`Moriarty et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,765,117 B2
`Jul. 20, 2004
`
`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 of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 10/184,907
`
`(22)
`
`Filed:
`
`Jul. 1, 2002
`
`(65)
`
`Prior Publication Data
`US 2002/0173672 A1 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, which is a continuation of application No.
`08/957,736, filed on Oct. 24, 1997, now abandoned.
`
`Int. Cl.7 ........................ .. C07C 37/00, co7c 33/34
`(51)
`(52) U.S. Cl.
`...................................... .. 568/806; 568/807
`(58) Field of Search ............................... .. 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
`
`12/1981 Aristoff
`4,306,075 A
`10/1992 Tadepalli et al.
`5,153,222 A
`FOREIGN PATENT DOCUMENTS
`
`EP
`W0
`
`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 E1 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. Takano et 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:
`Development of 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
`C2R2)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. Chung et 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-Khand Reaction,” J. Am. Chem. Soc., vol. 116, pp.
`3159-3160 (1994).
`F. A. Hicks et al., “A Practical Titanium-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. ANew 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-
`PGF1-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-PGF1-type compounds.
`
`4 Claims, No Drawings
`
`SteadyMed - Exhibit 1003 - Page 1
`
`SteadyMed - Exhibit 1003 - 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 by the trivial, art-recognized system of nomen-
`clature described by N. A. Nelson, J. Med. Chem. 172911
`(1974) for prostaglandins. Accordingly, all of the novel
`prostacyclin derivatives herein will be named as 9-deoxy-
`PGF1-type compounds.
`The prostacyclin derivatives prepared by the method
`disclosed in the ’075 patent are as follows:
`
`
`
`(X-R42 [3-R3, or a mixture of
`wherein L1 is ot-R3:[3-R4,
`ot-R3:[3-R4 and (X-R42 [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;
`wherein M1 is (X-OH: [3-R3 or (X-R52 [3-OH, wherein R5 is
`hydrogen or methyl;
`wherein R7 is
`(1) -CmH2m-CH3, wherein m is an integer from one to 5,
`inclusive,
`(2) phenoxy optionally substituted 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, 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 option-
`ally 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,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`(4) cis—CH=CH-CH2-CH3,
`(5) (CH2)2-CH(OH)-CH3, or
`(6) -(CH2)3—CH=C(CH3)2;
`wherein -C(L2)-R7 taken together is
`(1) (C4-C7)cycloall<yl optionally substituted by one to 3
`(C1-C5) alkyl;
`(2) 2-(2-furyl)ethyl,
`(3) 2-(3thienyl)ethoxy, or
`(4) 3-thienyloxymethyl;
`wherein R8 is hydroxy, hydroxymethyl, or hydrogen;
`wherein
`
`(1) R20, R21, R22, R23, and R24 are all hydrogen with R22
`being either ot-hydrogen or [3-hydrogen,
`(2) R20 is hydrogen, R21 and R22 taken together form a
`second valence bond between C-9 and C-6a, and R23
`taken together form a second valence bond between
`C-8 and C-9 or are both kydrogen, or
`(3) R22, R23, and R24 are all kydrogen, with R22 being
`either ot-hydrogen or [3-hydrogen, and
`(a) R20 and R21 taken together are oxo, or
`(b) R20 is kydrogen and R21 is hydroxy, being
`ot-hydroxy or [3-hydroxy;
`wherein X1 is
`(1)( -)Ct(1)C()iR1, wherein R1 is
`a
`y rogen,
`(b) (C1'C12)a1ky1>
`(c) (C3-C10)cycloall<yl,
`(d) (C0-C12)arall<yl,
`(e) phenyl, optionally substituted with one, 2 or 3
`chloro or (C1-C1)alkyl,
`(f) phenyl substituted in the para position by
`(i) -NH-CO-R25,
`(ii) -CO-R20,
`(iii) -O-CO-R34, or
`(iv) -CH=N-NH-CO-NH2 wherein R23 is methyl,
`phenyl, acetamidophenyl, benzamidophenyl, or
`-NH2: R20 is methyl, phenyl, -NH2, or methoxy;
`and R34 is phenyl or acetamidophenyl; inclusive,
`or
`
`(g) a pharmacologically acceptiable cation;
`(2) -CH2OH,
`(3) -COL4, wherein L4 is
`(a) amino of the formula - - NR31R32, wherein R31 and
`R32 are
`(i) hydrogen,
`(ii) (C1- C12)alkyl,
`(iii) (C3-C10)cycloall<yl,
`(iv) (C7- C12)arall<yl,
`(v) phenyl, optionally substituted with one, 2 or 3
`chloro, (C1-C3)all<yl, hydroxy, carboxy, (C2-C5)
`alkoxycarbonyl, or nitro,
`(vi) (C2-C5)carboxyall<yl,
`(vii) (C2-C3)carbamoylalkyl,
`(viii) (C2-C3)cyanoalkyl,
`(ix) (C3-C0)acetylall<yl,
`(X) (C7-C11)benzoall<yl, optionally substituted by oe,
`2 or 3 chloro,
`(C1-C3)all<yl, hydroxy,
`(C1-C3)
`alkoxy, carboxy, (C2-C3)all<oxycarbonyl, or nitro,
`(xi) pyridyl, optionally substituted by one, 2 or 3
`chloro, (C1-C3)alkyl, or (C1-C3)alkoxy,
`(xii) (C0-C9)pyridylall<yl optionally substituted by
`one, 2 or 3 chloro,
`(C1-C3)all<yl, hydroxy, or
`(C1-C3)alkyl,
`(xiii) (C1-C4)l<ydroxyall<yl,
`
`SteadyMed - Exhibit 1003 - Page 2
`
`SteadyMed - Exhibit 1003 - Page 2
`
`
`
`US 6,765,117 B2
`
`3
`
`(xiv) (C1-C4)dihydroxyalkyl,
`(xv) (C1-C4)trihydroxyalkyl,
`with the further proviso that not more than one of R51 and
`R52 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 (C1-C12)alkyl of one to 12 carbon atoms,
`inclusive,
`(c) carbonylamino of the formula -NR55COR51,
`wherein R55 is hydrogen or (C1-C4)alkyl and R51 is
`other than hydrogen, but otherwise as defined above,
`(d) sulfonylamino of the formula -NR55SO2R51,
`wherein R51 and R55 are as defined in (c),
`(4) -CH2NL2L5, wherein L2 and L5 are kydrogen or
`(C1-C4)alkyl, being the same or different, or the phar-
`macologically acceptable acid addition salts thereof
`when X1 is -CH2NL2L5,
`wherein Y1 is trans-CH=CH-, cis-CH=CH-, CH2CH2-, or
`-CEC-; and
`wherein Z4 is -CH2- or -(CH2)-CF2, wherein f is zero,
`one, 2 or 3.
`When X1 is -COOR1 of the Formulac in the ’075 patent,
`the novel compounds so 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 R1. 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 analogs of 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,
`ot-phenylethylamine, [3-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
`
`15
`
`20
`
`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 amine salts
`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 number of steps. It is an object of
`the present invention to provide an improved method of
`preparing prostacyclin derivatives involving fewer steps.
`
`SUMMARY OF THE INVENTION
`
`The present invention relates to a process for preparing
`9-deoxy-PGF1-type compounds by a process that is stereo-
`selective and requires fewer steps than the prior art. The
`invention also relates to novel intermediates prepared during
`the synthesis of the 9-deoxy-PGF1-type compounds.
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`
`In one embodiment, the present invention relates to an
`improved stereoselective method for making 9-deoxy-
`PGF1-type compounds comprising converting a compound
`of the formula:
`
`OR1
`
`Z(CH2)nX
`
`C\§C\ Y1—C—C—R
`\
`1.
`1
`
`1
`
`1
`
`into a compound of the following formula:
`
`OR1
`
`Y1—C—C—R7
`||
`||
`M1
`L1
`
`.3 0
`
`H
`
`Z(CH2),,X
`
`wherein Z is O, S, CH2, or NR8 in which R8 is H, alkyl
`or aryl;
`X is H, CN, OR9, or COOR9 in which R9 is alkyl, THP
`or TBDMS;
`wherein n is 0, 1, 2, or 3;
`wherein Y1 is trans-CH=CH—, cis-CH=CH—, —CH2
`(CH2)m—, or —CEC—; m is 1,2, or 3;
`wherein R1 is an alcohol protecting group;
`
`SteadyMed - Exhibit 1003 - Page 3
`
`SteadyMed - Exhibit 1003 - Page 3
`
`
`
`US 6,765,117 B2
`
`wherein R7 is
`
`5
`
`(1) —CpH2p—CH3, wherein p is an integer from one to
`5, inclusive,
`
`(2) 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 pro-
`viso that R7 is phenoxy or substituted phenoxy, only
`when R3 and R4 are hydrogen or methyl, being the
`same or different,
`
`(3) phenyl, benzyl, phenylethyl, or phenylpropyl
`optionally substituted on the aromatic ring by one,
`two or three chloro, fluoro, trifluoromethyl, (C1-C3)
`alkyl, or (C1—C3)alkoxy, with the proviso that not
`more than two substituents are other than alkyl,
`(4) cis-CH=CH—CH2—CH3,
`(5) —(CH2 2—CH(OH)—CH3, or
`(6) —(CH2)3—CH=C(CH3)2§
`
`wherein —C(L1)—R7 taken together is
`(1) (C4—C7)cycloalkyl optionally substituted by one to
`3 (C1-C5) alkyl;
`(2) 2-(2-furyl)ethyl,
`(3) 2-(3-thienyl)ethoxy, or
`(4) 3-thienyloxymethyl;
`
`wherein M1 is ot-OH:[3-R5 or ot-R5:[3-OH, wherein R5 is
`hydrogen or methyl; and
`
`wherein L1 is ot-R3:[3-R4, ot-R4:[3-R3, or a mixture of
`ot-R3:[3-R4 and ot-R4:[3-R3,
`
`wherein R3 and R4 are hydrogen, methyl, or fluoro, being
`the same or different, with the proviso that one of R3
`and R4 is fluoro only when the other is hydrogen or
`fluoro.
`
`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 upon heating to form a tricyclic structure. More
`preferably, this cyclization is carried out by reacting C02
`(CO)8 with the above compound of the formula:
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`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 CH2Cl2, toluene, isooctane, and heptane.
`In the case of carrying out the cobalt-mediated cyclization
`with CH2Cl2, after reacting Co2(CO)8 with the above com-
`pound of the formula:
`
`OR1
`
`(3%:
`
`\
`
`Z(CH2)nX
`
`7
`
`l
`\Y ’C*C?R
`1.
`1
`
`1
`
`1
`
`in the presence of CH2Cl2 to form a complex with the
`alkynyl group, preferably the CH2Cl2 is removed in a
`subsequent step and replaced with CH3CN followed by
`heating in an inert gas atmosphere, such as argon, nitrogen,
`or carbon monoxide, which decomposes the complex to
`form the above tricyclic compound.
`Although Co2(CO)8 contributes a carbonyl during the
`reaction, it is not necessary to react equal amounts of the
`starting compound of the above formula and Co2(CO)8. It is
`also possible to use the Co2(CO)8 in a catalytic way, by
`introducing a relatively small amount of Co2(CO)8 and also
`introducing CO into the reaction mixture (e.g., by bubbling
`CO into 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:
`
`OR1
`
`C\\:
`
`\
`
`Z(CH2)nX
`
`7'
`
`l
`\Y —C—C:R
`1.
`1
`
`1
`
`1
`
`In another preferred embodiment, the present invention
`relates to an improved stereoselective method for making
`9-deoxy-PGF1-type compounds comprising the following
`reaction:
`
`OR1
`
`Y1:C*CjR7
`II
`II
`M1
`L1
`
`3 o
`
`H
`
`4
`1) Co2(CO)8/CH2Cl2
`2) CH3CN, reflux
`
`OR1
`
`C\\C\ Y1:C*CjR7
`\
`II
`II
`M1
`L1
`
`O (CHZ)nCH3
`
`0(CHZ)nCH3
`
`60
`
`65
`
`wherein n is 0, 1, 2, or 3;
`wherein Y1 is trans-CH=CH—, cis-CH=CH—, —CH2
`(CH2)m—, or —C=C—; m is 1,2, or 3;
`wherein R1 is an alcohol protecting group;
`wherein R is
`(1) —Cp7H2P—CH3, wherein p is an integer from one to
`5, inclusive,
`(2) 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 pro-
`
`SteadyMed - Exhibit 1003 - Page 4
`
`SteadyMed - Exhibit 1003 - Page 4
`
`
`
`US 6,765,117 B2
`
`7
`viso 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)
`allyl, or (C1—C3)alkoXy, with the proviso that not
`more than two substituents are other than alkyl,
`(4) cis-CH=CH—CH2—CH3,
`(5) —(CH2)2—CH(OH)—CH3, or
`(6) —(CH2)3—CH=C(CH3)2§
`wherein —C(L1)—R7 taken together is
`(1) (C4—C7)cycloal<lyl optionally substituted by one to
`3 (C1-C3) alkyl;
`
`8
`
`(2) 2-(2-furyl)ethyl,
`(3) 2-(3-thienyl)ethoXy, or
`(4) 3-thienyloxymethyl;
`wherein M1 is ot-OH:[3-R3 or ot-R3:[3-OH, wherein R3 is
`hydrogen or methyl;
`
`wherein L1 is ot-R3:[3-R4, ot-R4:[3-R3, or a mixture of
`ot-R3:[3-R4 and ot-R4:[3-R3,
`
`10
`
`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.
`
`The present invention also relates to a method of making
`the following compounds utilizing the foregoing reaction:
`
`OH
`
`T»
`R1X/Imidazole
`CHZCIZ
`80%
`
`OR1
`
`
`Br
`
`BuLi/A/
`40%
`
`OR1
`
`\
`
`O(CH2)nCH3
`I1 = 0-8
`1
`
`O(CH2)nCH3
`2
`
`O(CH2)nCH3
`3
`
`LTBAF/TBF 70%
`
`O
`
`H
`
`\
`
`O(CH2)nCH3
`5
`
`O
`
`Cl
`
`QR1
`
`Cl/DMSO/Et3N CHZCIZ
`
`O
`
`70%
`
`O(CH2)nCH3
`4
`
`OH
`
`\
`
`/\/9H\
`/EtMgBr
`-50%
`
`OH
`
`OH
`
`C
`C
`
` W /V
`m _
`m
`FCC/CHZCLZ
`m _
`m
`\
`g
`70%
`\
`g
`(_)R1
`(_)R1
`
`O(CHZ)nCH3
`
`7
`
`---u||I%OH
`
`Ph
`
`PH
`
`+
`
`2) BH3Megs/THF
`
`70%
`
`HN
`
`1)
`
`6
`
`0 (CHZ)nCH3
`
`TH3B
`T/ \T
`B
`B
`H3C/ \o/ \CH3
`
`SteadyMed - Exhibit 1003 - Page 5
`
`SteadyMed - Exhibit 1003 - Page 5
`
`
`
`US 6,765,117 B2
`
`-continued
`
`10
`
`OH
`
`.
`Alcohol protectmg
`group
`Irnidazole
`DMF
`10
`
`15
`
`20
`
`T»
`Pd/C, N2
`KZCO3/ETOH
`25
`
`30
`
`\
`
`O(CH2)nCH3
`
`8
`
`=
`E
`OTHP
`
`OR1
`
`H X
`
`In
`
`In
`
`0
`
`1 1
`
`H
`
`O(CHZ)nCH3
`
`NaBH2/EtOH
`10% NaOH
`
`95%
`
`C
`%
`
`O(CH2)nCH3
`
`m
`
`In
`
`_
`
`OR1
`
`1
`
`1) Co2(CO)8/CHZCIZ
`2) CH3CN, reflux
`
`I
`
`O(CHZ)nCH3
`
`10
`
` 35
`
`H
`
`eP
`
`TSA
`Paratoluene
`sulfonic acid
`75%
`
`H
`
`O(CH2),,CH3
`
`13
`
`Ph2PH/BuLi
`THF
`70%
`
`O(CH2),,CH3
`
`12
`
`40
`
`45
`
`
`
`H
`
`O(CH2)mCN
`
`15
`
`T»
`5(K2CO3
`Acetone
`
`C1(CH2)mCN
`
`55
`
`60
`
`65
`
`KOH/MeOH
`90%
`
`
`
`O(CH2)mCOOH
`
`1 6
`
`SteadyMed - Exhibit 1003 - Page 6
`
`SteadyMed - Exhibit 1003 - Page 6
`
`
`
`US 6,765,117 B2
`
`11
`wherein R1 is in each case an independently selected
`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)1,X
`O
`
`(3%:
`
`\
`
`1
`7,
`\Y *C:C?R'
`1 1
`1
`1
`
`C\\C\ Y1:C*CjR7;
`\
`1 1
`1
`1
`
`Z(CH2)1,X
`OR1
`
`(3%:
`
`\
`
`7,
`
`1
`\Y —C:C?R
`1 1
`1
`
`1
`
`Z(CH2)nX
`HO
`
`C\§C\ Y1—C:C:R7;
`\
`1 1
`1
`
`1
`
`and
`
`Z(CH2)nX
`
`OR1
`
`Y1—fi—fi—R7.
`‘ 0
`M1
`L1
`
`H
`
`Z(CH2)1,X
`
`wherein X, Z, Y1, M1, L1, R1 and R7 are as defined above.
`The present invention is further illustrated by, though in
`no way limited to, the following examples.
`
`EXAMPLE 1
`
`9-Deoxy-2',9ot-methano-3-oxa4,5,6-trinor-3,7-(1‘,3’-
`inter-phenylene)-13,14-dihydro-PGF1
`
`OH
`
`+
`
`Imid.
`
`+
`
`tBuMe2Si: Cl
`
`—>
`
`OMe
`138.17
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`-continued
`
`Procedure
`
`0—s|i
`
`OMe
`
`252.42
`2
`
`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 was stirred overnight at room temperature. The
`mixture was filtered and washed with water and then brine.
`
`The organic layer was separated, dried over MgSO4, filtered,
`and evaporated to afford 53 g of a clear yellow oil that was
`used in the next step without further purification.
`
`O:Si
`
`+
`
`n-BuLi
`
`+
`
`OMe
`
`252.43
`2
`
`Br/V Ar
`
`OMe
`
`120.98
`d = 1.398
`
`Procedure
`
`64.06
`2.5M
`
`O:S|i
`\
`
`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 NH4Cl. The organic layer was separated and washed
`with Brine, dried over MgSO4, and filtered. Evaporation of
`the solvent yielded a yellow oil which was used in the next
`reaction without further purification.
`
`SteadyMed - Exhibit 1003 - Page 7
`
`SteadyMed - Exhibit 1003 - Page 7
`
`
`
`US 6,765,117 B2
`
`+
`
`TBAF
`
`:>
`
`261.47
`1M
`
`OMe
`178.23
`4
`
`o —si
`
`|
`
`OMe
`
`\
`292.49
`3
`
`OH
`
`\
`
`OMe
`178.23
`4
`
`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 was stirred
`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 MgSO4. Filtration and evaporation of the solvent
`produced an orange oil which was purified by flash column
`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.
`
`10
`
`20
`
`25
`
`30
`
`35
`
`OH
`
`\
`
`O
`
`C1
`
`O
`
`C1
`
`DMSO + Et3N ?>
`
`O
`
`H
`
`OMe
`176.22
`
`\
`
`Procedures
`
`To a solution of 20.6 g (162 mmol, 1.2 eq.) of oxalyl
`chloride in 250 ml of CH2Cl2 under Ar at —78° C. were
`added dropwise 24.2 g (310 mmol) of DMSO in 100 ml of
`CH2Cl2. After 10 minutes, 24 g (135 mmol) of 4 in 100 ml
`of CH2Cl2 were added dropwise. The mixture was stirred at
`—78° C. for 30 min., and then 68.3 g (675 mmol, 5.0 eq.) of
`Et3N were added. Stirring continued as the reaction warmed
`to room temperature. The reaction was quenched with H20,
`Washed with saturated NH4Cl solution and Brine. The
`organic layer was separated and dried over MgSO4. 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 brown oil.
`
`O
`
`H
`
`5
`
`C2H5MgBr
`
`+
`
`O
`
`
`OMe
`00 C. - Lt.
`3h
`
`THF
`reflux
`20 min.
`
`
`
`SteadyMed - Exhibit 1003 - Page 8
`
`SteadyMed - Exhibit 1003 - Page 8
`
`
`
`US 6,765,117 B2
`
`15
`Procedure
`
`-continued
`
`TH3
`O/B\O
`I
`I
`B
`B
`H3C/ \O/ \CH3
`
`PhCH3
`
`7, BH3, M625
`THF -30° C 1 h
`
`C P
`
`rocedure
`
`STEP I: Preparation of Reagent:
`Compound B may be synthesized according to D. S.
`Mathre et al., J. Org. Chem. 1991, Vol. 56, p. 751; P. Beak,
`Org. Synth., 1997, p. 23. Compound B (1.08 g, 4.26 mmol)
`was dissolved in 30 ml of anh. toluene under argon. Trim-
`ethylboroxine (C) (0.357 g, 2.84 mmol) was added dropwise
`and the resulting solution was stirred 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. (CH3CN, CO2) 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 NH4Cl,
`NaHCO3 solution and brine, dried (MgSO4) 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 on silica gel to give 770 mg of 8 as a
`colorless oil (87%).
`
`8
`
`+
`
`TBDMSCI
`
`+
`
`DMF
`Imidazole mr.t. 3-4
`OTBDMS
`
`
`
`9
`
`Procedure
`
`TBDMSCI (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
`
`SteadyMed - Exhibit 1003 - Page 9
`
`Compound A may be 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
`NH4Cl solution, concentrated, extracted with ethyl acetate
`(4><25 ml), dried (MgSO4) and the solvent distilled off in
`vacuo. The crude product (2.65 g) was purified by flash
`chromatography using 10-30% ether in hexane on silica gel
`to obtain a colorless oil 1.45 g (52%) of 6.
`
`
`
`10
`
`15
`
`20
`
`25
`
`30
`
`
`
`Procedure
`
`To a solution of alcohol 6 (1.27 g, 13.07 mmol) in dry
`CH2Cl2 (20 ml) was added pyridinium chlorochromate
`(PCC) (1.32 g, 6.12 mmol) and the mixture was stirred 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 plug of silica gel.
`The solid was washed 3 times with ether (3><50 ml). After the
`solvent was removed, the crude product (1.3 g) was purified
`by flash chromatography using 10% ether in hexane on silica
`gel to give 900 mg light yellow oil (71%).
`
`Ph
`
`Ph
`
`OH
`
`+
`
`.\‘\\\
`
`"
`
`NH
`
`B
`
`45
`
`50
`
`55
`
`60
`
`65
`
`SteadyMed - Exhibit 1003 - Page 9
`
`
`
`17
`
`US 6,765,117 B2
`
`mmol) in DMF (20 ml) at room temperature under argon,
`and the mixture was stirred at room temperature for 3-4 hrs.
`After the reaction was quenched with sat. NH4Cl,
`the
`reaction mixture was extracted with ether (3><50 ml). The
`combined ether extracts were dried (MgSO4) and concen-
`trated in vacuo. The crude oil was purified by chromatog-
`raphy using 5% ether in hexane on silica gel to yield 860 mg
`of 9 as a colorless oil (88%).
`
`18
`-continued
`
`9
`
`+
`
`Co2(CO)3
`
`1. CH2Cl2
`
`r. t., 30 min.
`2. CH3CN
`reflux, 2 h
`
`OTBDMS
`
`to 0
`
`OCH3
`
`10
`
`Procedure
`
`STEP I: Complex formation:
`
`Compound 9 (0.840 g, 1.59 mmol) was dissolved in dry
`CH2Cl2 (15 ml) under argon, and CO2(CO)8 (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
`
`CH2Cl2 was distilled out from the above solution. The
`complex was dissolved in dry CH3CN (50 ml), and the
`solution was refluxed under argon for 2 hrs. This solvent was
`distilled out,
`the crude mass was dissolved in ether and
`passed quickly through a short column of neutral alumina to
`yield 850 mg of light brown oil (96%).
`
`OTBDMS
`
`O
`
`0
`
`H
`
`OCH3
`
`O
`
`10
`
`H2, 20 P.S.I.
`Pd/C + anh. KZCO3
`abs. EtOH
`
`r.t., 13 h
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`OCH3
`
`11
`
`Procedure
`
`Compound 10 (0.850 g, 1.53 mmol) was dissolved in
`absolute ethanol (50 ml). Anh. KZCO3 (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 on silica gel to
`yield 440 mg of colorless oil (67%).
`
`0Q
`
`NaBH4, NaOH
`95% EtOH
`-10° C. 6 h.
`
`H
`
`H
`
`0
`
`1 1
`
`OCH3
`
`
`
`OCH3
`
`12
`
`Procedure
`
`A solution of ketone 11 (0.430 g) in 95% ethanol was
`cooled to —10° C. 10% NaOH (6 ml) and NaBH4 (0.080 g)
`were added and the mixture was stirred at —10° C. for 1 hr.
`
`Then one more eq. of NaBH4 (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. NaHCO3, brine,
`dried (MgSO4) and concentrated in vacuo to obtain 430 mg
`of colorless oil (98%) which has a single spot on TLC.
`Further purification was not required.
`
`SteadyMed - Exhibit 1003 - Page 10
`
`SteadyMed - Exhibit 1003 - Page 10
`
`
`
`US 6,765,117 B2
`
`20
`
`CH3OH, p-TSOH >
`
`TLC shows 80-90% conversion (14). The reaction mixture
`was cooled to —5° C. and then an aqueous solution of NaCl
`containing 5% conc. HCl was added dropwise to quench the
`reaction. The reaction mixture was extracted with ethyl
`acetate 3><20 ml and the combined organic layers were
`washed with brine and dried (Na2SO4), filtered and concen-
`trated. The crude product was purified by silica gel column
`chromatography (50% EtOAc/Hex. as eluent) to give 0.12 g
`10 of product (75%) (22 mg of starting diol was recovered).
`
`OH
`
`OCH3
`
`
`
`..n|IOH
`
`CICHZCNT»
`KZCO3/Acetone
`
`OH
`
`OCH3
`
`13
`
`20
`
`r.t., 2 h
`
`25
`
`Procedure
`
`To 400 mg (0.93 mmol) of compound 12 dissolved in
`methanol (10 ml) was added p-TsOH (20 mg), and the
`solution was stirred at room temperature until TLC showed
`completion of the reaction (2 hrs). The solvent was removed
`in vacuo, the residue was dissolved in CH2Cl2, washed with
`sat. NaHCO3, dried(MgSO4), and concentrated in vacuo.
`The crude product was purified by silica gel column chro-
`matography (30% ether in hexanes as eluent) to give 250 mg
`13 (78%).
`
`OCHZCN
`
`15
`
`30
`
`Procedure
`
`
` 14
`
`
`A suspension of compound (14) (0.12 g. 0.37 mmol),
`chloroacetonitrile (0.56 g, 7.4 mmol) and KZCO3 (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
`filtered, the solvent was removed under reduced pressure.
`The crude product was purified by silica gel column chro-
`matography using 1: 1 EtOAc/hexanes as eluent to yield 0.12
`g of product (95%).
`
`aq. KOH
`MeOH
`
`OCHZCN
`
`15
`
`H
`
`35
`
`40
`
`50
`
`55
`
`60
`
`OCHZCOOH
`
`1 6
`
`Procedure
`
`Aqueous KOH (0.4 g, 7.12 mmol, water 1.2 ml, 35%
`65 solution) was added dropwise to a stirred solution of nitrile
`compound (15) (0.072 g, 0.21 mmol) in methanol (4 ml) and
`the reaction mixture was refluxed for 3 hrs. The reaction
`
`SteadyMed - Exhibit 1003 - Page 11
`
`n-BuLi/ph3pHA
`THF
`
`OCH3
`
`13
`
`Procedure
`
`n-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 (0.2