
`2.0
`
`0.11
`0.03
`XX
`XX
`
`[0037]
`
`A 50—L, three—neck, round—bottom flask equipped with a mechanical stirrer and a
`
`thermocouple was charged with benzindene 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/CH2Cl2; 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 (10L). 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
`
`HO
`
`
`
`H20, Reflux
`
`KOH, MeOH T,
`
`(E
`
`CN
`
`WAS H_51 42948.1
`
`_ 12 _
`
`SteadyMed - Exhibit 1002 - Page 15
`
`SteadyMed - Exhibit 1002 - Page 15
`
`

`

`Name
`
`Amount
`
`M01.
`
`Benzindene Nitrile
`
`1397 g*
`
`3 .76
`
`Eq.
`
`1.0
`
`4.25 L
`
`Methanol
`
`Water
`
`12 L
`
`*Note: This weight is based on 100% yield from the previous step. This is not isolated yield.
`
`[0038]
`
`A 50-L, cylindrical reactor equipped with a heating/cooling system, a mechanical
`
`stirrer, a condenser, and a thermocouple was charged with a solution of benzindene nitrile in
`
`methanol (12 L) and a solution of KOH (844 g of KOH dissolved in 4.25 L of water). The
`
`reaction mixture was stirred and heated to reflux (temperature 722°C). The progress of the
`
`reaction was monitored by TLC (for TLC purpose, 1-2 mL of reaction mixture was acidified
`
`with 3M HC1 to pH 1-2 and extracted with ethyl acetate. The ethyl acetate extract was used
`
`for TLC; Eluent: methanol/CHZCI2; 1:9, and developed by 10% ethanolic solution of PMA).
`
`After completion of the reaction (~5 h), the reaction mixture was cooled to -5 to 10°C and
`
`quenched with a solution of hydrochloric acid (3M, 3.1 L) while stirring. The reaction
`
`mixture was concentrated in vacuo at 50-55°C to obtain approximately 12-14 L of
`
`condensate. The condensate was discarded.
`
`[0039]
`
`The aqueous layer was diluted with water (7-8 L) and extracted with ethyl acetate
`
`(2 X 6 L) to remove impurities soluble in ethyl acetate. To aqueous layer, ethyl acetate (22
`
`L) was added and the pH of reaction mixture was adjusted to 1-2 by adding 3M HC1 (1.7 L)
`
`with stirring. The organic layer was separated and the aqueous layer was extracted with ethyl
`
`acetate (2 X 11 L). The combined organic layers were washed with water (3 X 10 L) and
`
`followed by washing with a solution of NaHCO3 (30 g of NaHCO3 dissolved in 12 L of
`
`water). The organic layer was further Washed with saturated solution of NaCl (3372 g of
`
`NaCl dissolved in water (12 L)) and dried over anhydrous Na2SO4 (950-1000 g), once
`
`filtered.
`
`[0040]
`
`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 (1 10-130 g). The suspension was heated to reflux (temperature 68—70°C) for at least
`
`one hour. For filtration, a pad of Celite®545 (300—600 g) was prepared in sintered glass
`
`WASH_5142948. 1
`
`_
`
`_
`
`SteadyMed - Exhibit 1002 - Page 16
`
`SteadyMed - Exhibit 1002 - Page 16
`
`

`

`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 of the
`
`washings.
`
`[0041]
`
`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) EtO H, EtOAc
`
`(II) Heptane Slurry
`l464g*
`
`390.52
`
`*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 of ethanol used). Approximately 35 L of ethyl acetate was carried over from previous step
`
`and additional 1.0 L of ethyl acetate was used for rinsing the flask.
`
`[0042]
`
`A 50-L, cylindrical reactor equipped with a heating/cooling system, a mechanical
`
`stirrer, a condenser, and a thermocouple 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 reaction mixture was heated to 60-75°C, for 0.5-1.0 h to obtain a
`
`clear solution. The clear solution was cooled to 55::5°C. At this temperature, the seed of
`
`WASH_5142948. 1
`
`_ 14 _
`
`SteadyMed - Exhibit 1002 - Page 17
`
`SteadyMed - Exhibit 1002 - Page 17
`
`

`

`polymorph B of treprostinil diethanolamine salt (~12 g) was added to the clear solution. The
`
`suspension of polymorph B was stirred at this temperature for 1 h. The suspension was
`
`cooled to 20::2°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 (2 X 8 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
`
`50::5°C under high Vacuum.
`
`[0043]
`
`At this stage, if melting point of the treprostinil diethanolamine salt is more than
`
`104°C, it was considered polymorph B. There is no need of recrystallization. If it is less than
`
`104°C , it is recrystallized in EtOH-EtOAc to increase the melting point.
`
`Data on Treprostinil Diethanolamine Salt (1 :1)
`
`Wt. of Treprostinil
`Wt. of
`Benzindene Trio] Diethanolamine Salt (1:1)
`(g)
`(g)
`
`Batch N0-
`
`1
`
`2
`
`3
`
`4
`
`1250
`
`1250
`
`1250
`
`1236
`
`1640
`
`1528
`
`1499
`
`1572
`
`Yield Melting point
`(%)
`(°C)
`
`88.00
`
`104.3-106.3
`
`8200*
`
`105.5-107.2
`
`80.42**
`
`104.7-106.6
`
`85.34
`
`105-108
`
`*N0te: In this batch, approximately 1200 mL of ethyl acetate solution of treprostinil before carbon
`
`treatment was rcmovcd for R&D carbon trcatmcnt cxpcrimcnts.
`
`**Note: This batch was recrystallized, for this reason yield was lower.
`
`Example 4.
`
`Heptane Slurry of Treprostinil Diethanolamine Salt (1 :1)
`
`BatchN°- Treprostinil
`
`Diethanolamine Salt
`
`1
`
`3168 g
`37-5 L
`
`WASH_5142948. 1
`
`_
`
`_
`
`SteadyMed - Exhibit 1002 - Page 18
`
`SteadyMed - Exhibit 1002 - Page 18
`
`

`

`Trepro stinil Diethanolamine Salt
`
`Batch N°-
`
`2
`
`3071 g
`
`[0044]
`
`A 50-L, cylindrical reactor equipped with a heating/cooling system, a mechanical
`
`stirrer,
`
`a condenser,
`
`and a
`
`thermocouple was charged with slurry of treprostinil
`
`diethanolamine salt in heptane (35-40 L). The suspension was heated to 70-80°C for 16-24 h.
`
`The suspension was cooled to 22i2°C over a period of 1-2 h. The salt was collected by
`
`filtration using Aurora filter. The cake was washed with heptane (15-30 L) and the material
`
`was dried in Aurora filter for 1 h. The salt was transferred to trays for air—drying overnight in
`
`hood until a constant wcight of trcprostinil dicthanolaminc salt was obtained. The material
`
`was dried in oven under high vacuum for 2-4 h at 50-55°C.
`
`Analytical data on and Treprostinil Diethanolamine Salt (1 :1)
`
`Test
`
`IR
`
`Residue on Ignition (ROI)
`
`Water content
`
`Melting point
`
`Batch 1
`
`Conforms
`
`<0.l% W/W
`
`0.1% W/W
`
`105.0-106.5°C
`
`Specific rotation [0L]255g9
`
`+34.6°
`
`Organic volatile impurities
`
`Batch 2
`
`Conforms
`
`<0.1% W/W
`
`0.0% W/W
`
`104.5-105.5°C
`
`+35°
`
`Ethanol
`
`- Not detected
`
`- Not detected
`
`-
`
`-
`
`Ethyl acctatc
`
`- Not dctcctcd
`
`- Heptane
`
`HPLC (Assay)
`
`Diethanolamine
`
`-
`
`<0.05% w/w
`
`100.4%
`
`Positive
`
`°
`
`°
`
`<0.05% W/W
`
`<0.05% W/W
`
`99.8%
`
`Positive
`
`WAS H_51 42948.1
`
`_ 16 _
`
`SteadyMed - Exhibit 1002 - Page 19
`
`SteadyMed - Exhibit 1002 - Page 19
`
`

`

`Example 5.
`
`Conversion of Treprostinil Diethanolamine Salt (1 :1) to Treprostinil
`
`
`
`Recrystallization
`in EtOH-H20
`
`H CI, H 20-EtOAC
`
`[0045]
`
`A 250-mL, round-bottom flask equipped with magnetic stirrer was charged with
`
`treprostinil diethanolamine salt (4 g) and water (40 mL). The mixture was stirred to obtain a
`
`clear solution. To the clear solution, ethyl acetate (100 mL) was added. While stirring, 3M
`
`HC1 (3.2 mL) was added slowly until pH ~1 was attained. The mixture was stirred for 10
`
`minutes and organic layer was separated. The aqueous layer was extracted with ethyl acetate
`
`(2 X 100 mL). The combined organic layers was washed with water (2 X 100 mL), brine
`
`(1 X 50 mL) and dried over anhydrous Na2SO4. The ethyl acetate solution of treprostinil was
`
`filtered and the filtrate was concentrated under vacuum at 50°C to give off—white solid. The
`
`crude treprostinil was recrystallized from 50% ethanol
`
`in water (70 mL).
`
`The pure
`
`treprostinil was collected in a Buchner funnel by filtration and cake was washed with cold
`
`20% ethanolic solution in water. The cake of treprostinil was air-dried overnight and further
`
`dried in a vacuum oven at 50°C under high vacuum to afford 2.9 g of treprostinil (Yield
`
`91.4%, purity (HPLC, AUC, 99.8%).
`
`Analytical data on Treprostinil
`
`from Treprostinil Diethanolamine Salt
`
`(1:1) to
`
`Treprostinil
`
`Batch No.
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`WAS H_51 42948.1
`
`Yield
`
`91.0%
`
`92.0%
`
`93.1%
`
`93.3%
`
`99.0 %
`
`94.6%
`
`Purity (HPLC)
`
`99.8% (AUC)
`
`99.9% (AUC)
`
`99.7% (AUC)
`
`99.7% (AUC)
`
`99.8% (AUC)
`
`99.8% (AUC)
`
`_ 17 _
`
`SteadyMed - Exhibit 1002 - Page 20
`
`SteadyMed - Exhibit 1002 - Page 20
`
`

`

`Example 6.
`
`Comparison of the former process and a working example of the process
`
`according to the present invention
`
`Step
`No.
`
`Steps
`
`Former Process
`(Batch size: 500g)
`
`Nitrile
`
`Working example of the
`Process according to the
`present invention
`(Batch size: 5 kg)
`
`1
`
`2
`
`3
`
`4
`
`6
`
`7
`
`8
`
`9
`
`Triol weight
`
`500 g
`
`5,000 g
`
`Acetone
`
`Potassium
`
`carbonate
`
`20 L (1 :40 wt/wt)
`
`75 L (1:15 wt/wt)
`
`1,300 g (6.4 eq)
`
`5,200 g (2.5 eq)
`
`Chloroacetonitrile
`
`470 g (4.2 eq)
`
`2,270 g (2 eq)
`
`Tetrabutylammoniu
`m bromide
`
`42 g (0.08 eq)
`
`145 g (0.03 eq)
`
`Reactor size
`
`72-Liter
`
`50- gallon
`
`Reflux time
`
`8 hours
`
`Hexanes addition
`
`before filtration
`
`Yes (10 L)
`
`Filter
`
`Celite
`
`No heating,
`Room temperature (r.t.) 45 h
`
`No
`
`Celite
`
`10 Washing
`
`Ethyl acetate (10 L)
`
`Acetone (50 L)
`
`1 1
`
`Evaporation
`
`Yes
`
`Yes
`
`12
`
`Purification
`
`Silica gel column
`Dichloromethane:0.5 L
`
`Ethyl acetate: 45 L
`Hexane: 60 L
`
`13
`
`Evaporation after
`column
`
`Yes
`
`No column
`
`No
`
`14
`
`Yield of nitrite
`
`109-112 %
`
`Not chcckcd
`
`Treprostinil (intermediate)
`
`15 Methanol
`16
`P°taSS‘?”“
`17 Water
`
`7.6 L (50-L reactor)
`650 g (8 eq)
`2.2 L
`
`50 L (50-gal reactor)
`3,375g (4 eq)
`17 L
`
`18
`
`% of KOH
`
`30%
`
`20%
`
`WAS H_51 42948.1
`
`_ 18 _
`
`SteadyMed - Exhibit 1002 - Page 21
`
`SteadyMed - Exhibit 1002 - Page 21
`
`

`

`19
`
`20
`
`21
`
`22
`
`23
`
`Reflux time
`
`3-3.5 h
`
`4-5 h
`
`Acid used
`
`Removal of
`
`impurities
`
`2.6 L (3 M)
`
`12 L (3 M)
`
`3 X 3 L Ethyl acetate
`
`2 X 20 L Ethyl acetate
`
`Acidification
`
`0.7 L
`
`6.5 L
`
`Ethyl acetate
`extraction
`
`5 X 17 L = 35 L
`
`90+45+45 = 180 L
`
`24 Water Washing
`
`2 X 8 L
`
`3 X 40 L
`
`Sodium bicarbonate
`washing
`
`Not done
`
`Brine washing
`
`Not done
`
`Sodium sulfate
`
`1 kg
`
`25
`
`26
`
`27
`
`120 g in 30L water + 15 L
`brine
`
`1 X 40 L
`
`Not done
`
`Sodium sulfate
`
`Before charcoal, 6 L
`
`28
`
`filtration
`
`ethyl acetate
`
`N/A
`
`29
`
`Charcoal
`
`30
`
`Evaporation
`
`170 g, reflux for 1.5 h,
`filter over Celite, 11 L
`ethyl acetate
`
`Pass hot solution (75°C)
`through charcoal cartridge
`and clean filter, 70 L ethyl
`acctatc
`
`Yes, to get solid
`intermediate treprostinil
`
`Yes, adjust to 150 L
`solution
`
`Treprostinil Diethanolamine Salt
`
`31
`
`Salt formation
`
`Not done
`
`32
`
`Cooling
`
`33
`
`Filtration
`
`34
`
`Drying
`
`N/A
`
`N/A
`
`N/A
`
`1,744 g diethanolamine,
`20 L ethanol at 60-75°C.
`
`To 20°C over weekend;
`
`add 40 L ethyl acetate;
`cooled to 10°C
`
`Wash With 70 L ethyl
`acetate
`
`Air-dried to constant wt.,
`
`2 days
`
`Treprostinil (from 1.5 kg Treprostinil diethanolamine salt)
`
`35
`
`36
`
`Hydrolysis
`
`Extraction
`
`37 Water wash
`
`38
`
`Brine wash
`
`N/A
`
`N/A
`
`N/A
`
`N/A
`
`15 L Water + 25 L ethyl
`acetate + HCl
`
`2 X 10 L ethyl acetate
`
`3 X 10 L
`
`1 X 10 L
`
`WAS H_51 42948.1
`
`_19_
`
`SteadyMed - Exhibit 1002 - Page 22
`
`SteadyMed - Exhibit 1002 - Page 22
`
`

`

`39
`
`Sodium sulfate
`
`40
`
`Filter
`
`Evaporation
`
`N/A
`
`N/A
`
`N/A
`
`1 kg, stir
`
`Wash With 6 L ethyl
`acetate
`
`To get solid, intermediate
`Treprostinil
`
`41
`
`42
`
`43
`
`44
`
`45
`
`46
`
`Crude drying on tray
`
`1 or 3 days
`
`Same
`
`Ethanol & water for
`
`cryst.
`
`5.1 L+5.1 L
`
`10.2L+10.2L(same%)
`
`Crystallization in
`
`20—L rotavap flask
`
`50—L jacketed reactor
`
`Temperature of
`crystallization
`
`2 h r.t., fridge -0°C 24 h
`
`50°C to 0°C ramp, 0°C
`overnight
`
`Filtration
`
`Buchner funnel
`
`Aurora filter
`
`47 Washing
`
`20% (10 L) cooled
`ethanol—water
`
`20% (20 L) cooled
`ethanol—water
`
`Drying before oven
`
`Buchncr funncl (20 h)
`T