Atty. Dkt, No. 080618—1256
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`First Inventor Name: Hitesh BATRA
`
`Title:
`
`AN IMPROVED PROCESS TO PREPARE
`
`TREPROSTINIL, THE ACTIVE INGREDIENT
`IN REMODULIN®
`
`Prior Appl. N0.:
`
`13/548,446
`
`Prior Appl. Filing
`Date:
`
`7/13/2012
`
`Examiner:
`
`Unassigned
`
`Art Unit:
`
`Unassigned
`
`CONTINUING PATENT APPLICATION
`TRANSMITTAL LETTER
`
`Commissioner for Patents
`PO. Box 1450
`
`Alexandria, VA 22313—1450
`
`Commissioner:
`
`Transmitted herewith for filing under 37 CFR. § l.53(b) is a:
`
`[X] Continuation
`
`[ ]Division
`
`[
`
`] Continuation-In-Part (CIP)
`
`of the above-identified copending prior application in which no patenting, abandonment, or
`
`termination of proceedings has occurred. Priority to the above-identified prior application is
`
`hereby claimed under 35 U .S.C. § 120 for this continuing application. The entire disclosure
`
`of the above~identified prior application is considered as being part ofthe disclosure ofthc
`
`accompanying continuing application and is hereby incorporated by reference therein.
`
`[
`
`]
`
`Applicant claims small entity status under 37 CFR 1.27.
`
`Enclosed are:
`
`[X] Description, Claims, and Abstract (23 pages).
`
`[ X ] Executed Declaration (4 pages).
`
`|PR2020-00770
`
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`Page 1 of 265
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`IPR2020-00770
`United Therapeutics EX2028
`Page 1 of 265
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`

`

`Atty. Dkt. No. 080618—1256
`
`[X] Power of Attorney (1 page).
`
`[ X ]
`
`Information Disclosure Statement, Form PTO—SB08.
`
`[X] Application Data Sheet (37 CFR 1.76).
`
`The adjustment to the number of sheets for EFS—Web filing follows:
`
`Number of
`
`EFS-Web
`
`Number of Sheets for EFS-Web
`
`Adjustment
`Sheets
`
`23 1 8 x 75%
`
`
`
`
`The filing fee is calculated below at the large entity rate:
`
`
`
`Number
`Filed
`
`Included
`in
`Basic Fee
`
`Extra
`
`Rate
`
`Basic Filing
`Fee
`Search Fee
`
`Examination
`Fee
`
`Size Fee
`Total
`Claims:
`
`18
`9
`
`»
`-
`
`100
`20
`
`= 0
`T 0
`
`$280.00
`
`$600.00
`$720.00
`
`$400.00
`$80.00
`
`X + +
`
`= 0
`3
`—
`1
`Independent:
`If any Multiple Dependent Claim(s) present:
`Surcharge under 37 CFR 1.16(e) for late filing of
`Executed Declaration or late payment of filing fee
`Prioritized Examination fee (Track I) under 37 CFR. § 1.1 7 (0)
`
`$420.00
`$780.00
`$140.00
`
`Processing Fee (Track I) under 37 CPR. § 1.17 (i)
`TOTAL FILING FEE:
`
`$40.00
`$140.00
`
`+ +
`
`Assignment Recordation Fee:
`Processing Fee under 37 CFR 1170) for Late Filing
`of English Translation of Application:
`Publication Fee
`
`TOTAL FEE
`$1 600 .00
`
`Fee
`Totals
`
`$280.00
`
`$600.00
`$720.00
`
`$0.00
`
`$0.00
`$1600.00
`$0.00
`
`$000
`
`ll
`
`11
`
`II
`II
`
`11
`
`11
`
`11
`
`The above-identified fees of $1600.00 are being paid by credit card via EFS-Web.
`
`The Commissioner is hereby authorized to charge any additional fees which may be
`
`required regarding this application under 37 CFR. §§ 1.16-1.17, or credit any overpayment,
`
`to Deposit Account No. 19-0741. Should no proper payment be enclosed herewith, as by the
`
`|PR2020-00770
`
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`Page 2 of 265
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`Page 2 of 265
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`Atty. Dkt. No. 080618—1256
`
`credit card payment instructions in EFS-Web being incorrect or absent, resulting in a rejected
`
`or incorrect credit card transaction, the Commissioner is authorized to charge the unpaid
`
`amount to Deposit Account No. l9~0741.
`
`Please direct all correspondence to the undersigned attorney or agent at the address
`
`indicated below.
`
`Date July 2, 2013
`
`FOLEY & LARDNER LLP
`Customer Number: 22428
`
`Telephone:
`Facsimile:
`
`(202) 672—5569
`(202) 672-5399
`
`Respectfully submitted,
`
`
`
`Stephen B. Maebius
`Attorney for Applicant
`Registration No. 35,264
`
`|PR2020-00770
`
`United Therapeutics EX2028
`Page 3 of 265
`
`IPR2020-00770
`United Therapeutics EX2028
`Page 3 of 265
`
`

`

`Atty. Dkt, No. 080618—1256
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`First Inventor Name: Hitesh BATRA
`
`Title:
`
`AN IMPROVED PROCESS TO PREPARE
`
`TREPROSTINIL, THE ACTIVE INGREDIENT
`IN REMODULIN®
`
`Prior Appl. N0.:
`
`13/548,446
`
`Prior Appl. Filing
`Date:
`
`7/13/2012
`
`Examiner:
`
`Unassigned
`
`Art Unit:
`
`Unassigned
`
`CONTINUING PATENT APPLICATION
`TRANSMITTAL LETTER
`
`Commissioner for Patents
`PO. Box 1450
`
`Alexandria, VA 22313—1450
`
`Commissioner:
`
`Transmitted herewith for filing under 37 CFR. § l.53(b) is a:
`
`[X] Continuation
`
`[ ]Division
`
`[
`
`] Continuation-In-Part (CIP)
`
`of the above-identified copending prior application in which no patenting, abandonment, or
`
`termination of proceedings has occurred. Priority to the above-identified prior application is
`
`hereby claimed under 35 U .S.C. § 120 for this continuing application. The entire disclosure
`
`of the above~identified prior application is considered as being part ofthe disclosure ofthc
`
`accompanying continuing application and is hereby incorporated by reference therein.
`
`[
`
`]
`
`Applicant claims small entity status under 37 CFR 1.27.
`
`Enclosed are:
`
`[X] Description, Claims, and Abstract (23 pages).
`
`[ X ] Executed Declaration (4 pages).
`
`|PR2020-00770
`
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`Page 4 of 265
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`IPR2020-00770
`United Therapeutics EX2028
`Page 4 of 265
`
`

`

`Atty. Dkt. No. 080618—1256
`
`[X] Power of Attorney (1 page).
`
`[ X ]
`
`Information Disclosure Statement, Form PTO—SB08.
`
`[X] Application Data Sheet (37 CFR 1.76).
`
`The adjustment to the number of sheets for EFS—Web filing follows:
`
`Number of
`
`EFS-Web
`
`Number of Sheets for EFS-Web
`
`Adjustment
`Sheets
`
`23 1 8 x 75%
`
`
`
`
`The filing fee is calculated below at the large entity rate:
`
`
`
`Number
`Filed
`
`Included
`in
`Basic Fee
`
`Extra
`
`Rate
`
`Basic Filing
`Fee
`Search Fee
`
`Examination
`Fee
`
`Size Fee
`Total
`Claims:
`
`18
`9
`
`»
`-
`
`100
`20
`
`= 0
`T 0
`
`$280.00
`
`$600.00
`$720.00
`
`$400.00
`$80.00
`
`X + +
`
`= 0
`3
`—
`1
`Independent:
`If any Multiple Dependent Claim(s) present:
`Surcharge under 37 CFR 1.16(e) for late filing of
`Executed Declaration or late payment of filing fee
`Prioritized Examination fee (Track I) under 37 CFR. § 1.1 7 (0)
`
`$420.00
`$780.00
`$140.00
`
`Processing Fee (Track I) under 37 CPR. § 1.17 (i)
`TOTAL FILING FEE:
`
`$40.00
`$140.00
`
`+ +
`
`Assignment Recordation Fee:
`Processing Fee under 37 CFR 1170) for Late Filing
`of English Translation of Application:
`Publication Fee
`
`TOTAL FEE
`$1 600 .00
`
`Fee
`Totals
`
`$280.00
`
`$600.00
`$720.00
`
`$0.00
`
`$0.00
`$1600.00
`$0.00
`
`$000
`
`ll
`
`11
`
`II
`II
`
`11
`
`11
`
`11
`
`The above-identified fees of $1600.00 are being paid by credit card via EFS-Web.
`
`The Commissioner is hereby authorized to charge any additional fees which may be
`
`required regarding this application under 37 CFR. §§ 1.16-1.17, or credit any overpayment,
`
`to Deposit Account No. 19-0741. Should no proper payment be enclosed herewith, as by the
`
`|PR2020-00770
`
`United Therapeutics EX2028
`Page 5 of 265
`
`IPR2020-00770
`United Therapeutics EX2028
`Page 5 of 265
`
`

`

`Atty. Dkt. No. 080618—1256
`
`credit card payment instructions in EFS-Web being incorrect or absent, resulting in a rejected
`
`or incorrect credit card transaction, the Commissioner is authorized to charge the unpaid
`
`amount to Deposit Account No. l9~0741.
`
`Please direct all correspondence to the undersigned attorney or agent at the address
`
`indicated below.
`
`Date July 2, 2013
`
`FOLEY & LARDNER LLP
`Customer Number: 22428
`
`Telephone:
`Facsimile:
`
`(202) 672—5569
`(202) 672-5399
`
`Respectfully submitted,
`
`
`
`Stephen B. Maebius
`Attorney for Applicant
`Registration No. 35,264
`
`|PR2020-00770
`
`United Therapeutics EX2028
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`Atty. Dkt. No. 0806l 8—l256
`
`AN IMPROVED PROCESS TO PREPARE TREPROSTINIL, THE ACTIVE
`INGREDIENT IN REMODULIN®
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`[0001]
`
`This application is a Continuation of U.S. Application No. 13/548,446, filed July
`
`13, 2012, which is a Continuation of U.S. Application No. 12/334,731, filed December 15,
`
`2008, which 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 usefill 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 and 6,809,223. 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 oftreprostinil for treatment ofpulmonary
`
`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. 2005/01 651 1 l 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 neuropathie foot ulcers. U.S. application No. 12/028,471 filed February 8, 2008,
`
`4833-6891-16364
`
`,1,
`
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`Atty. Dkt. No. 080618—1256
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`discloses treprostinil treatment of pulmonary fibrosis. US. 6,054,486 discloses treatment of
`
`peripheral vascular disease with treprostinil. US. patent application 11/873,645 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.
`
`US. application No. 12/028,471 filed February 8, 2008 discloses treatment of asthma with
`
`treprostinil.
`
`US. 7,417,070, 7,384,978 and US. publication Nos. 2007/0078095,
`
`2005/0282901, and 2008/0249167 describe oral
`
`formulations of treprostinil and other
`
`prostacyclin analogs.
`
`[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.
`
`W
`
`[0007]
`
`The present invention provides in one embodiment a process for the preparation of
`
`a compound of formula I, hydrate, solvate, prodrug, or pharrnaceutically acceptable salt
`
`thereof.
`
`Y1_fi_fi_R7
`M1 L1
`OH
`
`H
`
`H
`
`o (c H2)WCOOH
`
`(I)
`
`[0008]
`
`The process comprises the following steps:
`
`(a)
`
`alkylating a compound of structure II with an alkylating agent to produce a
`
`compound of formula 111,
`
`Y1_fi_fi_R7
`M1 L1
`OH
`
`H
`
`H
`
`OH
`
`“Ti—FR?
`M1 L1
`OH
`
`H
`
`H
`
`(11:)
`
`O(CH21~CN
`
`(111)
`
`4833-6891-16364
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`2 2 ,
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`Atty. Dkt. No. 080618—1256
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`wherein
`
`W: 1, 2, or 3;
`
`Y1 is trans—CH2CH—, eis—CHZCH—, —CH2(CH2),,,—, or —CEC-; m is 1, 2, or 3;
`
`R7 is
`
`(1)
`
`(2)
`
`-CPl-l_7p-Cl-lg, 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)alkoxy, with the proviso that not more than two
`
`substituents are other than alkyl, with the proviso that R7 is phenoxy or substituted phenoxy,
`
`only when R3 and R4 are hydrogen or methyl, being the same or different,
`
`(3)
`
`phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on
`
`the aromatic ring by one,
`
`two or three chloro, fluoro,
`
`trifluoromethyl,
`
`(C1-C3)alkyl, or
`
`(Cl-Cg)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
`
`(1)
`
`(2)
`
`(3)
`
`(4)
`
`(C4—C7)cycloalkyl optionally substituted by 1 to 3 (C1-C5)alkyl;
`
`2—(2—furyli)ethyl,
`
`2-(3 -thienyl)ethoxy, or
`
`3—thienyloxymethyl;
`
`M1 is OL-OHZB-R5 or OL-R5zl3-OH or Ot-ORlifi-Rs or a-Rszfi-ORZ, wherein R5 is
`
`hydrogen or methyl, R2 is an alcohol protecting group, and
`
`L1 is Ot-RgIB-R4, Ot-R4IB-R3, or a mixture of (l-RgIB-R4 and a-R4zl3-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)
`
`(0)
`
`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 Is
`
`4833-6891-16361
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`H
`
`H
`
`Yrfi-fi-Rv
`M1 L1
`OH
`
`HB
`
`O(CH2)WCOOe
`
`(Is)
`
`(d)
`
`reacting the salt from step (c) with an acid to fonn the compound of fonnula I.
`
`[0009]
`
`The present
`
`invention provides in another embodiment a process for
`
`the
`
`preparation of a compound of formula IV.
`
`(IV)
`
` k
`
`COOH
`
`[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,
`
`(VI)
`
` k
`
`CN
`
`
`
`(V)
`
`(b)
`
`(0)
`
`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 le,
`
`4833-6891-16361
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`
`
`
`(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-alkyl
`
`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-cyeloalkyl is an optionally substituted monoeyelie, bicyclic or tricyelic 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,
`
`4833-6891-16361
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`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.
`
`[002]]
`
`“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,
`
`fiamarate,
`
`gluceptate,
`
`gluconate,
`
`glutamate,
`
`glycollylarsanilate,
`
`hexafluorophosphate,
`
`hexylresorcinate,
`
`hydrabamine,
`
`hydrobromide,
`
`hydrochloride,
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`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
`
`(l , l —methene-bis -2 —hydroxy—3 —naphtho ate,
`
`einbonate),
`
`pantothenate,
`
`phosphate/diphosphate, picrate, polygalacturonate, propionate, p-tolucnesulfonate, salicylate,
`
`stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,
`
`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 1, or a hydrate, solvate, prodr'ug, or pharmaceutically acceptable salt
`
`thereof.
`
`Y1—fi_fi_R7
`M1 L1
`OH
`
`H
`
`H
`
`o (c H2)WCOO H
`
`(I)
`
`[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,
`
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`
`VFW—R?
`M1 L1
`OH
`
`H
`
`H
`
`(II)
`
`O(CH2)WCN
`
`(111)
`
`H
`
`Y1— _ _R7
`3 9
`M1 L1
`OH
`
`OH
`wherein
`
`H
`
`W: I, 2, or 3;
`
`Y, is trans-CH=CH-, cis-CH=CH-, -CH2(CH2)m-, or -CEC-; m is l, 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, (Cl-C3) alkyl, or (Cl-Cg)alkoxy, with the proviso that not more than two
`
`substituents are other than alkyl, with the proviso that R7 is phenoxy or substituted phenoxy,
`
`only when R3 and R4 are hydrogen or methyl, being the same or different,
`
`(3)
`
`phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on
`
`the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C 1-C3)alkyl, or (C 1-
`
`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—C7i)eycloalkyl optionally substituted by l to 3 (C1-C5)alkyl;
`
`2-(2-furyl)ethyl,
`
`2—(3 —thienyl)ethoxy, or
`
`3—thienyloxymethyl;
`
`M1 is OL—OH:[3—R5 or OL—R5:[3—OH or OL-OR] ZB-Rs or OL—R51B-OR2, wherein R5 is
`
`hydrogen or methyl, R2 is an alcohol protecting group, and
`
`L1 is or-R32B-R4, OL-R42B-R3, or a mixture of OL-Rgzfi-R4 and OL-R42B-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,
`
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`(c)
`
`contacting the product of step (b) with a base B to for a salt of formula Is
`
`Atty. Dkt. No. 080618—1256
`
`H
`
`H
`
`Yrfi-fi—Rv
`M1 L1
`OH
`
`(-9
`
`HB
`
`O(CH2)WCOOe
`
`(Is)
`
`((1)
`
`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 US. Pat.
`
`No. 6,441,245.
`
`0R1
`
`Y _ _ _R
`\ 1
`
`a. it
`
`7
`
`0R1
`WSW—F”
`M1 L1
`CC? 0
`H
`
`0(CH2)nCH3
`
`(X)
`
`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
`
`US. Pat. No. 6,700,025.
`
`OR
`
`1
`C \
`\\c\ _ _ _
`\ Y1 fi E R7
`M1 L1
`
`OBn
`
`VFW—R7
`M1 L1
`OH
`
`(XII)
`
`OB n
`
`H
`
`(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.
`
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`Atty. Dkt. N0. 080618—1256
`
`(IV)
`
` k
`
`COOH
`
`[0030]
`
`The process comprises
`
`(a)
`
`alkylating a compound of structure V with an alkylating agent such as
`
`ClCHgCN to produce a compound of formula VI,
`
` L
`
`CN
`
`(V1)
`
`(V)
`
`(b)
`
`(c)
`
`hydrolyzing the product of step (a) with a basc such as KOl—l,
`
`contacting the product of step (b) with a base B such as diethanolamine to for
`
`a salt of the following structure, and
`
`H0
`
` (D NH2(C HZCHZOH)2
`
`(d)
`
`reacting the salt from step (b) with an acid such as HCl to form the compound
`
`of formula IV.
`
`[003]]
`
`In one embodiment, the purity of compound of formula IV is at least 90.0%,
`
`95.0%, 99.0%, 99.5%.
`
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`[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 1.
`
`Alkylation of Benzindene Triol
`
`EXAMPLES
`
`
`
`K2003, BU4N Br
`Acetone, RT
`
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`
`
`Name
`
`Amount
`
`M01.
`
`Eq
`
`
`
`
`
`
`
`
`Benzindene Triol
`
`K2C03 (powder)
`
`CICH2CN
`
`Bu4NBr
`
`Acetone
`
`Celite®545
`
`1250 g
`
`1296 g
`
`567 g
`
`36 g
`
`29 L
`
`115 g
`
`3.76
`
`9.38
`
`7.51
`
`0.11
`
`——
`
`--
`
`1.00
`
`2.50
`
`2 0
`
`0.03
`
`——
`
`-—
`
`——
`
`--
`
`[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 K2CO}
`
`(powdered) (1296 g). Chloroacetonitrile (567 g), tetrabutylammonium bromide (36 g). The
`
`reaction mixture was stirred vigorously at room temperature (23::20C) for 16—72 h. The
`
`progress of the reaction was monitored by TLC.
`
`(methanol/CH2C12; 1:9 and developed by
`
`P
`10% ethanolic solution of PMA . After com,letion 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
`
`
`
`
`KOH, MeOH—>
`
`H20, Reflux
`
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`
`
`Name
`
`Benzindene Nitrile
`
`KOH
`
`Methanol
`
`Water
`
`MW
`
`Amount
`
`M01.
`
`
`
`
`
`
`
`1397 g*
`
`844 g
`
`12 L
`
`4.25 L
`
`Eq.
`
`1.0
`
`4.0
`
`--
`
`-—
`
`*Note: This weight is based 011 100% 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, l-2 mL of reaction mixture was acidified
`
`with 3M HCl to pH 1—2 and extracted with ethyl acetate. The ethyl acetate extract was used
`
`for TLC; Eluent: methanol/CHzClz; 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 l—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 X 11 L). The combined organic layers were washed with water (3 X 10 L) and
`
`followed by washing with a solution of NaHC03 (30 g of NaHC03 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 Na2804 (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 (110—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
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`Atty. Dkt. No. 080618—1256
`
`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
`
`vacua at 50-55°C for direct use in next step.
`
`Example 3.
`
`Conversion of Treprostinil to Treprostinil Diethanolamine Salt (1:1)
`
`(I) EtOH, EtOAc—.
`
`Name
`
`Treprostinil
`
`
`
`
`
`
`
`(II) Heptane Slurry
`Diethanolamine
`
`
`
`
`
`Ethyl acetate __ -— 3 5L* * __
`
`Treprostinil Diethanolamine
`Salt (seed)
`
`-—
`
`12 g
`
`_-
`
`__
`
`*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.] 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::50C. At this temperature, the seed of
`L 14 L
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`
`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 l 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
`Benzindene Trio]
`
`Batch No.
`
`1
`
`$03M
`
`(g)
`
`1250
`
`1250
`
`1250
`
`1236
`
`Wt. of Treprostinil
`Diethanolamine Salt (1:1)
`(g)
`
`1 640
`
`1528
`
`1499
`
`1572
`
`Yield
`
`(0%)
`
`88.00
`
`Melting point
`(°C)
`
`1043—1063
`
`8200*
`
`1055—1072
`
`80.42**
`
`104.7—106.6
`
`85.34
`
`105—108
`
`*Note: In this batch, approximately 1200 mL of ethyl acetate solution of treprostinil before carbon
`
`treatment was removed for R&D carbon treatment experiments.
`
`**Note: This batch was recrystallized. for this reason yield was lower.
`
`Example 4.
`
`Heptane Slurry of Treprostinil Diethanolamine Salt (1 :1)
`
`Name
`
`
`
`Batch No.
`
`Amount
`
`
`
`Ratio
`
`l
`
`12
`
`
`
`
`
`Treprostinil
`Diethanolamine Salt
`
`Heptane
`
`1
`
`——
`
`3168 g
`
`37.5 L
`
`
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