[19]
`United States Patent
`4,739,073
`‘[11] Patent Number:
`Kathawala
`[45] Date of Patent:
`Apr. 19, 1988
`
`[54]
`
`INTERMEDIATES IN THE SYNTHESIS OF
`INDOLE ANALOGS OF
`MEVALONOLACI‘ONE AND DERIVATIVES
`THEREOF
`
`[75]
`
`Inventor:
`
`Faizulla G. Kathawala, Mountain
`Lakes, N.J.
`
`R511
`
`and the other is primary or secondary C1-5a1kyl not
`containing an asymmetric carbon atom, C3.5cyc1oa1kyl
`or phenyl(CH2),,,—, wherein
`R4 is hydrogen, C1.3alkyl, n-butyl, i-butyl, t-butyl, C1-
`3alkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro,-
`chloro, phenoxy or benzyloxy,
`R5 is hydrogen, C1-3alkyl, C1.3a1koxy, trifluoromethyl,
`fluoro, chloro, phenoxy or benzyloxy,
`R5,, is hydrogen, C1.2alkyl, C1.2a1koxy, fluoro or chloro,
`and
`
`In is 1, 2 or 3, with the provisos that both R5 and R5,,
`must be hydrogen when R4 is hydrogen, R5,, must be
`hydrogen when R5 is hydrogen, not more than one of
`R4 and R5 is trifluoromethyl, not more than one of R4
`and R5 is phenoxy, and not more than one of R4 and
`R5 is benzyloxy,
`R2 is hydrogen, C1-3alkyl, n-butyl, i-butyl, t-butyl, C3-
`scycloalkyl, C1-3alkoxy, n-butoxy, i-butoxy, trifluoro-
`methyl, fluoro, chloro, phenoxy or benzyloxy,
`R3 is hydrogen, C1.3alkyl, C1.3alkoxy, trifluoromethyl,
`fluoro, chloro, phenoxy or benzyloxy, with the provi-
`sos that R3 must be hydrogen when R2 is hydrogen,
`not more than one of R2 and R3 is trifluoromethyl, not
`more than one of R2 and R3 is phenoxy, and not more
`than one of R2 and R3 is benzyloxy,
`X is —(CH2),,— or —-CHiH-—, wherein n is 0, 1, 2 or
`3, and
`Z is
`
`,
`
`CH2
`R5
`Z \ /
`I
`—oi1H—cH2—c|:—cH2—cooR7 or -(|2l—l
`c|:—R,«,
`OH
`OH
`o\ /CH2
`|0
`
`c 1
`
`OH
`
`wherein
`R5 is hydrogen or C1-3a1kyl, and
`t-butyl,
`i-butyl,
`R7 is hydrogen, C1-3alkyl, n-butyl,
`benzyl or M, wherein M is a pharmaceutically
`acceptable cation,
`the use thereof for inhibiting cholesterol biosynthesis
`and lowering the blood cholesterol level, and, there-
`fore, in the treatment of hyperlipoproteinemia and ath-
`erosclerosis, pharmaceutical compositions comprising
`such compounds and processes for and intermediates in
`the synthesis of such compounds.
`
`[73] Assignee:
`
`Sandoz Pharmaceuticals Corp., E.
`Hanover, N.J.
`
`[21] Appl. No.: 707,354
`
`[22] Filed:
`
`Mar. 4, 1985
`
`Related U.S. Application Data
`
`[63]
`
`Continuation of Ser. No. 548,850, Nov. 4, 1983, which
`is a continuation-in-part of Ser. No. 443,668, Nov. 22,
`1982.
`7
`
`Int. Cl.‘ ................... C07D 405/06; C07D 209/12
`[51]
`[52] U.S. C1. .................................. .. 548/406; 548/414;
`'
`548/494
`[58] Field of Search ............. .. 548/465, 467, 494, 468,
`548/414, 406
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`7/1966 Metlesics et al.
`................. .. 548/493
`3,259,633
`2/1981 Oka et al. ............................ 514/532
`4,248,889
`
`3/1981 Oka et al. ...................... .. 514/460
`4,255,444
`6/1981 Gradient et al. .................. .. 514/212
`4,272,533
`3/1983 Willard et al.
`.................... .. 514/460
`4,375,475
`4,474,971 10/1984 Wareing ............................ .. 549/214
`
`Primary Examiner——Donald G. Daus
`Assistant Examiner——-William A. Teoli, Jr.
`Attorney, Agent, or Firm—Gerald D. Sharkin; Richard
`E. Vila; Melvyn M. Kassenoff
`
`[57]
`
`ABSTRACI‘
`
`Compounds of the formula
`
`X"'Z,
`
`R \
`
`T
`R0
`
`R2
`
`R3
`
`wherein one of R and R,, is
`
`20 Claims, No Drawings
`
`Mylan Exhibit 1010, Page 1
`
`
`
`Mylan Exhibit 1010, Page 1
`
`
`
`

`
`1
`
`4,739,073
`
`INTERMEDIATES IN THE SYNTHESIS OF
`INDOLE ANALOGS OF MEVALONOLACI‘ONE
`AND DERIVATIVES THEREOF
`
`This application is a division of application Ser. No.
`06/548,850, filed Nov. 4, 1983 and now abandoned,
`which in turn is a continuation-in-part of application
`Ser. No. 06/443,668, filed Nov. 22, 1982 and now aban-
`doned.
`
`This invention relates to compounds of the formula
`
`(1)
`
`
`
`wherein one of
`R and R0 is
`
`R511
`
`and the other is primary or secondary C1-5alkyl not
`containing an asymmetric carbon atom, C3.5cy-
`cloalkyl or phenyl-(CH2),,,—, wherein
`R4 is hydrogen, C1-3alkyl, n-butyl, i-butyl, t-butyl,
`C1-3a1koxy, n-butoxy, i-butoxy, trifluoromethyl,
`fluoro, chloro, phenoxy or benzyloxy,
`trifluoro-
`R5 is hydrogen, C1.3alky1, C1.3alkoxy,
`methyl, fluoro, chloro, phenoxy or benzyloxy,
`R5,, is hydrogen, C1.2alkyl, C1.2alkoxy, fluoro or
`chloro, and
`'
`m is 1, 2 or 3, with the provisos that both R5 and
`R5,, must be hydrogen when R4 is hydrogen, R5,,
`must be hydrogen when R5 is hydrogen, not
`more than one of R4 and R5 is trifluoromethyl,
`not more than one of R4 and R5 is phenoxy, and
`not more than one of R4 and R5 is benzyloxy,
`R2 is hydrogen, C1.3alkyl, n-butyl, i-butyl, t-butyl,
`C3.5cycloalkyl, C1.3alkoxy, n-butoxy,
`i-butoxy,
`trifluoromethyl, fluoro, chloro, phenoxy or ben-
`zyloxy,
`trifluoro-
`R3 is hydrogen, C1-3a1kyl, C1-3alkoxy,
`methyl,
`fluoro, chloro, phenoxy or benzyloxy,
`with the provisos that R3 must be hydrogen when
`R2 is hydrogen, not more than one of R2 and R3 is
`trifluoromethyl, not more than one of R2 and R3 is
`phenoxy, and not more than one of R2 and R3 is.
`benzyloxy,
`X is —(CH2),,—— or —CH=:CH——, wherein n is 0, 1,
`2 or 3, and
`Z is
`
`Rs
`5
`4
`3 I
`2
`1
`—(|IH'—CH2" (|3—CH2—COOR7
`OH
`OH
`
`01'
`
`(11)
`
`5
`
`l0
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`-continued
`5
`OH
`
`6 /C}\I24/
`“CH
`C-R6,
`I
`I 3
`1o\ /CH2
`C2
`II0
`
`(111)
`
`wherein
`
`R5 is hydrogen or C1.3alkyl, and
`R7 is hydrogen, C1-3alkyl, n-butyl, i-butyl, t-butyl,
`benzyl or M, wherein M is a pharmaceutically
`acceptable cation,
`processes for and intermediates in the synthesis thereof,
`pharmaceutical compositions comprising a compound
`of Formula I and the use of the compounds of Formula -
`I for inhibiting cholesterol biosynthesis and lowering
`the blood cholesterol level and, therefore, in the treat-
`ment of hyperlipoproteinemia and atherosclerosis.
`The compounds of Formula I may be divided into
`two groups, the compounds of Formula IA and those of
`Formula IB:
`
`Rsa
`
`(IA)
`
`R2
`
`5
`
`6
`
`R3
`
`R2
`
`5
`
`6
`
`R3
`
`R4
`
`R5
`
`| \ X—Z
`‘T
`R1
`
`and
`
`R1
`
`l \ X—Z,
`N
`
`R4
`
`R5
`
`Ria
`
`(IB)
`
`wherein
`R1 is primary or secondary C1.5alky1 not containing
`an asymmetric carbon atom (e.g., methyl, ethyl,
`n-propyl, i-propyl, n-butyl, i-butyl, 1-ethylpropyl,
`neopentyl and n-hexyl), C3.5cycloalkyl or phenyl-
`(CH2),,,-, and
`R2—R5,,, X, Z and In are as defined above.
`The compounds of Formula IA may be divided into
`two subgroups, the compounds wherein Z is a group of
`Formula II (Group (IAa) and those wherein Z is a
`group of Formula III (Group IAb). Likewise, the com-
`pounds of Formula IB may be divided into two sub-
`groups, the compounds wherein Z is a group of For-
`mula II (Group IBa) and those wherein Z is a group of
`Formula III (Group IBb).
`As is self-evident to those in the art, each compound
`of Formula I (and every subscope and species thereof)
`has two centers of asymmetry (the two carbon atoms
`bearing the hydroxy groups in the group of Formula II
`
`I ll/Iylan Exhibit 1010, Page 2
`
`Mylan Exhibit 1010, Page 2
`
`
`
`

`
`4,739,073
`
`4
`tion, more preferably the para position. The most pre-
`ferred monosubstituted phenyl group is 4-fluorophenyl.
`Preferably, when both R4 (R4’, R4”, etc.) and R5 (R5’,
`R5", etc.) are other than hydrogen and R55 (R5,,’, etc.) is
`hydrogen, at least one of R4 (R4’, etc.) and R5 (R5’, etc.)
`is in a meta or para position (more preferably both are),
`and not more than one of them is a member of the group
`consisting of t-butyl, trifluoromethyl, phenoxy and ben-
`zyloxy; more preferably, R4 (R4’, etc.) and R5 (R5’, etc.)
`are not ortho to each other when neither of them is a
`member of the group consisting of methyl, methoxy,
`fluoro and chloro. The most preferred disubstituted
`phenyl groups are 3,4— and 3,5-dimethylphenyl and
`4-fluoro-3-methylphenyl, especially 3,5-dimethylphenyl
`and 4—fluoro-3-methylphenyl.
`Preferably, when each of R4 (R4’, etc.), R5 (R5’, etc.)
`and R5,, (R5a’, etc.) is other than hydrogen, at least two
`of them (more preferably all three) are in meta or para
`positions, and not more than one of them is a member of
`the group consisting of t-butyl trifluoromethyl, phe-
`noxy and benzyloxy; more preferably, no two of them
`are ortho to each other unless at least one member of the
`or each pair of substituents that are ortho to each other
`is a member of the group consisting of methyl, methoxy,
`fluoro and chloro. The most preferred trisubstituted
`phenyl group is 3,5-dimethyl-4-fluorophenyl.
`R5 is preferably R5’, where R5’ is hydrogen or C1.2al-
`kyl, more preferably R5", where R5” is hydrogen or
`methyl, and most preferably hydrogen.
`R7 is preferably R7’, where.R7’ is hydrogen, C1-3alkyl
`or M, more preferably R7", where R7” is hydrogen,
`C1-2alkyl or M, and most preferably M, especially so-
`dium. M is preferably M’ and more preferably sodium.
`X is preferably X’, where X’ is —(CH2),,,- or
`
`H
`
`,
`
`/
`
`\
`
`c=c
`
`\ /
`
`H
`
`more preferably X”, where X” is —CH2CH2— or
`
`3
`and the carbon atom bearing the hydroxy group and the
`carbon atom having the free valence in the group of
`Fromula III) and, therefore, there are four stereoiso-
`meric forms (enantiomers) of each compound (two
`racemates or pairs of diastereoisomers), provided that
`M does not contain any center of asymmetry. The four
`stereoisomers may be designated as the R,R; R,S; S,R
`and S,S enantiomers, all four stereoisomers being within
`the scope of this invention.
`R1 is preferably R1’, where R1’ is primary or second-
`ary C1.5alkyl not containing an asymmetric carbon
`atom, more preferably C1.3alkyl and most preferably
`methyl, ethyl or i-propyl, especially i-propyl.
`R2 is preferably R2’, where R2’ is hydrogen, C1-3alkyl,
`C1.3alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or
`benzyloxy, more preferably R2”, where R2" is hydro-
`gen, C1-3alkyl, methoxy, fluoro, chloro or 4-, 5- or 6-
`benzyloxy, and most preferably R2"', where R2"’ is
`hydrogen, C1.3a1kyl or 4- or 6-benzyloxy, especially
`hydrogen or methyl and most especially hydrogen.
`R3 is preferably R3’, where R3’ is hydrogen, C1.3alkyl,
`C1-2alkoxy, fluoro or chloro, more preferably R3”,
`where R3” is hydrogen or C1-3alkyl, and most prefera-
`bly R3~', where R3”’ is hydrogen or methyl, especially
`hydrogen. R3 (R3’, etc.) must be hydrogen when R2
`(R2’, etc.) is hydrogen.
`Preferably, when R2 (R2’, R2”, etc.) is other than
`hydrogen and R3 (R3’, R3", etc.) is hydrogen, R2 (R2’,
`etc.) is in the 4-, 5- or 6-position.
`Preferably, when both R2 (R2’, R2”, etc.) and R3 (R3’,
`R3", etc.) are other than hydrogen, at least one of them
`is in the 5- or 6-position, neither of them is in the 7-posi-
`tion, and not more than one of them is a member of the
`group consisting of t-butyl, C3-5cycloalkyl, trifluoro-
`methyl, phenoxy and benzyloxy; more preferably, they
`are not ortho to each other when neither of them is a
`
`member of the group consisting of methyl, methoxy,
`fluoro and chloro. Most preferably, one is in the 4—posi-
`tion and the other is in the 6-position.
`Except where otherwise indicated: (a) Any C1-3alkyl,
`n-butyl, i-butyl, t-butyl or C3.5cycloalkyl group as R2,
`R2’, R3, R3’, etc. is more preferably in the 4- or 6-posi-
`tion. (b) Any C1-3alkoxy, n-butoxy, i-butoxy, fluoro or
`chloro substituent as R2, R2’, R3, R3’, etc. is more pref-
`erably in the 5-position. (c) Any benzyloxy as R2, R2’,
`R3, R3’, etc. is more preferably in the 4-, 5- or 6-position
`and most preferably in the 4- or 6-position, especially
`the 6-position.
`R4is preferably R4’, where R4’ is hydrogen, C1-3alkyl,
`C1-3alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or
`benzyloxy, more preferably R4”, where R4” is hydro-
`gen, methyl, methoxy, fluoro or chloro, and most pref-
`erably R4’”, where R4’” is hydrogen, methyl or fluoro,
`especially R4”", where R4”” is hydrogen, 3- or 4-methyl
`or 4-fluoro and most especially 4-fluoro.
`R5 is preferably R5’, where R5’ is hydrogen, C1-2alkyl,
`C1-2alkoxy, fluoro or chloro, more preferably R5”,
`where R5” is hydrogen, methyl, methoxy, fluoro or
`chloro, and most preferably R5’”, where R5"’ is hydro-
`gen or methyl, especially hydrogen. R5 (R5’, R5”, etc.)
`must be hydrogen when R4 (R4’, R4”, etc.) is hydrogen.
`R5,, is preferably R55’, where R5,,’
`is hydrogen or
`methyl, and most preferably hydrogen. R5,, (R5a’, etc.)
`must be hydrogen when at least one of R4 (R4’, R4",
`etc.) and R5 (R5’, R5”, etc.) is hydrogen.
`Preferably, when R4 (R4’, R4”, etc.) is other than
`hydrogen and R5 (R5’, R5”, etc.) and Rsa (R5g', etc.) are
`both hydrogen, R4 (R4’, etc.) is in a meta or para posi-
`
`5
`
`l0
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`55
`
`65
`
`50
`
`especially
`
`H
`
`/
`
`\
`
`c=c
`
`\
`
`/
`
`H
`
`H
`
`/
`
`\
`
`c=
`
`\
`
`/
`
`H
`
`,
`
`.
`
`Z is preferably a group of Formula II wherein R5 is
`R5’ and R7 is R7’ or a group of Formula III wherein R5
`is R5’; more preferably a group of Formula II wherein
`R5 is R5” and R7 is R7” or a group of Formula III
`wherein R5 is R5" and most preferably a group of For-
`mula II wherein R5 is hydrogen and R7 is R7” or a group
`of Formula III wherein R5 is hydrogen, especially a
`group of Formula II wherein R5 is hydrogen and R7 is
`M, especially M’ and most especially sodium, or a group
`of Formula III wherein R5 is hydrogen.
`n is preferably m, where m is 1, 2 or 3, preferably 2 or
`3 and most preferably 2.
`
`Mylan Exhibit 1010, Page 3
`
`
`
`Mylan Exhibit 1010, Page 3
`
`

`
`4,739,073
`
`5
`
`10
`
`5
`M is. usually free from centers of asymmetry and is
`preferably M’,
`i.e., sodium, potassium or ammonium,
`and most preferably sodium. For simplicity, all of the
`formulae in which M appears have been written as if M
`were monovalent and, preferably, it is. However, it may
`also be divalent or trivalent and, when it is, it balances
`the charge of two or three carboxy groups, respec-
`tively.
`Insofar as the compounds of Groups IAa and IBa are
`concerned, the erythro isomers are generally preferred
`over the threo isomers, erythro and threo referring to
`the relative positions of the hydroxy groups in the 3-
`and 5-positions (of the group of Formula II).
`As between compounds of Formula I having identi-
`cal R, R0, R2, R3, R6 and X groups, those wherein Z is
`a group of Formula II are generally preferred over
`those wherein Z is a group of Formula III.
`The preferred stereoisomers of the compounds of
`Formula I wherein X is a direct bond or —CH=CH—,
`and Z is a group of Formula II are the 3R,5S and 3R,5R
`isomers and the racemate of which each is a constituent,
`i.e., the 3R,5S-3S,5R (erythro) and 3R,5R-3S,5S (threo)
`racemates, with the 3R,5S isomer and the racemate of 25
`which it is a constituent being more preferred and the
`3R,5S isomer being most preferred.
`The preferred stereoisomers of the compounds of
`Formula I wherein X is —-(CH2),,,—, and Z is a group of
`Formula II are the 3R,5R and 3R,5S isomers and the 30
`racemate of which each is a constituent, i.e., the 3R,5R-
`3S,5S (erythro) and 3R,5S-3S,5R (threo) racemates,
`with the 3R,5R isomer and the racemate of which it is
`a constituent being more preferred and the 3R,5R iso-
`mer being most preferred.
`The preferred stereoisomers of the compounds of
`Formula I wherein X is a direct bond or -CH=CH—,
`and Z is a group of Formula III are the 4R,6S and
`4R,6R isomers and the racemate of which each is a 40
`
`R5
`
`and the other is C1.3alkyl, n-butyl or i-butyl,
`R1 is C1.3alkyl, n-butyl or i-butyl, R2 is hydrogen, C1.
`zalkyl, n-butyl, i-butyl, C1.3alkoxy, n-butoxy, i-butoxy,
`trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
`R4 is other than t-butyl, R5,,
`is hydrogen, and X is
`—(CH2),,— or
`
`each of the other variables being as defined above.
`Preferred groups of compounds of Formula I include
`the compounds
`(i) of Group IAa wherein R1 is R1’, R2 is R2’, R3 is R3’,
`R4 is R4’, R5 is Rs’, Rsa is R5,,’, R6 is R6’, R7 is R7’, and
`X is X’,
`(ii) of (i) wherein when R2’ is other than hydrogen
`and R3’ is hydrogen, R2’ is in the 4-, .5- or 6-position;
`when both R2’ and R3’ are other than hydrogen, at least
`one of them is in the 5- or 6-position and neither of them
`is in the‘7-position; when both R4’ and R5’ are other
`than hydrogen and R56’ is hydrogen, at least one of R4’
`and R5’ is in a meta or para position; and when each of
`R4’, R5’ and R5,,’ is other than hydrogen, at least two of
`them are in meta or para positions,
`(iii)-(iv) of (i) and (ii) wherein R6 is R6”, especially
`hydrogen,
`(v)-(vi) of (i) and (ii) wherein R1 is C1.3alkyl, R2 is
`R2”, R3 is R3”, R4is R4”, R5 is R5”, R6 is R6”, especially
`hydrogen, R7 is R7”, and X is X”,
`(vii) of (i) wherein R1 is C1-3alkyl, R2 is R2”’, R3 is
`R3”’, R4is R4”’, R5 is R5’”, R5,, is hydrogen, R6 is hydro-
`gen, R7 is R7”, and X is
`
`\
`
`c=
`
`/
`
`\
`
`,
`
`H
`
`(viii)—(xiii) of (i)—(vi) wherein any M is M’,
`(xiv) of Group IAb wherein R1 is R1’, R2 is R2’, R3 is
`R3’, R4is R4’, R5 is R5’, R5,, is R5,,’, R6 is R6’, and X is X’,
`(xv) of (xiv) wherein when R2’ is other than hydrogen
`and R3’ is hydrogen, R2’ is in the 4-, 5- or 6-position;
`when both R2’ and R3’ are other than hydrogen, at least
`one of them is in the 5- or 6-position and neither of them
`is in the 7-position; when both R4’ and R5’ are other
`than hydrogen and R5,,’ is hydrogen, at least one of R4’
`and R5’ is in a meta or para position; and when each of
`R4’, R5’ and R5,.’ is other than hydrogen, at least two of
`them are in meta or para positions,
`‘
`(xvi)—(xvii) of (xiv) and (xv) wherein R6 is R6”, espe-
`cially hydrogen,
`(xviii)—(xix) of (xiv) and (xv) wherein R1 is C1.3a1kyl,
`R2 is R2”, R3 is R3”, R4 is R4”, R5 is R5”, R6 is R6",
`especially hydrogen, and X is X”,
`
`Mylan Exhibit 1010, Page 4
`
`20
`
`35
`
`constituent, i.e., the 4R,6S-4S,6R (trans lactone) and
`4R,6R-4S,6S (cis lactone) racemates, with the 4R,6S
`isomer and the racemate of which it is a constituent
`being more preferred and the 4R,6S isomer being most
`preferred.
`The preferred stereoisomers of the compounds of
`Formula I wherein X is ——(CH2),,.—, and Z is a group of
`Formula III are the 4R,6R and 4R,6S isomers and the
`
`45
`
`racemate of which each is a constituent, i.e., the 4R,6R- 50
`45,68 (trans lactone) and 4R,6S-4S,6R (cis lactone)
`racemates, with the 4R,6R isomer and the racemate of
`which it is a constituent being more preferred and the
`4R,6R isomer being most preferred.
`Each of the preferences set forth above applies, not
`only to the compounds of Formula I, but also to the
`compounds of Formulae IA and IB and those of Groups
`IAa, IAb, IBa and IBb as well as to every other sub-
`group thereof set forth infra, e.g., Groups (i)-(cxiv),
`unless otherwise indicated. When any preference con-
`tains a variable, the preferred significances of that vari-
`able apply to the preference in question, unless other-
`wise indicated.
`'
`
`60
`
`55
`
`Representative groups of compounds of Formulae I,
`Ia and Ib and of Groups IAa, IAb, IBa and IBb include
`those of each of these seven groups wherein one of R
`and R0 is
`‘
`
`65
`
`
`
`Mylan Exhibit 1010, Page 4
`
`

`
`7
`‘(xx) of (xiv) wherein R1 is C1-3alkyl, R2 is R2”, ’R3 is
`R3"’, R4is R4”', R5 is R5”’, R5,, is hydrogen, R5 is hydro-
`gen, and X is
`
`4,739,073
`
`10
`
`H
`
`,
`
`/
`
`\
`
`c=
`
`\ /
`
`H
`
`and the 4R,6R enantiomers of the compounds of these
`groups wherein X is ——(CH2),,,—.
`Groups (xxxix)-(lxiii) embrace the 3R,5S-3S,5R race-
`mate and the 3R,5S and 3S,5R enantiomers of the com-
`pounds wherein X is
`
`(the 3S,5R enantiomer being least preferred) and the
`3R,5R-3S,5S racemate and the 3R,5R and 3S,5S enan-
`tiomers of the compounds wherein X is —(CH2),,.-
`(the 3S,5S enantiomer being least preferred).
`Groups (lxxxix)-(ci) embrace the 4R,6S-4S,6R race-
`mate and the 4R,6S and 4S,6R enantiomers of the com-
`pounds wherein X is
`
`(the 4S,6R enantiomer being least preferred) and the
`4R,6R-4S,6S racemate and the 4R,6R and 4S,6S enan-
`tiomers of the compounds wherein X is —-(CH2),,,—
`(the 4S,6S enantiomer being least preferred).
`’
`The compounds of Formula I may be synthesized as
`follows:
`
`REACTION SCHEME I
`
`The compounds of Formula I wherein R5 is hydrogen
`may be synthesized by the following series of reactions:
`
`R2
`
`R
`
`(IV)
`
`| \ X—CHO
`N
`
`R3
`
`IRa
`
`(1) Strong base +
`CH3-CO—CH2—COOR7,,
`(2) Aldehyde of Formula IV
`
`(IVA)
`
`R
`
`(V)
`
`x—$n-cH2—c—cH2—cooR7,,
`II
`OH
`O
`
`N
`
`IR
`
`a
`
`A
`
`|
`
`Bl/Mild reducing agent
`
`Mylan Exhibit 1010, Page 5
`
`(xxi) of Group IBa wherein R1 is R1’, R2 is R2’, R3 is
`R3’, R4is R4’, R5 is R5’, R5“ is R5,’, R5 is R5’, R7 is R7’,
`and X is X’,
`(xxii) of (xxi) wherein when R2’ is other than hydro-
`gen and R3’ is hydrogen, R2’ is in the 4-, 5- or 6-position;
`when both R2’ and R3’ are other than hydrogen, at least
`one of them is in the 5- or 6-position and neither of them
`is in the 7-position; when both R4’ and R5’ are other
`than hydrogen and R5,,’ is hydrogen, at least one of R4’ 20
`and R5’ is in a meta or para position; and when each of
`R4’, R5’ and R5,,’ is other than hydrogen, at least two of
`them are in meta or para positions,
`(xxiii)-(xxiv) of (xxi) and (xxii) wherein R5 is R5”,
`especially hydrogen,
`(xxv)-(xxvi) of (xxi) and (xxii) wherein R1 is C1.3al-
`kyl, R2 is R2”, R3 is R3”, R4is R4”, R5 is R5”, R5 is R5",
`especially hydrogen, R7 is R7”, and X is X”,
`(xxvii)—(xxxii) of (xxi)—(xxvi) wherein any M is M’,
`(xxxiii) of Group IBb wherein R1 is R1’, R2 is R2’, R3
`I
`is R3’, R4is R4’, R5 is R5’, R5,, is R50’, R5 is R6’, and X is i
`X 5
`(xxxiv) of (xxxiii) wherein when R2’ is other than
`hydrogen and R3’ is hydrogen, R2’ is in the 4-, 5- or
`6-position; when both R2’and R3’ are other than hydro-
`gen, at least one of them is in the 5- or 6-position and
`neither of them is in the 7-position; when both R4’ and
`R5’ are other than hydrogen and R5,,’ is hydrogen, at
`least one of R4’ and R5’ is in a meta or para position; and
`when each of R4’, R5’ and R54’ is other than hydrogen,
`at least two of them are in meta or para positions,
`(xxxv)-(xxxxvi) of (xxxiii) and (xxxiv) wherein R5 is
`R5”, especially hydrogen,
`(xxxvii)-(xxxviii) of (xxxiii) and (xxxiv) wherein R1 is
`C1-3alkyl, R2 is R2”, R3 is R3”, R4 is R4", R5 is R5”, R5
`is R5”, especially hydrogen, and X is X",
`(xxxix)—(lxiii) of (i)—(xiii) and (xxi)—(xxxii) wherein the
`hydroxy groups in the 3- and 5-positions (of the group
`of Formula II) have the erythro configuration,
`(lxiv)—(1xxxviii) the 3R,5S enantiomers of the com-
`pounds of (xxxix)-(lxiii) wherein X is
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`and the 3R,5R enantiomers of the compounds of these
`groups wherein X is —(CH2),,,—,
`(xxxiii)—(xxxviii)
`(lxxxix)—(ci) of
`(xiv)—(xx)
`and
`wherein the hydroxy group on the lactone ring is trans
`to X (i.e., the trans lactones), and
`(cii)—(cxiv) the 4R,6S enantiomers of the compounds
`of (lxxxix)-(ci) wherein X is
`
`65
`
`
`
`Mylan Exhibit 1010, Page 5
`
`

`
`9
`
`-continued
`
`4,739,073
`
`R2
`
`R
`
`(VI)
`
`10
`
`7‘ CH0
`
`R2
`
`R3
`
`I
`
`R
`
`\
`
`1"‘
`R0
`
`(IV)
`
`F
`
`(1) Strong base +
`(IVB)
`CI-l3—CO-R5‘,
`(2) Aldehyde of Formula IV
`
`R;
`
`R
`
`.
`
`(X)
`
`| \ x—<|:n—cH2-fi—-Rea
`
`OH
`
`0
`
`N
`I
`R"
`
`or
`
`(X1)
`
`(R11—C0)2O
`
`(XA)
`
`G \L R11-CO-Y (XB)
`
`R
`I \ X"‘|3”‘CH2"f|3‘.R6a
`1"‘
`‘I’
`0
`Ra
`(l:=O
`R11
`
`H
`
`(1) Stfoflg base +
`(XIA)
`CI-l3—C0OR11,,
`(2) Ketoester of Formula XI
`
`(XII)
`
`R3
`
`R;
`
`R3
`
`R;
`
`R3
`
`| \ X--Clil-I-CH2-(|2H—Cl~l2-C0OR7a
`N
`OH
`OH
`II“,
`
`c
`
`M6560]-1
`
`R
`
`l
`
`5
`
`10
`
`15
`
`(VII)
`
`| \ X-<l?H-CH2—Cl1H—CH2'-COOM2 -
`
`OH
`
`OH
`
`N
`I
`R”
`
`D 1/399
`R
`I \ X-(III-I—CH2—(|2H—Cl-l2—C0OH
`N
`OH
`OH
`1'10
`
`E
`
`A or
`Lactonization agent
`
`R2
`
`R
`
`x
`
`H
`
`OH
`
`20
`
`R3
`
`(VIII) 25
`
`R2
`
`30
`
`R3
`
`(IX) 35
`
`R;
`
`R
`\
`
`N
`R0
`
`R
`
`\
`
`If
`R”
`
`|
`
`l
`
`|
`
`\
`If
`R0
`
`R
`
`N
`
`1I{0
`
`R
`\
`
`7
`R0
`
`H
`0
`
`///
`5c
`
`H
`
`0
`
`1;
`
`IO]
`
`OH
`
`H
`
`V
`
`5.
`
`X
`“ 0
`/,/0
`
`ll
`0
`
`0H
`H
`
`0/,
`
`R3
`
`R;
`
`R3
`
`R;
`
`R3
`
`40
`
`45
`
`50
`
`R3
`
`R;
`
`R
`
`,
`
`“
`
`I
`
`(IXt)
`
`.
`
`(IXc)
`
`55
`
`R3
`
`6°
`
`REACTION SCHEME II
`The compounds of Formula I wherein R5 is C1_3alkyl
`may be synthesized by the following series ofreactions: 65
`
`I
`
`I
`
`R2
`
`R3
`
`X—(|2H-Cl-{2—(|3R6,,-CH2-COOR11,,
`(I)
`OH
`I =0
`R“
`1
`
`M26990]-1
`
`X--(III-I-CH2—(|JR5,,-CH2-C0OM2
`OH
`OH
`
`J
`
`H39
`
`(XIII)
`
`(XIV)
`
`X-(III-I—CH;-$R5,,—CH2-COOH
`OH
`OH
`
`R
`
`\
`N
`
`l
`
`1'10
`\l/RMOH or
`
`CHzN259
`
`K
`
`Mylan Exhibit 1010, Page 6
`
`
`
`Mylan Exhibit 1010, Page 6
`
`

`
`11
`
`-continued
`
`4,739,073
`
`(XVI)
`
`12
`
`-continued
`
`L
`
`A or
`Lactonization agent
`
`R2
`
`R
`
`5
`
`10
`
`(C5H5)3P=CH—CHO P
`(XIXA)
`
`(XX)
`
`REACTION SCHEME IV
`
`The compounds of Formula XVII wherein Rois R1
`may be synthesized as follows:
`
`
`
`(XXI)
`
`(1) Strong base
`(2) 111-1
`
`R51:
`
`R5
`
`Q
`
`R4
`
`I X COOR11
`T‘
`R‘
`
`(XXII)
`
`R2
`
`R3
`
`REACTION SCHEME V
`
`The compounds of Formula IX wherein X is —CH=
`CH— may also be synthesized by the following series of
`reactions:
`
`Mylan Exhibit 1010, Page 7
`
`| \ x—eH—cH2—<|:Rg;,-CH;-cooR7,
`
`on
`
`OH
`
`N
`1&0
`
`R3
`
`R;
`
`R3
`
`R
`
`H
`i \ XW
`T
`0
`R0
`
`El)
`
`.
`
`OH\‘R6a
`
`REACTION SCHEME III
`
`(Xv) 15
`
`20
`
`25
`
`30
`
`35
`
`The compounds of Formula IV wherein X is a direct
`
`bond and those wherein X is
`
`H
`
`\c C/=
`/
`\
`
`I-I
`
`may be synthesized by the following series of reactions: 40
`
`R2
`
`R
`
`3
`
`R
`
`I \ COOR11
`N
`
`|
`R0
`
`(XVII)
`
`M \L Reducing agent
`
`R2
`
`R
`
`I \ CH20H
`3“
`R0
`
`R3
`
`(XVIII)
`
`N \1/ Mild oxidizing agent
`
`45
`
`50
`
`55
`
`50
`
`55
`
`
`
`
`
`
`
`Mylan Exhibit 1010, Page 7
`
`
`
`
`
`

`
`13
`
`4,739,073
`
`R2
`
`R
`
`14
`
`-continued
`
`| \ cHz4-P$<caHs>sY9
`
`N IR
`
`0
`
`R3
`
`(XXIV)
`
`(1) Strong base
`‘E655 H
`(2) g-C41-I9--?i—O~«
`C5H5
`
`w
`
`_OCI-I3
`
`0
`
`H
`
`CH0
`
`(xxv)
`
`<l3eHs
`0-?i—g-c4H9
`C6H5
`
`CH=C§H-(
`44.
`H O
`
`R \
`
`xlgg
`
`I
`
`(XXVI)
`
`OCI-I3
`
`X \L H9
`
`R \
`
`I
`
`CI-I=CQ\‘
`
`R ?
`
`’
`
`R0
`
`R2
`
`R3
`
`(XXIIA)
`
`R
`
`(1) POY3 (XXIIB) + (R;2)2N—CI-IO (XXIIC)
`(2) Compound of Formula XXIIA
`(3) 901-!
`
`R2
`
`R
`
`'
`
`R3
`
`1 \ crio
`?‘
`R0
`
`(XIX)
`
`S \L Reducing agent
`
`20
`
`R2
`
`R3
`
`R2
`
`25
`
`30
`
`35
`
`R3
`
`XIV’
`R0
`
`(XXVII)
`
`0
`
`H
`
`(|36H5
`o—s|i—;-c4H9
`C6Hs
`
`H
`
`Y \L Mild oxidizing agent
`
`R \
`
`1?:
`R0
`
`i
`
`CH=CH
`H
`
`C|:6H5
`r’O"S'I"t_-C4H9
`«.1
`CeHs
`H
`
`0
`
`LI,
`
`(XXVIII)
`Z \L Desilylation reagent
`
`R
`
`I X CI-I=CI-I
`1“
`Ir
`R0
`
`H o
`
`(XXIX)
`
`OH
`‘H./"
`“~
`
`H
`
`II
`0
`
`REACTION SCHEME VI
`
`R2
`
`45
`
`R3
`
`50
`
`55
`
`R2
`
`R3
`
`65
`
`The compounds of Formula XX are preferably syn-
`' thesized by the following reaction:
`
`Mylan Exhibit 1010, Page 8
`
`R2
`
`R
`
`l X CH2OH
`7
`R0
`
`.
`
`(XVIII)
`
`R3
`
`T
`
`PY3 (XVIIIA),
`SOY; (XVIIIB) or
`Y—CO-CO—Y (xvmc)
`
`U
`
`P(C6Hs)3
`CY4
`
`R2
`
`R
`
`| \ CH2Y
`T
`R0
`
`R3
`
`(XXIII)
`
`V \L P(C6H5)3
`
`Mylan Exhibit 1010, Page 8
`
`
`
`
`
`

`
`15
`
`R
`
`I \
`T
`R0
`
`R2
`
`R3
`
`/H (XXIID) + POY3
`(1) (R12)2N\
`\
`/
`CH0
`H
`(2) Compound of Formula XXIIA
`
`c=c
`
`AA
`
`(3) 90H
`
`R2
`
`R3
`
`R
`
`\
`NH
`1&0
`
`l
`
`-c/
`/C‘ \
`
`H
`
`CHO
`
`4,739,073
`
`16
`-continued
`
`(XXIIA)
`
`R2
`
`R
`
`(XXIXC)
`
`5
`
`10
`
`15
`
`2°
`
`(XXIIB)
`
`(xx)
`
`R3
`
`DD
`
`R2
`
`R3
`
`l \ CH2CH2"CI-[O
`?‘
`R0
`9
`(1) (C5H5)3P""CH2—OCH3 Cl
`+ Strong base
`(2) Aldehyde of Formula XXIXC
`(3) H93
`
`6
`
`(XXIXA)
`
`R
`
`(XXIXD)
`
`| \ CI-I2CH2Cl-I2-Cl-IO
`T
`Ro
`
`REACTION SCHEME VIII
`
`The compounds of Formula I wherein Z is a group of
`25 Formula 11 wherein R7 is M2 may also be synthesized as
`REACTION SCHEME VII
`The compounds of Formula IV wherein X is ———(CI-I2.
`follows:
`),,,— may be synthesized by the following series of
`reactions:
`
`R3
`
`R
`
`(XCIX)
`
`BB
`
`R;
`
`I
`
`R
`
`3
`
`CC
`
`CHO
`
`-=
`
`(xxx)
`
`30
`
`35
`
`R6
`
`OH
`
`H
`xv}
`°
`
`II
`0
`
`I
`
`?‘
`R0
`
`R
`
`3
`
`(XXIXA)
`
`EB M26390“
`
`40 R2
`
`R
`
`(C)
`
`R;
`
`R3
`
`R
`I \
`N
`1'“
`
`99
`(1) (C6H5)3P“CH2—OCH3 C19
`‘ + Stro g base
`(2) Aldehydenof Formula XIX
`(3) H9’
`
`R
`
`(XXIXB)
`
`45
`
`R
`
`1:6
`l \ X-CH-CH2-C—CH2-COOMZ
`N
`Clm
`(Im
`I
`
`T
`:0
`(1) (C61-[5)3P-—C1-[2-—-()C]-[3 (319
`+ Strong base
`(2) Aldehyde of Formula XXIXB
`(3) H69
`
`(XXIXA) 50
`
`REACTION SCHEME IX
`Two isomers ofthe compound of Formula XXV may
`be synthesized by the following series of reactions:
`
`H
`
`AcO
`AC0
`
`‘
`
`H
`
`o
`OA
`
`9
`
`H
`
`(C1)
`
`AB
`—_>
`
`H
`
`I-lgOAc
`0“
`O
`H (CII)
`OCH3
`
`H
`
`HO
`HO
`
`H
`
`AC
`
`Mylan Exhibit 1010, Page 9
`
`
`
`Mylan Exhibit 1010, Page 9
`
`

`
`17
`
`0Cd>3
`O
`
`$.45
`
`H
`OCH;
`
`4,739,073
`
`-continued
`
`"HO
`HO
`
`H
`
`,
`
`H
`
`(CIV)
`
`0018
`0
`
`H
`OCH;
`
`18
`
`H
`
`OH
`0
`
`H (CIII)
`OCH;
`
`EAD
`
`HO
`HO
`
`H
`
`*
`
`(CV) H
`
`H
`
`I
`O
`
`AF
`
`(CV1) H
`
`AG 9
`
`05¢:
`H
`
`H
`
`0§¢3
`H
`
`AH E
`
`H
`
`0:
`H (CVIII)
`
`OH
`
`OCH3
`
`d>2§iO
`
`OCH3
`
`d>2§iO
`
`OCH3
`
`1§
`
`'
`
`(CV11)
`
`OCd>3
`0
`
`0%
`
`H (ex)
`OCH;
`
`All
`
`CHOO
`
`H (CIX)
`OCH;
`
`H
`
`¢2SiO
`+
`
`'
`
`(CXI) HO
`
`AK\L
`
`H
`
`AG’
`
`OC¢3
`O
`
`H
`OCH;
`
`001);
`O
`
`+
`
`H
`
`OH
`
`H (CV1)
`OCH;
`
`0Cd>3
`O
`
`AH’ 9
`
`_
`
`-
`
`0H
`0
`
`(Cxm mile
`
`H
`OCH3
`
`H
`
`Wife
`
`H
`
`H (CXIII)
`OCH3
`
`AI’
`
`CHOO
`
`dniio
`
`H
`
`H (CXIV)
`OCH;
`
`In the above formulae,
`R6,, is C1-3alkyl, preferably C1_2alkyl and most pref-
`-
`erably methyl,
`R7,, is C1-3alkyl, n-butyl, i-butyl, t-butyl or benzyl, 60
`preferably C1_3alkyl and most preferably C1_2al-
`kyl,
`R11 is C1_2alkyl, preferably methyl,
`R11‘, is C1_3alkyl, n-butyl or t-butyl, preferably ethyl
`or t-butyl,
`
`65
`
`each
`R12 is independently C1_3alkyl, preferably C1_2alkyl
`and more preferably methyl,
`
`each
`Y is chloro or bromo, preferably chloro,
`M2 is M, preferably sodium or potassium, and each of
`the other variables is as set forth above.
`In Reaction Scheme IX,
`Ac is acetyl,
`qb is phenyl, and
`+ is t-butyl.
`As utilized herein, terms such as “solvent” and “sol-
`vent system” embrace mixtures of solvents and imply
`that the reaction medium is a liquid at the desired reac-
`tion temperature. It should, therefore, be understood
`
`Mylan Exhibit 1010, Page 10
`
`
`
`Mylan Exhibit 1010, Page 10
`
`

`
`4,739,073
`
`19
`that not all of the solvents listed for a particular reaction
`may be utilized for the entire recited temperature range.
`It should also be understood that the solvent must be at
`least substantially inert to the reactants employed, inter-
`mediates generated and end products‘ under the reaction
`conditions utilized.
`The term “an inert atmosphere”, as utilized herein,
`means an atmosphere that does not react with any of the
`reactants, intermediates or end products or otherwise
`interfere with the reaction. While a carbon dioxide
`atmosphere is suitable for some reactions, the inert at-
`mosphere is usually nitrogen, helium, neon, argon or
`krypton, or a mixture thereof, and preferably is nitro-
`gen. Most reactions, including those where the use of an
`inert atmosphere is not specified, are carried out under
`such an atmosphere for convenience.
`In reaction A, the dianion of the acetoacetic acid
`ester of Formula IVA is generated with 2-2.2 equiva-
`lents of a strong base per mole of said ester, and the
`resulting dianion is reacted with the compound of For-
`mula IV. Among the strong bases that may be employed
`are n-butyllithium,
`lithium diisopropylamide and so-
`dium hydride. However, sodium hydride can be used
`only to generate a monoanion; it cannot be used to
`generate a dianion. Consequently, when sodium hy-
`dride is used to generate the monoanion, 1-1.1 equiva-
`lents thereof are utilized and then 1-1.1 equivalents of
`n-butyllithium or lithium diisopropylamide are utilized
`to generate the dianion from the monoanion. The molar
`ratio of the acetoacetic acid ester of Formula IVA to
`the compound of Formula IV is preferably 1-2.1, more
`‘ preferably 1.4-—1.8:1. The temperature for both steps is
`. conveniently -80“-10° C., preferably —20°—5° C. Both
`. steps of the reaction are relatively rapid; the dianion is
`typically generated over the course of 20-90 minutes
`while the reaction of the dianion with the compound of
`Formula IV is generally run for 20-120 minutes. The
`reaction is carried out under an inert atmosphere in an
`anhydrous inert organic solvent, for example an ether
`._ solvent such as tetrahydrofuran, diethyl ether, 1,2-dime-
`thoxyethane or 1,2-diethoxyethane, or a mixture
`thereof. The resulting compound of Formula V is a
`racemate.
`
`I
`
`The initial step of Reaction A is preferably carried
`out by generating the monoanion of the acetoacetic acid
`ester of Formula IVA with 1—1.05 equivalents of so-
`dium hydride which is then treated with 1—1.05 equiva-
`lents of n-butyllithium, per mole of said acetoacetic acid
`ester in each case, at a temperature of about -15“
`C-10“ C.
`
`In Reaction B, the keto group of the compound of
`Formula V is reduced to a hydroxy group with a mild
`reducing agent such as sodium borohydride or, prefera-
`bly, a complex of t-butylamine and borane in an inert
`organic solvent such as a lower alkanol, preferably
`ethanol, conveniently at a temperature of — l0°—30° C.,
`utilizing at least 1, for example 2-4, equivalents of trans-
`ferable hydride per mole of compound of Formula V,
`under an inert atmosphere. The reaction time is suitably
`1-8 hours. The compounds of Formula VI exist in four
`stereoisomeric forms; however,
`if an optically pure
`starting material of Formula V is utilized, only two
`optical isomers (diastereoisomers) of the resulting com-
`pound of Formula VI are obtained.
`However, it is preferred to utilize a stereoselective
`reduction in order to maximize production of a mixture
`of the erythro stereoisomers (racemate) of which the
`preferred stereoisomer (as set forth above) is a constitu-
`
`20
`ent. Stereoselective Reaction B is preferably carried out
`in three steps. In the first step, the ketoester of Formula
`V is treated with a tri(primary or secondary C2.4,alkyl)-
`borane, preferably triethylborane or tri-n-butylborane,
`and air to form a complex. The molar ratio of the trialk-
`ylborane to the ketoester of Formula V is preferably
`1-1.25:1, more preferably 1.02-l.2:l, and 0.5-8 liters,
`preferably 0.75-6.5 liters, of air (at 25° C. and 760 mm.
`Hg) per mole of the ketoester of Formula V are typi-
`cally used. The reaction temperature is suitably 0°—50"
`C., preferably 20°-30° C., and the reaction time is suit-
`ably 0.5-6 hours, preferably 0.5-3.5 hours. The first step
`is carried out in an anhydrous inert organic solvent,
`preferably an ether solvent such as tetrahydrofuran,
`diethyl ether, 1,