Mevalonolactone analogs, their preparation and pharmaceutical compositions.

The Invention coπcerns πaphthalene and tetrahydronaphthalene analogs of mevalonolactone and derivatives thereof, processes for their production, pharmaceutical compositions containiπg them and thei use as pharmaceuticals in particular as hypolipoprotelnenrlc and antl- atherosclerotlc agents.

The invention is especially concerned with compounds of formula I

wherein the two groups Ro together form a radical of formula

R ₂ R ₃ wherein R _≥ is hydrogen, C alkyl, C^alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

R- is hydrogen, C^alkyl, C^alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of R ₂ and R ₃ is trifluoromethyl, not more than one of R ₂ and R ₃ 1s phenoxy, and not more that one of R ₂ and R ₃ 1s benzyloxy,

R ₁ is hydrogen, C^al yl, fluoro, chloro or benzyloxy,

R ₄ 1s hydrogen, C^alkyl, C _1-4 alkoxy,

(except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy

R ₅ is hydrogen, C^al yl, C _1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

^R s _a ^{1s n} y ^dr °9 ^en » ^c -j. ₂ ^ ^y1 » c _1-2 aiko ^χy , fluoro or chloro, and with the provisos that not more than one of ₄ and Rg 1s trifluoromethyl, not more than one of ₄ and _g is phenoxy and not more than one of ₄ and Rς 1s benzyloxy,

wherein n is 0, 1, 2 or 3 and both q's are 0 or one 1s 0 and th other is 1

wherein Rg is hydrogen or C, -alkyl, with the general proviso that -X-Z and t R ₄ bearing phenyl group are ortho to eac otherj in free acid form or in the form of a physioiogically-hydrolysable a -acceptable ester or a $ lactone thereof or in salt form.

By the term ' ^• physioiogically-hydrolysable and -acceptable ester is meant an ester of a co pound in accordance with the invention in hich the carboxyl oiety Is esterified, and hich

O PI

1s hydrolysäble under physlologlcal condltloπs to yleld an alcohol which Is Uself physiologlcally acceptable, e.g, πon- toxlc at deslred dos gβ levels. Preferred such esters as Z can be represented together with the free acid by formula Ha

Ha wherein R71s hydrogen, Cι.4alkyl or benzyl preferably hydrogen, n«butyl, 1-butyl, t-buty or benzyl and Rg 1s as deflπed above. hen in salt form R7. represents a catlon.

When Z is 1n lactone form 1t forms cS-lactone of formula Ilb

5

and references to "l actone" hereinafter refer to 5-l actones.

Salts of the compounds of the Invention, e.g. of the compounds of formula I, include in particular their pharma¬ ceutical ly acceptable salts. Such pharmaceutical ly acceptable salts Include e.g. alkall metal salts such as the sodium and potasslu salts and amranlum salts.

X-Z, R, and the R^-beariπg phenyl ring occupy any of positions 1 , to 4 subjβct to the proviso that X-Z and the R ₄ -bearing phenyl group are ortho to each other. R ₂ and R, occupy any of positions 5 to 8.

-4-

References to compounds of formula I, II and sub-species thereof are iπteπded to cover all for s uπless otherwise stated.

The compounds of formula I ay be divided into two groups, the compounds of formula IA and IB:

wherein R, to R- , X and Z are as defined above.

The compounds of formula IA may be divided 1nto two sub- groups, the compounds wherein Z is a group of formula I in other than lactone form (Group IAa) and those wherein Z 1s a group of formula IIb(Group lAb). Ukewise, the compounds of formula IS may be divided 1nto two sub-groups, the compounds wherein Z is a group of formu a II tn other than lactone form (Group IBa) and those wherein Z 1s a group of formula Ilb (Group IBb).

Each of those four sub-groups may be further divided into three further sub-groups, v1z., the compounds wherein the -X-Z group is 1n the 1-position and the R^-bearing phenyl group is in the 2-position (Groups Aal, IAbl, IBal and IBbl), the compounds wherein the -X-Z group is in the 2-ρosit1on and the R,-bear1ng phenyl group is in the 1-positiαn (Groups IAa2, IAb2, I3a2, IBb2) and the compounds wherein the -X-Z group is in the 2-pos1tion and the R.-bearing phenyl group 1s 1n the 3-position (Groups IAa3, IAb3, IBa3 and IBb3).

As is self-evident to those in the art, each co pound of formula (and every sub-scope and spedes thereof) has at least two centers of asymmetry (e.g. the two carbon ato s bearlng the hydroxy groups in the group of formula ∑∑a and the carbon atom beariπg the hydroxy grou and the carbon atom having the free valence in the group of formula I

and these lead (e.g. with two centers) to four stereolso eric forms (enantiomers) of each compound (two racemates or pairs of dlastereo- isomers). In the preferred compounds having only two such centers of asymmetry these 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 thls Invention. Depeπdiπg on the nature of substituents further asy metric carbon ato s may be present and the resultlng Isomers and ixtures thereof also form part of the Invention. Compou containlng only two centers of asymmetry (four mentioned stereoisome are preferred.

R«l 1s preferably R-', where R.' 1s hydrogen, C ^ l l not containlng an asymmetric carbon atom or chloro, more preferably R,", where R," 1s hydrogen or C« ,alkyl, and ost preferably R^"', where R-"' is hydrogen, C, -alkyl or isopropyl. Preferably, R, (R.' etc.), when other than hydrogen, 1s in the 3-positioπ in compounds of Groups IAa2, IAb2, IBa2 and IBb2 and 1n .

Alkyl as R _j > 1s preferably C, , or n-, 1- or t-buty and alkoxy C, , or n- or 1-butoxy. ₂ 1s preferably R-'- where R-' 1s hydrogen, C, ^alkyl, C, ,- alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, more preferably R ₂ ". where R«" is hydrogen, ethyl, methoxy, fluoro or chloro, and most preferably hydrogen.

R, is preferably R**', where R,' 1s hydrogen, C.^^ ¹ » C, -- alkoxy, fluoro or chloro, more preferably R,", where R-»" is hydrogen, methyl, methoxy, fluoro or chloro, and most preferably hydrogen.

Preferably, when both g and R- are other than hydrogen, at leas one of them Is in the 6- or 7-pos1t1on and not more than one of them 1s a member of the group conslsting of t-butyl. trifluoromethyl, phenoxy and benzyloxy.

Alkyl as R ₄ 1s preferably C, ₃ or π-, 1- or t-butyl and alkoxy ^c l-3 ^{or n} " ^or 1-butoxy.

R ₄ 1s preferably R^', where R^' Is hydrogen, ^^]ky ^^

alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy. more preferably R ₄ ", where ₄ " 1s hydrogen, methyl, methoxy, fluoro or chloro, and most preferably R ₄ ^,π , where ₄ ^,M 1s hydrogen or fluoro, espedally hydrogen or 4-fluoro and most espedally 4-fluoro. R ₅ 1s preferably Rg', where Rg' is hydrogen, C-^a kyl, C._ ₂ alkoxy, fluoro or chloro, more preferably R-\ where g" is hydrogen, methyl, methoxy, fluoro or chloro, and most preferably hydrogen.

R _5a 1s preferably Rg _a ', where g' is hydrogen or methyl and most preferably hydrogen. Preferably, when ₄ (R ₄ ', R ₄ ", etc.) is other than hydrogen and R ₅ (Rg ¹ , Rg ^» , etc.) and R _ga (Rg _a ' _f etc.) are both hydrogen, R ₄ ( ₄ ', etc.) is in a meta or para position, more preferably the para positioπ. The most preferred onosubstituted phenyl group 1s 4-fluoropheny .

Preferably, when bot ₄ ( ₄ \ R ₄ ", etc.) and g (Rg ¹ , Rg", etc.) are other than hydrogen and _ga (R _a \ etc.) 1s hydrogen, at least one of ₄ (R', etc.) and Rg (Rg ¹ , etc.) is in a meta or para Position (more preferably both are), and not more than one of them 1s a member of the group consisting of t butyl, trifluoromethyl phenoxy and benzyloxy; more preferably, R ₄ ( ₄ ', etc.) and g (Rg ¹ , etc.) are not ortho to each other when neither of them is a member of the group consisting of methyl, methoxy, fluoro and chloro.

Preferably, when each of ₄ (R ₄ \ etc.), g (Rg ¹ , etc.) and Rg _a (Rg •, 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, trifluoro¬ methyl, phenoxy and benzyloxy; more preferably, no two of them are ortho to each other unless at least one member of each of the pair of substituents that are ortho to each other 1s a member of the group consisting of methyl, methoxy, fluoro and chloro. g 1s preferably Rg', where Rg* is hydrogen or C-_ ₂ alkyl, more preferably Rg", where g" is hydrogen or methyl, and most preferably hydrogen.

OMPI

R ₇ is preferably R , where R ₇ * 1s hydrogen or C._ ₃ alkyl ^ more preferably R-," 1s hydrogen or C. _-2 alkyl.

Compounds of formula I wherein Z is of formula II or Ila are most preferably in salt form. Preferred salt-forming cations are those free from centers of asymmetry espedally e.g. sodium, potasslum or a moniu most preferably sodium.

X _; is preferably X*, where X' is -(CHg)«..- or

\ / \ /

OC , wherein is 1, 2 or 3, espedally OC / ^/ N

Z is preferably a group of formula I∑a wherein R _g is Rg' and R-, is R-' or a group of formula Ilb wherein Rg is Rg', more preferably a group of formula Ila wherein Rg is Rg" and R-, is R-," or a group of formula ifb wherein R _ß is R _g " and most preferably a group of formula Ila wherein R _g is hydrogen and R, is R," or a group of formula Ilb wherein R _g is hydrogen, espedally a group of formula Ila 1n sodium salt form wherein Rg 1s hydrogen or a group of formula Ilb wherein Rg is hydrogen. n is preferably , where is 1, 2 or 3, preferably 2 or 3 and most preferably 2.

Insofar as the compounds of Groups IAa and IBa and each of the sub-groups thereof are concerned, the erythro isomers are 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 and Ila).

As between otherwise identical compounds of formula I, free acid salt and ester forms are generally preferred to lactone forms.

The traπs lactones are generally preferred over the c lactones eis and trans referring to the relative positions of R _fi and the hydrogen atom in the 6-pos1tion of the group of formula Ilb.

The preferred stereoisomers of the compounds of formula I having only two centers of asyrjnetry wherein X 1s a dlrect bond,

» wherein the * denotes the bond to the Z group, and Z is 1n other than lactone form are the 3R,5S and 3R,5R isomers and the racemate of which each is a constitue i.e., the 3R,5S-3S,5R (erythro) and 3R.5R-3S.5S (threo) racemates, wi the 3R.5S isomer and the racemate of which 1t is a constituent being more preferred and the 3R,5S isomer being most preferred.

The preferred stereoisomers of the compounds of formula I having only two centers of asymmetry wherein X is

•(CH , and Z is in other than lactone form are the 3R,5R and 3R,55 isomers and the 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 1s a constituent being more preferred and the 3R,5R isomer being most preferred.

The preferred stersoisomers of the compounds of formula I having only two centers of asymmetry wherein X

1s a dlrect bond, , wherein the * denotes the bond to the Z group, and Z is a group of Formula Ilb are the 4R,6S and 4R,6R isomers and the racemate of which each fs a constituent, i.e., the 4R,6S-4S,6R (trans lactone) and 4R,βR-4S,6S (eis lactone) racemates, with the 4R,6S Isomer and th racemate of which it is a constituent being mors preferred and the 4R,6S Isomer being most preferred.

„g.

The preferred stereoisomers of the compounds of formula I havin only two centers of asymmetry wherein X 1s -(CH ₂ ) _m - or

c»C , and Z is a group of formula Ilb \ are the 4R,6R and 4R,6S Isomers and the racemate of which each 1s a constituent, I.e., the 4R,6R-4S,6S (trans lactone) and 4R,5S-4S,6R ( . lactone) racemates, with the 4R,6R Isomer and the racemate of which i is a constituent being more preferred and the 4R,6R Isomer being most preferred.

The preferences set forth in the precedlng four paragraphs also apply to the compounds of formula Σ having more than two centers of ^■ asymmetry and represent the preferred configura lons of the indlcated positions.

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 and those of Groups IAa, IAb, IBa, ISb, IAal, IAa2, IAa3, IAbl, IAb2, IAb3, IBal, IBa2, IBa3, ΣBb , IBb2 and IBb3 as well as to every other subgroup thereof set forth 1nfra, e.g. Groups (1) et seq., unless otherwise Indlcated. When any preference contalns a variable, the preferred s1gn1f1cances of that variable apply to the preference in question, unless otherwise Indlcated.

Preferreύ groups of compounds of formula I include the compounds

(I) of Group IAal wherein R. 1s R-', R ₂ Is R ₂ ', ₃ 1s R-', ₄ 1s R ₄ ^« , Rg Is Rg ^» , _5a is R _5a ', Rg is Rg ^» , R _; is R-', and X is X'.

(II) of (1) wherein when both R ^l and R _* ,' are other than hydrogen, at least of of them 1s 1n the 6- or 7-pos1tion, when both R ₄ ' and g' are other than hydrogen and Rg ' is hydrogen, at least one of R ₄ * and R _ς ' and R- * 1s 1n a meta or para osition, and when each of R ₄ ^« , Rg ^« and g _a ' is other than hydrogen, at least two of the are 1 ^ή meta or para positions,

OMPI

(111)-(1v) of (1) and (11) wherein Rg 1s Rg", espedally hydroge

(v)-(vi) of (i) and (11) wherein R- is R-\ Rg s ₂ \ ₃ 1s ₃ ^{U R} 4 ^1s V» ^R 5 ^1s » ^R 5a ^{1s h} y ^dr °9 ^β n. g s Rg ^M , espedally ^hy drogen R, is R, ^M and X 1s ^{7 H}

, ' \ (vi1) of (1) wherein R- 1s R- ^w , R ₂ 1s hydrogen, ₃ is hydrogen, R ₄ is R ₄ ^,n , Rg is hydrogen, R _ga 1s hydrogen, . g 1s hydrogen, ₇ is R and X

(v111)-(x1i1) of (1)-(v1) wherein any salt form is preferably a sodium, potassiu or airmonlum, espedally a sodium salt form. (x1v) of Group IAbl wherein R. is R-', R-, 1s R ₂ ', R ₃ Is R ₃ ', R ₄ 1s R ₄ ', g is Rg', R _ga 1s Rg _a ', Rg is Rg', and X is X*,

(xv) of (xiv) wherein when both R ₂ ' and R-*' are other than hydrogen, at least one of them is in the 6- or 7-pos1tion, when both ₄ ' and R-' are other than hydrogen and Rg * 1s hydrogen, at least one of R ₄ ' and Rg' 1s in a meta or para position; and when each of Ri ¹ , R- ¹ and R _g ' is other than hydrogen, at least two of them are in meta or para positions,

(xvi)-(xv11) of (xiv) and (xv) wherein g 1s Rg", espedally hydrogen, (xviil)-(xlx) of (xiv) and (xv) wherein R- _j is R-", R ₂ is g", ₃ Is R ₃ ", R ₄ 1s R ₄ ", g 1s Rg", Rg _a 1s hydrogen, Rg is Rg", espedally hydrogen, and X is

\ '

OMPI

(xx) of (x1v) wherein R.1s R."', R ₂ is hydrogen, R ₃ is hydrogen, ₄ 1s R ₄ "', Rg 1s hydrogen, _ga 1s hydrogen, g is hydrog and X 1s _u

\ / / ^H

(xx1) of Group IBal wherein R^ is R«', R ₄ 1s R ₄ ', g 1s Rg ^» , Rg 1s Rg', R ₇ 1s R ₇ ', and X is X',

(xxii) of (xx1) wherein when both R ₄ ' and Rg' are other than hydrogen and g ^• is hydrogen, at least one of ₄ ' and Rg' 1s In a or para position, and when each of R ₄ ', R _g ' and Rg * 1s other than hydrogen, at least two of them are in meta or para positions, (xxlii)-(xxiv) of (xx1) and (xxii) wherein Rg is Rg", espedal hydrogen,

(xxv)-(xxvl) of (xxi) and (xx11) wherein R- 1s R-\ R ₄ 1s ₄ ", g is Rg", Rg Is hydrogen, Rg 1s Rg", espedally hydrogen, R ₇ is

(xxvii) of (xxi) wherein R« is R«" e

R _5a 1s hydrogen, Rg is hydrogen, R*. is

(xxviH)-(xxxili) of (xxi)-(xxvl) wherein any salt form 1s preferably a sodium, potassium or amonium, espedally a sodium sal form. (xxxiv) of Group IBbl wherein R^ is R-\ ₄ is R ₄ \ g is Rg*,

R _5a 1s R _5a ', Rg 1s Rg', and X 1s X',

(xxxv) of (xxxiv) wherein when both R ₄ ' and R _g ' are other than hydrogen and R _g ' is hydrogen, at least one of R ₄ ' and R _g ' 1s 1n a meta or para position, and when each of R , Rg' and Rg _a ' 1s other than hydrogen, at least two of them are 1n meta or para positions,

(xxxvi)-(xxxvü) of (xxxiv) and (xxxv) wherein Rg 1s Rg", espedally hydrogen,

(xxxv111)-(xxx1x) of (xxxiv) and (xxxv) wherein R. is R-", ₄ is R ₄ ", R _g 1s Rg", R _ga 1s hydrogen, g 1s Rg", espedally hydrogen, and

X is u

(xl) of (xxxiv) wherein R- is R."\ R ₄ 1s R ₄ ^,M , _. Rg is hydrogen, Rg is hydrogen, Rg Is hydrogen, and X 1s

(xli)-(lxvi) of (i)-(xiii) and (xxi)-(xxxlli) wherein the hydroxy groups In the 3- and 5-posit1ons (of the group of formula Ila have the erythro confIguration,

(Ixvii)-(xcii) the 3R.5S enantiomers of the compounds of (xI1)-(lxv1) wherein X is _H

\ /

OC and the 3R,5R enantiomers o

' \ the compounds of these groups wherein X is -( ^CH 2^m~ _*

(xciii)-(cvi) of (xiv)-xx) and (xxxiv)-(xl) wherein the hydroxy group on the lactone ring is trans to X (the trans lactones) and (cvii)-(cxx) the 4«,6S enantiomers of the compounds of (xcii.1)- (cv1) wherein X Is _H

OC and the 4R,δR enantiomers of the

compounds of these groups wherein X 1s -( H ₂ ).,.-.

Groups of (xli)-(lxvi) embrace the 3R,5S-3S,5R racemate and the 3R,5S and 3S,5R enantiomers of the compounds wherein X is _u /

OC. / H

(the 3S,5R enantlo er being least preferred) and the 3R,5R-3S,5S racemate and the 3R,5R and 3S,5S enantiomers of the compounds wherein

X 1s -(CHg)^-. (the 3S,5S enantlomer being least preferred).

GMH

-13-

Groups (xc111)-(cvl) embrace the 4R,6S-4S,6R racemate and the 4R.6S and 4S,δR enantiomers of the compounds wherein X 1s

(the 4S,6R enantlomer being least preferred) and the 4R,6R-4S,6S racemate and the 4R,6R and 4S,βS enantiomers of the compounds wherein X 1s M _? ) _m ^m te 45,65 enantlomer being least preferred).

Insofar as Groups IAa2, IAh2, ISa2, IBb2, IAa3, IAb3, IBa3 and

IBb3 are concerned, the preferred sub-groups are ^' those that correspon to Groups (1)-(cxx). As should be evident, the preferred groups of compounds of Groups IAa2 and IAa3 are those that correspond to Groups (1)-(xi11), (xl1)-(lii1) and (Ixvii)-(lxxlx), the preferred groups of compounds of Groups IAb2 and IAb3 are those that correspond to Groups (xiv)-(xx), (xc11i)-(xdx) and (cv11)-(cx111), the preferre groups of compounds of Groups I8a2 and IBa3 are those that correspond to Groups (xxi)-(xxxiil), (Hv)-(lxvi) and (Ixxx)-(xcH) and the preferred groups of compounds of Groups ΣBb2 and IBb3 are.those that correspond to Groups (xxxiv)-(xl), (c)-(cvi) and (cxiv)-(cxiv)- (cxx). It is as if each of these additlonal groups were set forth herein in Its entlrety.

A particular compouπd group Covers those of formula I wherein the two Ro groups together form a radical of the formula

or -CH ₂ CH ₂ CH ₂ CH ₂ -,

wherein R ₂ 1s hydrogen, C._ ₃ a1ky1, ni-butyl, j.-butyl, C._-alkoxy, jv-bυtoxy, J-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R-.1s hydrogen, C-_ ₃ a1kyl, C- _-3 alkθxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, withtheprovisos that not more than one of R ₂ and R ₃

1s trifluoromethyl, not more than one of ₂ and R, is phenoxy, and not more than one of ₂ and R. is benzyloxy, R- 1s hydrogen, C, -alkyl, fluoro, chloro or benzyloxy, R ₄ 1s hydrogen, C- -alkyl, rπbutyl, j-butyl, C, ,alkoxy, -butoxy, J_-butoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,

Rg is hydrogen, C-_ ₃ alkyl, C .*alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, g _a is hydrogen, with the proviso that not more than one of ₄ and R _g is trifluoro¬ methyl, not more than one of R ₄ and R _g is phenoxy, and not more than one of R ₄ and Rg 1s benzyloxy,

5 4 is -CH-CH _jj - ϊC-CHg-toOR-," ¹ or OH ÖH

5

OMPI

whereln Rg is hydrogen or C-^alkyl, and

Ra."' is hydrogen, C _j ^alkyl, n.-butyl, j-butyl, t-butyl, benzyl or M, wherein M 1s a pharmaceutlcally acceptable catlon, with the proviso that the -X-Z group and the R ₄ -bear1ng phenyl group are ortho to each other.

The compounds of formula I can be prepared by the following met whereby

§5 represents the baslc ring structure

^R0 ' ^R T. ^R 4 ^{f R} 5a ^{δπd R} S

as deflned above. Thus φR Stands for

-^JRE

OMPI

a) When Rg 1s hydrogen reducing a compound of formula VI

X-CH-CH ₂ -C-CH ₂ -C00R. ₄ VI

OH 0 wherein R- ₄ 1s a radical forming a physioiogically-hydrolysable and acceptable ester and X, is as defined above, b) when R- » XVII

wherein R _g 1s C-μ-a ky , R.g 1s part of an ester forming group and

X and R- ₄ are as defined above, c) when X 1s H

C-C deprotecting a compound of formula LIX

wherein Pro 1s a protectiπg group d) hydrolysing a compound of formula I in the form of a physioiogicall hydrolysable ester or a lactone or e) esterifyingorlactonising a compound of formula I in free acid form

and when a free carboxyl group is present, recovering the compound obtained in free add form or in the form of a salt. In processes a) and b) . ₄ is preferably C. ,alkyl, jv-butyl, j.-butyl, t-butyl or benzy more preferably C- _β3 alkyl, most preferably C. «alkyl and .g is prefer ably C^-alkyl, 1n particular methyl..

∑t will readlly be appreciated that the various forms of the compounds of formula I may Iπterconverted as Indlcated 1n d) and e) above.

In the sa e way compounds obtained accordlng to a), b), and . c) may be hydrolysed to free acid forms and free acid forms may be esterlfled or lactonised to produce a deslred end-product. The Invention thus also provides a p ocess for prepaHng a compound of formula I which comprlses hydrolysing a compound of formula I 1n ester or lactone form or esterifying or lactonising a compound of formula I In free acid form and when a free carboxyl group 1s present recovering the compound obtained 1n free add form or in the form of a salt.

Unless otherwise stated reactlons are performed In a anπer conventlonal for the type of reactlon Involved. Molar ratlos and reactlon tlmes are as a rule conventlonal and non-cr1t1cal and are chosen accordlng to prlnciples well established 1n the art on the basls of reactants and conditlons employed.

Solven s, alone or as mlxtures, are generally chosen which re ain Inert and liquid durlng the reactlon 1n quβstlon. Exa ples of inert atmospheres are carbon dioxide (some reactlons) and more usually nitrogen or a nobel gas, nltrogeπ being preferred. Most reactlons, including those wherein use of an inert atmosphere is not mentioned, are carried out uπder such for convenience

-13-

Reductlon accordlng to a) 1s preferably carrled out using a mild reducing agent such as sodium borohydrlde or, a complex of t-butylamine and borane in an inert organlc solvent such as a lower alkanol, preferably ethanol, convenlently at a ζ temperature of -10 ^* to 30"C, under an inert atmopshere.

Use of an optical ly pure s artlng materlal will lead to ♦ only two optical Isomers (dlastereolsomers) of the resultiπg end product. However, if stereospeclficity 1s desired it is preferred to utillze a stereoselective reductlon in Order to aximlze io production of a mixture of the erythro stereoisomers (racemate) of which the preferred stereoisomer (as set forth above) 1s a constituent. Stereoselective reductlon 1s carrled out in three Steps. For example in the first step, the ketoester of formula V is treated wi h a tri(primary or secondary C2-4alkyl)borane, preferably tri-n-butylborane, and air to form a complex. The reactlon temperature is suitably O ^β to 50'C, preferably 20 ^* to 30'C. The first step 1s carrled out 1n an anhydrous inert organlc solvent, preferably an ether solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane or io 1,2-diethoxyethaπe, with tetrahydrofuran, being the most preferred solvent. In the second step, for example, the complex is reduced with sodium borohydrlde, preferably 1π the same solvent as utHlzed for the first step, at -80° to -40 ^* C, preferably -80° to -70"C. In the third step, the product of the

1$ second step 1s, for example, treated with, aqueous e.g.3QX H ₂ 0 ₂ , an aqueous buffer, preferably a phosphate buffer.to maintain a pH of 7.0 to 7.2, and a lower alkanol preferably ethanol. The H ₂ 0 ₂ is in large molar excess e.g.50 to 70 oles per mole of VI. The reactants are added slowly to the mixture frorn step 2 at e.g. -80° to -4Q°C 0 preferably -80* to -70 ^β C with subsequent warming to 20° to 30°C. Hydrolysis accordlng to b) or d) is carrled out in a manner conventlonal for such reactlons e.g. employlng an inorganlc

OMPI

hydroxlde such as NaOH or KOH with, 1f deslred subsequent addlflcatlon to glve the free acid form. Suitable solvents are mlxtures of water and water misdble solvents such as lower alkanols e.g. methanol or ethanol and reactlon convenlently takes place at te peratures from 20'C to reflux preferably not more than 80 most preferably 20° to 30°C. If it 1s desired to recover the compound a salt form correspondlng to the catlon.of the hydroxide employed the slightly less than equlvalent aounts of the latter may be employed. In b) R12 will convenlently be the sae as χ5 e.g. Cj^alkyl, espedally Cj^alkyl, preferably methyl. Lactonisatlon accordlng to e) is carrled out 1n conventlonal manner .e.g. by heating the correspondlng add In an anhydrous Inert organlc solvent e.g. a hydrocarbon such as benzenβ, toluene or a xylene or mlxtures thereof, preferably at temperatures of 75 ^* C to reflux although more preferably not above 150'C.

As 1s evident to those in the art, a racemlc threo 3,5-d1- hydroxycarboxy ic acid ylelds a racemlc c lactone and a racemlc erythro 3,5-d1hydroxycarboxy11c add ylelds a racemlc trans lactone. Use of a mixture of threo and erythro 3,5-d1carboxyl1c acid ylelds a mixture of _ and trans lactones (al four poss1ble ^' d1astereo1somers). Ukewlse 1f a Single enantlomer of the 3,5-dihydroxycarboxylic acid 1s utillzed, a Single enantlomer of the lactone 1s obtained. For example, lactonisatlon of a 3R,5S erythro dihydroxvcarboxvllc acid ylelds a 4R,6S lactone.

Esteriflcation accordlng to e) Is conventlonal employlng e.g. a large excess of a compound ^OH wherein R141s as defined above at 20 ^* C to 40'C optlonally 1n a solvent (espedally when R _u 0H is not liquid) and 1n the presence of a catalytic aount of an add such as £-toluenesulfonic acid. Where methyl esters are requlred these can also be obtained e.g. uslng diazomethane in an anhydrous inert ether solvent such as tetr«.hydrofurαπ,

1,2-dlmtthoxyethant or l,2-d1ethoxyethane and espe ally dlethyl- ether at e.g. 0* to 30 ^* C preferably 20 ^* to 30 ^* C -

Exa ples of protecting groups in reactlon c) are diphenyl- t-butylsilyl, tri-1sopropylsilyl or d1methyl-t-butylsilyl _t C^n- alkyl , benzyl, triphenyl ethyl , tetrahydrof uran-2-y , tetrahydropyran-2-yl , 4-methoxytetrahydroöyraπ-4-yl ,

C _j .5n-alkanoyloxy. Esped al ly preferred are trisubstituted silyl radicals in particular diphenyl -t-butylsilyl .

Oeprotectlon is carrled out in Convention al manner e.g. by cleavage under mild condltlons such as emplσying e.g. for removal of a silyl containlng group such as d1phenyl-t-butyls1lyl a fluoride reagent e.g. tetra-π-butyl- ammonlum fluoride in an anhydrous inert organic medlum preferably tetrahydrofuran containlng glacial acetic acid at temperagures of 20 ^* to 60 ^* C esped al ly 20 ^* to 30"C. Preferably 1-5 moles of fluoride are used per mole of si lyl group with 1.2 to 1.8 moles of. gladal acetic add to each mole of fluoride.

The requlred starting ateri als may be prepared for example as il lustrated in the fol lowing reactlon schemes. The Symbols used are defined as fαl lows

R, R ₀ , Rχ _t Rj, R3, R4. 5. ^R 5a» Rδ» ^R 6a» Rll. Rl2» *» @ ■ as defi above,

M ₂ ^» a catlon preferably Na or K 13 ^{* C} l-6^ ^ky1 P ^rβfer aoly C _j .-alkyl V _. ^■ chloro or bromo Ac » acetyl

Con - 0CH ₃ (LVI), OH (LVIΣ) or * 0 (LVIII) ]

XVII (starting Material process b)

- ^ξ JRE

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Reaction Scheine IV

Two Isomers of the compound of formula XXV may be synthesized by the following series of reactions:

Unless otherwise stated reactions are performed in a manner conventlonal for the type of reactlon involved. Mol ratios and reactlon ti βs are as a rule conventioπal and non-crit1cal and are chosen accordiπg to prlnciples well estabüshed in the art on the basis of reactants and condltlons employed.

Solvents, alone or as mixtures, are generally chosen which remain inert- and liquid during the reaction in question.

Examp.es of inert atmospheres are carbon dioxide (some reactions) and more usually πitrogen or a noble gas, nitrogen being preferred. Most reactlons, includlng thόse wherein use of an Inert atmosphere is not mentioned, are carried out under such for conveni

The following tables give examples of typlcal reaction condltlons. In the reaction schemes temperatures are 1n degrees centigrade.'

Abbreviations THF (tetrahydrofuran) OMF (dlmethylformaffllde) LOA (lithiu d11sopropylam1de) DEA (diethylaceta lde)

BuL. (n-butyllithium) TsOH (p-toluenesulfonic add)

NCS (N-chlorosuccinimide)

NBS (N-bromosucc1n1m1de)

OIBAH (d11sobutylalum1nium hydrlde)

OMSO (dimethylsulfoxide)

CI is the commerdally available compound trl-o-acetyl-D-glucal. The preferred reactions condltlons for Reactions AB-AI are: AB: (1) sodium, methanol, 20"C, 15 lnutes; (2) ercurlc acetate, 25 ^* C. S AC: sodium Chloride, sodium borohydrlde, methanol + Isopropanol, 20 ^* C. AO: trlphenylmethyl Chloride, pyridine, 35 ^# C. . kl: (1) sodium hydrlde, tetrahydrofuran, 20 ^* C, (2) l-(2 ^, ,4',6 ^, -tri1soppopylbenzenesulfony.l}1m1 ^* dazole, -30 ^* rising t ι« AF: lithiu alumlnium hydrlde, methyl j^-butyl ether, -10'C. AG: t-butyldiphenylchorosllane, 1m1dazole, N,N,d1methyl- foramlde, 20 ^# C AH: 70% aqueous trlfluoroace lc add, methylene Chloride, -80 ^* to -50 ^* C espedally -55 ^* C rising over 1 hour to -10 ^* to +10* »S ^* -io° to +10 ^β and keeping at latter for 3-5 hours Ep1mer1- sation can be lnlmized by employlπg low temperatures and/or Short times and ter lnatlng the reactlon before completlon. AI: pyridinium chlorochro ate or espedally chro lum trloxlde (e.g. as ColUns oxidation) 1π molar excess (e.g.8 mole per &° mole of CVIII)/pyr1d1ne, pyridine, methylene Chloride,

20 ^* -25 ^* C. AJ: oxidation cf. AI. AK: reduction cf. a) and® above espedally NaBHa.

Resulting compounds may be conventlonally separated (e.g. a-r HPLC or column chromatography) or dlrectly further reacted.

The compounds of formulae V, XI, XIII, XIV, XVI, XX, XXIII- XXV, XXVII, XXXI, XXXIVA, XU, Cl, CXV, CXXIII, CXXIIIA and CXXVIII and the reagents not designated by a Roman numeral are known or, 1f unknowπ, may be synthesized by processes analogous to those described 30 1n the literature for slmllar known compounds. As for the compound of formula LV, one isomer 1s dlsclosed in Yang et al., Tetrahedron Letters 23.4305-4308 (1982) and the synthesis of the other Isomers 1s dlsclosed 1n Reactlon Scheme IV.

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The isomer of Yang et al. and the isomer dlsclosed In React on Scheme IV yleld lactones having the 4R,δS conflguratlon. Lactones having the 4S,6S conflguratlon may be Obtained from the other isomer whose synthesis is dlsclosed in Reaction Scheme IV.

The aval abil1ty of these Inter edlates enables synthesis of optically pure end products.

Reactlon products both intermediale and final can be isola- ted and purified in conventlonal mannr whereby intermedlates can where appropriately be employed dlrectly in a subsequent reaction

Mlxtures of stereoisomers (ds. trans and optical) may be separated by conventlonal means at whatever stage of synthesis is appropriate. Such methods Include re-crysta isat1on, chromatography, formation of esters with optical y pure aclds and alcohols or of amides and salts (cf also Sommer et al. «3.A.C. S. 0.3271 (1958)) with subsequent reconverslon under retentlon of optical purity. For example dlastereoisomeric (-)- -naphthyl- phenyl ethylsilyl derivatives of a lactone type end product of formula I may be separated by conventional means.

Salts may be prepared in conventlonal manner from free aclds, lactones and esters and vice-versa. Whilst all salts are - covered by the invention pharmaceutlcally acceptable salts espedally sodium, potassium and ammonium partlcularly sodium salts are preferred.

The various forms of the compounds of formula I are by virtue of their Interconver abllity useful as intermedlates in additlon to the use set out below.

Also within the scope of this invention are the . intermedlates of formulae VI, XII, V; XVII, XXVIΣ -XXX, XXXII, XXXII

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XXXV-XL, XLII-L, LII-LIV, LVI-LVIII, CXIX-CXXII, CXXΣV-CXXVII, CXXXI and CXXXII. The-preferences for each variable are the same as those set forth for the compounds of formula I, with the preferred groups of such compounds including those that correspond to Groups (1)-{xi1i (xxi)-(XXX111) and (xl1-xc11) (for formulae VI, XII, XV, XVII, XXVIII XXX, XXXII, XXXIII, XXXV-XL, XLII-L, LII-LIV, CXIX-CXXII and CXXIV-CXXVII) and Groups (xiv)-(xx), (xxxiv)-(xl) and (xciii)-(cxx) (for formula LVI-LVIII), to the extent conslstent therewith, and the correspondlng groups for the compounds of Groups IAa2. IA.2, I8a2, ISb2, IAa3, IAb3, IBa3 and I8b3.

The compounds of formula I possess pharmacologlcal actlvity 1n particular they are Inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and as a consequence Inhibitors of cholesterol blosynthesls as demonstrated in the following three tests.

Test A: In Vitro Mlcrosomal Assay of HMG-CoA Reductase Inhibition:

200 ul . al lquo.ts { 1.08-1.50 mg. /ml . ) of rat Hver mlcrosomal suspensions, freshly prepard from male Spargue-Oawley rats ( 150-225 g. body wβlght) , in Buffer A with 10 mmol . dlthlo- threltol are Incubated with 10 ul . test substance dlssolved in dlmethyl acetamlde and assayed for HMG-CoA reductase act lvity as described by Ackerman et al . , J. Llpld Res. J , 408-413 ( 1977) . In the assay the microsomes are the source of the HMG-CoA reductase enzyme which catalyses the reductlon of HMG-CoA to evalonate. The assay employs a Chloroform extraction to separate the product, C^C]mevalono lactone, for ed by the HMG-CoA reductase reactlon from the Substrate, C^C.HMG-CoA. _ ³ H_mevaloπo- actone is added as an internal referencβ. Inhibition of HMG-CoA reductase 1s calculated from the decrease 1π speciflc actlvity C-^C/^H.mevalonate) of test groups co pared to controls.

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-35-

Test B: In Vitro Cβll Culture Cholesterol B1osynthes1s Screens

The cel culture 1$ prepared as follows: Stock monolayer cultures of the FuδAH rat hepatoma cell Une (original ly obtained from G. Rothblat; see Rothblat, Llpids _» 525-535 (1974) are routlnely aintained In Eagle's Minimum Essential Medium (EMEM) supplemented with 10* fetal bovine serum (FBS) in 75 cπ.2 tissue culture flasks. For these studles, when tht cultures rβach confluence, they are removed by mild enzymatlc treat ent with 0.25% trypsin in Hanks' balanced salt solutlon (without calclum and magnesium). After centrifugatlon of the cell Suspension and aspiratlon of the enzymatlc solutlon, a cell pellet is resuspended in an appropriate volu e of medla for seediπg into 60 mm. tissue culture dishes. The cultures are incubated at 37'C in an atmosphere of high humidity and 53. carbon dioxlde. When the cultures are confluent (approximately 5 d'ays), they are ready for use. The culture medla 1s aspirated from the dishes and replaced with 3 ml of EMEM suplemented with 5 mg/ml of dllipidized serum protein (OLSP) prepared by the mβthod of Rothblat et al., In Vi ro _L2, 554-557 (1975). Replacemeπt of the FBS with OLSP has been shown to stimulate the incorporation of C* C]acetate into sterol by removing the exogenous sterol supplied by the FBS, thereby requiriπg the cells to synthesized sterol. Enthaπced 3-hydroxy-3-methy1 tutaryl Coeπzyme A reductase (HMG-CoA reductase) actlvity is mβasurable in the cells 1n response to the lack of exogenous sterol. Following approximately 24 hours 1ncubat1on at 37 ^* C in the OLSP supplemented medla, the assay is iπitlated by the addition of 3uCi of C ¹⁴ C]acetate and the test substances solubllized in dlmethyϊsulfαx.de (DMSO) or distllled water. Solvent coπtrols and compactin-trsated coπtrσts are always prepared. Triplicatβ 60mm. tissue culture dishes are run for each group. After 3 hours incubation at 37 ^* C, the

cultures are examined mlcroscoplcally uslng an inverted p ase contrast microscopβ. Notatioπs are madβ of any morphologlcal changes which may havβ occurred 1n ths cultures. The medl 1s aspl ated and the cell layer is gtn ly washed twice with 0.9% sodium Chloride solutlon (saline). The cell layer 1s then harvestβd in 3 ml. of 0.9* sallnt b gentle scraplng with a rubber poHceman and transferred to a clean g ass tube with Teflon linβd cap. The dishes are rlnsed with 3 ml. of 0.9X sallnβ and rescrapβd, and tht cells are combfned with the first harvest. The tubes are centr.fuged at 1500 r.p.tn. for 10 minutes 1n an 1EC PR-J centrifugt, and the supernatant 1s asperated.

The cells are then extracted as follows: One ml. of 100* ethanol 1s added to the cell pellet follo ed by sonicatlon for 10 seconds with a "IQ" settlng of 50 on a Bron ell Biosoπi IV. One hundre il. are taken for proteln determlnatlon. One ml. of 15X potassium h droxide (KOH) 1s added, and the samples are thoroughly vortexed. Saponlflcatlon 1s accomplished by heatlng the ethanol-KOH treated samples at 60 ^* C for 60 mlnutes 1n a water bath. Following dllutlon of the samples with 2ml. of distllled water, they are extracted three tl es with 7 ml. of petroleu ether. The petroleum.ether extracts are then washed three tlmes with 2 ml, of distllled water and finally taken to dryness under a strem of nitrogen.

The obtained samples are then analyzed by thln ayβr chro atography (TLC) as follows: Residues from the petroleum ether extractlon are taken up In a s all volu e of hexane and spotted on slHca ge 60 TLC plates (E. Merck). Development of the plates Is carrled out 1n a 150 parts by volume hexane: 50 parts by volume dlethyl ether: 5 parts by volume galdal acetic add solvent System using a three phase development procedure. Visuallzatlon 1s accomplished 1n an 1od1ne vapor chamber. The plates are divided 1nto Ive sectlons such that each sectlon contalns the olecules having the following approximate Rf

.OMPI

values: sectlon 1- 0-0.4, sec ion 2- 0.4-0.55, sectlon 3- 0.55-0.7, section 4- 0.7-0.9 and sectlon 5- 0.9-1.0. Section 2 cohtains the non-saρon1f1able sterols. The five sectlons of the TLC plates are scraped Into sdntl Tatlon vla s. 81an s are also prepared from scrapings of Chromatograph ed non- abel led Standards. AC5 scintWatlon cocktail is added, and the rad1oact1v1ty Is determlned 1n a liquid scIntH Tation spectro eter. [ ¹⁴ C] e adecaπe Standards are used to determlne countlng eff iciencies. The total protein contenf of the samples is determlned employlng the Bio-Rad Protein Assay System.

The results are reported as dis1ntegra 1ons per mlnute per mg protein (d. .m. /mg protein) for each of the Hve TLC sectlons. Meaπ d.p.m./mg protein ± Standard error of the meaπ are co pared for percentage change (?.-_) and statistical signlficancβ with solvent control means. TLC section 2 data 1s taken as a measure of HMG-CoA reductase actlvity Inhibition.

Test C: In V1vo Cholesterol 81osynthes1s Inhibition Tests: In vivo studles uti l ize male Wlstar Royal Hart rats weighing 150+20 g which have been kept for 7-10 days on an altered Hght cyc e (6:30 a.m. - 6:30 p.m. dark) housed two per cage and fed powdered Purina Rat Chow and water ad libitum. Three hours before the dlumal maxl um of cholesterol synthesis at m1d-dark, the rats are admln ister ed the test substances dissolved or as a Suspension 1n 0.55» carboxymethylcellulose in a volume of 1 ml/100 g body weight. Controls recelve vβhlcle a one. One hour after receiving the test substance, the rats are Iπjected intraperitoneally with about 5^ /100 g body weight of sodium Cl-* ⁴ C_acetate 1-3 mC1/mmol . Two hours after mid-dark, b ood samples are obtained under sodium hexobarbltol anesthesl a and the serum separated by centrlfugatlon.

Serum samples are saponlfled and neutral ized, and the 3ß-hydroxy sterols are predplated with d1g1ton1n baslcal ly as described by Sperry et al . , «3. Blol . Chem. 187, 97 (1950) . The C^Cldigitonides are then counted by liquid sdn n ation

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spectro etry. After corrsctlng for efflciendes, the results are calculated 1n nC1 (nanocuHes) of sterol for ed per 100 ml of serum. Inhibition of sterol synthesis 1s calculated from the reductlon 1n the nC1 of sterols formed from test groups compared to controls. The compounds are thus Indlcated for use as hypoHpoprotelnemic and ant1-atherosclerot1c agents.

An indlcated sultable daily dosage for use in the treatment of pyperllpoproteinemla and athersclerosls 1s from about 4 to 2000 mg suitably 4-200 e.g. 10 to 100 for the more actlve compounds sυitably ad lnistered in divided dosages of 1 to 1000 mg suitably 0.5 to 50 m two to four tlmes daily or 1n retard form.

The compounds of formula I may be admlnistered 1n slmllar manne as known compounds suggested for use in such indications e.g. Co pac The suitable daily dosage for a particular compound wil depend on a number of factors such as 1ts relative potency of activity. It has, for example been determlned that the preferred compound (compound no. 11) obtained an IC _ς « of 0.1 u-molar in test A compared with 0.5 u-molar for Compactin. It is therefore indlcated that the compounds may be admlnistered at slmllar or lower dosages than conventlonally proposed for Compactin e.g.25-150 mg/day..

They may be admlnistered in free acid form or in the form of a physioiogically-hydrolysable and -acceptable ester or a lactone there or in pharmaceutically acceptable salt form.

The invention therefore also concerns a method of treating hyperliproproteinemia or atherosclerosis by ad inistratlon of a compound of formula I in free add form or 1n the form of a physioio¬ gically-hydrolysable and -acceptable ester or a lactone thereof or in pharmaceuticals e.g. as hypolipoproteine ic and antl-atherosclerotic agents.

The compounds may be admlnistered a one. or 1n admlxture with« a pharmaceutlcal ly acceptable dlluent or carHer, and, optionally other exciplents, and admlnistered oral ly in such forms as tablets, el ixirs, capsules or suspensions or parente- ral ly 1π such forms as ϊnjectable Solutions or suspensions,

The preferred pharmaceutical compositions from the stand- polnt of ease of pr eparat Ion and administration are solid compositions, particularly tablets and hard-fi l led or liquid« fi led capsules. Such compositions also form part of the invention.

The fol lowing examples, in which all temperatures are in ^* C 11 lustrate the invention.

Example 1 Ethyl erythro-(E)-3,5-dihydroxy-7-(2 ^, -C4"-fluorophenynnaphth-T-yl)- heot-β-enoate (compound no. 1)

Step 1 : 2- ethoxy-l-naphthoyl Chloride (Reactlon M: compound XXVla)

6.06 g of 2-methoxy-l-πaphtholc add and 7.62 ml of oxalyl Chloride are added to 50 ml of anhydrous toluene, and the obtained react on mixtur Is refluxed for 2 hours and evaporated to dryness at reduced pressure to obtain the crude product.

Step 2 : 2-Methoxy-l-naphthoic acid N-l,l-d1methyl-2-hydroxyethylam1de (Reaction Nj compound XXVIIIa) 50 ml of methylene Chloride (dried over olecular sleves) and 5.4 g of 2-am1no-2-methyl-l-propanol are added to the crude 2-methoxy-l- naphthoyl Chloride produced In Step 1 whüe cooling in an 1ce bath. The reaction mixture is stirred at roo temperature overnight, 50 ml of methylene Chloride is added, and the reactlon mixture is quenched with water. The methylene Chloride phase is separated, washed twice with 10% aqueous sodium blcarboπate, dried over anhydrous sodium sulfate and evaporated at reduced pressure to near dryness. Oiethyl ether is added to the residue, and the pre pitate is dried under vacuu to obtain the colourless product, .p. 160 ^β -163°C. When this reactlon is scaled up, the yleld is i proved if one adds a solutlon of 2-methoxy-l-naphthoyl Chloride in methylene Chloride to a solutlon of 2-am1no-2-methyl-l-propanol in methylene Chloride stirred at 0 ^β -5°C.

Step 3 : 4,4-01methyl-2-(2 ^, -methoxynaphth-l ^, -yl)-2-oxazol1ne.hydrochlorid (Reactlon 0; compound XXIXa)

4.8 ml of thlonyl Chloride is slowly added to 6.0 g of Compound XXVIIIa, the obtained Suspension is stirred under nitrogen at room temperature for 4 hours, 10 ml of methylene Chloride dried over molecular sleves is added, and the reaction mixture is stirred overnight unde nitrogen.50 ml of «Methyl ether 1s added, and the predpitated

soHd is washed with diethyl ether and dried under vacuum to obtain the colourless product* m.p. 168 ^β -171°C.

Step 4 : 4,4-01methyl-2-{2 ^, -methoxynaphth-r-yl)«2-oxazol1ne (Reaction P: compound XXXa) 75 ml of 20* aqueous sodium hydroxl e Is added to 13 g of Compound XXΣXa and the reactlon mixture is extracted four tlmes with diethyl ether The diethyl ether extracts are co bined, dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure, and the residue is triturated with diethyl ether/petroleum ether. The resultlng solid is dried under vacuum to obtain the colourless product, m.p.98°-101°C.

Step 5 : 4,4-D1methyl-2-(2 ^, -C4 ^,, -fluorophenyl]naphth-T-yl)-2-oxazo11ne (Reactlon Q; compound XXXIla)

A Grignard reagent prepared from 4.2 g of £-bromb-fluorobenzeπe and 0.583 g of agnesiu turnings in 20 ml of dry tetrahydrofuran (distllled over sodium) is slowly added to a solutlon of 5.1 g of

Compound XXXa in 30 ml of dry tetrahydrofuran stirred at room temperature under nitrogen. The reaction mixture is stirred overnight at room tempera ture under nitrogen and, while slightly cooling, Is quenched with 20 ml of saturated ammonium Chloride solution. The reaction mixture is extracte with diethyl ether, and the diethyl ether extract 1s dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure. The residue is triturated with diethyl ether/petroleum ether, and the precipltate is dried under vacuum to obtain the colourless product, m.p. 115 ^β -117°C.

Step S : 2-(2*-_4"-Fluorophenyl_naphth-l'-yl)-3,4,4-tr1methy1-2-oxazo 1inl iodlde (Reaction R; compound XXXIIla)

7 ml of methyl iodide is added to a solution of 4.34 of Compound XXXΣIa in 30 ml of nitro ethane, and the reaction mixture is stirred at 80*-90 ^β C under nitrogen overnight. The reaction mixture is cooled to room temperature, and 200 ml of diethyl ether is added; the resultlng gu my precip,1tate solidlfies on standlng. The solid 1s washed with diethyl ether, dried under vacuum and recrystallised from acetoπitrile/ ether to obtain the yellow product, m.p.220 ^β -222°C.

Step 7 : 2-(4'-F1uoroρheny1)-1-naphtha1dehvde (Reaction S; compound IVa)

0.936 g of sodium borohydrlde 1s added portlon-wise over a 2 minute peHod to a Suspension of 11.36 g of Compound XXXIIIa in 120 ml of absolute ethanol stirred at about 0 ^β C..The reaction mixture is stirred at about 0°C under nitrogen for 2 hours, and 200 ml of 2N.hydrochlo 1c add 1s added, cooling being aintained durlng the additlon. The reaction mixture Is stirred at room temperature under nitrogen for 40 hours, conceπtrated at reduced pressure and extracted.three"tlmes with diethyl ether. The diethyl ether extracts are combined, washed twlce with 3% aqueous sodium thlosulfate, washed once with water, dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure. The residue is dissolved in methylene Chloride, and the solutlon 1s treated with charcoal, fil ered and evaporated at reduced pressure to a s all volume. A s all amount of isopropanol is added, and the solutlon 1s evaporated under vacuum without heating. The predpitated colourless solid is washed with cold Isopropanol, washed with petroleum ether and dried under vacuum to obtain the product, m.p. 78 ^β -80 ^β C.

Step 8 : (E)-3-(2 ^, -C4"-F1uoropheny1]naphth-l'-yl)prop-2-ena1 (Reactlon W; compound Vb) 3.16 ml of 1.3M ^-butyllithiumrv-hexane is added dropwise to a solutlon of 1.414 g of cis-l-ethoxy-2-tri-π-butylstanπylethyleπe in 40 ml of dry tetrahydrofuran (distllled over sodium) stirred at -78°C under nitrogen, stlrring 1s maintained for 2 hours nder the sae conditions, and a solutlon of 0.888 g of Compound IVa in 10 ml of dry tetrahydro- furan (distllled over sodium) 1s added. The reactlon mixture 1s stirred at -78 ^β C under nitrogen for 1.5 hours and allowed to warm to room temperature. 5 m of saturated aqueous sodium bicarbonate is added followed by 50 ml of water. The reaction mixture Is extracted twice with 50 ml portlons of diethyl ether, and the diethyl ether extracts are combined, washed twlce with 50 ml portlons of saturated aqueous sodium Chloride, dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure. The residue Is distributed between acetonltrile

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and ^-hexane. The acetonitrile layer is extracted twice with π ^« .hexan ^β . and evporated to dryness at. reduced pressuf- to obtain a dark greeπ gu . 30 ml of 80K aqueous tetrahydrofuran and 5 mg of p_-to1uenesulfon1c acid monohydrate are added, and the reaction mixture-is stirred at room temperature for 4 hours. Water and 0.5 g of solid sodium bicarbonate are added, and the reaction mixture 1s extracted with ethyl acetate. The ethy acetate extract is dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure to obtain a yel ow sticky solid. The solid is triturated with diethyl ether/petroleum ether to obtain the colourless product, m.p. U9 ^β -122 ^β C.

Step 9 : Ethyl {E}-7-(2 ^, -_4 ^,, -fluoropheny1_naphth-1 ^, --y1)-5-hydroxy-3- oxoheρt-6-enoate (Reaction A; compound Via)

29.1 ml of 1.7 M -buty11ithium/jn-hexaπe ^" is slowly added to a solutl of 6.9 ml of diisopropylamine in 140 ml of dry tetrahydrofuran stirred at 0 ^β C under nitrogen. The reaction mixture is stirred at 0 ^β C under nitrogen for 20 mlnutes, 3.14 ml of ethyl acetoacetate is slowly added, and the reaction mixture is stirred under the sae conditions for 1 hour and cooled to -40° to -30 ^β C. A solution of 3.4 g of Compound IVb 1π 75 of dry tetrahydrofuran is slowly added to the reaction mixture stirred at -40° to -30°C under nitrogen. The reaction mixture 1s stirred for an additlonal 45 inutes under the same conditions, quenched with 150 ml of saturated aqueous amonium Chloride and allowed to warm to room tempe ture overnight. Water is added to the reactlon mixture, and the reaction mixture is extracted with ethyl acetate. The ethyl acetate extract 1s washed with water, dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure. The gumy residue 1s triturated with a small a ount of diethyl ether, and the precipitated colourless solid is ^• washed with cold 1:1 (by volume) diethyl ether/petroleum ether and dried under vacuum to obtain the product, m.p. ^' 84 ^β -86*C. The product is a racemate that may be resolved into its R and S components.

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Step 10 : Ethyl erythro-(E)-3,5rd1hydroxy-7-(2 ^, -C4' ^, -f1uoropheny1lnaphth- T-yDhept-δ-enoate (process a): co oound πo. 1)

6,52 ml of IM tr1-n,-butylborane/tetrahydrofu an is added to a solut of 2.42 g of Compound Via in 200 ml of dry tetrahydrofuran stirred at room temperature, and 34 ml of air (at 25 ^β C and 760 mm Hg) is slowly bubbled in. The reactlon mixture is stirred at room temperature for 2 hours and cooled to -78° to -75°C, and 0.248 g of sodium borohydrlde 1 added portlon-wlse. The reaction mixture 1s stirred at -78° to -75 ^β C under nitrogen for 3 hours, and a solution of 33.8 ml of 30* aqueous hydrogen peroxIde, 67.5 ml of an aqueous phosphate buffer having a pH of 7.2 (0.047M. sodium phosρhate/0.024M. potassium phsophate/0.054M. sodium hydroxldβ) and 67.6 m1 of methanol 1s slowly added, the aforementioπed temperature being maintained during the addltlon. The reaction mixture 1s allowed to warm to room temperature overnight, water is added,and the reactlon mixture 1s extracted three tlmes with methylene Chloride. The methylene Chloride extracts are combined, dried over anhydrous sodiu sulfate and evaporated to dryness at reduced pressure. Methanol is added to the residue, it 1s heated at 40° to 45 ^β C for 30 seconds, and the methanol is evaporated at reduced pressure at room temperature; thls procedure 1s repeated twlce. The residue is triturated with a small a ount of diethyl ether while being cooled. The precipltated colourless solid is washed with diethyl ether/petroleum ether and dried under vacuum to obtain the product, m.p. 114 ^β -116 ^β C.

The product is a racemlc mixture which may be resolved into two optlcally pure enantiomers, the 3 ,5S and 3S,5R isomers, of which the for er 1s preferred. The use of a non-stereoselect1ve reductlon, a t-buty1amine-borane complex 1n abs. CgH-OH at 0 ^β for 1 hour, affords a mixture of all four enatlomers (compound no. 12).

Example 2 : Erythro-(E)-3 _t 5-d1hydroxy-7-(2 ^t -C4 ^w -f1uorophenyππaphth-T-yl hept-6-eno1c add and its sodium salt (process d); compound nos.2 and 3)

A mixture of 0.30 g of Compound 1, 10 ml of ethanol and 0.88 ml of I aqueous sodium hydroxldβ 1s stirred at room temperature for 1.5 hours,

water is added and the reactlon mixture 1s extracted with diethyl ether. The aqueous phase, which contains racemlc sodium salt can ei her be evaporated to dryness, m.p.210°-220°C (decomp.) (compound 3) or acdlfied with 2N. hydrochlorlc add, to yield a gu my precipitate which is extracted with ethyl acetate. The ethyl acetate extract is dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure to obtain the crude free acid as a sticy pale yellow foam, m.p.

>43 ^β -102 ^β C (compound 2).

The products are racemlc mlxtures which may be resolved into optlcally pure enantiomers, the 3R.5S and 3S,5R isomers, of which the former is preferred.

Example 3 : (E)-Trans-6-(2'-C2"-(4 ^IM -f1uoropheny1)naphth-1"-y1.etheny1)- 4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (process e); compound no.4) A solution of 0.223 g of Compound 2 in 40 ml of dry toluene is refluxed for 5 hours, the water formed being reoved by the use of a Oean-Starke apparatus. The reaction mixture is cooled and extracted with 105. aqueous sodium bicarbonate and with water. The toluene solutlo is dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure. The residue 1s dissolved in diethyl ether and evaporated at _. reduced pressure and room temperature unti precip1tat1on com ences. The solutlon 1s cooled, and the precipitated pale yellow soli 1s washed with petroleum ether and dried under vacuum to obtain the product, m.p. 152-154 ^β C. The product 1s a racemate that may be resolved by conventlonal mea 1nto two optlcally pure enantiomers, the 4R.6S and 4S,6R Isomers, of wh the former 1s preferred. The product contains about 1?« of the correspon eis racemate, which may be separated from the trans racemate by, for example, colurnn chromatography. The d_s_ racemate may be resolved by conventlonal'means into two optlcally pure enantiomers, the 4R,6R and 4S,6S isomers. The eis _, racemate results from a small aount of the thr Isomer of Compound 1 formed 1n Step 10 of Example 1 and not separated therefrom which Is carried through process d) (Example 2) and process e

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(thls example). A sample of the trans lactone free of any detectable cis_ lactone elted at 153° to 150 ^β C.

Example 4 : Ethyl erythro-3,5-dihydroxy-7-( ^, -C4"-f1uoropheny13-5 ^, ,6 ^, ,7 ^, , tetrahydronaphth-1'-y1)heptanoate (compound no. 5) Step 1 : Ethyl 7-(2 ^, -C4' ^, -f1uoropheny13-5 ^, ,6 ^l ,7 ^I ,8 ^, -tetrahydronaphth-T-yl 5-hydroxy-3-oxoheptanoate (reaction JJ, compound Vlb)

A solutlon of 406 mg ( Immole) of Compound Via in 20 ml of glacial acetic add Is contacted with a large excess of hydrogen at an initial pressure of 50 p.s.1. at room temperature In the presence of 40 mg of platlnum dloxide until 3 moles of hydrogen (7.5 p.s.1.) are taken up. The platlnum dloxide is removed by fUtratlon, and the filtrate is evaporated to dryness at reduced pressure. The residue (397 mg) is dlssolved in a small a ount of methylene Chloride and applied to sllica gel preparatlve thln layer chromatography plates; methylene Chloride 1s used as the chromatography solvent. The bands containlng the product are eluted with ethyl acetate. The ethyl acetate 1s evaporated at reduce pressure to obtain the crude product as a yellow gum.

The product 1s a racemate that may be resolved into 1ts R and S components. Step 2 : Ethyl er thro-3,5-dihydroxy-7-(2 ^, -C "-f^uoropheny^3-5 ^, ,6 ^> _> 7 8 ^, - tetrahydroπaphth-V-y1)heptanoate (process a compound no. 5)

Analogous to Example 1. Step 10 starting from Vlb. Product (compound no. 5) is obtained as a yellow gum.

The product 1s a racemate that may be resolved 1nto two optlcally pure enantiomers, the 3R,5R and 35,5S isomers, of which the former 1s preferred.

Example 5 : Ethyl erythro-(E)-7-(4'-ch1oro-2 ^, -[4"-f1uorophenyl3naphth-l'- 3.5-dihydroxyhept-6-enoate (compound no. 6)

Step 1 : 4-Ch1oro-2-πaphthol (reactlon DA; compound no. cxxix)

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A solution of 406 mg (1 mole) of Compound Via in 20 ml of glacial acetic acid is _. contracted with a large excess of hydrogen at an initial pressure of 50 p.s.i. at room temperature in the presence of 40 mg of platlnum dloxide until 3 mmoles of hydrogen (7.5 p.s.i.) are taken up. The platlnum dloxide is removed by filtratloπ, and the filtrate is evaporated to dryness at reduced pressure. The residue (397 mg) is dissolved in a small amount of methylene Chloride and applied to silica gel preparative thin layer chromatography plates; methylene Chloride Is used as the chromatography solvent. The bands containlng the product are eluted with ethyl acetate. The ethyl acetate is evaporated at reduced pressure to obtain the crude product as a yellow gum.

The product is a racemate that may be resolved into its R and S co ponents.

Step 2 : Ethyl erythro-3 ₁ 5-dihydroxy-7-(2'-C4"-f1uoropheny13-5 ^, .6'. '.8' tetrahydronaphth-l'-ypheptanoate (process a); compound no.5)

Analogous to Example 1, Step 10 startlng from V b. Product (compound 5) is obtained as a yellow gum. The product 1s a racemate that may be resolved into two optically pure enantiomers, the 3R,5R and 3S,5S Isomers, of which the former is preferred.

Exaple 5 : Ethyl erythro-(E)-7-(4'-ch^oro-2 ^, -C4"-f^uoropheny^ naph h-1 ^, yl-3.5-d1hydroxy.)hept"6-enoate (comoound no.6)

Step 1 : 4-Chloro-2-naphthol (Reactlon DA; compound CXXIX)

A mixture of 90 g (0.42 mole) of 1,4-dichloro-2-naphthol, 420 g of stannous chlor1de.dihydrate and 1.5 Hters of gladal acetic acid is refluxed for about 80 hours, gaseous hydrogen Chloride being slowly bubbled In throughout. The reactlon mixture is added to 9 Hters of Ice water, the resultlng mixture is stirred for 1 hour,.and the product 1s collected by filtration, washed with 4 Hters of water, washed with 2 li of petroleum ether, air dried and dried at 40 ^β C under high vacuum for 5 hours, m.p.93°-95 ^β C.

Step 2 : l-Chloro-3-methoxynaphthalene (Reaction OB; compound CXXX)

23.2 g (0.414 mole) of ground potassium hydroxide is added to a mixture of 65.4 (0.366 mole) of 4-chloro-2-naphtho1 and 370 ml of dl ethylformamide stirred at 0 ^Ö -5°C. The reactlon mixture is stirred at 0°-5 ^β C for 3 hours, 58.8 g (0.414 mole) of methyl lodide 1s added over a 5 minute perlod, and the reaction mixture is allowed to warm to 2 to 25°C and is _. stirred at that temperature for 16 hours. 2 Liters of water is added, and the mixture is extracted with diethyl ether. The diet ethyl 1s evaporated at reduced pressure untll the onset of turbidity, an petroleum ether is added to obtain the solid product, m.p. 35°-39°C.

Step 3 : 4-Chloro-2-methoxy-l-naphthaldehyde (Reaction OC; compound CXXXI

50 g (0.326 mole) of phosphorus oxychloride is slowly added to a mixture of 24 g (0.125 mole) of 1-chloro-3-methoxynaphthalene and 30 g (0.411 mole) of di ethylformamdie stirred at 20°-25°C. The reaction mixture is stirred at 80 ^β C for 16 hours, cooled in an ice bath and made basic by the dropwlse addltlon of 10* aqueous sodium hydroxide solution with vlgorous stirrlng. The precipitate is collected by filtration, washed with water, washed with petroleum ether and air dried to obtain the crude product, m.p. 145 ^β -160 ^β C (dec.) (shrinks at 105°-145'C).

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An analytical sample may be obtained by (a) dissolving the crude product 1n ethyl acetate, (b) adding petroleum ether, (c) decantlng the solution from the 1nsolub1e tar, (d) repeating (b) and (c) until no more tar resu and (e) adding addltional petroleum ether to obtain the pure product, m.p. 154 ^β -157 ^β C.

Step 4 : 4-Ch1oro-2-methoxy-1-naphthoic add (Reaction OE, compound XXII

18.6 g (0.175 mole) of sodium carbonate is added to a mixture of 37.2 g (0.169 mole) of crude 4-chloro-2-methoxy-l-naphthaldehyde, 450 ml of acetone and 92 ml of water stirred at 20°-25 ^β C. 27.9 g (0.177 mole) o potassium permanganate is added over a 2.5 hour period with stirrlng at 40 ^β -45°C. The reaction mixture is stirred at room temperature for 16 ho 400 ml of water is added, and the reactlon mixture 1s fUtered through Celite, acidified with 2N. hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract 1s extracted, three tlmes with 10% aqueous sodium carbonate solution, and the combined aqueous extracts are carefully acidified with 2N hydrochloric acid. The obtained product Is washed with water and w«ιshed with petroleum ether, m.p. 199.5 ^β -202°C.

Step 5 to 14

Proceed analogously to Steps 1 to 10 of Example 1 through the intermedlates llsted hereafter.

Step 5 : 4-Chloro-2 ^« methox -l-naphthoyl Chloride (Reaction M; compound XXVIb), oll)

Step 6 : 4-Chloro-2-methoxy-ϊ-naphthoic add N-1,1-dimethyl-2-hydroxy- ethyla ide (Reactlon N compound XXVIIlb), m.p. 142° to 146° Step 7 and 8 : 2-(4 ^, -Ch1oro-2'-m ^β thoxynaphth-l ^, -y1)-4,4-d1methyl-2-oxa2θl1ne and its hydrochloride salt (Reactlons 0 and P; compound XXXb and XXIXb). m.p.91-94° (XXXb)

Step 9 : 2-(4 ^, -Chloro-2 ^, -C4"-f1uoropheny13πaphth-l ^« -yl)-4,4-dimethyl-2- oxazollne (Reaction Q; compound XXXIIb), m.p, 150°-152°

Grlngard reageπt cf. Example 10.7.

Step 10: 2-(4 ^» -ChToro-2 ^, -C4"-fluoropheny13naphth-l ^, -y1)-3,4,4-trimethyl 2-oxazol1n1um iodide (Reactlon R; compound XXXIIIb), m.p. 224°-226° -

Step 11 : 4-Chloro-2-(4'-f1uorophenyl)-l-naphthaldehyde (Reaction S; compound IVc), m.p. 137°-139°

Step 12 : (E)-3-(4'-Chloro-2'-C4"-fluoropheny13naphth-l ^l -yl)prop-2-enal (Reactlon W: compound IVd). m.p. 143-147° Step 13 : Ethyl (E)-7-(4 ^, -ch1oro-2'-C4 ^,, -fluorophenyl3naphth-T-yl)-5- hydroxy-3-oxohept-6-enoate (Reactlon A; compound VIc), m.p. m.p. 87°-89°

Step 14 : Ethyl erthro (E)-7-(4'-chloro-2 ^, -C4"-fluorophenyl3naphth-1 ^, -yl 3,5-dihydroxyhept-6-enoate (process a); compound no. 6), m.p. 121-124°

The principal (erythro) product is a racemate that may be resolved into two optlcally pure enantiomers, the 3R,5S and 3S,5R isomers, of which the former is preferred. The threo lnor product is a racemate that may be resolved into the 3R,5R and 3S,5S isomers, of which the former 1s preferred. The use of a noπ-stereoselect1ve reduction would afford all four stereoisomers in approximately equal a ounts.

The crude reaction mixture of Step 14 also contains threo isomer. Example 6 : Erythro-(E)-7-(4'-chloro-2 ^, -[4 ^,, -fluorophenyl]naphth-l'-yl)-

3,5-dihydroxyhept-δ-eno1c acid and its sodium salt (process compounds 7 and 8)

Analogous to Example 2 starting from compound 6, m.p. 201°-204° (dec.) for salt. Free acid as crude oil contaiπing a small amount of threo compound.

The principal (erythro) product is a racemate which may be resolved into two optlcally pure enantiomers, the 3R,5S and 3S,5R isomers, of whic the former is preferred. The inor (threo) product is also a resolvable racemate, the two enantiomers being the 3R,5R and 3S,5S isomers, of which the former is preferred.

Example 7 : (E)-Trans-6-(2 ^, -C4 ^H -ch1oro-2"-(4 ^,,, -fluorophenyl)naphth-1 ^l, -y1] etheny1-4-hydroxy-3,4,5,6-tetrahydro-2H-pyraπ-2-one (Process e); compound 9)

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Analogous to Example 3 starting from Compound 7, m.p. of product 131°-134°.

Example 8 : (E)-Trans-6S-2'-C2"-(4'"-f1uoropheny1)naphth-l"-y13etheπyl) - 4R-hydroxy-3.4.5,6-tetrahydro-2H-pyran-2-one (compound no. 10 Step 1 : 2-(4'-f1uorophenyl)-1-naphthalenemethanol (Reactlon K , compound Lila)

75 g (1.94 moles) of powdered sodium borohydride Is added to a mixtu of 497 g (1.988 moles) of 2-(4'-f1uoropheny1)-l-napnthaldehyde and 6.6 liters of absolute ethanol stirred at 2Q°-25°. The reactlon mixture is stirred at this temperature for 16 hours, suction filtered through 1 kg. of silica gel (EM-60, 230-240 esh ASTH) and evaporated at reduced pressu to obtain a crystalline residue. The sollds are collected by filtration, washed with 100 ml of cold (0°) methylene Chloride and taken up in 1 Hte of diethyl ether. The insoluble residue is removed by filtration, and the filtrate 1s evaporated to dryness at reduced pressure. The residue is dissolved 1n 500 ml of methylene Chloride, and the solution is cooled to 0° to obtain the product, m.p.91-93°.

Step 2 : l-Ch1oromethyl-2-(4 ^, -fluorophenyl)naphthalene (Reaction LL; compound Ulla) A solution of 45 g (0.378 mole) of thionyl Chloride in 500 ml of methylene Chloride is added over a 20 inute period to a mixture of 237 g (0.94 mole) of 2-(4'-f1uoropheny1)-l-naphthalenemethanol and 3 liters of methylene Chloride stirred at 20°-25° under nitrogen, and the reaction mixture is stirred at this temperature for 16 hours. An addltional 25 g (0.31 mole) of thionyl Chloride is added, the reaction mixture is stirred at 20°-25° for 2 hours and cooled to 0°. 1 liter of 10?« aqueous sodium bicarboπate solution is cautiously added, the organlc layer is separated, and the aqueous phase 1s extracted with 500 ml of methylene Chloride. The two organlc phases are combined, washed with 1 liter of saturated aqueous sodium Chloride solution, dried over anhydrous sodium sulfate, filtered through 1 kg of silica gel (EM-60, 230-400 mesh ASTH) and concentrated at reduced pressure to obtain the crystalline product, m.p.93-95°.

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Step 3 : C(2-C4 ^, -Fluoropheπyl3-l-naphthalenyl)iτιethy13tr1phenylpho sphon1u Chloride (Reactlon NN. compound LIVa)

A mixture of 218 g (0.81 mole) of 1-chloromethyl-2-(4 ^l -fluorophenyl) naphthalene, 214 g (0.81 mole) of triphenylphosphine and 4 liters of toluene 1s refluxed under nitrogen for 16 hours, cooled, concentrated at reduced pressure, to about 3 of its original volume, filtered through 1 kg of silica gel (E -60, 230-400 mesh ASTM) and evaporated to dryness at reduced pressure. 500 ml of anhydrous diethyl ether is added to the crystalline residue, the mixture is cooled to 0°, and the pre pitate is collected by filtration, washed twlce with a total of 500 ml of anhydrous diethyl ether and vacuum dried at 70° for 5 hours to obtain the product as a colourless solid, m.p. >250°.

Step 4 : (E)-4ßR-(l ^, ,T-0imethy^ethy^-diphenylsπyloxy)-6αS-(2 ^, -C2"-(4 ^, "- f1uorophenyl)naphth-l"-yl]ethenyl)-2-methoxy-3,4,5,6-tetrahy dro- 2H-pyran (Reaction 00; compound LVIa)

115.6 ml of 1.65M. π-butyllithium/^-hexane (0.191 mole) is added over a period of 5 inutes to a mixture of 100 g (0.188 mole) of Compound LIVa in 1.5 liters of dry tetrahydrofuran stirred at -15° under nitrogen. The reactlon mixture is stirred at about 0° for 1 hour and cooled to -55°, a solutlon of 71.5 g (0.179 mole) of Compound LVa

a in 600 ml of dry tetrahydrofuran Is added over a period of about 20 minutes, the temperature of the reaction mixture being -55° to -50° durlng the additlon, and the reactlon mixture is allowed to slowly warm to 20°-25° over a 16 hour period, stirring under nitrogen being maintaine

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throughout. The reaction mixture is cooled to 0°, quenched with 1 liter of saturated aqueous amoniu Chloride solution and filtered through Cel The organlc phase is separated, and the aqueous phase 1s extracted twice with 750 ml portlons of diethyl ether. The three organlc phases are combined, washed with 1 liter of saturated aqueous sodium Chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure to obtain an oll. The oil is dissolved in 150 ml of 2:1 (by volume) methylene chloride/n _> -hexane and flash chro atographe on a colu n packed with 1 kg of silica gel (EM-60, 230-400 mesh ASTM) utilizing the same solvent as the eluant. The fractlons containlng the product (as determlned by thin layer chromatography) are combined and evaporate to dryness at reduced pressure to obtain the product as a gu my solid, _α3 _n ²⁵ * +24.51° (CH ₂ C1-, c * 0.01).

Step 5 : (E)- |3 -(l^^ ^, -Dimethy^ethy^-dipheny^si^y^oxy)-6αS-(2 ^, -C2 ^, '-( ^,,, f1uoropheny1}naphth-l ^,, -y13etheny1)-2-hydroxy-3,4,5,6-tetra- hydro-2H-pyran (Reaction ?Pι compound LVHa)

A mixture of 121 g (0.196 mole) of Compound LVIa and 2 liters of 3:2:4 (by volume) acetic acid/water/tetrahydrofuran is heated to 65 ^β with stirring, stirred at 65° for 16 hours and cooled to 20°-25°, and 1.5 liter of methylene Chloride is added. With stirring and cooling, t mixture is carefully washed with saturated aqueous sodium carbonate solution unt11 sllghtly basic. The organic phase 1s separated, and the aqueous phase is extracted with 1 liter of methylene Chloride. The organic phases are combined, washed with saturated aqueous sodium Chlori solution, dried over anhydrous sodium sulfate and evaporated at reduced pressure to obtain a light brown oil. The oil is dissolved in 1:1 (by volume) diethyl ether/petroleum ether and flash chromatographed on a column packed with 1 kg of silica gel (EM-60, 230-400 mesh ASTM) utiliz the same solvent as the eluant. The fractions containlng the product an little or nothing eise (as determlned by thin layer chromatography) are combined and evaporated at reduced pressure to obtain the product as a gummy solid, Cα3J; ^δ * +5.00° (CHgCl,,, c - 0.01).

Step 6 : (E)-4 R-(1\1 ^, -Diπ«thy1ethyl-dpheny1s1ly1oxy)-eιS-(2 ^, -C2"-

(4 ^,,, -f1uoropheny1)naphth-l ^,, -yl3ethenyl)-3,4,5,6-tetrahydro-2H pyran-2-one (Reaction QQ; compound LVIHa)

A mixture of 89 g (0.147 mole) of Compound LVIIa, 2liters of methylene Chloride, 64 g (0.317 mole) of pyridinium chlorochromate and 60 g of #3A molecular sleves is stirred at 20°-25 under nitrogen for 16 hours and filtered through Celite and about 100 . of neutral aluminl oxide. The Celite and aluminlum oxide are washed several tlmes with methylene Chloride and the filtrate and washings are combined and evaporated at reduced pressure to obtain an oil. The o11 1s dissolved in 100 ml of methylene Chloride and flash chromatographed on a column packed with 800 g of silica gel (EM-60, 230-400 mesh ASTM) utilizing methylene Chloride as the eluant. The fractions containlng the product and little or nothing eise (as determlned by thin layer chromatography) are combined and evaporated at reduced pressure to obtain the product a an oil, Cαg ^S - +12.32° (CH3OH, c * 0.0215).

Step 7 : (E)-Trans-6S-(2 ^, -C2 ^,, -(4"-fluorophenyl)naphth-1"-yl3etheny1)- 4R-hydroxy-3,4,5,5-tetrahydropyran-2H-one (process c); compound no. 10) 26.3 ml (0.46 mole) of gladal acetic acid is added with stirring to a mixture of 63 g (0.105 mole) of Compound LVIIIa in 2.3 Hters of dry tetrahydrofuran stirred at 20°-25°. 425 ml of IM. tetra-in-butyl- anmonium fluoride/tetrahydrofuran (0.425 mole) is added, and the reacti mixture 1s stirred at 20°-25° for 2 hours. 157 g of solid sodium bicarb nate is added, and the reaction mixture 1s stirred for 30 minutes and filtered through 800 g of silica gel (EM-60, 230-400 mesh ASTM). The silica gel is washed twlce with 500 ml portlons of diethyl ether, and th washings are combined with the filtrate. The combined filtrate and washings are evaporated to dryness at reduced pressure, 200 ml of diethyl ether is added, and the mixture is cooled to 0 ^β . The waxy crystals are collected by filtration, washed twice with 100 ml portlons

of diethyl ether and dissolved in 300 ml of ethyl acetate. The ethyl acetate solution is washed twice-with 500 ml portions of saturated aqueou sodium bicarbonate solution and once with saturated aqueous sodium Chloride solution, dried over anhydrous sodium sulfate and evaporated at reduced pressure to about ^3 of its original volume. 100 ml of diethyl ether is added, the mixture is cooled to 0°, and the obtained solids are collected by filtration and washed twice with diethyl ether to obtain the product, m.p. 184°-186°, ^~ tαljj ⁶ - +44.31° (CH ₂ C1 ₂ , c - 0.0053).

Example 9 : Sodium erythro-(ε)-3 ,5S-dihydroxy-7-(2 ^t -C4 ^,, -fluorophenyl]- πaphth-1'-yl)hept-6-enoate (process d); compound no. 11)

5.06 ml of IN. aqueous sodium hydroxide solution (5.06 moles) is added to a solutlon of 2.0 g (5.52 mmoles) of Compound 101n ISO ml of absolute ethanol, and the reactlon mixture is stirred at 20°-25° for 2 hours. 50 g of sodium sulfate is added, and the mixture is stirred for 1 hour and filtered. The salt is washed three times with 100 ml portions of diethyl ether, and the washings are combined with the ethano filtrate. The combined washings and filtrate are evaporated to dryness a reduced pressure, and the crystalline residue is dissolved 1n Chloroform The Chloroform 1s evaporated at reduced pressure, 300 ml of petroleum is evaporated at reduced pressure, 300 ml of petroleum ether is added to the residue, and the mixture is stirred for about 60 hours. The solid product is collected by filtration and washed twice with petroleum ether m.p. 215°-220 ^β (dec.) C<-3Q ⁸ = +26.283° (CH-OH, c * 0.0047).

Example 10 : Ethyl er_thro-(E)-3,5-dihydroxy-7-(l ^, -C4 ^,, -fluorophenyπ-3 ^l - ,l"-methylethyl3naphth-2 ^> -.yl)hept-6-enoate (Compound no. 13

Step 1 : 1,3-Dimethoxynaphthalene (Reaction BA; compound XVla)

A solution of 32.1 g (0.801 mole) of sodium hydroxide in 80.3 ml of water and 96 g (0.763 mole) of dimethyl sulfate are slmultaneously added over a period of 30-45 minutes to 50 g (0.312 mole) of 1,3-dihydro naphthalene in 250 ml of absolute ethanol stirred at -5° - 0°C, the form

belπg added slightly faster than the latter. The reactlon mixture is allowed to gradually warm to 20° - 25°C with stirring over a 16 hour period. Most of the ethanol 1s evaporated at reduced pressure, water is added, and the mixture Is extracted three tlmes with methyl t-butyl ether. The extracts are combined, washed with 2N. aqueous sodium carbonate solution, dried over anhydrous sodium sulfate and evaporated dryness at reduced pressure to obtain an oil. The oil 1s chromatographed σn a Waters Prep-500 high pressure liquid chromatography apparatus havin a silica gel column and utilizing 5J. ethyl acetate/n-hexane as the eluan The fractlons containlng the product are combined and evaporated at reduced pressure to obtain the product as a yellow oil.

Step 2 : l,3-01methoxy-2-naphtho1c add (Reaction BC. compound CXVIIa)

62 ml of 1.55M. -butyllithium/n-hexane (96 mmoles) is slowly added to 15.04 g (80 mmoles) of l,3-d1methoxynaphthalene in 250 ml of anhydrous diethyl ether stirred at 0°C under nitrogen. The-reaction mixture is allowed to warm to 20°-25°C and 1s stirred at this temperatur for 20 hours, the reaction mixture being stirred under nitrogen througho Excess anhydrous carbon dloxide is bubbled in for 30 minutes. The reacti mixture is stirred at 20 ² 25°C for 4 hours, queπched with water and. extracted thoroughly with ethyl acetate. The al aHπe aqueous phase is acidified with 2N. hydrochloric acid (to a pH of 1-2) and extracted with ethyl acetate. This ethyl acetate extract is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is dried under high vacuu to obtain the product, m.p. 119°-123°C. Step 3 : 1.3-Dirnethoxy-2-πaphthoyl Chloride (Reaction BP; compound CXVIII

Analogous to Example 1, Step 1..

Step 4 : l,3-D1methoxy-2-naphtho1c acid N-l,l-dimethyl-2-hydroxyethylami (Reaction BE; compound CXIXa)

Analogous to Example 1, Step 2. Steps 5 and 6 : 2-(l ^, ,3 ^, -dimethoxynaphth-2 ^, -yl)-4,4-d1methyl-2-oxazol1ne and 1ts hydrochloride salt (Reactlons BF and BG; . compound CXXIa * HC1 salt

Analogous to Example 1, Steps 3 and 4. Step 7 : 4,4-0imethyl-2-(T-C4 ^M -fluorophenyl3-3'-mδthoxynaphth-2 ^, -yl)-2- oxazotine (Reaction BH; compound CXXIIa)

A Grignard reagent is prepared by the drop ise addltion of 7.7 g (0.044 mole) of £-bromofluorobenzene to a mixture of 1.1 g (0.045 mole) of magneslum tu niπgs, one crystal of iodlne and 40 ml of dry tetra¬ hydrofuran stirred at 65°C under nitrogen, the addition being at a rate sufficient to aintain reflux without external heating. Upoπ completion of the addition (30-45 minutes), the reaction mixture is refluxed under πitrogen for 1.5 hours and cooled to obtain a solution of the Grignard reagent.

18 ml of a IM. solution of the Grignard reagent is slowly added to 4.25 g (14.9 mmoles) of Compound CXXIa in 80 ml of dry tetrahydro¬ furan (distllled from sodium) stirred at 20°-25°C under nitrogen, and the reaction mixture is stirred at 20°-25°C under nitrogen for 16 hours and quenched with ice and saturated aqueous a monium Chloride solutlon. The mixture Is extracted with ethyl acetate, and the ethyl acetate extract is dried over anhydrous sodium sulfate and evaporated to a small volume at reduced pressure to obtain the product. The product is collected by filtration, washed with a small a ount of diethyl ether, washed with a-small amount of petroleum ether and dried under high vacuum, m.p. 169°-171°C.

Step 8 : 4,4-0imethyl-2-(l ^, -[4 ^,, -fluorophenyl]-3 ^, -Cl"-methylethyl]naphth- 2 ^, -yl)-2-oxazoline (Reaction BI; compound CXXIVa) 13.25 ml of 2H. isopropylmagnesium chloride/diethyl ether (25.5 mwle is slowly added to 1.54 g (4.41 mmoles) of Compound CXXIIa in 90 ml of dr tetrahydrofuran (distilled from sodium) and 22 ml of dry toluene (dried over molecular sieves) stirred at 20°-25°C, the reaction mixture is stirred at 20°-25°C for 30 minutes and at 70°-80°C for 18 hours an additional 13.25 ml of 2M. isopropylmagnesium chloride/diethyl ether (26.5 mmoles) 1s added, and the reactlon mixture is stirred at 70°-80°C for an additional 20 hours, the reaction mixture being maintained under nitrogen throughout. The reaction mixture is quenched with 1ce and

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saturated aqueous arrmonium Chloride solutlon and extracted with ethyl acetate. The ethyl acetate extract 1s dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure. The residue 1s dissolved in methylene Chloride, and the solution is dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure. The obtained gum 1s dissolved 1n about 10 ml of methylene Chloride, a small amount of charcoal is added, and the solution is filtered through silica gel column utilizing methylene Chloride as the eluant. The fracti containlng the product as determined by thin layer chromatography are combined and evaporated to dryness at reduced pressure to obtain the product as an a ber-green gum.

Step 9 : 2-(l ^, -C4 ^,, -Fluorophenyl]-3- ^, -Cl"-methylethyl]naphth-2 ^, -y1)-

3 _t 4.4-trimethyl-2-oxazo1inium iodide (Reactlon R; c pd. XXXIIIc

Analogous to Example 1, Step 6: m.p. 233°-243 ^β C (dec). Step 10 : l-(4-Fluorophenyl)-3-(l ^, -methylethyl)-2-naphthaldehyde (Reactlon S; compound IVe) ^{■ '}

205 mg (9.37 mmoles) of Hthium borohydride is added to 2.35 g (4.67 mmoles) of Compound XXXIIIc stirred in 105 ml of dry tetrahydrofur (distllled from sodium) and 42 ml of absolute ethanol (dried over molecular sieves) at -30°C under nitrogen. The reaction mixture is stirr at -40° to -30°C under nitrogen for 2 hours and allowed to warm to 0° to 5°C, and 62 ml of 2N. hydrochloric acid is slowly added. The reaction mixture is stirred at 70°-80°C for 2 hours, cooled to 20°-25°C, quenched with water and thoroughly extracted with diethyl ether. The diethyl ethe extract is washed with saturated aqueous sodium Chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure. The residue is triturated with diethyl ether and then petroleu ether. The insolüble solids are removed by filtration, and the filtrate is evaporated to dryness at reduced pressure to obtain the crud product as a light orange-yellow stic y solid, m.p.80°-90°C.

Steo 11 _. : (E)-3-(1'-C4 ^,, -Fluorophenyl]-3 ^, -(l"-methylethyl)naphth-2 ^, -yl)- pfop-2-ertaT(Reaction ; compound IVF)

Analotgous to Example 1* Step 8; m.p, 102°-105 ^β C.

Step 12 : Ethyl (E)-7-(T-C4"-fluoropheπyl]-3'-CT ^, -methylethyl]naphth- T-yl)-5-hvdroxy-3-oxohept-6-enoate (Reaction A; c pd. V d)

Analogous to Example 1, Step 9: m.p.73-76°C.

Step 13 : Ethyl erythro-(ε)-3,5-dihydroxy-7-(T-C4"-fluoropheπyn-3'-Cl"- methylethyπnaphth-Σ'-yphept-e-eπoate (Process a); cmpd. no. 13

Analogous to Example 1, Step 10: yellow gummy foa . The principal (erythro) product is a racemate that may be resolved into two optica ly pure enantiomers, the 3R,5S and 3S.5R Isomers, of which the former is preferred. The threo miπor product (about 8%) is a racemate that may be resolved into the 3R,5R and 3S,5S isomers, of which the former is preferred. The use of a non-stereoselective reduction would afford all four stereoisomers in approximately equal a ounts.

Example 11 : Erythro-(E)-3,S-dihydroxy-7-(l 4^1uorophenyl,-3 ^, -π"- methylethyl3naphth-2'-yl)hept-6-enoic acid and its sodium salt (Process d. c pds. πos. 14 (acid) and 15 (salt)

Analogous to Example 2 (without Isolation of inter ediate sodium salt The principal (erythro) product is a racemate which may be resolved into two optlcally pure enantiomers, the 3R,5S and 3S.5R isomers, of which the former is preferred. The minor (threo) product is also a resolvable racemate, the two enantiomers being the 3R.5R and 3S,5S isomers, of which the former Is preferred. Example 12 : (E)-Trans-6-(2 ^t -C4" ^, -f1uorophenvl)-3 ^,, -(l ^, "-methylethyl)- naphth-2"-yl]ethenyl)-4-hydroxy-3,4,5,6-tetrahydro-2H-py 2-one (Process e); compound no. 15)

Analogous to Example 3.

The crude product is purified by preparative thin layer chro atσ- graphy on silica gel plates utilizing 2% methanol/methylene Chloride as

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the solvent and ethyl acetate to elute the product from the plates. Evaporatlon of the ethyl acetate at reduced pressure ylelds the product as a pale yellow foam.

Separation of isomers cf. Example 3. Example 13 : Sodium erythro-(E)-3 _> 5-dihydroxy-7-(T-C4"-fluorophenyl3-3'- Cl"-methylethyl]naphth-2'-y1)hept-6-eπoate (Process d); compound no. 15)

0.19 ml of IN. aqueous sodium hydroxide solution is added to 80 mg (0.2 mmole) of Compound no. 16 in 5 ml of absolute ethanol. The reaction mixture is stirred at 20°-25°C for 1 hour and evaporated to dryness at reduced pressure. The residue is dissolved in Chloroform, the obtained solution is dried over anhydrous sodium sulfate and evaporated to dryness and the residue is dried under high vacuum to obtain the product as a pale yellow foam. The principal product is the erythro racemate which may be resolved to obtain the 3R,5S and 3S,5R enantiomers, of which the former 1s preferred. A e y small amount of the threo racemate is present; it may b resolved to obtain the 3R,5R and 3S,5S enantiomers, of which the former 1s preferred. Example 14 : Ethyl erythro-(E)-3,5-dihydroxy-7-{1 ^• -C4"-fluorophenyπ-3'- methylnaphth-2'-yl)hept-6-enoate (Compound no. 17)

Step 1/2 : 1-Methoχy-2-naphthoic acid (Compound no. XXHIb) l-Hydroxy-2-naphtho1c acid is dlmethylated substantially as describe 1n Example 5, Step 2 and the resultlng Ethyl-l-methoxy-2-naphthoate hydrolysed substantially accordlng to Example 2: m.p. of product 126°-128

Steps 3 to 7 : 4,4-D1methyl-2-(l ^l -_4 ^,, -f1uorophenyl_πaphth-2 ^, -yl)-2- oxazollne (Reactions - Q; compound XXXIIc)

Analogous to to Example 1, Steps 1 to 5: m.p. Step 4 product » 95°-97° m.p. Step 6 product » 75°-78° m.p. Step 7 product (XXXIIc) • 9δ°-98°

Step 8 : 4,4-Dimethyl-2-(l ^, -C4 ^,, -fluorophenyl]-3'-methylnaphth-2 ^, -yl)-2- oxazollne (Reactlon CA; compound XXXIId)

16.16 ml of 1.7M. -buty>lith1um/n _t -hexane (27.5 mmoles) is added dropwise to 7.9 g (24.8 mmoles) of Compound XXXIIc in 185 ml of anhydrous diethyl ether stirred at 0°C under πitrogen. The reaction mixture 1s stirred at 0°C for 30 minutes, 3.9. g (27.5 mmoles) of methyl iodlde is added and the reaction mixture is allowed to warm to 20°-25°C and stirred at' this temperature for 20 hours, the reaction mixture being maintained under nitrogen throughout. Saturated aqueous so ^' dluπrchloride solution and additional diethyl ether are added. The diethyl ether phase is separated, dried over anhydrous sodium sulfate and evaporated at reduced pressure until the onset of turbidity, and petroleum ether 1s added. The precipitate is washed with petroleum ether and dried under high vacuum, m.p. 125°-129°C. Steps 9 to 13 : Ethyl erythro-(E)-3,5-dihydroxy-7-(T-[4"-fluorophenyl]-3 methy1naphth-2'-y1)hept-6-enoate (Compound no. 17)

Analogous to Example 1, Step 6; Example 10, Step 10; Example 1, Steps 8 to 10. m.p. product of Step 10 first reaction isolated, 115°-118° m.p. product of Step 10 second reaction, 104-107° m.p. product of Step 11. 143°-147° m.p. product of Step 12, 89°-92° m.p. product of Step 13 (compound no. 17), 121°-124°.

The product, the erythro racemate, may be resolved 1nto two optlcally pure enantiomers, the 3R,5S and 3S,5R isomers, of which the former is preferred. It contains a small amount (less than about 5%) of the corresponding threo compound, a racemate that may be resolved into the 3R,5R and 3S,5S Isomers, of which the former is preferred. The use of a noπ-stereoselective reduction would afford all four stereoisomers in approximately equal aounts.

Example 15 : Sodium erythro-(E)-3,5-dih droxy-7-(^ ^, -[4 ^,, -f^uo opheny^]-3 ^, methvInaphth-Σ'-yDhept-e-enoöte (Process d). compound no.

Analogous to Example 2 with Isolation of sodium salt; m.p.222°-225° (dec). The erythro componeπt of the product, the erythro racemate, may be resolved 1nto two optically pure enantiomers, the 3R.5S and 3S,5R Isomer of which the former is preferred. The product contains a small amount (less than about 55.) of the corresponding threo, compound also a resolva racemate, the two enantiomers being the 3R,5R and 3S,5S isomers, of whic the former is preferred.

Example 16 : Ethyl erythro-(E)-3,5-d1hydroxy-7-(3'-ethyl-1'-.4"-fluoro- phenyl,naphth-2'-yl)hept-6-enoate (Compound no. 19)

Step 1 : 2-(3 ^, -Ethyl-l ^, -C4"-fluorophenyl]πaphth-2 ^, -yl)-4,4-d1methyl-2- oxazoline (Reactlon CB; compound XXX Ie) Analogous to Example 14, Step 8 starting from XXXIId; m,p. product 106°-109°.

Step 2 to 6 : Ethyl erythro-(E)-3,5-dihydroxy-7-(3 ^, -ethyl-1'-C4' ^> -fluoro- phenyl]naphth-2'-yl)hept-6-enoate (Compound no. 19)

Analogous to Example 1, Step 6; Example 10, Step 10; Example 1, Steps 8 to 10. m.p. product of Step 2 ^» 200° (dec.) m.p. product of Step 5 ■ 92°-98° m.p. product of Step 6 - (compound no. 19) * 101°-10δ°.

The principal co ponent of the product, the erythro racemate, may be resolved into two optlcally pure enantiomers, the 3R,5S and 3S,5R isomers, of which the former is preferred. The use of a noπ-stereo- selective reduction would afford all four stereoisomers in approximately equal a ounts.

Example 17 : εrythro-(ε)-3,5-dihydroxy-7-(3 ^l -ethyl-1'-[4"-f1uorophenyl]- naphth-Σ'-ylJhept-δ-enoic add and its sodium salt

(Process d); compound nos. 20 and 21)

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Analogous to Example 2 (without Isolation of inter edlate sodium salt); Separation of isomers as Example 16.

Example 18 ; (E)-Trans-5-(2 ^, -C3"-ethy1-T'-(4 ^l,, -fluoropheny1)naphth-2"-y1) ethenyl)-4-hydroxy-3,4,5,δ-tetrahydropyran-2-one (process e) compound no.22)

Analogous to Examples 3 and 12; m.p. 118°-122°; Separation of isomers cf. Example 3 (about 9% of eis racemate).

Example 19 : Sodium erythro-(ε)-3,5-d1hydroxy-7-(3 ^l - ^' ethyT-r-[4 ^l> -f1uoro- pheny1,naphth-2'-y1)hept-6-eπoate (process d) compound no. 2 Analogous to Example 13 starting from compound no.22.

The principal component of the product is the erythro racemate which may be resolved to obtain the 3R,55 and 3S,5R enantiomers, of which the former is preferred. The product contains a small amount of the correspondlng threo racemate, which may be resolved to obtain the 3R,5R and 3S,5S enantiomers, of which the former 1s preferred.

TABLE I The following coapoυnds of Groups IAa1-IAa3 nay be synthesized by the processes set forth above: ft-slt-tan -te tion

H H ihU 4-F B (E)CH=CH B c _Λ B 114-116«

2 H B 4-F H H CgHg 4 enantlcβers gw

töiϊϊtlön Fosl ion d. R _{j 2} R ₃ R^ _j . , of RfH-ta-dr- of -X-X ing Ptentyl -X- -co-p H. a-aOMMC M.p.

'5 Gtx>uρ

4-Cl B B 4-F B (E)CH-CH i _H II B 011

4-Cl H H 4-F B 1 B Na B 201-204°(dec

1 H B B 4-F B 1 B Na ^β (3ft,5S) 215-220°(dec.

3- •C ₃ H ₇ B B 4-F B 2 B C ₂ H ₅ E gumniy f oaa

3-iC ₃ H _y B B 4-F B B 11 E

M M M M

w

94 I

iji,

Stall

Boc-iti n Pαsition pd. R. R- _* Um. R. R-, of R4-ba__r-- -X- of -X-X . * * * * _ß ⁵ ing Fht-πyl Group »7 Iaff-Wpr m.ρ. ^κ 5a Gkoup

21 3-C ₂ H ₅ B H 4-F B (E)CH'CH B NA E 230° (dec.

23 H H ■ "■ 4-F B -CH ₂ CH ₂ - B C ₂ H ₅ E Gua

24 H B B 4-F B B _Na B 180-190*

5 H B B 4-F B H H E Solid foaa

u H W w

*9 m se B

<N u a

... 3* rc CM «N

«M

0

«-) f

J II

X ι Ü υ S

«N

B U I

IN IN

roε kn ft∞itit-n

Cnpd. » _l H _j . R ₃ B ₄ RJJ ,

33 3-CB, B B 4-F B -CB ₂ CB ₂ - 2 B Na B

34 3-CH-. B B 4-F B -CB ₂ CB ₂ - 2 B B E

35 1-CB ₃ B B 4-F B (E)CI CH 2 B C ₂ U ₅ B

36 1-CM. B H 4-F B B K

37 1-CB ₃ B B 4-F B B B

38 ι-ca ₃ B B 4-F B -CH ₂ CH ₂ - B CB-. E

β ■i

B

Cd M H H U

tΛ »IM o

. I ^ä » x ft I tN <N

I tN «N

B

* CJ II

IN «N s I 8

Kl «N «N ^• tN

44 B 6-OC _j -H _j - 7-CB3 -CF3 B -CB _* >- 1 ^' CB3 CR3 B

45 B 6-OC.Λ _j . 7-CB3 -α? ₃ B -CB.,- CB3 Ha E

1

46 B -tJ

^Λ « * ^« 3 ^B -CB ₂ - CII, B

47 B B B 4-F B (E)CH=C1, B B

^C 2 ^B 5 Oil

48 B B B 4-F B B Na >220»C.« (dec.

49 B B H 4-F B -CB ₂ CB ₂ - 2 N C ₂ I. ₅ E Oil

TABLE I!

The following coapounds of Groups IΛb1-Iλb3 nay be synthesized by the processes set forth above.

152-154°

H B B 4-F B (E)CH*CH B ans (no detectabl eis 153-156

4-Cl B B 4-F B B trans 131-134°

0 II B B 4-F B B -rjQS 184-186° (6S.4R)

6 3-.C3.l7 B fl 4-F B B trans foaa

2 B B 4-F B B fXäns 110-122 ^«

tM «_> CM U CM t II II

X

* M u CM I "CM C

U U- «J

I I I

FttBition Posi xαn of I -iι--ar- of -X-Z

Cnpd. R, », ^R 3 ^{R R} ₅ . ing Rienyl -X- Group R- IsoatBX H.p.

MO. R _5a G_oqp

61 B ^β ^Λ ⁷ - ^ca 3 - _P ₃ B 2 -CH ₂ - 1 B trans

2 B B H 4-F H (E)CH ^« CH 1 H eis 143°-146°C.

mixtures ^• »«53t ci£ 3 B B B 4-F H II *-47t trans 134°-137fC.

4 B B H 4-F H -CH ₂ CH ₂ - 2 II trans Oil

5 B B π 4-F H (E)CH*CH H trans Solid foam

Table III

The following c∞apounds of Groups IBal-IBa3 may be synthesized by the processes set forth above _t

66 B 4-F B 2 -CB ₂ CB ₂ - 1 B K E

67 B 4-F B 2 -CBJCBJ- 1 B B E

68 B 4-F B 2 (E)CH=CH 1 B C ₂ B ₅ E Gum

69 B 4-F B 2 m 1 B Na B 220 ^# -2.7 ^r C. (dec .

70 B 4-F B 2 M 1 B B B

71 4-Cl 4-F B C ₂ B _S E

t-ι

«

u B U a M a

B*

^' ¥ IS

u

H

* l

a

IA "tN

* II

a a a H

»1

2 B 3-CB- 4-OCH, 2 -CB ₂ - 1 CB3 CH ₃ B

3 B 3-CB ₃ 4-OCB3 2 -CB _j - 1 CH3 Na B

4 B 3-CB3 4-OCB ₃ 2 -CB ₂ - 1 B E

^CH 3

5 B 4-F B 3 (E)CH ^» CH 2 B C _{2 5} E Gut*

6 4-F B H B Solid foam

7 B 4-F B B Na 215»-230 ^β C. (dec.)

Table IV

The following conpounds of Groups lBbl-IBb3 aay be synthesized by the processes set forth above:

-V-tsition Pot-ition of R _j -bt= _* _r- of -X-Z

Cwpd. ing nieπyl

"c ι -X- Group Group Isomer

". a.p. o. «Sa 8 B 4-F fl 2 -CB ₂ CB ₂ - 1 B trans 18β*-l91*C.

9 B 4-F B 2 1 II trans

2 3-CH _j 4-F B 1 2 B trans

3 3-CB3 4-F B 1 -CH ₂ CB ₂ - 2 B trans

B _* , 4 1-CB, 4-F II C-C^ _j . B trans

05 I-CB3 4-F B 3 -CB ₂ CB,- 2 B trans

06 B B B 2 (E)CH=CH 1 B trans

07 B 3 -CB3 4-OCB ₃ 2 -CH ₂ - 1 CB3 trans

08 B 4-F B 2 (E)CH=CH 1 B eis

09 B 4-F B 3 II 2 B trans Solid foaa

10 fl 4-F B B •trans 168 -172*C.

In Tables I and III,

^B " orythro racemate (two stereoisomers unless otherwise stated)

The principal component of each of Compounds 23-25, 32-34, 38-40, 44-46, 49, 50, 66, 67, 80-82, 86-88, 92-94 Is the erythro racemate which may be resolved, the two enantiomers being the 3R,5R and 3S,5S somers. The minor component {usually about 1-15Ü.) of each example s the correspondlng threo racemate which may be separated therefrom and resolved to obtain the 3R,5S and 3S,5R somers. If, however, a πon- stereoselectlve process were utnized 1n process a) to reduce the 3-oxo group to the 3-hydroxy group, a resolvable mixture containlng approximately equal amounts of the four stereoisomers would be obtained. Preferred are the 3R,5R and 3R,5S Isomers and the racemate of which each is a constituent, viz., the 3R,5R-3S,5S and 3R,5S-3S,5R racemates, with the 3K,5R Isomer and the 3R,5R-3S,5S racemate being more preferred.

The principal component of each of Compounds 26-31, 35-37, 41-43, 47, 48, 51-53, 68-79, 83-85, 89-91, 95-97 is li ewlse ther erythro racemate which may be resolved into two optlcally pure enantiomers, viz., the 3R,5S and.3S,5R isomers. The minor component (usually about 1-15J.) of each example is the correspondlng threo racemate which may be separated therefrom and resolved to obtain the 3R,5R and 3S,5S isomers. If, however, a πon-stereoselective process were utnized in process a) to reduce the 3-oxo group to the 3-hydroxy group, a resolvable mixture containlng approximately equal amounts of the four stereoisomers would be obtained. Preferred are the 3R,5R and 3R.5S isomers and the racemate of which each is a constituent, viz., the 3R,5R-3S,5S and 3R.5S-3S.5R racemates, with the 3R,5S isomer and the 3R,5S-3S,5R racemate being more preferred.

The principal component of each of Compounds 54, 57, 59, 61, 64, 98, 103, 105 and 107 is the trans racemate which may be resolved into two optlcally pure enantiomers, viz., the 4R.6R and 4S,6S isomers. The minor component {usually about 1-15K) of each example is the correspondlng eis. racemate which may be separated therefrom and resolved to obtain the 4R,6S and 4S.6R Isomers. The use in process e) of a mixture containlng approximately equal amounts of the four Stereoisomer1c carboxyl1c aclds

would yield a mixture containlng approximately equal amounts of the four stereoisomer1c lactones. Preferred are the 4R,6R and 4R.6S isomers and the racemate of which each is a constituent, with the 4R.6R isomer and the 4R,6R-4S,6S racemate being more preferred. The principal component of each of Compounds 55, 56, 58, 60, 65, 99-102, 104, 106, 109, 110 is the trans racemate which may be resolved 1 two optlcally pure enantiomers, viz.-, the 4R,6S and 4S,6R isomers. The minor component (usually about 1-15%) of each example 1s the correspondl eis racemate which may be separated therefrom and resolved to obtain the 4R,6R and 4S.6S Isomers. The use in process e) of a mixture containlng approximately equal amounts of the four stereolsomeric carboxyl1c aclds would yield a mixture containing approximately equal amounts of the four stereolsomeric lactones as in Compound 63. Preferred are the 4R,6R and 4R.6S isomers and the racemate of which each is a constituent, with the 4R,6S isomer and the 4R,6S-4S,6R racemate being more preferred.

The principal component of each of Compounds 62 and 108 is the eis racemate which may be resolved into two optlcally pure enantiomers, viz. the 4R,6R and 4S,6S isomers. The minor component (usually about 1-15 ) of each example is the correspondlng trans racemate which may be separat therefrom and resolved to obtain the 4R.6S and 4S,5R isomers. The preferred isomers are ad indlcated in the preceding paragraph.

Each of the compounds of the exa ples wherein -, is a catlon may be converted into the correspoπding free acid and into the correspondlng compounds wherein R, is a different by conventlonal means. Throughout the examples, the term "reduced pressure" denotes aspirator pressure, and where no solvent 1s spedfied in connection with a solution, the solvent is water. All solvent mixtures are by volume.

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The following data were obtained for the preceding compounds. Unless otherwise stated the data are NMR spectra raeasured at 200 mHz. Shifts are in ppm. relative to tetramethylsllane.

Abbreylatioπs: s * slnglet d ^» doublet dd = doublet of a doublet t » trlplet q = quartet . m * multiplet br * broad b ^» broad multiplet bs * broad singlet

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-87-

Cmpd. No. 2 C0C1 ₃ : (90mHz); 1.59(m,2H); 2.53(d,2H,J*2.5Hz); 4.24(m,lH); 4.52(m,lH); 5.62(m,lH); 6.83(m,lH); 7.23(m,7H); 7.79(m,2H); 8.13(m,lH).

CDC1 ₃ « 1.23(t,3H,J*1.5Hz); 1.42(m,6H); 1.8(m,2H); 2.4(m,2H); 2.8(m,4H)j 3.12(m,2H); 3.78(m,2H)j 4.16{q,2H,v I.5Hz); 7.15(m,4H)j 7.52(m,lH); 7.82(m,lH).

12 C0CΪ ₃ : 1.28(t,3H,J=1.5Hz)i 1.6(m,2H); 2.43(m,2H); 2.95(br,2H); 4.2(q,2H,J-1.5Hz); 4.2(br,lH); 4.51(br,lH); 5.65(m,lH); 6.9{dd,lH, _* 3 and 3 Hz); 7.07 (t,2H,t>1.5Hz); 7.41(m,5H) 7.82 (m,2H); 8.17(m.lH).

13 C0C1 ₃ : 1.31(m,llH); 2.41(m,2H); 2.88(s,lH); 3.32(m,lH); 3.61(s,lH); 4.09(m,lH); 4.19(q,2H,t lHz); 4.33 (m,!H); 5.28(m,lH); 6.54(d,lH,J*2Hz); 7.23(m,7H); 7.77(m,2H). 4 CDC1-*: 1.3 (m,8H); 2.49{d,2H); 3.3{m,lH); 3.57(bm,lH); 4.12(bm,2H); 4.36(m,lH); 5.3(dd,lH,J*1.5Hz); 6.56(d,lH,_-3Hz); 7.25(m,8H); 7.78(m,2H). 5 0 ₂ 0: 0.9(m,7H) 1.27(m,lH); 2.03(m,2H); 3.0(m,lH); 3.43(m,lH); 3.97(m,lH); 4.9(m,lH); 6.29(d,lH,J=2Hz); 6.72(m,7H); 7.2δ(m,2H 6 C0C1 ₃ : 1.3(m,6H); 1.45(bm,2H); 1.82(bs,lH); 2.61(m,2H); 3.3{m,lH); 4.12(m,lH); 5.1(m,lH); 5.31{dd.lH,J»lHz); 6.64(d,lH,J»2.5Hz); 7.25(m,7H); 7.78(m,2H). 8 CD ₃ S0C0 ₃ : l.l(m,2H); 1.85(m,2H); 2.5(s,3H)j 3.5(m,lH); 4.1{m,lH); 5.4(q,lH,J*1.25Hz); 6.3(d,lH,v 3.5Hz); 7.3(m,7H); 7.83(m,2H). 1 CDC1 ₃ + CD ₃ 0D: 1.25(πv,2H); 1.35(t,3H,,*1.5Hz); 2,25(m,2H); 2.89(q,2H, 1.5Hz); 3.88(m,lH); 4.27(m,lH); 5.39(q,lH,J=»1.5Hz) 6.52(d,lH,t,-3Hz); 7.25(m,5H); 7.72(m,4H).

Cmpd. No, 23 C0C1 ₃ : 1.29(t,3H,« 1.5Hz); 1.80(m,4H); 2.43{m,2H); 3.13(m,2H); 3.92(m,2H); 4.20(q,2,« 1.5Hz); 7.25(m,5H); 7.56(t,2H,t]-1.5Hz); 7.75{d,lH,ι>1.5Hz); 7.90{d,lH,tM.5Hz); 8.17(m,lH).

25 CDC1 ₃ : 1.45{m,2H); 1.80(m,2H); 2.45(m,2H); 3.10(m,2H)j 3.95(bm,2H)j 7.5(bm,lQH). _.

47 CDC1 ₃ : 1.26(t,3H,.»1.5Hz); 1.75(m,2H); 3.13(d,lH,. 0.5Hz); 3.66(d,lH,.-0.5Hz); 4.17{q,2H,ι 1.5«z); 4.25(m,lH)i 4.45(m,lH)j 6.23(dd,lH,J-1.5 and 2 Hz); 6.47(d,lH,J-3.5Hz); 7.25{m,4H); 7.4(m,3H)j 7.8(m,3H).

49 C0C1 ₃ : 1.23{t,3H,J*1.5Hz); 1.40(m,2H) 1.65(m,2H)j 2.41{d,2H, ,.5Hz); 2.60(m,2H) 3.25(d,lH,J»0.5Hz); 3.70(d,lH,J ^» 0.5Hz); 3.75{m,lH)i 4.15(q,2H,J»1.5Hz); 4.2{m,lH); 7.3{m,8H); 7.83(m.2H).

51 CDC1 ₃ ; 1.27(t,3H,-=1.5Hz); 1.72(m,2H); 2.5(d,2H,.»1.5Hz); 3.22(s,lH); 3.69(s,lH); 4.15(q,2H,ι 1.5Hz)j 4.27{m,lH); 4.51(m,lH)j 6.22(dd,lH, 3 and 1.5 Hz}; 6,61(d,lH,J*3Hz)i 7.11(t,2H,t3«2Hz); 7.38(m,4H); 7.67(s,lH)j 7.78{m,2H); 7.97(s,lH).

52 CDC1 ₃ : 1.73(m,2H); 2.55(d,2H,,M.5Hz}; 4.3(m,lH); 4.5(m,lH); 6.2^,1^,1*3 and 1.5 Hz); δ.5(d,lH,ι 3Hz); 7.1{m,2H); 7.4(m,4H); 7.6δ(s,lH); 7.78(m,2H); 7.97(s,lH).

54 CDC1 ₃ : 1.82(m,4H); 2.57(m,2H); 3.05(m,lH); 3.26{m,lH)j . 4.32(m,lH); 4.61{m,lH); 7.10(m,2H); 7.28(m,3H); 7.51(m,2H); 7.72(d,!H,-=1.5Hz); 7.86(m,lH); 8.Il(d,lH,,»1.5Hz).

64 CDC1 ₃ : 1.7(m,2H); 1.7(m,2H); 1.75(s,lH); 2.7(m,2H); 2,7(m,2H) 4.35(m,lH); 4.56(m,lH); 7.3(m,8H); 7.85(d,2H),

OMPI

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Cmpd.No. 65 CDC1 ₃ : 2.0(m,2H); 2.71{m,2H); 4.41(m.lH); 5.29(m,lH); 6.23(dd,lH,t>3 and 1.5 Hz); 6.7(d,lH,«>3Hz); 7.13(m,2H); 7.4T(m,4H); 7.68(s,lH);.7.79{m,2H); 7.98(s,lH).

68 CDC1 ₃ : 1.3(t,3H,J*1.5Hz); 1.75(m,6H)j 2.43(m,2H); 2.78(m,4H); 4.18(m,3H); 4.37(m,lH); 5.25(dd,lH,J»3 and 1.5 Hz); 6.5(d,lH,t>3Hz); 7.02(m,.3H); 7.22(m,3H). 5 C0C1 ₃ : 1.24(t,3H,t>1.5Hz); 1.76(m,6H); 2;5(m,2H); 2.8(m,4H); 4.17(m,3H); 4.14{m,lH); 6.06(dd,lH,J-3 and 1.5 Hz); 6.5(d,lH,v 3Hz); 7.1(m.6H). 6 CDC1 ₃ : 1.83(m,6H); 2.69(m,6H); 4.26{m,lH); 4.43(m,lH); 6.06(m,lH); 6.52(m,lH); 7,12(m,6H). 09 CDC1-.: 1.96(m,6H); 2.73{m,6H); 4.4(m,lH); 5.22(m,lH); 6.1(dd,!H,t 3 and 1.5 Hz); 6.57(d,lH,J=3Hz); 7.17(m,6H).

OMPI_