NO172538B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 6-PHENOXYMETHYL-4-HYDROXYTETRAHYDROPYRANE-2-ONER AND 6-THIOPHENE OXYMETHYL-4-HYDROXYTETHYTHROPYRANE - Google Patents

Description

The present invention relates to the production of new, therapeutically active 6-phenoxymethyl-4-hydroxytetrahydropyran-2-ones and 6-thiophenoxymethyl-4-hydroxytetrahydropyran-2-ones.

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase (HMG-CoA reductase) plays a central role in the biosynthesis of cholesterol [A. Endo, J. Med. Chem. 28, 401 (1985)]. The emmable substance for this enzyme, especially mevinolin [A.S. Pappu et al., Clin. Res. 34, 684 A (1986)], synvinolin [A.S. Olsson et al., The Lancet, 381 (1986); M.J.T.M. Mol et al., The Lancet, 936 (1986)] and eptastatin [Drugs of the Future 12, 437 (1987); N. Nakaya et al. Atherosclerosis 61, 125 (1986) was tested clinically for the treatment of hypercholesterolemics. Structurally simplified, fully synthetic analogs of these compounds have been described [G.E. Stokker et al., J. Med. Chem. 29, 170 and 852 (1986), W. F. Hoffman et al., J. Med. Chem. 29, 159 (1986)].

European patent publication A-0216127 describes compounds of formula Ia

in which

R<1> and R<5> are the same or different and mean a) hydrogen or halogen, b) cycloalkyl with 4-8 C atoms or a phenyl radical which in the nucleus may be substituted one to three times by halogen, trifluoromethyl and/ or alkyl or alkoxy with 1-4 C atoms or c) a straight-chain or branched alkyl radical with 1 to 18 carbon atoms or a straight-chain or branched alkenyl radical with 2 to 18 car-

bon atoms, whereby alkyl or the alkenyl radicals can again be substituted one to three times with

a) straight-chain or branched olefinic acid residues with up to 10 carbon atoms or cycloalcoic acid residues with 3 to 7

carbon atoms or straight-chain or branched alkenyloxy or alkynyloxy radicals with 3 to 6 carbon atoms,

g) halogen, hydroxy, cycloalkyl with 3-7 C atoms, unsubstituted phenyl-, a- or p<->thienyl residues, or phenyl-, a- or p<->thienyl residues, which in turn are substituted in the nucleus one to three times with halogen, trifluoromethyl and/or alkyl or alkoxy with 1-4 C atoms, "Y) unsubstituted phenoxy-, benzyloxy-, a- or p-thienyloxy residues, or phenoxy-, benzyloxy-, a- or p- thienyloxy acid residues, which in turn may be substituted in the nucleus one to three times by halogen, trifluoromethyl and/or alkyl or alkoxy with 1 to 4 carbon atoms, the S) group where r<6> means: a straight-chain or branched alkyl or alkenyl residue with up to 8 carbon atoms, or a cycloalkyl or cycloalkenyl residue with 3-8 C atoms, or an unsubstituted phenyl residue or a phenyl residue which is again substituted in the nucleus one to three times by halogen, trifluoromethyl and /or alkyl or alkoxy with 1-4 C atoms, or a 3-pyridyl residue,

R<2> and R<4> are the same or different and mean hydrogen, alkyl with 1-4 C atoms, halogen or alkoxy with 1-4 C atoms, and

R<3> is hydrogen, alkyl or alkenyl with up to 4 C atoms, halogen or alkoxy with 1-4 C atoms, as well as the corresponding open-chain dihydroxycarboxylic acids, their pharmacologically acceptable salts with bases or their pharmacologically acceptable esters.

The compounds mentioned in this publication inhibit HMG-CoA reductase with IC 50 values in the 10-<5> to 10~<8> mol range. According to information in the description, compound Ia has the strongest effect (R<1> = R<3> = Cl, R<2>=R<4> = H, R5 =

CH2- H ) IC50 = 2.5 x IO-<8> M.

The German interpretation document 36 32 893 (= Derwent Referat 88-99 366/15) concerns, among other things, compounds of the general formula Ib

in which

R<1> and R<5> are the same or different and mean

a) hydrogen or halogen

b) a phenyl radical which in the nucleus may be substituted one to three times with halogen, trifluoromethyl, methyl, ethyl, methoxy,

ethoxy,

c) an alkyl residue with 1-5 carbon atoms which may be substituted one to three times by a) Cj-C3 olefinic acid residue or cycloalkoic acid residue with 3 to 7 carbon atoms, e) phenoxy or benzyloxy acid residue, which may be substituted in the nucleus one to three times with halogen, trifluoromethyl,

methyl, ethyl, methoxy, ethoxy,

y) halogen, cycloalkyl with 3-7 C atoms, phenyl residues which can

be substituted in the nucleus one to three times by halogen, trifluoromethyl, methyl, ethyl, isopropyl, methoxy, ethoxy,

alkyl groups with a total of 3-8 carbon atoms,

R<2> and R<4> are the same or different and mean hydrogen,

halogen, methyl, ethyl, methoxy, ethoxy, benzyloxy,

R<3> is hydrogen, halogen, trifluoromethyl, methyl, ethyl, methoxy,

ethoxy,

as well as the corresponding open-chain dihydroxycarboxylic acids, their pharmacologically acceptable salts with bases and their pharmacologically acceptable esters.

The mentioned compounds of formula Ib are, according to the information in this publication, as a rule, with the same substitution pattern R^-R<*5>, only slightly less active than Ia.

It was now surprisingly found substitution patterns (R<1> to R<5>) which are not described by examples in these publications, which give the compounds of general formulas Ia and Ib an activity which is up to a third power higher than that obtained by the best examples given in EP-A-0216127 and DE-A-36 32 893. The substitution pattern lies, in terms of the substituents R<1>, R<2>, R<4>, R<5> completely within, in terms of R<3> only partially within the general patent claims of EP-A-0216127 and DE-A-36 32 893, it being further found that R<3> can also exhibit meanings not stated in the two older patent publications.

The invention relates to the preparation of new compounds of general formula I as well as the corresponding open-chain dihydroxycarboxylic acids of formula II

where

X stands for oxygen or sulphur,

Y means

a) a straight-chain or branched alkyl radical with 3 to 4 carbon atoms, b) cyclohexyl or a phenyl radical which can be substituted in the nucleus with halogen, as well as their pharmacologically acceptable salts with bases and their pharmacologically acceptable esters. The compounds with formulas I and II are prepared according to the invention by a) transferring correspondingly substituted phenols or thiophenols of formula III wherein X and Y have the meanings given by formulas I and II, with the optically pure iodide of formula IV wherein R^ represents a protecting group which is stable to bases and weak acids, to the lactoether of formula V in which X and Y have the meanings given by formulas I and II and R 7 has the meaning given by formula IV, b) the lactoleether of formula V is hydrolysed to the corresponding the lactoles of formula VI in which X and Y have the meanings given by formulas I, II and R has the meaning given by formula IV, c) the lactols of formula VI are oxidized to the corresponding the lactones of formula VII in which X and Y have the meanings indicated by formulas I/II and R^ has the meaning indicated by formula IV, d) the obtained protected lactones of formula VII are transferred in a manner known per se to compounds of formula I and e) optionally the obtained compounds of formula I are transferred to the corresponding open-chain dihydroxycarboxylic acids

of formula II, their salts or their esters, optionally the obtained salts or esters are transferred to the free dihydroxycarboxylic acids or optionally the free carboxylic acids to the salts or esters.

The procedure is appropriately carried out under the conditions described in the aforementioned older publications. Depending on the meaning of the substituents, the process conditions can be varied (cf. e.g. execution example 1.8). The compounds of formula III are novel. The iodides of formula IV are e.g. described in EP-A-0216127.

The synthesis of the necessary phenol- or the thiophenol components III are outlined in Formula Scheme 1 and described later. The compounds of formula III can be obtained from 2-isopropylphenol XII or from in the 4-position with Y-substituted 2-isopropyl-phenols XIII by palladium(0) catalyzed aryl-aryl coupling as the key step. An overview of palladium(0) catalyzed aryl-aryl coupling can be found in E. Negishi, Acc. Chem. Res. 15, 340 (1982) and R.F. Eeck "Palladium Reagents in Organic Synthesis", Academic Press (1985), ch. 6.

According to a recently published strategy (D.A. Widdowson, Y.-Z. Zhang, Tetrahedron 42, 2111 (1986)) arylgrignard compounds show an enhanced reactivity with respect to Pd(0)-catalyzed coupling with aryl halides when they bear ortho- alkoxy substituents . If you therefore brominate XIII to XIV, then protect XIV with a benzyl group while forming XV and form the Grignard reagent XVI in THF, this reacts already under mild conditions (10 to 65°C) with excellent yields (90 to 98$ ) under Pd(0) catalysis with the aryl halide XVII (Hal = Br or I) to coupling product XVIII. The removal of the protecting group by catalytic hydrogenation gives III (X = 0). With this strategy, the coupling product III (X = 0) is obtained in very high yield and with high purity. In this method, the necessity consists of protecting the phenolic OH group and, after the reaction, removing the protecting group.

Pd(0)-catalyzed aryl-vinyl couplings in the presence of unprotected phenol groups are known (R.F. Heck, Acc. Chem. Res. 12, 146 (1979); C.B. Ziegler Jr,. R.F. Heck, J. Org. Chem. 43 , 2941 (1978)). This reaction is not completely comparable to aryl-aryl couplings, since strongly basic organometallic reagents (such as the Grignard compound XX) are not used.

Aryl-aryl couplings in the presence of unprotected phenolic groups are new. In connection with the present invention, this exchange of the above-mentioned conventional strategy has been carried out successfully, namely Pd(0)-catalyzed reaction of unprotected ortho-iodophenols XIX with Grignard reagents from p-bromofluorobenzenes XX. One equivalent of XX is used for deprotonation of XIX and a further equivalent of XX is used for coupling reaction. Since oligomerization of the grignard component XX also occurs as a side reaction, in order to achieve a complete conversion to III (X = 0), 2.5 to 3.0 equivalents of XX must be used.

In this way, it is also possible to carry out quantitative dicouplings to unprotected diiodide XXI. If you work with three equivalents of XX, you obtain a mixture at room temperature

of the monocoupling product XIX' (Y =

) and of the dicoupling product III' (Y = ). If, on the other hand, you work with > 4 equivalents of XX, then the temporarily detectable monocoupling product is finally completely converted to III'. As this dicoupling reaction succeeds without purification of the rather sensitive<**> diiodide XXI, one obtains III<*> (Y =

) very directly from XII with 40 to

60$ total dividend (not optimized!).

This phenolic component III' is suitably prepared by this method, since in the conventional method one still had to make use of the formed compound XIX', as aryl digrignard compounds are unstable [F. Bickelhaupt, Angew. Chem. 99, 1020 (1987)].

The direct coupling of unprotected iodophenols XIX with arylgrignard compounds saves two synthesis steps compared to the conventional coupling, and enables the use of cheaper fluorobromobenzenes. Therefore, one must accept a lower yield for the switching stage.

As palladium catalysts, tetrakis-(triphenylphosphine)palladium (0), bis(triphenylphosphine)palladium dichloride or a mixture of palladium dichloride and triphenylphosphine are used. It is known that similar catalysis can also be achieved with nickel-phosphine complexes and related transition metal complexes [see e.g. E. Negishi, Acc. Chem. Res. 15, 340 (1982); J. K. Hush, Angew. Chem. 98, 504 (1986); R.F. Heck, Acc. Chem. Res. 12, 146 (1979); E. Negishi et al., J. Org. Chem. 42, 1821 (1977)].

The thiophenols of formula III are obtained analogously to the methods described in the literature from the corresponding phenols of formula III by reaction with a dialkylthiocarbamic acid chloride, subsequent thermal Newman-Kwart rearrangement and reductive cleavage of the formed S-aryldialkylthiocarbamate to thiophenols of formula III (cf. also DE -A-36 32 893).

*see CV. Bordlianu, Arch. d. Pharmazie 272, 8 (1934)

Synthesis methods for the preparation of compounds of formula XIII (formula scheme I) are partly outlined in formula scheme 2 and described below.

The preparation of the starting compound XIII with certain substituents Y depends on the availability of the starting materials.

XIII (Y = i-Pr) results from dicarboxylation of commercially available 3,5-diisopropyl-2-hydroxybenzoic acids of formula XI (Janssen). The decarboxylation can be carried out by heating the pure substance or the solution in an inert solvent (e.g. nitrobenzene) to 210 to 220°C. Significantly better yields and purity are obtained when the solution is heated in quinoline in the presence of a copper chromite catalyst to approx. 190°C.

XIII (Y = tert.-butyl) is obtained highly para-selectively according to G. Sartori et al., Chem. and Industry, 762 (1985), when stirring isopropylphenol in CHgC^ solution with methyl tert-butyl ether (MTBE) and zirconium(IV) chloride. A good yield of XIII is obtained when XII (1.0 equivalent) is reacted with MTBE (1.05 equivalent) and ZrCl4 (2.4 equivalents in 2 portions) at "C.

Conventional Friedel-Crafts alkylations of XII with corresponding alkyl halides/aluminum trichloride or with alcohols Y-OH/Lewis or protonic acids can also serve to prepare XIII [see K.-D. Lived in Houben-Weyl "Methoden der organischen Chemie", volume VI/lc "Phenole Teil 2", Georg Thieme Verlag, Stuttgart (1976), page 925 ff.].

4-Hydroxy-3-isopropyl-biphenyl XIII (Y =

)

is obtained from commercially available p-nitrobiphenyl VIII by o-alkylation with isopropylmagnesium bromide [overview G.

Baretoli, Acc. Chem. Res. 17, 109 (1984)] to IX, reduction of IX to amine X, diazotization and phenol boiling (Scheme 2).

The catalytic hydrogenation of an ethyl acetate solution to

XIII (Y =

) over 5% palladium on charcoal at 50°C and 4 to 6 kg cm <2> hydrogen pressure gives, in 85 to 90$ yield, XIII (Y = )<: >Formula scheme 2

The lactones of formula I can be converted by conventional methods (cf. e.g. EP-A-0216127 and DE-A-36 32 893) into the corresponding open-chain dihydroxycarboxylic acids of formula II, their pharmacologically acceptable salts with bases and their pharmacologically acceptable esters .

The enzyme HMG-CoA reductase is widespread in nature. It catalyzes the formation of mevalonic acid from HMG-CoA. This reaction is a key step of cholesterol biosynthesis (I.R. Sabine, "3-hydroxy-3-methylglutaryl Coenzyme A Eeductase", CEC Press, 1983). High cholesterol levels are associated with a number of diseases, such as coronary heart disease or atherosclerosis. Therefore, the lowering of elevated cholesterol levels for the prevention and treatment of such diseases is a therapeutic goal. An effort point lies in the inhibition or the reduction of endogenous cholesterol synthesis. HMG-CoA reductase inhibitors block cholesterol biosynthesis at an early stage. They are therefore suitable for the prevention and treatment of diseases caused by an elevated cholesterol level. A reduction or reduction of the endogenous synthesis leads to an increased uptake of cholesterol from the plasma into the cells. A further effect can be achieved by the simultaneous administration of bile acid-binding substances such as anion exchangers. The increased bile acid excretion leads to increased new synthesis and thus to increased cholesterol breakdown (M.S. Brown, P.T. Kovanen, J.L. Goldstein, Science 212, 628 (1981): M.S. Brown, J.L. Goldstein Spektrum der Wissenschaft 1985 (1), 96). The compounds produced according to the invention are inhibitors of HMG-CoA reductase. They are therefore suitable for inhibition or reduction of cholesterol biosynthesis and thus for the prevention or treatment of diseases caused by elevated cholesterol levels, especially coronary heart disease, atherosclerosis, hypercholesterolemia, hyperlipoproteinemia and similar diseases.

The compounds produced according to the invention can be used as lactones of general formula I, in the form of the free acids of formula II or in the form of pharmaceutically acceptable salts or esters, and dissolved or suspended in physiologically acceptable organic solvents, such as monohydric or polyhydric alcohols, which e.g. ethanol or glycerol, in triacetin, oils such as sunflower oil or cod liver oil, ethers such as diethylene glycol dimethyl ether or also polyethers such as e.g. polyethylene glycol or also in the presence of other pharmacologically acceptable polymer carriers such as e.g. polyvinylpyrrolidone or other pharmaceutically acceptable additives such as starch, cyclodextrin or polysaccharides. Furthermore, the compounds produced according to the invention can be combined with additives that bind the bile acid, especially non-toxic, basic anion exchangers, which bind the bile acid in a non-resorbable form in the gastrointestinal tract. The salts of the dihydroxycarboxylic acids can also be processed as aqueous solutions.

The HMG-CoA reductase activity of the sodium salt of the compounds of formula II produced according to the invention was determined in two experimental systems. 1) Inhibition of the HMG-CoA reductase activity on solubilized enzyme preparations from rat liver microsomes. The HMG-CoA reductase activity was measured on solubilized enzyme preparations from liver microsomes from rats which, after the rearrangement of the day-night rhythm, were induced with cholestyramine ("Cuemid"). As substrate served (S,R) <14>C-HMG-CoA, the concentration of NADPH was maintained during the incubation by means of a regenerating system. The separation of <14>C-HMG mevalonate from substrate and other products (e.g. <14>C-HMG) took place by column elution, whereby the elution profile was determined for each individual sample. The constant entrainment of <3>H-mevalonate was waived, because the determination involved a relative indication of the inhibitory effect. In a series of experiments, the enzyme-free control, the enzyme-containing normal mixture (= 100$) and those with preparation additives were treated together. Each individual value was determined as the mean value from 3 parallel samples. The significance of the mean value differences between preparation-free and preparation-containing samples was assessed by the t-test. In the above-mentioned method, for the compounds prepared according to the invention, e.g. the following inhibition values of the HMG-CoA reductase determined (IC5Q-(mol/l); molar concentration of the compound per liter required for a 50% inhibition).

2) Suppression or inhibition of the HMG-CoA reductase in HEP GZ cell cultures (a human hepatoma cell line)

A determination was made of the inhibition of the incorporation of <14>C-sodium acetate into cholesterol.

Monolayers of HEP G2 cells in RPMJ 1640 medium with 1056 fetal calf serum freed from lipids were preincubated for 1 hour with various concentrations of the sodium salts of the dihydroxycarboxylic acids of formula II. After addition of <14>C-labeled sodium acetate, the incubation was continued for 3 hours. Tritium-labelled cholesterol was added as an internal standard and a portion of the cells saponified alkaline. The lipids were extracted with chloroform/methanol 2:1. After addition of Baerer cholesterol, the lipid mixture was preparatively separated on DC plates with chloroform/acetone 9:1. The cholesterol zones were visualized by staining with iodine vapor, further detected using a DC radio sweep device and then scraped off. The amount of <14>C-cholesterol was determined scintigraphically. In another portion of the cell monolayer, the cell protein was measured (for calculation of the ^<4>C-cholesterol biosynthesis per mg of cell protein). The same procedure was carried out with cells from the same culture without preincubation with a test compound (so-called "solvent control"). The potency of the test compound was determined by comparison with the biosynthesized ^<4>C-cholesterol at trial and by "solvent control". The potency was calculated on the basis of mevinolin sodium salt as an external standard. The I<C>5Ø and I<C>7ø values (IC5Q and IC70 (M) are the molar concentration of the compound per liter required to achieve a 50 and 70% inhibition, respectively) varied somewhat for the different cell charges. The mean values for mevinolin sodium salt were IC50 = 5'10"<8>M, IC70 = 1.5-10~<7>M. The measured ICs for the test compounds (the sodium salts of the dihydroxycarboxylic acids of formula II (Table 2) were corrected for the deviation from mevinolin sodium from the mean value Mevinolin sodium was set to a relative potency of 100.

By means of the following examples, the synthesis of compounds of formula will be illustrated in more detail.

Example 1

Synthesis of 4(R)-hydroxy-6(S)-[(2,4-diisopropyl-6-p-fluorophenyl)-phenoxymethyl]tetrahydro-2H-pyran-2-one

(formula I, X=0, Y=i-Pr, Z=E).

Example 1. 1

2,4-diisopropylphenol (formula XIII, Y=i-Pr)

The mixture of 145 g (0.65 mol) 3,5-diisopropyl-2-hydroxy-benzoic acid (XI), 540 ml (588 g, 4.55 mol) quinoline and 7.5 g (0.024 mol) copper chromite (2CuO. Cr2C>3) is stirred for 2 hours at 190"C (external temperature 225"C). It cools to approx. 10° C, acidified during further cooling with approx. 1 1 semi-concentrated hydrochloric acid to pH 1 to 2, extracted with toluene and the extract washed with 2 N hydrochloric acid, then with water and then with NaHCO 3 solution. It is dried, filtered, evaporated and distilled in a high vacuum. 105 g of the compound in heading XIII is obtained as a clear yellow oil, boiling point 81 to 84°C/0.2 Torr.

<1>E-NMR(CDCl 3 ): S 1.20 (6H,d); 1.25 (6E,d); 3.00 (2H,2xhept. );

4.10 (1H,s,br); 6.50-7.00 (3H,m).

Example 1. 2

2,4-diisopropyl-6-bromophenol (formula XIV, Y=i-Pr)

To a 95°C hot solution of 102.3 g (0.57 mol) 2,4-diisopropylphenol in 900 ml glacial acetic acid, 1 g of iron powder is added, then 101 g (32.2 mol, 0.63 mol) of bromine is added dropwise during of 90 minutes. It is stirred for a further 1 hour at 100°C, cooled, the reaction mixture is distributed between toluene and water, and the toluene phase is washed with NaHCC 3 solution. It is dried, filtered, evaporated and the residue is distilled under high vacuum. 125 g of the compound in title XIV is obtained as a clear yellow oil, boiling point 85°C/0.15 Torr.

<*>E-NMR (CFC13) : S 1.20 (6H,d); 1.25 (6H,d), 2.80 (1H.hept.);

3.25 (1H.hept.); 5.33 (1H,s); 6.87-7.20

(2E,m)

MS (70eV): m/e = 256/258 (M<+>), 241/243 (M<+->CH3)

Example 1. 3

1-benzyloxy-2,4-diisopropyl-6-bromobenzene (formula XV, Y=i-Pr)

The suspension of 166.5 g (1.2 mol) of potassium carbonate in 124 g (0.48 mol) of the above-mentioned bromophenol, 91.52 g (0.72 mol) of benzyl chloride and 2 1 2-butanone is heated under reflux for 24 hours. It is cooled, the inorganic solid is sucked off, the filtrate is evaporated in vacuo and the residue is distributed between toluene and water. The toluene phase is washed with saturated sodium chloride solution, dried, filtered and evaporated. The residue is chromatographed with cyclohexane/toluene 9:1 over silica gel. 155 g of the compound in heading XV is obtained as a colorless oil. Small residues of benzyl chloride are removed under high vacuum. Purification can also be achieved by distillation (boiling point 150°C/0.15 Torr).

<1->H-NMR (CDCl 3 ): S 1.18 (6E,d); 1.22 (6E,d), 2.80 (1E,hept.);

3.32 (lE.hept.); 4.90 (2H,s); 6.93-7.60

(7E,m)

MS (70eV): m/e = 346/348 (M<+>), 267, 254/256, 91

Example 1. 4

1,4-benzyloxy-2,4-diisopropyl-6-p-fluorophenyl-benzene (formula XVIII, Y=i-Pr, Z=H)

The Grignard compound XV (Y=i-Pr) is prepared from 48.62 g (0.14 mol) of the bromide from example 1.3 and 3.53 g (0.147 mol) Mg shavings in 120 ml absolute TEF (~ 60°) C, 1 hour). This Grignard solution is quickly added to a solution of 31.08 g (0.14 mol) of 4-fluoroiodobenzene and 3.23 g (2.8 mmol) of tetrakis-(triphenylphosphine)palladium (0) in 140 ml of absolute TEF. The internal temperature increases within 15 minutes to 55 to 60°C. After 7 minutes a precipitate forms. It is stirred for 1 hour at 50 to 58°C, the mixture is allowed to stand overnight at room temperature, partitioned between ether and 1 N hydrochloric acid, the ether phase is washed with 1 N hydrochloric acid, then with water and then with saturated NaSCC^ solution. It is dried, filtered and evaporated. If necessary, the product is purified by chromatography with cyclohexane/toluene 4:1 over silica gel by distillation (boiling point 1SO^C/O.S Torr). 49.3 g of the compound in title XVIII are obtained as a colorless solid, melting point 65 to 67°C.

ifl-NMR (CDC13): § 1.30 (12E,d); 2.95 (lE.hept.); 3.45

(lE.hept.); 4.40 (2E,s); 6.90-7.80 (HE,m) MS (CI) : m/e = 363 (M+H<+>), 362 (M<+>), 285m 263

Example 1. 5

2,4-diisopropyl-6-p-fluorophenyl-phenol (formula III, Y=i-Pr,

Z=E)

To dissolve 49.3 g (0.136 mol) of the benzyl ether XVIII from example 1.4 in 1 liter of acetic acid and 100 ml of glacial acetic acid, 4 g of 10$ Pd on charcoal are added and shaken for 20 minutes in a hydrogen atmosphere (strong H2 uptake). The catalyst is filtered off, evaporated, the residue is taken up several times in toluene and it is evaporated each time under vacuum. 34.4 g of the compound in heading III is obtained as a colorless oil, boiling point 115°C/0.1 Torr.

<1->E-NMR (CDCl 3 , 270 MBz) : S 1.25 (6E,d); 1.29 (6E,d); 2.87

(lE.hept.); 3.31 (1E,hept.); 4.95 (lE,s,br); 6.88 (1H,d); 7.08 (lE,d)

7.18 (2E,m); 7.45 (2E,m).

MS (70eV) : m/e = 272 (M<+>), 257 (M<+->CE3)

Example 1. 6

6(S)-[(2,4-diisopropyl-6-p-fluorophenyl)-phenoxymethyl]-3,4,5,6-tetrahydro-2(R,S)-methoxy-4(R)-(t- butyldiphenylsilyloxy)-2E-pyran (formula V, Y=i-Pr, Z=H)

For a suspension of 27.6 g (0.2 mol) of potassium carbonate and a spatula tip of hydroclinone in 250 ml of absolute DMSO, 27.2 g (0.1 mol) of the phenol from example 1.5 is added. It is stirred for 1 hour at room temperature and then the solution of 56 g (0.11 mol) of the lactoleteriodide IV (preparation see EP-A 0 216 127, R7 = t-butyldiphenylsilyl) in 250 ml of absolute DMSO is added. It is stirred for 4 hours at an internal temperature of 50-55°C. DC (silica gel, 1st development with cyclohexane/acetic ester 9:1, 2nd development with cyclohexane/acetic ester 15:1) shows complete reaction of the iodide IV (Rf 0.5 ), some residual starting phenol (Rf 0.7), mainly product of formula V

(Rf 0.6). The mixture is allowed to cool and the reaction mixture is distributed between ether and semi-saturated sodium chloride solution. The aqueous phase is extracted once more with ether. The combined organic phases are washed with sodium chloride solution, dried over MgSO 4 , filtered and evaporated. The crude product is chromatographed with toluene/cyclohexane 2:1, then 100$ toluene, then toluene/acetic ester 30:1 over silica gel. 51 g of the title compound is obtained as a colorless resin. 1-H-NMR (CDCl 3 ): S 1.10 (9H,s); 1.28 (12H,d), 1.4-2.2 (4E,m); 2.93 (2E.2xhept.); 3.40 (2H,m); 3.52 (3E,s);

3.97-4.40 (2H,qui+m); 4.87 (1E,dd);

6.87-7.90 (16E,m)

MS (CI): m/e = 654 (M+), 597 (M<+->tert.-Bu), 539, 519, 323,

283, 185, m 127

Example 1. 7

6(S)-[2,4-diisopropyl-6-p-fluorophenyl)-phenoxymethyl]-3,4,5,6-tetrahydro-2-(R,S)-hydroxy-4(R)-(t -butyldiphenylsilyloxy)-2E-pyran (formula VI, Y=i-Pr, Z=E)

The solution of 40.2 g (61.4 mmol) of the lactoether from example 1.6 in 3 1 THF, 3 1 water and 4.2 1 glacial acetic acid is stirred for 24 hours at 80-85"C (external temperature). The solvent is removed in vacuo and the residue is evaporated three times with toluene in vacuo Chromatography with cyclohexane/acetate 12:1 through 2 L silica gel affords 33.4 g (yield 85$) of the title compound as a colorless amorphous powder.

MS (FAB): m/e = 640 (M<+>), 519, 367, 323, 283, 271, 257

Example 1. 8

6(S)-[2,4-diisopropyl-6-p-fluorophenyl)-phenoxymethyl]-3,4,5,6-tetrahydro-4(R)-(t-butyldiphenylsilyloxy)-2H-pyran-2 -on

(formula VII, Y=i-Pr, Z=H)

To dissolve 33.4 g (52.1 mmol) of the lactol from example 1.7 and 19.25 g (52.1 mmol) of tetrabutylammonium iodide in 2.5 1 of absolute methylene chloride, 46.9 g (208, 4 mmol) N-iodosuccinimide. The mixture is stirred under exclusion of light under nitrogen for 1 hour at 10°C, 20 hours at room temperature. The reaction solution is washed with water, then twice with NaHSO 3 solution, then with saturated NaCl solution, dried, filtered and evaporated. The residue is dissolved in a little methylene chloride and filtered with cyclohexane/acetic ester 92:8 through silica gel. 32.1 g of the title compound is obtained as a colorless resin.

%-NMR (CDCl 3 , 270MHz): δ 1.06 (9H,s); 1.23 (6H,d); 1.26

(6H,d); 1.59 (2H,m); 2.41 (1H, dd);

2.59 (lH.dm); 2.90 (1H,hept.); 3.36 (1H.hept.); 3.48 (2H,AB of ABX);

4.29 (1H.qui); 4.80 (1H,m); 6.96 (1H,d); 7.03 (2H,m); 7.10 (1H,d);

7.36.-7.52 (8H,m); 7.58-7.73 (4H,m) MS (70eV, 70°C): m/e = 638 (M<+>), 581 (M<+->tert.-Bu), 539

(581 - propene), 283, 199

Example 1. 9

4(R)-hydroxy-6(s)-[(2,4-diisopropyl-6-p-fluorophenyl )-phenoxymethyl]-tetrahydro-2H-pyran-2-one

(formula I, X=0, Y=i-Pr, Z-H)

To dissolve 31.0 g (48.5 mmol) of the silyl compound from example 1.8 in 1.5 1 tetrahydrofuran (filtered over basic AI2O3), 11.65 g (194 mmol) of glacial acetic acid is added, followed by 45.92 g (145 .5 mmol) tetrabutylammonium fluoride trihydrate. It is stirred for 20 hours at room temperature. The solvent is removed in vacuo, and the residue is quickly distributed between ether and water. The aqueous phase is extracted twice more with ether. The combined organic phases are washed with saturated sodium chloride solution, dried over MgSO4, filtered and evaporated. The residue is taken up in toluene and evaporated in vacuo. The crude product is chromatographed with cyclohexane/acetic ester 1:1 through 2 kg of silica gel. 15.7 g (yield 8156) of the title compound is obtained as a colorless solid, melting point 145-147°C.

1 H-NMR (CDCl 3 , 270 MHz): S 1.25 and 1.27 (12H,2xd); 1.67

(lH,s,br.); 1.76 (1H.dtd); 1.87 (1H,ddd); 2.58 (1E.ddd); 2.69 lH.dd); 2.91 (1H.hept); 3.39 (1H.hept.), 3.54 (2H,AB of ABX );

4.38 (1H.qui), 4.68 (1H,m); 6.97

(1H,d); 7.10 (3H,d+m); 7.51 (2H,m)

MS (FAB): m/e = 400 (M<+>), 257

Example 2

Synthesis of 4(R)-hydroxy-6(S)-[(2-isopropyl-4-tert-butyl-6-p-fluorophenyl)-phenoxymethyl]tetrahydro-2H-pyran-2-one

(formula I, X=0, Y=tert.-Bu, Z-H)

Example 2. 1

2-isopropyl-4-tert-butyl-phenol (formula XIII, Y=tert-Bu)

For a suspension of 70 g (0.3 mol) zlrkonium tetrachloride 1 100 ml absolute CH2CI2 is added dropwise at -5 to 0°C under nitrogen, slowly the solution of 34 g (0.25 mol) o-isopropylphenol (formula XII) and 22 g (0.26 mol) of tert-butyl methyl ether in 150 ml of absolute CH 2 Cl 2 . The mixture is stirred for 1 hour at 0°C. DC (1005é toluene) shows approx. 5056 turnover. A further 70 g (0.3 mol) ZrCl4 is quickly added in one portion, and the brown suspension is stirred for 15 minutes at 0°C. DC now shows > 9556 turnover and no pollution.

(If the reaction mixture is allowed to stand for 10 hours at room temperature under nitrogen, then DC again shows 3056 starting material and numerous by-products.) At -10 to 0°C, under very good cooling, slowly add 500 ml saturated NaHCOs solution (very exothermic ). A colorless solid is produced, which greatly complicates mechanical stirring. The organic phase is separated, dried and evaporated in vacuo. If necessary, the product is chromatographed with cyclohexane/toluene 1:2 through 800 g of silica gel, or distilled in a vacuum. 43.1 g of the compound in heading XIII is obtained as a colorless solid, melting point 55 to 57°C, boiling point 134 to 135°C/12 Torr.

1- H-NMR (CDCl 3 ): S 1.27 (6E,d); 1.28 (9H,s); 3.17 (1H,hept.);

4.61 (1H,s); 6.62 (1H,d); 7.05 (lH.dd); 7.17

(lH,d)

MS (70eV): m/e = 192 (M<+>)

Example 2. 2

2- isopropyl-4-tert-butyl-6-bromophenol

(formula XIV, Y=tert.-Bu)

To dissolve 65.8 g (0.34 mol) of the phenol XIII from example 2.1 in 375 ml of CCI4, 18 ml (55.8 g, 0.35 mol) of bromine is added dropwise. Complete conversion of the starting material is checked with DC (cyclohexane/ethyl acetate 5:1, Rf XIII 0.37, XIV: 0.33), taken up in ether and washed twice with Na 2 S 2 O 3 solution, once with saturated NaCl solution. It is dried, evaporated and distilled in a high vacuum. 86.1 g of the compound in heading XIV is obtained as a pale yellow oil, boiling point 105 to 106°C/1 Torr.

1-H NMR (CDCl 3 ): S 1.25 (6E,d); 1.29 (9H,s); 3.47 (1E.hept.);

6.17 (lE.br.); 7.09 (1E,d); 7.24 (lE,d)

MS (70eV): m/e = 270/272 (M<+>)

Example 2. 3

2- isopropyl-4-tert-butyl-6-iodophenol

(formula XIX, Y=tert.-Bu)

To dissolve 19.2 g (0.1 mol) of the phenol XIII from example 2.1 in 150 ml of 50% aqueous ethylamine solution and 120 ml of ethanol, the solution of 30.4 g (0, 12 mol) of iodine and 40.0 g (0.24 mol) of potassium iodide in 120 ml of water. It is stirred for 1 hour at room temperature, taken up in ether, washed twice with Na2S2C-3 solution, then with saturated NaCl solution, dried, evaporated in vacuo, taken up in toluene and evaporated in vacuum at < 25°C. 26.0 g of the compound in title XIX is obtained as an oil.

^■E-NMR (CDCl3): S 1.15-1.50 (15H,s+d); 3.06 (1E.hept.);

4.60 (lE,s,br.); 6.86 (1E,s); 7.73 (lH,s)

MS (70eV, <50°C): m/e = 318 (M<+>), 303 (M<+->CE3), 275, 177, 161

Example 2. 4

1-Benzyloxy-2-isopropyl-4-tert-butyl-6-bromobenzene

(formula XV, Y=tert.-Bu)

one obtains analogously to example .1.3 from compound XIV, example 2.2.

Colorless crystals, melting point 47 to 49°C.

1-H NMR (CDCl 3 ): S 1.23 (6H,d); 1.48 (9H,s); 3.33 (1H.hept.);

5.12 (2H,s); 7.02 (1H,s); 7.44 (6H,s,br.)

MS (70eV): m/e = 360/362 (M<+>), 268/270, 91

Example 2. 5

1-Benzyloxy-2-isopropyl-4-tert-butyl-6-p-fluorophenyl-benzene

(formula XVIII, Y=tert.-Bu, Z-H)

one obtains analogously to example 1.4 from the corresponding Grignard compound XVI.

Colorless solid, melting point 126 to 128°C.

1-H-NMR (CDCl3): S 1.1-1.3 (15H,s+d); 3.38 (1H.hept.); 5.16

(2H,s); 6.83 (1H,s); 7.0-7.7 (10H,m)

MS (7+eV): m/e = 376 (M<+>), 282, 91

Example 2. 6

2- isopropyl-4-tert-butyl-6-p-fluorophenyl-phenol

(formula III, Y=tert.-Bu, Z=H)

is obtained analogously to example 1.5 from compound XVIII from example 2.5.

Colorless solid, melting point 109 to 111°C.

1-H-NMR (CDCl 3 ): S 1.15 (9H,s); 1.23 (6H,d); 3.16 (1H,hept.);

4.65 (1H,s); 6.80 (1H,s); 6.9-7.4 (5H,m)

MS (70eV): m/e = 286 (M<+>), 271 (M<+->CH3), 229

Example 2. 7

2- isopropyl-4-tert.-butyl-6-p-fluorophenyl-phenol (formula III, Y=tert.-Bu, Z=H) by direct coupling of the iodide XIX with the Grignard reagent from p-bromofluorobenzene XX.

To dissolve 25.7 g (81 mmol) of the iodophenol from example 2.3 in 150 ml of absolute THF, 1.87 g (1.6 mmol) of tetrakis(triphenylphosphine) palladium (0) is added and stirred for 30 minutes at room temperature. 42.6 g (243 mmol) of 4-bromofluorobenzene and 6.2 g (255 mmol) of Mg shavings in 170 ml of THF are added in one portion of the Grignard reagent. Thereby the internal temperature rises to approx. 50°C. The reaction mixture is kept for 3 hours at 55°C, during which a colorless solid (magnesium;) od id) is separated. <*> The reaction mixture is taken up in ether, washed twice with IN hydrochloric acid, once with water, once with saturated sodium bicarbonate solution, dried and evaporated in vacuo. The residue is chromatographed with cyclohexane/ethyl acetate 9:1 over 1 kg of silica gel. The obtained fractions XIII, XIX, III are evaporated together. The remainder is dissolved in the smallest possible amount of n-pentane. 9.8 g pure III is crystallized in a deep freezer. The melting point and spectrum for this material was identical to that given in example 2.6.

<*> The course of the reaction cannot be followed with DC, as the iodide XIX, the coupling product III and the phenol XIII, which is formed as a by-product during coupling, are co-chromatographed in all common eluents. Suitable separation conditions: HPLC on 250x4.6 column RP 18.5 pm "Nucleosil", 64# (CH30E + 0.156 NH4OAc)/365é H20, 1.2 ml/min., 40°C, UV detection 254 nm.

Examples 2. 8 to 2. 11

4 (R)-hydroxy-6(S)-[2-isopropyl-4-tert-butyl-6-p-fluorophenyl)-phenoxymethyl]-tetrahydro-2H-pyran-2-one

(formula I, X=0, Y=tert.-Bu, Z-H)

is obtained from the phenol III (example 2.6 or 2.7) analogously to examples 1.6 to 1.9.

Colorless solid, melting point 178-179°C.

<1->H-NMR (CD2Cl2): S 1.13-1.20 (15H,,), 2.02 (1H,s,br.),

2.10-2.16 (2H,m), 2.71 (2H,AB from ABX),

3.24 (1H, hept.), 4.22 (2H; AB from ABX), 4.50 (lH.s.br.), 5.03-5.13 (lH,m), 6.79 ( 1H,s), 6.98-7.07 (3H,m), 7.19-7.25

(2H,m)

MS (70 ev): m/e = 414 (M<+>), 359

IR (KBr): 3560/2460 (OH), 1745 (C=0), 1500, 1235, 1220 cm-<1>

Example 3

Synthesis of 4(R)-hydroxy-6(S)-[(2-isopropyl-4,6-di-p-fluorophenyl)-phenoxymethyl]tetrahydro-2H-pyran-2-one

Formula I, X=0, Y =

, Z=E

Example 3. 1

2-isopropyl-4,6-diiodo-phenol (formula XXI)

To dissolve 40.8 (0.3 mol) of o-isopropylphenol in 630 ml of 50% aqueous ethylamine solution and 525 ml of ethanol, the solution of 160 g (0, 63 mol) of iodine and 209 g (1.26 mol) of potassium iodide in 300 ml of water. It is stirred for 20 minutes at room temperature, and the reaction mixture is poured onto 200 ml of saturated Na 2 S 2 O 3 solution plus 600 ml of water. Extract with 3 x 500 ml of ether, the combined extracts are washed with E./2N hydrochloric acid, then with water. It is dried over MgSO 4 , decanted again with MgSO 4 , filtered and evaporated in vacuo at < 20°C. 100 ml of toluene is added and evaporated in vacuum at < 20°C. The evaporation with toluene is repeated once in a water jet vacuum, once in a high vacuum. 99.0 g of the title compound is obtained as a red oil. With NMR, MS and DC, no contamination is recorded.

%-NMR (CDCl 3 ): S 1.2 (6E,d), 3.2 (1H.hept.), 3.5 (1H,s), 7.35 (1E,d), 7.75 (1H ,d)

MS (70 eV): m/e 388 (M<+>), 373 (M<+->CH3), 246 (M<+->CE3J)

Example 3. 2

2-isopropyl-4,6-di-p-fluorophenyl-phenol

(formula III', Z=H)

To dissolve 125 g (0.32 mol) of the diiodide XXI from example 3.1 and 5 g (7.1 mmol) of bis-(triphenylphosphine)-palladium(II) chloride (Aldrich) in 300 ml of absolute THF is added dropwise under argon and ice-cooling the Grignard solution of 219 g (1.25 mol) p-bromofluorobenzene and 31.3 g (1.3 mol) magnesium filings in 600 ml absolute THF (internal temperature 25-30°C). It is stirred for 25 hours at 40-50°C, then another 2.5 g (PPhs^PdClg) is added and stirred overnight at about 45°C. It is cooled to 0°C and 50 ml of water is added in such a way ( exothermic reaction) that the internal temperature remains below 25°C. A tough, slimy precipitate is formed. At < 25°C, 300 ml of semi-concentrated hydrochloric acid is added dropwise (the precipitate dissolves, pH ~ 1). The mixture is extracted several times with ether . The combined extracts are washed with 1N hydrochloric acid, then with saturated NaHCO 3 solution and then with saturated sodium chloride solution and then dried and evaporated. A black, viscous oil is obtained which is first chromatographed with 4 L of cyclohexane/toluene (4:1), then with 10 1 cyclohexane/toluene (3:1), then with cyclohexane/toluene (2.5:1) through 1 kg silica gel 70-200 mp.

First, 10.2 g of a colorless solid is eluted, which according to NMR (only aromatic protons), MS: 360, 342, 284, 266 (base peak), 248 and analysis (C+H+F = 10056) is an oligomeric mixture arising from the Grignard compound XX

(Z=H).

m/e = 266 corresponds to

248 is 266-F+H, 284 is 266+F-H, 360 is 266+C6H4F-H, 342 is 360-F+H.

2.1 g of monocoupling product is then isolated, whereby it is 2-isopropyl-4-p-fluorophenyl-6-iodo-phenol XIX'

(Y = p-fluorophenyl).

MS (70 eV=: m/e = 356 (M<+>), 341 (M<+->CH3), 214

Finally, 45.1 g of the compound in the heading III' is eluted as a tough, colorless oil, which crystallizes on prolonged standing at room temperature.

<1->H-NMR (CDCl3): § 1.35 (6H,d); 3.4 (1H.hept.); 5.1 (1H,s);

6.8-7.6 (10H,m)

MS (70eV): m/e = 324 (M<+>), 309 (M<+->CH3)

DC (toluene/cyclohexane 1:2) Rf values: oligomer mixture 0.61, starting material XXI 0.53, monoiodide XIX' 0.50,

product III' : 0.35.

Examples 3. 3 to 3. 6

4(R)-hydroxy-6(S)-[(2-isopropyl-4,6-di-p-fluorophenyl)-phenoxymethyl]-tetrahydro-2H-pyran-2-one

(formula I, X=0, Y =

, Z=H)

is obtained from the phenol III' (example 3.2) analogously to examples 1.6 to 1.9.

Colorless solid, melting point 190-192°C.

%-NMR (CDCl 3 , 279 MHz): S 1.31 (6H,2xd), 1.72-1.95 (3H,m),

2.66 (2H.AB from ABX), 3.47 (1H, hept.), 3.59 (2H,AB from ABX),

4.40 (1H,m), 4.70 (1H,m), 7.12 (4E,m), 7.28 (1H,d), 7.42 (1H,d).

7.55 (4H,m)

MS (DCI): m/e = 452 (M<+>), 437 (M<+->CH3), 129

IR (KBr): 3480 (OE), 1715 (C=0), 1510, 1255, 1220, 1200, 1160, 830 cm-<1>.

Example 4

Synthesis of 4(R)-hydroxy-6(S)-[(2-isopropyl-4-phenyl-6-p-fluorophenyl)-phenoxymethyl]tetrahydro-2H-pyran-2-one

(formula I, X=0, Y=phenyl, Z=H)

Example 4. 1

2-isopropyl-4-phenyl-nitrobenzene (formula IX)

To dissolve 20.0 g (0.1 mol) of 4-nitroMphenyl VIII in 400 ml of absolute THF, add dropwise at -70°C under nitrogen during 3 hours Grignard solution of 30.7 g (0.25 mol ) 2-bromopropane and 5.85 g (0.24 mol) magnesium filings in 300 ml of absolute THF. It is stirred for a further 1 hour at -70°C (DC: VIII completely reacted) and then rapidly added dropwise at -40°C the solution of 22.7 g (0.1 mol) 2,3-dichloro-5,6- dicyano-p-benzoquinone (DDQ) in 200 ml of absolute THF. The mixture is allowed to warm to room temperature, stirred for a further 1 hour and poured into 1.2 1 water. The THF is removed in vacuo, the aqueous residue is extracted twice with acetic acid, the extracts are washed well with water, dried and evaporated. Chromatography with cyclohexane CH2CH2 4:1 through 1 kg of silica gel gives 8.9 g of the title compound IX as a clear red oil.

% NMR (CDCl 3 ): S 1.37 (6H,d); 3.58 (1H.hept.); 7.36-7.97

(8H,m)

MS (70eV, 50°C): m/e = 241 (M<+>), 224, 174, 152

Example 4. 2

2-isopropyl-4-phenyl-aniline (formula X)

13.1 g (54.3 mmol) of the nitro compound IX from example 4.1 are dissolved in the solution of 10 g of ammonia in 400 ml of methanol. Under nitrogen, 10 g of Raney nickel, which has been washed three times with methanol, is added. The suspension is shaken for 2 hours at room temperature and normal pressure in a hydrogen atmosphere.

The catalyst is filtered off, the filtrate is evaporated and the residue is chromatographed with 2 1 cyclohexane/toluene 1:2, then with 5 1 toluene over 400 g silica gel. 11.2 g of the compound in the heading X is obtained as a colorless oil.

<1>H-NMR (CDCl 3 ): S 1.33 (6H,d); 3.00 (lH.hept.); 3.45 (2H,s,br.); 6.80 (1H,d); 7.2-7.7 (7H,m)

MS (70eV): m/e = 211 (M<+>), 196 (M<+->CE3)

Example 4. 3

2-isopropyl-4-phenyl-phenol

(Formula XIIII', Y =

)

To dissolve 11.2 g (53.1 mmol) of the amine X from example 4.2 in 50 ml of glacial acetic acid, the solution of 4.26 g (62 mmol) of sodium nitrite in 50 ml of water is added dropwise at 10 to 12°C. The diazonium salt is precipitated. The suspension is difficult to move. After 5 minutes, the suspension is poured slowly into the boiling solution of 32 ml of concentrated sulfuric acid in 65 ml of water. It is stirred for a further 5 minutes, then cooled and partitioned between toluene/ether and saturated sodium chloride solution. The organic phase is washed twice with saturated NaECOs solution and once with sodium chloride solution, then dried and evaporated. Chromatograph i with 10056 toluene through 500 g of silica gel gives 4.9 g of the compound in title XIII as a yellow oil.

% NMR (CDCl 3 ): S 1.30 (6H,d); 3.25 (1E.hept.); 7.1-7.7

(8H,m)

MS (70eV): m/e = 212 (M<+>), 197 (M<+->CE3), 178

Example 4. 4

2-isopropyl-4-phenyl-6-bromo-phenol

(formula XIV, Y = phenyl)

analogous to example 2.2 is obtained from the phenol XIII from example 4.3.

1 H NMR (CDCl 3 ): S 1.26 (6H,d); 3.40 (1H.hept.); 5.63 (1H,s);

7.2-7.7 (7H,m)

MS (70eV): m/e = 290/292 (M<+>), 275/277 (M<+->CH3), 196, 165

Example 4. 5

1-Benzyloxy-2-isopropyl-4-phenyl-6-bromobenzene

(formula XV, Y = phenyl)

analogous to example 1.3 is obtained from the phenol XIV (example 4.4) as a colorless oil which slowly crystallizes.

<1->H-NMR (CDCl3): S 1.24 (6H,d); 3.45 (1H.hept.); 5.05 (2H,s);

6.95-7.70 (12H,m)

MS (70eV): m/e = 380/382 (M<+>), 91

Example 4. 6

1-Benzyloxy-2-isopropyl-4-phenyl-6-p-fluorophenyl-benzene

(formula XVIII, Y = phenyl, Z = H)

one obtains analogously to example 1.4 from the corresponding Grignard compound XVI as a colorless oil that slowly crystallizes.

<i>H-NMR (CDCl 3 ): S 1.28 (6H,d); 3.52 (1H.hept.); 5.00 (2H,s);

6.95-7.70 (16E,m)

MS (70EV): m/e = 396 (M<+>)

Example 4. 7

2-isopropyl-4-phenyl-6-p-fluorophenyl-phenol

(formula III, Y = phenyl, Z=H)

one obtains analogously to example 1.5 from compound XVIII from example 4.6 as a colorless solid.

1-H NMR (CDCl 3 ): S 1.35 (6H,d); 3.40 (1H,hept.); 5.10

(lE,s,br.); 6.85-7.45 (llH,m)

MS (70eV): m/e = 306 (M<+>), 291 (M<+->CE3)

Example 4. 8 to 4. 11

4(R)-hydroxy-6(S)-[(2-isopropyl-4-phenyl-6-p-fluorophenyl)-phenoxymethyl]tetrahydro-2H-pyran-2-one

(formula I, X=0, Y=phenyl, Z=H)

is obtained from the phenol (example 4.7) analogously to that of examples 1.6 to 1.9.

Colorless solid, melting point 184-187"C.

<i>NMR (CDCl3): S 1.30 (6E,2xd), 1.7-2.0 (3H,m), 2.65 (2H,m),

3.50 (lH.hept.), 3.60 (2E,m), 4.40 (lH,m),

4.70 (lH,m), 7.1-7.6 (HH,m)

MS (DCI): m/e = 434 (M<+>), 4.9 (M<+->CH3)

Example 5

Synthesis of 4(R)-hydroxy-6(S)-[2-isopropyl-4-cyclohexyl-6-p-fluorophenyl)-phenoxymethyl]tetrahydro-2E-pyran-2-one

(formula I, X=0, Y = cyclohexyl, Z=H)

Example 5. 1

2- isopropyl-4-cyclohexyl-phenol

(Formula XIII, Y = cyclohexyl)

2.0 g of 55é palladium on charcoal, suspended in 50 ml of acetic acid is shaken for 30 minutes at room temperature in a hydrogen atmosphere. The solution of 31.2 g (0.1 mol) of

the phenol XIII from example 4.3 in 250 ml of acetic acid under the exclusion of oxygen and shaking for 5 hours at 50°C under 5 kg/cm<2> hydrogen pressure. The course of the reaction can be followed gas chromatographically [1 m SP 1000 on "Chromosorb WAW" 80 to 100 mesh,

220°C, 1.0 kg/cm<2> N2 carrier gas, wood: XIII (Y =

starting compound) 13.8 min, product XIII (Y = cyclohexyl): 4.6 min.].

The GC analysis shows that approx. 9056 XIII (Y = cyclohexyl) and several by-products are formed, none above 356. The catalyst is filtered off and the residue is recrystallized from cyclohexane. 25.0 g of the compound in heading XIII is obtained as a colorless solid.

1-H-NMR (CDCl 3 ): S 0.8-1.2 (10H,m); 1.25 (6H,d); 3.00 (1H,m);

3.11 (1H.hept.); 4.24 (lH.s.br.); 6.50-7.10

(3E,m)

MS (70eV): m/e = 218 (M<+>), 203 (M<+>), 203 (M<+->CH3)

Example 5. 2

2- isopropyl-4-cyclohexyl-6-iodophenol

(formula XIX, Y = cyclohexyl)

is obtained analogously to example 2.3 from the phenol XIII from example 5.1.

<1->H-NMR (CDCl3): S 0.7-1.2 (10H,m); 1.26 (6H,d); 3.0-3.1

(2H,m); 4.60 (lH,s,br.); 6.88-7.40 (2H,m)

MS (70eV): m/e = 344 (M<+>), 329 (M<+->CH3)

Example 5. 3

2-isopropyl-4-cyclohexyl-6-p-fluorophenyl-phenol

(formula III, Y = cyclohexyl, Z=H)

is obtained analogously to example 2.7 from the iodophenol XIX from example 5.2.

^H-NME (CDcl3): S 0.7-1.2 (10H,m); 1.25 (6H,d); 3.0-3.2

(2H,m); 4.90 (lH,s,br.); 6.9-7.4 (6H,m)

MS (70eV): m/e = 312 (M<+>), 297 (M<+->CH3)

Examples 5. 4 to 5. 7

4 (R)-Hydroxy-6(S)-[(2-isopropyl-4-cyclohexyl-6-p-fluorophenyl)-phenoxymethyl]tetrahydro-2H-pyran-2-one

(formula I, X=0, Y = cyclohexyl, Z=H)

is obtained from the phenol III from example 5.3 analogously to examples 1.6 to 1.9. Colorless solid, melting point 158 to 160°C.

1 H-NMR (CDCl 3 ): δ 0.8-1.1 (10 H,m); 1.25 (6H,d); 1.68

(LH,s,br.); 1.75 (1H,m); 1.90 (1H,m); 2.55-2.70 (2H,m); 3.0-3.2 (2H,m); 3.55 (2H,m);

4.40 (LH.gui); 4.70 (1E,m); 7.0-7.5 (6H,m) MS (70eV): m/e = 440 (M<+>)

Example 6

Synthesis of 4(R)-hydroxy-6(S)-[(2,4-diisopropyl-6-p-fluorophenyl)-phenylthiomethyl]tetrahydro-2H-pyran-2-one

(formula I, X=S,Y=i-Pr, Z=H)

Example 6. 1

N,N-dimethyl-[2,4-diisopropyl-6-p-fluorophenyl]thiocarbamic acid ester

3.6 g of 5056 sodium hydride are suspended in 60 ml of absolute DMF. 21.76 g (80 mmol, 1 equivalent) 2,4-diisopropyl-6-p-fluoro-

phenyl-phenol (example 1.5) is introduced under ice cooling. The solution is stirred for 30 minutes at room temperature and cooled to 0°C. The solution of 12.4 g (1.25 equivalents) of dimethylthiocarbamic acid chloride (Aldrich) in 20 ml of DMF is added, and the reaction mixture is stirred for 5 hours at 80-90°C. After cooling, dilute with 500 ml of ether, wash twice with water and once with potassium bicarbonate solution, dry over magnesium sulphate and remove the solvent. The residue is recrystallized from methanol. 25.6 g (yield 8956) of the compound in the title is obtained as a solid,

melting point 182°C.

MS: m/e = 359 (M<+>)

Example 6. 2

S-[(2,4-diisopropyl-6-p-fluorophenyl)phenyl]-N,N-dimethylthiocarbamate

25.0 g of the thiourea ester from example 6.1 was heated under nitrogen for 1 hour to 270-300°C. After obtaining, the residue was dissolved in the smallest possible amount of hot n-hexane, boiled with the addition of activated charcoal for 10 minutes under reflux and filtered while hot. From the filtrate, on slow cooling, 20.0 g (8056 yield) of the title compound crystallized out as colorless needles.

MS: m/e = 359 (M<+>)

Example 6. 3

2,4-diisopropyl-6-p-fluorophenyl-thiophenyl

(formula III, X=S, Y=i-Pr, Z=H)

For a suspension of 3.2 g of lithium aluminum hydride in absolute ether, a solution of 19.7 g of the thiocarbamate from example 6.2 in ether is added dropwise under ice cooling. It is stirred for 2 hours at room temperature and hydrolysed under ice-cooling with 2N sulfuric acid (up to pH 3). It is extracted several times with ether, dried over magnesium sulphate and the solvent is evaporated. 16.8 g of the title compound are obtained as a viscous oil.

MS: m/e = 288 (M<+>), 273 (M<+> - CH3)

Example 6. 4

6(S)-[(2,4-Diisopropyl-6-p-fluorophenyl)-phenyltriornethyl]-3,4,5,6-tetrahydro-2(R,S)-methoxy- 4(R)-(t-butyl-diphenyl-silyloxy)-2H-pyran

(formula V, X=S, Y=i-Pr, Z=E, R<7> = t-butyl-diphenylsilyl)

The suspension of 13.8 g (100 mmol) of potassium carbonate, 14.4 g (50 mmol) of the thiophenol from Example 6.3 and 20.4 g (40 mmol) of the lactoether iodide IV (R<7> - t-butyl-diphenylsilyl, preparation see EP-A 0 216 127) in 300 ml of absolute DMSO was stirred for 1 hour at 50°C. The cooled reaction mixture was mixed with water and extracted three times with ether. The combined organic phases were washed with water, then with saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed with toluene/acetate 95:5 over silica gel to give 21.4 g (8056 yield) of the title compound as a colorless viscous oil.

MS (CI): m/e = 670 (M<+>), 613 (M<+->tert.-Bu)

Example 6. 5

6(S)-[(2,4-Diisopropyl-6-p-fluorophenyl)-phenylthiornethyl]-3,4,5,6-tetrahydro-2(R,S)-hydroxy- 4(R)-(t-butyldiphenylsilyloxy)-2H-pyran

(formula VI)

The solution of 20.1 g (30 mmol) of the lactoether V from example 6.4 in 2 liters of THF, 1 liter of water and 1 liter of trifluoroacetic acid was stirred for 1 hour at 50-60° C. After cooling to room temperature, it was added 1.5 kg sodium acetate. The organic solvent was removed in vacuo. The aqueous residue was mixed with 1 liter of saturated sodium chloride solution and extracted several times with ether. The combined organic extracts were washed with water and dried over magnesium sulfate. The ether was removed and the residue was chromatographed with cyclohexane/acetic ester 4:1 over silica gel. 13.8 g (70% yield) of the title compound were obtained as a colorless, viscous oil.

MS (Cl): m/e = 656 (M<+>), 638 (M<+> - E2O), 581 (M<+>t-Bu-H2O).

Example 6. 6

6(S)-[(2,4-diisopropyl-6-p-fluorophenyl)-phenylthiornethyl]-3,4,5,6-tetrahydro-4(R)-(t-butyldiphenylsilyloxy) -2H-pyran-2-one (formula VII)

The solution of 13.0 g (19.8 mmol) of the lactol VI from Example 6.5, 7.4 g (20 mmol) of tetrabutylammonium iodide and 22.5 g (100 mmol) of N-iodosuccinimide in 200 ml of methylene chloride was stirred for 12 hours at room temperature. 500 ml of toluene was added and the methylene chloride was removed in vacuo. The precipitate was filtered off and washed with toluene. The combined filtrates were washed once with aqueous sodium thiosulfate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was chromatographed with toluene/acetic ester 10:1 over silica gel. 11.6 g (90% yield) of the title compound were obtained as a colorless, viscous oil.

MS (70ev, 70°C): m/e = 654 (M<+>), 597 (M<+->t-Bu)

Example 6. 7

4(R)-hydroxy-6(S)-[(2,4-diisopropyl-6-p-fluorophenyl)-phenylthiomethyl]tetrahydro-2H-pyran-2-one

Analogously to Example 1.9, 4.9 g (7056 yield) of the title compound is obtained as a viscous, colorless oil from 11.0 g of the protected lactone (Example 6.6).

%-NMR (CDCl 3 ): S 1.25 (12H,2xd), 1.65 (OH.s.br.), 1.7-1.9

(2H,m), 2.5-2.6 (2E,m), 2.75 (2H,m), 2.90 (lH,hept.), 3.40 (lH.hept.), 4, 35 (lH.gui),

4.50 (lH,m), 7.0-7.5 (6E,m).

MS (FAB): m/e - 416 (M<+>)

Example 7

Synthesis of 4(R)-hydroxy-6(S)-[(2-isopropyl-4,6-di-p-fluorophenyl)-phenylthiomethyl]tetrahydro-2H-pyran-2-one

(formula I, X=S, Y=p-fluorophenyl, Z=H)

The compound in the title is obtained by converting 2-isopropyl-4,6-di-p-fluorophenyl-phenol (example 3.2) analogously to examples 6.1 to 6.3 into 2-isopropyl-4,6-di-p-fluorophenyl-thiophenol, and converts this analogously to examples 6.4-6.7 to the compound in the title. Colorless, sticky solid, which became mostly crystalline when washed with n-hexane,

melting point > 6CC.

1-H-NMR (CDCl 3 ): S 1.3 (6H,d), 1.7-1.95 (3H,m), 2.5-2.7 (2H,m)

2.75 (2H,m), 3.4 (1H,hept.), 4.4 (1H,m),

4.6 (1H,m), 7.0-7.5 (10H,m).

MS (FAB): m/e = 468 (M<+>), 453 (M<+->CE3)

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

Example 8

Preparation of the sodium salts of the open-chain dihydroxycarboxylic acids (formula II, sodium salt) from the lactones of formula I.

Example 8a

3(R ),5(S)-dihydroxy-6-[2-(4-fluorophenyl)-4,6-diisopropyl-phenoxy]-hexanoic acid sodium salt

To dissolve 7.0 g (17.5 mmol) of the lactone from example 1.9 in 800 ml of absolute ethanol, 17.7 ml of 1N caustic soda is rapidly added dropwise under ice-cooling. It is stirred for 5 minutes under ice cooling, then for two hours at room temperature. According to DC, the starting material is completely converted. Solvent is removed in vacuo at bath temperature

< 30°C. The residue is dissolved twice in ethanol and each time evaporated to dryness in vacuo, then dissolved in ether and evaporated to dryness in vacuum. The residue is suspended in toluene and evaporated to dryness in vacuo. The residue is stirred with n-pentane, then suctioned off and dried in high vacuum over phosphorus pentoxide

and potassium hydroxide pellets. 6.25 g of the title compound are obtained as colorless, amorphous powder. When the pentanic mother liquor is evaporated, a further 0.43 g of amorphous product is obtained. Melting point 240-244"C (decomposition). The decomposition temperature depends on the heating rate.

Example 8b

3( R ) , 5 ( S )-dihydroxy-6-[2-isopropyl-4-tert-butyl-6-(4-fluorophenyl)-phenoxy]-hexanoic acid sodium salt

is obtained analogously to example 8a from the lactone from example 2.11. Colorless powder, melting point 256-258°C (decomposition).

Example 8c

3 (R ), 5 (S )-dihydroxy-6-[2-isopropyl-4,6-bis-(4-fluorophenyl)-phenoxy]-hexanoic acid sodium salt

is obtained analogously to example 8a from the lactone from example 3.6. Colorless powder, melting point 235-237"C (decomposition).

Example 8d

3(R),5(S)-dihydroxy-6-[2-isopropyl-4-phenyl-6-(4-fluorophenyl)-phenoxy]-hexanoic acid sodium salt

is obtained analogously to example 8a from the lactone from example 4.11. Colorless powder, melting point 238-240°C (decomposition).

Example 8e

3 (R),5(S)-dihydroxy-6-[2-isopropyl-4-cyclohexyl-6-(4-fluorophenyl)-phenoxy]-hexanoic acid sodium salt

is obtained analogously to example 8a from the lactone from example 5.7. Colorless powder, melting point 230-233"C (decomposition).

Example 8f

3(R),5(S)-dihydroxy-6-[2-(4-fluorophenyl)-4,6-diisopropyl-thiophenoxy]-hexanoic acid sodium salt

is obtained analogously to example 8a from the lactone from example 6.7. Colorless powder, melting point 230-234°C (decomposition).

Example 8g

3 ( R ),5( S )-dihydroxy-6-[2-isopropyl-4,6-(4-fluorophenyl)-thiophenoxy]-hexanoic acid sodium salt

is obtained analogously to example 8a from the lactone from example 7.

Claims (1)

Analogous process for the preparation of therapeutically active 6-phenoxymethyl-4-hydroxy-tetrahydro-pyran-2-ones and 6-thiophenoxymethyl-4-hydroxy-tetrahydropyran-2-ones of general formula I as well as the corresponding open-chain dihydroxycarboxylic acids of formula II in which X is for oxygen or sulphur, Y means a) a straight-chain or branched alkyl radical of 3 to 4 carbon atoms, b) cyclohexyl or a phenyl radical which may be substituted in the nucleus with halogen, as well as their pharmacologically acceptable salts with bases and their pharmacologically acceptable esters, characterized in that one a) transfers correspondingly substituted phenols or thiophenols of formula III wherein X and Y have the meanings given by formulas I and II, with the optically pure iodide of formula IV wherein R<7> represents a protecting group which is stable to bases and weak acids, to the lactoether of formula V in which X and Y have the meaning given by formulas I and II and R<7> the meaning given by formula IV, b) the lactoether of formula V is hydrolysed to the corresponding the lactoles of formula VI in which X and Y have the meanings given by formulas I, II and R<7> has the meaning given by formula IV, c) the lactols of formula VI are oxidized to the corresponding the lactones of formula VII in which X and Y have the meanings given by formulas I/II and R<7> has the meaning given by formula IV, d) the obtained protected lactones of formula VII are transferred in a manner known per se to compounds of formula I and e ) optionally the obtained compounds of formula I are transferred to the corresponding open-chain dihydroxycarboxylic acids of formula II, their salts or their esters, optionally the obtained salts or esters are transferred to the free dihydroxycarboxylic acids or optionally the free carboxylic acids of the salts or esters.