UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Vi.rgLnia 22313-1450
`WvWv.uspto.gov
`
`APPLICATION
`NUMBER
`
`FILING or
`371(c) DATE
`
`GRP ART
`UNIT
`
`61/014,232
`
`12/17/2007
`
`F
`
`FEE REC'D
`
`105
`
`22428
`FOLEY AND LARDNER LLP
`
`3333;,:;§ToREET NW
`
`WASHINGTON, DC 20007
`
`ATTY.DOCKET.NO
`
`080618-0570
`
`TOT CLAIIVIS IND CLAIMS
`
`CONFIRMATION NO. 1248
`
`FILING RECEIPT
`
`lllllllllIllllmlmlllllllllllllllllllllllllnllllll
`
`Date Mailed: 01/03/2008
`
`It will not be examined for patentability and will
`Receipt is acknowledged of this provisional patent application.
`become abandoned not later than twelve months after its filing date. Any correspondence concerning the application
`must include the following identification information: the U.S. APPLICATION NUMBER, FILING DATE, NAME OF
`APPLICANT, and TITLE OF INVENTION. Fees transmitted by check or draft are subject to collection. Please verify
`the accuracy of the data presented on this receipt. If an error is noted on this Filing Receipt, please write to the
`Office of Initial Patent Examination's Filing Receipt Corrections. Please provide a copy of this Filing Receipt
`with the changes noted thereon. If you received a "Notice to File Missing Parts" for this application, please
`submit any corrections to this Filing Receipt with your reply to the Notice. When the USPTO processes the
`reply to the Notice, the USPTO will generate another Filing Receipt incorporating the requested corrections
`
`App|icant(s)
`
`Hitesh Batra, Herndon, VA;
`Sudersan M. Tuladhar, Silver Spring, MD;
`Raju Penmasta, Herndon, VA;
`David A. Walsh, Palmyra, VA;
`Power of Attorney: The patent practitioners associated with Customer Number 22428
`
`If Required, Foreign Filing License Granted: 01/02/2008
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is us 61/014,232
`Projected Publication Date: None, application is not eligible for pre—grant publication
`Non-Publication Request: No
`Early Publication Request: No
`** SMALL ENTITY **
`Title
`
`Process to prepare treprostinil, the active ingredient in remodulin®
`
`PROTECTING YOUR INVENTION OUTSIDE THE UNITED STATES
`
`Since the rights granted by a U.S. patent extend only throughout the territory of the United States and have no
`effect in a foreign country, an inventor who wishes patent protection in another country must apply for a patent
`in a specific country or in regional patent offices. Applicants may wish to consider the filing of an international
`application under the Patent Cooperation Treaty (PCT). An international (PCT) application generally has the same
`effect as a regular national patent application in each PCT-member country. The PCT process simplifies the filing
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`
`of patent applications on the same invention in member countries, but does not result in a grant of "an international
`patent" and does not eliminate the need of applicants to file additional documents and fees in countries where patent
`protection is desired.
`
`Almost every country has its own patent law, and a person desiring a patent in a particular country must make an
`application for patent in that country in accordance with its particular laws. Since the laws of many countries differ
`in various respects from the patent law of the United States, applicants are advised to seek guidance from specific
`foreign countries to ensure that patent rights are not lost prematurely.
`
`Applicants also are advised that in the case of inventions made in the United States, the Director of the USPTO must
`issue a license before applicants can apply for a patent in a foreign country. The filing of a U.S. patent application
`serves as a request for a foreign filing license. The application's filing receipt contains further information and
`guidance as to the status of applicant's license for foreign filing.
`
`Applicants may wish to consult the USPTO booklet, "General Information Concerning Patents" (specifically, the
`section entitled "Treaties and Foreign Patents") for more information on timeframes and deadlines for filing foreign
`patent applications. The guide is available either by contacting the USPTO Contact Center at 800-786-9199, or it
`can be viewed on the USPTO website at http://www.uspto.gov/web/offices/pac/doc/general/index.html.
`
`For information on preventing theft of your intellectual property (patents, trademarks and copyrights), you may wish
`to consult the U.S. Government website, http://www.stopfakes.gov. Part of a Department of Commerce initiative,
`this website includes self—help "toolkits" giving innovators guidance on how to protect intellectual property in specific
`countries such as China, Korea and Mexico. For questions regarding patent enforcement issues, applicants may
`call the U.S. Government hotline at 1-866-999-HALT (1—866-999-4158).
`
`LICENSE FOR FOREIGN FILING UNDER
`
`Title 35, United States Code, Section 184
`
`Title 37, Code of Federal Regulations, 5.11 & 5.15
`
`GRANTED
`
`if the phrase "lF REQUIRED, FOREIGN FILING
`The applicant has been granted a license under 35 U.S.C. 184,
`LICENSE GRANTED" followed by a date appears on this form. Such licenses are issued in all applications where
`the conditions for issuance of a license have been met, regardless of whether or not a license may be required as
`set forth in 37 CFR 5.15. The scope and limitations of this license are set forth in 37 CFR 5.15(a) unless an earlier
`license has been issued under 37 CFR 5.15(b). The license is subject to revocation upon written notification. The
`date indicated is the effective date of the license, unless an earlier license of similar scope has been granted under
`37 CFR 5.13 or 5.14.
`
`This license is to be retained by the licensee and may be used at any time on or after the effective date thereof unless
`it is revoked. This license is automatically transferred to any related applications(s) filed under 37 CFR 1.53(d). This
`license is not retroactive.
`
`The grant of a license does not in any way lessen the responsibility of a licensee for the security of the subject matter
`as imposed by any Government contract or the provisions of existing laws relating to espionage and the national
`security or the export of technical data. Licensees should apprise themselves of current regulations especially with
`respect to certain countries, of other agencies, particularly the Office of Defense Trade Controls, Department of
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`State (with respect to Arms, Munitions and Implements of War (22 CFR 121-128)); the Bureau of Industry and
`Security, Department of Commerce (15 CFR parts 730-774); the Office of Foreign AssetsControI, Department of
`Treasury (31 CFR Parts 500+) and the Department of Energy.
`
`NOT GRANTED
`
`No license under 35 U.S.C. 184 has been granted at this time, if the phrase "IF REQUIRED, FOREIGN FILING
`LICENSE GRANTED" DOES NOT appear on this form. Applicant may still petition for a license under 37 CFR 5.12,
`if a license is desired before the expiration of 6 months from the filing date of the application. If 6 months has lapsed
`from the filing date of this application and the licensee has not received any indication of a secrecy order under 35
`U.S.C. 181, the licensee may foreign file the application pursuant to 37 CFR 5.15(b).
`
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`IN THE UNITED STATES PATENTAND TRADEMARK OFFICE
`
`Atty. Dkt. N0. 080618-0570
`
`Applicant:
`
`Hitesh BATRA et al.
`
`Title:
`
`AN IMPROVED PROCESS TO PREPARE
`
`TREPROSTINIL, THE ACTIVE INGREDIENT
`IN REMODULIN®
`
`Appl. No.:
`
`Unassigned
`
`Filing Date:
`
`12/17/2007
`
`PROVISIONAL PATENT APPLICATION
`TRANSMITTAL
`
`Commissioner for Patents
`PO. Box 1450
`
`Alexandria, VA 22313-1450
`
`Sir:
`
`Transmitted herewith for filing under 37 C.F.R. § 1.53(c) is the provisional patent
`
`application of:
`
`Hitesh BATRA
`
`Sudersan M. TULADHAR
`
`Raju PENMASTA
`David A. WALSH
`
`[ X ] Applicant claims small entity status under 37 CFR 1.27(c)(1).
`
`Enclosed are:
`
`[ X ] Cover page, Description, Claims, and Abstract
`
`[ X ] Application Data Sheet (37 CFR 1.76).
`
`The adjustment to the number of sheets for EFS—Web filing follows:
`
`Number
`
`EFS—Web
`
`Number of Sheets for EFS—Web
`
`of Sheets
`27
`
`Adjustment
`75%
`
`x
`
`WASH_2157918.1
`
`21
`
`-1-
`
`4
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`Atty. Dkt. No. 080618-0570
`
`The filing fee is calculated below:
`
`
`Basic Fee
`
`Size Fee
`
`21
`
`- 100
`
`=
`
`0
`
`Surcharge under 37 CFR 1.16(e) for late
`payment of filing fee
`
`Rate
`
`$210.00
`
`$260.00
`
`$5000
`
`X
`
`+
`
`SUBTOTAL:
`
`[ X ]
`
`Small Entity Fees Apply (subtract ‘/2 of above):
`
`TOTAL FILING FEE:
`
`=
`
`=
`
`=
`
`=
`
`Assignment Recordation Fee:
`
`=
`$40.00
`+
`TOTAL FEE =
`
`Fee
`
`Totals
`
`$210.00
`
`$0.00
`
`$0.00
`
`$210.00
`
`$105.00
`
`$105.00
`
`$0.00
`$105.00
`
`The above-identified fees of $105.00 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 C.F.R. §§ 1.16-1.17, or credit any overpayment,
`
`to Deposit Account N0. 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 N0. 19-0741.
`
`Please direct all correspondence to the undersigned attorney or agent at the address
`
`indicated below.
`
`Respectfully submitted,
`
`Date December 17 2007
`By
`
`
`
`
`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_2157918.1
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`Application Data Sheet
`
`Application Information
`
`Application Type::
`
`Subject Matter::
`
`Suggested classification::
`
`Suggested Group Art Unit::
`
`Provisional
`
`Utility
`
`CD-ROM or CD-R?::
`
`None
`
`Computer Readable Form (CRF)?::
`
`No
`
`Title::
`
`AN IMPROVED PROCESS TO PREPARE
`
`Attorney Docket Number::
`
`080618-0570
`
`TREPROSTINIL, THE ACTIVE
`
`INGREDIENT IN REMODUL|N®
`
`Request for Early Pub|ication?::
`
`Request for Non-Pub|ication?::
`
`Suggested Drawing Figure::
`
`Total Drawing Sheets::
`
`Small Entity?::
`
`Petition included?::
`
`Secrecy Order in Parent Appl.?::
`
`No
`
`No
`
`0
`
`Yes
`
`No
`
`No
`
`Applicant Information
`
`Applicant Authority Type::
`
`Inventor
`
`Primary Citizenship Country::
`
`India
`
`Status::
`
`Given Name::
`
`Family Name::
`
`City of Residence::
`
`Full Capacity
`
`Hitesh
`
`BATRA
`
`Herndon
`
`State or Province of
`
`VA
`
`Residence::
`
`Country of Residence::
`
`US
`
`Street of mailing address::
`
`2461 Leyland Ridge Road
`
`City of mailing address::
`
`Herndon
`
`WASH_2157904_1
`
`Page # 1
`
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`State or Province of mailing
`
`VA
`
`address::
`
`Postal or Zip Code of mailing
`
`20171
`
`address::
`
`Applicant Authority Type::
`
`Inventor
`
`Primary Citizenship Country::
`
`Nepal
`
`Status::
`
`Given Name::
`
`Family Name::
`
`Full Capacity
`
`Sudersan M.
`
`TULADHAR
`
`City of Residence::
`
`Silver Spring
`
`State or Province of
`
`Residence::
`
`Country of Residence::
`
`MD
`
`US
`
`Street of mailing address::
`
`1501 Haddon Manor Court
`
`City of mailing address::
`
`Silver Spring
`
`State or Province of mailing
`
`MD
`
`address::
`
`Postal or Zip Code of mailing
`
`20904
`
`address::
`
`Applicant Authority Type::
`
`Primary Citizenship Country::
`
`Status::
`
`Given Name::
`
`Family Name::
`
`City of Residence::
`
`State or Province of
`
`Residence::
`
`Country of Residence::
`
`Inventor
`
`US
`
`Full Capacity
`
`Raju
`
`PENMASTA
`
`Herndon
`
`VA
`
`US
`
`Street of mailing address::
`
`12953 Centre Park Circle #115
`
`City of mailing address::
`
`State or Province of mailing
`
`Herndon
`
`VA
`
`address::
`
`WASH_2157904_ 1
`
`Page # 2
`
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`Postal or Zip Code of mailing
`
`20171
`
`address::
`
`Applicant Authority Type::
`
`Inventor
`
`Primary Citizenship Country::
`
`US
`
`Status::
`
`Given Name::
`
`Family Name::
`
`City of Residence::
`
`State or Province of
`
`Residence::
`
`Full Capacity
`
`David A.
`
`WALSH
`
`Palmyra
`
`VA
`
`Country of Residence::
`
`US
`
`Street of mailing address::
`
`56 Wildwood Drive
`
`City of mailing address::
`
`Palmyra
`
`State or Province of mailing
`
`VA
`
`address::
`
`Postal or Zip Code of mailing
`
`22963
`
`address::
`
`Correspondence Information
`
`Correspondence Customer Number::
`
`22428
`
`E-Mail address::
`
`PTOMai|Washington@fo|ey.com
`
`Representative Information
`
`Representative Customer
`
`22428
`
`Number::
`
`Domestic Priority Information
`
`Application::
`
`Continuity Type::
`
`Parent
`
`Parent Filing
`
`
`
`App|ication:: Date::
`
`WASH_2157904_ 1
`
`Page # 3
`
`8
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`Foreign Priority Information
`
`Country::
`
`Application
`
`Filing Date::
`
`Priority C|aimed::
`
`number::
`
`
`
`Assignee Information
`
`Assignee Name::
`
`United Therapeutics Corporation
`
`WASH_2157904_ 1
`
`Page # 4
`
`9
`
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`Atty. Dkt. No.: 080618-0570
`
`U.S. PATENT APPLICATION
`
`for
`
`AN IMPROVED PROCESS TO PREPARE TREPROSTINIL, THE
`
`ACTIVE INGREDIENT IN REMODULIN®
`
`Inventors:
`
`Hitesh Batra
`
`Sudersan M. Tuladhar
`
`Raju Penrnasta
`
`David A. Walsh
`
`WASH_2065937.1
`
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`
`Atty. Dkt. No.: 08061 8-0570
`
`AN IMPROVED PROCESS TO PREPARE TREPROSTINIL, THE ACTIVE
`INGREDIENT IN REMODULIN®
`
`BACKGROUND OF THE INVENTION
`
`[0001]
`
`The present invention relates to a process for producing prostacyclin derivatives
`
`and novel intermediate compounds useful in the process.
`
`[0002]
`
`Prostacyclin derivatives
`
`are useful pharmaceutical
`
`compounds possessing
`
`activities such as platelet aggregation inhibition, gastric secretion reduction, lesion inhibition,
`
`and bronchodilation.
`
`[0003]
`
`Treprostinil,
`
`the active ingredient
`
`in Remodulin®, and other prostacyclin
`
`derivatives have been prepared as described in Moriarty, et al in J. Org. Chem. 2004, 69,
`
`1890-1902, U.S. Pat. Nos. 6,441,245, 6,528,688, 6,700,025, and 6,809,223. Their teachings
`
`are incorporated by reference to show how to practice the embodiments of the present
`
`invention.
`
`[0004]
`
`It is evident that these compounds are of great importance from a medicinal point
`
`of view. There is, therefore, a need for an efficient process to synthesize these compounds on
`
`a large scale suitable for commercial production.
`
`SUMMARY OF THE INVENTION
`
`[0005]
`
`The present invention provides in one embodiment a process for the preparation of
`
`a compound of formula I, hydrate, solvate, prodrug, or pharmaceutically acceptable salt
`
`thereof
`
`Y1"|Cf_fi—R7
`M1 L1
`OH
`
`H
`
`H
`
`O(CH2)WCOOH
`
`(1)
`
`[0006]
`
`The process comprises the following steps:
`
`(a)
`
`alkylating a compound of structure II with an alkylating agent to produce a
`
`compound of formula III,
`
`WASH_2065937.1
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`
`Atty. Dkt. No.: 080618-0570
`
`Y1'fi_fi_R7
`
`OH
`
`H
`
`H
`
`(11)
`
`O(CH2x~CN
`
`(111)
`
`Y1‘fi_fi_R7
`M1 L1
`OH
`
`H
`
`H
`
`OH
`
`wherein
`
`w= 1, 2, or 3;
`
`Y1 is trans-CH=CH-, cis-CH=CH-, -CH2(CH2)m-, or -CEC-; m is l, 2, or 3;
`
`R7 lS
`
`(l)
`
`(2)
`
`-CPHZP-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 phcnoxy or substituted phcnoxy,
`
`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)cycloalkyl optionally substituted by l to 3 (C1-C5)alkyl;
`
`2-(2-furyl)ethyl,
`
`2-(3 -thienyl)ethoXy, or
`
`3-thienyloxymethyl;
`
`M1 is oc—OH:B—R5 or oc—R5:B—OH or oc—OR1:B—R5 or oc—R5:B—OR2, wherein R5 is
`
`hydrogen or methyl, R2 is an alcohol protecting group, and
`
`L1 is 0L-R3:[3-R4, 0L-R4:[3-R3, or a mixture of 0L-R3:[3-R4 and 0L-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,
`
`WASH_2065937.1
`
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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.: 080618-0570
`
`H
`
`H
`
`Y1‘fi—fi—R7
`M1 L1
`OH
`
`ea
`
`HB
`
`O(CH2)WCOOe
`
`as)
`
`(d)
`
`reacting the salt from step (C) With an acid to form the compound of formula I.
`
`[0007]
`
`The present
`
`invention provides in another embodiment a process for
`
`the
`
`preparation of a compound of formula IV.
`
` K
`
`COOH
`
`(IV)
`
`[0008]
`
`The process comprises the following steps:
`
`(a)
`
`alkylating a compound of structure V with an alkylating agent to produce a
`
`compound of formula VI,
`
`
`
`(V)
`
` K
`
`C“
`
`(V1)
`
`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,
`
`(b)
`
`(c)
`
`and
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`
`
`(IVs)
`
`(d)
`
`reacting the salt
`
`from step (b) with an acid to fonn the compound of
`
`formula IV.
`
`DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
`
`[0009]
`
`The various terms used, separately and in combinations, in the processes herein
`
`described are defined below.
`
`[0010]
`
`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.
`
`[0011]
`
`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.
`
`[0012]
`
`C1_3-alkoxy is a straight or branched alkoxy group containing 1-3 carbon atoms.
`
`Exemplary alkoxy groups include methoxy, ethoxy, propoxy, and isopropoxy.
`
`[0013]
`
`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.
`
`[0014]
`
`Combinations of substitucnts and variables cnvisioncd by this invcntion 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.
`
`[0015]
`
`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,
`
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`derivatives of a compound that include biohydrolyzable groups such as biohydrolyzable
`
`amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates,
`
`biohydrolyzable urcidcs, and biohydrolyzable phosphatc analogucs (e.g., monophosphatc,
`
`diphosphate or triphosphate).
`
`[0016]
`
`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.
`
`[0017]
`
`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.
`
`[0018]
`
`“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 pharmaccutical use.
`
`[0019]
`
`“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.
`
`lncluded in the invention are pharmaceutically acceptable salts or compounds of
`
`any ofthe formulae herein.
`
`[0020]
`
`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,
`
`camsylatc, carbonatc, chloridc, citratc, clavulariatc, dihydrochloridc, cdctatc, cdisylatc,
`
`estolate,
`
`esylate,
`
`fi1marate,
`
`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
`
`(1 , l -methene-bis-2-hydroxy-3 -naphthoate,
`
`einbonate),
`
`pantothenate,
`
`phosphate/diphosphate, pierate, polygalacturonate, propionate, p-toluenesulfonate, salicylate,
`
`stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate,
`
`tannate,
`
`tartrate,
`
`teoclate,
`
`tosylate, triethiodide, and valerate salts.
`
`[0021]
`
`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.
`
`[0022]
`
`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)
`
`[0023]
`
`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)
`
`Y1—fi—fi—R7
`M1 L1
`OH
`
`H
`
`H
`
`OH
`
`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 lS
`
`(l)
`
`(2)
`
`-CpH2p-CH3, wherein p is an integer from l 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)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)all<yl;
`
`2—(2—furyl)ethyl,
`
`2—(3 —thienyl)ethoxy, or
`
`3—thienyloXymethyl;
`
`M1 is oc-OH:B-R5 or oc-R5:B-OH or oc-OR1:B-R5 or oc-R5:B-OR2, wherein R5 is
`
`hydrogen or methyl, R2 is an alcohol protecting group, and
`
`L1 is 0c—R3:B—R4, 0c—R4:B—R3, or a mixture of 0c—R3:B—R4 and 0c—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,
`
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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.: 080618-0570
`
`H
`
`H
`
`Y1‘fi—fi—R7
`M1M
`O H
`
`ea
`
`HB
`
`O(CH2)WCOOe
`
`as)
`
`(d)
`
`reacting the salt from step (C) With an acid to form the compound of formula I.
`
`[0024]
`
`In one embodiment, the compound of formula I is at least 90.0%, 95.0%, 99.0%.
`
`[0025]
`
`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
`
`\ Y1'fi_fi_R7
`M L
`O(CH2)nCH3
`1
`1
`
`(X)
`
`Wherein n is 0, l, 2, or 3.
`
`OR1
`Y1-|Ci—|Cf—R7
`M L
`0.3 O"
`"
`H
`O(CH2)nCH3
`
`(XI)
`
`[0026]
`
`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 dcscribcd in
`
`U.S. Pat. No. 6,700,025.
`
`OR
`
`‘
`
`\ Y1‘fi‘fi"R7
`M1 L1
`
`Yrfi-9-R7
`gm“
`
`H
`
`H
`
`OBn
`
`(XII)
`
`OBn
`
`(XIII)
`
`[0027]
`
`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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` K
`
`COOH
`
`(IV)
`
`[0028]
`
`The process comprises
`
`(a)
`
`alkylating a compound of structure V with an alkylating agent such as
`
`ClCH2CN to produce a compound of formula VI,
`
`
`
`(V)
`
` K
`
`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
`
`H0
`
` ea NH2(CH2CH2OH)2
`
`(d)
`
`reacting the salt from step (b) with an acid such as HCl to form the compound
`
`of formula IV.
`
`[0029]
`
`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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`[0030]
`
`In one embodiment, the process further comprises a step of isolating the salt of
`
`formula IVS.
`
`[0031]
`
`In one embodiment, the base B in step (c) may be ammonia, N-methylglucamine,
`
`procaine, tromethanine, magnesium, L-lysine, L-arginine, or triethanolamine.
`
`[0032]
`
`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.
`
`[0033]
`
`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.
`
`[0034]
`
`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 l.
`
`Alkylation of Benzindene Triol
`
`EXAMPLES
`
`
`
`K2003, Bu4NBr
`Aeeto ne, RT
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`Name
`
`MW
`
`Atty. Dkt. No.: 080618-0570
`
`Benzindene Triol
`K2CO3 (powder)
`
`CICH2CN
`
`332.48
`
`1250 g
`
`1.00
`
`9.38
`
`2.50
`
`7.51 2.0
`
`322-37
`
`36g
`
`0.03
`
`Celite®545
`
`——
`
`115 g
`
`[0035]
`
`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 KQCO3
`
`(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/CH2C
`
`12; 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
`
`nitrilc. The crude bcnzindcnc nitrilc was uscd as such in thc ncxt stcp without further
`
`purification.
`
`Example 2.
`
`Hydrolysis of Benzindene Nitrile
`
`HO
`
` KOH, MeOH
`
`H2O, Reflux
`
`(E
`
`CN
`
`
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`Name
`
`MW
`
`Amount
`
`M01.
`
`Eq.
`
`Atty. Dkt. No.: 080618-0570
`
`KOH
`
`Methanol
`
`844 g
`
`12 L
`
`15.04
`
`——
`
`4.0
`
`--
`
`
`
`—Z
`
`*Note: This weight is based on 100% yield from the previous step. This is not isolated yield.
`
`[0036]
`
`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 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.
`
`[0037]
`
`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