FI96684B - Process for Preparation of 6-Phenoxymethyl-4-hydroxytetrahydropyran-2-one and 6-thiophenoxymethyl-4-hydroxytetrahydropyran-2-one and corresponding dihydroxycarboxylic acid derivatives, salts and esters useful as pharmaceuticals - Google Patents

Description

96684

Process for the preparation of 6-phenoxymethyl-4-hydroxytetrahydropyran-2-ones and 6-thiophenoxymethyl-4-hydroxytetrahydropyran-2-ones and their corresponding dihydroxycarboxylic acid derivatives, salts and esters useful as medicaments

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A-reductase (HMG-CoA reductase) plays an important role in cholesterol biosynthesis [A. Endo, J. Med. Chem. 28 10 (1985) 401]. Inhibitors of this enzyme, especially mevinolin [A.S. Pappu et al., Clin. Res. 34 (1986) 684 A], synvinoline [A.S. Olsson et al., The Lancet (1986) 391; M.J.T.M. Mol et al., The Lancet (1986) 936] and eptastinia [Drugs of the Future 12 (1987) 437; N. Nakaya et al., 15 Atherosclerosis 61 (1986) 125] was tested clinically in patients with high cholesterol. Structurally simplified, fully synthetic analogs of these compounds have been described [G.E. Stokker et al., J.

Med. Chem. 29 (1986) 170 and 852; W. F. Hoffman et al., J.

20 Med. Chem. 29 (1986) 159].

EP-A-0 216 127 discloses compounds of formula Ia HO * ___. 0

«” XX

Y .: o'7 (Ia) RW5:: ·: 30 r2A £ Tr4 • · · ^ wherein R1 and R5 are the same or different and are a) '; hydrogen or halogen, b) cycloalkyl having 4 to 8 carbon atoms or a phenyl group which may have 1 to 3 substituents at its core which are halogen, trifluoromethyl and / or alkyl or alkoxy, each of which has 1 to 4 C atoms, or c) a straight-chain or branched alkyl group having 1 to 18 carbon atoms or a straight-chain or branched alkenyl group having 2 to 18 carbon atoms, the alkyl or alkenyl groups in turn having 1 to 3 substituents which are а) straight-chain or branched alkoxy groups having up to 10 carbon atoms, or cycloalkoxy groups having 3 to 7 carbon atoms, or straight-chain or branched alkenyloxy or alkynyloxy groups having 3 to 6 carbon atoms, β) haloalkyl, hydroxyl, having 3 to 7 C atoms, unsubstituted phenyl, α- or β-thienyl groups or phenyl, α- or β-thienyl groups, the cores of which may in turn have 1 to 3 substituents which are halogen, trifluoromethyl and / or alkyl or alkoxy having 1 to 4 carbon atoms, r) unsubstituted phenoxy, benzyloxy, α-20 or β-thienyloxy groups, or phenoxy, benzyloxy, α- or β-thienyloxy groups, which in turn may have 1 to 3 substituents on the ring which are halogen, trifluoromethyl and / or alkyl or alkoxy of 1 to 4; carbon atoms,

: 25 O

·· g 6 б) group -0-C-R, where R is straight-chain or * · · •. a branched alkyl or alkenyl group having up to 8 carbon atoms, or a cycloalkyl or cycloalkenyl group each having 3 to 8 carbon atoms, or subs-: .i .: 30 unsubstituted a phenyl group or a phenyl group having in the ring • · · V ί in turn 1 to 3 substituents selected from halogen, trifluoromethyl and / or alkyl or alkoxy having 1 to 4 carbon atoms, or a 3-pyridyl group,: · 2 4 'I * R and R are the same or different and are hydrogen, alkyl having 1 to 4 carbon atoms, halogen or alkoxy having 1 to 4 carbon atoms, and 3 3 96684 R is hydrogen, alkyl or alkenyl having up to 4 carbon atoms, halogen or alkoxy having 1 to 4 carbon atoms, and the corresponding open-chain dihydroxycarboxylic acids, their pharmacologically tolerable salts with bases and their pharmacologically tolerable esters.

The compounds described in this patent application inhibit HMG-CoA reductase, with IC 50 values in the 10 10 10 8 molar range. Corresponding values in the explanatory part sa have the most potent compound Ia (R1-R3 = Cl, R2 = R4 = H, R5 = CH2-) IC50 = 2.5 x 10 "8 M.

DE application publication 36 32 893 (= Derwent reference 15 88-99 366/15) relates to e.g. compounds of general formula Ib H0 * Cf ° 20 / K'vJL'R5 <Ib) ... R3: 25 wherein R and R3 are the same or different and are • · ·; a) hydrogen or halogen, b) a phenyl group which may have 1 to 3 substituents in the core which are halogen, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, • · ·: c) an alkyl group in which has 1 to 5 carbon atoms and may have 1 to 3 substituents which are a) C 1 -C 4 alkoxy groups or cycloalkoxy groups having 3 to 7 carbon atoms, ·. · * 35 β ) phenoxy or benzyloxy groups, which in turn may have 1 to 3 substituents on the core which are 4 96684 halogen, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, τ) halogen, cycloalkyl having 3 to 7 C atoms , phenyl groups which may have 5 to 3 substituents in the core which are halogen, trifluoromethyl, ethyl, ethyl, isopropyl, methoxy, ethoxy,

6) O-C 1-4 alkyl groups having a total of 3-8 O

carbon atoms, 2 4 10 R and R are the same or different and are hydrogen, halogen, methyl, ethyl, methoxy, ethoxy, benzyloxy, 3 R is hydrogen, halogen, trifluoromethyl, methyl, ethyl, methoxy, ethoxy, and the like open chain dihydroxycarboxylic acids, their pharmacologically tolerable base salts and their pharmacologically tolerable esters.

According to the information in this patent application, the described compounds of the formula Ib are generally insignificantly less potent than the compounds Ia, 15 when the groups R to R have the same substitution pattern.

Surprisingly, it was now invented in these patent applications. . substitution patterns not shown in the examples (R - • ·· 5 I! 25 R), by which the compounds of the general formulas Ia and Ib * ·, * · obtain up to 10 times the potency

t · I

to the examples given in EP-A-0 216 127 and DE-A-V: 36 32 893. The substituent patterns are for the substituents R, R, R and R. 3 ::: 30 in full, for the substituent R only partially within the scope of the general claims of EP-A-0 216 127 and DE-A-36 32 893, in addition to which it is assumed that the group R may also have meanings not set forth in either of the earlier patent applications.

5 96684

The present invention relates to a process for the preparation of 6-phenoxymethyl-4-hydroxytetrahydropyran-2-ones and 6-thiophenoxymethyl-

4-hydroxytetrahydropyran-2-ones of general formula 5 I

"tr ίΗ3χ / * 10 7w®-r U) ch3 [LJJ -

Y

and the corresponding open-chain dihydroxycarboxylic acids,

15 of formula II

] COOH

Ι ^, ΟΗ CH3 .1 20 i χκ / ^ \ (11)

CH3IVJJ

: Y

where; X is oxygen or sulfur, and Y is a) a straight-chain or branched alkyl group. or having 3 to 4 carbon atoms, or • ♦ · ***** (b) cyclohexyl or a phenyl group which may be substituted by halogen, and their pharmacologically tolerable salts with bases and their • · · ; pharmacologically tolerable esters.

: * ·.. Preferred are compounds of general formulas. ···, you have the following substituents: X is oxygen, and 6 96684 Y is isopropyl, tert-butyl, cyclohexyl, phenyl, p-fluorophenyl.

The compounds of the formulas I and II are prepared according to the invention in such a way that (a) the correspondingly substituted phenols or thiophenols of the formula III

CHo I XH

1 ° 2 ^ 0 (III,

Y

wherein X and Y are as defined in formulas I and II, are converted by means of an optically pure iodide of formula IV r7 ° a ^ och3 20 * (IV)

wherein R7 is a base and a weak acid stable protecting group, to lactol ethers of formula V

: 25 V · * · OCH3: X: SY5 'HV (v) 30

ch3KJJ

Y

Wherein X and Y are as defined in formulas I and II and '. * 35 group R7 is as defined in formula IV, 7 96684 b) lactol ethers of formula V are hydrolysed to the corresponding lactols of formula VI

RXcroH

cn3 / 'Ζφ © -'

10 Y

wherein X and Y are as defined in formulas I and II and R7 is as defined in formula IV, c) the lactols of formula VI are oxidized to the corresponding lactones of formula VII R7cu s o n ch3 /

Y

wherein X and Y are as defined in formulas I and II and R7 is as defined in formula IV, d) the protected lactones of the formula VII obtained are converted into 1 · «I. compounds of the formula I in a manner known per se and • · · • ♦ · * * e) the compounds of formula I obtained are optionally converted into the corresponding open-chain dihydroxycarboxylic acids of formula II, their salts or esters, and any salts or esters obtained are converted into the free dihydroxycarboxylic acids or possible, · ·. free carboxylic acids are converted into salts or esters.

8 96684

The method is expediently carried out under the conditions described in said older patent applications. The process conditions can always be modified according to the meaning of the substituents (cf. e.g. Example 1 1.8).

The compounds of formula III used as starting materials are new. Iodides of the formula IV are described, for example, in EP-A-0 216 127.

The syntheses of the necessary phenol and thiophenol moieties III are described in Scheme I and are clarified below.

Compounds of formula IIi can be obtained from 2-isopropylphenols XIII substituted in the 4-position by Y using a palladium (0) catalyzed aryl-aryl coupling as a key step. Overviews of palladium (0) catalyzed aryl-aryl coupling are given in E. Negishi, Acc. Chem. Res. 15 (1982) 340 and R.F. Heck, Palladium Reagents in Organic Synthesis, Chapter 6, Academic Press 1985.

20 According to the latest published results (D.A. Widowson, Y.-Z. Zhang, Tetrahedron 42 (1986) 2111), aryl

Grignard compounds have increased reactivity in Pd (0) -catalyzed coupling with aryl halogens if they have ortho-alkoxy substituents. Therefore, bromine,. : When converting compounds XIII to compounds XIV, the compound • · • j · is protected. XIV with a benzyl group to give compound XV and form T · «I. Grignard reagent XVI is formed in THF, and this already reacts «· · •« ·

* 'under mild conditions (10 to 65 ° C) aryl halide XVII

with (Hai = Br or I) to the coupling product XVIII in excellent yields (90-98%) using Pd (0) - • · · V · catalysis. Deprotection by catalytic hydrogenation gives compound III (X = O). In this way, coupling product III (X = O) is obtained, so that the yield and purity are good. In this method, it is necessary to protect the OH group of the phenol and subsequently remove the protecting group.

Pd (O) -catalyzed aryl-vinyl couplings in the presence of unprotected phenol groups are known (RF Heck, Acc. Chem. Res. 12 (1979) 146; CB Ziegler Jr., RF Heck, J. Org. Chem. 43 (1978) 2941). This reaction is not fully comparable to aryl-aryl coupling because it does not use strongly basic metal-10 organo-reagents (such as Grignard compound XX).

Aryl-aryl linkages in the presence of unprotected phenol groups are novel. We have successfully carried out the reverse of this traditional method described above, namely the Pd (0) -catalyzed reaction of unprotected ortho-iodophen-15 (XIX) with p-bromofluorobenzenes (XX) with Grignard reagents. A product compatible with Compound XX is used to de-protonate Compound XIX and another product compatible with Compound XX is used for the coupling reaction. Since it further results in the oligomerization of the Grignard component as a side reaction, 2.5 to 3.0 equivalents of compound XX must be used to achieve a complete reaction leading to compound III (X = O).

In this way, double protection of the unprotected diode XXI XXI is also achieved. If 3 equivalents are used. compound XX, at room temperature a mixture is obtained which • · «t '· * ·' contains the individual coupling product XIX '(Y = - ^^ - F) *; ··' 30 * -.

V: and double coupling product III '(Y = - (f JVF). If, on the other hand, 4 equivalents of compound XX are used, the momentarily detectable single coupling product 10 96684 finally reacts completely to product III'. this double coupling reaction is possible without purification of the highly sensitive diiodide XXI, compound III '(Y =) 5 is obtained quite directly from compound XII, so that the overall yield is 40-60% (not optimized!).

* see C.V. Bordlianu, Arch. d. Pharmazie 272 (1934) 8 10 It is expedient to prepare this phenol part III 'in this way, because the conventional method would have to make use of the inevitably formed compound XIX', since the aryl-di-Grignard compounds are unstable [F. Bickelhaupt, Angew. Chem. 99 (1987) 1020].

The direct incorporation of unprotected iodophenols XIX into aryl-Grignard reagents saves two synthetic steps compared to conventional coupling and allows the use of cheaper fluorobromobenzenes. Therefore, a lower yield of the coupling step must be allowed.

The palladium catalysts used are tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium dichloride or a mixture of palladium dichloride and triphenylphosphine. It is known that similar kata- '! lyses can also be obtained with nickel phosphine complexes.

• I

: 25 with and with similar transition metal complexes • j1. [See. e.g., E. Negishi, Acc. Chem. Res. 15 (1982) 340; J.K.

• i i

Stille, Angew. Chem. 98 (1986) 504; R.F. Heck, Acc. Chem * 'Res. 12 (1979) 146; E. Negishi et al., J. Org. Chem. 42 (1977) 1821].

• ♦ i * ·? · 1 30 Thiophenols of the formula III are obtained according to the methods described in the literature from the corresponding phenols of the formula III by reacting them with * 9, ', dialkylthiourea chloride, followed by tl 11 96684 using thermal Newman-Kwart thermal rearrangement and reductive cleavage of the resulting S-aryldialkylthiocarbamate to thiophenols of the formula III (cf. also DE application 36 32 893). ^ «· · • ♦ · ♦ • ·« I «· • · ♦ • · · · · • · ·« · · • · · · 1 · · • • 1 · · • • • 96684 12

Scheme 1 Y Ö: ί \> * Ρ 'm \ / en \ / / ~ rS "ö = Φ 0' p-.; S t ä <E>: .Λ- · <\ 1 - /> \

O \ x I

.... * L_ * Ό. * I *. N \ C) / rn u.

... X \ N— / σ _c ί

* O S Σ CL

0 ·! ^ "- pt> - ... CD - w 5-Ö- * ä-fe ^; - <\ - <i * -ö ~. 4 ^ p / i;; ru \, -o ··· c. Oj L- ^ q_:!: \ / \ Λ O. r

«Λ ·: \ / Ö ^" Ί I

S-Ö-> l „· ... · m £ Λ *, 4 * x γ \" "': i-O-

\ - <N - (X

X X

13 96684

Synthetic routes for the preparation of compounds of formula III (Scheme 1) are shown in part in Scheme 2 and are described below.

The preparation of the compounds XIII used as starting materials, which have certain substituents Y, is determined by the availability of the starting materials.

Compound XIII (Y = i-Pr) is formed by decarboxylation of a commercially available (Janssen) 3,5-diisopropyl-2-hydroxybenzoic acid of formula XI. Decarboxylation 10 can be performed by heating the pure starting material or solution in an inert solvent (e.g., nitrobenzene) to 210-220 ° C. Substantially better yield and purity are obtained when the solution is heated in quinoline in the presence of a copper chromite catalyst to a temperature of about 190 ° C.

Compound XIII (Y = tert-butyl) is obtained very para-selectively by G. Sartorin et al. (Chem. and Industry (1985) 762) when isopropylphenol is mixed in a solution of CH 2 Cl 2 with methyl tert-butyl ether (MTBE) and zirconium (IV) chloride. Good yields of compound XIII are obtained by reacting compound XII (1.0 equiv.) With MTBE (1.05 equiv.) And ZrCl 2 (2.4 equiv. In two batches) at 0 ° C.

: Also with alkyl halides / aluminum trichloro- • · · I corresponding to the traditional Friedel-Crafts alkylations of compound XII. with rides or alcohols Y-OH / Lewis or protic acids • · · can be used to prepare compound XIII [see K.-D.

Bode in Houben-VJeyl, Methoden der organischen Chem-mie, Part VI / lc, Phenols Part 2), Georg Thieme Verlag, V: 30 Stuttgart 1976, from p. 925].

# ···. 4-hydroxy-3-isopropylbiphenyl XIII (Y =

Is obtained from commercially available p - nitrobiphenyl VIII

35 by o-alkylation with isopropylmagnesium bromide [review G.

14 96684

Bartoli, Acc. Chem. Res. 17 (1984) 109] to compound IX, by reducing compound IX to amine X, by diazotization and phenol boiling (Scheme 2).

Catalytic hydrogenation of a solution of compound XIII (Y =) in ethyl acetate with palladium on carbon (5%) at a temperature of 50 ° C and a hydrogen pressure of 3.92 to 5.88 bar

10 gives a yield of 85-90% of compound XIII (Y = O

Figure 2

NC> 2 I NOg I NH ^ I OH

fOl 1> | () | s ΙΟ] 1> NoN02 / fic0H μ)] FTddö 'S ^ 2) h2o / δ. * Sr

OOP O

V1 1 1> x x XIII

20 4 ° * sss' Y e}

S: V Hg Pd / c, iO

i! XI11 (Y - ((Qj)) xm (Y - <^)) .S! 25

V · I 0H __ I OH

\ X COpH —l, φτ. ^, ιφ) X Λ ·, ·, · X 1 XI 1 I (Y -.-Pnepyl> • · · • · · 30 OH I oh • · j ^ l C 1 “C 4“ PII ylKologenid / K ot · * * XII C) -C4-phenyl X 1 I 1 (Y - C1-C 1-6 yl) 15 96684

The lactones of the formula I can be converted in the customary manner (cf. e.g. EP-A-0 216 127 and DE-A-36 32 893) into the corresponding open-chain dihydroxycarboxylic acids of the formula II, their pharmacologically tolerable salts with their bases and their pharmacologically acceptable salts.

The enzyme HMG-CoA reductase is widely distributed in nature. It catalyzes the formation of mevalonic acid from HMG-10 CoAr. This reaction is a key step in cholesterol biosynthesis (I.R.Sabine, 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase, CRC Press 1983). A high cholesterol mirror is associated with a number of diseases such as coronary heart disease or atherosclerosis. Therefore, lowering the high cholesterol mirror is a therapeutic goal in the treatment and prevention of such diseases. The goal is to inhibit or reduce endogenous cholesterol synthesis. HMG-CoA reductase inhibitors arrest cholesterol at an early stage of biosynthesis. They are therefore suitable for the prevention and treatment of diseases due to elevated cholesterol nipples. Reducing or impairing endogenous synthesis results in increased cholesterol migration! from plasma to cells. The effect can be enhanced by the concomitant administration of bile acid sequestrants such as anion exchangers. Increased bile acid secretion results in enhanced resynthesis and thus increased cholesterol degradation (M.S. Brown, P.T. Kovanen, J.L. Goldstein, Science 212 (1981) 628; M.S.

: 30 Brown, J.L. Goldstein, Spektrum der Wissenschaft 1985 (1) ··] ·. 96). The agents of the invention are inhibitors of HMG-CoA reductase. They are therefore suitable for preventing or reducing: cholesterol biosynthesis and thus for prophylaxis or treatment of diseases due to high cholesterol, in particular coronary artery disease, macular degeneration, hypercholesterolemia, hyperlipolemia.

The compounds (I) and (II) can be used as pharmaceutical preparations based on the compounds of the formula I or the corresponding dihydroxycarboxylic acids of the formula II, their salts or esters, as medicaments, in particular for the treatment of excessive cholesterol levels.

The compounds of formula I or the corresponding acids, salts or esters are administered in various forms of administration, preferably orally in the form of tablets, capsules or liquids. The daily dose ranges from 3 mg to 2500 mg, depending on the patient's body weight and general structure, but preferably in the dose range of 10 mg to 500 mg.

The compounds of the invention may be used as lactones of the general formula I, as free acids of the formula II or as pharmaceutically acceptable salts or esters dissolved or suspended in pharmacologically innocuous organic solvents such as monohydric or polyhydric alcohols such as ethanol or glycerol, triacetin, oil sunflower oil or cod liver oil, ethers such as, for example, diethylene glycol dimethyl ether or also polyethers such as polyethylene glycol or also

I I I

*; * * in the presence of other pharmacologically innocuous polymeric carriers such as, for example, polyvinylpyrrolidone or other pharmaceutically tolerable additives such as starch, cyclodextrin or polysaccharides . In addition, the compounds according to the invention can be combined with additives which bind bile acid, in particular with non-toxic, basic anion exchange resins which bind bile acids in the gastrointestinal tract in an unbound form. Salts of dihydroxycarboxylic acids can also be converted to aqueous solutions.

tl · 17 96684

The HMG-CoA reductase activity of the sodium salts of the compounds of formula II according to the invention was determined by two test methods: 1) Inhibition of HMG-CoA reductase activity using a dissolved enzyme preparation prepared from rat liver microsomes. preparation induced after day-night rhythm adjustment with cholestyramine (RCuemid). The substrate was (S, R) 14C-HMG-CoA, the concentration of NADPH during the incubation was maintained by a regenerative system. Separation of 14C-mevalonate from substrate and other products (e.g., 14C-HMG) was performed by column elution, reporting the elution profile of each individual sample. Continuous entry of 3 H-mevalonate was avoided because it is a determination of the relative value of the inhibitory effect. The enzyme-free control sample, the normal enzyme-containing sample (= 100%) and the sample containing 20 preparations were always treated together in the test series. Each individual value was averaged over three replicates. The significance of outliers between non-product and product-containing samples was assessed by t-test. Using the method described above, the compounds of the invention were reported *. eg the following HMG-CoA reductase inhibition values (IC50 values • · · ***** (mol / l); molar concentration of compound per liter required for 50% inhibition)

Table 1 • · ·::: 30 •: · * ·. Example IC50 (mol / l) * ..! 8a 2.3 * 10 "9 t: 8b> 10" 7 8c 1.7-10-8 35 8d 2.3 * 10'® 18 96684 8e 5.2-10-9 8f 4.8-10-9 8g 3.6-10-8 2) Suppression or cleavage of HMG-CoA reductase in HEP G2 cell cultures (human hepatoma cell line) 14

An assay for inhibition of C-sodium acetate formation in cholesterol was performed.

Single layers of HEP G2 cells in RPMJ 1640 medium containing 10% lipid-free fetal grade 10 calf serum were preincubated for 1 hour using various concentrations of dihydroxycarboxylic acids of formula II. After addition of C-labeled sodium acetate, the incubation was continued for 3 hours. Tritium-labeled cholesterol-15 was added as an internal standard and the cell solution was saponified alkaline. The lipids were extracted with a mixture of trichloromethane and methanol (2: 1). After the addition of Carrier cholesterol, the lipid mixture was preparatively separated using thin layer chromatography plates with a mixture of trichloromethane and acetone (9: 1). The Koles-20 terine zone was visualized by iodine vapor staining, further measured with a DC radio scanner, and then scraped off. The amount of C-cholesterol is determined; with a scintillation counter. From another equal batch! ! individual cell layers (to determine B-cholesterol biosynthesis per milligram of cellular protein) were measured. The same assay was performed using cells of the same culture that had not been preincubated (so-called "solvent control"). Test compounds or - !, ·.! The intensity of the test was determined by comparing a series of 30 biosynthesized β-cholesterols and a "solvent control". The potency of the effect was calculated using the sodium salt of mevinoline used as a standard.

*: O

The IC 50 and IC 7 values (IC 50 and IC 7 (M) is the molar concentration of compound per liter required for: 50 and 70% inhibition) varied somewhat in different cell batches. The mean values for the sodium salt of mevinoline were IC50 = 5 * 10 "0 M, IC70 = 1.5 * 10 ~ 7 M. The measured IC values of the test compounds (sodium salts of dihydroxycarboxylic acids of formula II) (Table 2) were corrected by the mean decomposition of me-5 vinolinium sodium. The relative potency of mevinolin sodium is 100. Table 2

Example IC50 (M) IC70 (M) Rel. intensity of effect 10 8a 2.7 · 10-8 7 · 10-8 185 <214) 8b ~ 10 "5 <1 8c g. ίο-8 56 8d 9.5 · ΙΟ'8 53

The synthesis of the compounds I according to the invention is further illustrated by the following examples.

Example 1 Synthesis of 4 (R) -hydroxy-6 (S) - [(2,4-diisopropyl-6-p-fluorophenyl) phenoxymethyl] tetrahydro-2H-pyran-2-one (Formula I, X = O, Y = i-Pr) Example 1.1 2,4-Diisopropylphenol (formula XIII, Y = i-Pr)

A mixture of 145 g (0.65 mol) of 3,5-diisopropyl-2-hydroxybenzoic acid (XI), 540 ml (588 g, 4.55 mol) of quinoline and 7.5 g (0.024 mol) of copper chromite «· · * · * * 25 (2CuO · Cr 2 O 3), stirred for 2 hours at a temperature of * · '· * 190 ° C (outdoor temperature 225 ° C). Cool to a temperature of n.

10 ° C, acidified with cooling with about 1 liter of 1: 1 dilute hydrochloric acid to a pH of 1 to 2, extracted with toluene and the extract washed with 2M hydrochloric acid, then with water and then with NaHCO 3. solution. Dry, filter, evaporate and distill under high vacuum. 105 g of the title compound XIII are obtained in the form of a bright yellow oil, b.p. 81-84 ° C / 0.27 mbar. 35 H-NMR (CDCl 3): δ 1.20 (6H, d); 1.25 (6 H, d); 3.00 (2H, 2x hept); 4.10 (1H, s, broad); 6.50-7.00 (3 H, m) 20 96684

Example 1.2 2,4-Diisopropyl-6-bromophenol (Formula XIV, Y = i-Pr)

To a solution of 95 ° C containing 102.3 g (0.57 mol) of 2,4-diisopropylphenol in 900 ml of glacial acetic acid is added 1 g of iron powder, followed by dropwise addition over 90 minutes. sheet 101 g (32.2 mL, 0.63 mol) of bromine. Stir for an additional 1 h at 100 ° C, cool, extract the reaction mixture with toluene / water, and wash the toluene phase with NaHCO 3 solution. The residue is dried, filtered, evaporated and distilled under high vacuum. 125 g of the title compound XIV are obtained in the form of a bright yellow oil, boiling point 85 ° C / 0.2 mbar.

1 H-NMR (CDCl 3): δ 1.20 (6H, d); 1.25 (6 H, d); 2.80 (1H, hept); 3.25 (1 H, hept); 5.33 (1 H, s); 6.87-7.20 (2H, m) MS (70 eV): m / e = 256/258 (M +), 241/243 (M + -CH 3)

Example 1.3 1-Benzyloxy-2,4-diisopropyl-6-bromobenzene 20 (Formula XV, Y = i-Pr)

A suspension of 166.5 g (1.2 mol) of potassium carbonate in 124 g (0.48 mol) of the above bromine! . phenol, 91.52 g (0.72 mol) of benzyl chloride and 2 L; ; 2-butanone, heated at reflux for 24 hours. After cooling, the inorganic solid is filtered off with suction, the filtrate is evaporated off under reduced pressure and the residue is partitioned between toluene and water. The toluene tree is washed with saturated sodium chloride solution, dry ί |! filtered and evaporated. The residue is chromatographed on silica gel using a mixture of cyclohexane and toluene (9: 1) as eluent. 155 g of the title compound * .. * are obtained in the form of a colorless oil.

:: ·; · Minor residues of benzyl chloride are removed under high::: vacuum. Purification can also be performed by distillation ·; · 35 (boiling point 150 ° C / 0.2 mbar).

21 96684 1 H-NMR (CDCl 3): δ 1.18 (6H, d); 1.22 (6 H, d); 2.80 (1 H, hept); 3.32 (1H, hept); 4.90 (2 H, s); 6.93-7.60 (7H, m) MS (70 eV): m / e = 346/348 (M +), 267, 254/256, 91 Example 1.4 1 - Bent Cause 1 to 2.4 - di - i sopropyl 1 i - 6-p - fluoro 1 phenyl phenylbenzene (formula XVIII, Y = i-Pr)

Grignard compound XV (Y = i-Pr) is prepared using 48.62 g (0.14 mol) of the bromide of Example 1.3 and 3.53 g (0.147 mol) of Mg chips in 120 ml of absolute THF (n 60 ° C, 1 hour). This Grignard solution is added rapidly 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. THF. The internal temperature rises to 55-60 ° C within 15 minutes. After 7 minutes a precipitate forms. Stir for 1 hour at 50-58 ° C, allow to stand at room temperature overnight, partition with ether and 1 M hydrochloric acid, wash the ether phase with 1 M hydrochloric acid, then with water and then with saturated NaHCO 3 solution. Dry, filter and evaporate. If necessary, the product is purified by chromatography on silica gel using a mixture of cyclohexane and toluene (4: 1) as eluent or by distillation (b.p. 180 [deg.] C./0.4 mbar). 49.3 g of the title compound XVIII are obtained in the form of a colorless solid. mp 65-67 ° C;

1 H-NMR (CDCl 3): δ 1.30 (12H, d); 2.95 (1 H, hept); 3.45 (1 H, hept); 4.40 (2 H, s); 6.90 - 7.80 811H, m) 5.0 MS (CI): m / e = 363 (M + H +), 285, 263 Example 1.5 / t 2,4-diisopropyl-6-p-fluorophenylphenol (formula

III: To a solution of 49.3 g (0.136 mol) of benzyl ether XVIII from Example 1.4 in 1 l of ethyl acetate-35 and 100 ml of glacial acetic acid is added 4 g of palladium on carbon. (10%) and shake for 20 min under a hydrogen atmosphere 22 96684 (vigorous H2 evolution). The catalyst is removed by suction filtration, evaporated, the residue is extracted several times with toluene and is always evaporated under reduced pressure. 34.4 g of the title compound III are obtained in the form of a colorless oil, b.p. 115 ° C / 0.13 mbar.

1 H-NMR (CDCl 3, 270 MHz): δ 1.25 (6H, d); 1.29 (6 H, d); 2.87 (1H, hept); 3.31 (1H, hept); 4.95 (1H, s, broad); 6.88 (1 H, d); 7.08 (1 H, d); 7.18 (2 H, m); 7.45 (2 H, m).

MS (70 eV): m / e = 272 (M *), 257 (M + -CH 3) 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) -2H-pyran (Formula V, Y = i-Pr) To a suspension containing 27.6 g (0.2 mol) of potassium 15 carbonate and spatula tip hydroquinone in 250 ml of abs. DMSO, 27.2 g (0.1 mol) of the phenol of Example 1.5 are added. After stirring for 1 hour at room temperature, a solution of 56 g (0.11 mol) of lactol ether iodide IV (preparation instructions in EP-A-0 216 127, R7 = t-butyldiphenylsilyl) in 250 ml of abs. DMS0: a. Stir for 4 hours at an internal temperature of 50-55 ° C. According to thin layer chromatography (silica gel, 1st evolution cyclohexane / ethyl acetate 9: 1, 2nd evolution cyclohexane / ethyl acetate 15: 1) iodine-25 di IV has reacted completely (Rf 0.5), starting material ·. some of the phenol used remains (Rf 0,7) and the product J · * · * is essentially of formula V (Rf 0,6). The mixture is allowed to cool and the reaction mixture is extracted with a mixture of ether and half-saturated sodium chloride solution. The aqueous phase is extracted once more with ether. The combined organic phases are washed with brine, dried over MgSO 4, filtered and evaporated. The crude product is chromatographed on silica gel using a mixture of toluene and cyclohexane (2: 1) as eluent, then 100% toluene-35, then a mixture of toluene and ethyl acetate 23 96684 (30: 1). 51 g of the title compound are obtained in the form of a colorless resin.

1 H-NMR (CDCl 3): δ 1.10 (9H, s); 1.28 (12 H, d); 1.4-2.2 (4 H, m); 2.93 (2H, 1 x hept); 3.40 (2 H, m); 3 * 52 (3H, 5 s); 3.97-4.40 (2H, quint + m); 4.87 (1 H, dd); 6.87-7.90 (16H, m) MS (CI): m / e = 654 (M +), 597 (M + -tert.-but); 539, 519, 323, 283, 135, 127 Example 1.7 10 6 (S) - [2,4-Diisopropyl-6-p-fluorophenyl) phenoxymethyl] -3,4,5,6-tetrahydro-2 - (R, S) -hydroxy-4 (R) - (t-butyldiphenylsilyloxy) -2H-pyran (formula VI, Y = i-Pr)

A solution of 40.2 g (61.4 mmol) of the lactol ether of Example 15 1.6 in 3 l of THF, 3 l of water and 4.2 l of glacial acetic acid is stirred for 24 hours at 80-85 ° C. (outdoor temperature). The solvent is removed under reduced pressure and the residue is evaporated to dryness three times from toluene. Chromatograph on silica gel (2 L) using a mixture of cyclohexane and ethyl acetate (12: 1) as eluent to give 33.4 g (85% yield) of the title compound as a colorless amorphous powder.

MS (FAB): m / e = 640 (M +), 519, 367, 323, 283, 271, 257 Example 1.8 *. ·: (S) - [2,4-diisopropyl-6-p -fluorophenyl) phenoxy- (N, N, N-methyl) -3,4,5,6-tetrahydro-4 (R) - (t-butyldiphenylsilyloxy) -2H-pyran-2-one (Formula VII, Y = i-Pr) s; *; To a solution of 33.4 g (52.1 mmol) of the lactol of Example 1.7 and 19.25 g (52.1 mmol) of tetrabutylammonium iodide in 2.5 l of absolute dichloromethane. t '## · * dane, 46.9 ♦ ·' ·· 'g (208.4 mmol) of N-iodosuccinimide are added with stirring and cooling. Stir under light under nitrogen for 1 hour at 35 10 ° C and 20 hours at room temperature. The reaction solution is washed with water, then twice with NaHCO3 solution, then with saturated NaCl solution, dried, filtered and evaporated. The residue is dissolved in a small amount of dichloromethane and filtered through silica gel using a mixture of cyclohexane and ethyl acetate (92: 8) as eluent. 32.1 g of the title compound are obtained in the form of a colorless resin.

1 H-NMR (CDCl 3, 270 MHz): δ 1.06 (9H, s); 1.23 (6 H, d); 1.26 (6 H, d); 1.59 (2 H, m); 2.41 (1 H, dd); 2.59 (1 H, dm); 2.90 (1 H, hept); 3.36 (1H, hept); 3.48 (2H, ABX of ABX); 4.29 (1H, quint); 4.80 (1 H, m); 6.96 (1 H, d); 7.03 (2 H, m); 7.10 (1 H, d); 7.36 - 7.52 (8H, m); 7.58 - 7.73 (4H, m) MS (70 eV, 70 ° C): m / e = 638 (M +), 581 (M + -tert.-but), 539 (581-propylene), 283 Example 19 4 (R) -Hydroxy-6 (S) - [(2,4-diisopropyl-6-p-fluorophenyl) phenoxymethyl] tetrahydro-2H-pyran-2-one (Formula I, X * 0, Y = i-Pr)

To a solution of 31.0 g (48.5 mmol) of the silyl compound of Example 1.8 in 1.5 L of tetrahydrofuran (filtered through basic Al 2 O 3) is added 11.65 g (194 mmol) of glacial acetic acid and then 45.92 g (145.5 mmol) of tetrabutylammonium fluoride trihydrate. Stir for 20 hours at room temperature. The solvent is removed under reduced pressure and the residue is immediately extracted with a mixture of ether and water. The aqueous phase is further extracted with% «V .: twice with ether. The combined organic phases are

Take up in saturated sodium chloride solution, dry over MgSO 4, filter and evaporate. The residue is taken up in toluene and evaporated under reduced pressure. The crude product is chromatographed on silica gel (2 kg) using a mixture of cyclohexane and ethyl acetate (1: 1) as eluent.

15.7 g (yield 81%) of the title compound are obtained in the form of a colorless solid, m.p. 145-147 ° C.

1 H-NMR (CDCl 3, 270 MHz): δ 1.25 and 1.27 (12H, 2 x d); 1.67 81H, s, broad); 1.76 (1 H, dtd); 1.87 (1 H, ddd); Δ 96684 2.58 (1H, ddd); 2.69 (1 H, dd); 2.91 (1 H, hept); 3.39 (1H, hept); 3.54 (2H, ABX of ABX); 4.38 (1H, quint); 4.68 (1 H, m); 6.87 (1 H, d); 7.10 (3 H, d + m); 7.51 (2H, m) MS (FAB): m / e = 400 (M +), 257 ^ 5 Example 2 4 (R) -Hydroxy-6 (S) - [(2-isopropyl-4-tert.- Synthesis of butyl-6-p-fluorophenyl) phenoxymethyl [] tetrahydro-2H-pyran-2-one (Formula I, X = O, Y = tert.-Bu)

Example 2.1 2-Isopropyl-4-tert-butylphenol (formula XIII, Y = tert.-Bu)

To a suspension of 70 g (0.3 mol) of zirconium tetrachloride in 100 ml of absolute dichloromethane at a temperature of -5 ° C to 0 ° C under a nitrogen atmosphere is slowly added dropwise a solution containing 34 g (0.25 mol) of zirconium tetrachloride. ) o-isopropylphenol (formula XII) and 22 g (0.26 mol) of tert-butyl methyl ether in 150 ml of absolute dichloromethane. Stir for one hour at 0 ° C. According to thin layer chromatography (100% toluene), the reaction takes place at about 50%. An additional 70 g (0.3 mol) of ZrCl 4 is added rapidly in one portion and the brown suspension is stirred for 15 min at 0 ° C. According to thin layer chromatography, the reaction is now more than 95% complete and no impurities are observed. * Drop at -10 to 25 ° C using efficient cooling 500 ml of saturated NaH * * * * CO3 solution (highly exothermic). A colorless * * «'·' · * solid is formed which makes mechanical mixing considerably more difficult. The organic phase is separated, dried and evaporated under reduced pressure. If necessary, the product s *: *: 30 is chromatographed on 800 g of silica gel using a mixture of cyclohexane and toluene (1: 2) as eluent or distilled under reduced pressure. 43.1 g of the title compound XIII are obtained in the form of a colorless solid, m.p. 55-57 ° C, b.p. 134-135 ° C / 16 mbar.

26 96684 1 H-NMR (CDCl 3): δ 1.27 (6H, d); 1.28 (9 H, s); 3.17 (1 H, hept); 4.61 (1 H, s); 6.62 (1 H, d); 7.05 (1 H, dd); 7.17 (1H, d) MS (70 eV): m / e = 192 (M +) ^ 5 * If the reaction mixture is allowed to stand at room temperature under nitrogen for 10 hours, about 30% of the starting material and numerous by-products are again detected by thin-layer chromatography. .

Example 2.2 2-Isopropyl-4-tert-butyl-6-bromophenol (Formula XIV, Y = tert-Bu)

To a solution of 65.8 g (0.34 mol) of the phenol XIII of Example 2.1 in 375 ml of CCl 4 is added dropwise 18 ml (55.8 g, 0.35 mol) of bromine. Observe by thin layer chromatography (cyclohexane / ethyl acetate 5: 1, Rf XIII 0.37, XIV 0.33) that all the starting material reacts, transfer to ether and wash twice with Na 2 S 2 O 3 ~ Liu, once with saturated NaCl solution. Dry, evaporate and distill under high vacuum. 86.1 g of the title compound XIV are obtained in the form of a pale yellow oil, b.p. 105-106 ° C / 1.3 mbar 1 H-NMR (CDCl 3): δ 1.25 (6H, d); 1.29 (9 H, s); 3.47: (1H, hept); 6.17 (1H, broad); 7.09 (1 H, d); 7.24 (1H, d) MS (70 eV): m / e = 270/272 (M +) Example 2.3 4 · 4 - - - · · * / 2-isopropyl-4-tert. -butyl-6-iodophenol (formula: * V XIX, Y = tert.-Bu)

To a solution of 19.2 g (0.1 mol) of the phenol of Example 2.1 in 150 ml of a 50% aqueous solution of ethylamine and in 120 ml of ethanol is added dropwise at a temperature of 20 to 25 ° C. ° C solution containing 30.4 g (0.12 mol) of iodine and 40.0 g (0.24 mol) of potassium iodide in 120 ml of water. Stir for 1 hour at room temperature, transfer: to ether, wash twice with Na 2 S 2 O 3 solution, then with saturated NaCl solution, dry, evaporate under reduced pressure, transfer to toluene and evaporate

II

27 96684 under reduced pressure at a temperature below 25 ° C. 26.0 g of the title compound XIX are obtained in the form of an oil.

1 H-NMR (CDCl 3): δ 1.15-1.50 (15H, s + d); 3.06 (1 H, hept); 4.60 (1H, s, broad); 6.86 (1 H, s); 7.73 (1H, s) δ MS (70 eV, <50 ° C): m / e = 318 (M +), 303 (M + -CH 3), 275, 177, 161

Example 2.4 1-Benzyloxy-2-isopropyl-4-tert-butyl-6-bromobenzene (Formula XV, Y = tert.-Bu) is obtained according to Example 1.3 from compound XIV, Example 2.2.

Colorless crystals, m.p. 47-49 ° C

1 H-NMR (CDCl 3): δ 1.23 (6H, d); 1.48 (9 H, s); 3.33 (1 H, hept); 5.12 (2 H, s); 7.02 (1 H, s); 7.44 (6H, s, broad) 15 MS (70 eV): m / e = 360/362 (M +), 268/270, 91

Example 2.5 1-Benzyloxy-2-isopropyl-4-tert-butyl-6-p-fluorophenylbenzene (formula XVIII, Y = tert.-Bu) is obtained according to Example 1.4 from the corresponding Grignard compound XVI.

Colorless solid, m.p. 126-128 ° C.

1 H-NMR (CDCl 3): δ 1.1-1.3 (15H, s + d); 3.38 (1H, hept); 5.16 (2 H, s); 6.83 (1 H, s); 7.0-7.7 (10H, m) MS (70 eV): m / e = 376 (M +), 282, 91 Example 2.6 * * * 2-isopropyl-4-tert-butyl-6 -p-Fluorophenylphenyl [* * · * phenol (Formula III, Y = tert.-Bu) is obtained according to Example 1.5 from the compound XVIII of Example 2.5.

Colorless solid, m.p. 109-111 ° C.

V *: 30 "1 H-NMR (CDCl 3): δ 1.15 (9H, s); 1.23 (6H, d); 3.16 rl ·. (1H, hept); 4.65 (1H, s 6.80 (1H, s), 6.9-7.4 (5H, m) MS: 70 eV: m / e = 286 (M +), 271 (M + -CH 3) , 229 28 96684

Example 2.7 2-Isopropyl-4-tert-butyl-6-p-fluorophenylphenol (Formula III, Y = tert.-Bu) by direct addition of iodide XIX to a Gj ^ Lgnard-5 reagent prepared from p-bromofluorobenzene XX

To a solution of 25.7 g (81 mmol) of the iodophenol of Example 2.3 in 150 mL of absolute THF is added 1.87 g (1.6 mmol) of tetrakis (triphenylphosphine) palladium (0) and stirred for 30 min at room temperature. temperature-10 sa. Grignard reagent prepared from 42.6 g (243 mmol) of 4-bromofluorobenzene and 6.2 g (255 mmol) of Mg chips in 170 ml of THF is added in one portion. In this case, the internal temperature rises to approx. 50 ° C. The mixture is kept for three hours at 55 [deg.] C., whereupon a colorless solid (magnesium iodide) separates. * The reaction mixture is taken up in ether, washed twice with 1M hydrochloric acid, once with water, once with saturated sodium hydrogen carbonate solution, dried and evaporated under reduced pressure. The residue is chromatographed on silica gel (1 kg) using a mixture of cyclohexane and ethyl acetate (9: 1) as eluent. The fractions containing compounds XIII, XIX, III are co-evaporated. The residue is dissolved in as little n-pentane as possible. 9.8 g of pure compound III crystallize out in the freezer. The melting point 25 and spectral data of this material were the same as shown in Example 2.6.

• · · * · * · * * The progress of the reaction cannot be monitored by thin-layer chromatography, because the coupling product of iodide XIX, compound III and phenol XIII, which is formed as a by-product during the coupling, is chromatographed by all methods. # with eluents. Suitable separation conditions: HPLC, • · * ..! column 250 x 4.6 RP 18.5 μm Nucleosil, 64% (CH 3 OH + 0.1;% NH 4 OAc) / 36% H 2 O, 1.2 mL / min, 40 ° C, UV measurement 254 nm.

29 96684

Examples 2.8 - 2.11 4 (R) -Hydroxy-6 (S) - [2-isopropyl-4-tert. butyl-6-p-fluorophenyl) phenoxymethyl] tetrahydro-2H-pyran-2-one (formula I, X = O, Y = tert.-Bu) is obtained from phenol III 5 (Example 2.6 or 2.7) according to Examples 1.6 to 1.9.

Colorless solid, m.p. 178-179 ° C

1 H-NMR (CD 2 Cl 2): δ 1.13-1.20 (15H, m); 2.02 (1H, s, broad); 2.10 - 2.16 (2H, m); 2.71 (2H, ABX of ABX); 3.24 (1 H, hept); 4.22 (2H, ABX of ABX); 4.50 (1H, s, broad); 5.03 - 5.13 (1H, m); 6.79 (1 H, s); 6.98 - 7.07 (3H, m); 7.19 - 7.25 (2H, m) MS (70 eV): m / e = 414 (M +), 359 IR (KBr): 3560/3460 (OH), 1745 (C = O), 1500, 1235 1220 cm-1 Example 3 Synthesis of 4 (R) -hydroxy-6 (S) - [(2-isopropyl-4,6-difluorophenyl) phenoxymethyl] tetrahydro-2H-pyran-2-one

Formula I, X = O, Y = -U 2) Yf, Example 3.1 '-' 2-Isopropyl-4,6-diiodophenol (Formula XXI)

A solution of 40.8 g (0.3 mol) of o-isopropylphenol in 630 ml of a 50% aqueous solution of ethylamine and 525 ml of ethanol is added dropwise over 10 minutes at a temperature of 0 to 15 ° C. solution containing 160 g (0.63 mol) of each

0 «I

dia and 209 g (1.26 mol) of potassium iodide in 300 ml of water.

• · · '· * · * Stir for 20 min at room temperature and pour the reaction mixture into 200 ml of saturated Na 2 S 2 O 3 solution and 600 ml of water. Extract three times with 500 ml of ether, wash: [:: 30 combined extracts with a mixture of ether and 2 M hydrochloric acid. then with water. Dry over MgSO 4, decant to fresh MgSO 4, filter and evaporate; under reduced pressure at a temperature below 20 ° C. This evaporation from toluene is carried out once under the reduced pressure produced by the water jet pump 35, once under vacuum. 99.0 g of the title compound are obtained in the form of a red oil.

No impurities are detected by NMR, MS and DC.

1 H-NMR (CDCl 3): δ 1.2 (6H, d); 3.2 (1 H, hept); 3.5 (1 H, s); 7.35 (1 H, d); 7.75 (1H, d), δ MS (70 eV): m / e 388 (M +), 373 (M * -CH 3), 246 (M + - CH 3 I)

Example 3.2 2-Isopropyl-4,6-di-p-fluorophenylphenol (Formula III ') To a solution of 125 g (0.32 mol) of the diiodide XXI of Example 3.1 and 5 g (7.1 mmol) of bis (triphenyl) -phosphine) palladium (II) chloride (Aldrich) in 300 ml abs. THF, is added dropwise under ice-cooling under an argon atmosphere to a Grignard solution containing 219 g (1.25 mol) of p-bromofluorobenzene and 31.3 g (1.3 mol) of magnesium turnings in 600 ml of abs. THF (internal temperature 25-30 ° C). Stir for 5 hours at 40-50 ° C, then add another 2.5 g of (PPh 3) 2 PdCl 2 and stir overnight at about 45 ° C. Cool to 0 ° C and add 50 ml of water dropwise (exothermic reaction) so that the internal temperature remains below 25 ° C. Forms a tough, mucous :; precipitation. At a temperature below 25 ° C, 300 ml of 1: 1 dilute hydrochloric acid are added dropwise (the precipitate dissolves, pH about 1). The mixture is extracted several times with ether. The combined extracts are washed with 1 M hydrochloric acid, then

«I I

I, 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 chromatographed on silica gel (1 kg, 70-200 [mu] m) using 4 l of a mixture of cyclohexane and toluene (4: 1) as eluent, then 10 l of a mixture of cyclohexane and toluene. (3: 1) and • · ···. then a mixture of cyclohexane and toluene (2.5: 1).

Elute first with 10.2 g of a colorless solid which is subject to NMR (aromatic protons only), MS (360, 35 342, 284, 266 (base peak), 248) and elemental analysis.

II

31 96684 (C + H + F = 100%) based on the oligomer mixture formed from Grignard compound XX.

m / e = 266 corresponding to p% ir '248 is 266-F + H, 284 is 266 + F-H, 360 is 266 + C 6 H 4 F-H, 342 is 360-F + H.

2.1 g of single coupling product 15-2-isopropyl-4-p-fluorophenyl-6-iodophenol XIX '(Y = p-fluorophenyl) are then eluted.

MS (70 eV): m / e = 356 (M +), 341 (M * -CH 3), 214 Finally, 45.1 g of the title compound III 'are eluted as a viscous, colorless oil which crystallizes after standing for a long time at room temperature. .

1 H-NMR (CDCl 3): δ 1.35 (6H, d); 3.4 (1H, hept); 5.1 (1H, s =; 6.8-7.6 (10H, m) MS ( 70 eV): m / e = 324 (M +), 309 (M * -CH 3) Thin layer chromatography (toluene / cyclohexane 1: 2) 25 Rf values: oligomer mixture 0.61, starting material XXI 0.53, monojo- * ♦ * * Didi 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-H-pyran-2-one: T: 30 .-- (formula I, X = 0, Y =) • · · t: is obtained from phenol III '(Example 3.2) according to Examples 1.6 to 1.9.

35 Colorless solid, m.p. 190-192 ° C

32 96684 1 H-NMR (CDCl 3, 270 MHz): δ 1.31 (6Η, 2 χ d); 1.72-1.95 (3Η, m); 2.66 (2Η, ΑΒΧ: η AB); 3.47 (1Η, hept); 3.59 (2H, ABX of ABX); 4.40 (1 H, m); 4.70 (1 H, m); 7.12 (4 H, m); 7.28 (1 H, d); 7.42 (1H, d), 7.55 (4H, m) + 5 MS (DCI): m / e = 452 (M +), 437 (M + -CH 3), 129 IR (KBr): 3480 (OH ), 1715 (C = O), 1510, 1255, 1220, 1200, 1160, 830 cm-1 Example 4 4 (R) -Hydroxy-6 (S) - [(2-isopropyl-4-phenyl-6-p -10 fluorophenyl) phenoxymethyl] tetrahydro-2H-pyran-2-one (Formula I, X = O, Y = phenyl)

Example 4.1 2-Isopropyl-4-phenylnitrobenzene (Formula IX) A solution of 20.0 g (0.1 mol) of 4-nitro-15-phenyl VIII in 400 ml of absolute THF is added dropwise at -70 ° C under a nitrogen atmosphere for 3 hours. Grignard solution prepared from 30.7 g (0.25 mol) of 2-bromopropane and 5.85 g (0.24 mol) of magnesium turnings in 300 ml of absolute THF. Stir for a further 1 hour at -70 ° C (thin layer chromatography: VIII completely reacted) and then rapidly drop the solution containing 22.7 g (0.1 mol) of 2,3-dichloro-5 at -40 ° C. 6-dicyano-p-benzoquinone (DDQ) in 200 ml of absolute THF. Allow to warm to room temperature, stir for a further hour and pour into 1.2 liters of water. The THF is removed under reduced pressure, the aqueous residue is extracted twice with ethyl acetate, the extracts are washed well with water, dried and evaporated.

: Chromatograph on silica gel (1 kg) using a mixture of cyclohexane and dichloromethane (4: 1) as eluent to give 8.9 g of the title compound as a clear oil.

1 H-NMR (CDCl 3): δ 1.37 (6H, d); 3.58 (1 H, hept); 7.36-7.97 (8H, m) 35 MS (70 eV, 50 ° C): m / e = 241 (M +), 224, 174, 152 11 33 96684

Example 4.2 2-Isopropyl-4-phenylaniline (Formula X) 13.1 g (54.3 mmol) of the nitro compound IX of Example 4.1 are dissolved in a solution of 10 g of am-5 polyacia in 400 ml of methanol. Under a nitrogen atmosphere, 10 g of Raney nickel, washed three times with methanol, are added. Shake the suspension for 2 hours at room temperature and normal pressure under a hydrogen atmosphere. The catalyst is removed by filtration, the filtrate is evaporated and the residue is chromatographed on silica gel (400 g) using 2 l of a mixture of cyclohexane and toluene (1: 2) as eluent, followed by 5 l of toluene. 11.2 g of the title compound X are obtained in the form of a colorless oil.

1 H-NMR (CDCl 3): δ 1.33 (6H, d); 3.00 (1H, hept); 3.45 (2H, s, broad); 6.80 (1 H, d); 7.2 - 7.7 (7H, m) MS (70 eV): m / e = 211 (M +), 196 (M + -CH 3)

Example 4.3 2-Isopropyl-4-phenylphenol (Formula XIII, 2 ° Y - - <Q>)

To a solution of 11.2 g (53.1 mmol) of the amine X of Example 4.2 in 50 ml of glacial acetic acid is added dropwise at 10 to 12 ° C a solution containing 4.26 g (62 mmol) of sodium nitrite in 50 ml. of water. Diazonium; / salt precipitates. The suspension is difficult to mix. After 5 minutes * · * · *, the suspension is poured into a slowly boiling solution of 32 ml of concentrated sulfuric acid in 65 ml of water. Stir for a further 5 min, then cool and extract with a solution of toluene, ether and saturated NaHCO3 solution. mixture. The organic phase is washed twice with saturated • *

NaHCO 3 solution and once with brine, then dried and evaporated. Chromatography on silica gel (500 g) using 100% toluene as eluent gives 4.9 g of the title compound XIII as a yellow oil.

1 H-NMR (CDCl 3): δ 1.30 (6H, d); 3.25 (1 H, hept); 7.1-7.7 (8H, m) -r 5 MS (70 eV): m / e = 212 (M +), 197 (M + -CH 3), 178

Example 4.4 2-Isopropyl-4-phenyl-6-bromophenol (formula XIV, Y »phenyl) is obtained according to Example 2.2 from the phenol XIII of Example 4.3.

1 H-NMR (CDCl 3): δ 1.26 (6H, d); 3.40 (1H, hept); 5.63 (1 H, s); 7.2-7.7 (7H, m) MS (70 eV): m / e = 290/292 (M +), 275/277 (M * -CH 3), 196, 165

Example 4.5 1-Benzyloxy-2-isopropyl-4-phenyl-6-bromobenzene (Formula XV, Y = phenyl) is obtained according to Example 1.3 from phenol XIV (Example 4.4) as a colorless oil which crystallizes slowly.

1 H-NMR (CDCl 3): δ 1.24 (6H, d); 3.45 (1 H, hept); Δ 5.05 (2H, s); 6.95-7.70 (12H, m) MS (70 eV); m / e = 380/382 (M +), 91 Example 4.6

1-Benzyloxy-2-isopropyl-4-phenyl-6-p-fluorophenylbenzene (formula XVIII, Y = phenyl) is obtained according to Example 1.4 from the corresponding Grignard compound XVI

J I I

*. as a colorless oil which crystallizes slowly.

V · 1 H-NMR (CDCl 3): δ 1.28 (6H, d); 3.52 (1H, hept); 5.00 (2H, s); 6.95-7.70 (16H, m ) MS (70 eV); m / e = 396 (M *) s J ϊ 30 Example 4.7 * I - I 1 .....— ··, ·, 1-isopropyl-4-phenyl-6-p-fluoro phenyl phenol h «(formula III, Y = phenyl, Z = H) is obtained according to Example 1.5 from compound XVIII (Example 4.6) as a colorless solid.

1 H-NMR (CDCl 3): δ 1.35 (6H, d); 3.40 (1H, hept); 5.10 (1H, s, broad); 6.85-7.45 (UH, m) MS (70 eV); m / e = 306 (M +), 291 (M4-CH3) 35 96684

Examples 4.8-4.11 4 (R) -Hydroxy-6 (S) - [(2-isopropyl-4-phenyl-6-p-fluorophenyl) phenoxymethyl] tetrahydro-2H-pyran-2-one (Formula I, X = O , Y = phenyl) is obtained from phenol (Example 5 4.7) according to Examples 1.6 to 1.9.

Colorless solid, m.p. 184-187 ° C

1 H-NMR (CDCl 3): δ 1.30 (6H, 2 x d); 1.7 - 2.0 (3 H, m); 2.65 (2 H, m); 3.50 (1 H, hept); 3.60 (2 H, m); 4.40 (1 H, m); 4.70 (1 H, m); 7.1-7.6 (UH, m) 10 MS (DCI): m / e = 434 (M +), 419 (M1-CH 3)

Example 5 Synthesis of 4 (R) -hydroxy-6 (S) - [2-isopropyl-4-cyclohexyl-6-p-fluorophenyl) phenoxymethyl] tetrahydro-2H-pyran-2-one (Formula I, X = O, Y = cyclohexyl) Example 5.1 2-Isopropyl-4-cyclohexylphenol (formula XIII, Y = cyclohexyl) 2.0 g of palladium on carbon (5%) suspended in 50 ml of ethyl acetate are shaken for 30 min at room temperature under a hydrogen atmosphere. A solution of 31.2 g (0.1 mol) of the phenol XIII according to Example 4.3 in 250 ml of ethyl acetate under oxygen is added and shaken for 5 hours at 50 [deg.] C. under a hydrogen pressure of 5.9 bar. The progress of the reaction can be monitored by gas chromatography at 25 [1 m SP 1000 with Chromosorb WAW 80-100 mesh, 220 ° C, • · · • · · 0.98 bar, N 2 carrier gas, tert: XIII (Y =: starting material ) 13.8 min, product XIII (Y = • k · 30 * · '1 - # i ·, \ cyclohexyl): 4.6 min] Gas chromatographic analysis shows that n. 90% of compound XIII (Y = cyclohexyl) and several by-products, of which nothing more than 3% is obtained, the catalyst is removed by filtration and the residue is recrystallized from cyclohexane to give 25.0 g of the title compound XIII as a colorless solid.

1 H-NMR (CDCl 3): δ 0.8-1.2 (10H, m); 1.25 C6H, d); Δ 3.00 (1 H, m); 3.11 (1H, hept); 4.24 (1H, s, broad); 6.50 - 7.10 (3H, m) MS (70 eV): m / e = 218 (M +), 203 (M * -CH 3)

Example 5.2 2-Isopropyl-4-cyclohexyl-6-iodophenol (Formula XIX, Y = cyclohexyl) is obtained according to Example 2.3 from the phenol XIII of Example 5.1.

1 H-NMR (CDCl 3): δ 0.7-1.2 (10H, m); 1.26 (6 H, d); 3.0 - 3.1 (2 H, m); 4.60 (1H, s, broad); 6.88 - 7.40 (2H, m) 15 MS (70 eV): m / e = 344 (M +), 329 (M * -CH 3)

Example 5.3 2-Isopropyl-4-cyclohexyl-6-p-fluorophenylphenol (Formula III, Y = cyclohexyl) is obtained according to Example 2.7 from the iodophenol XIX of Example 5.2.

1 H-NMR (CDCl 3): δ 0.7-1.2 (10H, m); 1.25 (6 H, d); 3.0-3.2 (2 H, m); 4.90 (1H, s, broad); 6.9 - 7.4 (6H, m) MS (70 eV): m / e = 312 (M +), 297 (M * -CH 3)

Examples 5.4 to 5.7 4 (R) -Hydroxy-6 (S) - [(2-isopropyl-4-cyclohexyl-25-p-fluorophenyl) phenoxymethyl] tetrahydro-2H-pyran-2-yl] -one (Formula I, X = O, Y = cyclohexyl) is obtained from the phenol of Example 5.3 according to Examples 1.6 to 1.9. Colorless solid, m.p. 158-160 ° C.

1 H-NMR (CDCl 3): δ 0.8-1.1 (10H, m); 1.25 (6 H, d); Δ 1.68 (1H, s, broad); 1.75 (1 H, m); 1.90 (1 H, m); 2.55 - 2.70 (2 H, m); 3.0 - 3.2 (2 H, m); 3.55 (2 H, m); 4.40 (1H, • · · *> <· ‘quintet); 4.70 (1 H, m); 7.0 - 7.5 (6H, m) MS 870 eV): m / e = 440 (M +) 37 96684

Example 6 Synthesis of 4 (R) -hydroxy-6 (S) - [(2,4-diisopropyl-6-p-fluorophenyl) phenylthiomethyl] tetrahydro-H-pyran-2-one (Formula I, X = S, Y - i-Pr) Example 6.1 N, N-Dimethyl- [2,4-diisopropyl-6-p-fluoro-phenyl] -thiourea ester 3.6 g of 50% sodium hydride are suspended in 60 ml of abs. . DMF. 21.76 g (80 mmol, 1 equiv) of 2,4-diisopropyl-10β-6-p-fluorophenylphenol (Example 1.5) are added under ice-cooling. The mixture is stirred at room temperature for 30 min and cooled to 0 ° C. A solution of 12.4 g (1.25 equiv.) Of dimethylthiourea chloride (Aldrich) in 20 ml of DMF is added and the reaction mixture is stirred for 5 hours at 80-90 ° C. After cooling, the mixture is diluted with 500 ml of ether, washed twice with water and once with potassium hydrogen carbonate solution, dried over magnesium sulphate and the solvent is removed. The residue is recrystallized from methanol.

25.6 g (89% yield) of the title compound are obtained in the form of a solid, m.p. 182 ° C

MS: m / e = 359 (M &lt; + &gt;)

Example 6.2 S - [(2,4-diisopropyl-6-p-fluorophenyl) phenyl] -25 N, N-dimethylthiocarbamate · 25.0 g of the thiourea acid ester of Example 6.1 were heated under nitrogen for 1 hour at 270-300 ° C. The residue was then dissolved in: as little hot n-hexane as possible, active; After the addition of 30 charcoal, it was refluxed for 10 min and filtered hot. 20.0 g (80% yield) of the title compound crystallized slowly from the filtrate on colorless needles.

MS: m / e = 359 (M &lt; + &gt;) 38 96684

Example 6.3 2,4-Diisopropyl-6-p-fluorophenylthiophenol (Formula III, X = S, Y = i-Pr)

To a suspension containing 3.2 g of lithium aluminum hydride was abs. in ether, dropwise with ice-cooling a solution of 19.7 g of the thiocarbamate of Example 6.2 in ether. Stir for 2 hours at room temperature and hydrolyze under ice-cooling with 1 M sulfuric acid (until pH 3). Extract several times with ether, dry over magnesium sulfate and remove the solvent. 16.8 g of the title compound are obtained in the form of a viscous oil.

MS: m / e = 288 (M +), 273 (M + -CH 3)

Example 6.4 6 (S) - [(2,4-Diisopropyl-6-p-fluorophenyl) phenylthiomethyl] -3,4,5,6-tetrahydro-2 (R, S) -methoxy-4 ( R) - (t-butyldiphenylsilyloxy) -2H-pyran (formula V, X = S, Y * i-Pr, R7 = t-butyldiphenylsilyl)

Preparation of a suspension containing 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 lactol ether iodide IV (R7 = t-butyldiphenylsilyl) In EP-A-0 216 127) in 300 ml of abs. DMSO, was stirred for 1 hour at 50 ° C. The cooled reaction mixture was stirred in water and extracted three times with J. ether. The combined organic phases were washed with water, then with saturated sodium chloride solution, dried over magnesium sulphate and evaporated under reduced pressure. pressure. The residue was chromatographed on silica gel using • · ·. ·; ·. 30 g (95: 5) of toluene and ethyl acetate as eluent to give 21.4 g (80% yield) of the title compound as a colorless oil.

: MS (CI): m / e = 670 (M +), 613 (M * -tert.-but) 39 96684

Example 6.5 6 (S) - [(2,4-Diisopropyl-6-p-fluorophenyl) phenylthiomethyl] -3,4,5,6-tetrahydro-2 (R, S) -hydroxy-4 (R ) - (t-butyldiphenylsilyloxy) -2H-pyran (Formula VI) 5 A solution of 20.1 g (30 mmol) of the lactol ether V of Example 6.4 in 2 l of THF, 1 l of water and 1 l of trifluoroacetic acid, stirred for 1 hour at 50-60 ° C. After cooling to room temperature, 1.5 kg of sodium acetate was added. The organic solvents were removed under reduced pressure. The aqueous residue was mixed with 1 L of saturated sodium chloride solution and extracted several times with ether. The combined organic phases were washed with water and dried over magnesium sulfate. The ether was removed and the residue Kro-15 was chromatographed on silica gel using a mixture of cyclohexane and ethyl acetate (4: 1) as eluent. 13.8 g (70% yield) of the title compound are obtained in the form of a colorless viscous oil.

MS (CI): m / e = 656 (M +), 638 (M + -H 2 O), 581 (M + -t-20 Bu-H 2 O), Example 6.6 6 (S) - [(2,4-diisopropyl- 6-p-fluorophenyl) phenylthiomethyl] -3,4,5,6-tetrahydro-4 (R) - (t-butyldiphenylsilyloxy-2H-pyran-2-one (Formula VII) 25 A solution containing 13 0.0 g (19.8 mmol) of the lactol VI of Example * 6.5, 7.4 g (20 mmol) of tetrabutylammonium iodide and 22.5 g (100 mmol) of N-iodosuccinimide in 200 ml of dichloromethane were stirred at room temperature. 500 ml of toluene were added and the dichloromethane was removed under reduced pressure, the precipitate was filtered off with suction and washed with toluene, and the combined filtrates were washed each time with aqueous sodium thiosulfate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure, and the residue was chromatographed on silica gel using a mixture of toluene and ethyl acetate as eluent ( 11.6 g (90% yield) of the title compound are obtained in the form of a colorless, viscous oil.

MS (70 eV, 70 eC): m / e = 654 (M *), 597 (M + -t-but) Example 6.7 ^ 4 4 (R) -hydroxy-6 (S) - [(2,4-di -isopropyl-6-p-fluorophenyl) phenylthiomethyl] tetrahydro-2H-pyran-2-one

According to Example 1.9, 4.9 g (yield 70%) of the title compound are obtained from 11.0 g of protected lactone (Example 6.6) as a viscous, colorless oil.

1 H-NMR (CDCl 3): δ 1.25 (12H, 2 x d); 1.65 (OH, s, broad); 1.7 - 1.9 (2 H, m); 2.5 - 2.6 (2 H, m); 2.75 (2 H, m); 2.90 (1 H, hept); 3.40 (1H, hept); 4.35 (1H, quint); 4.50 (1 H, m); 7.0 - 7.5 (6 H, m).

MS (FAB): m / e = 416 (M +) Example 7 4 (R) -Hydroxy-6 (S) - [(2-isopropyl-4,6-di-p-fluorophenyl) phenylthiomethyl] tetrahydro- Synthesis of 2H-pyran-2-one (Formula I, X = S, Y = p-fluorophenyl)

The title compound is obtained by converting 2-isoprop-20-yl-4,6-di-p-fluorophenylphenol (Example 3.2) to 2-isopropyl-4,6-di-p-fluorophenylthiophenol according to Examples 6.1 to 6.3 and reacting it with according to Examples 6.4 to 6.7 to give the title compound.

25 Colorless, sticky solid which crystallizes on washing

* in n-hexane, m.p. above 60 ° C

1 H-NMR (CDCl 3): δ 1.3 (6H, d); 1.7 - 1.95 (3 H, m); 2.5-2.7 (2 H, m); 2.75 (2 H, m); 3.4 (1 H, hept); 4.4 (1 H, m); 4.6 (1 H, m); 7.0 - 7.5 (10 H, m).

. ·: ·. MS (FAB): m / e = 468 (M *), 453 (M + -CH 3) e 1 IR (KBr): 3480 (OH), 1715 (C = 0) • · ·: ♦ * Example 8 φ ♦ ♦ 1

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

II

41 96684

Example 8a Sodium salt of 3 (R), 5 (S) -dihydroxy-6- [2- (4-fluorophenyl) -4,6-diisopropylphenoxy] hexanoic acid

To a solution of 7.0 g (17.5 mmol) of the lactone of Example 1.9 in 800 mL of abs. ethanol, dropwise with rapid cooling with 17.7 ml of 1 M sodium hydroxide. Stir for 5 min under ice-cooling, then for 2 h at room temperature. Based on thin layer chromatography, the starting material has reacted completely. The solvents are removed under reduced pressure at a bath temperature below 30 ° C. The residue is dissolved twice in ethanol and evaporated to dryness under reduced pressure on both occasions, then dissolved in ether and evaporated to dryness under reduced pressure. The residue is suspended in toluene and evaporated to dryness under reduced pressure. The residue is taken up in n-pentane, then separated by suction filtration and dried under high vacuum over phosphorus pentoxide and potassium hydroxide tablets. 6.25 g of the title compound are obtained in the form of a colorless, amorphous powder. By evaporation of the pentane-containing mother liquor. a further 0.43 g of amorphous product is obtained in solution. Sp. 240-244 ° C (decomposes). The decomposition temperature depends on the heating rate.

Example 8b 3 Sodium salt of 3 (R), 5 (S) -dihydroxy-6- [2-isopropyl-4-tert-butyl-6- (4-fluorophenyl) phenoxy] hexanoic acid::: laa is prepared according to Example 8a from the lactone of Example 2.11.

j Colorless powder, m.p. 256-258 ° C (decomposes)

• · I

Example 8c 1 - "• m 3 (R), 5 (S) -dihydroxy-6- [2-isopropyl-4,6-bis- (4- * · · · * · * fluorophenyl) phenoxy] the sodium salt of hexanoic acid is prepared according to Example 8a from the lactone of Example 3.6.

.35 Colorless powder, m.p. 235-237 ° C (decomp.) 42 96684

Example 8d The sodium salt of 3 (R), 5 (S) -dihydroxy-6- [2-isopropyl-4-phenyl-6- (4-fluorophenyl) phenoxy] hexanoic acid is prepared according to Example 8a from the lactone of Example 4.11.

Colorless powder, m.p. 238-240 ° C (decomposes)

Example 8e 3 (R), 5 (S) -Dihydroxy-6- [2-isopropyl-4-cyclohexyl-6- (4-fluorophenyl) phenoxy] Sodium salt of hexanoic acid is prepared according to Example 8a from the lactone of Example 5.7.

Colorless powder, m.p. 230 - 233 ° C (decomposes)

Example 8f The sodium salt of 3 (R), 5 (S) -dihydroxy-6- [2- (4-fluorophenyl) -4,6-di-15-isopropylthiophenoxy] hexanoic acid is prepared according to Example 8a from the lactone of Example 6.7.

Colorless powder, m.p. 230 - 234 ° C (decomposes)

Example 8g 20 Sodium salt of 3 (R), 5 (S) -dihydroxy-6- [2-isopropyl-4,6-bis- (4-fluorophenyl) thiophenoxy] hexanoic acid or

I I

prepared according to Example 8a from the lactone of Example 7.

t * · i k · • ♦ • * · • »« • · • · t · f • I · »· · • k f V ♦« • «k · f« * • ·

• M

f «i <· 1 t *« • ·

Claims (3)

A process for the preparation of 6-phenoxymethyl-4-hydroxytetrahydropyr-5-ran-2-ones and 6-thiophenoxymethyl-4-hydroxytetrahydropyran-2-ones useful as medicaments of the general formula I 10 ch3 * HAÄC> r CH3> i »y Y 15 and the corresponding open-chain dihydroxycarboxylic acids of the formula II T COOH L OH 20 * 9h3 / (II) Y · _ | Wherein X is oxygen or sulfur, and Y is a) a straight or branched alkyl group having 3-4 carbon atoms, or. b) a cyclohexyl or phenyl group which may be • · · 30 substituted by halogen, and their pharmacologically tolerable salts with bases and their pharmacologically tolerable esters, characterized in that, a) correspondingly substituted phenols or thiophenols of formula III 44 96684 ch3 1 XH rp = r \ 4ΠΓ ^ (I ^> 5 Y where X and Y have the same meanings as in formulas I and II, is converted by means of an optically pure iodide of the formula IV 10 R70a___ V "^ w-vyOCH3 / (IV) 15 where R7 is a protecting group stable to bases and weak acids, to lactol ethers of formula V R70a _ 20 ^^ Y ^ 0CH3 ΐΗ3χ / (V) CH3IWJ 25 T • · · • · · wherein X and Y are as defined in formulas I and II and the group R7 is as defined in formula IV,. b) the lactol ethers of the formula V are hydrolysed to the corresponding lactols of the formula VI • · · • · OH 4o <vi> rv '_ 7SfW-r CH3O Y 45 96684 in which X and Y have the same meaning as in the formulas I and II and R7 has the same meaning as in in formula IV, c) the lactols of formula VI are oxidized to the corresponding lactones of formula VII 5 -VJ-CH3 / H -AA / Of <vii) 10 / ch3I ^ JJ y wherein X and Y are as defined in formulas I and II and R7 is as defined in d) the protected lactones of the formula VII obtained in the formula IV are converted into the compounds of the formula I in a manner known per se, and e) the compounds of the formula I obtained are optionally converted into the corresponding open-chain dihydroxycarboxylic acids of the formula II, their salts or esters, or esters are optionally converted to free dihydroxycarboxylic acids or free carboxylic acids are optionally converted to salts or esters. · 1 · · • · · • · I · • · · «T I • · · • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · roxetetrahydropyran-2-one, which is an anhydrous barley and a compound of formula I 10 ch3 1 (I) IX '/ -— N ch3 [VJJ y 15 velvet motsvarande öppenkedjade dihydroxycarboxylsyror med formuleln II T C00H 20 k ^ OH ( II) rv '„ch3 | VJJ Y 25 där s / ·! X is a substituent or a hydrogen group, and: Y: Y is a) en rakkedjad or förgrenad alkylgroup med 3-4 cholatomer, eller: b) cyclohexyl or a phenyl group, which may be «φ · 30 substituents with halogen,« · · velvet pharmacologically godtagbara salter därav med • * · «·«:. * baser och pharmacologiskt godtagbara estrar därav, kän n - • · · netecknat därav, att a) phenoler ochi thiophenoler, som harel formeln III och 35 som substituerats pä motsvarande sätt, li 47 96684 9H3 (III)