`Case 3:l4—cv—05499—PGS—LHG Document 42-3 Filed 07/07/15 Page 1 of 206 Page|D: 686
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`
`
`EXHIBIT 11
`EXHIBIT 11
`
`
`
`
`
`Case 3:14-cv-05499-PGS-LHG Document 42-3 Filed 07/07/15 Page 2 of 206 PageID: 687
`me‘ . 42-3 Filed 07/07/15 Page 2 of 206 Page|D:
`
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`
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`
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`
`Cs::'E§i"j,’iz§;‘§ *?{§fi‘”im:'
`
`UTC_REM_||_000003371
`
`
`
`
`Case 3:14-cv-05499-PGS-LHG Document 42-3 Filed 07/07/15 Page 3 of 206 PageID: 688
`Case 3:14—cv—O5499—PGS—LHG Document 42-3 Filed 07/07/15 Page 3 of 206 Page|D: 688
`
`Atty. Dkt.No. 080618-1162
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Applicant:
`
`Hitesh BATRA et al.
`
`Title:
`
`AN IMPROVED PROCESS TO PREPARE
`
`TREPROSTINIL, THE ACTIVE
`INGREDIENT IN REMODULIN®
`
`Prior Appl. No.1
`
`I2/334,731
`
`Prior Appl.
`Filing Date:
`
`12/15/2008
`
`Examiner:
`
`Unassigned
`
`Art Unit:
`
`Unassigned
`
`CONTINUING PATENT APPLICATION
`TRAN SMITTAL LETTER
`
`Commissioner for Patents
`PO. Box 1450
`
`Alexandria, VA 223 I 3-I450
`
`Commissioner:
`
`Transmitted herewith for filing under 37 C.F.R. § I.53(b) is a:
`
`[X] Continuation
`
`[ ]Division
`
`[
`
`j Continuation—In—Part (CIP)
`
`of the aboveddentifled 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 of the disclosure of the
`
`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 (27 pages).
`
`4822-4896-5392.1
`
`UTC_REM_||_000003372
`
`
`
`
`Case 3:14-cv-05499-PGS-LHG Document 42-3 Filed 07/07/15 Page 4 of 206 PageID: 689
`Case 3:14—cv—O5499—PGS—LHG Document 42-3 Filed 07/07/15 Page 4 of 206 Page|D: 689
`
`I X 1 Copy of Executed Declaration and Power of Attorney from prior application (4
`pages).
`
`Atty. D1(t.No. 0806181 162
`
`[ X ]
`
`Information Disclosure Statement, Form PTO—SB08.
`
`[ X ] Application Data Sheet (37 CFR 1.76).
`
`The adj ustment to the number of sheets for EFS—Web filing follows:
`
`‘ Niimber of
`
`Sheets
`_ 27
`
`x
`
`EFS-Web
`
`Adjustment
`75%
`
`The filing fee is calculated below:
`
`Number
`Filed
`
`Included
`in
`
`Basic Fee
`
`Number of Sheets for EFS—Web 0*
`
`21
`
`Extra
`
`Rate
`
`Fee
`Totals
`
`Basic Filing
`
`Fee
`Search Fee
`Examination
`
`Fee
`Size Fee
`Total
`
`21
`21
`
`—
`-
`
`100
`20
`
`= 0
`= 1
`
`Claims:
`= 0
`3
`—
`2
`Independent:
`If any Multiple Dependent C1aim(s) present:
`Surcharge under 37 CFR 1.16(e) for late filing of
`Executed Declaration or late payment of filing fee
`
`$380.00 =
`
`$620.00
`$250.00
`
`$310.00
`$60.00
`
`1*
`
`__*"___’_”___
`$380.00
`
`gnflémw
`
`$250.00
`
`_'_w_”___
`
`$60.00
`
`’_N_W"_gq_
`$250.00 3 v L 7?
`_
`$450.00 =
`$0.00
`$130.00 ‘
`T fiwfiééw
`
`M
`
`x
`it
`
`x
`+
`+
`
`[I
`
`]
`
`SUBTOTAL:
`Small Entity Fees Apply (subtract ‘/2 of above): = m_N_H_”,()__
`Basic Filing Fee Reduction for Filing via EFS-Web
`Prioritized Examination fee (Track 1) under 37 C.F.R. § 1.17 (c)
`
`$000
`
`Processing Fee (Track 1) under 37 CFR. § 1.17 (i)
`TOTAL FILING FEE: = *_g__ $1310.00”
`a‘
`$40.00
`=
`Assignment Recordation Fee:
`Processing Fee under 37 CFR 1.17(i) for Late Filing +
`$130.00
`,
`of English Translation of Application:
`F
`Publication Fee
`_ TOTAL FEE
`
`gfi
`_*___W_SiQ._(£)__
`$1310.00
`
`2
`
`$0.00
`
`The above—identified fees of $13 1 0.00 are being paid by credit card via EFS—Web.
`
`4822-4896-5392.1
`
`UTC_REM_||_000003373
`
`
`
`
`Case 3:14-cv-05499-PGS-LHG Document 42-3 Filed 07/07/15 Page 5 of 206 PageID: 690
`Case 3:14—cv—O5499—PGS—LHG Document 42-3 Filed 07/07/15 Page 5 of 206 Page|D: 690
`
`Atty. Dkt.No. 080618-1162
`
`The Commissioner is hereby authorized to charge any additional fees which may be
`
`required regarding this application under 37 C.F.R. §§ l.l6—l .l7, or credit any overpayment,
`
`to Deposit Account No. 19-0741. Should no proper payment be enclosed herewith, as by the
`
`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. 19-0741.
`
`Please direct all correspondence to the undersigned attorney or agent at the address
`
`indicated below.
`
`Date_
`
`JUL 3 3 Elli?
`
`FOLEY & LARDN ER LLP
`Customer Number: 22428
`
`Telephone:
`Facsimile:
`
`(202) 672-5569
`(202) 672-5399
`
`Respectfully submitted,
`
`By
`
`57’
`i
`if
`/I
`/A4
`)£
`
`Stephen B. Maebius
`Attorney for Applicant
`
`Registration No. 35,264
`
`4822-4BEl6A5392.‘l
`
`UTC_REM_l|_000003374
`
`
`
`
`Case 3:14-cv-05499-PGS-LHG Document 42-3 Filed 07/07/15 Page 6 of 206 PageID: 691
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`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. 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 usefitl in the process.
`
`[0003]
`
`Prostacyclin derivatives
`
`are useful pharmaceutical
`
`compounds possessing
`
`activities such as platelet aggregation inhibition, gastric secretion reduction, lesion inhibition,
`
`a11d 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 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,
`
`4819-1483-6493.2
`
`_1_
`
`UTC_REM_l|_000003375
`
`
`
`
`Case 3:14-cv-05499-PGS-LHG Document 42-3 Filed 07/07/15 Page 7 of 206 PageID: 692
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`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 filcd 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, hydratc, solvatc, prodrug, or pharmaccutically acceptable salt
`
`thereof.
`
`Y1"fi—fi_R7
`M1 L,
`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(CH2)WCN
`
`(111)
`
`4819-1483-6493.2
`
`_ 2 _
`
`UTC_REM_||_000003376
`
`
`
`
`Case 3:14-cv-05499-PGS-LHG Document 42-3 Filed 07/07/15 Page 8 of 206 PageID: 693
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`
`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, (C 1-C3) alkyl, or (C 1-C 3)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)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
`
`(1)
`
`(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—thicnyloXymcthyl;
`
`M1 is ot—OH:B—R5 or ot—R5:B—OH or ot—OR1:B—R5 or ot—R5:[3—OR2, wherein R5 is
`
`hydrogen or methyl, R2 is an alcohol protecting group, and
`
`L1 is ot—R3:[3—R4, ot—R4:B—Rg, 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)
`
`(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
`
`4819-1483-6493.2
`
`UTC_REM_||_000003377
`
`
`
`
`Case 3:14-cv-05499-PGS-LHG Document 42-3 Filed 07/07/15 Page 9 of 206 PageID: 694
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`
`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,
`
` L
`
`(V)
`
`0“
`
`(V1)
`
`
`
`(b)
`
`(e)
`
`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,
`
`4819-1483-6493.2
`
`UTC_REM_||_000003378
`
`
`
`
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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—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—cycloall<yl is an optionally substituted monoeyclic, bicyclic or trieyelic alkyl
`
`group containing between 4-7 carbon atoms. Exemplary Cyeloalkyl 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 “prodrng” 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,
`
`4819-1483-64932
`
`_ 5 _
`
`UTC_REM_||_000003379
`
`
`
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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 ofthe structure complex ofthe 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]
`
`“Pharmaeeutically 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 aeid, 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,
`
`fumarate,
`
`gluceptate,
`
`gluconate,
`
`glutamate,
`
`glycollylarsanilate,
`
`hexafluorophosphate,
`
`hexylresorcinate,
`
`hydrabamine,
`
`hydrobromide,
`
`hydrochloride,
`
`4819-1483-6493.2
`
`_ 6 _
`
`UTC_REM_||_000003380
`
`
`
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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,
`
`pamo ate
`
`(1 , 1 —methene—bis -2 —hydroxy—3 —naphtho ate ,
`
`einbonate) ,
`
`pantothenate,
`
`phosphate/diphosphate, picrate, polygalacturonate, propionate, p—toluenesulfonate, salicylate,
`
`stearate, subacetate, succinate, sulfate, sulfosalicylatc, suramatc, tannate, tartrate, 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,
`
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`
`Y1‘fi_fi_R7
`M1 L1
`OH
`
`H
`
`H
`
`(11)
`
`O(CH2)wCN
`
`(111)
`
`Y-|—fi—fi—R7
`M1 L1
`OH
`
`H
`
`H
`
`on
`
`wherein
`
`w= 1, 2, or 3;
`
`Y1 is trans-CH=CH-, Cis-CH=CH-, -CH2(CH2),,,-, or -C=C-; m is 1, 2, or 3;
`
`R7 lS
`
`(l)
`
`(2)
`
`—C1,Hg,,—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)alkyl, or (C1-
`
`C 3)alkoxy, with the proviso that not more than two substitucnts 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)cycloa.lkyl optionally substituted by l to 3 (C1—C5)all(yl;
`
`2-(2-furyl)ethyl,
`
`2—(3 -thienyl)ethoxy, or
`
`3-thienyloxymethyl;
`
`M1 is oi—OH:B—R5 or oL—R5:[3—OH or oL—OR1:B—R5 or (l—R5IB—OR2, wherein R5 is
`
`hydrogen or methyl, R2 is an alcohol protecting group, and
`
`L1 is 0.-R3:B-R4, oL—R4:B-R3, or a mixture of on-R3:B-R4 and ot-R4:[3-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,
`
`4819-1483-6493.2
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`
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`
`(C)
`
`contacting the product of step (b) with a base B to for a salt of formula 15
`
`H
`
`H
`
`Y*‘fi“fi‘R7
`M1 L1
`OH
`
`63
`
`HB
`
`9
`O(CH2)WCOO
`
`as)
`
`(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 CorI1pour1d of formula II can be prepared from a compound of formula X],
`
`which is a cyclization product of a compound of formula X as described in U.S. Pat.
`
`No. 6,441,245.
`
`OR1
`
`OR1
`
`Y1'fi—|Cl3—R7
`M1 L1
`3 0
`
`O(CH 2)nCH3
`
`(X)
`
`M1 L1
`
`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.
`
`OR
`
`‘
`_ _ _
`°\\‘c.
`\ Y1 E if R7
`M1 L1
`
`Yrs-9—Rv
`M L
`oi.
`1
`
`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.
`
`4819-1483-6493.2
`
`UTC_REM_||_000003383
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`
`
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`
` 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,
`
` L
`
`(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%.
`
`4819-1483-6493.2
`
`_
`
`_
`
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`
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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—methylglueamine,
`
`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.
`
`“Fq.” 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
`
`EXAMPLE S
`
`
`
`KZCO3, Bu4NBr
`Acetone, RT
`
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`
`Name
`
`Benzindene Triol
`
`K2CO3 (powder)
`CICHZCN
`
`138.20
`75.50
`
`l296g
`567 g
`
`M01.
`
`3.76
`
`7.51
`
`Eq.
`
`1.00
`
`2.50
`2.0
`
`
`
`——
`
`[0037]
`
`A 50—L, three—neck, round—bottom flask equipped with a mechanical stirrer and a
`
`thermocouple was charged with benzindene triol (1250 2;); acetone (19 L) and KZCO3
`
`(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 (l0L). 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
`
`(ECN
`
`4819-1483-6493.2
`
`_ 12 _
`
`UTC_REM_||_000003386
`
`
`
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`
`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 heatingcooling 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 HCl 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 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 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 NaHCO3 (30 g of 1\IaHCO3 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 (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
`
`4819-1483-6493.2
`
`_
`
`_
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`UTC_REM_||_000003387
`
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`
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`
`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) EtO H, EtOAc
`(II) Heptane Slurry
`
`Trepro stinil
`Diethanolamine
`
`
`
`Ethanol
`
`Ethyl acetate
` Treprostinil Diethanolamine
`Salt (seed)
`
`
`*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::S°C. At this temperature, the seed of
`
`4819-1483-6493.2
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`
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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 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 EtOl-1-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 No.
`
`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
`
`*N0le: 111 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)
`
`Batch M Treprostinil
`
`Diethanolamine Salt
`
`1
`
`3168 g
`37-5 L
`
`4819-1483-6493.2
`
`_
`
`_
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`UTC_REM_||_000003389
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`
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`Batch N°-
`
`Treprostinil
`Diethanolamine Salt
`
`Heptane
`
`[0044]
`
`A 50-L, cylindrical reactor equipped with a heating/cooling system, a mecl1a11ical
`
`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 22::2°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 weight of treprostinil diethanolamine 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
`
`<0.1% W/W
`
`0.1% W/W
`
`Batch 2
`
`Conforms
`
`<0.1% W/W
`
`0.0% W/W
`
`105.0-106.5°C
`
`104.5-105.5°C
`
`Specific rotation [OL]25589
`
`+34.6°
`
`+35°
`
`Organic volatile impurit