a2, United States Patent
`US 6,765,117 B2
`(10) Patent No.:
`Moriartyetal. Jul. 20, 2004
`
`(45) Date of Patent:
`
`US006765117B2
`
`(54) PROCESS FOR STEREOSELECTIVE
`SYNTHESIS OF PROSTACYCLIN
`DERIVATIVES
`
`(75)
`
`Inventors: Robert M. Moriarty, Oak Park, IL
`(US); Raju Penmasta, Bolingbrook, IL
`(US); Liang Guo, Chicago, IL (US);
`Munagala S. Rao, Westmont, IL (US);
`James P. Staszewski, Naperville, IL
`(US)
`
`(73) Assignee: United Therapeutic Corporation,
`Washington, DC (US)
`
`(*) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`US.C. 154(b) by 0 days.
`
`(21) Appl. No.: 10/184,907
`
`(22)
`
`Filed:
`
`Jul. 1, 2002
`
`(65)
`
`Prior Publication Data
`US 2002/0173672 Al Nov. 21, 2002
`
`Related U.S. Application Data
`
`(62) Division of application No. 09/541,521, filed on Apr. 3,
`2000, now Pat. No. 6,441,245, which is a continuation-in-
`part of application No. 09/481,390, filed on Jan. 12, 2000,
`now abandoned, whichis a continuation of application No.
`08/957,736, filed on Oct. 24, 1997, now abandoned.
`
`(SL) Unt. C17 ooeeccecccccccccecsseseeee C07C 37/00; CO7C 33/34
`(52)
`UWS. Ch.eee eee 568/806; 568/807
`(58) Field of Search oo... cece 568/379, 338,
`568/311, 316, 322, 327, 807, 806, 632,
`633, 634, 715; 560/56, 121, 503
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,306,075 A
`5,153,222 A
`
`12/1981 Aristoff
`10/1992 Tadepalli et al.
`FOREIGN PATENT DOCUMENTS
`
`EP
`WO
`
`0087237
`WO 98/39337
`
`8/1983
`9/1998
`
`OTHER PUBLICATIONS
`
`J.J. F. Belch et al., “Randomized, Double-Blind, Placebo—
`Controlled Study Evaluating the Efficacy and Safety of
`AS-013, a Prostaglandin EI Prodrug, in Patients with Inter-
`mittent Claudication,” Circulation, vol. 95, No. 9, pp.
`2298-2302 (1997).
`N. A. Nelson, “Prostaglandin Nomenclature,” Journal of
`Medicinal Chemistry, vol. 17, No. 9, pp. 911-918 (1974).
`S. Takanoet al., “Enantiodivergent Synthesis of Both Enan-
`tiomers of Sulcatol and Matsutake Alcohol from ®-Epichlo-
`rohydrin,” Chemistry Letters, pp. 201 7—2020 (1987).
`
`D. J. Mathre et al., “A Practical Enantioselective Synthesis
`of
`a,cz—Diaryl—2—pyrrolidinemethanol, Preparation and
`Chemistry of the Corresponding Oxazaborolidines,” J. Org.
`Chem., vol. 56, pp. 762-762, (1991).
`B. L. Pagenkoph, “Substrate and Reagent Control of Dias-
`teroselectivity in ‘Transition Metal—Mediated Process:
`Developmentof a Catalytic Photo Promoted Pauson—Khand
`Reaction,” Diss. Abstr. Int., vol. 57, No. 12, p. 7535 (1997)
`Abstract XP—002097925.
`
`J. Mulzer et al., “Asymmetric Synthesis of Carbacyclin
`Precursors by PausonKhand Cyclization,” Liebigs Ann.
`Chem., vol. 9, pp. 891-897 (1988) Abstract XP-002097924.
`I. U. Khand et al., “Organocobalt Complexes. Part
`II.
`Reaction of Acetylenehexacarbonyldicobalt Complexes, (RI
`C2R’)Co2(CO)6, with Norbomene and its Derivatives,” J.
`Chem. Soc, Perkin Trans., pp. 977-981, (1973).
`P. L. Pauson, “A Convenient and General Route to a Wide
`Range of Cyclopentenone Derivatives,” Tetrahedron, vol.
`41, No. 24, pp. 5855-5860 (1985).
`N. E. Schore, “Transition—Metal—Medicated Cycloaddition
`Reactions of Alkynes in Organic Synthesis,” Chem. Rev.,
`vol. 88, pp. 1081-1119 (1988).
`S. Shambayati et al., “N—Oxide Promoted Pauson—Khand
`Cyclizations at Room Temperature,” Tetrahedron Letters,
`vol. 31, pp. 5289-5292 (1990).
`V. K. Chunget al., “Promoters for the (Alkyne)hexacarbo-
`nyldicobalt-Based Cyclopentenone Synthesis,” Organome-
`tallics, vol. 12, pp. 220-223 (1993).
`N. Jeong et al., “Catalytic Version of the Intramolecular
`Pauson—KhandReaction,” J. Am. Chem. Soc., vol. 116, pp.
`3159-3160 (1994).
`F. A.Hicks et al., “A Practical Titantum—Catalyzed Synthe-
`sis of Bicyclic A17 Cyclopentenones and Allylic Amines,”
`J. Org. Chem., vol. 61, pp. 2713-2718 (1996).
`M. Zhang et al, “A Nickel(O)—Catalyzed Process for the
`Transformation of Enynes to Bicyclic Cyclopentenones,”J.
`Org. Chem., vol. 61, pp. 4498-4499 (1996).
`B. L. Pagenkopf et al., “Photochemical Promotion of the
`Intramolecular Pauson—Khand Reaction. A New Experimen-
`tal Protocol for Cobalt—Catalyzed [2+2+11 Cycloadditions,”
`J. Am. Chem. Soc., vol. 118, pp. 2285-2286 (1996).
`
`Primary Examiner—James O. Wilson
`Assistant Examiner—Sikarl A. Witherspoon
`(74) Attorney, Agent, or Firm—Foley & Lardner LLP
`
`(57)
`
`ABSTRACT
`
`An improved method is described for making 9-deoxy-
`PGF,-type compounds.
`In contrast
`to the prior art,
`the
`method is stereoselective and requires fewer steps than the
`known methods for making these compounds. The invention
`also relates to novel
`intermediates prepared during the
`synthesis of the 9-deoxy-PGF,-type compounds.
`
`4 Claims, No Drawings
`
`Liquidia - Exhibit 1007 - Page 1
`
`Liquidia - Exhibit 1007 - Page 1
`
`

`

`US 6,765,117 B2
`
`1
`PROCESS FOR STEREOSELECTIVE
`SYNTHESIS OF PROSTACYCLIN
`DERIVATIVES
`
`This application is a divisional of U.S. patent application
`Ser. No. 09/541,521, filed Apr. 3, 2000, now U.S. Pat. No.
`6,441,245, which is a continuation-in-part of U.S. patent
`application Ser. No. 09/481,390, filed Jan. 12, 2000, now
`abandoned, which is a continuation of U.S. patent applica-
`tion Ser. No. 08/957,736, filed Oct. 24, 1997, now aban-
`doned.
`
`FIELD OF THE INVENTION
`
`The present application relates to a process for producing
`prostacyclin derivatives and novel intermediate compounds
`useful in the process.
`BACKGROUND OF THE INVENTION
`
`Prostacyclin derivatives are useful pharmaceutical com-
`pounds possessing activities such as platelet aggregation
`inhibition, gastric secretion reduction, lesion inhibition, and
`bronchodilation.
`
`For convenience, the novel prostacyclin derivatives will
`be referred to bythetrivial, art-recognized system of nomen-
`clature described by N. A. Nelson, J. Med. Chem. 17:911
`(1974) for prostaglandins. Accordingly, all of the novel
`prostacyclin derivatives herein will be named as 9-deoxy-
`PGF, -type compounds.
`The prostacyclin derivatives prepared by the method
`disclosed in the ’075 patent are as follows:
`
`2
`(4) cis—CH=CH-CH,-CH,,
`(5) (CH;).-CH(OH)-CH,, or
`(6) -(CH);—CH=C(CH5)9;
`wherein -C(L,)-R, taken togetheris
`(1) (C,-C,)cycloalkyl optionally substituted by one to 3
`(C,-C.) alkyl
`(2) 2-(2-furyDethyl,
`(3) 2-Gthienylethoxy, or
`(4) 3-thienyloxymethyl;
`wherein Rg, is hydroxy, hydroxymethyl, or hydrogen;
`wherein
`
`(1) Ray, Roy, Roo, Roz, and R,, are all hydrogen with R,,
`being either a-hydrogen or B-hydrogen,
`(2) R2, is hydrogen, R,, and R,, taken together form a
`second valence bond between C-9 and C-6a, and R,,
`taken together form a second valence bond between
`C-8 and C-9 or are both kydrogen, or
`(3) Ro>, R23, and R,, are all kydrogen, with R,,. being
`either a-hydrogen or B-hydrogen, and
`(a) Rap and R,, taken together are oxo, or
`(b) Roo is kydrogen and R,,
`is hydroxy, being
`a-hydroxy or B-hydroxy;
`wherein X, is
`(1) -COOR,, wherein R, is
`(a) hydrogen,
`(b) (C,-C,,)alkyl,
`(c) (C3-C,,)cycloalkyl,
`(d) (C,-C,,)aralkyl,
`(e) phenyl, optionally substituted with one, 2 or 3
`chloro or (C,-C,alkyl,
`(f) phenyl substituted in the para position by
`(i) -NH-CO-R,;,
`(ii) -CO-R3.,
`(iii) -O-CO-R5,, or
`(iv) -CH=N-NH-CO-NH, wherein R,; is methyl,
`phenyl, acetamidophenyl, benzamidophenyl, or
`-NH.: R., is methyl, phenyl, -NH., or methoxy;
`and R,, is phenyl or acetamidopheny]; inclusive,
`or
`
`(g) a pharmacologically acceptiable cation;
`(2) -CH,OH,
`(3) -COL,, wherein L, is
`(a) amino of the formula - - NR;,R;,, wherein Rs, and
`R,, are
`(i) hydrogen,
`(il) (C,- C,)alkyl,
`(iti) (C3-C,,)cycloalkyl,
`(iv) (C,- Cy,)aralkyl,
`(v) phenyl, optionally substituted with one, 2 or 3
`chloro, (C,-C,)alkyl, hydroxy, carboxy, (C,-Cs)
`alkoxycarbonyl, or nitro,
`(vi) (C,-C,)carboxyalkyl,
`(vii) (C,-C,)carbamoylalkyl,
`(viii) (C,-C,)cyanoalkyl,
`(ix) (C3-C,)acetylalkyl,
`(x) (C,-C,,)benzoalkyl, optionally substituted by oe,
`2 or 3 chloro, (C,-C,)alkyl, hydroxy, (C,-C;)
`alkoxy, carboxy, (C,-C,)alkoxycarbonyl, or nitro,
`(xi) pyridyl, optionally substituted by one, 2 or 3
`chloro, (C,-C,)alkyl, or (C,-C,)alkoxy,
`(xii) (Cg-C.)pyridylalkyl optionally substituted by
`one, 2 or 3 chloro, (C,-C,)alkyl, hydroxy, or
`(C,-C,)alkyl,
`(xiii) (C,-C,)kydroxyalkyl,
`Liquidia - Exhibit 1007 - Page 2
`
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`25
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`30
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`40
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`50
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`55
`
`60
`
`65
`
`Xi Z4 al @)
`
`Rao
`Rat
`Rao
`
`Rag
`
`Rg3
`
`we”|
`M ly
`
`Rg
`
`is a-R3:B-R,, a-R,: B-R;, or a mixture of
`wherein L,
`a-R,:B-R, and a-R,: B-R,, wherein R, and R, are
`hydrogen, methyl, or
`fluoro, being the same or
`different, with the proviso that one of R, and R, is
`fluoro only when the other is hydrogen or fluoro;
`wherein M,is a-OH: B-R; or a-R;: B-OH, wherein R; is
`hydrogen or methyl;
`wherein R, is
`(1) -C,,,H.,,-CH;, wherein m is an integer from one to 5,
`inclusive,
`(2) phenoxy optionally substituted by one, two or three
`chloro, fluoro, trifluoromethyl, (C,-C,)alkyl, or (C,-
`C,)alkoxy, with the proviso that not more than two
`substituents are other than alkyl, with the proviso that
`R, is phenoxy or substituted phenoxy, only when R,
`and R, are hydrogen or methyl, being the same or
`different,
`(3) phenyl, benzyl, phenylethyl, or phenylpropyl option-
`ally substituted on the aromatic ring by one, two or
`three chloro, fluoro, trifluoromethyl, (C,-C,)alkyl, or
`(C,-C,)alkoxy, with the proviso that not more than two
`substituents are other than alkyl,
`
`Liquidia - Exhibit 1007 - Page 2
`
`

`

`US 6,765,117 B2
`
`3
`(xiv) (C,-C,)dihydroxyalkyl,
`(xv) (C,-C,)trihydroxyalkyl,
`with the further proviso that not more than one of R,, and
`R,, is other than hydrogen or alkyl,
`(b) cycloamino selected from the group consisting of
`lyrolidino, piperidino, morpholino, piperazino,
`hexamethyleneimino, pyrrolino, or 3,4-
`didehydropiperidinyl optionally substituted by one
`or 2 (C,-C,,)alkyl of one to 12 carbon atoms,
`inclusive,
`(c) carbonylamino of the formula -NR5,COR;,,
`wherein R,, is hydrogen or (C,-C,)alkyl and R., is
`other than hydrogen, but otherwise as defined above,
`(d) sulfonylamino of the formula -NR,,SO.R,,,
`wherein R;, and R,, are as defined in (c),
`(4) -CH,NL.L;, wherein L, and L; are kydrogen or
`(C,-C,alkyl, being the same or different, or the phar-
`macologically acceptable acid addition salts thereof
`when X, is -CH,NL;L;,
`wherein Y, is trans-CH=CH-, cis-CH=CH-, CH,CH,-, or
`-C=C-; and
`wherein Z, is -CH,- or -(CH,)-CF,, wherein f is zero,
`one, 2 or 3.
`When X, is -COOR,of the Formulac in the ’075 patent,
`the novel compoundsso described are used for the purposes
`described and are in free acid form, in ester form, or in
`pharmacologically acceptable salt form. When the ester
`form is used,
`the ester is any of those within the above
`definition of R,. However, it is preferred that the ester be
`alkyl of one to 12 carbon atoms, inclusive. Of the alkyl
`esters, methyl and ethyl are especially preferred for optimum
`absorption of the compound by the body or experimental
`animal system; and straight-chain oxtyl, nonyl, decyl,
`undecyl, and dodecyl are especially preferred for prolonged
`activity.
`Pharmacologically acceptable salts of the novel prostag-
`ladin analogsof this invention for the purposes described are
`those with pharmacologically acceptiable metal cations,
`ammonia, amine cations, or quaternary ammonium cations.
`Especially preferred metal cations are those derived from
`the alkali metals, e.g., lithium, sodium, and potassium, and
`from the alkaline earth metals, e.g., magnesium and calcium,
`although cationic forms of other metals, e.g., aluminum,
`zinc, and iron are within the scope of this invention.
`Pharmacologically acceptable amine cations are those
`derived from primary, secondary, and tertiary amines.
`Example of suitable amines are methylamine,
`dimethylamine, trimethylamine, ethylamine, dibutylamine,
`triisopropylamine, N-methylhexylamine, decylamine,
`dodecylamine, allylamine, crotylamine, cyclopentylamine,
`dicyclohexylamine, benzylamine, dibenzylamine,
`a-phenylethylamine, }-phenylethylamine, ethylenediamine,
`diethylenetriamine, adamantylamine, and the like aliphatic,
`cycloaliphatic, araliphatic amines containing up to and
`including about 18 carbon atoms, as well as heterocyclic
`amines, e.g., piperidine, morpholine, pyrrolidine, piperazie,
`and lower-alkyl derivatives thereto, e.g.,
`1-methylpiperidine,
`4-ethylmorpholine,
`1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-
`dimethylpiperazine, 2-methylpiperidine, and the like as well
`as amines containing water-solubilizing or hydrophilic
`groups, e.g., mono-, di-, and triethanolamine,
`
`10
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`15
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`20
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`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`ethyldiethanolamine, N-butylethanolamine, 2-amino-1-
`butanol, 2-amino-2-ethyl,-1,3-propanediol, 2-amino-2-
`methyl-1-propanol,
`tris(hydroxymethyl) aminomethane,
`N-phenylethanolamine, N-(p-tert-amylphenyl)-
`diethanolamine, galactamine, N-methylglycamine,
`N-methylglucosamine, ephedrine, phenylephrine,
`epinephrie, procaine, and the like. Further useful aminesalts
`of the basic amino acid salt, e.g., lysie and arginine.
`Examples of suitable pharmacologically acceptable qua-
`ternary ammonium cations are tetramethylammonium,
`tetraethylammonium, benzyltrimethylammonium,
`phenyltriethylammonium, and the like.
`U.S. Pat. No. 4,306,075 discloses methods for making
`prostacyclin derivatives. However, these and other known
`processes involve a large numberofsteps. It is an object of
`the present invention to provide an improved method of
`preparing prostacyclin derivatives involving fewer steps.
`
`SUMMARYOF THE INVENTION
`
`The present invention relates to a process for preparing
`9-deoxy-PGF,-type compounds bya processthatis stereo-
`selective and requires fewer steps than the prior art. The
`invention alsorelates to novel intermediates prepared during
`the synthesis of the 9-deoxy-PGF,,-type compounds.
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`
`In one embodiment, the present invention relates to an
`improved stereoselective method for making 9-deoxy-
`PGF,-type compounds comprising converting a compound
`of the formula:
`
`OR;
`
`SS
`Syc—c—R,
`Stl
`M Lj
`
`Z(CH2).X
`
`into a compoundof the following formula:
`
`Z(CH).X
`
`wherein Z is O, S, CH,, or NRg in which Rg is H,alkyl
`or aryl;
`X is H, CN, OR,, or COOR, in which Rg is alkyl, THP
`or TBDMS;
`wherein n is 0, 1, 2, or 3;
`wherein Y, is trans-CH—=CH—, cis-CH—=CH—, —CH,
`(CH,),,—, or —C=C—; m is 1,2,or 3;
`wherein R,is an alcohol protecting group;
`Liquidia - Exhibit 1007 - Page 3
`
`Liquidia - Exhibit 1007 - Page 3
`
`

`

`wherein R, is
`(1) —C,H.,—CHs,wherein p is an integer from one to
`5, inclusive,
`(2) phenoxy optionally substituted by one, two or three
`chloro,
`fluoro,
`trifluoromethyl,
`(C,—-C,)alkyl, or
`(C,-C,)alkoxy, with the proviso that not more than
`two substituents are other than alkyl, with the pro-
`viso that R, is phenoxy or substituted phenoxy, only
`when R, and R, are hydrogen or methyl, being the
`same or different,
`(3) phenyl, benzyl, phenylethyl, or phenylpropyl
`optionally substituted on the aromatic ring by one,
`two or three chloro, fluoro, trifluoromethyl, (C,-C,)
`alkyl, or (C,-C,)alkoxy, with the proviso that not
`more than two substituents are other than alkyl,
`in the presence of CH,Cl, to form a complex with the
`(4) cis-CH=CH—CH,—CH,,
`alkynyl group, preferably the CH,Cl,
`is removed in a
`(5) —(CH,),—CH(OH)—CH,, or
`subsequent step and replaced with CH3CN followed by
`heating in an inert gas atmosphere, such as argon,nitrogen,
`(6) —(CH3)3—CH=C(CH3).;
`or carbon monoxide, which decomposes the complex to
`wherein —C(L,)—R, taken together is
`form the above tricyclic compound.
`Although Co,(CO), contributes a carbonyl during the
`(1) (C,-C,)cycloalkyl optionally substituted by one to
`reaction, it is not necessary to react equal amounts of the
`3 (C,-C5) alkyl;
`starting compoundof the above formula and Co.(CO)s. It is
`(2) 2-(2-furylethyl,
`also possible to use the Co,(CO), in a catalytic way, by
`(3) 2-(3-thienyl)ethoxy, or
`introducingarelatively small amount of Co,(CO), and also
`introducing CO into the reaction mixture(e.g., by bubbling
`(4) 3-thienyloxymethyl,
`COinto the reaction mixture) in the presence of light which
`catalyzes the transfer of CO through a Co-mediated complex
`formed with the above compound of the formula:
`
`OR;
`
`XS
`Syc—c—R,
`Std
`M Ly
`
`Z(CH2).X
`
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`25
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`30
`
`US 6,765,117 B2
`
`5
`
`6
`using a suitable non-reactive solvent. Preferably, the non-
`reactive solvent
`is a chlorinated solvent, a hydrocarbon
`solvent, or an aromatic solvent. More preferably, the non-
`reactive solvent is CH,Cl., toluene, isooctane, and heptane.
`In the case of carrying out the cobalt-mediated cyclization
`with CH,CL,, after reacting Co,(CO), with the above com-
`pound of the formula:
`
`wherein M, is a-OH:B-R; or a-R;:6-OH, wherein R; is
`hydrogen or methyl; and
`
`is a-R,:B-R,, a-Ry:B-R;, or a mixture of
`wherein L,
`a-R,:6-R, and a-R,:B-R;,
`
`wherein R, and R, are hydrogen, methyl, or fluoro, being
`the same or different, with the proviso that one of R;
`and R, is fluoro only when the other is hydrogen or
`fluoro.
`
`Preferably, the above conversion is carried out through
`cobalt-mediated cyclization, in which a complex is formed
`with the alkynyl group of the starting compound, which
`decomposes uponheating to form a tricyclic structure. More
`preferably, this cyclization is carried out by reacting Co,
`(CO), with the above compound of the formula:
`
`OR;
`
`Ss
`Sy-c—c—R,.
`S|
`M Ly
`
`Z(CHa),X
`
`In another preferred embodiment, the present invention
`relates to an improved stereoselective method for making
`9-deoxy-PGF,-type compounds comprising the following
`reaction:
`
`OR,
`
`Yy—C——C——R7
`|
`ll
`M,
`
`lyoo
`
`«
`
`1) Co2(CO)g/CH2Cl2
`2) CH3CN,reflux
`
`H
`
`Oo (CH2),CH3
`
`OR,
`
`oS
`on
`SS “TT
`M li
`
`O(CH2)nCH3
`
`OR,
`
`O
`4
`
`/
`
`Z(CH2).X
`
`Yy—C——C——R7
`
`M Ly
`
`60
`
`wherein n is 0, 1, 2, or 3;
`wherein Y, is trans-CH—=CH—, cis-CH—=CH—, —CH,
`(CH,),,—, or —C=C—; m is 1,2,or 3;
`wherein R,is an alcohol protecting group;
`wherein R, is
`(1) —C,H.,—CH,,whereinp is an integer from oneto
`5, inclusive,
`(2) phenoxy optionally substituted by one, two or three
`chloro,
`fluoro,
`trifluoromethyl,
`(C,—-C,)alkyl, or
`(C,-C,)alkoxy, with the proviso that not more than
`two substituents are other than alkyl, with the pro-
`Liquidia - Exhibit 1007 - Page 4
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`Liquidia - Exhibit 1007 - Page 4
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`

`

`US 6,765,117 B2
`
`7
`viso that R, is phenoxy or substituted phenoxy, only
`when R, and R, are hydrogen or methyl, being the
`same or different,
`(3) phenyl, benzyl, phenylethyl, or phenylpropyl
`optionally substituted on the aromatic ring by one,
`two or three chloro, fluoro, trifluoromethyl, (C,-C,)
`allyl, or (C,-C,)alkoxy, with the proviso that not
`more than two substituents are other than alkyl,
`(4) cis-CH=CH—CH,—CH,,
`(5) —(CH,),—CH(OH)—CH,, or
`(6) —(CH,)3—CH=C(CHs).;
`wherein —C(L,)—R, taken together is
`(1) (C,-C,)cycloaklyl optionally substituted by one to
`3 (C,-C5) alkyl;
`
`10
`
`8
`
`(2) 2-(2-furyl)ethyl,
`(3) 2-(3-thienyl)ethoxy, or
`(4) 3-thienyloxymethyl,
`wherein M,is a-OH:6-R; or a-R;:$-OH, wherein R; is
`hydrogen or methyl;
`wherein L,
`is a-R,:B-R,, a-R,:6-R;, or a mixture of
`a-R,:B-R, and a-R,:B-R;,
`wherein R, and R, are hydrogen, methyl,or fluoro, being
`the same or different, with the proviso that one of R;
`and R, is fluoro only when the other is hydrogen or
`fluoro.
`
`The present invention also relates to a method of making
`the following compounds utilizing the foregoing reaction:
`
`OH
`
`CHCl,
`
`RpX/Imidazole
`80%
`
`aN
`
`~~Br
`40%
`
`OR,
`
`SS
`
`O(CH2),CH3
`n=0-8
`1
`
`O(CH2),CH3
`2
`
`SS
`
`Cl/DMSO/Et;N CH,Cly
`
`oes
`
`70%
`
`OR,
`
`O(CH2),CH3
`3
`
`|Patrme710%
`
`OH
`
`SS
`
`O(CH3),CH3
`
`4
`
`ZVOWNS
`/EtMgBr
`-50%
`
`OH
`
`OH
`
`NOAA —_—___» Ae
`
`O(CH2),CH3
`
`i
`OR,
`
`Sy
`
`O(CH2),CH3
`
`i“
`
`IN
`i
`OR,
`
`PCC/CH>CLs
`70%
`
`Ph
`
`PH
`
`+
`
`HR
`
`Q st 2) BH3Me2S/THF
`
`70%
`
`rB
`ryB
`
`B
`“aa™Nae ™~CH
`
`H3C
`
`Liquidia - Exhibit 1007 - Page 5
`
`Liquidia - Exhibit 1007 - Page 5
`
`

`

`US 6,765,117 B2
`
`-continued
`
`10
`
`OH
`
`Ss
`
`S
`
`~
`
`i
`OR,
`
`m
`
`O(CH2),CH3
`
`—___
`Alcoholprotecting
`group
`Imidazole
`DME
`10
`
`—N
`
`i
`=
`OTHP
`
`O(CH2),CH3
`
`1) Co2(CO)g/CH2Cly
`2) CH3CN,reflux
`
`15
`
`
`
`OR,
`
`m
`
`» 'OROX‘m
`
`|
`
`O(CH)),CH3
`
`10
`
`Pd/C, No
`K,CO,/ETOH
`
`O(CH),CH3
`
`NaBH,/EtOH
`10% NaOH
`
`95%
`
`30
`
`°
`
`d1
`
` H
`
`O(CH2),CH3
`
`13
`
`PhoPH/BuLi
`THE
`10%
`
`
`
`
`OR,
`
`tilOH.
`
`14
`
`OH
`
`35
`
`PTSA
`Paratoluene
`sulfonic acid
`75%
`
`40
`
`45
`
`5(K2CO3
`Acetone
`
`Cl(CH3)CN
`
`55
`
`60
`
`65
`
`H
`
`O(CH5),CH3
`
`12
`
`
`
`
`
`OR,
`
`MtiOH
`
`15
`
`tt
`
`O(CH)CN
`
`KOH/MeOH
`90%
`
`OR,
`
`MOH
`
`
`
`
`O(CH5)COOH
`
`16
`
`Liquidia - Exhibit 1007 - Page 6
`
`Liquidia - Exhibit 1007 - Page 6
`
`

`

`US 6,765,117 B2
`
`11
`is in each case an independently selected
`wherein R,
`alcohol protecting group. Preferred alcohol protecting
`groups are tertiary butyl dimethyl sily (TBDMS)and
`tetra hydro pyranyl (THP).
`The present invention also relates to the following novel
`intermediate compounds:
`
`HO
`
`Z(CH2).X
`Oo
`
`Z(CH2).X
`OR,
`
`Z(CH3)aX
`HO
`
`XS
`Syc—c—R:
`Std
`M Li
`
`SS
`~S
`
`Sy-c—c—R::
`Il
`M li
`
`SS
`Sy—c—c—R,;
`Std
`M Lj
`
`‘So Yy-—C——C——R;;
`~S
`Il
`M
`
`and
`
`Z(CHa)pX
`
`OR,
`
`7Ss OM Ly
`
`H
`
`Z(CH2).X
`
`wherein X, Z, Y,,M,, L,, R, and R, are as defined above.
`The present invention is further illustrated by, though in
`no way limited to, the following examples.
`
`EXAMPLE1
`
`9-Deoxy-2',9a-methano-3-0xa4,5,6-trinor-3,7-(1',3'-
`inter-phenylene)-13,14-dihydro-PGF,
`
`+
`
`Imid.
`
`+
`
`tBuMe,Si—cl —
`
`OMe
`138.17
`
`°
`
`10
`
`15
`
`20
`
`25
`
`30
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`
`
`oO|
`
`OMe
`
`252.42
`2
`
`-continued
`
`Procedure
`
`To a solution of imidazole (29.6 g, 434 mmol, 2.8 eq.) in
`1.0 L of methylene chloride were added 25 g (181 mmol) of
`3-methoxybenzyl alcohol (1) in 200 ml of methylene chlo-
`ride. After all material was dissolved, 32.7 g (217 mmol, 1.2
`eq.) of t-butyldimethylsilyl chloride was added in portions.
`The reaction wasstirred overnight at room temperature. The
`mixture was filtered and washed with water and then brine.
`
`The organic layer was separated, dried over MgSO,,filtered,
`and evaporated to afford 53 g of a clear yellow oil that was
`used in the next step without further purification.
`
`oO_
`
`+
`
`n-BuLi
`
`+
`
`OMe
`
`252.43
`2
`
`Br —_
`
`OMe
`
`120.98
`d= 1.398
`
`Procedure
`
`64.06
`2.5M
`
`oOyl
`\
`
`292.49
`3
`
`To a solution of 95 g (376 mmol) of 2 dissolved in 400 ml
`of hexane under Ar at room temperature were added drop-
`wise 26.5 g (414 mmol, 1.1 eq.) of BuLi in 166 ml of
`hexane. The mixture was stirred for 2 hours at room
`
`temperature, and then the reaction was cooled in an ice bath
`and 54.6 g (452 mmol) of allyl bromide were added drop-
`wise. The reaction was allowed to warm to room tempera-
`ture overnight. After stirring for 24 hours, TLC indicated
`60% conversion, and the reaction was quenched with satu-
`rated NH,Cl. The organic layer was separated and washed
`with Brine, dried over MgSO,,andfiltered. Evaporation of
`the solvent yielded a yellow oil which wasused in the next
`reaction without further purification.
`Liquidia - Exhibit 1007 - Page 7
`
`Liquidia - Exhibit 1007 - Page 7
`
`

`

`US 6,765,117 B2
`
`13
`
`+
`
`TBAF — 5
`261.47
`
`1M
`
`OMe
`178.23
`4
`
`OH
`
`q
`
`O—Si
`|
`
`OMe
`
`\
`
`292.49
`3
`
`OMe
`178.23
`4
`
`10
`
`OH
`
`\ 15
`
`20
`
`25
`
`Procedure
`
`To a solution 3 (110 g, 376 mmol) in 2.0 L of THF were
`added 128 g (489 mmol, 1.1eq.) of tetrabutyl ammonium
`fluoride (TBAF) in 489 ml of THF. The reaction wasstirred 30
`at room temperature and was complete after 4 hours. The
`reaction was quenched by adding 500 ml of water. The
`organic layer was separated and washed with brine and dried
`over MgSO,. Filtration and evaporation of the solvent
`produced an orange oil which was purified by flash column 35
`chromatography,on silica gel using 10-30% ethyl acetate in
`hexanes as the eluent. The fractions containing the desired
`product were evaporated to afford 24 g (36% from
`3-methoxybenzyl alcohol) of a yellow oil.
`
`Procedures
`
`To a solution of 20.6 g (162 mmol, 1.2 eq.) of oxalyl
`chloride in 250 ml of CH,Cl, under Ar at -78° C. were
`added dropwise 24.2 g (310 mmol) of DMSO in 100 ml of
`CH,Cl,. After 10 minutes, 24 g (135 mmol) of 4 in 100 ml
`of CH,Cl, were added dropwise. The mixture wasstirred at
`-78° C. for 30 min., and then 68.3 g (675 mmol, 5.0 eq.) of
`Et,N were added. Stirring continued as the reaction warmed
`to room temperature. The reaction was quenched with H,O,
`washed with saturated NH,Cl solution and Brine. The
`organic layer was separated and dried over MgSO,,.Filtra-
`tion and evaporation of the solvent produced a brown oil
`which was purified by flash column chromatography, on
`silica gel using 5% ethyl acetate in hexanes as the eluent.
`The fractions containing the desired compound were evapo-
`rated to afford 20.5 g (86%) of a brownoil.
`
`Oo
`
`H
`
`5
`
`C2HsMgBr
`
`+
`
`On
`
`oO.
`
`THE
`reflux
`20 min.
`
`OMe
`
`
`O°C-rt.
`3h
`
`\
`
`
`
`Liquidia - Exhibit 1007 - Page 8
`
`Liquidia - Exhibit 1007 - Page 8
`
`

`

`US 6,765,117 B2
`
`15
`Procedure
`
`-continued
`
`Compound A maybe synthesized according to S. Takano
`et al., Chemistry Lett., 1987, p. 2017. To a solution of side
`chain (A) (1.6 g, 6.72 mmol) in dry THF (10 ml) which was
`heated to gentle refluxing under argon was added EtMgBr
`(2.24 ml, 6.72 mmol, 3M solution). After the addition was
`complete, the resultant solution was refluxed for 20 mil.
`
`The solution was cooled to 0° C. (under argon) and a
`solution of 5 (1.183 g, 6.72 mmol) in THF (10 ml,dried over
`molecular sieves) was added dropwise with stirring. After
`the complete addition, the reaction mixture was allowed to
`warm to room temperature and stirred for 2—3 hrs. The
`reaction mixture was cooled to 0° C., diluted with saturated
`NH,Cl solution, concentrated, extracted with ethyl acetate
`(4x25 ml), dried (MgSO,) and the solvent distilled off in
`vacuo. The crude product (2.65 g) was purified by flash
`chromatography using 10-30% ether in hexaneonsilica gel
`to obtain a colorless oil 1.45 g (52%) of6.
`
`
`
`10
`
`15
`
`20
`
`25
`
`30
`
`
`
`Procedure
`
`To a solution of alcohol 6 (1.27 g, 13.07 mmol) in dry
`CH,Cl, (20 ml) was added pyridinium chlorochromate
`(PCC) (1.32 g, 6.12 mmol) and the mixture wasstirred at
`room temperature. PCC slowly dissolved and the color of
`solution turned orange-black after approx. 5 min. Stirring
`was continued for 3 hrs. The reaction mixture was diluted
`with ether (100 ml) and filtered through a plugofsilica gel.
`The solid was washed 3 times with ether (3x50 ml). After the
`solvent was removed,the crude product (1.3 g) was purified
`by flash chromatography using 10% ether in hexane onsilica
`gel to give 900 mg light yellow oil (71%).
`
`Ph
`
`Ph
`
`OH
`
`+
`
`wo
`
`)
`NH
`B
`
`45
`
`50
`
`60
`
`65
`
`I.
`07 No
`l
`l
`B
`B
`HyC™ So” “cu,
`
`PhCH;
`
`7, BH3, Mes
`THF, -30°C. 1h
`
` OMe
`
`Procedure
`
`STEPI: Preparation of Reagent:
`Compound B may be synthesized according to D. S.
`Mathreet al., J. Org. Chem. 1991, Vol. 56, p. 751; P. Beak,
`Org. Synth., 1997, p. 23. Compound B (1.08 g, 4.26 mmol)
`wasdissolved in 30 ml of anh. toluene under argon. Trim-
`ethylboroxine (C) (0.357 g, 2.84 mmol) was added dropwise
`and the resulting solution wasstirred at room temperature.
`White solid separated out after 3-4 min. After stirring for 30
`min.,
`toluene was distilled out at atmospheric pressure.
`Again 20 ml of dry toluene were added and distilled out.
`This distillation was repeated for 2 more times. The solution
`of reagent in toluene was allowed to cool under argon.
`STEP II: Reduction:
`
`Asolution of ketone 7 (0.88 g, 2.14 mmol) in dry THF (20
`ml) was dried over molecular sieves for 2 hrs and added to
`the above reagent solution. The resulting solution was
`cooled to -30° C. (CH;CN, CO.) under argon and borane-
`methylsulfide complex (1.07 ml, 10.71 mmol) was added
`dropwise with stirring. After stirring at -30° C. for 1 hr, the
`reaction was quenched with methanol (10 ml), diluted with
`ether (100 ml), washed successively with saturated NH,Cl,
`NaHCO, solution and brine, dried (MgSO,) and concen-
`trated in vacuo to yield a crude product (2.3 g). The crude
`product was purified by flash chromatography using 10%
`ether in hexanes onsilica gel to give 770 mg of 8 as a
`colorless oil (87%).
`
`8
`
`+
`
`TBDMSCI
`
`+
`
`Imidazole
`
`DMF
`—_——_
`r.t. 34
`
`OTBDMS
`
`
`
`9
`
`Procedure
`
`TBDMSC1(0.337 g, 2.23 mmol) and imidazole (0.335 g,
`4.65 mmol) were added to the solution of 8 (0.770 g, 1.86
`Liquidia - Exhibit 1007 - Page 9
`
`Liquidia - Exhibit 1007 - Page 9
`
`

`

`US 6,765,117 B2
`
`17
`mmol) in DMF (20 ml) at room temperature under argon,
`and the mixture wasstirred at room temperature for 3—4 hrs.
`After the reaction was quenched with sat. NH,Cl,
`the
`reaction mixture was extracted with ether (3x50 ml). The
`combined ether extracts were dried (MgSO,) and concen-
`trated in vacuo. The crude oil was purified by chromatog-
`raphy using 5% ether in hexaneonsilica gel to yield 860 mg
`of 9 as a colorless oil (88%).
`
`9
`
`+
`
`Co(CO)g
`
`1. CH2Cly
`r. t., 30 min.
`2. CH3CN
`reflux, 2h
`
`OTBDMS
`
`Oe
`
`OCH,
`
`10
`
`Procedure
`
`STEP I: Complex formation:
`
`Compound 9 (0.840 g, 1.59 mmol) wasdissolved in dry
`CH,Cl, (15 ml) under argon, and CO,(CO), (0.653 g, 1.91
`mmol) was added to it and stirred at room temperature under
`argon. carbon monoxide evolved out slowly, and the solu-
`tion turned dark brown after 5 min. Stirring was continued
`for 30 min. at room temperature.
`
`STEP II: Pauson Khand Cyclization
`
`CH.CL, was distilled out from the above solution. The
`complex was dissolved in dry CH,;CN (50 ml), and the
`solution wasrefluxed under argon for 2 hrs. This solvent was
`distilled out,
`the crude mass was dissolved in ether and
`passed quickly through a short columnof neutral alumina to
`yield 850 mg oflight brown oil (96%).
`
`OTBDMS
`
`°
`
`°
`
`oH
`
`OCH
`
`oO
`
`10
`
`Hp, 20 P.S.L.
`Pd/C + anh. K2CO3
`abs. EtOH
`
`rt, 13h
`
`10
`
`15
`
`20
`
`25
`
`30
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`18
`-continued
`
`OCH;
`
`u
`
`Procedure
`
`Compound 10 (0.850 g, 1.53 mmol) was dissolved in
`absolute ethanol (50 ml). Anh. K,CO, (0.020 g) and Pd/C
`(0.550 g, 10%, wet) were added and the mixture was
`hydrogenated at 20 psi pressure for 13 hrs. The reaction
`mixture was filtered through celite and concentrated in
`vacuo. The crude product (800 mg) was purified by chro-
`matography using 10-30% ether in hexane onsilica gel to
`yield 440 mg of colorless oil (67%).
`
`Oo1S
`
`NaBHy, NaOH
`95% EtOH
`“10°C. 6h.
`
`H
`
`H
`
`oO
`
`d1
`
`OCH,
`
` OCH;
`
`12
`
`Procedure
`
`A solution of ketone 11 (0.430 g) in 95% ethanol was
`cooled to -10° C. 10% NaOH (6 ml) and NaBH, (0.080 g)
`were added and the mixture wasstirred at -10° C. for 1 hr.
`Then one more eq. of NaBH, (0.080 g) was added and
`stirring was continued for another 5 hrs. at -10° C. After
`quenching carefully with glacial acetic acid, the solvent was
`removed under reduced pressure. Resulting oil was dis-
`solved in ethyl acetate, washed with aq. NaHCO,, brine,
`dried (MgSO,) and concentrated in vacuo to obtain 430 mg
`of colorless oil (98%) which has a single spot on TLC.
`Further purification was not required.
`Liquidia - Exhibit 1007 - Page 10
`
`Liquidia - Exhibit 1007 - Page 10
`
`

`

`US 6,765,117 B2
`
`CH;0OH,p-TsOHeee
`rt., 2h
`
`
`
`
`OCH;
`
`13
`
`Procedure
`
`To 400 mg (0.93 mmol) of compound 12 dissolved in
`methanol (10 ml) was added p-TsOH (20 mg), and the
`solution wasstirred at room temperature until TLC showed
`completion of the reaction (2 hrs). The solvent was removed
`in vacuo, the residue was dissolved in CH,Cl,, washed with
`sat. NaHCO, dried(MgSO4), and concentrated in vacuo.
`The crude product was purified by silica gel column chro-
`matography (30% ether in hexanes aseluent) to give 250 mg
`13 (78%).
`
`10
`
`15
`
`20
`
`25
`
`30
`
`20
`TLC shows 80-90% conversion (14). The reaction mixture
`wascooled to —5° C. and then an aqueoussolution of NaCl
`containing 5% conc. HC] was added dropwise to quench the
`reaction. The reaction mixture was extracted with ethyl
`acetate 3x20 ml and the combined organic layers were
`washed with brine and dried (Na,SO,), filtered and concen-
`trated. The crude product was purified by silica gel column
`chromatography (50% EtOAc/Hex. as eluent) to give 0.12 ¢
`of product (75%) (22 mg ofstarting diol was recovered).
`
`OH
`
`K,CO3/Acetone
`
` CICH2CNeel
`OH OCHCN
`
`15
`
`Procedure
`
`35
`
`A suspension of compound (14) (0.12 g. 0.37 mmol),
`chloroacetonitrile (0.56 g, 7.4 mmol) and K,CO, (0.51 g,
`3.7 mmol) in dry acetone (15 ml) was refluxed under Ar for
`20 hrs. The reaction mixture was cooled to room tempera-
`ture and celite (0.5 g) was added. After the mixture was
`n-BuLi/phspHacoal
`filtered, the solvent was removed under reduced pressure.
`The crude product was purified by silica gel column chro-
`matography using 1:1 EtOAc/hexanesas eluent to yield 0.12
`g of product (95%).
`
`THF
` 14
` H
`
`OCH;
`
`1B
`
`Procedure
`
`o-BuLi (1.1 ml, 1.72 mmol)(1.6 M in hexanes) was added
`dropwise to a cold (-20° C.) and stirred solution of diphe-
`nylphosphine (0.28 g, 1.5 mmol) in anhydrous THF (8 ml)
`under argon. The reaction mire was warmed to room tem-
`perature (20° C.). Asolution ofdiol (13) (0.17 g, 0.49 mmol)
`in dry THF (0.6 ml) was added dropwise to the reaction
`mixture and the whole solution washeated to reflux for 3 hrs
`
`(TLC showsstarting material), heating was stopped and the
`reaction mixture was cooled again to —20° C. and diphe-
`nylphosphine (0.37 g, 1.96 mmol) was added followed by
`dropwise addition of n-BuLi (1.5 ml, 2.38 mmol)(1.6M in
`hexanes) under argon. After complete addition, the reaction
`mixture was warmedto 20° C. and then refluxed for 18hrs.
`
`aq. KOH
`MeOH
`
`OCH,CN
`
`1s
`
`50
`
`55
`
`60
`
`65
`
`OCH,COOH
`
`16
`
`Procedure
`
`Aqueous KOH (0.4 g, 7.12 mmol, water 1.2 ml, 35%
`solution) was added dropwise to a