NO863460L - PROCEDURE FOR THE PREPARATION OF 6-PHENOXYMETHYL-4-HYDROXYTETRAHYDROPYRAN-2-ON, PROCEDURE FOR THEIR PREPARATION, THEIR USE AS A MEDICINE, PHARMACEUTICAL PREPARATE PREPARATE PREPARATE. - Google Patents

Description

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase (HMG-CoA-reductase) catalyzes the formation of mevalonic acid from 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA). This reaction plays a central role in the biosynthesis of cholesterol. Derivatives of 3-hydroxy-3-methyl-glutaric acid (HMG) and mevalonic acid are reported to facilitate cholestrcbl biosynthesis (M.R. Boots et al, J. Pharm. Sei. 69, 306 (1980), F. M. Singer et al. Proe. Soc. Exper. Biol. Med. 102, 270 (1959), H. Feres Tetrahedron Lett. 24, 3769 (1983)). 3-hydroxy-3-methyl-glutaric acid itself shows a clear cholesterol-lowering effect in rats and in human experiments (Z. Beg. Experientia 23, 380 (1967), ibid 24

15 (1968), P.J. Lupien et al. Lancet 1978, 1, 283). It was

now found that 6-phenoxymethyl-4-hydroxytetrahydrofuran-2-one with the general formula I resp. those of the corresponding dihydroxycarboxylic acids, their salts and esters are inhibitors of HMG-C6A reductase. The invention therefore relates to new 6-phenoxymethyl-4-hydroxytetrahydropyran-2-one with the general formula I

in which

R-in 1- and R 5 are the same or different and mean a) hydrogen or halogen, b) cyclohexyl with 4-8 C atoms or a phenyl residue, which in the nucleus may be substituted 1- to 3-fold by halogen, trifluoromethyl and /or alkyl or alkoxy each with 1-4 C atoms, or c) a linear or branched alkyl radical with 1 to 18 carbon atoms or a linear or branched alkenyl radical with 2 to 18 carbon atoms, the alkyl or Alke-nyl residues, on the other hand, can be substituted 1-3 times with

a) linear or branched carboxylic acid residues with up to

10 carbon atoms or cycloalcotic residues with 3 to 7

carbon atoms or linear or branched alkenyloxy or alkynyloxy radicals with 3 to 6 carbon atoms,

g) halogen, hydroxy, cycloalkyl with 3-7 C atoms, unsubstituted phenyl-, α- or 3-thienyl residues, or phenyl-, α-:- or 3-thienyl residues which in turn are substituted 1 r to 3 times in the nucleus, with halogen, trifluoromethyl, and/or alkyl or alkoxy with 1-4 C atoms, y) substituted phenoxy-, benzyloxy-, a- or 3-thienyloxy residues, or phenoxy-, benzyloxy-, a- or 8 -thienyloxy acid residues, which in turn are substituted 1 to 3 times by halogen, trifluoromethyl, and/or alkyl or alkoxy with 1 to 4 carbon atoms. 6) The group

\ where R means: a rectilinear or

branched alkyl or alkenyl residue with up to 8 carbon atoms or a cycloalkyl or cycloalkyl residue resp. 3-8 C atoms or an unsubstituted phenyl radical or a phenyl radical which in turn is substituted in the nucleus 1- to 3-fold 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 means 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 tolerable salts with bases and their pharmacologically tolerable esters.

The substituents preferably have the following meanings:

R1 i and R 5, both the same or different:

a) hydrogen or halogen,

b) cycloalkyl with 5 to 6 C atoms, phenyl, which in the nucleus may be substituted 1 to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy with each 1 to 4 C atoms or c) . 1. straight or branched alkyl or alkenyl with up to 12 carbon atoms, where alkyl or the alkenyl radical, on the other hand, can be substituted 1 to 2 times by phenyl radicals, which in turn can be substituted 1 to 3 times in the nucleus by halogen, trifluoromethyl, and/or alkyl or alkoxy with 1-4 C atoms, 2. linear with

substituted alkyl of formula

in which n = 1 to 3 and R means a linear or branched alkyl or alkenyl residue with up to 8 C atoms, a cycloalkyl residue with 5 to 6 C atoms, or a phenyl residue, which on its side of the nucleus may be substituted 1-3 times with halogen, trifluoromethyl and/or alkyl or alkoxy with 1 to 4 C atoms.

3. Straightened with OR 7 substituted alkyl of formula

in which n = 1 to 3 and R 7 means hydrogen or a straight or branched alkyl or alkenyl residue with up to 8 C atoms, a cycloalkyl residue with 5 to 6 C atoms or a phenyl residue, or a benzyl residue which in turn may be substituted with the aromatic nucleus 1 to 3 times with halogen, trifluoromethyl, and/or alkyl or alkoxy with 1 to 4 C atoms,

2 4

R and R mean hydrogen,

R 3 means hydrogen, methyl, ethyl, propyl, 1-propenyl, allyl, fluorine or chlorine.

In particular, the substituents mean:

R"*" and , where R"*" and R^ are the same or different:

1) hydrogen, methyl, ethyl, propyl, allyl, 1-propenyl, isopropenyl, isopropyl, cyclopentyl, cyclohexyl, or 2) the group

with n = 1-3, wherein R^ means: methyl, ethyl, propyl, i^-propyl, n-butyl, 1-butyl, t-butyl, phenyl or in the nucleus 1-3 times substituted phenyl with halogen, methyl or methoxy, or 7 7 3) the group -(CH2)nOR with n = 1 to 3, where R means: hydrogen, methyl, straight or branched alkyl or alkenyl with 3-5 carbon atoms, cyclopentyl, cyclohexyl, phenyl or benzyl, where the aromatic nucleus may be substituted 1-3 times with fluorine, chlorine, methyl or methoxy, or

4) an alkyl group of formula

wherein n = 0 to 2, and R° q and R y are the same or different and mean hydrogen, methyl, ethyl, propyl, allyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclohexyl, cyclopentyl, benzyl or phenyl, the aromatic nucleus may be substituted 1 to 3 times by fluorine, chlorine, methyl or methoxy,

2 4

R and R mean hydrogen,

R 3 means hydrogen, methyl, chlorine, fluorine.

As pharmacologically tolerable salts of dihydroxycarboxylic acids corresponding to formula VII in which R 1 to R 5 have the meaning given under formula I, mention should be made of alkali metal salts or ammonium salts, pharmaceutically acceptable esters are e.g. alkyl esters with 1 to 4 G atoms, phenyl esters, benzyl esters or also 2,3-dihydroxypropyl esters.

The invention relates to an enantiomer with the absolute configuration 4R, 6S indicated by the general formula I, the open-chain dihydroxycarboxylic acids VII, their esters and salts having the absolute configuration 3R, 5S indicated by the general formula VII.

The invention relates to a method for producing a compound of the general formula I, the method being characterized by

a) correspondingly substituted phenols of formula II

wherein R''", R<2>, R^, R<4>and R^ have the indicated meaning, with

the chiral iodide of formula III

in which R"^ means a protecting group stable against bases and weak acids, e.g. the t-butyldiphenylsilyl group, (t-BuPh2Si),

are transferred to ethers of formula IV

in which R"*" to R^ has the meaning under formula I and R"^ has the meaning given under formula III, b) ethers of formula IV are hydrolyzed to the corresponding hemiacetals of formula V in which R<1> to R<5> and R<1Q> has the meaning given under formula I or III, c) hemiacetals of formula V are oxidized to corresponding lactoms of formula VI

III stated meaning, and

d) the protected hydroxylactones of formula VI are transferred to 6-phenoxymethyl-4-hydroxytetrahydropyran-2-ones with

formula I

optionally, the formed compounds of formula I are transferred

to the corresponding open-chain dihydroxycarboxylic acids, their salts or esters, optionally transferring formed salts or esters to the free dihydroxycarboxylic acids, or optionally the free carboxylic acids to the salts or esters.

The esterification of the compounds of formula II with a compound of formula III to a compound of the general formula IV takes place, e.g. a solvent in the presence of a base, preferably in dimethylsulfoxide using potassium carbonate at 50-80°C.

Hydrolysis of the acetals IV to the hemiacetals V is suitably carried out under aqueous, acidic conditions, preferably with acetic acid in tetrahydrofuran/water mixtures, or also with hydrochloric acid in THF/water or trifluoroacetic acid at 0 - 80°C.

The transfer of the hemiacetals V to the lactones VI is carried out by means of an oxidizing agent, preferably by chromium dioxide in pyridine/methylene chloride.

The removal of the t-butyldiphenylsilyl group to the free hydroxylactones I is preferably carried out in acetonitrile with aqueous hydrogen fluoride at 40 - 60°C or with tetrabutylammonium fluoride in glacial acetic acid/THF at room temperature or slightly elevated temperature.

The hydroxylactones I are transferred with aqueous alkali, optionally i

a solvent, for example alcohol or tetrahydrofuran, in the usual way in the alkali salts where, after acidification, the free acids can be obtained. The ammonium salts are obtained by corresponding amines from the free acids in a generally known manner. The esters of the free acids can be obtained from these themselves from the corresponding alkali salts or from the lactones I according to usual known methods.

If the individual reaction products do not appear in an already sufficiently pure form, so that they can be used for the following reaction step, purification by means of crystallization, column or high-pressure liquid chromatography is suitable.

If iodides of formula III are not present as pure enantiomers, mixtures of enantiomeric end products can also occur which can be separated according to generally common methods.

The chiral iodide III can, for example, be prepared according to a known method (J. R. Falck, Tetrahedron Lett 23, 4305

(1982)) from tri-O-acetyl-D-glucal.

Insofar as the phenols II used as starting materials are not mentioned in the literature, they can be prepared in analogy to known methods (Houben-Weyl, Methoden der organisch-en Chemie, volume VI/1 c, 1976). A preferred process for the preparation of phenols II, which have the general formulas XVII, XVIII, and XIX indicated in formula core 1 in the residues R<1->

R 4 has the above meaning, based on correspondingly substituted phenols X (formula scheme 1). These are transferred to the corresponding allyl ester XI, preferably with allyl bromide in acetone or dimethylformamide at elevated temperature using a suitable base, e.g. potassium carbonate. The allyl ethers XI are rearranged at elevated temperature in the corresponding allylphenols XII in many cases without solvents,

but also possibly using diethylaniline as solvent. The phenols XII thus formed are protected by the OH group. As a protective group (Z), the benzyl group is suitable, but also others such as e.g. THP can be used.

The protected allylphenols XIII are preferably hydroborated in diborane or 9-borabicyclo (3,3,1)nonane (9-BBN) in tetrahydrofuran to the alcohols XV (n = 3). The aldehydes XIV are obtained either directly from the protected phenols XIII in oxidizing agents such as e.g. NaJO^/OsO^ or ozone, or is produced by glycol cleavages of the 1,2-diols obtained from XIII. The reduction of the aldehydes XIV preferably with sodium borohydride leads to the alcohols XV (n = 2). The alcohols of formula XV (n = 2 or 3) are optionally transferred in a reactive derivative, preferably tosylate, methylate or iodide and etherified with corresponding phenols or alcohols in the presence of a base such as potassium carbonate in suitable solvents, e.g. dimethylsulfoxide or dimethylformamide, (compound with formula XVII according to formula scheme imideltime protected). Alternatively, the alcohols XV (n = 2, 3) can be reacted with suitable alkyl halides, e.g. with dimethylformamide using sodium hydride as bases for the protected ethers corresponding to XVII. After removal of the protecting group Z, the phenols XVII are obtained. Acylation of the alcohols XV in a reactive derivative of a carboxylic acid according to generally customary methods leads to removal of protective groups Z to phenols of formula XVIII. Action of suitable Grignard reagents on the aldehydes XIV leads to alcohols XVI. From alcohols are transferred by generally known methods to the phenols of formula.'XIX

(R 9 = H). The alcohols XVI can be transferred with the oxidizing agents to the corresponding ketones, then by renewed action in Grignard reagent and corresponding generally known methods transfer to the phenols XIX (R 8 , R Q =H).

For phenols XIX with n = 0, the appropriate starting point is the corresponding benzaldehydes, benzoic acid esters or aromatic ketones.

The enzyme HMG-CoA reductase is widespread in nature. It analyzes the formation of mevalonic acid from HMG-GoA. This reaction is a central step of cholestrol biosynthesis (I.R. Sabine, 3-hydroxy-3-methylglutaryl coenzyme A reductase, CRC Press 1983). A high cholesterol level is associated with a number of diseases, such as coronary heart disease or atherosclerosis. Therefore, the lowering of an elevated cholesterol level is therapeutically measured for the prevention and treatment of such diseases. An employment point lies in inhibition or to the reduction of endogenous cholesterol synthesis. Inhibitors of HMG-CoA reductase block cholesterol biosynthesis at an early stage. They are therefore suitable for the prevention and treatment of diseases caused by an increased cholesterol level. A reduction or reduction of the endogenous synthesis leads to an increased absorption of * cholestrol from the plasma in the cells. An additional effect can be achieved by simultaneous administration of bile acid-binding substances such as anion exchangers. The increased bile acid excretion leads to an enhanced new synthesis, and thus to an increase in 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 invention according to the invention is HMG-CoA reductase inhibitors. They are therefore suitable for inhibition or for the reduction of cholesterol biosynthesis and thus for the prevention or treatment of diseases caused by increased cholesterol levels, especially coronary heart disease, atherosclerosis, hypercholesterolemia, hyperlipoproteinemia, and similar diseases.

The compounds of formula I or corresponding dihydroxycarboxylic acid, their salts and esters, are therefore used in pharmaceutical preparations, and the compounds are used as drugs especially for the treatment of hypercholesterolemia.

The compounds of formula I or the corresponding acids, salts or esters are administered in different dosage forms, preferably orally in the form of tablets, capsules or liquids.

The daily dose varies according to the patient's body weight

and constitution in the range from 3 mg to 2500 mg, preferably however in the dose range of 10 - 500 mg.

The compound according to the invention can be used as lactones with the general formula I, in the form of the free acids VII or in the form of pharmaceutically acceptable salts or esters, namely dissolved or suspended in pharmacologically tolerable organic solvents such as monohydric or polyhydric alcohols,

like for example. ethanol or glycerol, in triacetin, oils, such as e.g. 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 tolerable polymer carriers, such as e.g. polyvinylpyrrolidone or other pharmaceutically acceptable additives, such as starch, cyclodextrin or polysaccharides. Furthermore, the compounds according to the invention can be combined with additives that bind bile acids, especially the non-toxic basic anion exchange resins, which bind the bile acids in a non-resorbable form in the gastrointestinal tract. The salts of the dihydroxycarboxylic acid can also be administered as aqueous solutions.

The compounds with formula IV - VI are new and e.g. valuable intermediates for the preparation of the compounds of formula I. The invention therefore also relates to the compounds of formula IV, V and VI, as well as methods for their preparation.

HMG-CoA reductase activity was determined in the following test system: 1) Inhibition of 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 conversion to a day-night rhythm, were induced with cholestyramine ("Cuemid").

As substrate served (S,R) 14C-HMG-CoA, the concentration of NADPH was maintained during the incubation by a regenerating system.

14

The separation of C-mevalonate from substrate and other products

14

(e.g. C-HMG) took place over column elution as the elution profiles of each individual sample were determined. The constant lowering of <3>H-mevalonate was disregarded because the determination concerns a relative indication of the inhibitory effect. In experiments, it was resp. treated the enzyme-free control, the enzyme-free normal mixture (= 100%), and such with preparation additives. Each individual value was formed as the mean value of 3 parallel samples. The significance of the mean value differences between preparation-free and preparation-containing samples was assessed according to the p-test. According to the above-mentioned method, the compound according to the invention, e.g. determined the following heme values of HMG-CoA reductase (IC^. Q-value M = molar concentration of the compound, which is necessary for a 50%-

ig inhibition).

2) Suppression or inhibition of HMG-CoA reductase in cell cultures of fibroblasts.

Monolayers of fibroblasts (L cells) in lipoprotein-free nutrient medium were incubated with corresponding concentrations of the test substances for a specific time (e.g. 3 hours), then the HMG-CoA reductase activity of the cells was determined, modified according to Chang et al, (J. Biol. Chem. 256, 6174 (1981)). In addition, the cell extracts were incubated with D,L-/ 3h7_HMG-CoA, and under the influence of the present HMG-CoA reductase activity from the cells formed product /3H7~mevalonate until cyclization to /3H/-mevalonolactone separated by thin layer chromatography from the starting product , and using an internal standard of / 14g7-mevalonate, determined the amount of /_ 3H7-mevalonate formed in the time unit referred to the amount of sample protein. The HMG-CoA reductase activity of the cell culture found during the addition of a specific concentration of a sample preparation was referred to as a percentage to each of the correspondingly treated without sample preparation, however of the same solvent concentration.

Biological test results:

Under the conditions of a three-hour incubation time, confluent L cells in lipoprotein-free nutrient medium with the investigated compounds, the following was determined for a 5% inhibition of HMG-CoA reductase activity (IC^q) necessary molar concentration of the test preparation:

Preparation of the starting compounds of formula II

Example 1:

2- allyl- 4, 6- dimethylphenol ( 1) (formula scheme 1, XII)

150 g (1.23 mol) of 2,4-dimethylphenol, 330 g (2.4 mol) of potassium carbonate and 180 g (1.5 mol) of allyl bromide were stirred in 900 ml of acetone

20 hours during reflux. After cooling, the precipitate was sucked off and washed with acetone. The filtrate was evaporated in vacuo and the residue diluted between petroleum ether and 2 N caustic soda. The organic phase was washed 3 times with 2 N sodium

lye and twice with water. Drying with magnesium sulfate, evaporation in vacuo and distillation gave 178.7 g (1.08 mol 88 %), 2,4-dimethylphenyl allyl ether, bp. 86°C/7 torr. The allyl ether was heated with stirring without solvent for 3 hours at 210°C. Distillation gave 165.4 g (1.02 mol, 94%) of 2-allyl-4,6-dimethylphenyl (1) bp. 96 - 100°C/8 torr.<1>H-NMR

(CDC13, 60 MHz): 6 = 2.2 (s. 6H, methyl-H), 3.3 (d. 2H. - CE2~), 4.6 (s, 1H, -OH), 4.8 -6.2 (m, 3H, olefinic H), 6.7 (m, 2H, aromatic H).

Example 2

2- allyl- 4, 6- dimethylphenylbenzyl ether ( 2) lformula scheme 1, XIII)

76.15 g (0.47 mol) of 2-allyl-4,6-dimethylphenol, 130 g (0.94 mol) of potassium carbonate and 65.5 g (0.52 mol) of benzyl chloride were

heated in 1 liter of acetone for 20 hours under reflux. After 20 hours, 26 g of potassium carbonate and 13 g of benzyl chloride were again added. It was sucked off and the filtrate evaporated in vacuo,

and absorbed in toluene. The organic phase was washed 2 times with 2 N sodium hydroxide solution and 2 times with water. Drying with magnesium sulfate, removal of the solvent and distillation gave 109.5 g (0.44 mol, 85%) of benzyl ether 2 , bp. 147-153°C/0.2 torr, "'"H-NMR (CDC130 MHz): <5 = 2.2 (s, 6H, methyl-H), 3.4

(d, 2H, allyl-CH2-), 4.7 (s, 2H, benzyl-CH2"), 4.8 - 6.2 (m,

3H, olefinic H), 6.8 (s, 2H, aromatic H), 7.0 - 7.4 (;m, 5H, aromatic H).

Analogous to example 1, the allylphenols 3,5,7,10, 13 and 15 were prepared and in analogy to example 2 protected as benzyl ethers 4,6,8,11,14 and 16.

Example 17

3-(2-benzyloxy-3,5-dimethylphenyl)propan-l-ol (17)

( formula form 1, XV

108.5 (0.43 mol) of 2-allyl-4,6-dimethylphenylbenzyl ether (Example 2) was mixed with 9.76 g (0.258 mol) of sodium borohydride in 250 ml of dry tetrahydrofuran under an argon atmosphere. During

5 minutes, 32.5 g (0.258

moles) of dimethyl sulfate. The reaction mixture is heated to approx.

40°C. It was allowed to stir for 4 hours at 35-40°C. Then, at 5°C, 43 ml of water and then 320 were carefully added dropwise

ml 14 n aqueous caustic soda. Finally, while cooling, 65 ml of a 35% strength (0.75 mol) hydrogen peroxide solution was added dropwise and stirred for 30 minutes. The reaction mixture was poured into toluene and washed 4 times with ice water and 2 times with aqueous sodium chloride solution. Drying with magnesium sulfate and evaporation in vacuo gave 110.4 g of pale yellow oil. HPLC on silica gel (cyclohexane/acetic ester = 5:1) can give 89.15 g (0.33 mol, 76%) of alcohol as a pale yellow oil.

<1>H-NMR (CDC13, 60 MHz(: 6 = 1.8 (m, 2H, - CH2~),

2.2 (d, 6H, methyl-K), 2.7 (t, 2H, Ar-CH2~),

3.4 (t, 2H, -CH2O-), 4.8 (s, 2H, benzyl, -CH2"),

6.8 (s, 2H, aromatic H), 7.0 - 7.4 (m, 5H, aromatic H).

Example 18

3- i2-benzyloxy-3-/ 3-(4-fluorophenoxy)propyl/-4-chlorophenyl^ propane- 1-01 ( 18) (formula scheme 1, XV).

72.6 ml of a 0.5 m 9-BBN solution (35 mmol) in tetrahydrofuran was dissolved in 50 ml of dry tetrahydrofuran. At room temperature, 9.5 g (23.1 mmol) of the allyl compound from example 11 was added dropwise and stirred for 30 minutes. It was then heated for 1 hour under reflux. On cooling, 14 ml of ethanol, 23 ml of 2-N aqueous NaOH (46 mmol) and finally 6.1 ml (59 mmol) of 30% hydrogen peroxide were carefully added in order. It was allowed to boil for 1 hour under reflux. The reaction mixture was poured into toluene. The organic phase was washed

three times down. ice water and once with saturated aqueous sodium chloride solution. Drying with magnesium sulfate, evaporation in vacuum and chromatography on silica gel (cyclohexane/acetic ester = 5:1) gave 9.0 g (21 mmol, 91%) of alcohol on 18.

<1>H-NMR (CDC1 , 60 MHz): 6 = 1.4-2.5 (m, 4H, -CH2~),

2.5-3.0 (m, 4H, Ar-CH2~), 3.5 and 3.8 (resp. t,

respectively 2H, -OCH2-), 4.8 (s, 2H, benzyl-CH2~), 6.6-7.5

(m, 11H, aromatic H).

Analogy to examples 17 and 18 is produced in the alcohols listed in Table 2.

Example 24:

2-/ 3-(4-fluorophenoxy)propyl/-4,6-dimethylphenol (24)

( formula form 1, XVII)

1. 43.5 g (162 mmol) (17) was dissolved in 160 ml of methylene chloride and 160 ml of pyridine, and while cooling is mixed in portions with 37 g (194 mmol) of p-toluenesulfonic acid chloride. It is allowed to reach 1°C. After 18 hours, the solvent was removed in vacuo, and the residue taken up with toluene, washed twice with water and twice with saturated sodium bicarbonate solution, finally with saturated aqueous sodium chloride solution. Drying with magnesium sulfate, removal of the solvent, and chromatography on silica gel (CH 2 Cl 2 ) afforded 51 g (120 mmol, 74%) of tosylate 17a as a colorless oil. 2. 51 g (120 mmol) of tosylate (17a) was heated with 90 g (600 mmol) of sodium iodide in 900 ml of acetone for 4 hours under reflux. One aspirates from insoluble. The filtrate was evaporated in vacuo, and the residue taken up in toluene. The organic phase was washed once with water, twice with 2% aqueous sodium bisulfite solution and once with saturated aqueous sodium bicarbonate solution. Drying with magnesium sulfate, removal of the solvent in vacuo and chromatography on silica gel (cyclohexane/acetic ester = 92:8) gave 40.6 g (107 mmol, 89%) of iodide (17b) as a colorless oil. 3. 9.62 g (86 mmol) of 4-fluorophenol were obtained with 23.7 g (172 mmol) of potassium carbonate in 75 ml of dimethylsulfoxide. 21.8 g (47.3 mmol) of iodide (17b) were added and heated for 4 hours at 50°C. The reaction mixture was partitioned between ether and water. The aqueous phase is extracted once with ether. The combined ether phases were washed once with water and dried over magnesium sulfate. Removal of the solvent in vacuo and chromatography on silica gel (cyclohexane/acetic ester = 9:1) gave 20.5 g (56.3 mmol 98%) of 4-fluorophenyl ether.

4. 20.5 g (56.3 mmol) of 4-fluorophenyl ether was hydrogenated in

200 ml of methanol with 1 g of Pd/C (10%) at room temperature

and normal pressure. After chromatography, 13.3 g (48.5 mmol, 86 %), 2-/~3-(4-fluorophenoxy)propyl7~4,6-dimethylphenol (24) were obtained.

MS: 274 (M<+>).

<1>H-NMR (CDC13, 60 MHz): δ = 1.8 - 2.3 (s and m, 8H, methyl-

H, -CH2-), 2.8 (t, 2H, Ar-CH2-), 3.9 (t, 2H, OCH2~), 5.1

(s, 1H, OH), 6.7 - 7.2 (m, 6H, aromatic H).

Example 25

2-/" 2-( 4- fluorophenoxyethyl)/- 4, 6- dimethyl phenol ( 25)

Analogous to example (24), from example 38 the tosylate was prepared according to reaction 24.1, and reacted directly in dimethylformamide using 1.05 equivalents of potassium carbonate at 150°C with 4-fluorophenol. Removal of the protecting group according to 24.4 gave phenol (25).

MS: 260 (M<+>).

<1>H-NMR (CDCl 3 , 60 MHz): = 225 (s, 6H,~CH 3 ), 3.06 (t, 2H, Ar-CH 2 -), 4.20 (t, 2H, -CH 2 O), 6.50 (s, 1H, OH), 6.67-7.00

(m, 6H, arom. H).

Analogously to example 24, the phenols listed in Table 3 were produced. Cleavage of the benzyl group was carried out with chlorine aromatics by adding acetic acid.

Example 32 2-/3-(4-Fluorophenoxy)propyl/-4-chloro-6-(3-pivaloyloxy-propyl)phenylbenzyl ether (32) sml. formula sheet 1, XVIII, protected. 9 g (21 mmol) of alcohol (18) was dissolved in 90 ml of methylene chloride and 90 ml of triethylamine, and stirred with 3.4 g (28 mmol) of pivaloyl chloride overnight. The mixture was poured onto ice/conc. hydrochloric acid, and the organic phase washed once with 2 N hydrochloric acid and once with saturated aqueous sodium bicarbonate solution. Drying with magnesium sulfate, removal of the solvent and chromatography on silica gel (cyclohexane/acetic ester 2 5:1) gave 5.13 g (10 mmol, 48%) of pivaloyl ester (32).

<1>H-NMR (CDC13, 60 MHz): δ = 1.2 (s, 9H, methyl-H),

1- 7-2.3 (m, 4H, -CH2-), 2.5-3.0 (m, 4H, Ar-CH2~), 3.7-4.3

(m, 4H, -OCH2~), 4.8 (s, 2H, benzyl-CH2~), 6.5-6.6 (m, 11M, aromatic H).

Example 33: 2- / 3-(4-Fluorophenoxy)propyl/-4-chloro-6-(pivaloyloxypropyl)phenol ( 33) ( sml, formula scheme 1, XVIII).

5.1 (10 mmol) pivaloyl ester was hydrogenated in 200 ml acetic acid ethyl ester and 20 ml glacial acetic acid with 500 mg palladium on charcoal (10%) at room temperature and normal pressure. After chromatography on silica gel: 3.7 g (8.8 mmol, 87%) of phenol (33) were obtained. Sm.p. 78oc,

MS: 422 (M<+>), 320.

Analogous to examples 32 and 33, the compound according to examples 34-36 was prepared.

Example 34

2-[3-(4-fluorophenoxy)propyl]-4-methyl-6-(3-pivaloyloxy-propyl)phenol, MS: 402 (M<+>), 300, starting from (22).

Example 35

4,6-dimethyl-2-(3-pivaloyloxypropyl)phenol, MS: 264 (M<+>),

162, starting from (17).

Example 36

4,6-dimethyl-2-[2-(R,S)-pivaloyloxypropyl-7-phenol, MS: 264

(M<+>), 162, starting from 4,6-dimethyl-2-[2(R,S)-piva-loyloxypropyl/phenylbenzyl ether, which appears in the preparation of (17) .

Example 37

2-(2-benzyloxy-3,5-dimethylphenyl)acetaldehyde (37), (see formula 1 XIV) .

1. 205 g (0.81 mol) of 2-allyl-4,6-dimethylphenylbenzyl ether (example 2) and 147 g (1.25 mol) of N-methylmorpholine-N-oxide are added to 100 ml of acetone and 750 ml of water, mixed with 200 ml (0.79 mmol) of osmium tetroxide. It is allowed to stir for 20 hours at room temperature, 5 g of sodium pyrosulphite saturated with sodium chloride are added. The acetone was removed as best as possible in a vacuum, and the residue extracted with acetic acid. The combined acetate phases were washed once with aqueous NaCl/HCl and once with aqueous NaCl/KHCO^ solution, drying with magnesium sulfate and removal

of the solvent in vacuo on ball tube distillation (170-180°C, 0.1 torr), gave 114.8 g (0.40 mol, 50%) of diol. Rf (silica gel), ethyl acetate/methylene chloride = 1:1): 0.35. 2. 8.3 g (29.0 mmol) of diol and 14.5 g (67.8 mmol) of sodium periodate were stirred in 50 ml of tetrahydrofuran and 10 ml of water at 20-25°C under cooling for 30 minutes. Diluted with water and extracted with ether. The combined ether phases were washed once with water and once with potassium bicarbonate solution. Drying with magnesium sulfate and removal of the solvent gave, after mixing with toluene and renewal, derotation and drying of the oil pump, 7.1 g (28 mmol, 96%) of 2-(2-benzyloxy-3,5-dimethyl-phenyl)-acetaldehyde (37 ).

<1>H-NMR (CC14, 60 MHz): δ = 2.1 (s, 6H,~CH3), 3.4 (d, 2H,

-CH2~), 4.6 (s, 2H, -CH2-), 6.6 and 6.8 (resp. s, resp. 1H,

aroma. H), 7.2 ("s", 5H, arom. H), 9.2 (t, 1H, -CHO).

Example 38

2-(2-benzyloxy-3,5-dimethylphenyl)ethanol (38) (cf. formula scheme 1, XV) .

7.7 g (30.3 mmol) of aldehyde (37) was dissolved in 50 ml of methanol and 0.9 g (23.8 mmol) of sodium borohydride in ice water at 15°C was added dropwise. After 30 minutes, it was acidified while cooling with elevated acetic acid, stirred with 100 ml of saturated aqueous sodium chloride solution, extracted with ether. The combined ether phases were washed once with saturated aqueous sodium hydrogen carbonate solution. Drying with magnesium sulfate, removal of the solvent in vacuo and bubble tube distillation (140°C/ 0.05 torr) gave 6 [ ;9 g (27.0 mmol, 89%) of alcohol (38). -""H-NMR (CC14, 60 MHz): δ = 2.2 (s, 6H, -CH3), 2.7 (t, 2H, -CH2"), 3.6 (t, 2H, -CH2 ~), 4.7 (s, 2H, benzyl-CH 2 ), 6.7 (s, 2H arom. H), 7.2 (m, 5H, arom. H).

Example 3 9

4,6-Dimethyl-2-[2-(4-fluorophenyl)ethyl-7-phenol (39) (see formula 1, XIX) . 1. To a Grignard solution in ether from 2.7 g (111 mmol) magnesium and 19 g (108 mmol) 4-fluorobromobenzene, 18.4 g (72 mmol) aldehyde (37) in ether was added dropwise at room temperature and stirred 2 hours at room temperature. Under ice cooling, it was hydrolysed with 4N acetic acid and extracted with ether.

The combined ether phases were washed once with water and once with saturated potassium bicarbonate solution. Drying with magnesium sulfate and removal of the solvent in vacuo gave, after crystallization from cyclohexane, 18.4 g (52.6 mmol, 73%) of 2-(2-benzyloxy-3,5-dimethyl-phenyl)-1-(4- fluoro enyl)-ethanol m.p. 74°C.

2. 7 g (20 mmol) of alcohol according to step 1, 2.55 g (25 mmol) of acetic anhydride and 2.4 g (30.3 mmol) of pyridine were heated 2

hours in a steam bath. Toluene was added and distilled off at 50°C in vacuum. The residue was taken up in ether, washed twice with 2N hydrochloric acid and once with saturated aqueous potassium hydrogen carbonate solution. Drying with magnesium sulfate and removal of the solvent in vacuo gave 7.7 g (19.6 mmol, 9b%) of 1-acetoxy-2-(2-benzyloxy-3,5-dimethylphenyl)-1-(4-fluorophenyl)-ethane . 3. 18.4 g (46.9 mmol) of acetate according to step 2 was hydrogenated in methanol with 3 g of palladium on charcoal (10%) with the addition of 4 g of sodium acetate for 6 hours at room temperature and normal pressure. After completion of hydrogen uptake, it was sucked off and the filtrate evaporated, the residue taken up in ether, and the etheric phase washed once with water. Drying with magnesium sulfate and evaporation in vacuo gave, after crystallization from cyclohexane, 6.6 g (27 mmol, 57%) of phenol (39).

Sm.p. 70-72°C.

<1>H-NMR (CC14, 60 MHz): δ = 2.2 ("s", 6H, -CH3), 2.8 ("s",

4H, -CH2~), 4.1 (s, 1H, OH), 6.5-7.2 (m, 6H, arom. H)

NM: 244 (M<+>).

Example 4 0

4, 6- dimethyl- 2-/~ 2-( 4- methylphenyl) ethyl/ phenol ( 40).

Analogous to example 39, the compound (40) was prepared.

Example 41

4,6-dimethyl-2-_~2,2-bis-(4-fluorophenyl)ethyl_7phenol (41) (cf. formula scheme 1, XIX).

1. To 4.75 g (37.4 mmol) of oxalychloride in 10 ml of methylene chloride, 5.8 g (74.2 mmol) of dimethyl sulfoxide in 10 ml of methylene chloride are added dropwise at -65°C. It is allowed to stir for 30 minutes at this temperature, and then 9.5 g (27.1 mmol) of alcohol according to example 39 step in 20 ml of methylene chloride are added dropwise and allowed to stir for 30 minutes at -65°C. 15 g (148 mmol) of triethylamine were then added dropwise. It was washed twice with water, dried with magnesium sulfate and the solvent removed in vacuo. The residue was recrystallized with cyclohexane. 8 g (23 mmol, 85 %), 2-(2-benzyloxy-3,5-dimethylphenyl)-1-(4-fluorophenyl)-ethan-1-one (56) were obtained.

Sm.p. 99°C.

<1>H-NMR (CC14, 60 MHz): δ = 2.2 ("d", 6H,~CH3), 4.0 (s,

2H, -CH2-), 4.7 (s, 2H, OCH2-), 6.6-7.8 (m, 11H, arom. H).

2. 6.4 g (34 mmol) of 1,2-dibromoethane was added dropwise to 0.85 g (35 mmol) of magnesium in diethyl ether and heated under reflux for 1 hour. With a syringe, the solution was dripped into a Grignard solution of 0.85 g (35 mmol) magnesium and 6 g (34.3 mmol) 4-fluorobromobenzene in diethyl ester. Then 6.8 g (19.5 mmol) of ketone according to step 1 were added dropwise in ether and heated for 4 hours under reflux. It was hydrolysed with ice/HCl>extracted three times with ether, the combined ether phases were washed once with saturated aqueous sodium bicarbonate solution and dried with magnesium sulfate. Removal of the solvent in vacuo and recrystallization from cyclohexane gave 7.3 g (16.4 mmol, 84%) of alcohol.

Melting point: 119 - 120°C. 3. 7.0 g of alcohol according to step 2 bee boiled in toluene with a catalytic amount of p-toluenesulfonic acid for 1 hour in a water separator. The solution was then washed once with saturated aqueous sodium bicarbonate solution and vortexed. The residue was hydrogenated with palladium on charcoal (10%) in methanol at room temperature and normal pressure. Normal processing. Ball tube distillation: 150 - 160°C 0.05 torr.

<1>H-NMR (CDCl 3 , 60 MHz): δ = 2.16 ("d", 6H, -CH 3 ), 3.25

(d, 2H, -CH2-), 4.17 (s, 1H, -OH), 4.30 (t, 1H, methine-H), 6.42-7.33 (m, 10H, arom. H ).

MS: 338 (M<+>).

Example 42: 4,6-dimethyl-2-[2-(4-fluorophenyl)-2-isobutylethyl]phenol (42).

Analogous to example 41, the compounds (42) were formed. Instead of the Grignard compound, i-butyllithium was reacted with ketone according to Example 41 step 1.

<1>H-NMR (CDC13, 60 MHz): δ = 0.66-1.0 (m, 6Hf'-CH3), 1.2-1.8

(m, 3H, -CH2- and methine-H), 2.17 ("s", 6H, -CH3), 2.6-3.1 (m,

3H, -CH2- and methine-H), 4.1 (s, 1H, OH), 6.4-7.2 (m, 6H, arom. H), MS, 300 (M<+>).

Oak Sempe1 43-45:

Analogous to examples 41 and 42, starting from 4,6-dimethyl-2-(4-fluorobenzoyl)phenol (cf. Houben-Weyl, Methoden der Orga-nischen Chemie, volume 7/2a 1973) the compounds according to examples 43 were prepared , 43a, 43b, 44 and 44a. The reaction of the above-mentioned phenol with cyclohexyl with magnesium bromide and subsequent hydrogenolysis gave the compounds according to example 44b. The compounds according to example 45 were obtained by reduction of the above-mentioned phenol with sodium borohydride and subsequent hydrogenolysis using 2-methyl-4-chloro-phenol or of 2-chloro-4-methyl-phenol (G. Mazzara, M. Lamberti-Zanardi, Gazz.

Chim. Ital. 399 (1986)) as starting material one got 43c resp. 43d analogous to 43, with 2,4-dichlorophenol, as starting material 43e analogous to example 43 was obtained.

From Friedel-Crafts acylation products of 2,4-dimethylphenol, 2-methyl-4-chlorophenol, 2,4-dichlorophenol resp. 2-chloro-4-methyl-phenol with cyclohexanecarboxylic acid chloride gave 45a, 45b,

45c, resp. 45d analogous to 45. The compounds according to examples 43f, 43g, 43h, 43i were obtained analogously to example 43, starting from the above-mentioned phenols by Fridel-Crafts acylation with 4-fluoro-3-methyl-benzoyl chloride, reaction of the formed ketones with 4-fluoro-3-methyl-phenylmagnesium bromide and subsequent

end hydrogenolysis of the alcohols formed. 2-Fluoro-5-bromo-toluene was formed by the reaction of 2-fluorotoluene with bromine (Varma, Råman, Nilkantiah, J. Ind. Chem. Soc. 21, 112 (1944)). 4-fluoro-3-methylphenylmagnesium bromide is obtained analogously to example 41-2. The reaction of this Grignard compound with a large excess of finely powdered dry ice gives, after recrystallization, the pure 4-fluoro-3-methyl-benzoic acid, m.p. 168°C. By reacting this acid with oxalkyl chloride in toluene, 4-fluoro-3-methyl-benzoyl chloride is obtained.

2-phenyl-4,6-dichlorophenol 45e is obtained by introducing chlorine into a glacial acetic acid solution of commercial 2-hydroxybiphenyl (I. Leupold, H. Musso, Liebigs Ann. Chem. 746, 144 (1971)).

3-(p-fluorobenzyloxy)-4,6-dichlorophenol 45f is obtained by the reaction of commercial 4,6-dichlororesorcin with p-fluorobenzyl bromide analogous to example 2.

43: 4,6-dimethyl-2-(bis-(4-fluorophenyl)methyl-7-phenol).

43a: 4,6-dimethyl-2-_~(4-fluorophenyl-4-methoxyphenyl)methyl_7phenol.

43b: 4,6-dimethyl-2-_~(4-fluorophenyl-3-trifluoromethylphenyl)methyl<_>7

phenol.

43c: 4-chloro-6-methyl-2-bis-(4-fluorophenyl)methyl-7-phenol.

43d: 6-chloro-4-methyl-2-(bis-(4-fluorophenyl)methyl)thenol.

43e: 4,6-dichloro-2-/bis-(4-fluorophenyl)methyl-7phenol 43f: 4,6-dimethyl-2-_~bis-(4-fluoro-3-methyl-phenyl)methyl<_>7phenol.

43g: 4-chloro-6-methyl-2-[bis-(4-fluoro-3-methyl-phenyl)methyl-7

phenol.

4 3h: 4,6-dichloro-2-(bis-(4-fluoro-3-methyl-phenyl)methyl-7-phenol. 4 3i: 6-chloro-4-methyl-2-_bis-(4-fluoro-3-methyl-phenyl)methyl/phenol.

4 4: 4,6-dimethyl-2-_ 1-(4-fluorophenyl)ethyl/phenol.

44a: 4,6-dimethyl-2-(4-fluorophenyl,isobutyl)methyl-7-phenol.

44b: 4,6-dimethyl-2-(4-fluorophenyl, cyclohexyl)methyl/phenol.

45: 4,6-dimethyl-2-(4-fluorobenzyl)phenol.

45a: 4,6-dimethyl-2-(cyclohexylmethyl)-phenol.

45b: 4-chloro-6-methyl-2-(cyclohexylmethyl)-phenol.

45c: 4,6-dichloro-2-cyclohexyl-methyl-7-phenol.

45d: 6-chloro-4-methyl-2-cyclohexyl-methyl-7-phenol.

45e: 2-phenyl-4,6-dichlorophenol.

45f: 3-(p-fluorobenzoyloxy)-4,6-dichlorophenol.

Preparation of the starting compounds of formula III.

Example 46: 4(R)-(t-butyldiphenylsilyloxy)-2(R,S)-methoxy-6(S)-(4-methyl-phenylsulfonyloxymethyl)-3,4,5,6-tetrahydro-2H-pyran ( 46).

Tetrahedron Easy. 23, 4305 (1982).

60 g (150 mmol) alcohol 4(R)-(t-butyldiphenylsilyloxy)-2-(R,S)-methoxy-6(5)-hydroxymethyl-3,4,5,6-tetrahydro-2H-

pyran (Tetrahedron Lett. 23, 4305 (1982)) was dissolved in 240

ml of dry methylene chloride and 240 ml of dry pyridine, mixed in portions at room temperature with 46 g (293 mmol) of p-toluenesulfonic acid chloride. It is left to stir for 3 hours at room temperature.

raw ride. The solvent was removed as much as possible under vacuum and the residue distributed between toluene and water. The organic phase was washed twice with water and twice with saturated aqueous sodium bicarbonate solution, and once with saturated aqueous sodium chloride solution. Drying with magnesium sulfate, removal of the solvent in vacuo (for complete removal of pyridinium, the residue was further mixed twice with toluene and then rotated in) and chromatography from silica gel (CH 2 Cl 2 ) gave 79 g (142 mmol, 95%) tosylate (46 ) as colorless oil.

(DC: chloroform/acetic ester = 9:1, Rf = 0.63).

Example 47, (III): 4(R)-(t-butyldiphenylsilyloxy)-6(S)-iodomethyl-2(R,S)-methoxy-3,4,5,6-tetrahydro-2H-pyran (47) .

Tetrahedron Lett 23, 4305 (1982)).

79 g (142 mmol) of tosylate (46) was heated in dry acetone with 43 g (286 mmol) of sodium iodide under reflux. For complete reaction, 107 g (713 mmol) of sodium iodide, DC control (chloroform) were additionally added.

The solvent was removed as best as possible under vacuum and the residue distributed between water and ether. The ether phase was successively washed twice with water and once with a little sodium bisulfite solution and once with saturated sodium bicarbonate solution. Drying with magnesium sulfate, removal of the solvent and chromatography on silica gel (toluene) gave 68 g (134 mmol, 94%) of iodide (47) (III) as a colorless oil.

Production of the final product.

Conversion of compounds of formula II + III to compound of formula IV.

Example 48a:

6(S)-$ 4,6-dimethyl-2-_ 3-(4-fluorophenoxy)propyl/phenoxymethyl} - 3,4,5,6-tetrahydro-2(R,S)-methoxy-4(R) -(t-butyldiphenylsilyloxy)-2H-pyran (48a).

14.5 g (53 mmol) of phenol (24) and 14.6 g (105 mmol) of potassium carbonate are added to 100 ml of dimethylsulfoxide and mixed with 18 g (35 mmol) of iodide (47) in 200 ml of dimethylsulfoxide. After 10 hours at 60°C, it was mixed with water and ether and the aqueous phase was again extracted twice with ether. The combined ether phases were washed once with water. Drying with magnesium sulfate and removal of the solvent gave, after chromatography on silica gel (cyclohexane/acetic ester = 9:1), 18.3 g (28 mmol, 80%) of alkylation product 48a).

MS: C4QH49<F>05Si, 656 (M<+>).

<1>H-NMR (CDC13, 60 MHz): δ = 1.1 (s, 9H, t-Bu), 2.3 ("d",

6H, -CH3), 3.5 (s, 3H, OCH3), 3.7-5.1 (m, 7H, methine-H and

-OCH2-), 6.7-7.8 (m, 16H, arom. H).

Analogously to example 48a, the compounds listed in Table 4 according to examples 48b-48vv were obtained from corresponding phenols and iodides (47).

Conversion of the compound of formula IV to compound of formula V.

Example 4 9a:

6(S)-f 4,6-dimethyl-2-_ 3-(4-fluorophenoxy)propyl_7phenoxymethylj - 3,4,5,6-tetrahydro-2 (R,S)-hydroxy-4 (R)-(t -butyldiphenyl-silyloxy)-2H-pyran (49a).

1.4 g (2.13 mmol) alkylation product (48a) was kept in 75 ml tetrahydrofuran, 75 ml water and 105 ml glacial acetic acid for 18 hours between 70 and 80°C. The solvent was removed in vacuo and the residue mixed with toluene to remove any acetic acid residues still present and rotated again. Chromatography on silica gel (cyclohexane/acetic ester = 8:2) gave 950 mg (1.48

mmol, 70%) hydrolysis product (49a) .

MS: C3gH47<F>04Si, 642 (M<+>), 624 (M<+->H2O),

DC: Rf = 0.18 (cyclohexane/acetic ester = 5:1).

Analogous to example 49a, it was obtained from examples 48b-48vv

the compounds listed in Table 5 according to examples 49b-49vv.

Conversion of the compound of formula V to compound of formula VI.

Example 5 0a

6(S)-[ 4,6-dimethyl-2-_ 3-(4-fluorophenoxy)propyl/phenoxymethyl] - 3,4,5,6-tetrahydro-4(R)-(t-butyldiphenylsilyloxy)-2H- pyran-

2- on ( 50a) .

9.66 g (96.6 mmol) of chromium trioxide are dissolved in 250 ml of dry methylene chloride and at room temperature 15.3 g (193.3 mmol) of pyridine are added dropwise. It is allowed to stir for 20 minutes at room temperature and then 6.2 g (9.66 mmol) of hydrolysis product (49a) in 250 ml of methylene chloride are added dropwise at room temperature. After 30 minutes at room temperature, it was diluted with methylene chloride, filtered off with suction over silica, and the residue washed out thoroughly

with methylene chloride. The filtrate was evaporated in vacuo and the residue taken up with cyclohexane/acetic acid = 1:1) and again suctioned off over celite. Evaporation in vacuo and chromatography on silica gel (cyclohexane/acetic ester = 8:2) gave 5.34 g (8.34 mmol), 86%) lactone (50a).

MS: C3gH45F05Si, 640 (M<+>)

<1>H-NMR (CDC13, 60 MHz) in 6 = 1.1 (s, 9H, t-Bu), 1.8-2.9

(m, 14H, -CH3 and -CH2-), 3.9 (m, 4H, -OCH2-), 4.4 and 5.1

(resp. m, each 1H, methine-H), 6.7-7.8 (m, 16H, arom. H).

Analogous to example 50a, the compounds listed in Table 5 according to examples 50b-50vv were prepared from examples 49b-49vv.

The conversion of compounds of formula VI to compounds of formula I.

Example 51a

6(S)- [ 4,6-dimethyl-2-_ 3-(4-fluorophenoxy)propyl/phenoxymethyl} - 3, 4, 5, 6- tetrahydro- 4( R)- hydroxy- 2H- pyran- 2- on ( 5le) .

950 mg (1.48 mmol) of silyl compounds (50a) are taken at room temperature in 60 ml of tetrahydrofuran and mixed with 355 mg

(5.92 mmol) of glacial acetic acid. Then 1.4 g (4.44 mmol) of tetrabutylammonium fluoride trihydrate was added. After 16 hours at room temperature, the solvent was removed as best as possible and the residue distributed between ether and water. The aqueous phase was once more extracted with ether. The combined ether phases were washed once with water. Drying with magnesium sulfate, removal of the solvent in vacuo and chromatography on silica gel (cyclohexane/acetic ester = 1:1) gave 470 mg (1.17 mmol, 79%) of hydroxylactone (51a).

MS: C23H27<F>05'402 (M<+>)'384 (M<+->H2°)•

<1>H-NMR (CDC13, 270 MHz): δ = 1.82 (broad, 1H, OH), 2.00-2.20

(m, 4H, methylene-K), 2.25 and 2.27 (resp. s, each 3H, -CH3), 2.68-2.83 (,. 4H, Ar-CH2 and -CH2CO), 3 .88 - 4.01 (m, 4H, -OCH2), 4.50 and 5.00 (resp. m, 1H, methine-H), 6.80 - 7.10 (m, 6H, arom. H) .

Analogous to example 51a, the compounds according to examples 51b - 51vv listed in Table 5 were prepared from the compound according to examples 50b - 50vv.

Example 521:

3(R),5(S)-dihydroxy-6-{ 4-chloro-2-_~3-(4-fluorophenoxy)-propyl/phenoxyj hexanoic acid sodium salt ( 52 1) .

200 mg (0.49 mmol) of lactone 51 1 was mixed in 15 ml of tetrahydrofuran with 4.6 ml of 0.1 N aqueous sodium hydroxide solution (0.46 mmol).

After 1 hour at room temperature, the solvent was removed in vacuo, and the residue was mixed several times with toluene and rotated. Crystallization with diisopropyl ether gave 175 mg (0.39 mmol 80%) of sodium salt 52 1.

sm.p. 215°C during decomposition.

<1>H-NMR (270 MHz, D20); 6 = 1.75, 2.00, 2.35 and 2.78 (resp.

m, 2H, methylene-H), 3.80-4.20 (m, 6H, -OCH2~and methine-H), 6.80-7.25 (m, 7H, arom. H),

Analogous to example 52 1, it was prepared in corresponding sodium salts of the hydroxylactones 51 a - 51 vv (table 5). In some cases, instead of tetrahydrofuran, meta-

nol as a solvent.

Claims (2)

1. Process for the preparation of 6-phenoxymethyl-4-hydroxy-tetrahydrofuran-2-ones with the general formula 15 R and R 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 1 to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy with each 1-4 C atoms, or c) a straight or branched alkyl residue with 1 to 18: carbon atoms or a straight or branched alkylene residue with 2 to 18 carbon atoms, the alkyl resp. The alkenyl radicals, on the other hand, can be substituted 1-3 times with a) straight or branched olefinic acid residues with up to 10 carbon atoms, or cycloalcoic acid residues with 3 to 7 carbon atoms, or straight or branched alkenyloxy or alkynyloxy acid residues with 3 to 6 carbon atoms, 6) halogen, hydroxy, cycloalkyl with 3-7 C atoms, unsubstituted phenyl, α- or 3-thienyl residues, or phenyl, a- or B~ thienyl residues, which in turn are substituted in the nucleus 1 to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy with 1-4 C atoms, y) unsubstituted phenoxy-, benzyloxy-, a- or g-thienyloxy acid residue or phenoxy-, benzyloxy-, a- or $-ti-enyloxy acid residue, which in turn is substituted in the nucleus 1 to 3 times by halogen, trifluoromethyl, and/or alkyl or alkoxy with 1 to 4 carbon atoms, 0 "6 6 6) the group -O-C-R /' where R means: a straight or branched alkyl or alkenyl residue with up to 8 carbon atoms, or a cycloalkyl or cycloalkenyl residue with resp. 3-8 C atoms, or an unsubstituted phenyl radical or a phenyl radical, which in turn is substituted in the nucleus 1 to 3 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 means 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 tolerable salts with bases and their pharmacologically tolerable esters, characterized by ata) corresponding substituted phenols of formula II wherein r\ R<2> , R<3> , R<4> and R^ have the indicated meaning, is transferred with the chiral iodide of formula III in which R"^ means an above base and weakly acidic stable protecting groups for ethers of formula IV 1 5 R 10 in which R to R has the meaning given under formula I and R the meaning given under formula III. b) the ethers of formula IV are hydrolysed to the corresponding hemiacetals of formula V in which R <1> to R <5> and R <10> has the formula I or III stated meaning, c) the hemiacetals of formula V are oxidized to the corresponding ones in which R"'" to R^ has the meaning given under formula I and R^ has the meaning given under formula III, and d) the protected hydroxylactones of formula VI are transferred to 6-phenoxymethyl-4-hydroxytetrahydropyran-2-ones with formula I optionally, the formed compounds of formula I are transferred to the corresponding open-chain dihydroxycarboxylic acids their salts or their esters, optionally transferred together with salts or esters to the free hydroxycarboxylic acids or optionally the free carboxylic acids to salts or esters. 2. Method according to claim 1, characterized in that compounds of formula I are prepared, in which F" and R^ are both the same or different and mean a) hydrogen or halogen, b) cycloalkyl with 5 to 6 C atoms, phenyl, which in the nucleus may be substituted 1-3 times by halogen, trifluoromethyl, and/or alkyl or alkoxy with 1-4 C atoms each, or c) 1. straight or branched alkyl or alkenyl with up to 12 carbon atoms, whereby alkyl or the alkenyl residue, on the other hand, can be substituted 1-2 times with phenyl residues which, on the other hand, in the nucleus can be substituted 1 to 3 times with halogen, trifluoromethyl, and/or alkyl or alkoxy with 1-4 C atoms,2. linearized with G-COR substituted alkyl of formula in which n = 1 to 3, and R means a linear or branched alkyl or alkenyl residue with up to 8 C atoms, a cycloalkyl residue with 5 to 6 C atoms or a phenyl residue, which in turn may be substituted in the nucleus 1 -3 times with halogen, trifluoromethyl and/or alkyl or alkoxy with 1 to 4 C atoms, 3. rectilinear with OR' substituted alkyl of formula zn - wherein n = 1 to 3, and R means hydrogen or a straight or branched alkyl or alkenyl radical of up to 8 C atoms, a cycloalkyl radical of 5 to 6 C atoms, or a phenyl radical or benzyl radical which in turn in the aromatic nucleus may be substituted 1-3 times by halogen, trifluoromethyl, and/or alkyl or alkoxy with 1 to 4 C atoms, 2 4 R and R are hydrogen, and R 3 means hydrogen, methyl, ethyl, propyl, 1-propenyl, allyl, fluorine or chlorine. 3. Method according to claim 1, characterized in that compounds of formula I are prepared, in which R <1> and R <5> are the same or different and mean 1) hydrogen, methyl, ethyl, propyl, allyl, 1-propenyl, isopropenyl, isopropyl, cyclopentyl, cyclohexyl or 2) the group with n = 1-3, wherein R means methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl, phenyl or in the nucleus 1 to 3 times substituted phenyl with halogen, methyl or methoxy, or 3) the group -(CH2)nOR7 with n = 1 to 3, wherein R <7> means hydrogen, methyl., linear or branched alkenyl or alkyl with 3-5 carbon atoms, cyclopentyl, cyclohexyl, phenyl or benzyl, wherein the aromatic nucleus may be substituted 1-3 times with fluorine, chlorine, methyl, methoxy, or 4) an alkyl group of formula wherein n = 0 to 2, and R o and R Q are the same or different and represent hydrogen, methyl, ethyl, propyl, allyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclohexyl, cyclopentyl, benzyl or phenyl, the aromatic core being substituted 1-3 times with fluorine, chlorine, methyl or methoxy, 2 4 R and R are hydrogen, and R 3 means hydrogen, methyl, chlorine, fluorine. 4. Process for the production of a pharmaceutical preparation, characterized by a compound obtained according to the method according to claim 1, transferred in a suitable administration form. 5. Method according to claim 1, characterized in that an intermediate product with formula IV is isolated in which R , R , R , R R and R have the meaning given under formula I and R the meaning given under formula III. 6. Method according to claim 1, characterized in that intermediate products with formula are isolated in which R<1> to R<5> and R10 have the formula I or III stated meaning. 7. Method according to claim 1, characterized in that intermediate products of formula VI are isolated wherein R to R has the meaning given in formula I and R"^ the meaning given under formula III.