Européischas Patentamt
`
`.o)
`
`European Patent Office
`
`63 Publication number:
`
`O 179 559
`
`Office européen des brevets
`
`A2
`
`69
`
`EUROPEAN PATENT APPLICATION
`
`@ Application number: 85306382.4
`
`@ Date offilingz o9.o9.s5
`
`@ men.-; c 07 D 405/06
`A 61 K 31/40
`
` Priority: 24.09.84 us 653798
`
`
`
`® Applicant: WARNER-LAMBERT COMPANY
`201 Tabor Road
`Morris Plains New Jersey 07950(US)
`
`10.12.34 Us 679676
`
`
`
`Representative: Jones, Michael Raymond et al,
`HASELTINE LAKE 8: CO. Hazlitt House 28 Southampton
`Buildings Chancery Lane
`London WC2A 1AT(GB)
`
`@ Trans-6-)2-(substitutedpyrro|-1-y|)alkyl[-pyran-2-one inhibitors of cholesterol synthesis.
`
`6-[2-(Substituted-pyrrol-1-yl)alkyl]pyran-2-ones of for-
`mula l
`H
`OH
`
`
`
`"3
`
`R“
`
`(I)
`
`and the corresponding ring-opened hydroxy-acids derived
`therefrom are potent inhibitors of the enzyme 3-hydroxy-3-
`methylglutarylcoenzyme A reductase (HMG-CoA reductasa),
`and are thus useful hypolipidemic and hypocholesterolemic
`agents. Pharmaceutical compositions containing such com-
`pounds, and a method of preparing the compounds are also
`disclosed.
`
`EP0179559A2
`
`Croydpn Printing Company Ltd
`
`Mylan Exhibit 1035, Page 1
`
`@ Date of publication of application:
`30.04.86 Bulletin 86/18
`
`Designated Contracting States:
`AT BE CH DE FR GB IT LI LU NL SE
`
`® Inventor: Hoefle, Milton L.
`1020 Belmont
`Ann Arbor Michigan 48104(US)
`
`63 Inventor: Roth, Bruce D.
`1440 King George Boulevard
`Ann Arbor Michigan 48104(US)
`
`@ Inventor: Stratton, Charlotte D.
`1523 Covington Drive
`Ann Arbor Michigan 48103lUS)
`
`Mylan Exhibit 1035, Page 1
`
`
`
`
`
`

`
`01 79559
`
`-1-
`
`
`
`TRANS-6 — [ 2 —( SUBSTITUTEDPYRROL-1-YL ) ALKYL] -
`
`PYRAN-2—ONE INHIBITORS OF CHOLESTEROL SYNTHESIS
`
`The present
`
`invention is related to compounds and
`
`5
`
`pharmaceutical compositions useful as hypocholesterolemic
`and hypolipidemic agents. More particularly, this
`i
`
`invention concerns certain trans—6-[2-(substitutedpyrrol-
`
`1-y1)a1kyl]-2—ones and the corresponding ring-opened
`
`acids derived therefrom which are potent inhibitors of
`
`the enzyme 3—hydrOxy—3-methylglutaryl-coenzyme A reduct-
`
`1o
`
`ase (HHS-COA reductase), pharmaceutical composition
`
`containing such compounds, and a method of lowering blood
`-:-:.- :— serum cholesterol
`levels employing such pharmaceutical
`
`compositions.
`
`15
`
`20
`
`Mylan Exhibit 1035, Page 2
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`Mylan Exhibit 1035, Page 2
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`

`
`_2_
`
`0179559
`
`ligh levels of blood cholesterol and blood lipids
`
`are conditions which are involved in the onset of_
`
`arteriosclerosis.
`
`It is well known that
`
`inhibitors of
`
`HMG-CoA reductase are effective in lowering the level of
`blood plasma cholesterol, especially low density lipo-
`protein cholesterol
`(LDL—C),
`in can (cf. M. S. Brown and
`
`J. L. Goldstein, New England Journal of Medicine (1981),
`_;_g§, No. 9, 515-517).
`1: has now been established that
`
`lowering LDL-C levels affords protection from coronary
`
`10
`
`heart disease (cf. Journal of the American Medical
`
`Association (1984) ggl, No. 3, 351-374).
`
`Moreover, it is known that certain derivatives of
`
`mevalonic acid (3,5-dihydroxy-3-methylpentanoic acid) and
`the corresponding ring-closed lactone form, nevalono-
`I
`
`15
`
`lactone,
`
`inhibit the biosynthesis of cholesterol (cf. F.
`
`M. Singer et al., Proc. Soc. Exper. Biol. Med.
`
`(1959).
`
`igg, 276) and F. B. Kulcher, Arch. Biochen. Bioghys.
`
`(1971): 146, 422.
`
`United states Patents 3,983,l4l; 4,l49,495 and
`
`20
`
`4,137,322 disclose the fernentative production of a
`
`‘
`
`natural product, now called conpactin. having an inhibi-
`
`tory effect on cholesterol biosynthesis. Conpactin
`
`has been shown to have a complex structure which includes
`
`a uevalonolactone moiety (Brown et al., J. Chem. Soc.
`
`25
`
`Perkin I,
`
`(1976), 1165.
`
`30
`
`35
`
`Mylan Exhibit 1035,
`
`e13
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`
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`Mylan Exhibit 1035, Page 3
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`

`
`United States Patent 4,255,444 to Oka eO'I17.9j55.9
`
`closes several synthetic derivatives of mevalonolactone
`
`having antilipidemic activity.
`
`United States Patents 4,198,425 and 4,262,813 to
`
`Hitsue et al. disclose aralkyl derivatives of mevalono-
`
`lactone which are useful
`
`in the treatment of hyperlipid-
`
`emia.
`
`United States Patent 4,375,475 to Hillard et al.
`
`discloses certain substituted 4—hydroxytetrahydropyran-
`
`2-ones which,
`
`in the 4(R)-trans stereoisomeric form, are
`
`inhibitors of cholesterol biosynthesis.
`
`In accordance with the present
`
`provided certain trans-6-[2-(substitutedpyrrol—1—yl)—
`
`invention,
`
`there are
`
`alkyllpyran-2-ones and the corresponding ring-opened
`
`hydroxy-acids derived therefrom which are potent inhibi-
`
`tors of cholesterol biosynthesis by virtue of their
`
`ability to inhibit the enzyme 3-hydroxy-3-methylglutaryl-
`
`coenzyme A reductase (HMG-CoA reductase).
`
`In particular,
`
`in its broadest chemical compound
`
`aspect,
`
`the present
`
`invention provides compounds of
`
`structural formula I
`
`
`
`R3./
`
`R‘
`
`I
`
`19
`
`15
`
`29
`
`25
`
`3B
`
`-CHZCHZ-, or —CH(CH3)Cu2—.
`wherein X is —CH2-,
`l—naphthy1; 2—naphthyl; cyclohexyl; norbornenyl;
`
`R1 is
`
`35
`
`phenyl; phenyl substituted by fluorine, chlorine,
`
`hydroxy,
`
`trifluoromethyl, alkyl of from one to four
`
`carbon atoms, alkoxy of from one to four carbon
`
`Mylan Exhibit 1035, Page 4
`
`
`
`Mylan Exhibit 1035, Page 4
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`

`
`atoms, or alkanoyloxy of from two to eight carbon atoms;
`
`2-, 3-, or 4-pyridinyl; 2-. 3-, or 4-pyridinyl-§-oxide;
`
`01 79559
`
`of
`
`.
`
`4
`
`’, Nzfls hal
`\ I
`
`where R5 is alkyl of from one to four carbon atoms and
`hal- is chloride, bromide, or iodide.
`R2 and R3 are
`independently hydrogen; chlorine; bromine: cyano;
`
`trifluoromethyl; phenyl; alkyl of from one to four carbon
`
`atoms; carboalkoxy of from two to eight carbon atoms;
`
`—CH2OR6 where R6 is hydrogen, alkanoyl of from one to six
`carbon atoms, or where R2 and R3 are -CHZOCONHR7 where R7
`is alkyl of from one to six carbon atoms, phenyl, or
`
`phenyl substituted with chlorine, bromine, or alkyl of
`
`R2 and R3 may also, when
`from one to four carbon atoms.
`taken together with the carbon atoms to which they are
`
`attached,
`
`form a ring denoted by
`
`(ff‘\
`
`where n is three or four; a ring denoted by
`
`O
`
`/’
`
`\\
`
`0 N
`
`/
`‘x
`
`o
`
`R-
`8
`
`a ring denoted by
`
`18
`
`15
`
`25
`
`25
`
`39
`
`35
`
`Mylan Exhibit 1035, Page 5
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`
`
`Mylan Exhibit 1035, Page 5
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`

`
`0179559
`-$‘-
`where R8 is hydrogen, alkyl of from one to six carbon
`atoms, phenyl, or benzyl: or a ring denoted by
`0
`
`5
`
`R9‘?
`“mm
`
`’,
`\
`
`uhere R9 and R1’ are hydrogen, alkyl of from one to four
`carbon atoms, or benzyl.
`
`R‘ is alkyl of from one to four carbon atoms,
`cyclopropyl, cyclobutyl, or trifluoromethyl.
`
`15
`
`Also contemplated as falling within this aspect of
`
`the invention are the corresponding dihydroxy-acid
`
`compounds of formula 11 corresponding to the opened form
`
`of the lactone ring of compounds of formula I
`
`15
`
`29
`
`
`
`3
`
`II
`
`where X, R1, R2, R3, and R4 are as defined above, and the
`pharmaceutically acceptable salts thereof. all of the
`
`compounds being in the trans racemate of the tetrahydro—
`
`25
`
`pyran moiety.
`
`In another aspect of the present
`
`invention,
`
`there is
`
`provided a method of preparing compounds of formula I
`
`"’above by (a) first reacting a substituted [(pyrrol-l—yl)-
`
`alkyllaldehyde compound of formula III
`
`3:
`
`35
`
`*1
`
`111
`
`where X, R1, R2, R3, and R‘ are as defined above, with
`the alkali metal salt of the dianion of methyl aceto-
`
`acetate to form a compound of structural formula IV
`
`Mylan Exhibit 1035, Page 6
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`
`
`Mylan Exhibit 1035, Page 6
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`

`
`R1
`R2~./ N’
`
`on
`o
`X—éHCH gen coocn
`2
`2
`
`3
`
`0179559
`
`R3
`
`R‘
`
`IV
`
`then
`where X, R1, R2, R3, and R‘ are as defined above,
`successivly (b)
`reducing compound IV with a trialkyl-
`
`borane and sodium borohydride and (c) oxidizing with
`
`alkaline hydrogen peroxide to produce an acid compound of
`
`formula V
`
`and finally (d) cyclizing, if desired,
`
`the acid compound
`
`of formula V to a lactone compound of formula I by
`
`heating in an inert solvent or, alternatively converting,
`
`if desired,
`
`the acid compound of formula V to a pharma-
`
`ceutically acceptable salt.
`
`In another aspect,
`
`the present
`
`invention provides
`
`pharmaceutical compositions, useful as hypolipidemic or
`
`hypocholesterolemic agents, comprising a hypolipidemic or
`
`hypocholesterolemic affective amount of a compound in
`
`accordance with this invention as set forth above,
`
`in
`
`combination with a pharmaceutically acceptable carrier.
`
`In another aspect,
`
`the present invention provides a
`
`19
`
`15
`
`29
`
`25
`
`—-3flH.nethod of inhibiting cholesterol biosynthesis in a
`
`patient in need of such treatment by administering a
`
`pharmaceutical composition in accordance with the present
`
`invention as defined above.
`
`35
`
`In a first preferred subgeneric chemical compound
`
`aspect,
`
`the present
`
`invention provides compounds of
`
`formula I above wherein X is —CH2CH2—, R1 is
`
`Mylan EXhibit_1035, Page 7
`
`
`
`Mylan Exhibit 1035, Page 7
`
`

`
`-;L_
`as defined above, R2 and R3 are independentlychgdzghédig
`chlorine, or bromine, and R‘
`is as defined above.
`In a second preferred subgeneric chemical compound
`
`aspect,
`
`the present invention provides compounds of
`
`formula I above where X is -CHZCHZ-, R1 is
`phenyl or phenyl substituted by fluorine, chlorine,
`
`hydroxy,
`
`trifluoromethyl, alkyl of from one to
`
`four carbon atoms, alkoxy of from one to four carbon
`atoms, or alkanoyloxy of from two to eight carbon atoms,
`
`or where R1 is 2-, 3-, or 4—pyridinyl; 2-, 3-, or
`4-pyridinyl-g-oxide, or
`
`ll
`
`-
`
`hal
`
`\ :3/‘*5
`
`/’
`
`15
`
`where as is alkyl of from one to four carbon atoms and
`hal-
`In this aspect of
`is chloride, bromide, or iodide.
`
`and R3 are preferably independently
`‘the invention, R2
`hydrogen, chlorine, or bromine, and R4 is alkyl of from
`one to four carbon atoms or trifluoromethyl.
`
`2B
`
`In a third preferred subgeneric chemical compound
`
`aspect,
`
`the present
`
`invention provides compounds of
`
`formula I above where X is —CH2CH2-, R1 is phenyl or
`phenyl substituted by fluorine, chlorine, hydroxy,
`
`25
`
`trifluoromethyl, alkoxy of from one to four carbon atoms,
`
`or alkanoyloxy of from two to eight carbon atoms, R2 and
`R
`are independently hydrogen, chlorine, or bromine, and
`
`3
`
`35
`
`R
`
`is isopropyl or trifluoromethyl.
`In a fourth preferred subgeneric chemical compound
`‘
`aspect,
`the present invention provides compounds of
`
`formula I above where X is -CH2CH2e, and R1
`is phenyl or phenyl substituted by fluorine, chlorine,
`
`trifluoromethyl, alkyl of from one to four
`
`35
`
`carbon atoms, alkoxy of from one to four carbon atoms, or
`
`alkanoyloxy of from two to eight carbon atoms, or where
`R1 is 1—naphthyl, or 2-naphthyl.
`In this preferred
`aspect of the invention, R2 and R3 are independently
`
`Mylan Exhibit 1035, Page 8
`
`
`
`Mylan Exhibit 1035, Page 8
`
`
`
`
`
`

`
`0179559
`_,_
`hydrogen, chlorine, bromine, cyano, trifluoromethyl,
`phenyl, alkyl of from one to four carbon atoms,
`-CH2oR6
`carboalkoxy of from two to eight carbon atoms,
`where R‘ is hydrogen or alkanoyl of from one to six
`carbon atoms,
`-CHZOCONHR7 where R7 is alkyl of from one
`to six carbon atoms, phenyl, or phenyl substituted with
`
`chlorine, bromine, or alkyl of from one to four carbon
`atoms-~ In this aspect of the invention, R2 and R3 may’
`also, when taken together with the carbon atoms to which
`
`5
`
`18
`
`they are attached,
`
`form a ring denoted by
`
`/
`
`(CHZIH \
`
`15 where n is three or four; a ring denoted by
`
`28
`
`a ring denoted by
`
`0
`
`R"'N
`3
`
`o
`
`/
`
`\
`
`25 where R8 is hydrogen, alkyl of from one to four carbon
`atoms, phenyl, or benzylg or a ring denoted by
`0
`
`39
`
`“9‘u
`I
`2'
`
`R10
`
`/
`
`\
`
`where R9 and R1“ are hydrogen, alkyl of from one to four
`carbon atoms, or benzyl.
`In this aspect of the
`invention, R‘ is preferably alkyl of from one to four
`carbon atoms, cyclopropyl, cyclobutyl, or trif1uoro-
`35 methyl.
`
`In a fifth preferred subgeneric chemical compound
`aspect,
`the present
`invention provides compounds of
`formula I above where X is -CH2CH2—, and R1
`
`Mylan Exhibit 1035, Page‘9
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`
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`Mylan Exhibit 1035, Page 9
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`

`
`0179559
`-'5-
`is phenyl or phenyl substituted by fluorine, chlorine,
`trifluoromethyl, alkyl of from one to four carbon atoms,
`alkoxy of from one to four carbon atoms, or alkanoyloxy
`of from two to eight carbon atoms.
`R2 and R3
`are preferably independently hydrogen, chlorine, bromine,
`phenyl, or carboalkoxy of from two to eight carbon atoms.
`In this aspect of the invention R2 and R3 may also, when
`taken together with the carbon atoms to which they are
`attached,
`form a ring denoted by
`
`5
`
`16
`
`/’
`
`(cazin \
`
`15 where n is three or four; a ring denoted by
`0
`\
`
`/
`
`n-N
`3
`
`o
`
`\
`
`28 where R8 is hydrogen, or alkyl of from one to four carbon
`atoms; or a ring denoted by
`
`O
`
`,8
`
`R10
`
`\
`
`where R9 and R15 are hydrogen or alkyl of from one to
`four carbon atoms.
`In this aspect of the invention, R
`is preferably alkyl of from one to four carbon atoms,
`or trifluoromethyl.
`
`4
`
`25
`
`3!
`
`In-1 sixth preferred subgeneric chemical compound
`aspect,
`the present invention provides compounds of
`formula I above where x is -CH2CH2-, R1 is is phenyl or
`phenyl substituted by fluorine, chlorine, trifluor-
`35 methyl, alkyl of from one to four carbon atoms, alkoxy of
`from one to four carbon atoms, or alkanoyloxy
`of from two to eight carbon atoms.
`R2 and R3 are
`
`Mylan Exhibit 1035, Page 10
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`
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`Mylan Exhibit 1035, Page 10
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`

`
`01 795%:
`we
`preferably independently carboalkoxy of from two to e
`carbon atoms or, when taken together with the carbon
`
`atoms to which they are attached form a ring denoted by
`
`5
`
`o
`\
`
`n-x
`9
`
`o
`
`I
`
`\
`
`18 where R8 is hydrogen or alkyl of from one to four carbon
`atoms.
`In this aspect of the invention, R‘ is preferably
`
`isopropyl or trifluoromethyl.
`
`As used throughout this specification and the
`
`appended claims,
`
`the term 'alkyl' denotes a branched or
`
`15 unbranched saturated hydrocarbon group derived by the
`
`removal of one hydrogen atom from an alkane.
`
`The term ‘alkoxy' denotes an alkyl group, as just
`
`defined, attached to the parent molecular residue through
`
`an oxygen atom.
`
`26
`
`The term 'alkanoyloxy' is meant to denote an alkyl
`
`group, as defined above, attached to a carbonyl group and
`
`thence,
`
`through an oxygen atom,
`
`to the parent molecular
`
`residue.
`
`The term 'carboalkoxy'
`
`is meant to denote an alkyl
`
`25 group, as defined above, attached to an oxygen atom and
`
`thence,
`
`through a carbonyl group,
`
`to the parent molecular
`
`residue.
`
`The term 'norbornenyl' denotes a group derived by
`
`the removal of a hydrogen atom (other than at a
`
`from bicyc1o[2.2.llhept-2-ene.
`36 bridgehead carbon atom)
`
`
`ylan Exhibit 1035, Page 11
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`
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`Mylan Exhibit 1035, Page 11
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`

`
`Specific examples of compounds contemplated as
`
`falling within the scope of the present
`
`invention include
`
`..//.»
`
`0179559
`
`the following:
`
`trans-6-[2-[2-Cyc1obuty1—5-(4-fluorophenyl)-1§-
`
`pyrrol-1-y1]ethy1]tetrahydto-4-hydroxy-Zg-pyran—2-one.
`
`trans-6-[2-I2-Cyc1ohexy1-5-(4-tluorophenyl)-lg:
`
`pyrrol-1-yllethylltetrahydro-4-hydroxy-pyran-2—one.
`
`trans-Tetrahydro-4-hydroxy—6-[2—(2-methyl-5-
`
`phenyl-lg-pyrrol-1-yl)ethyl]-2§—pyran-2-one.
`
`trans-6—[2-[2-(4-Chlorophenyl)-5-methy1-1§-
`
`pyrro1—1—y1]ethy1]tetrahydro-4-hydroxy-2g-pyran-2-one.
`
`trans-Tetrahydro—4-hydroxye6-[2-[2-(4-methoxy-
`
`phenyl)-5-methyl-1§-pyrrol-1-yl1ethyl]-2g-pyran~2-one.
`
`trans-6-{2—(2-([1,1'-Biphenyll-4-y1)—S-methy1-
`
`lg-pyrrol-1-y1)ethy1]tetrahydro—4—hydroxy-2§—pyran-2-one.
`
`trans-Tettahydro-4-hydroxy—6-[2—[2-methyl-5-
`
`[3-(trifluoromethyl)phenyll-1§-pyrrol-1-y1]ethy1]-2§-
`
`pyran-2-one.
`
`trans-6-[2-[2-(2,5-Dimethy1pheny1)-S-
`
`(1-methylethyl)—1§fpyrro1-1-y1]ethy1]tetrahydro-4-
`
`hydroxy-Zgfpyran-2-one.
`
`trans-6—[2—[2-(2,6—Dimethoxypheny1)-5-
`
`(1-methylethyl)—1§-pyrrol-1-yllethylltetrahydro-4-
`
`hydroxy-2§—pyran-2—one.
`
`trans-Tetrahydro-4-hydroxy-6-[2—[2—methy1-5-
`
`(2-naphthalenyl)-lg-pyrrol-1-y1]ethyl]-2§-pyran—2-one.
`
`trans—6-[2-(2-(Cyc1ohexy1—5—tr1f1uoromethy1—1§-
`
`pyrrol-1-y1)ethy1]tetrahydro-4-hydroxy-2§:pyran—2—one.
`
`trans—6—[2-[2-(4-Pluorophenyl)-3,4-dimethy1—5-
`
`(1—nethy1ethy1)-lgfpyrrol-1—y1]ethy1]tetrahydro-4-
`
`hydroxy—2§-pytan—2-one.
`
`1B
`
`15
`
`28
`
`25
`
`3!
`
`trans—2—(4—F1uoropheny1)—S-(1—nethy1ethy1)-1-[2-
`
`(tetrahydro—4-hydroxy-6-oxo-zg-pyran-2-yl)ethy1]—1§-
`
`pyrrole-3,5—dicarboxy1ic acid.
`trans-2-(4-Fluoropbenyl)-N3,N3,N‘,N‘-tetranethy1-
`
`35
`
`S—(1—methy1ethy1)-1-[2-(tetrahydro-4-hydroxy—6-oxo—2§—
`
`pyran~2—y1)ethyl]-lg-pyrro1e—3,4—dicarboxauide.
`
`Mylan Exhibit 1035, Page 12
`
`
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`Mylan Exhibit 1035, Page 12
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`

`
`_.42 _
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`0179559
`
`trans-6-[2-[3,4—Dich1oro-2-(3-£1uoropheny1)-5-
`
`(1—methy1ethy1)-lgfpyrrol-1-yllethylltetrahydro-4-
`
`hydroxy-2§-pytan-2-one.
`
`trans-2-(4-Fluorophenyl)-5-(1—methy1ethy1)-1-[2-
`
`S
`
`(tetrahydro)-4—hydroxy-6-oxo-2g-pytan-2-ylJethyl]-15-
`
`pyrrole-3,4-dicarbonitrile.
`
`trans—6-[2-[3,4—Diacety1-2-(4-f1uoropheny1)-S-
`
`(1-methylethyl)-lg-pyrro1~1—y1]ethy1]tetrahydro-4-
`
`hydroxy—2§fpyran—2-one.
`
`trans—Diethy1 2-(4-Fluorophenyl)-1-[2-(tettahydro)-
`
`19
`
`4-hydroxy-6-oxo-2§—pyran-2-yl)ethy1]-S-(trif1uoromethy1)-
`
`lg-pyrrole-3,4—dicarboxy1ate.
`
`trans-Bis(1-methylethyl) 2—(4-F1uoropheny1)-5-
`
`(1—methy1ethy1)—1—[2—(tetrahydro)-4—hydroxy-6-oxo-2§f
`
`15 pyran-2-yl)ethyl]—1§fpytro1e-3,4—dicarboxy1ate.
`
`trans-6-[2-{3,4—Diethy1-2-(4—f1uoropheny1)-5-
`
`(1-methylethyl)—1§-pyrrol-1-yl]ethyl}tettahydro—4-
`
`hydroxy-Zfl-pyran-2—one.
`
`_
`
`trans—6-[2-[2-(4-F1uoropheny1)—3,4-
`
`29 bis(hydroxymethy1)-5-(1-methylethyl)-lg-pyrrol-1-y1]—
`
`ethyl]tetrahydro-4-hydtoxy-2§—pyran-2-one.
`
`trans—1—Methy1ethy1 4—Ch1oro-2-(4-f1uorapheny1)-5-
`
`(1—methy1ethy1)—l-[2—(tetrahydto)-4-hydroxy-6-oxo-Z§-
`
`pyran~2-yl)ethyl]-lg-pyrrole-3-carboxylate.
`
`25
`
`ttans-6-I2-[4-(4-Fluorophenyl)—6—(1—methy1ethy1)—
`
`lg-furo[3,4-glpyrrol-5(3§)—y1]ethy1]tetrahydro-4—hydroxy-
`
`Zgfpyran-2—one.
`
`trans-6—[2-[2-(4-Fluorophenyl)-5-(1—methy1ethy1)-
`
`36
`
`3,4—bis[[[(phenylamino)carbonyl]oxy]methy1]—1§fpyrro1-
`1-yllethylltetrahydro—4—hydroxy-Zg-pyran—2-one.
`
`trans-1—Hethy1ethy1 4—Ch1oro-5-(4-f1uoropheny1)-2-
`
`(1-methylethyl)-1—[2-(tetrahydto)-4-hydroxy-6-oxo-Zg:
`pyran-2-y1)ethy1]-lg-pyrrole-3-carboxylate.
`
`trans—£thy1 5-(4-Fluorophenyl)-1-[2—(tetrahydro)—4-
`
`35 hydroxy-6-oxo—2§—pyran-2-yl)ethy1]-2-(trif1uoronethy1)-
`
`1gfpyrro1e—3-carboxylate.
`
`Mylan Exhibit 1035, Page 13
`
`
`
`Mylan Exhibit 1035, Page 13
`
`
`
`
`
`

`
`../5-
`
`0179559
`
`trans-Ethyl 5-(4—F1uoropheny1)-2-(1-methy1ethy1)-
`
`4-pheny1-1-[2-(tetrahydto-4-hydroxy—6-uxo-2§-pyran—2-
`
`yl)ethyl]-lg-pyrrole-3-carboxylate.
`
`trans-6-[2-(1-(4-Fluorophenyl)-4,5,6,7-tetrahydro-3-
`
`methyl-25-isoindol-2-y1]ethyl]tetrahydro-4-hydroxy-2g-
`
`pyran-2-one.
`
`trans-4-(4-Fluorophenyl)-2-nethy1-6-(1-methy1ethy1)-
`
`5-[2-(tetrahydro-4-hydroxy-6-oxo-2§—pyran-2—y1)ethyl]-
`
`pyrrolo[3,4j5]pyrrole-1,3(2§,5§)—dione.
`
`trans-6-[2-[1-(4-Fluorophenyl)-5,6-dihydro-3-
`
`(1—methy1ethy1)pyrro1o[3,4-glpyrrol-2(4§)-y1]ethy1]-
`
`tetrahydto-4-hydroxy-2g-pytan-2—one.
`
`trans~6-[2-[1-(4-Fluorophenyl)-S,6-d1hydro—S-
`
`methyl-3-(1—methy1ethy1)pyrro1o[3,4—g]pyrrol-2(4§)—y1]—
`
`ethyl]tetrahydto-4-hydroxy-2g-pyran—2-one.
`
`trans—6—[2—[3-Ch1oro—S-(4—f1uoropheny1)-2-
`(1-methylethyl)-4-phEny1—1§fpyrro1-l—y1Iethyl]tettahydro—
`4—hydroxy-2g-pyran-2-one.
`
`trans-6-[2-[2-(4-F1uoropheny1)-5-(1-methy1ethy1)-
`
`3,4—diphenyl-1§—pyrro1-1-yl]ethyl]tetrahydro—4-hydroxy-
`
`2§—pyran-2-one.
`
`Particularly preferred compounds in accordance with
`
`the present
`
`invention are:
`
`trans-6-[2-[3,4-Dich1oro-2-(4-£1uoropheny1)-S-
`
`(1—methy1ethy1)-lg-pyrrol-1-yllethylltetrahydro~4-
`
`hydroxy-Zgfpyran-2-one.
`
`trans-6-[2-[3,4-Dibromo-2-(4—£1uoropheny1)-5-
`
`(1-methylethyl)—1§fpyrro1-1-yllethylltetrahydro-4-
`
`19
`
`15
`
`20
`
`25
`
`hydroxy-Z§—pyran-2-one.
`
`ttans—6—[2-[2-(4-F1uoropheny1)-5-(tr1£1uoromethy1)-
`
`30
`
`lg-pyrrol-1-y1)ethy1]tetrahydro-4-hydroxy-2§fpyran—2-one.
`
`trans-Dimethyl 2-(4-Flhorophenyl)-5-(1-nethy1ethy1)-
`
`1-[2-(tetrahydto-4—hydroxy-6-oxo—Z§~pyran-2-yl)ethyl]-
`
`1§—pyrro1e-3,I-dicarboxylate.
`
`trans—6-[2-[2-(l—P1uorophenyl-5-methyl-Lg-pyrrol-
`
`35
`
`1-y1]ethyl]tetrahydro-4-hydroxy-zg-pyran—2-one.
`
`Mylan Exhibit 1035, Page 14
`
`Mylan Exhibit 1035, Page 14
`
`
`
`
`
`

`
`0179559
`___n/
`trans-6-[2-[2-(4—F1uoropheny1-5-(1-methy1ethy1)-
`
`lg-pyrrol-1-y1]ethyl]tetrahydro-4-hydroxy-25-pyran-2—one.
`
`trans—6-[2-[2-Cyc1opropy1-5-(4-£1uoropheny1)-1§-
`pyrrol-1—y1]ethy1]tetrahydto-4-hydroxy-2§—pyran-2-one.
`
`trans-6-[2—[2-(1,1-Dimethy1ethy1)-5-
`
`'
`
`(4-fluorophenyl)-1§—pyrro1-1-y1]ethy1]tetrahydro—4-
`
`hydroxy-2§—pyran-2—one.
`
`trans-Tetrahydro;4-hydroxy-5-[2-[2-(2—methoxy-
`
`phenyl)-5-trifluoromethyl-lg-pyrrol-1-y1]ethyl]-2§—2-one.
`
`trans—Tetrahydro-4-hydroxy-6-[2-[2-(2—methoxy-
`
`16
`
`phenyl)-5-(1-methylethyl)-lg-pyrrol-1—y1]ethy1]—2§—
`pyran-2—one.
`
`trans-Tetrahydro—4-hydroxy-6-[2—[2—methy1-5-
`
`15
`
`(1—naphtha1eny1)—l§—pyrro1—1—y1]ethyl]-2§—pyran—2—one.
`
`trans-6-[2-(2—Bicyc1o[2.2.1]hep—5-en-2-yl-5-methyl-
`
`1§—pyrro1-1—y1)ethy1]tetrahydro-4-hydroxy-2§—pyran-2-one.
`
`trans—6-[2-[2-(4—Fluoropheny1)-S—(1-methy1pheny1)-
`
`1§—pyrro1—1-y1]propylltetrahydro-4—hydroxy-2§—pyran-2-
`one.
`
`20
`
`25
`
`30
`
`35
`
`invention where R2 and R3
`Compounds of the present
`are hydrogen are prepared by the methods outlined in
`
`Reaction Sequence 1 or Reaction Sequence 2.
`
`As shown in Reaction Sequence 1,
`
`the aldehydes, VI, are
`
`reacted with the appropriately substituted vinylketones,
`
`VII,
`
`in the presence of the thiazolium salt, VIII, and a
`
`base such as triethylamine,
`
`to produce the diketones,
`
`IX.
`
`(see Ang. Chem. Int. Ed., 15: 639-712 (1976)).
`
`The diketones,
`
`IX, are reacted with an omega—amino-
`
`alkylnitrile (compound Roman numeral
`
`ten where the value
`
`of X is methylene, ethylene, or 1—methy1ethy1ene)
`
`in
`
`acetic acid to produce the disubstituted pyrrole
`
`nitriles, XI.
`
`Treatment of the pyrrole nitriles, II, with
`
`diisobutylaluminum hydride in an inert solvent such as
`
`dichloromethane produces the corresponding pyrrole
`aldehydes, XII.
`
`Mylan Exhibit 1035, Page 15
`
`
`
`Mylan Exhibit 1035, Page 15
`
`

`
`REACTIQN ssouzncr: 1
`
`01 79559
`
`9
`9
`RICCHZCHZCRZ
`zx
`
`HOAc
`
`H2N—X-C N
`X
`
`mscz) 3H
`
`
`°H
`
`H3c.(fis c1’
`
`+ -_—./
`}‘
`¢a2c
`
`VIII
`
`+
`
`9
`R2CCH=CH2
`VII
`
`0 "
`
`1
`nice
`
`VI
`
`R
`
`Z
`
`1
`
`R2
`
`xxx
`
`Diisobutylaluminum
`
`Ri
`'& N,X--CN
`
`_
`x1
`
`‘R2
`
`e 3e
`NaLi(CH2C—CH-COOCH3)
`
`R1
`
`O
`OH
`n
`u
`,/ N;CH2CH2CHCH2CCH COOCH
`2
`
`\R2
`
`xxx:
`
`
`
`‘'‘*‘‘---——Z-—--
`
`cnzcaz
`
`2
`
`3
`
`1) Tributylborane
`.________________________.
`
`2) Sodium borohydride
`3) H202, OH"
`
`H:
`
`1 1
`
`“1
`
`/
`
`__
`
`ca ca cca cca coon
`‘I
`'
`E on 3
`
`2,-‘D 2
`
`H
`
`2
`
`2
`
`XIV
`
`Mylan Exhibit 1035, Page 16
`
`
`
`Mylan Exhibit 1035, Page 16
`
`

`
`,/5 -2
`
`Reaction of the pyrrole aldehydes, XII. «nib-781559
`
`dilithium or lithium sodium salt methyl acetoacetate
`
`produces the 7-(substitutedpyrrolyl)—5—hydroxy-3-oxo-
`
`heptanoates, XIII.
`
`The heptanoates, XIII, are dissolved
`
`in a polar solvent such as tetrahydrofuran,
`
`through which
`
`a small quantity of air has been bubbled.
`
`A slight
`
`excess of a trialkylborane, such as tributylborane,
`
`is
`
`added to the mixture which is then cooled to a
`
`temperature of preferably between about 5°C and -78°C
`
`19
`
`after which sodium borohydride is added.
`
`‘
`
`After stirring this mixture for about one to two
`
`hours,
`
`the mixture is oxidized with basic hydrogen
`
`peroxide.
`
`The reaction produces the 7-(substituted-
`
`in which the
`pyrrolyl)—3,5—dihydroxyheptanoic acids, XIV,
`product contains a predominance of the desired R‘, R.
`
`15
`
`configuration at carbon atoms three and five which bear
`
`the hydroxy groups.
`
`The acids may be converted to a corresponding
`
`pharmaceutically acceptable salt by conventional methods
`
`or, alternatively, cyclized to the 6—[2—(substituted-
`
`pyrrol-l—yl)alkyllpyran-2-ones, I, by dehydration in an
`
`inert solvent such as refluxing toluene with azeotropic
`
`removal of water. This cyclization reaction is found to
`
`produce material containing from 85-96% of the desired
`
`active trans-configuration of the 4-hydroxy group
`
`relative to the 6~(substitutedpyrrolyl)alkyl group on the
`
`22
`
`25
`
`pyran-2~one lactone ring.
`
`H
`
`Alternative procedures for preparing compounds of
`formula I-of this invention where R2 and R3 are hydrogen,
`and for preparing intermediates, are illustrated in
`
`3B_
`
`Reaction Sequence 2. As shown in Reaction Sequence 2,
`the diketones, Ix, can be prepared by reacting the known
`
`alpha-haloketones, XV, with the sodium salt of known
`
`beta—ketoesters, XVI,
`
`followed by hydrolysis and
`
`35
`
`decarboxylation in the conventional manner.
`
`The
`
`diketones,
`
`IX, are reacted with ammonium acetate in
`
`acetic acid to produce the cyclized 2,5-disubstituted
`
`pyrroles, XVII.
`
`Mylan Exhibit 1035, Page 17
`
`
`
`Mylan Exhibit 1035, Page 17
`
`

`
`REACTION snouzncr. 2
`
`01 7 9 5 5 9
`
`O
`M
`
`O
`II
`
`O
`n
`
`O
`u
`
`+
`RICCHZX
`(X ; halogen)
`
`RZCCHZCOOCZHS -———a> RlCCH2?HCR2
`C°°C2HS'
`
`XV
`
`XVI
`
`“1
`H
`'
`/ u-’
`--
`
`R
`
`2
`
`XVIII
`
`NH OAC
`4
`-4——-—-———-——.
`HOAC
`
`O
`O
`ll
`u
`R1CCH2CH2CR2
`
`1) NaH
`
`IX
`
`
`
`IHZN-X~OH (XVIII)
`
`2) Br-X-CH(0CH3)2
`
`3) 3*, R20
`
`(xxx)
`
`R
`
`1
`
`/’ 3"
`
`CN
`
`X
`
`R2
`
`R1
`
`’’
`
`):-cao
`
`N
`
`R2
`XX (XIII in Reaction
`Sequence 1)
`
`‘XXII i“
`Reaction
`
`1) Tosyl chloride
`
`Sequence 1)
`
`2) cu”
`
`R
`
`.._.-...-......._..
`
`
`
` NbH1035,Page18
`
`
`
`Mylan Exhibit 1035, Page 18
`
`

`
`An alternative for this step, preferred w e1\7R?559
`and/or R‘ are sterically bulky groups,
`involves reaction
`of the diketones, Ix, with an omega-hydroxyalkyl amine
`
`-16‘-—
`
`(compound XVIII where X is methylene, ethylene,
`
`l-methylethylene),
`
`to produce the §¢(omega—hydroxy-
`
`alkyl)—2,S—disubstitutedpyrroles, XIX.
`
`The 2,5~disubstitutedpyrro1es, XVII, are converted
`
`to the omega-(substitutedpyrrolyl)aldehydes, XX, by
`
`sequential reaction with sodium hydride, a l,l-dimethoxy-
`
`10
`
`omega-bromoalkane (compound XXI where X is methylene,
`
`ethylene, 1-methylethylene, or vinyl), and then acid.
`
`The aldehydes, xx, are subsequently used in the
`
`preparation of compounds of formula I of this invention
`
`as illustrated above in Reaction Sequence 1.
`
`15
`
`The 2,5-disubstituted pyrroles, XVII, are converted
`
`to the corresponding (2,5-disubstitutedpyrrolyl)nitriles,
`
`XXII
`
`(when X is ethylene), by reaction with acrylonitrile
`
`or, alternatively (when X is other than ethylene), by
`In this latter
`
`starting with compounds of formula XIX.
`
`20
`
`instance,
`
`the hydroxy functionality of compounds of
`
`formula XIX is converted to the p-toluenesulfonate by
`
`conventional means, and the tosylate group is
`
`subsequently displaced by cyanide ion to produce the
`
`nitriles of formula XXII.
`
`The compounds of formula XXII
`
`25
`
`are subsequently used in the preparation of compounds of
`
`formula I of this invention by methods detailed in
`
`Reaction Sequence 1 above.
`
`Starting materials and intermediates employed in
`
`Reaction Sequences I and 2 above may be prepared by the
`
`39
`
`general methods outlined in Reaction Sequence 3.
`
`For
`
`example, as shown there,
`
`the vinyl ketones, VII, are
`
`prepared by either of the two methods illustrated.
`
`In
`
`one method,
`
`the known acid chlorides, XXIII, are reacted
`
`with the trinethylsilylethene, XXIV,
`
`in the presence of
`
`35
`
`anhydrous aluminum chloride in dichloromethane.
`
`In the alternative method of preparing the vinyl
`
`ketones, VII, which is preferred when R1 is an aromatic
`substitutent such as phenyl or substituted phenyl, the
`
`Mylan Exhibit 1035, Page 19
`
`
`
`Mylan Exhibit 1035, Page 19
`
`

`
`-1
`REACTION SEQUENCE 3
`
`01 79559
`
`9
`RCCI
`
`XXIII
`
`CH -CHSi(CH )
`2
`3 3
`
`XXIV
`
`3
`MC13
`-———————4- R-C-CH-CH
`CHZCIZ
`
`VII
`
`2
`
`‘P
`AICCH3
`
`XXV
`
`(CB ) NH-HC1
`3 2
`____————————————a»
`‘°H2°’n
`
`O
`,,
`ArCCH2CH2N(CH3)2
`xxvx
`
`1) C831
`
`2) NaHC03
`
`‘.3
`ArCCH=CH2
`
`VII
`
`Mylan Exhibit 1035, Page 0
`
`
`
`Mylan Exhibit 1035, Page 20
`
`

`
`0179559
`known methyl aryl ketones, XXV, are converted to
`
`..Zg-d
`
`(dimethylaninoethy1)aryl ketones, XXVI, and then by
`
`deamination to the vinyl ketones, VII.
`
`The compounds of the present
`invention of formula I
`where the groups R2 and R3 are other than hydrogen or
`halogen can be synthesized by the methods detailed in
`
`Reaction Sequences 4-8.
`
`Employing the method detailed in Reaction Sequence
`
`4 the compounds of the present invention where R
`2 and R
`are both halogen can be prepared by the halogenation of
`
`3
`
`18
`
`the unsubstituted compounds with g-halosuccinimide in a
`
`three—step process involving the prior protection of the
`
`4-hydroxy group of the lactone ring. Thus, for example,
`
`the 2,5-disubstitutedpyrrol—1-yl compounds, XXVII, are
`
`first converted to the corresponding tert—buty1-
`
`dimethylsilyl ethers, XXVIII.
`
`The protected compounds
`
`and then chlorinated with gfchlorosuccinimide in a polar
`
`solvent such as dimethylformamide to produce the
`
`silylated 3,4-dichloro compounds, XXIX.
`
`The protecting
`
`silyl ether group is then subsequently removed by
`
`reaction with a buffered fluoride reagent such as
`
`tetrabutylammonium fluoride in a mixed acetic
`
`acid/tetrahydrofuran solvent system to produce the
`
`dichloro compounds, XXX.
`
`Alternatively, as detailed in Reaction Sequence 5,
`
`the (2,S-disubstitutedpyrrol—l—yl)alkyl nitriles, XI
`
`(see
`
`Reaction Sequence 1) are halogenated by employing an
`
`5-halosuccinimide in dimethylformamide to provide the
`
`2,5-disubstituted-3,4—dihalopyrroles. XXXI.
`
`(See Aiello,
`
`et al., J. Bet. Chem., 19: 977 (1982)). These compounds
`
`can then be subsequently converted to the compounds of
`
`the present
`
`invention by conventional methods detailed in
`
`Reaction Sequence 1.
`
`15
`
`29
`
`25
`
`36
`
`A third method takes advantage of the chemistry of
`
`35
`
`aesionic compounds of the type described originally by R.
`
`Huisgen, et al., Ang. Chem. Int. Ed., 3: 136 (1964).
`
`In
`
`this procedure, detailed in Reaction Sequence 6, an
`
`Mylan Exhibit 1035, Page 21
`
`
`
`Mylan Exhibit 1035, Page 21
`
`

`
`-21 ..
`
`nsacn on ssouzncz 4
`
`01 7 9 5 5 9
`
`H01!”
`
`O
`
`31
`
`N
`
`I‘
`
`‘I
`
`R‘
`
`XXVII
`
`t-Buty1(Me)2SiC1
`"“"T“““""‘“*’
`Imadazole
`
`*4’
`
`O
`
`31
`
`I
`“
`
`|
`
`'
`
`I
`
`-
`XXVIII
`
`R4
`
`DMP
`
`§—Ch1oro—
`succinimide
`
`HO .,,,
`
`o
`
`O
`
`R4
`
`c1
`
`R1
`
`c1
`
`1
`
`I
`
`xxx
`
`t-Bu me) 2510,,’
`
`o
`
`Tetrabuty1-
`ammonium fluoride
`
`
`HOAc/ THF
`
`R1
`
`C1
`
`‘
`
`I
`
`4
`
`C1
`
`REACTI ON SEQUENCE 5
`
`cu
`F/J
`Rr1E:::U/ R‘
`
`§fCh1oro- or §-Bromo-
`succinimide
`
`Dimethylformamide
`
`/"W
`I
`I N‘
`
`4
`
`R1
`
`(Br)C1 T
`
`C1(Br)
`
`XI
`
`XXXI
`
`Mylan Exhibit 1035, Page 22
`
`
`
`Mylan Exhibit 1035, Page 22
`
`

`
`- 22 -
`
`0179559
`
`Q-alkyl-E-acylamino acid is treated with an acid
`
`anhydride and a substituted acetylenic compound to
`
`produce a pyrrole.
`
`For example, Reaction Sequence 6
`
`shops how reaction of an alpha-halo ester, XXXII, with
`2-(l-(2-aminoethyl))-1,3-dioxalane in triethylamine
`
`provides the N-alkyl-alpha-aminoester, XXXIII;
`
`The
`
`aminoester, XXXIII is acylated with an acid chloride and
`
`subsequently hydrolyzed in base to produce the
`
`gfacyl-§—alkyl aminoacid, XXXIV. Reaction of this latter
`compound with the desired substituted acetylenic
`
`18
`
`compound, XXXV, produces the substituted pyrrole
`
`compounds, XXXVI. Acidic hydrolysis of XXXVI yields the
`
`aldehyde compounds, XXXVII, analogous to compounds XII of
`
`Reaction Sequence 1. Compounds of formula XXXVII are
`
`used in subsequent steps in a manner detailed in Reaction
`
`sequence 1
`
`to produce compounds of the present invention;
`
`Preferred substituents for the substituted
`
`acetylenic compounds in this method of making compounds
`
`of the present
`
`invention include carboalkoxy groups,
`
`phenyl groups, alkanoyl groups, alkyl groups and cyano
`
`groups.
`
`The reaction between the disubstituted acetylene
`
`15
`
`28
`
`compound and the Q-acylj§—alkyl aminoacids, XXXIV,
`
`generally proceeds smoothly; for example,
`
`the
`
`25
`
`dicarbomethoxy acetylene reacts smoothly at 25°C.
`
`However, when only one activating group is attached to
`
`the reaction mixture must generally be
`the acetylene,
`warmed to 76-119°C to obtain high yields of the pyrrole
`
`compounds.
`
`,
`
`_
`
`A variety of other pyrroles can be derived from
`
`compounds of the general formula XXXVI when the groups R2
`and R3 are carbomethoxy.
`some of these transformations
`. For example,
`are detailed in Reaction Sequences 7 and 8.
`
`as shown in Reaction Sequence 7, reduction of XXXVI with
`
`a reducing agent such as lithium aluminum hydride results
`
`in the bis(hydroxymethyl)pyrrole which can be
`
`subsequently further reduced to the dimethyl compound,
`
`39
`
`35
`
`Mylan EXhibit.1035, Page 23
`
`
`
`Mylan Exhibit 1035, Page 23
`
`

`
`Br
`I
`RICHCODCH3
`
`XXXII
`
`.-23..
`
`REACTION SEQUENCE 6
`
`Triethylamine
`
`
`[::)_’/-NH2
`
`179559
`
`XXXIII
`
`goocaa O
`fipmm-
`K
`X
`‘L?
`
`1) R‘COC1
`2) NAOH
`
`R1
`
`COOH
`
`/’
`
`<*“'-‘-'—--—-———
`R -czc-R
`2
`
`3
`
`I
`N
`
`34
`
`‘c"
`
`O
`
`O
`
`XXXIV
`
`REACTION SEQUENCE 7
`
`f'_\
`o
`o
`
`2’
`
`R1.
`
`\¢/
`
`N
`
`4
`
`-
`
`H COOC
`3
`
`I
`
`I
`
`XXXV
`
`I
`
`OOCE3
`
`R4
`
`_R3
`
`f‘_\
`O
`O
`
`Y W N
`
`1
`
`I
`
`XXXVI
`
`R
`
`R2
`
`+
`
`830
`
`$30
`D/
`N
`
`R4
`
`I
`
`I
`
`R3
`
`XXXVII
`
`R
`
`32
`
`o
`
`o
`
`1) Liklfl‘
`(c2a5)3s1a. cracooa‘
`
`2)
`
`Mylan Exhibit 1035, Page 24
`
`
`
`Mylan Exhibit 1035, Page 24
`
`

`
`-29..
`
`0179559
`
`XXXVIII, by means of triethylsilane and trifluoroacetic
`acid employing the procedure of west, et al., J. Org.
`Chem.,38: 2675 (1973)).
`
`Alternatively, as shown in Reaction Sequence 8,
`reaction of the compounds of formula XXXVI with a
`
`Grignard reagent or an alkyl-lithium reagent
`
`in the
`
`conventional manner followed by reduction and standard
`
`work-up affords the higher dialkylpyrroles, XXXIX.
`
`19
`
`Reaction of the diesters, XXXVI, or the
`
`corresponding diacids (obtained by conventional
`
`hydrolysis) with secondary amines provides the
`
`bis(dialkylamides), XL.
`
`15
`
`Alternatively, reaction