`Approved for use throngs 07/31/2005. 0MB 06510032
`US. Patent and Trademark Office: U.S. DEPARTMBV'I‘ OF COMMERCE
`
`
`
`Attorney Docket No.
`
`2 I409Y
`
`First Inventor or Application Identifier Alex Minhua Chen, et al.
`
`PHOSPHORIC ACID SALT OF A DEPEPTIDYL PEPTIDAser
`INHIBITOR
`'-
`
`UTILITY
`PATENT APPLICATION
`TRANSMITTAL
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`llllllll
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`(Onlyfor new nonpmiirional application: under 37 CFR I.53(b))
`
`Express Mail Label Na. EL9895 89055US
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`ADDRESS TO:
`
`Commissioner for Patents
`P.0. Box 1450
`Alexandria, VA 22313-1450
`6. Nucleotide and/or Amino Acid Sequence Submission
`(ifapplicable, all necessary)
`a.
`
`C] Computer Readable Form (CR3
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`lllllilll
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`062304
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`APPLICATION ELEMENTS
`See MPEP chapter 600 concerning utility patent application contents.
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`1‘
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`Fee Transmittal Form
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`Drawing(s)(35 USC 113)
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`4. Oath or Declaration
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`[fa CONTINUWG APPLICATION, check appropriate box. and rupply the requisite information below and in thefirst sentence af the
`14.
`specificationfollowing the title, or in an Application Data Sheet under 37 CFR 1. 76.-
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`For CONTINUATION OR DIVISIONAL APPS only: 111: entire diodes”: of the prior applimtion, from which an oath or declaration is wpplied under Box 4b, is considered a
`port of the d‘mdosun ol' the accompanying continuation or divisional applimtion and is hereby incorporated by reference.
`15. CORRESPONDENCE ADDRESS
`Customer Number
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`
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`NAME
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`Philippe L. Durette
`
`ADDRESS
`
`Merck & Co., Inc., P. 0. Box 2000 - Patent Dept, RY60—30
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`Phil-WP“
`- Ii
`, ,
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`TELEPHONE
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`732-594_4568
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`EXPRESS MAIL CERTIFICATE
`DATE OF DEPOSIT June 23 2004
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`EXPRESS MAIL N0. EL989589055US
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`I HEREBY CERTIFY THAT THIS CORRESPONDENCE IS BEING DEPOSITED WITH THE
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`UNITED STATES POSTAL SERVICE AS EXPRESS MAIL "POST OFFICE TO ADDRESSEE"
`ON THE ADD
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`DATE IN AN ENVELOPE ADDRESSED T0 COMIMISSIONER FOR PATENTS,
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`EXAIKIA VA 22313:]450.
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`Computer generated form 'Transmitml Form Non—RV" (Application Filing Folder) Merck & Co., Inc. Sim/2004
`A
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`PATENT
`
`Commissioner for Patents
`
`PO. Box 1450
`Alexandria, VA 22313-1450
`
`Sir:
`
`Deposit Acct. 13-2755
`MERCK & CO., INC.
`Our Case Docket No. 21409Y
`
`Transmitted herewith for filing under 37 C.F.R. §1.53(b) is the patent application of Inventor(s):
`Alex Minhua Chen, Russell R. Ferlita, Karl Hansen, Ivan Lee, Stephen Howard Cypes. Vicky K. Vydra, Robert M Wenslow
`
`I
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`For: PHOSPHORIC ACID SALT OF A DIPEPTIDYL PEPTIDASE-IV INHIBITOR
`
`
`
`Basic Fee
`$770
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`Total Claims
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`TOTAL FILING FEE ——-——-%
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`multiple dependent claims, regardless
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`of number.
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`Please charge my Deposit Account No. 13-2755 in the amount of $ 1 040
`. The Commissioner is hereby
`authorized to charge any additional fees which may be required, or credit any overpayment to Account No. 13-2755.
`Duplicate copy of this sheet is enclosed.
`
`[:1 Under the provisions Of 37 C.F.R. §1.53, this application is being filed without the declaration of each inventor.
`
`MAILED B IN DUPLICATE
`
`
`
`By: Phi pe L. Durette
`
`Attorney
`For Applicant(s)
`
`Reg. NO. 35 125
`MERCK & 00-. INC-
`Patent Dept, RY60-30
`'30- 3°“ 2°00
`Ftahway. NJ. 07065-0907
`(732) 594- 4568
`
`Date: June 23 2004
`/
`
`.1
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`EXPRESS MAIL cER11FICATE
`
`J
`DATE °F ””3” ”"9
`axonsss MAIL NO. EL989589055US
`
`23 2004
`
`I HEREBY CER'ITFY THAT THIs CORRESPONDENCE Is BEING
`DEPOSITED WITH THE UNITED STATES POSTAL SERVICE As
`EXPRESS MAIL ”POST OFFICE To ADDRESSEE' ON THE ABOVE DATE
`IN AN ENVELOPE ADDRESSED To COMMISSIONER FOR PATENTS,
`PD. BOX 1450, ALEXANDRIA, VA 22313-1450.
`
`Corinne: generated Iorm 'Transrriual Leuer’ (Application filing Folder). Merck & 60.. tnI:.. Imovzooo
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`TITLE OF THE INVENTION
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`PHOSPHORIC ACID SALT OF A DIPEPTIDYL PEPTIDASE—IV INHIBITOR
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`CROSS-REFERENCE TO RELATED APPLICATIONS
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`The present invention is related to US. provisional application Serial No. 60/482,161,
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`filed June 24, 2003, the contents of which are hereby incorporated by reference.
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`FIELD OF THE INVENTION
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`The present invention relates to a particular salt of a dipeptidyl peptidase-IV inhibitor.
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`More particularly, the invention relates to a dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-
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`5,6—dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)—yl]—l-(2,4,5—trifluorophenyl)butan-2—arnine, which is a
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`potent inhibitor of dipeptidyl peptidase-IV. This novel salt and crystalline hydrates thereof are useful for
`
`the treatment and prevention of diseases and conditions for which an inhibitor of dipeptidyl peptidase-IV
`
`is indicated, in particular Type 2 diabetes, obesity, and high blood pressure. The invention further
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`concerns pharmaceutical compositions comprising the dihydrogenphosphate salt and crystalline hydrates
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`thereof- useful to treat Type 2 diabetes, obesity, and high blood pressure as well as processes for
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`preparing the dihydrogenphosphate salt and crystalline hydrates thereof and their pharmaceutical
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`compositions.
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`BACKGROUND OF THE INVENTION
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`Inhibition of dipeptidyl peptidase-IV (DP-IV), an enzyme that inactivates both glucose-
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`dependent insulinotropic peptide (GI?) and glucagon-like peptide 1 (GLP-l), represents a novel approach
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`to the treatment and prevention of Type 2 diabetes, also known as non—insulin dependent diabetes
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`mellitus (NIDDM). The therapeutic potential of DP-IV inhibitors for the treatment of Type 2 diabetes
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`has been reviewed: C. F. Deacon and 1.]. Holst, “Dipeptidyl peptidase IV inhibition as an approach to the
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`treatment and prevention of Type 2 diabetes: a historical perspective,” Biochem. Biophys. Res.
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`Commun., 294: 14 (2000); K. Augustyns, et al., “Dipeptidyl peptidase IV inhibitors as new therapeutic
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`agents for the treatment of Type 2 diabetes,” Expert. Opin. Ther. Patents, 13: 499-510 (2003); and DJ.
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`Drucker, “Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of Type 2
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`diabetes,” Expert Opin. Investig. Drugs, 12: 87—100 (2003).
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`WC 03/004498 (published 16 January 2003), assigned to Merck & Co., describes a class
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`of beta~amino tetrahydrotriazolo[4,3-a]pyrazines, which are potent inhibitors of DP—IV and therefore
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`useful for the treatment of Type 2 diabetes. Specifically disclosed in WC 03/004498 is 4-oxo—4-[3-
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`(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l—(2,4,5-trifluorophenyl)butan-2-
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`amine. Pharmaceutically acceptable salts of this compound are generically encompassed within the
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`scope of WO 03/004498.
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`However, there is no specific disclosure in the above reference of the newly discovered
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`monobasic dihydrogenphosphate salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3—
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`a]pyrazin—7(8H)-yl]—1-(2,4,5-trifluorophenyl)butan-2-amine of structural formula I below.
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`SUMMARY OF THE INVENTION
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`The present invention is concerned with a novel dihydrogenphosphate salt of the
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`dipeptidy] peptidase—IV (DP-IV) inhibitor 4-ox0-4—[3—(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-
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`a]pyrazin-7(8H)-yl]—1—(2,4,S—trifluorophenyl)butan-2—amine and crystalline hydrates thereof, in particular
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`a crystalline monohydrate. The dihydrogenphosphate salt and crystalline hydrates of the present
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`invention have advantages in the preparation of pharmaceutical compositions of 4—oxo—4-[3—
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`(trifluoromethyl)—5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1—(2,4,5-trifluorophenyl)butan—2-
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`amine, such as ease of processing, handling, and dosing. In particular, they exhibit improved physical
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`and chemical stability, such as stability to stress, high temperatures and humidity, as well as improved
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`physicochernical properties, such as solubility and rate of solution, rendering them particularly suitable
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`for the manufacture of various pharmaceutical dosage forms. The invention also concerns
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`pharmaceutical compositions containing the novel salt and hydrates as well as methods for using them as
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`DP-IV inhibitors, in particular for the prevention or treatment of Type 2 diabetes, obesity, and high blood
`pressure.
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`BRIEF DESCRIPTION OF THE FIGURES
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`FIG. 1 is a characteristic X—ray diffraction pattern of the crystalline monohydrate of the
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`dihydrogenphosphate salt of structural formula H.
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`FIG. 2 is a carbon-l3 cross—polarization magic-angle spinning (CPMAS) nuclear
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`magnetic resonance (NMR) spectrum of the crystalline monohydrate of the dihydrogenphosphate salt of
`structural formula H.
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`FIG. 3 is a fluorine-19 magic-angle spinning (MAS) nuclear magnetic resonance (NIVIR)
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`spectrum of the crystalline monohydrate of the dihydrogenphosphate salt of structural formula II.
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`FIG. 4 is a typical thermogravimetric analysis (TGA) curve of the crystalline
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`monohydrate dihydrogenphosphate salt of structural formula II.
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`FIG. 5 is a typical differential scanning calorimetry (DSC) curve of the crystalline
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`monohydrate of the dihydrogenphosphate salt of structural formula II.
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`DETAILED DESCRIPTION OF THE INVENTION
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`This invention provides a new monobasic dihydrogenphosphate salt of 4-oxo-4—[3—
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`(trifluoromethyl)-5 ,6-dihydro[ l,2,4]tn'azolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-
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`5
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`amine of the following structural formula I:
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`F
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`.
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`-H3PO4
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`NH2 0
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`*
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`(I)
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`N
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`/N\
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`0w”
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`CF3
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`or a crystalline hydrate thereof. In particular, the instant invention provides a crystalline monohydrate of
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`the dihydrogenphosphate salt of formula I.
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`stereogenic carbon atom indicated with an * and can thus occur as a racemate, racemic mixture, and
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`The dihydrogenphosphate salt of the present invention has a center of asymmetry at the
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`single enantiomers, with all isomeric forms being included in the present invention. The separate
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`enantiomers, substantially free of the other, are included within the scope of the invention, as well as
`mixtures of the two enantiomers.
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`One embodiment of the present invention provides the dihydrogenphosphate salt of (2R)-
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`4-oxo—4-[3-(trifluoromethyl)-5 ,6-dihydro[ 1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-
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`trifluorophenyl)butan-2-amine of structural formula II:
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`F
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`F
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`- H3PO4
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`NH2 0
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`*
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`(II)
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`N
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`/ N\
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`CNQ/N
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`CF3
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`or a crystalline hydrate thereof.
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`(ZS)-4-oxo-4-[3-(trifluoromethyl)—5 ,6-dihydro[1,2,4]triazolo[4,3—a]pyrazin—7(8H)-yl]-1—(2,4,5-
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`A second embodiment of the present invention provides the dihydrogenphosphate salt of
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`trifluorophenyl)butan-2-amine of structural formula II]:
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`or a crystalline hydrate thereof.
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`More specifically, the dihydrogenphosphate salt of the present invention is comprised of
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`one molar equivalent of mono-protonated 4~oxo-4-[3-(trifluoromethyl)-5,6—dihydro[1,2,4]triazolo[4,3-
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`a]pyrazin—7(8H)—yl]—1—(2,4,5-trifluorophenyl)butan-Z-amine cation and one molar equivalent of
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`dihydrogenphosphate (biphosphate) anion.
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`In a further embodiment of the present invention, the dihydrogenphosphate salt of
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`structural formulae I-III is a crystalline hydrate. In one class of this embodiment, the crystalline hydrate
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`is a crystalline monohydrate.
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`A further embodiment of the present invention provides the dihydrogenphosphate salt
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`drug substance of structural formulae I-III that comprises the crystalline monohydrate present in a
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`detectable amount. By “drug substance” is meant the active pharmaceutical ingredient (“API”). The
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`amount of crystalline monohydrate in the drug substance can be quantified by the use of physical
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`methods such as X-ray powder diffraction, solid-state fluorine-19 magic-angle 'spinning (MAS) nuclear
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`magnetic resonance spectroscopy, solid-state carbon-13 cross-polarization magic-angle spinning
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`(CPMAS) nuclear magnetic resonance spectroscopy, solid state Fourier-transform infrared spectroscopy,
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`and Raman spectroscopy. In a class of this embodiment, about 5% to about 100% by weight of the
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`crystalline monohydrate is present in the drug substance. In a second class of this embodiment, about
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`10% to about 100% by weight of the crystalline monohydrate is present in the drug substance. In a third
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`class of this embodiment, about 25% to about 100% by weight of the crystalline monohydrate is present
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`in the drug substance. In a fourth class of this embodiment, about 50% to about 100% by weight of the
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`crystalline monohydrate is present in the drug substance. In a fifth class of this embodiment, about 75%
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`to about 100% by weight of the crystalline monohydrate is present in the drug substance. In a sixth class
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`of this embodiment, substantially all of the dihydrogenphosphate salt drug substance is the crystalline
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`monohydrate of the present invention, i.e., the dihydrogenphosphate salt drug substance is substantially
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`phase pure monohydrate.
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`The crystalline dihydrogenphosphate salt of the present invention exhibits pharmaceutic
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`advantages over the free base and the previously disclosed hydrochloride salt (WO 03/004498) in the
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`preparation of a pharmaceutical drug product containing the pharmacologically active ingredient.
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`In
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`particular, the enhanced chemical and physical stability of the crystalline dihydrogenphosphate salt
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`monohydrate constitute advantageous properties in the preparation of solid pharmaceutical dosage forms
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`containing the pharmacologically active ingredient.
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`The dihydrogenphosphate salt of the present invention, which exhibits potent DP-IV
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`inhibitory properties, is particularly useful for the prevention or treatment of Type 2 diabetes, obesity,
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`and high blood pressure.
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`Another aspect of the present invention provides a method for the prevention or
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`treatment of clinical conditions for which an inhibitor of DP—IV is indicated, which method comprises
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`administering to a patient in need of such prevention or treatment a prophylactically or therapeutically
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`effective amount of the dihydrogenphosphate salt of structural formula I or a hydrate thereof, in
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`particular the crystalline monohydrate thereof. Such clinical conditions include diabetes, in particular
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`Type 2 diabetes, hyperglycemia, insulin resistance, and obesity.
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`The present invention also provides the use of the dihydrogenphosphate salt of structural
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`formula I or a hydrate thereof, in particular the crystalline monohydrate, for the manufacture of a
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`medicament for the prevention or treatment of clinical conditions for which an inhibitor of DP—IV is
`indicated.
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`The present invention also provides pharmaceutical compositions comprising the
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`dihydrogenphosphate salt of structural formula I or a hydrate thereof, in particular the crystalline
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`monohydrate, in association with one or more pharmaceutically acceptable carriers or excipients. In one
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`embodiment the pharmaceutical composition comprise a therapeutically effective amount of the active
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`pharmaceutical ingredient in admixture with pharmaceutically acceptable excipients wherein the active
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`pharmaceutical ingredient comprises a detectable amount of the crystalline monohydrate of the present
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`invention. In a second embodiment the pharmaceutical composition comprise a therapeutically effective
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`amount of the active pharmaceutical ingredient in admixture with pharmaceutically acceptable excipients
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`wherein the active pharmaceutical ingredient comprises about 5% to about 100% by weight of the
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`crystalline monohydrate of the present invention. In a class of this second embodiment, the active
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`pharmaceutical ingredient in such compositions comprises about 10% to about 100% by weight of the
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`crystalline monohydrate. In a second class of this embodiment, the active pharmaceutical ingredient in
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`such compositions comprises about 25% to about 100% by weight of the crystalline monohydrate. In a
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`third class of this embodiment, the active pharmaceutical ingredient in such compositions comprises
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`about 50% to about 100% by weight of the crystalline monohydrate. In a fourth class of this
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`embodiment, the active pharmaceutical ingredient in such compositions comprises about 75% to about
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`100% by weight of the crystalline monohydrate. In a fifth class of this embodiment, substantially all of
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`the active pharmaceutical ingredient is the crystalline dihydrogenphosphate salt monohydrate of the
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`present invention, i.e., the active pharmaceutical ingredient is substantially phase pure
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`dihydrogenphosphate salt monohydrate.
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`The compositions in accordance with the invention are suitably in unit dosage forms
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`such as tablets, pills, capsules, powders, granules, sterile solutions or suspensions, metered aerosol or
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`liquid sprays, drops, ampoules, auto-injector devices or suppositories. The compositions are intended for
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`oral, parenteral, intranasal, sublingual, or rectal administration, or for administration by inhalation or
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`insufflation. Formulation of the compositions according to the invention can conveniently be effected by
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`methods lmown from the art, for example, as described in Remington’s Pharmaceutical Sciences, 17‘h ed.,
`1995.
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`The dosage regimen is selected in accordance with a variety of factors including type,
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`species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated;
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`the route of administration; and the renal and hepatic function of the patient. An ordinarily skilled
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`physician, veterinarian, or clinician can readily determine and prescribe the effective amount of the drug
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`required to prevent, counter or arrest the progress of the condition.
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`Oral dosages of the present invention, when used for the indicated effects, will range
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`between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably
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`0.01 to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oral administration, the
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`compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0,
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`10.0, 15.0, 25.0, 50.0, 100, 200, and 500 milligrams of the active ingredient for the symptomatic
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`adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01
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`mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 200 mg of active
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`ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kglminute
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`during a constant rate infusion. Advantageously, the crystalline forms of the present invention may be
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`administered in a single daily dose, or the total daily dosage may be administered in divided doses of
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`two, three or four times daily. Furthermore, the crystalline forms of the present invention can be
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`administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes,
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`using those forms of transderrnal skin patches well known to those of ordinary skill in the art. To be
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`administered in the form of a transdermal delivery system, the dosage administration will, of course, be
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`continuous rather than intermittent throughout the dosage regimen.
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`In the methods of the present invention, the dihydrogenphosphate salt and crystalline
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`hydrates herein described in detail can form the active pharmaceutical ingredient, and are typically
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`administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively
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`referred to herein as 'carrier' materials) suitably selected with respect to the intended form of
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`administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional
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`pharmaceutical practices.
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`For instance, for oral administration in the form of a tablet or capsule, the active
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`pharmaceutical ingredient can be combined with an oral, non-toxic, pharmaceutically acceptable, inert
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`carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium
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`phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the
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`active pharmaceutical ingredient can be combined with any oral, non-toxic, pharmaceutically acceptable
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`inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable
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`binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
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`Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners,
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`natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose,
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`polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate,
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`sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
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`Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the
`like.
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`The dihydrogenphosphate salt of structural formula I and the crystalline monohydrate
`
`have been found to possess a high solubility in water, rendering it especially amenable to the preparation
`of formulations, in particular intr'émasal and intravenous formulations, which require relatively
`
`concentrated aqueous solutions of active ingredient. The solubility of the crystalline
`
`A
`
`dihydrogenphosphate salt monohydrate of formula I in water has been found to be about 72 mg/mL.
`
`According to a further aspect, the present invention provides a process for the
`
`preparation of the dihydrogenphosphate salt of formula I, which process comprises reacting 4—0xo-4-[3-
`
`(trifluoromethyl)-5 ,6-dihydro[ l ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5 -trifluorophenyl)butan-2—
`amine of structural formula IV below:
`
`F
`
`Ur,»
`
`(IV)
`
`CF3
`
`with approximately one equivalent of phosphoric acid in a suitable C1-C5 alkanol, such as methanol,
`
`ethanol, isopropyl alcohol (IPA), and isoamyl alcohol (1AA) or aqueous C1—C5 alkanol. The reaction is
`
`carried out at a temperature range of about 25 °C to about 80 °C. The phosphoric acid solution can be
`
`added to a solution of the amine, or the addition can be performed in the reverse direction. The
`
`crystalline dihydrogenphosphate salt monohydrate is obtained by crystallization from an aqueous C1-C5
`
`alkanol solution of the dihydrogenphosphate salt as described below.
`
`_7_
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`GENERAL lVIETHODS FOR CRYSTALLIZING THE MONOHYDRATE OF THE
`
`DIHYDROGENPHOSPHATE SALT OF STRUCTURAL FORMULA I:
`
`(a) In ethanol/water system at 25 °C:
`
`(1) crystallization from a mixture of compound I in ethanol and water, such that the water concentration
`
`is above 31 weight percent,
`
`(2) recovering the resultant solid phase, and
`
`(3) removing the solvent therefrom.
`
`(b) In isoamyl alcohol (IAA)/water system at 25 °C:
`
`(1) crystallization from a mixture of compound I in IAA and water, such that the water concentration is
`
`above 2.9 weight percent;
`
`(2) recovering the resultant solid phase; and
`
`(3) removing the solvent therefrom.
`
`(c) In IAA/water system at 40 °C:
`
`(1) crystallization from a mixture of compound I in IAA and water, such that the water concentration is
`
`above 3.6 weight percent;
`
`(2) recovering the resultant solid phase; and
`
`(3) removing the solvent therefrom
`
`(d) In IAA/water system at 60 °C:
`
`(1) crystallization from a mixture of compound I in IAA and water, such that the water concentration is
`
`25
`
`above 4.5 weight percent;
`
`(2) recovering the resultant solid phase; and
`
`(3) removing the solvent therefrom.
`
`30
`
`35
`
`(e) In Isopropyl alcohol (IPA)/water system at 25 °C:
`
`(1) crystallization from a mixture of compound I in [PA and water, such that the water concentration is
`
`above 7.0 weight percent;
`
`(2) recovering the resultant solid phase; and
`
`(3) removing the solvent therefrom
`
`(f) In IPA/water system at 40 °C:
`
`SUN - |PR2020-01072, Ex. 1010, p. 10 of 292
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`(l) crystallization from a mixture of compound I in IPA and water, such that the water concentration is
`
`above 8.1 weight percent;
`
`(2) recovering the resultant solid phase; and
`
`(3) removing the solvent therefrom.
`
`(g) In IPA/water system at 75°C:
`
`(1) crystallization from a mixture of compound I in IPA and water, such that the water concentration is
`
`above about 20 weight percent;
`
`(2) recovering the resultant solid phase; and
`
`(3) removing the solvent therefrom.
`
`The starting compound of structural formula IV can be prepared by the procedures
`
`detailed in Schemes 1-3 and Example 1 below.
`
`In a still further aspect, the present invention provides a method for the treatment and/or
`
`prevention of clinical conditions for which a DP-IV inhibitor is indicated, which method comprises
`
`administering to a patient in need of such prevention or treatment a prophylactically or therapeutically
`
`effective amount of the salt of Formula I as defined above or a crystalline hydrate thereof.
`
`The following non—limiting Examples are intended to illustrate the present invention and
`
`should not be construed as being limitations on the scope or spirit of the instant invention.
`
`Compounds described herein may exist as tautomers such as keto-enol tautomers. The
`
`individual tautomers as well as mixtures thereof are encompassed with compounds of structural formula
`I.
`
`The term “% enantiomeric excess" (abbreviated “ee”) shall mean the % major
`
`enantiomer less the % minor enantiomer. Thus, a 70% enantiomeric excess corresponds to formation of
`
`85% of one enantiomer and 15% of the other. The term “enantiomeric excess” is synonymous with the
`
`term “optical purity.”
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`trifluorophenyl )butan—Z—amine dihydrogenphosphate monohydrate
`
`Preparation of 3—;trifluoromethyl)—5,6,7,8—tetrahydro| 1,2,4Itriazolol4,3—a lpyrazine hydrochloride 11—41
`
`5.91%;
`
`1.CF3COOEt CH3CN
`NH2NH2 —___—> 1:30
`2. CICOCH2CI, NaOH
`
`H
`0
`A N
`\n/
`N/
`”1 10
`
`;
`
`CH CI
`2
`
`N‘N
`/
`
`Fac/(OkCHZCI
`
`POC|3
`
`CH3CN
`
`fl
`
`H2N’\/NH2
`
`,
`
`MeOH
`
`HCI
`
`HN/YI‘L J1\CF3
`
`N—>
`
`MeOH, HCI, 55 °C HU / N
`T»,
`
`/N\
`
`1-3
`
`3
`
`Step A:
`
`Pre aration of bish drazide 1-1
`
`Hydrazine (20.1 g, 35 wt% in water, 0.22 mol) was mixed with 310 mL of acetonitIile.
`
`31.5 g of ethyl trifluoroacetate (0.22 mol) was added over 60 min. The internal temperature was
`
`10
`
`increased to 25 °C from 14 °C. The resulting solution was aged at 22 - 25 °C for 60 min. The solution
`
`was cooled to 7 °C. 17.9 g of 50 wt% aqueous NaOH (0.22 mol) and 25.3 g of chloroacetyl chloride
`
`(0.22 mol) were added simultaneously over 130 min at a temperature below 16 °C. When the reaction
`
`was complete, the mixture was vacuum distilled to remove water and ethanol at 27 ~ 30 °C and under 26
`
`~ 27 in Hg vacuum. During the distillation, 720 mL of acetonitrile was added slowly to maintain
`
`15
`
`constant volume (approximately 500 mL). The slurry was filtered to remove sodium chloride. The cake
`
`was rinsed with about 100 mL of acetonitrile. Removal of the solvent afforded bis-hydrazide fl (43.2 g,
`
`96.5% yield, 94.4 area% pure by HPLC assay).
`
`1H-NMR (400 1V£Hz, DMSO-dfi): 6 4.2 (s, 2H), 10.7 (s, 1H), and 11.6 (s, 1H) ppm.
`
`13C-NMR (100 MHZ, DMSO—d6): 5 41.0, 116.1 (q, I = 362 Hz), 155.8 (q, J = 50 Hz), and 165.4 ppm.
`
`20
`
`-10-
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`3O
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`Step B:
`
`
`Preparation of Sitrifluoromethyl)-2-(chloromethyl)—1.3.4-oxadiazole
`
`(1:2)
`
`Bishydrazide _1—_l from Step A (43.2 g, 0.21 mol) in ACN (82 mL) was cooled to 5 °C.
`
`Phosphorus oxychloride (32.2 g, 0.21 mol) was added, maintaining the temperature below 10 °C. The
`
`mixture was heated to 80 °C and aged at this temperature for 24 h until HPLC showed less than 2 area%
`
`of g. In a separate vessel, 260 mL of IPAc and 250 mL of water were mixed and cooled to 0 °C. The
`
`reaction slurry was charged to the quench keeping the internal temperature below 10 °C. After the
`
`addition, the mixture was agitated vigorously for 30 min, the temperature was increased to room
`
`temperature and the aqueous layer was cut. The organic layer was then washed with 215 mL of water,
`
`215 mL of 5 wt% aqueous sodium bicarbonate and finally 215 mL of 20 wt% aqueous brine solution.
`
`HPLC assay yield after work up was 86—92%. Volatiles were removed by distillation at 75-80 mm Hg,
`
`55 °C to afford an oil which could be used directly in Step C without further purification. Otherwise the
`
`product can be purified by distillation to afford l_-2 in 70—80% yield.
`
`1H-NMR (400 MHz, CDC13)Z 5 4.8 (s, 2H) ppm.
`
`13C-NMR (100 MHz, CDC13): 8 32.1, 115.8 (q, I = 337 Hz), 156.2 (q, I = 50 Hz), and 164.4 ppm.
`
`Step C:
`
`Preparation of N—lg2;Q-piperazin—Z-ylideneltfifluoroacetohydrazide
`
`11—32
`
`To a solution of ethylenediamine (33.1 g, 0.55 mol) in methanol (150 mL) cooled at —20
`
`°C was added distilled oxadiazole H from Step B (29.8 g, 0.16 mol) while keeping the internal
`
`temperature at —20 °C. After the addition was complete, the resulting slurry was aged at —20 °C for 1 h.
`
`Ethanol (225 mL) was then charged and the slurry slowly warmed to —5 °C. After 60 min at —5 °C, the
`
`slurry was filtered and washed with ethanol (60 mL) at —5 °C. Arnidine g was obtained as a white solid
`
`in 72% yield (24.4 g, 99.5 area wt% pure by HPLC).
`
`1H-NMR (400 MHz, DMSO-dé): 6 2.9 (t, 2H), 3.2 (t, 2H), 3.6 (s, 2H), and 8.3 (b, 1H) ppm. 13C-NMR
`
`(100 MHz, DMSO-dfi): 5 40.8, 42.0, 43.3, 119.3 (q, I = 350 Hz), 154.2, and 156.2 (q, I = 38 Hz) ppm.
`
`Step D:
`
`Preparation of 3-gtrifluoromethyl [-5,6,7,8-tetrahydro| l,2,4|tn'azolo|4,3—a Ipyrazine
`
`hydrochloride g 1-4)
`
`A suspension of amidine g (27.3 g, 0.13 mol) in 110 mL of methanol was warmed to
`
`55 °C. 37% Hydrochloric acid (11.2 mL, 0.14 mol) was added over 15 min at this temperature. During
`
`the addition, all solids dissolved resulting in a clear solution. The reaction was aged for 30 min. The
`
`solution was cooled down to 20 °C and aged at this temperature until a seed bed formed (10 min to l h).
`
`300 mL of MTBE was charged at 20 °C over 1 h. The resulting slurry was cooled to 2 °C, aged for 30
`
`-11-
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`SUN - |PR2020-01072, Ex. 1010, p. 13 of 292
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`SUN - IPR2020-01072, Ex. 1010, p. 13 of 292
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`min and filtered. Solids were washed with 50 mL of ethanochTBE (1:3) and dried under vacuum at 45
`
`”C. Yield of triazole g was 26.7 g (99.5 area wt% pure by I-IPLC).
`
`1H-NMR (400 MHz, DMSO-d6): 5 3.6 (t, 2H), 4.4 (t, 2H), 4.6 (s, 2H), and 10.6 (b, 2H) ppm; l3C-NMR
`
`(100 MHz, DMSO-d6): 6: 39.4, 39.6, 41.0, 118.6 (q, J = 325 Hz), 142.9 (q, I = 50 Hz), and 148.8 ppm.
`
`F
`
`F
`
`o
`
`Scheme2
`
`o
`
`1K0
`0 0%
`
`F a
`
`‘
`
`OH
`
`léBUCOCI, IPerEt,
`.
`
`MAP, DMAc
`
`F
`
`F
`
`F
`
`OH 0
`\
`0
`0 OK
`
`fl
`
`F
`
`HCI
`
`HN/YNN
`.K/Nf
`L
`CF3
`
`
`
`F
`
`F
`
`o
`
`o
`
`E
`
`N/YNx
`K/N /N
`\(
`
`CF3
`
`NH4OAc
`MeOH
`
`F
`
`F
`
`F
`
`F
`
`F
`
`NH2 0
`\
`
`2:;
`
`NH2 0
`
`N/\|¢N\
`K/N /N
`
`CF3
`
`[Rh(00d)C|]2.
`R,S—t-BuJosiphos,—>
`H2, MeOH, 200 psi