PH26257A - Novel 6-phenoxymethyl-4- hydroxytetrahydropyran-2-ones and 6-thiophenoxymethyl-4-hydroxytetrahydropyran-2- ones and the corresponding dihydroxycarboxylic acid derivatives salts and esters processes for the preparation of these compounds their use as pharmaceuticals pharmaceutical preparations and novel phenols and thiophenols - Google Patents

Description

Description -

Novel 6-pheroxyme! hyl.fi-hydrexytetrahydrepyran- 2-ones and 6-thiophenoxymethyl-id-hydreoxytetra- hydropyran-2-cnes and the corresponding dihydroxycarboxylic acid derivatives, ralts and esters, processes for the preparation of these compounds, their use as rharmaceuticnls, pharmacr tical preparations and novel phenols and th*ophenols

The enzyme Z-hydroxy-’-methylglutaryl-coenzyme

A reductase (HIIG-Coi-reductase) plays a central role in the hiosynthesis of cholesterol /K. Indo,

J. Med. Chem. 28, 1&1 (108s _/. Inhibitors of this enzyme, in particular mevinolin /K.0L.

Iappu et al., Clin, Fes. _4, 684 4 (1986)7. synvinolin /i.... “lsien et al, The jancet,?9 (1986); and KH.J.T.!'. flol et al., The iancet, 9%6 (1986) 7and eptastatin /Trugs of the Future 42, 437 (1987); and ". Nakaya et al. Atherosclerosis 61, 125 (1986)_/have been clinically tested for the treatment of hyrercholesterolemice.

Structurally simplified completely synthetic analors o° these compounds have been described /C.U. tokker et al., J. led. Chem. 29, 170 and 852 (1986), ..¥. lioffman et.al., J. Med. Chem 29, 159 (1986) _7. -%-

BAD ORIGINAL 9

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{ ' : wv 26257

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European Patent Application A-0,216,127 (corresponding to U.S. Patent Application No. -900,848) claims compounds of the formula Ie v HO ,° i rR 0 nS k Jor. Ia : Rr? wherein CE "and R? are identical or different and denote a) hydrogen or halogen, b) cycloalkyl

Having 4-8 carbon atoms or a phenyl radical which can be substituted in the nucleus by. 1 to 3% substituents from the group comprising _ halogen, trifluoromethyl and/or alkyl or &lkoxy - having in each case 1-4 carbon atoms or a5 a ’ Fa straight-chain or branched alkyl radical havifig - 1 to 18 carbon atoms or a straight-chain or branched alkenyl radical having 2 to 8 carbon atoms, it being possible for the aligl and alkenyl radicals in turn to be substituted by 1 to 3 substituents from the group cquprising o | v 4) straight-chain or branched alkoxy fadicals . a .

Von ot oo J & fe ; PYF. its having up to 10 carbon atoms or cyclo- alkoxy radicals having 3 to 7 carbon atoms cor straight-chain or branched alkenyloxy or alkynyloxy radicals havinit 3 to 6 carbon atoms.

B haloren, hydroxyl, cycloalkyl having 2-7 carbon atome, and unsubstituted phenyl or «~ or fl -thienyl radickis:or : phenyl or .i,- or | -thienyl radicals which are in turn substituted in the nucleus by 1 to 3 substituents from the group : compriszineg hnloren, trifluoromethyl and/or alkyl ov alkowy hovine 1-4 carben atons, vr) unsubrtituted ;henoxy, benzyloxy or ri- or | -thienyloxy radicals, or phenoxy, benzyloxy or += or }.thienyloxy radicals which are in turn substituted in the a - _ nucleus by 1 to 7 substituents from the LA : ’ 20 i group comprising halogen, trifluoromethyl and/or alkyl or alkoxy having 1 to 4 carton atoms, and ; 0 . 5) the croup _0-A_iB a uhorein © denotes: | go —

Fo ORIGINAL oN oo a straight-chain or branched alkyl - or alkenyl radical having up to 8 . carbon atoms, or a cycloakyl or cycio-

RE alkenyl radical having in each case | Z-f3 carbon atoms, or an unsubstituted phenyl radical, or a phenyl radical - which is in turn substituted in the nucleus by 1 to 3 substituents from . ... the group comprising halogen, tri fluo- : 10 oo romethyl and/or alkyl or alkoxy having -» 1-4 carbon atoms, or a 3-pyridyl radical,

RZ and R* are identical or different and denote hydfogen, alkyl having 1-4 carbon atoms, halogen : 15 or alkoxy having 1-4 carbon atoms, and oo :

Rr? is hydrogen, eslkyl or alkenyl having up to : 4 carbon atoms, halogen or alkoxy having 158. : . carbon atoms, - hc . - i SL and ‘the corresponding open-chain dihydroxys’ TT carboxylic acids, pharmacologically tol: rated salts thereof with bases and pharmacologically tolerated esters thereof. o hE =

The compounds described in this Application inhibit HMG-CoA reductase with ICqq values. . -6- vo in the 10™° to 108 molar range. According to the data in the description, the most potent compound Ia (R' = k? = ¢1, g2 = j* = Hy | - I" 5 | SOM

German Offenlegungsschrift 3,632,893 (= Derwent

Abstract 88-99 266/15) relates inter alia to compounds of the general formula Ib Bh 0

Re:

Pp © 5° : rR’ | R - a ~pit . R- = in which Co Bad

RV ana BS are identical or different and denote - : 20 a): hydroges or halogen co b) a phenyl radical which can be substituted in the nucleus by 1 to 3 substituents : from the group comprising halogen, } trifluoromethyl, methyl, ethyl, methoxy : CL and ethoxy, i i - om . 26257 : c) an alkyl radical havingi1-5 carbon atoms, : which can be substituted by 1 to 3 substituents from the group comprising a) C,~Cz-alkoxy radicals or cycloalkoxy "radicals having 3 to 7 carbon atoms,’

B) phenoxy or benzyloxy radicals which cen in turn be substituted in the nucleus by 1 to 3 substituents from the group comprising halogen, trifluoromethyl; . methyl, ethyl, methoxy and ethoxy,

Y) | halogen, cycloskyl having 3-7 carbon oo atoms or phenyl radicals which can in turn be substituted in the nucleus by 1 to 3 gsubstitutents from the group o comprising halogen, trifluoromethyl, methyl, ethyl, isopropyl, methoxy and a ethoxy, and i - $00 0-C-alkyl groups with a total of 3:8 N - wr carbon atoms, on The

R? and r" are identical or different and denote ‘hydrogen, halogen, methyl, ethyl, methoxy, . ~ ethoxy or benzyloxy and Ei fie

R? is hydrogen, halogen, trifluoromethyl; methyl,

: . - CT be gb . ethyl, methoxy or ethoxy, and the corresponding open-chain dihydroxy- carboxylic acids, pharmacologically tolerated salts thereof with berces ang bharmacologically tolerated esters thereof,

According to the data in this ‘pplication, the compounds of the foraula Ib described are as a rule slirbtly leery potent thun 1g for the same substitution I'attern R115, oo ~ubstitution Patternc (r? tn 42) which | re not decribed by examples in thege Applications have now heen found, surprisingly, which impart to the compounds of the general formul ge Ia and Ib an activity which is up to one power of ten greater than the vest examples listed in

LF=A-0,216, 127 and Di=t-2,620 897, The substi- oo - 20 tution patterns in respect of substituents g?, Co : R?, B* ang R 1ie completely within and those with respect of i> lie only partly within the @eneral patent ol: im of 1i-A~0,716,127 and pE- 1-3,6%2,80z, since it hay furtherrore heen found that TE can also have the reanin«o whieh are not described in the two previcus Applications,

BAD ORIGINAL Y iin v . Clad fot pe, : hel La lyn gi ww Why RD @ Cd 26257 .

The invention relates to novel compounds’ of the reneral femula nF

CH : oe oo | | 5x” a

Co zy H- \—F 1 v / yr . | cli Lo) 7 and the correepondine open-chain dihydroxy- carboxylic acids of the formula 11 ie

HO or

OOH g < 7.

F cli, 11 > x 43T - - Co ” / OJ — ree big pe . . - is CH, ~~ Z HE > 3 L wi SAV. pharmacolorically tolerated salts thereof with bases and pharmacologsicnlly tolerated esters thereof. pve . so _

In the formulae, ~ :

X denctes oxypen or sulfur, I . -10- BAD ORIGINAL 9

Lo hea

: Yd ri r denotes a) a straight-chain or branched alkyl radical having 3 to 12 carbon atoms or b) cycloalkyl having 3 to 8 carbon atoms or a phenyl radical which can be substituted in the nucleus by 1 to 3 substituents from the group comprising halogen, trifluoro- ~ methyl and/or alkyl or alkoxy having in each case 1 to 4 carbon atoms and

Z denotes’ hydrogen or a straight-chain or branched alkyl radical having 1 to 8 carbon atous.

The charmcter' of a selection invention is asserted for compounds of the formulae I and II which do not fall within the patent claims of the previous patent applications referred to.

Lie ie - ‘The substituents in the general formulae } ‘preferably have the following meanings: xX oxygen Co

Y isopropyl, tert.-butyl, cyclohexyl,phenyl ~ or p-fluorophenyl pg

Z hydrogen. oo : jo

The invention furthermore relates to a process 1 B

1 , J ] , Ss

EE oredr oe RE 9 6 or 7 alos ne for the preparation of the compounds of ‘the formula I and of the corresponding ropenithdin “dihydroxycarboxylic acids of the formula II, of the pharmacologically tolerated salts thereof with bases and of the pharmacologically tolerated esters thereof. The process comprises a) converting correspondingly substituted

Sn phenols or thiophenols of the formula 111

Cn . 7 ¥ Q- Wl IIT os Hs C Oo

Bb in which X, Y and Z have the neadings - given in the case of formulae I and iI, g with the optically pure iodide of the 7, formula IV Cn, - R704 NY . —- 7 : oo

NE / EL oo 1 Lo < in which R’ denotes a protective group ph which is stable towards bases and’ Weak acids, into the lactol ether of the formula Vv or -12- ge

A - TE oo R70 o A aoe 3 {

CH, 3 1] - Vv x7 ; / \ ‘

Ch; Y : oo t ; in which X, Y and 2 have the meanings given in the case of forrulne 1 and 11 and R/ has the meanines given in the case of ~ formula Iv, b) hydrolyzine tha lactol ethers of the formula " ¥ to give the correspondingilactols of the formula VI > LL . R Mon SR

CH, ~ oo a . x yz — po Me [ pg . ters — eo Ch

B 40) Z -

Y ig “in which X, Y nd 7 have the meanings given in the case of formulae 1 and 1I and R’ has the meaninye given in the case of formula

LIV, f

INAL: DJ \s AD ORIG i , Wa pA oo : Ww igrgy eb “ fe Coan FL 26 on © Ret Ea oon ‘ . . c¢)’ oxidizing the lactols of the formula 129 to give the correspording lactones of ‘the formula VII Hi

R Cr Co oo CH, VII © . _ J ' : 7 SQ :

O ol ; 0 Bs : : . An which X, Y and “ have the meanings given .in the case of formulae I and 1I end rR? 1 a > “has the meanings Fiver in the case of 0. : formula 1V, . d) - converting the re-ulting protected lactones fn . of the fcrmula VII into compounds of the Lt “formula I in a manner which is known per, se B e) . if appropriate, converting the resulting "compounds of the formula I into the cotrés- 2 Go Y . ne - : > ponding open-chain dihydroxycarboxylic:. ..

WY Rod “acids of the forwula 11, salts thereof: or : eaters thereof, if appropriate converting ) BAD ORIGINAL 0 > “Ab 3 J

Ln i aE : oo resulting salts or ecters into the free dihydroxycarbov. lic acids or, if appropriate, " converting the free carboxylic acids into the salts or enters.

L

The process in advantageously carried out under the conditions whieh have been described in the Freviour Applications referred to. The oo Process conditions: can be modified according to. the meaning of the substituents (cf. for example Embodiment Lxamrle 1.8), -

The starting compeind: of the formula III are novel. The invention therefore also relates bo these compounds. The iodides of the formula 1V are described, for example, in iT -A-0,216, 127. Ta

Syntheses of the phenol and thiophenol units -

ITT required are outlined in equation 1 ard’ oo described below. pig

Compounds of the feruula IIT can be obtained. from 2-isopropylphenol XII or from 2-1sopropyl- oo phenols XIT1 sub %tituted in the 4-posi tion: by

Y by palladium (0)acatalyred aryl-aryl cgupling a BAD ORIGINAL 29 , =15=- SR

26257 1 as the key step. Reviews of palladium (0)= En catalyzed aryl-aryl coupling are to be found i in E. Negishi, Acc. Chem. Res. 15, 340 (1982) . and H.F. Heck "Palladium Reagents in Organise : :

Synthesis”, Academic Fress (1985), Chapter 6.

According to a recently published strategy. (D.A. Widdowson, Y.-Z. Zhang, Tetrahedron 42, 2111 (1986), aryl Grignard compounds i have an increased reactivity in respect of ) Pd(0)-catalyzed coupling with aryl halides if they carry ortho-alkoxy substituents. If XIII is therefore brominated to give XIV, XIV, is then protected with a benzyl group to form XV and the Grignard reagent XVI is formed in’ HP, this already reacts with the aryl halide XVII (Hal « Br or I) under mild conditions (10 to 65% and under Fd(0)-catalysis to give the coupling product XVIII in outstending yields (90 to :98%). - ~ 20 Rerigval of the protective group by means G2. — a catalytic hydrogenation gives III (X = 0)ei RL Cra

In’ this strategy, the coupling product tf; : (X= 0) is obtained in a very high yield did - purity. There is the need to protect the. phenolic )

OH “group and subsequently remove the protective 8 group in this process. = B -16- Lo i a Cp Ea

CR el

Fd(0)-catalyzed aryl-vinyl couplings in the presence of unprotected phenol groups are. known (R.F. Heck, Acc. Chem. Res. 12, 146 (1979); C.P. Ziegler Jr., R.F. Heck, J. Org.

Che. 43, 2941 (1978). This reaction is not completely comparable to aryl-aryl couplings, since no highly basic organometallic reagents (such as the Grignard compound XX) are used therein. oy .

Aryl-aryl couplings in the presence of unpro- tected phenol groups are novel. This reversal Co of the conventional strategy described above, that is to say Pd(0)-catalyzed reaction of unprotected ortho-iodophenols XIX with Grignard reagents from p-bromofluorobenzenes XX, has been succes- : fully carried out. One equivalent of XX is consumed for deprotonation of XIX and a further equivalent of XX is consumed for the-coupling hal = 20 resstion. Since oligomerization of the orignard ot : components XX moreover occurs 8s a side reaction, 2.5 to 3.0 equivalents of XX must be used ‘in: order to achieve complete conversion to 111 (X = 0). oo 25 .

It is in this way possible also to carry fout quantitative di-couplings on the unprotected gro CE Lo EET

LL IV 4

L Ln gE EY dilodide XXI. If 3 equivalents of XX are Used, EE

Ao mnt PRN Vl \ are U 2d, wh a mixture of the mono-coupling o product XIX' (Y = ©” ) and the di-coupling oo i F io 5 product III' (Y = ) is obtained at - SE ; room temperature. In contrast, if the 24 equivalents

SE of XX are used, the mono-coupling product detectable in the meantime is in the end converted completely : . into III'., Since this di-coupling reactish takes place without purification of the quite . sensitive’. diiodide XXI IIT’ Cu iy —_— Co ’ oo oo —F A s : (XY =. ) Fed »

SE py LAY

IE is. obtained very directly from XII in an overall Bh

SE y161d of 40 to 60% (not optimized!). -

This phenol unit I1I' is advantageously prépared by this process, since in the conventional method g 5 the compound XIX' which is in any case formed would have to be used because aryl di-Grignard = -18- Tv nie RIE i cy hE éompounds are unstable /F. Bickelhaupt, ‘Angew.

Chen. 99, 1020 (1987)"7. _

Compared with conventional coupling, direct coupling of unprotected iodophenols XIX with aryl Grignard compounds saves two synthesis steps and allows the usw of the less expensive f1luorobromobenzenes. The price which must be paid is a lower yield of the coupling step. oo

Co Tetrakis-(triphenylphosphine)palladiun (0); bis(triphenylphosphine)palladium dichloride or a mixture of palladium dichloride and. triphenyl- phosphine has been used as the palladium catalysts.

It is known that similar catalyses can also be =» achieved with nickel-phosphine complexes and related transition metal complexes [“sees~Tor example, i : i - *see C.V. Bordlianu, Arch. d. Pharmazie 278; 8 (1934) E. Negishi, Acc. Chem. Res. a5, 30 (1982); J.x. Stille, Angew, Chem. 98, 504 (1986); R.F. lleck, Acc. Chem. Kegs. a2, 145 (1979);

E. Negishi et al., J. Org. Chem. 42, 1821 (1977)_7. yf -19- CL

, gtd Pe Thi i 5: : : an aE i _ : LT ns ~ po . : , : ; 2625" -

The thiophenols of the formula III are obtained by methods analogous to those described in the literature from the corresponding phenols of the formula III by reaction with a dialkylthio- carbamoyl chloride, subsequent Newman-Kwart rearrangement by means of heat and reductive cleavage of the S-aryldialkylthiocarbamates formed to give thiophenols of the formula III (of. also DE-A-3,6%2,893). Lo 10 . ; on ta — Ce ame Re Ln fit hd ie 5 -20~ a os unr

Co oO 2 0 Co 1 . I \ Vi J ~ z s rd 1 - 0 ye ©

Ol - ra 0) : 7 =O) oO) ~ NN

IEE

© “dle > —~ x A HO € of D) q,

O)- IN | m ~ = o 2 <I ~ ~ x pia a cn . Ct re ae ali cm oe . rEg STurcosaltie ' : 1 gu fh! ee Wie pein) 13 AIAN) GIS = : Es hel -

A Fee . } CE or ,

Cy " Loire SRY 1 : Da ia

W > 257 Hh aseyg synthecis routea for the preparation of dompounds of the formula 111 (reaction scheme 1) are outlined in part in reaction scheme 2 and described below.

TT i

The preparation of the starting compound X1I1 with certain substituents Y depends on the availability of starting materials. da a RRR vn A) 1

XIT1 (Y = i-Ir) is formed by decarboxylation Co

L of commercially obtainable 3,5-diisopropyl- : 2-hydroxybenzoic acid of the formula XI (Janssen). CL

The decarboxylation cen te carried out by Heating the pure subatance or a solution in an inert : solvent (for exanp. : nitrobenz: ) to 240 to 1 220°C. A consider:bly better yield and purity - uk is obtained if a solution in quinoline ig heated : at: abcut 190°C in the presence of a copper: : chromite catalyst. EE ._ . di J STR na TTR - :

VEE SE 1

XIII (Y = tert.-butyl) is obtained highly, para=>- selectively accordin:m to G. .artori et aly; Chem. and Industry, 762 (1985) if isopropylphenol. is stirred in CIi,Cl, solution with methyl tagty~ ’ Co" Si butyl ether (Iilk) and zirconium(IV) chloride.

A Bood yield of X111 is obtained if XII [3:0 equivalent) is reacted with KIEE (1.05 equivalents) and 21Cl, (2.4 equivalents in 2 portions)iat 0% . on pa he pis = BAD ORIGINAL Pp) ~00- t BY

CoA at } : : SU $n BREN Sh ‘ ; EL NR ; : Sabet ©

Lo Ea : . ’ i sonventional Prieldel-.rafte alkylatione of

XII with correspondine alkyl halides/slumfnum trichloride or with nl ohols Y-CH/Lewis of proton acids c-n also te veed for the preparation of “111 [Fee F.-L. Poin in Kouter-Weyl "Hethoden der orranischen Chemie (Methods of Crranie:

Chemistry)" Volume V1/1¢c "ihenole Teil 2 . (Fhenols lart 2)", Georg Thieme Verlne, Stuttgart } (1976), rare 925 et req. 7 : h-liydroxy-?-icopropvl-tiphenyl ¥I11 (Y ne) ©) is obtained from commercinrlly available pe. nitrobiphenyl V1311 vv o-alkylation with igo- propylmagnesium hrerdde /[Teview by G. Bar#dli, fcc; Chem. Res. 17, “02 (1984) 7 to give IX, reduction of 1: to 'he amine %y diarotization »nd decompositien to the phenol hy boiling (reaction ccheme 2°. - kw Re ?0 uk | EL a

Catalytic hydrogenation of an ethyl acetate cnlution of oo a Si

YIIT (Y = “) ) over 5j palladium-on- = charcoal at 50°C under 4 hydrogen pressuré. 6f 2 EXE to 6 kp em™ rive S111 no i (Y =.» _ . ) in a yield of 8% to 90%: . BAD ORIGINAL @

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Ihe lactones of the formula 1 can be ccnverted oo into the correspondineg open-chain dihydroxy- carboxylic acids of the formula 11, pharmaco- logically tolernted o'te thereof with bases and phormacoloriczl!y tolerated esters thereof by 8 customary method (cf. for example I4A- 0,216,127 and Di -i-7,672,80%), Lo

The enzyme HhG-Coo reductase is widespread’ in “0 nature. lt catalyzes the formation of mevalonic - acid fron H5-Coe this reaction is a central step in cholesterol hionynthesis (I.k. shine,

Jel Suet ~hydroxy-3-methylrlutanyl coenzyme A reductase,

CRG 1 recs, 1987), “irh cholecterol levels are associated with a number of diseases, such as, for example coronary henrt direanse or atheros- clerosis. I'he reduction of in~reased cholesterol levels for prevention and treatment of such diseases is thercfore a therapeutic aim. Gne w. , a ren AEA at i Wo - 20 point of attack lies in inhibition or redugtion oo of erdorenous cholr "terol synthesis. Inhibitors oo of HMG-Col reductace 1'lock chonlecterecl biogyn- thesis at an early bape. They are therefore “uitable for the prevention and treatment of "isennen cau: od by on increased cholesterol’ ° level, A reducticr or decrenase in endoreptus synthesis leads tn n increased uptake of Sr vo ponent 9) - -5- i :

i HY ; AR io ab . : ie 7

B 26257 ! . i J Wa cholesterol from ploacmn in the celle. nn ; additional effect an te achieved hy simul taneous administration of cubstances which bind bile.. \ LO wp . acids, such as erion excrangers. The increased : secretion of bile rcide leads to an increase’ renewed synthesis an! therefcre to an increased cholesterol breakdown (i. .Brown, l.T. rovanen,

J.1l. Goldstein, ciecnce 212, 628 (1921): M.5.

Brown, J.L. Goldstein .pektrum der Wissen-' schaft 1985 (1). 9%). The compounds according . . to the invention are inhibitors of HMG-CoA . reductsne. They are therefore suitatle for : inhibition or reduction of cholesterol biosyn- thesis and hence for prevention or treatment of diseases caused bt. an incressed cholesterol i level, in particular coronsry heart disease, i oT ! Dr ] atherosclerosis, hyrercholesterolemia, hyper- ; lipoproteinenin and similar diseases. a wo i

Cw CE — ELL ad ] 20 The invention therefore alsc relates to Ll o an

Pp pharmaceutical preparations based on compounds “>. . of the formula 1 or the corresponding dihydroxy- carboxylic acids of the formula 11 or salts. and esters thereof and the use of these compounds as pharmaceuticals, in particular for the : treatment of hypercholesterolemia. fo - -26- i r Ba oo BAD ORIGINAL =

~ CE So wv CHEE 26o0x7

The compounds o! the formula 1 and the corpes- ponding acide, salts or esters are administered in various dosage forme, preferably orally in the form of tablets, c-praules or liquids, The daily dose varies in the ranre from 3 mg to 2,500 mg, hut preferably in the ‘cae ranrme from 10 to 500 mF, deperdine on the body weight Ande constitution of the pntient. i /

Ve 40 he compounds according to the invention gan

Ls be used as lactenes of the general formula I, in the form of the free acids of the formuld. 11 or in the form of pharraceutically acceptable salts or esters, and in particular as a solution or suspension in pharracologically acceptable : organic solvents, such as mono- or polyhydric alcohols, such ~s, for example, ethanol or mlyderol , in triacetin, oils, such as, for } example, sunflower oil or cod-liver oil, efhers, - 50 such as, for example, diethylene glycol aimethyl Lr ether or polyethers, such as, for example, poly- - ethylene glycol, or in the presence of other pharmacologically acceptable pol-rmeric car¥iers, ; auch es, for evample, rolyvinylpyrrolidone; or other pharmaceutically ~cceptable additives, such as starch, cyrl: dex rin or polysaccharides. _ -27- Te re tC oo BAD ORIGINAL 9

SE : The eE : ih A } , RK 2 CE

The compounds according to the invention can furthermore be combined with additives which bind bile acids, in particular non-toxic basic anion exchanger resins which bind bile acids ' in a non-resorbable form in the gastrointestinal tract. The salts of the dihydroxycarboxylic scids can also be processed as an aqueous solution. Lo

The HMG-CoA reductase activity of the sodium salts of the compounds of the formula II according to the invention has been determined in two test systems a 1); Inhibition of the HMG-CoA reductase activity De on solubilized enzyme preparaticns from rat liver microscmes el ur The HMG-CoA reductase activity was measured : oy on solubilized enzyme preparations from - oo 20 TET iver microsomes from rats, Which were . yr : : fe induced with cholestyramine Ruentd)’ after... -

Jo changing into the day/night rhythm."

RE (S,R) 146 _H1G-Coh was used as the substrate y and the concentration of NADIH was maintained :

Re during the incubation by means of a: regene- : Tt rating system. Yc _Mevalonate was separated ~ off from the ‘ubastrate and other products ne -28- .

CR

, (for example Me via) via column elution, the elution profile of each individual cumple beinp determined. Continuous simultaneous treatment of >H-mevalonate was dispensed with, since the determination relates to rel-tive information on the ~ inhibitine netien. In each cage the enzyme-free ccntrol, the enzyse-containing normal batch (= 1005) and batches containing - additions of prerrration were treated together in one test series. tach individual value was obtained 5 n mean value from 3 parallel gamplra. The «ifnificance of the differences os between the mean values of the rreparation- free and prercration-containing samples were evalueted hy the t-test. In the. method described above, the following inhibiting ~ values on HiG-"ni reductase were determined, for example, for the compounds sacording n> oo 20 bo the invention (ICc, (mole/1): molaf oo LAT : “concentration of the compound per liter co required for » "0% inhibiticn) He fo “00. ———

BAD ORIGINAL 9d

Eh Cadet - LN 7 Table 1 or ¢ Example IC¢n(mole/1) 8a 2.3 109 8b >1077 i

J Be 1.7 . 108 ad 23,108

Be 5.2 . 102 et 5.8 . 1070

SE 3.6 .1078 - 2) Suppression or inhibition of HMG-CoA 6duc tase i in HEF G2 cell cultures (of a human hepatona Co “1 © “cell 1ine) | Ti CT } oe ‘ SIE ! The inhibition of the incorporation of "C- sodium acetate into cholesterol wes aeternined.

Monolayers of HELI G2 cells in RPMI AHR? ined ium o

With 10% of fetal calf serum freed TEphciipide a “were. preincubated with various concentrativhe - "of the sodium salts of the dihydroxycarbo- j xylic acids of the formula II for 4 hor.

After addition of c-1aveled sodium acetate, the incubation was continued for 3 houps. i; Tritium-labeled cholesterol was addeg ks an ““internal standard and an aliquot of the cells - vw. was subjected to alkaline hydrolysis. The 7 14pids were extracted with ehloroforn/i "oa : 30 ethanol 2:1. After addition of cartier oo ~ noreoteror. the lipid mixture was sepiater

I | 30- in

' Eo WH LE on HL Rd

ER

EE a. Tot ERE SE 3 CLE SEY rt rol

Cae CEE “ gi pe be ia . = St BE i TRE Cy !preparatively on thin-layer chromatography ‘plates with chloroform/acetone 9:1. The ‘cholesterol zene was rendered visible by. "Btaining with iodine vapor and was alsg’ ‘detected with a thin layer chromatography ‘redioscanner and then scraped off. The amount of Me _echolecterol was determined by scintigraphy. In another aliquot of the cell monolayer, the cell protein was méaBured, (for caculation of the '‘C-cholesterol bio- synthesis per mg of cell protein). The same he . procedure was performed with cells of the same culture without preincubation with 'a test compound (so-called "solvent control").

The potency of the test compounds was determined by comparison of the biosynthesized Moa cholesterol in the test runs and in the: "&olvent éontrol®, The potency was calculated oi the basis of mevinclin sodium salt as an external - —- el STITT on standard. The ICeq and IChg values (1054 od : or IC, (M) is the molar concentration Bf - Pee : the compound per liter required for 50 6% 70% inhibition respectively)varied somewhat ‘for different cell batches. The mean values for , mevinolin sodium anlt were Ig, = 5 x 1078,

IChq = 1.5 x 10H. The IC's measured for

ALC AiGINAL gh , ~31~ wild be

: Eo rig tet compounds {roium gaatts of the dihydro- xycarboxylis =nci-i- of the formule 11) . (Table 2) were rnrrected by the deviation of mevinolin gedium from its average + 5 .value. Hevinclin sodium was attributed a »relative rotency cof 100, :

Table 2: | ' 1

I'xsmple 1Cga (1) 1g (M) relative potency 8a’ 2.7. 107% 7 1078 485 (21) 8b ~ 1077 Lq 8c 9 . 10~8 56 CL 8d 9.5 . 107" 53

Ce

The: synthesis of t“» compounds 1 according to the invention is t~ *e illustrated further by the following evaryplen, (a oo 5 we - n= Sie Lo —- eee Cg 0

Example 1 fal ET synthecis of 4(R)-hydroxy-6(t)=/"(2,4-diisopropyl- 6-p~flucrophenyl)pheroxymethyl 7 tetrahydro- \ 2Hepyran-2-one Re ad ! 25 . (Formula 1, X=C, Y-i-!r, &=I1) ; ou !

BAD ORIGINAL g}) roe oo & no i . ) : i oo Fw Bits i ARR Vi."

Tri SE IL i ~ 4 Ey.

Example 1.1 nL 2y4-Diisopropylphenocl (Formula XIII, Y=i-Pr) \

A mixture of 145 g (0.65 mole)of %,5-diigopropyl- 2-hydroxybenzoic acid (XI), 540 ml (588 g; 4.55 mole) of quinoline end 7.5 g (0.024 Hole) or canp of. copper chromite (2€u0.Cr,04) is stirred at 190°C (225°C external temperature) for 2 hours.

The mixture is cooled to about 10°, acidified : “ to PH 1 to 2 with about 1 1 of half-concentpated hydrochloric acid, while cooling further, and extracted with toluene and the extract 1s washed with 28 hydrochloric ncid, then with water and subsequently with NaHCO, solution, It 16 dried, filtered and concentrated and the residue is distilled under a biph vacuum. 105 g of the ’ title compound XJJI are obtained as a pale . yellow oil, boiling point 81 to 84°C/0.2 nm Hg. a 3 Try,

TH-NIR(0DO1,) ¢ 1.20 (6l,d); 1.25 (eH, a)s oo

Ce 3.00 (20, 2x hept.); 4.10 ji i (Miy3,br); 6.50-7.00 (3it,m)

Example 1.2 a

B fo 2,4-biisopropyl- -bromophenol (Formula XIV; co _73 = .

SHMEER Reale pr 7 a Ines

TR LL TREE

“ iN el ap

Y=i-Ir) 1g of iron powder is added to a hot : } solution, at a5°¢, of 102.3 g (0.57 mole) of

Py 4=diizopropylphensl in 20C ml of Flacial: :

So on acétic acid, and 4070 (72.2 ml. 0.67 mole) of bromine are then »lded dropwise in the course... of 90 minutes. The renction mixture is A i stirred at 100% far a further hour and paiti- tioned between toluene nnd water and the oo oC a : toluene phase is washed with "'alHC0, solutism, Ll

It is dried, filter ed and corecntrated end: a 3 the feridue ie distilled under a high vacut. CT 125'g of the title corpound X1V are obtainméd as 8 pale yellow oil, toiling point 85°C/0;15 ma Hg. i

TH-BtR (CDC) : § 1.70 (6l1,d)5 1.25 (6l,d)}

Ri SJ (11, hept.); 3.25 (18; oo i hert.); 5.73 (1H,s); 6.894 oo oo 7.00 (2H,m) Ea i.

Nor in Coe me RE fod Co 0 MS (70 eV): m/e = Oro/p58 (MY), 241/243 (MY2CH;) iT IN : Ril | CEE aan. als CL oo a TE ro cl

Yxample 1.3 SEA ° 1<Benizyloxy-2,/t-diicopropyl-6-hromohen zene... (Formula XV, Y-i-ir) 5 | 2 = Ji % CHAD ORIGINAL 7.0

Eo =

Lol SAREE CCAR ME i | Sa

Cie . h TF eve

A suspension of 166. 5 g (1.2 mole) of potassium carbonate in 124 g (0.48 mole) of the above bromophenol, 91.52 g (0.72 mole) of benzyl chloride and 2 1 of 2-butanone is heated under reflux for 24 hours. The suspension is cooled, the inorganic golid is filtered off with suction, the filtrate is concentrated in vacuo and the residue is partitioned hetween toluene and water. The toluene phase is washed with satu- rated sodium chloride solution, dried, filtered . and concentrated. The residue is chromatographed ) with cyclohexane/toluene 9:1 over silica gel. 155 g of the title compound XV are obtained as a colorless oil. i small residual amounts of benzyl chloride are removed under a high vacuum. The purification can also be achieved by distillation (boiling point 150°C/0.15 mm Hg). ol oe 1 — ST a ’ <5 oo 20 H-NMR(CDC1,): d 1.18 (6H,d); 1.22 (6H,d Jy" 4" 2.80 (MH, hept.); 3.32 i een (1, hept.): 4.90 (2H,8)% 6.9%-7.60 (7H,m) 7.

Hi (70 eV): m/e = 346/348 (IM), 267, 254/256,91 &

Example 1.4 J 3s. co

Cit CR 26257 1 -Benzyloxy-2,4-dji-opropyl-G-p-Lluorophenyi- LT benzene (Formula XVI111, Y=i-Ir, ZH) "he Grignard compound ¥ (Y=i-Ir) is yrenared from 48.62 pg (0.24 +~le) of the hromide from “xample 1.3% and 2." rn (0.147 mole) of lip filings in 120 ml of absolute tetrahydrofuran (~ 60%, 1 hour). Thieg Oripnard solution is added

Po rapidly to a =nlutiorn of 71,08 g (0.14 rnold)’ of h-fluorojodobenzenes nd 3,23 o (2.8 mmol) of tetrakis(tripherslphosphine)palladium (0) in 140 nl of absnlntne tetrahydrofuran. The internal temperature riser to 55 to 60°C " within 1% minuter. :fter 7 minutes, =a precipitate . 15 forms. The mixture is stirred at 50 to 58°C for’1 hour, left t- stand overnight at room" temperature and partitioned between ether and 1 N hydrochloric neid and the ether phase is . weshed with 1 MN byirechloric acid, then with | - water and subsequently with saturated NaHCOy Co : solution. It is dried, filtered and concentratdd,- 1f required, the product is purified by chroma~ tography with cycletexsne/toluene 4:1 over silica . mel or by distillation (boiling point 1p0%;) 0.% mm Hpg)e #49.%2 + ~f the title compound XVIII are obtained ns a colorless solid, velting point 65 to 67°C. so : Ce BaD ORG. _

RIE THCHEINE $1.70 (125i,d); 2.95 (1H, hept.); 74% (MH heptl)y 4.40 (2Hy8); ) 6.90-7.80 (111, m) SE

Ms (CI): m/e = 7% (MAY), Zon (MY), 285,263 f.xample 1.5 : : 2y4-Diisopropyl-6-p-fluorophenylphenol (iékdhiin 111, Yei-Fr, Z=H) ) 10 &

Lo 4 g of 10% ld-on-chnrcoal are added to a dplution - of 49,7 g (0.176 mole) of thr benzyl ether XVIII from Ixample 1.4 in 17 1 of ethyl acetate and 100 ml of glacial rcrtic acid and the mixture is shaken in a hydroren atmosphere for 20 minutes (vigorcus uptake of Ha). The catalyst is filtered off, the filtrate in concentrated and the residue is taken up several Limes in toluene and cncen- trated in vacuo each tine. 34.4 pg of the title a compound 111 are ohtained as a colorless oily a hoilipr point 115°:/0.1 mm He. STR

MH-RNR(CDO1 5, 270107) § 1.25 (6H,d); 1029 (6H,d); 2.87 (1H, hept.); os 5.31 (1H,hept.); 4.95 (11, s,br);6.88 (yd) . oo 7.00 (M,a) 7.18 { -

BAD ORIGINAL gl -27- - RE i FE : A CE oo (2H,m); 7.45 (2H, m)i Ce

MS (70 eV): m/e = 272 (M'), 257 (M*-CHy) i Co

Example 1.6 : En

Lo 6(5)={ (2,4-Diisopropyl-6-p-fluorophenyl) ] \ phenoxymethyly-3,4,5,6-tetrahydro-2(,5)- N

Fo methoxy-4(R)-(t-butyldiphenyleilyloxy)-2H=T pyran’ (Formula Vv, Y-i-ir, Z=H) : vo 3 » 27.2 g (0.1 mole) of the phenol from Example 1.5 are added to a suspension of 27. 6 g We (0i2 mole) of potassium carbonate and a spatula- tip of hydroquinone in 250 ml of absolute } dimethyl sulfoxide, The mixture is stirred at root temperature for 1 hour and a solution: of 56 g (0.11mole) of the lactol ether fodide

IV (for the preparation see El-A 0,216,127}; B, = t-butyldiphenylsilyl) in 250 ml of absolute oo - or 20 dimethyl sulfoxide is then added. The mixture” wi 1s stirred at an internal temperature of Re Le 50-55%C for 4 hours. Thin-layer chromatogfaphy > (silica gel, 1st development ith cyclohexie/ ethyl acetate 9:1, 2nd development with cyelo- hexane/ethyl acetate 15:1) indicates complate - } conversion of the iodide 1V (R, 0.5), a ible

Sa

Ly

Soper residual starting phenol (Rg 0.7) and mainly product of the formula V(R, 0.6). The reaction mixture is allowed to cool and is partitioned betieen ether and hnlf-saturated sodium chloride : solution. The aqueous phase is extracted mgain with ether. The combined organic phases are washed with sodium chloride solution, dried: over MgO, filtered and concentrated. The, crude product is chromatographed with tolaene/ cyclohexane 2:1, then 100% toluene and then : toluene/ethyl acetate %0:1 over silica gels 51g of the title compound are obtained aba oo colorless resin. - . H-N (CUel,): 4 1.10 (91,8); 1.28 (128d), o 1.4-2,2 (4H,m); 2.93 (2Hy2xhept.);

Z, 40 (2U,m); 3.52 (311,8)} 3.97- 1 n.40 (2H,quisn); 4.87 (Hid) 6.87-7.90 (16H,n) Ci - LE -

M8,{C1): m/e = 654 (11'),597 (M'-terti-bu);i539, nT : A. 519,323, 283, 135, 127 Aral

Ear hi

Example 1.7 i 6(sY={ 2,4-Diisopropy -6-p-fluorophenyl)phenoxy- me thyls- 3,4,5,6-tetrahydro-2-(R,5)-hydroxy-t« } (R)L(t-butyldiphenylsilyloxy)-2H-pyren (Formula ; -39- > - oe :

VI, Y=i-Pr, Z=H) ~ h solution of 40.2 ¢ (61.4 mmol) of the lactol ether from Example 1.6 in 3 1 of tetrahydrofuran, 3 1 of water and 4.2 1 of glacial acetic acid is stirred at 80-85°C (external temperature) for 24 hours. The solvents are removed in vacuo and the residue is evaporated with tuming 3 times with toluene in vacuo, Chromatography with cyclohexane/ethyl acetate 12:1 through 2 1

N of silica gel gives 33.4 (yield of 85%) of the title compound as a colorless amorphous powder. .

MS (FAB): m/e = 640 (1%), 519, 367, 323, 283, 271, 257 oo "

Example 1.8 6(S)-{ 2,4-Diisopropyl-6-p-fluorophenyl)phenoxy- methyl) - 3.4.5, 6-tetrahydro-4(R)-(t-butyldiphenyl- a 20 811310xy)~2H-pyran-2-one (Formula VII, Y=i-Pr, - -

ZH) Es co 46.9 g (208.4 mmol) of N-iodosuccinimide are added to a solution of 33.4 g (52.1 mmol) of the lactol from Fxample 1.7 and 19.25 g (52.1 mmol) of tetrsbutylammonium iodide in 2.5 1 of absolute 0 methylene chloride, while stirring and Jooling. _40- :

—_— vo . ro : Up N

To 2 6251 E . F

I'he mixture ie stirred under nitroren with oo exclusion of light ot 10% for 1 hour and at reom ‘temperature For 20 hours, I'he reaction colution ig wached 4p water, then twice with’ "al .Cy solution and heequer tly with saturated aC] solution, drier, Filtered ang concentrated,

Me residue 16 diac] vey in a little methylene chleride nnd Filtern throveh giljen rel with cyclohexane, cthy) neetate 0p.g, 72.7 poof the title compound are O'trined ag g colorlers regin. _ : "i-uti(ener,,, 270i). § 1.06(9, 8); 1.23 : . (61,4); 1.26 (611,a)01, 59 wo (PHym); 2.41 (1H,dd); : 15 yo 2.5% (1i,dm); 2.00 (1H, hept.); 2.76 (ii, hept);

TOR (20 KR of nix), oo He29 (11 qui); nono - (tym); 6,06 (*i,d) 59:03 oo ol (Pilym); 7.10 13d) 70 26m * 7.52 {Pri m); 7.58-7 53 (M1 ,m) . ;

P70 ev, 20%): pon 678 (NY), 6p (I1"-tert, =bu), 570 (gpg _ Prorene),

PE, 191 a

I'xample 1.9 oo a -N1. oo

Lyn 2698 1(R)-Hydroxy-6(5)-/"(?,4-d11is0prop:1-6-p=EIvoro- phenyl) -phenoxymethyl_7tetrahydro-2H-pyran-2-one (Formula I, X=0, Y=i-Ir, Z=H) 11.65 g (194 mmol) of glacial acetic acid, followed by 45.92 ¢ (145.5 mmol) of tetrabutyla- mmonium fluoride trihydrate, are added to a solution of 21.0 g (48,5mmol) of the silyl compound from Example 1.8 in 1.5 14 of berahydro- furan (filtered over basic A1,05). The mixture ] is stirred at room temperatufe for 20 hours.

Ihe solvents are removed in vacuo and the residue is immediately partitioned between ether and water. The aqueous phase is extracted twice more with ether. The combined orgaric phases are washed with saturated sodium chloride solu- tion, dried over ligiC,, filtered and concentrated.

The residue is taken up in toluene and the mixture is concentrated in vacuo. The crude Cw - 20 product is chromatographed with cyclohexane, xa ethyl acetate 1:1 through 2 kg of silica gels 15.7 g (yield of 81%) of the title compound are obtained as a colorless solid, melting i point 145-147°C, Co .

IE K

TH-NMR(CDC1,270MHz2) : §1.25 and 1.27 (12H,

oo | Tt Ca we | CE he

Co Le 9 625 Gp hi axa); 1.67 (1H, 81BELS ar 1.76 (AH,dtd); 4.87 SE (1H,ddd); 2.58 (AH,ddd); 5.69 (1H,dd); 2.91 (1H, oo 5 hept)s 3.39 (1 hept)s - 3.54 (2H,AB of ABX)} Co : 4.38 (All, qui) ,4.68(1H,m)3 6.97 (1,d); 7.10 (3H, dsm); 7.57 (2Hym)

Hs. (FA): m/e = 400 (H)y 257 ;

Example 2 fi

Synthesis of (yng roxy -6{1)-/~(2-1s0PFORIL- evs. -butyl--p- Fluoropheny phenoxyREthIL 7

Fetrahydro-2H-pyran=r-one i (Formula 1, X=0, Ystert.-bu, 7=H) Ge

Example 2.1 a : : “2:1p0propyl-A-tert.-Tutylphencl (Formul& X1TT%_ f=tert.-bu) wl, ~& solution of 34 g (0.25 mole) of o-- 160pTopyl- “phenol (formula X17) end 22 g (0.26 mols) of tert.- butyl methyl ether in 150 ml of absolute. CH,Clp is slowly added dropwise to a suspendiof of 70 g8 - (0.3 mole) of zirconium tetrachloride in 400 ml

RR i - Be Ea

Sy CES. 26257 of absolute CHCl, at -5 to 0°C under nitrogen.

The mixture is stirred at 0°C for 1 hour."

Thin-layer chromatography (100% toluene) , indicates a conversion of about 50%. A further 70 g (0.7% mole) of zrCl, are rapidly added all at once and the brown suspension: is stirred at 0°C for 15 minutes. Thin-layer chromatography now indicates a conversion of > 95% and no impurities at all.* 500.'ml of tr saturated NalCC, solution are slowly added’: . dropwise at -10 to n°, under very good cooling (very exothermic). A colorless solid which makes mechanical stirring very difficult forms. \

The organic phase is separated off, dried &nd : concentrated in vacuo. If required, the’ product is chromatographed with cyclohexane/toluens 112. through 800 g of silica gel or is distilled in vacuo. 43.1 g of the title compound XIE: LL . are obtained as a colorless solid, melting point 55 to 57°C, boiling point 134 to 135°C/12ik Hes id

CE Chal

TH-NMR(CDC1,) : § 1.77 (6H,d); 1.28 (98,83: 2,17 (1H, hept.); 4,61 (AR) 8) i 6.62 (111,d); 7.05 (AH,dd); oo 7.17 (11,4) a

MS (70 ev): m/e = 192 (M,) pe : Ek 3 i . | JE

. If the mixture is left to stand at rocit temperature under nitrogen for 10 hours, thin-layer chromatography again indicates about 30% or starting material ang numéreus oo by-products. Coa ome rs

Example 2.2 ) : 2-1sopropyl-4-tert.-butyl-6-bromophenol (Forditiia - 10 . XIV, Yetert.-bu) a i nA 118ml (55.8 gy 0.35 mole) of brominé are added . ha dropwise to a solution of 65.8 g (0434 mole) 1 3 ' - of the phenol XIII from Example 2.1 in 375 ml §f en : 15 col,. Complete conversion of the starting os Tg . material is checked by thin-layer chromatography ge i (eyclohexane/ethy acetate 5:1, Ry XIII: 0.37, Le ~ XIV: 0.33), the product is taken up in ether AE : 2 . and the solution is washed twice with RagB03 1... . SE solution and once with saturated NaCl solutions’ CL

It is dried, concentrated and distilied under i hign j . vacuum. 86.1 g of the title compound XIV are - ’ co " - obtained as a pale yellow oil, boils point a i 1105 to 106°0/1 mm Hg, ©. 00 oo CE 4 BEMR(ODOL) £25 (ema) 1.89 Qe) EE

Ai 3.47 (MH, bept.); 6.17 (MH,br.i} Ce ~45- wo

YuwY fa . YA ° 2.09 (MM,d); 7.24 (1H,d) oC

MS (70 eV): m/e = 270/272 oh)

Example 23 - 2-1gopropyl-4-tert.-butyl-6-iodophenol fPormula

XIX, Y=tert.-bu)

A solution of 30.4 g (0.12 mole) of iodine and 40.0 g (0.24 mole) of potassium iodide in 120 ml of water is added dropwise to a solution’ of 19,2 g (0.1 mole) of the phenol XIII from Example 2.1 in 150 ml of 50% strength aqueous ethylamine olution and 120 ml of ethanol at 20 to 25°C. The | mixture is stirred at room temperature For 1 hour, the product is taken up in ether, the s ¢ther extract is washed twice with Na,8505 golution and then with saturated NaCl solution, dried and concentrated in vacuo, the residue , 1s taken up in toluene and the soTut1sa" 18" : Rut ¢oncentrated in vacuo at &£ 25°C. 26.0 § of the title compound XIX are obtained as an oil. .

MH-NHR(CDCL5): f 1.15-1.50 (15H, 00d); 5.06 we (1H,hept.); 4.60 (1H,s,br.);

Co 6.86 (1H,8); 7.73 (1H,8)

Hs (70 eV, 50°C): m/e = 318 (M'), sds: (i -chy),

c ;

Co 275, 177, 161 :

Example 2.4 1-Benzyloxy-2-isopropyl-/-tert.-butyl-6- . bromobenzene (Formula XV, Y=tert.-bu) ig: obtained analogously to Example 1.3 from the compound XIV, Fxample 2.2. !

Colorless crystals, melting point 47 to 89°C.

TH-NMR(CDO15): § 1.23 (611,d); 1.48 (9H,8)} : 3.33 (1H,hept.); 5.12 (2Hy8); oo 2.02 (11,8); 7.44 (6H,s,br.)

Ms (70 eV): m/e = 360/262 (M'), 268/270,91

Example 2.5 1-Benzyloxy-2-isopropyl-i-tert.-butyl-6-p= -

Co Cees - wo: raha . fluorophenylbenzene (Formula XVIII, Y=tert.-bu, Co is obtained analogously to Example 1.4 from the corresponding Grignard compound XVI. nL

Colorless solid, melting point 126 to 128°C. 1 fo

H-NMR(CDCLz): fq, q-1.% (15H,8¢d); 3.38 (1H,

Umar a | 26257

Lo hept.); 5.16 (2H,8)3 6.83:

Ge (1H,8); 7.0-7.7 (AOH,m)

Ms (70 eV): m/e = 376 (M'), 282,91 :

Example 2.6 2_Isopropyl-4-tert.-butyl-6-p-fluorophenylphenol (Formula III, Y-tert.-bu, ZH) . ig obtained analogously to Example 1.5 from : the ‘compound XVIII from Example 2.5. oo

Colorless solid, melting point 109 to 111%.

TR-NMR(C1C1,): § 1.15 (9H,8); 1.23 (6i1,d)} oo 3.16 (1% ,hept.); 4.65 (1H,8)3 - ye 6.80 (11,8); 6.9-744 (S5Hym)"

MS (70 eV): m/e = 286 ('),271 (M'-CHj), 229

Example_ 2.7 SE —

Cn oe 2-18opropyl-4-tert.-butyl-6-p-fluorophenyls oo phetiol (Formula III, Y-tert.-bu,z=H) by direct’ coupling of the iodide X17 with the Grignard resgent from p-bromofluor(benzene XX ) - 1./87 g (1.6 mmol) of tetrakis(triphenylphospine) palladium (0) are added to a sclution of 35.7 oo | Broom Hy 26257 eg (81 mmol) of the iodophenol from xampls Tv 2.3 in 150 ml of absolute tetrahydrofuran and the mixture is stirred at room temperatiire for 30 minutes. The Grignard reagent obtained from 42.6 g (P4% mmol) of 4-bromofluorobenzene arid 6.2 g (255 mmol) of Mg filings in 176 m1 of tetrahydrofuran is added all at once. . During : this addition, the internal temperature rises to about 50°C. The mixture is kept at 569 for 3 hours, durins which a colorless solid (magnesium iodide) separates out.* The reaction mizture is taken up in ether and the ethei extract is washed twice with IN hydrochloric acid, once with water and once with saturated sodium bicarbonate sclution, dried and cancen- trated in vacuo. [he residue is chromatographed with cyclohexane/ethy] acetate 9:1 over 1 kg of allica gel. The fractions containing X1I1;

X1X and 111 are concentrated together. Tre Pp” residuc is dissolved in the minigun amount. of Co n-pentane. 9.8 g of pure 111 crystallize in a deep-freeze. The mel ting point and spec tim of this material were identical to those glven in Example 2.6. oo _ Lo * on The course of the reaction cannot pe ~19- rr - BAD ORIGINAL 9

Lo PA

Se igh “* monitored by thin-layer chromatography —- since the iodide XIX, the coupling ¥ "product III and the phenol XIII, which is formed as a by-product during coupling, 5 . cochromatograph in all the usual mobile phases. uitable separating conditions: high performance liquid chromatography on © a 250x#.6 RI’ column of 18.5 um Nucleosil, 64% (CH,CH + 0.7% um, one) 36% H,D, 1.2 ml/minute, #0°C, UV detection at — 254 nm.

Examples 2.8 to 2.11 a 4(R)-Hydroxy-6(;)-/2-isopropyl-4-tert.-butyl- : 6-p-fluorophenyl)phenoxymethyl_7tetrahydro-2H- pyran-2-one _ (Formula I, X=0, Y=tert.-bu,z=H) a | - oh we _ is obtained from the phenol III(Example 2.6 To or 2.7) analogously to Fxamples 1.6 to 1.9.

Colorless solid, melting point 178-179°%C

H-NHE(GD,OD,): § 1.13-1.20 (15i,m), 2.02

EN (,5,br0), 2.10-2.16(2H,m), 2.71 (2H,AB of ABK), 3.24 ., -50- nl

; (1H,bept.), 4.22 (2H,AB ‘of ABX), oo 4,50 (1H,s,br.), 5.03-5.43 (4H,m), 6.79 (1H,8), 6.98-7.07 (3H,m), 7.19-7.25 (2H,m)

M8 (70 eV): m/e = 414 (M'),359

IR (KBr): 3560/3460 (OH), 1745, (C=0), 1500, 1235, oo 1220 em”

Example 3 "

Synthesis of 4(R)-hydroxy-6(S)~/ (2-isopropyl- 4 ,6-di-p-fluorophenyl)phenoxymethyl 7tetrahydro- 2H-pyran-2-one :

Formula I, X«0, Y = -O)- Z2=H

Example 3.1 2-Isopropyl-4,6-diiodophenol (Formula XXI) r

A solution of 160 g (0.63 mole) of iodine and 209 g (1.26 mole) of potassium iodide in 300 ml of water is added dropwise to a solution of 40.8 g (0.3 mole) of o-isopropylphenol in 630 ml of 50% strength aqueous ethylamine solution and 525 ml of ethanol at O - 15°C in the course of 10. . minutes. The reaction mixture is stirred at

. 2 LT 26257 room. temperature for 20 minutes and poured onto 200 m1 of saturated Ra 5,05 solution plus 600 ml of water. The mixuture is extracted with 3 x 500. inl of ether and the combined extracts are washed with E./2 N hydrochloric acid and then - with water. They are dried over Mgso, and ) decanted onto fresh MgS0,, the mixture is filtered and the filtrate is concentrated in vacuo at £20°C. 100 ml of toluene are added and the mixture is concentrgted in vacuo at < 20%. . This operation of evaporation by fuming with toluene is repeated once under a waterpump vacuum and once under a high vacuum. 99.0 g of the title compound are obtained as a red oil. No impurities are detectable by NMR, MS or thin= layer chromatography.

TB-RMR(CDC1,): § 1.2 (6H,d), 3.2 (1H,hepti)q 5 Ce), 7.35 Cu, 75 (18,4) ae a

Ms (70 eV): m/e 388 (X'), 373 (M'-CH,), aug

Bh (1 ~CH, I) fk

Example 3.2 i 2 2-Isopropyl-4,6-di-p-fluorophenylphenol / (Formula III', Z=H) | oH . -52- Lo

El wr

The Grignard solution obtained from 219 g (4.25 mole of p-hromofluorobengene and 31.3 g (1:3 mole) of megnesium filings in 600 ml of absolute, tetra: hydrofuran is added dropwise to a solution of 125 g (0.32 mole) of the diiodide XXI from

Example 3.1 ahd 5 g (7.1 mmol) of bis-(triphenyl- phosphine)palladium(II) ahloride (Aldrich) in 300 ml of absolute tetrahydrofuran under afgon and while cooling with ice (internal température of 25 - 30°C). The mixure is stirred at 40 - 50°C Co for 5 hours, a further 2.5 g of (PPh, ) PAC, % ars then added and the mixture is stirred overnight ~~ . ~~ at about 45°c, It is cooled to 0°C and 50 mi of water are added dropwise (exothermic resction) at sugh a rate that the internal temperatiie remains below 25°C. A viscous slimy precipitate forme. 300 ml of half-concentrated hydrobhloric acid are added dropwise at 25°C (precipitate dissolves. pE ~ 1). The mixture is extracted

Co 20 several times with ether. The conbiBed extracts 7 are. washed with 1N hydrochloric acid, then with - saturated NeHCO, solution and subsequently with saturated sodium chloride solution and then dried and concentrated. A black viscous oil 4g obtained which is chromatographed through 1 kg of silica gel 70 & 200 ym, first with : 4 1 of cyclohexane/toluene (4:1), then Fe -53- i

£ IE 10:1 of cyclohexane/toluene (3:1) and subséquently | |\ ¥ ,

Eel BE pay with cyclohexane/toluene (2.5:1). CE EN 1042 g of a colorless solid which, according to wk

FMR (only aromatic protons) MS: 360, Bag, 28a, \i 4 ’ : 266 (base peak), 248 and analysis (C+B+F a 100%) , is an oligomer mixu Co Cy

E compound XX (Z=H . CA y . - : Se a 10 Code | Q - nfs - 266 coresponds to (3 | - : a : ~ nT ge oo

Be : . | gi ! 248 is 266-F+H, 284 is 266+F-H, 360 is 2664 a s ch ' . Ir

Co CB, P-H, 342 1s 360-F4+H. Te vip Ch :

TN | RE 246 of a mono-coupling product which is" : -241s6propyl-4-p-fluorophenyl-6-iodaphenol XIX' - ga REE (Tia p-fluorophenyl) are then eluted. SRE

ME (70 eV): m/e = 356 (If'), 381 (M*-CH,),24n

Fe oo

Fifidlly, 45. 1 g of the title compound IIi' are : 2 ce i > eluted as a viscous colorless oil which érystalliges off prolonged standing at room temperatufés . -

H-NMR(CDC1;): 4 1.35 (6H,d); 3.4 (18, hbpt. 3 ol

SE ~54_ Hr

Se Eh

Co Fah: Ce of Ho oR AIR

So wi 20 4 hn ALE

ER

TH

He 5.1 (1H,8); 6.8-7.6 (10H;m)

MS (70 eV): m/e = 324 (I), 309 (M'-CHy)

Thin-layer chromatography (toluene/cyclohexans . 112) R, values: oligomer mixture 0.61, starting material XXI 0.53, monoiodide XIX' 0.50, product III': 0.35 CT

Examples 3.3 to 3.6 - a(R)-Hydroxy-6(5)-¢~ (2-isopropyl-&,6-di-p-fluorq-

Co | t phenyl )-phenoxymethyl_Jtetrahydro-2H-pyrdn-2-one : (Formula 1 X=0, Y= <0)” 2«H) : oo oo . is obtained from the phenol 111 (Example 3.2) andlogously to Examples 1.6 to 1.9. N

Cqlorless solid, melting point 190-192°C ." . A JAR -

THSNMR(CDCL,, 270 Mis): 6 1.31 (6, 2xd)} . co

EE 1.72-1.95 (3H,m}§ 2.66 au (2H,AB of ABX); 3.47

Co (1H,hept.), 3.59 (2H, AB oo

CA 4.70 (1H,m), 7.12 (4H,m), 7.28 (AH,d), 7:82 ga ~ (18,4), 7.55 (8H,m).

i wr g ms (pe1)s m/e = 452 (M"), 437 (1 ~CB5) 129 - Lo : IR (KBr): 3480 (OH), 1715 (C=0), 1510, 1255, ) Cu © 1220, 1200, 1460, 830 on™" -

Example 4 n

Ar Co

Synthesis of 3(R)-hydroxy-6(5)-/" (2-4kopropyl-4- I phényl-6-p-fluorophenyl )-phenoxymethyl_7tetra- ener hydro-2R-pyran-2-one | . 0 1 (Formula I, X=0, Y = phenyl, Z=B) v

Example 4.1 241aopropyl-ti-phenylnitrobensene (Formula IX)

The Grignard solution obtained from 30. 7.8 (9:25 mole) of 2-bromopropane and 5.85 g (U2 noise) of magnesium filings in 300 ml of ibsolute - tetrahydrofuran is added dropwise to & soldtiod 0£20.0 g (0.1 mole) of A-mitiobiphenyl” VIII: .. 18 400 ml of absolute tetrahydrofuran at + 570% under nitrogen in the course of 3 hourss . The mixture is stirred at -70% for a furthest hour ; (thin-layer chromatography: VIII completely oo reacted) and a solution of 22. 7 g (0.1 mole) of 2,3-dlchloro-5,6-d1cyano-p-bensoquinbi (DBR) in 200 ml of absolute tetrahydrofufan is tien rapidly added dropwise at -40°c. The mixture 18 allowed to warm to room temperature and. is stirred for a further hour and poured onkd 1.2 »

it Cn oo WF i a : FE

A of water. The tetrahydrofuran is stripped off in vacuo, the aqueous residue is extracted twice with ethyl acetate and the extracts are washed thoroughly with water,, d:icd and concentrated. Chromatorraphy with cyclohexane/

CH,CH, 4:1 through 1 kg of silica gel gives 8.9 g of the title compound IX as a pale red oil.

TH-NME(CLG1): §1.37 (61,4); 3.58 (1H, hept.); 7.36-7.97 (81i,m)

MS (70 eV): m/e = 244 (1), 224, 174, 152

Lxample 4.2 2-Isopropyl-4-phenylaniline (Formula X) 13.1 8 (S4.%mmol) of the nitro compound me i from Lxample 4.1 are dissolved in a solution of - 10.g of ammonia in 4C0 ml of methanol. 10g Co of Raney nickel which has been washed three RE times with methanol are added, under nitro- ger. The suspension is shaken at room temperature under normal pressure in a hydgrogen atmosphere for 2 hours. The catalyst is filtered of, the oo filtrate is concentrated and the residug is chromatographed over 4CO g of silica gel with

2 1 of cyclohexane/toluene 1:2 gnd then with : ~ 1 of toluene. 11.2 pg of the title compound . X are obtained as a colorless oil. ~ 5 TH-RMR(CLOL,): §1.33 (611,d); 3.00 (10,hepti); 7.85 (PH,s,hr.)i 6.70 (1H,d); 7.8- 7.7 (7H,m) or 1.3 (70 ev): m/e = 214 (MY), 196 (M'-CH,) co

Lxample 4.3 2-1sopropyl-4-phenylphenol (Formula XIII, Y - OO )

A solution of 4.28 g (62 mmol) of sodium nitrite in 50 ml of water is ndded to a solution of 41.2 £ (53.1 mmol) of the amine X from Example 4.2 in 50'ml of -% cial acetic acid at 10 to 12%.

The’ diazonium salt precipitates. The suspérision - . - £0 is difficult to stir. After 5 minutes, the." a : suspension is poured slowly into a boiling: PL solution of 32 ml of concentrated sulfuricacid . in 65 ml of water. The mi:ture is stirred, for a further 5 minutes and then cooled and pattitioned : 25 between toluene/ether and saturated sodium’ chléride solution. The organic phase is yashed twice with saturated DaliCOy solution and onde “ - y — + -58- o

Bk, Ce

Cow 3 “EH with sodium chloride solution and then dried and concentrated. Chromatography with 100% toluene . through 500 g of silica pel gives 4.9 g of the title compound XI11 a= a y- low oil.

TH-NMR(CDC1,) : § 1.70 (6H,d); 3.25 (11,hept.); 7.1=7.7 (8H,m)

I. (70 eV): m/e = 212 (1'), 197 (M'-CH;), 178

Example 4.4 2-Isopropyl-4-phenyl-6-bromophenol (Formula X1V,

Y = phenyl) k is obtained analogously to Example 2.2 from the phenol XII1 from Lxample 4.7, i.

TH-NMR(CDC1,): § 1.26 (6l1,d); 3.40 (1 hepta); oo 5.63 (1,8); 7.2-7.7 (7H,m) ” . 20 Ns (70 eV): m/e = 200/292 (1), 275/277 (i*Gily), : 196, 165 CY

Ixample 4.5 oo 1-Benzyloxy-2-isopropyl-4-phenyl-6-bromobensene (Formula XV, Y = phenyl) joo i ; ~59- BAD ORIGINAL J b r .

is ‘obtained analogously to Example 1.3 from of the phenol X1V (lxample 4.4) as a colorless . oil which slowly crystallizes.

TH-NMR(CLC1,5) § 1.20 (6H,d); 3.45 (10, hept.); : 5.05 (2H,8); 6.95-7.70 (12H,m) 15 (70 eV): m/e = 380/772 (M7), 9 ne

Example 4.6 ou 1-Benzyloxy-2-isopropyl-4-phenyl-6-p-fluoro- - phenylbenzene (Formula xV111, Y = phenyl, Z=H) is obtained analogously to hxen le 1.4 from the corresponding Grignard compound XVI as’ a colorless oil which slowly crystallizesi __

THINNR(CDC1,): § 1.78 (6H,d); 3.52 (111, hepta );

Lo 5.00 (PH,5); 6.95-7.70 (16H;m) - vo Ces — . pags am Cx J. 15: (70 ev): m/e = 396 (Ii) Fn Lu

Example h.7 J : 2-Isopropyl-4-phenyl-G-p-fluorophenylphenol (Formula 111, Y = phenyl, 4=H) oo . , is obtained analogusly to Example 1.5 from. :

XVI1I from Example 4.6 as a colorless solid.

GR -60- r— = & w BAD ORIGINAL YP hain © ad pt Vig . ie ES CER $s : €,,, i "H-NMR(CDC1,): 4 1.35 (6H,d); 3.40 (1H,hept.); 5.10 (14, 8,br.); 6.85-7.45 (11H, m)

M5 (70 eV): m/e = A006 (I'D, 291 (MY-CH,)

Lxamples 4.8 to 4.11 4 (R)-Hydroxy-6(3)-/" (?-isoprop yl-4~phenyl-6-p- fluorophenyl )phenoxymethyl 7tetrahydro-2H-pyran- 2-one (Formula J, X=C, Y = phenyl, 2=H) } is obtained from the phenol (lLxample 4.7) analo- pously to Examples 1.6 to 1.9.

Colorless solid, melting point 184-187°C

TH-NMR(CIO1,4) § 1.70 (61,2xd), 1.7-2.0 (3H,m), 2.65 (2H,m), 3.50 (1H, hept.);

L | 3.60 (Pl,m), 4.80 - ) (MHym), 4.70 (i,m), 7.1-7.6 04H, m) oo : 20 15 (DCI): m/e = 434 (1'), 4219 (M*=CH,,) So ee

B I xample 5 . ‘ ynthesis of 4(R)=hydrexy-6()-/B-isopropyls 4-cyclohexyl-6-p-flucrophenyl)-phenoxymethyl_7 tetrahydro-2H-pyran-~-one | : . 1 Co or —61- AD ORIGINAL © . : We ot

Ct I. . k Li Lat cE i v hel “ , AN 3 A. Wns PEA : : oo a rs Cg ip (Formula I, X=0, Y = cyclohexyl, Z=H} 7

Lxample 5.1 bo) 2-Isopropyl-4-cyclohexyl-phenol (F,rmula XIII, Y = cyclohexyl) 2.0 g of 5% palladium-on-charcoal suspended in 50" ml of ethyl acetate are shaken at room’ tempe- rature in a hydrogen atmosphere for 70 minutes. . A solution of 31.2 g (0.1 mole) of the phenol

XIII from Fxample 4.3 in 250 ml of ethyl acetate is added, with exclusion of oxygen, and the: : mixture is shaken at f° upde a hydrogen pressure of 5 kg/cm” for 5 hours, Lhe course of the. . reaction can be monitcred by gas chromatography /™2 m of SF 1000 on ®Chromosort WAW 20 td;,100 mesh, 220°C, Por . ny Sr 2 . _ su a 1.0, kg/cm of NK, carrier gas, t ..: XITT AY = Or starting compound) 13.2 minutes, product XIII (Y = {5 cy&lohexyl): 4.6 minutes_/. i

The gas chromatography analysis shows that about 90 of X11I (Y = cyclohexyl) and several (By= products, no more than 3% of any, are formed. . -62- ro

Zoora

Cf CN ie

Co Hi eH

The catalyst is filtered off and the residue ig recrystallized from cyclohexane. 25.0 g of the title compound %J1]1 are obtained as a colorless solid.

TH-NHMR(CDC1,) § 0.8-1.2 (10H,m); 1.25 (6H,d); 2,00 (1H,m); *.11 (1H,hept.); 4.24 i (1,8,br); 6.50-7.10 (3H,m) ~

M5 (70 ev): m/e = 218 (MY), 203 (M*-ci,) x Bh

Co (xample 5.2 - 2_tsopropyl-4-cyclohexyl -6-iodophenol (Formula XIX,

Y & cyclohexyl) is obtained snalogously tr Lxample 2:3 from the phenol XIIT from Example 5.1. -

TH-NME(CIC1,). § 0.7-1,2(10H,m); 1.26 (6Hyd); -

Co 3,023.1 (2l1,m); 4.60 (11, 5,b8) 4 La

Co oo 6.88-7.40 (2H,m) Te

EG (70 eV): m/e = 344 (MY), 329 (ch) i i id rxample 5.3 pe a5 . 5. 2-Isopropyl-4-cyclohexyl-6-p~fluorophenyjphenol (Formula 111, Y - cyclohexyl, Z=1i) =

Co | Mae i i. ‘ Hed Los . a Fi a Sa ) On . is dbtained annlorously to Example 2.7 from: ' : the iodophenol X1X from Example 5,2, pe

VH-NMR(CDC1,): 4 0.7-1.72 (10h): 1.25 (6h,D); 3.0-".7 (Ph); 1.00 (1h, 84BR. );

Fi } 6.9-7.4 (6H,m) 5

BY (70 evr m/e = 312 (HY), 297 (M'-ci,)

Examples 5.1 to 6.7 “ Ce oo Cu { 4(RY-Hydroxy-6(::)-/"(2-isopropyl-4-cyclohexyls

Poy 7 TE I 6-p-flurophenyl)phenoxymethyl 7tetrahydro-2f=- iE pyran=o-one EE :

Sa EL bo (Formula 1, X=0, Y = cyclohexyl, Z=H) HL - = jE | : oa ie is obtained from the phenol II1 from Example *° £.3 snalogously to I'xamplea 1.6 to 1.9. Colorless solid; melting point 158 to 160°C. a

H-RMR(CDCL,): § 0.8-1.1 (10H,m); 1.27 (6H, Yj... = ~ } kr 3 tT : : A 1.68 (1H, s,br); 1.75 (AH,m)3; “ava. wr ol 1.90 (115m); 2.55-2.70 (2H,#}} or 3.0-7.7 (P1,m); 3.55 (2,m)}is 2 Ef

Th 4.7) (M,qui)y 4.70 (MH,m) 80 on re i

Vt 7.0-7.5(6H,m) dr

MS (70 eV): m/e = 440 (M*) i a BAD ORIGINAL A

© tyr TER

CL ' Ed

Fxample 6 ER _ynthesis of #(1)=hydroxy-6(5)=/"("," *1ipsépropyl- . 6-p=~fluorophenyl)phen.!thiomethyl 7tetrahydro- rll-pyran-c-cne 2 (Formula 1, X=", Y=i-ir, 2:1) ho 1 xample 6.1 v 2,4=-Diisopropy)-6-p-rluorophenyl N,l-dimethyl- thiocarbamate } 3.6 g of N00 strenrth ocdium hydride ore suspended in 60 ml of absolute Jirethylfeo-mamide, 21.76 g (80 mmol, 1 equivalent) of 2,4-0i1isopropyl=6-p- fluorophenyl-phenol ( x»mple 1.5) are introduced, while cooling with ice. The solution is stirred at room temperature for %0 minutes and cooled er to 0°: A solution of 12./ g (1.25 equivalents) -» of dimethylthiocarbamoyl chloride (Alirich): in 20 #1 of dimethylformamide ic added and the Ra resction mixture is stirred at P0-90°C for 5 hours.

Lftey cooling, the mi: ture is diluted with 500 m? of ether, washed twice with water and oto with potssgium bicarhen~te solution and dried over magnesium sulfate nnd the solvent in atripped . a off. The residue is recrystallized from methanol. ’ -65- BAD ORIGINAL A be Lo Th co ‘ i So 25.6 (yield of 89%) of the title compétind . are obtained as a solid, melting point 182°C.

Ms: m/e = 359 (MF)

Example 6.7 : ~~ 8-/7(2,4-Diisopropyl-6-p-fluorophenyl)phenyl_7 .N, N-dimethylthiocarbamate Ce . ” 1 oo 10 " 25.0 g of the thiocarbamate from Example 6.4 were heated at 270-300°C under nitrogen for 1 hour. After cooling, the residue was: dissolved “in the minimum amount of hot n-hexane ahd ‘after addition of active charcoal the mixture was boiled under reflux for 10 minutes and . filtered hot. 20.0 g (80% yield) of the ~ title compound crystallize out of the filtrate as colorless n«edles during slow coolifig. © 8: m/e = 359 (MM) po - : "Example 6.3 Aa 2,4-Diisopropyl-6-p-fluorophenyl-thioplienol +. (Formula 1II, X=3, Y= i-Fr, 2=H) - 25 . h - fo.

dro oN Bn x Wh

A solution of 19.7 g of the thiocarbamate from Example 6.2 in ether is added dropwise to a suspension of 3.2 g of lithium aluminum : hydride in absolute ether, while cooling With ice. The mixture is stirred at room tempera- ture for 2 hours and hydrolyzed with 2K ro sulfuric acid (to pH 3), while cooling with Co

Lee. The mixture is extracted several bides or vith ether, the extract is dried over nag nesiun gul fate and the solvent ig stripped off. 16:8 g of the title compound are obtained as © a viscous oil.

Co Mgr m/e - 288 (M*), 273 (rt ~CHy) ;

Exemple 6.4 2 6(8)_-("(2,4-Di1aopropyl-6-p-tluorophensl) heny1thionethyl_7-3,8,5,6-tetranyardse(R,9)- sethory—b()-(5-butyl-dipenylstiyiony)-2h- . pyren(Formula V, 58, Yei-Pr, zeH, R= ¥butyl- LT diphenylsilyl) Fhe : “A suspension of 13.8 g (100 mmol) of potassium ‘sarbonate, 14.4 g (50 mmol) of the thiephenol tron Example 6.3 snd 20.4 & (a0mmol) of the

Jactol ether iodide IV (7 - t-butyl-giphenyl- si171, for the preparation see EP-A 0,246,127) _67- Lo %

} in

EE

Fo te i if in 300 ml of absolute dimethyl sulfoxide: was stirred at 50°C for 1 hour. Water was added to the cooled reaction mixture and the mixture was extracted three times with ether. THe combined organic phases were washed with® : water and then with saturated sodium chlbride solution, dried over magnesium sulfate atid. Coe concentrated in vacuo. The residues was ghroma- tographed with toluene/-ethyl acetate 95.5 over silica gel and gave 21.4 g (80% yield) of the title compound as a colorless viscous oli ms (CI): m/e = 670 (M'), 613 (* —tert.-bt)

Example 6.5 v

Cs on a 6{8)-/(2,4-Di1s0propyl-6-p-tluorophenyl) phenylthionethyl 7-3,4,5,6~tetrahydro-2(k;8)- Lo hydroxy-4(R)-(t-butyl-diphenylsilyloxy)-2i=

B pyran (Formula VI) A | -

A'Solution of 20.1 g (30 mmol) of the label ether V from Example 6.4 in 2 1 of tetrahjdro- : | oo fran, 1 1 of water and 1 1 of triflvorcdeetic : acid was stirred at 50-60°C for 4 hour. After : : coling to room temperature, 1.5 kg of sodium Co . acetate were added. The organic solvent: Rn . wii stripped off in vacuo. 1 1 of saturdted - ; sodium chloride solution was added to the:

CE

~68- i : : - ER : o NO i wel : } aqueous residue and the mixture was extracted several times with ether. The combined organic extracts were washed with water and dried over sagnesiun sulfate. The ether was stripped off and the residue was chromatographed with cyclohexane/ethyl acetate 4:1 over silica gel. 13.8 ¢g (704.yield) of the title compound were or obtained as a colorless viscous oil.

MS(CI): m/d = 656 (M*), 638 (i* - H,0), 584 (M* ~-bu-H,0)

Example 6.6. 6(8)=/"(2,4-Di1s0propyl-6-p-fluorophenyl) oo phenylthiomethyl _7-3,4,5,6-tetrahydro-u(R)= | . (t=butyldiphenylsilyloxy)-2H-pyran-2-one (Formula viz) oo

A solution of 13.0 g (19.8 mmol) of the lagtsl - v1 from Example 6.5, 7.4 g (20mmol) of tetihd -- pr butylammonium iodide snd 22.5 g (100 mmol) 6f -

K-iodosuccinimide in 200 ml of methylene A , chloride was stirred at room temperature for 12 hours. $500 ml of toluene were added and’ the methylene chloride was removed in vacuo;

The precipitate was filteted off with suction and washed with toluene. The combined filtrates -69- i : / . od ;

co Pog 26957 vere washed once each time with aqueous sodium ~ thiosulfate solution and saturated sodium’ chloride solution, dried over magnesium sulfate, Co a filtered and concentrated in vacuo. The residue hE was chromatographed with toluene/ethyl .acetate 1014 over silica gel. 11.6 g (90% yield) of | ne the title compound were obtained as a colorless viscous oil. o

M8 (70 eV, 70°C): m/e = 654 (M'), 597 (Mt bobu)_

Example 6.7 4(R)-Hydroxy-6(8)-/ (2,4-diisopropyl-6-p- . fluorophenyl)-phenylthiomethyl_7tetrahydro- 2H-pyran-2-one oo Co

Analogously to Fxemple 1.9, 4.9 g (70% yield) of the title compound are obtained as a viééous colorless oil from 11.0 g of the protected | - ~ 20 lactone (Example 6.6.). TE Co "B-NMR(CDOL,): §1.25 (12H), 2xd), 1.65 (oH,

BY br.), 1.7-1.9 (2H,m), 2.5-2.6 or (2H,m), 2.75 (28,m), 2.90 (1, hept.), 3.40 (1H, hept.), 4.35

C (1H,qui), 4.50 (1H,m), 7.9 7.5 (6H,m). BE

NE (PAB): m/e = 416 (M) . =70- ¥ wy

Example 7

Synthesis of 4(R)-hydroxy-6(5)-/ (2-isopropyl- 4 ,6-di-p-fluorophenyl)phenylthiomethyl/tetra- hydro-2H-pyran-2-one (Formula I, X=S, Y = p-fluorophenyl, Z=H)

The title compound is obtained by converting. 2-isopropyl-4,6-di-p-fluorophenyl-phenol (Example 3.2)into 2-isopropyl-4,6-di-p- — fluorophenyl-thiophenol analogously to Examples 6.1 to 6.3 and reacting this to give the title compound analogously to Examples 6.4-6.7. oo

Colorless tacky solid which becomes crystalline when washed with n-hexane, melting point 5 60°C. "B-FMR(CDC,): § 1.3 (6H,d), 1.7-1.95 (3H,m), ! Bn 3.4 (1H,hept.), 4.4 (1Hym), "

MS (FAB): m/e = 468 (M*), 453 (If-CHy) ©

IR (KBr): 3480 (OH), 1715 (C=0) Sn

Example 8 Ce

Freparation of the sodium salts of the oppn~ chain dihydroxycarboxylic acids (Formula 11, .

sodium salt) from the lactones of the formuld I 3

Example 8a

Sodium 3(R),5(S)-dihydroxy-6-/ 2-(4-fluoro- phenyl)-4,6-diisopropylphenoxy_7/-hexanoate i 17.7 ml of AN sodium hydroxide solution are. Cm rapidly added dropwise to a solution of 7.8 8 “0 (17.5 mmol) of the lactone from Example 19° in 800 ml of absolute ethanol, while, cooling with ice. The mixture is stirred for S minutes, while cooling with ice, and then at room tom- perature for 2 hours. According to thin-layer ~ chromatography, the starting material has wn reacted completely. The solvents are stripped - off in vacuo at a bath temperature of 30°C,

The residue is twice dissolved in ether and the solution is concentrated to dryness euch he 20 tine}’ the residue ie then dissolved ih §bheH dnd ’ Ea ] the solution is concentrated to dryness in vacuo.

The residue is suspended in toluene and the suspension is concentrated to dryness in vacuo.

The residue is stirred with n-pentane and thn : oo filtered off with suction and dried under a high vacuum over phosphorus pentoxide and - potassium hydroxide losenges. 6.25 g of tile - 90a para i . Sgt

N :

Lo .

Li oo title compound are obtained as a colorless : amo#phous powder. Concentration of the 2 . ; pentane~containing mother liquor gives a i. further 0.43 g of amorphous product. Melting point 240-244°C (decomposition). The decoipo- sition point depends on the rate of heating up.

Example 8b a.

MI

Sodium 3(R),5(5)-dihydroxy-6/2-180propyl-ts tert.-butyl-6-(4-fluorophenyl)phenoxy_7-he¥anoate is obtained analogously to Example 8a from the lactone from Example 2.11. i

Colorless powder, melting point 256-258°C . (decomposition) i: ne 4

Example 8c A

Sodium 3(R) ,5(8)-dihydroxy-6-/3-isopropyls - 4 ,6~b18-(4-fluorophenyl)phenoxy_7-hékancata - is obtained analogusly to Example Ba from |i the lactone from Example 3.6. fo - Colofiess powder, melting point 235-237°C ia (decomposition) "

Example 8d 4 3 )

Sodium 3(R) ,5(S)-d1hydroxy-6-(3-1sopropyl-4= « Wl -73~ x \

Co CA | #

; ° ! a By : phenyl-6-(4-fluorophenyl )phenoxy_7-hexenoate is obtained analogously to Example 8a from thé lactofie from Example 4.11.

Colorless powder, melting point 2%8-240°C (decom- . J position) .

C0 —— 8e ol

Lo sodiug 3(R_45(8)-dihydroxy-6-/2-isopropyl-4- cyslohe 1-6-(4-fluorophenyl)phenoxy_7-hexanoate « ghe ned analogusly to Example 8a from. the IE re from Example 5.7. :

Colorless powder, melting point 230-233°C (aokomposttion

Ex al Lo tT po ; - - TRE or JX; : yr : ot

Sodium j 3(R), 5(8)-dihydfoxy-6-/ 2-4=fluorophenyl- at ’ s/t assapropyi-thsophenory 7-hexsnoats NL ee ; \ . A

Ie obtained analogously to Example 8a froti the /lajotone from Example 6.7. Yo

Jo lorless powder, melting point 230-234°C / (@ecomposition) fi

Example 8g -74- Bg : . | ;

Sodium 3(R'), 5(8)-di hydroxy-6-(2-180propyl- 4 ,6-bia-(4-rluorophenyl)-thiophenoxy_7-hexsnoate is obtained analogously to Example 8a froft the lactone from Example 7. =

Te - EV a yo ~75- i

Claims (5)

1. CL . meg mag! Sepia . ST ; A el fv) ok So Sa etm i ve : ro : Le i) CoE EL '

   } . Sf FAY , Ry. WF 5 HR ns of ET - he CU . DN HAE ) i 7 ; : el He SH) . . oT Patent Claims: 3 of 1. xA 6<phenoxymethyl-4-hydroxy-tetrahydroe v Se } C ee : ~&:pyran-2-one: and 6-thiophenoxymethyl=4=" ‘ 'hydroxy-tetrahydropyran-2-one of the: Hi oy Le ao 4 s»formula I ol ps ") y° CE A : 2 - i CH : : % 7s Co . + :. \ EES O : ] X CH, 2 we ; fo Y rr and; a corresponding open-chdin dihydroxy=': carboxylic acid of the formula II Ea oa a I A ; Be a HO o Hl AE “CooH CE La OH dE boo a | “X I Bia 2 a 4 SERVE 2: He 2 A) RETA Ce TN ey oo Eee / CF ane wo “s : go i Eo TEE \ s i in which dh ; xX is oxygen’ or sulfur, LE i \ | J Co

   : 5. figs

   Ly . SEE k ; Ll y Le ve) - 1 : ts i l ol Lh SBIR hn a de a7 BRA go oo HIT aN - mga vA a To al CORE © 269257 | ow CE f a CE Lo ‘ Y is a straight chain or branched alkyl’ SE i radical having 3 to 12 carbon atoms, cycloalkyl having 3» to 8 carbon atoms or a phenyl radicals, which can be substituted in the nucleus by : halogen; -

   / . ,

   /
2. 2. Z is hydrogen A compound as claimed in claim 1, in which, / in the formula I or II i

   XxX. is oxygen Ta on NN YY is isopropyl, tert.-butyl, cyclohexyl, ’ phenyl or p-fluorophenyl and Sr Cl z is hydrogen. iE Co

   :
3. 3. A pharmaceutical preparation comprising an CC effective amount of a compound as claimed in Cy claim 1, in admixture with a suitable cafrier. : ! Cu Cher i . : ov Lo : } Yo Lo Gr i
4. 4, A method for the prophyloxis and treatméfit i I PN Ce ei - ge NY of arteriosclerosis and hyperchlol8sterolemia TC Ce v/ . in mammals which comprises administering to ~°. .. ER said mammal an effective amount of a compound 1 i Yo as ¢laimed in claim 1 and a pharmacologibnily 1 . : télerated ester thereof. i . |
5. 5 . Co SE : -77- oe i