CS233718B2 - Process for preparing acyloxy polyhydronaphthyl derivatives of 2H-pyran-2-one - Google Patents

Abstract

A method for preparing acyloxypolyhydromethyl derivatives of 2H-pyran-2-one of general formula I and corresponding dihydroxy acids of general formula II, in which a compound of general formula III is heated with an alkali metal hydroxide in a protic solvent, followed by acidification and lactonization to obtain a compound of general formula IV, which is reacted with tert-butyldimethylchlorosilane in an inert atmosphere at room temperature in the presence of an acid acceptor, the resulting 4-tert-butyldimethylsilyloxy compound is acylated with a corresponding acylating agent containing a radical in the meaning of R, in the resulting compound the silyl group is removed at room temperature in tetrahydrofuran in the presence of 3 equivalents of tetrabutylammonium fluoride and 4 equivalents of acetic acid per equivalent of silyl compound. The compounds according to the invention are potent inhibitors of cholesterol synthesis.

Description

The invention relates to a group of 6(R)-[2-(8*-cyclohexyl-2'-methyl-6'-methyl(or hydrogeno)-polyhydronaphthyl-1')-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyren-2-ones and the hydroxy acid form of these pyranones and pharmaceutically acceptable salts of these hydroxy acids and lower alkyl and phenyl, dimethylamino or acetylamino substituted alkyl esters of these hydroxy acids.

More specifically, the invention relates to compounds of general formula 1 shown in Table I, where the dashed lines X, Y and Z represent possible double bonds, where these double bonds, if present, are either X and Z together or X, X or Z alone, R is straight or branched alkyl of 1 to 10 carbon atoms (except (S)-2-butyl), cycloalkyl of 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, alkyl of 1 to 10 carbon atoms substituted with CF, halophenyl, and free hydroxy acids of formula II formed by opening the lactone ring of formula I in Table I.

The invention also relates to 6(R)-[2-(8'-hydroxy-2*,6'-dimethylpolyhydronaphthyl-1')-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones as intermediates for the above-described 8*-acyloxy compounds.

It is known that certain derivatives of mevalonic acid inhibit cholesterol biosynthesis, see F.M. Singer et al., Proc. Soc. Exper. Biol. Med., 102. 370 (1959) and F.H. Hulcher, Arch. Biochem. Biophys., 146. 422 (1971). Although the activity of these known compounds is not always sufficient, these compounds have practical applications.

U.S. Patent Nos. 4,049,495, 4,137,322 and 3,983,140 disclose the preparation of fermentation products which are fully active in inhibiting cholesterol biosynthesis. The most active member of this group of natural substances now called Compactin (lila) was reported by Brome et al. [j; Chem. Soc. Perkin I, 1165 (1976)] and this compound has the structure of a derivative of mevalolactone,

U.S. Patent No. 4,231,938 discloses an inhibitor, designated MK-803, structure IIIa in Table I, which was isolated from a completely different fermentation.

Further described is the dihydro MK-803 designated by formula IIIl _and in Table I, which has the same effect as MK-803. MK-803 isolated from the same fermentation as MK-803. In addition, dihydro- and tetrahydro-derivatives of MK-803 of structures III _b θ (Table I) are known, which are prepared by catalytic hydrogenation of MK-803.

It has now been found that the -methyl-butyryl group in the compound of formula III _a · in the hydrogenated derivatives of formula III _b _ _e and ae can readily be cleaved to form the 6(R)-[2-(8-hydroxy-2,6-dimethylpolydyhronaphthyl)-1-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one group, which are also hypocholesteremic agents and which are useful as intermediates for the preparation of new esters which are even more effective in this application.

It has been found that 8'-hydroxy compounds of structural formula IV can be acylated to form a new group of 8-acyloxyalloys of formulae I and II as defined below. These new compounds are inhibitors of cholesterol synthesis in vivo.

The subject of the invention is a method for preparing acyloxypolyhydronaphthyl derivatives of 2H-pyran-2-one of general formula I

where S is optionally branched alkyl with 1 to 10 carbon atoms, with the exception of 2-(S)-butyl, cycloalkyl and 3 to 10 carbon atoms, alkenyl and 2 to 10 carbon atoms, alkyl with 1 to 10 carbon atoms substituted by the group CF^, halophenyl, the symbols X, X and Z represent possible double bonds, and if these double bonds are present, then they are either in combination with X and Z or alone with the bonds X, X or Z and the corresponding dihydroxy acids of general formula II

where the symbols R, X, X and Z have the above meaning or pharmaceutically acceptable salts of these acids, alkyl esters and 1 to 4 carbon atoms of these acids or phenyldimethylemino- or acetylamino-substituted alkyl esters and 1 to 4 carbon atoms of these acids, which is carried out by heating the compound of general formula III

where the symbols X, X * Z have the above meaning, and with an alkali metal hydroxide in a protic solvent, followed by acidification and lactonization to obtain the compound of general formula IV

where the symbols X, X and Z have the above meaning, which is reacted with tert-butyldimethylchlorosilane in an inert atmosphere at room temperature in the presence of an acid acceptor, the resulting 4-tert-butyldimethylalyloxy compound is acylated with a corresponding acylating agent containing a radical having the meaning of R, in the resulting compound the silyl group is removed at room temperature in tetrahydrofuran in the presence of 3 equivalents of tetrabutylammonium fluoride and 4 equivalents of acetic acid per equivalent of silyl compound.

The absolute configuration of these compounds is known from the structure determined by X-ray diffraction. Table I shows these structures and their ethereochemical relationships. The reference numbers of the various compounds, including compounds of the various series of polyhydronaphthyl structures, remain the same throughout the description and are used as such. Each of the esters of formula I _and _ _e of this invention contains seven to eight chiral centers. The relative and absolute configurations of these asymmetric centers are shown in Table X. More specifically, for the ester of formula X _a , the Cahn, Xngold, Prelog absolute configuration designations are 4(R), 6(R), 1 *(S), 2*(S), 6*(R), 8*(S) and 8a'(R) fs.S. Cahn, C. Ingold and V. Prelog, Angew. Chem. Int. Ed., 5, 385 (1966)].

As shown in formulas X _and _ _e all of these compounds have the same spatial orientation of the groups on each of the chiral carbon atoms and therefore belong to the same stereochemical series. The RS designation for each center may not be identical to the designation found for the ester of formula X _and due to the details of the sequence rule used to determine this designation.

In the two esters of formula a I* which have an additional chiral carbon atom not present in the ester of formula I _a , the hydrogen atom at 4a* is oriented below the plane (or ar) as shown in Table I and therefore has a trans ring connection.

Table I sub.,

Stereochemistry of the hydronaphthyl series

Present

double bond Structure and X and Z po·**»**»*·»*·^ ch ₃ AX/ b X CH3 c Y f*****T* ^zv * ^M l ch/-^ d From CHj _with

H none

The 8'-acyloxy compounds of the invention are useful as antihypercholesterolemic agents suitable for the treatment of atherosclerosis, hyperlipemia and similar diseases in humans. They can be administered orally or parenterally in the form of capsules, tablets, injectable preparations, etc. It is usually desirable to use the oral route. The dosage may vary and depend on the age, severity of the disease, body weight and other conditions of the patient, but the daily dosage for an adult is in the range of 2 to 2000 mg (preferably 10 to 100 mg) in three to four divided doses. Higher doses may be administered if necessary.

The compounds of the invention can also be used as antifungal agents. For example, they can be used to control the growth of strains of Fenicillium sp., Aspergillus nigeri, Cladosporium sp., Cochliobolus miyabeanus and Helminthosporium cynonotis. For such use, they are mixed with a suitable formulation agent such as powders, emulsifiers or solvents (for example, aqueous ethanol) and sprayed or dusted onto the plants to be protected.

The preparation of compounds of the invention is illustrated in Scheme A.

Scheme A

III —iv--* ae ae ch ₃ ch ₃

a-e a-e.

a-e

VI ©

II

AND

The designations - X, ϊ, 2 and H have the meaning given in the description and the series a-e as defined in Table 1.

Reaction - 1)

Lithium hydroxide, heating, acidification and lactonization.

2) Tert-butyldimethylchlorosilane and imidazole in dimethylformamide at room temperature in an inert atmosphere.

3) Reaction with RCOCl and 4-dimethylaminopyridine in pyridine solution, preferably in an inert atmosphere.

4) Reaction of RCOCH with ηί,Ε'-dicyclohexylcarbodiimide and 4-pyrrolidinopyridine in dichloromethane, preferably in an inert atmosphere.

5) Three equivalents of tetrabutylammonium fluoride and four equivalents of acetic acid per equivalent of ester in tetrahydrofuran, preferably in an inert atmosphere.

6) Aqueous alkali metal hydroxide followed by careful acidification with dilute acid.

7) See reactions, reagents and scheme for the synthesis of compounds of formula III _h

D|b| β

The preparation of the new alcohols according to the invention is carried out by heating esters of formula HI _and _ _e with an alkali metal hydroxide, such as lithium hydroxide, potassium hydroxide or sodium hydroxide in a protic solvent, such as water or alcohols, at boiling for 50 to 72 hours or under pressure at elevated temperatures of 120 to 180 °C for a shorter period of 8 to 24 hours.

The pyranone ring is readily opened, but removal of the subtertiary acyl group is not readily accomplished. Heating must be prolonged and/or pressure must be applied. The use of an inert atmosphere is also advantageous. It is completely unexpected that a molecule with so many sensitive functional centers can withstand the conditions required for the removal of the highly hindered α-methylbutyryl ether. It is completely unexpected that the compound is obtained in high yield.

The products are isolated by acidification and extraction with organic solvents to give the trihydroxy acid form of the compound of formula ΐν*_*. These trihydroxy acids can be relactated by heating a solution of the acid in a suitable organic solvent such as toluene or benzene in an apparatus allowing continuous separation of the water formed.

Alcohols that form part of the present invention include structures of Formulae IV* _{_e} as well as trihydroxy acids resulting from the opening of lactone rings.

An alternative synthetic route to compounds of formulae IV _bc * involves the steps of hydrolysis of compounds of formulae IX1* to IV*, as described above, followed by hydrogenation of the compound of formula XV*, under the conditions described previously for the preparation of compounds of formula III _{b 0} *, to give compounds of formulae IV _b , IV* or IV*, depending on the reaction conditions.

Preparation of compounds of formulae IV*_*

The starting materials, the 8o-hydroxy compounds of formulae IV _and _ _e described by Willard, are prepared from various 8*-esters described by Uonaghan et al. (III*), Albers-Schonberg et al. (III^) and Patchett et al. (IH _bce ) by heating with sodium hydroxide solution for a prolonged period. The pyran ring is readily opened, but removal of the side group is not easy. Heating must be carried out for a prolonged period and/or pressure must be applied. The use of an inert atmosphere is also convenient.

2337.8

In the case of compounds of formulae III _{and e,} saponification of the 8'-esters proceeds more easily, and saponification is complete within about 20 hours.

The 8'-hydroxy products are isolated by acidification and extraction with organic solvents, which will provide the compounds in the hydroxy acid form in which the pyranone ring is still open.

These hydroxy acids are relactonized by heating a solution of the acid in a suitable organic solvent, such as benzene or toluene, in an apparatus that allows continuous separation of the water formed.

In lecton form, these alcohols are compounds of formula IV _and _ _e listed in Table I and are prepared according to the following preparations:

Preparation of 6(R)-[2-8'(S)-hydroxy-2'(S),n'(R)-dimethyl-1',2',6',7',8',8a (R)-hexahydronaphthyl-1'(S))-ethyl-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, IV _g

A mixture of 8.0 g (19.78 mmol) of MK-803 (IU,) and 8.31 g (0.97*.8 mmol) of LiOH . HgO in 600 ml of water was stirred and heated to reflux for 56 hours under nitrogen. The reaction mixture was cooled to 0 °C and, with stirring, 20 ml of concentrated hydrochloric acid were added. The mixture was then extracted with three 250 ml portions of ether and the combined extracts were washed successively with three 200 ml portions of water and then with 200 ml of saturated sodium chloride solution. After drying over magnesium sulfate, the solution was filtered and the solvent was evaporated in vacuo to give an oily residue. The residue was redissolved in 200 ml of toluene and heated to reflux for two hours with continuous separation to allow relactonization. Evaporation of the toluene and trituration of the residue in hexane afforded 5.15 g (81%) of the title compound of formula IV. (R' = CH^) as a white solid which did not require further purification.

An analytical sample was prepared by recrystallizing a portion of this material from butyl chloride to give crystals, mp 128-131 °C, HwLR (CDCl2) δ 0.87 (d, 3, J = 7 Hz, CH^), 1.16 (d, 3,

J = 7 Hz, , 2.64 (m, 2, pyran C^H' s), 4.27 (brm, 1, naphthalene CgH), 4.37 (m, 1, pyran G^H), 4.71 (m, 1, pyran C^H), 5.56 (m, 1, naphthalene C^H), 5.79 (dd, 1 , J = 6.10 Hz, naphthalene, C' ₃ H), 6.03 (d, 1, J = 10 Hz, naphthalene C ₄ H). IR (CHCl-j) 3400 (OH), 1725 (0=0), 1240, 1120, 1080 cm"'.

Analysis for ^5^28^4 . 0.1 C^H^Cl:

calculated: C 70.67%, H 8.84% found: C 70.77%, H 8.75%.

Alternative preparation of 6(R)-[2-(8'(S)-hydroxy-2'(S)-6'(R)-dimethyl-l,2',6',7',8',8*a(R)-hexahydronaphthyl-1'(S)-ethyl]-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, IV _and

A suspension of 188 mg (0.463 mmol) of MK-803 (III _a ) in 5 ml (5 mmol) of aqueous 1 N lithium hydroxide solution was shaken for 12 hours at 135 °C in a 30 ml stainless steel pressure vessel. The cooled reaction mixture was acidified with 1 M phosphoric acid and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate and the solvent was evaporated after filtration. The residue was dissolved in 20 ml of toluene and heated to boiling in a Dean-Stark apparatus for 4 hours to undergo relactoniation. Evaporation of the toluene gave the title compound.

In the novel process of the invention, the 4-hydroxyl group of the pyranone ring of alcohols of formula IV _and _ _e is first protected with a tert-butyldimethylsilyl group by reaction with tert-butyldimethylchlorosilane in an inert atmosphere at room temperature in the presence of acid acceptors such as imidazole to give protected alcohols of formula V _and _ _e and the 8-hydroxyl on the polyhydronaphthyl ring is then acylated in one of two ways. The first involves reaction with the acid chloride of the desired acyl group in pyridine in the presence of 4-dimethylaminopyridine as a catalyst. The second involves reaction of 8'-hydroxypolyhydronaphthol with the free acid of the desired acyl group and a carbodiimide such as Ν,Ν'-dicyclohexylcarbodiimide with 4-pyrrolidinopyridine as a catalyst in dichloromethane. This process provides protected esters of formula ^{V VI} and _ _e ·

Removal of the silyl protecting group from the 4-hydroxyl of the pyranone ring is then carried out using three equivalents of tetrabutylammonium fluoride and four equivalents of acetic acid per equivalent of esters of formula VI _and _ _# and to obtain the desired compounds of formula I _and _ _e · The ratio of reactants in this reaction is not critical to the yield of the process and the purity of the products.

The acyl groups that attach to the 8'-hydroxyl group are those where R in the compounds of formulae I. " are:

“•“β

1) straight or branched alkyl chain and 1 to 10 carbon atoms with the exception of (S)-2-butyl,

2) cycloalkyl with 3 to 10 carbon atoms,

3) alkenyl with 2 to 10 carbon atoms,

4) alkyl substituted by a CFj group and having 1 to 10 carbon atoms,

5) halogenophenyl, where the halogen atom is a chlorine, fluorine, bromine or iodine atom.

Preferred R substituents are:

straight-chain alkyl with 2 to 5 carbon atoms, branched-chain alkyl with 3 to 10 carbon atoms and excluding (S)-2-butyl, cycloalkyl with 3 to 10 carbon atoms, alkenyl with 3 to 10 carbon atoms in which the double bond is not conjugated and carbonyl, and branched-chain alkyl with the exception of (S)-2-butyl are particularly preferred.

Preferred individual R groups are 1,1-diethylpropyl or 1-ethyl-1-methylpropyl. Further preferred compounds are those wherein none of X, X or Z represents a double bond.

Compounds of formula I _and _ _e can be hydrolyzed with bases such as NaOH to form salts such as the sodium salt of compounds of formula H _and _ _e . Using bases with other pharmaceutically acceptable cations gives salts of these cations. Careful acidification of the salts gives hydroxy acids of formula ΙΙ _# _ _β , which are converted at acidic pH to compounds of formula I _and _ _e . Reaction of compounds of formula I _and _ _e under acidic or basic catalysis with methanol, ethanol, propanol or butanol or with phenyl-, dimethylamino-, or acetylaminoalkanols gives the corresponding esters of compounds of formula H _and _ _e , which are also within the scope of this invention.

Pharmaceutically acceptable salts of the invention include those formed from sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium cations, as well as salts derived from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine, piperazine and tri-(hydroxymethyl)aminomethane.

The preparation of starting materials of Formula III is carried out by fermentation of Aspergillus terreua ATttC strain No. 20542, designated MF-4845 in the Merck & Co. Inc. culture collection, Rahway, New Jersey.

Preparation of compounds of formulae III _and *

A. Fermentation

A tube of lyophilized culture MF-4845 in a 250 ml Erlenmeyer flask (inoculation flask) contains: i aseptically open containing about 10 and the contents are suspended in ml of the following medium Medium: corn liquors 5 grams tomato paste 40g oatmeal 10g glucose 10g trace element solution 10g distilled water 1,000ml pH 6.8 adjusted with HaOH Trace element solution _{FeSO4.7H20 ​} 1,000 mg MnSO^.4 H ₂ 0 1,000 mg CuC1 ₂ .2 H ₂ 0 25 mg _{CaCl2.2H20 ​} 1 00 mg ^h 3bo ₃ 56 mg (ΝΗ ₄ ) ₆ Μο _γ 0 ₂₄ .4 H ₂ 0 19 mg ZnS0 ₄ .7 HgO 200mg distilled water deionized 1,000ml The inoculated flask is incubated for 24 hours at 28°C on a rotary shaker with 220 rpm

per minute (5.4 cm displacement). A 2-liter, unbaffled Erlenmeyer flask containing 500 ml of medium is inoculated with 10 ml of fermentation medium and the grown inoculum mixture. Both flasks are shaken for 24 hours at 28°C.

A 910 litre stainless steel fermentation tank is filled with 485 litres of medium containing cerelos peptonised milk autolysed yeast polyglycol P 2000 ♦.5 SS w/v 2.5% w/v 0.25% w/v 0.25% w/v, the pH of which is adjusted to 7.0. The medium is aged for 15 minutes at 121°C. One litre of the above prepared second stage is added and the mixture is incubated for >2 hours at 85 rpm and then for 84 hours at 28°C and 130 rpm, with an air flow of 0.14 m^/min for 12 hours and then 0.28 m^/min for 84 hours.

B. Isolation

1. Extraction

Two batches of 454.6 liters of total medium are combined, acidified with stirring to pH 4.1 by the careful addition of 800 ml of concentrated hydrochloric acid and extracted by the addition of 341 liters of ethyl acetate and the mixture is stirred for a further two hours.

About 11.3 kg of silica filter aid is then added and the total slurry is pumped through a 61 cm filter press. Another 341 liters of ethyl acetate are used to wash the press cake and its extraction is carried out by four repeated pumpings in opposite directions. All wash solvent is then removed from the cake and combined with the first filtrate. The two-phase filtrate is allowed to settle and the aqueous phase is removed. The ethyl acetate phase is washed with 45.5 liters of deionized water, the phases are allowed to separate and the ethyl acetate extracts are concentrated in vacuo to a residue of about 45.5 liters.

2. Lactonization

The ethyl acetate extracts from another 1304 liters of fermentation broth are added to the extract prepared above and the volume is reduced to about 136 liters by distillation under vacuum. 227 liters of toluene are added and the batch is concentrated under vacuum to 145 liters. This step is repeated and then sufficient fresh toluene is added to give a volume of 341 liters. Without vacuum, the mixture is then heated to reflux for two hours and the temperature is maintained above 106 °C.

The solution is then concentrated in vacuo to a small volume, which is further concentrated to an oily residue in a large rotary evaporator under vacuum.

3. Silica gel chromatography

The extract obtained in the above manner is freed from other solvents by adding 9.1 liters of methylene chloride and concentrating to an oily residue.

The residue is dissolved in 22.7 liters of ethyl acetate-methylene chloride (30/70 v/v) and a suspension is prepared by adding 2.8 kg of silica gel, which is applied to the top of a 30.5 x 127 cm column packed with silica gel in the same solvent mixture.

Elution is carried out with a mixture of ethyl acetate-methylene chloride (40:60 v/v) at a rate of 800 ml/min. An initial 45 liters is taken and then fractions of 18 liters are taken.

Fractions 6 to 10 inclusive are concentrated in vacuo and the oily residue is dissolved in hot ethyl acetate, treated with activated charcoal, filtered hot and cooled. The crystals of the compound of formula ΙΙΙ _# ae are filtered off and the mother liquors are concentrated to an oil which is rechromatographed. The pure compound of formula lll _a has a mp of 170-171 °C.

4. Rechromatography on Sillkagel

The mother liquors from similar extracts equivalent to the treatment of another 2,700 liters of fermentation broth are combined with the methylene chloride solution obtained above. One half of this solution is taken for further chromatography on silica gel. A small aliquot shows that the total solids content is 325 g. The solution is treated with 40 g of activated carbon, filtered through silica gel and the filter cake is rinsed with methylene chloride. The combined filtrates and washings are concentrated in vacuo to an oily residue. This is redissolved in 800 ml of a mixture of ethyl acetate and methylene chloride (30/70 v/v) and mixed with 225 g of silica gel. The suspension is applied to the top of a 14 x 36 cm column containing silica gel in the same solvent mixture. The column is eluted with a mixture of ethyl acetate and methylene chloride (40/60 v/v). The first three liters are removed and discarded, and then 800 ml fractions are collected.

5. Reversed-phase chromatography ml from fraction 22 of the above chromatography is concentrated to an oil of 500 mg with the oil redissolved in 5 ml of acetonitrile. The acetonitrile solution is applied to a 1.5 x 180 cm stainless steel column packed with preparative phase for reversed-phase liquid chromatography (Bondapak C18/Poraail B, octadecasilane-modified silica gel/silica gel). The column is eluted with a mixture consisting of (v/v) 55% acetonitrile and 45% 0.05 M ammonium phosphate pH 3. Elution volumes between 1360 ml and 1700 ml are combined according to refractive index detection. The organic solvent is removed in vacuo and the remaining aqueous solution is extracted with ethyl acetate. Removal of the ethyl acetate in vacuo gave 120 mg of the compound which crystallized from a concentrated acetonitrile solution to give crystals of the compound of formula III _a , mp .29-.31°C.

Preparation of compounds of formula lilu . .

u, c, e

Starting materials of formulas III, III ₀ ^{and Se} P^IP ^rav I according to the following scheme and the indicated prepaaative methods.

For the preparation of the compound of formula III, it is advantageous to reduce the compound of formula III if the desired trans linkage of the perhydronaphthalene ring, which is present in the starting materials, is retained in the final product. This eliminates the need to separate the isomers.

(1)

ch ₃

III,

III, .o ch ₃ '

III c

2337.8

from U(i)

CHj-CHj-CH-C, <

*

H

III

^IIJ d

Reactions and reagents

1. Hydrogenation at a temperature of 20 to 75 °C under atmospheric pressure up to about 0.4 MPa and is carried out on tris-(triphenylphosphine)rhodium chloride in an aromatic solvent such as benzene, toluene or xylene, and preferably in toluene. Preferably, the hydrogenation is carried out at 40 °C and 0.2 to 0.7 MPa in toluene.

2. Hydrogenation at 20-25°C under atmospheric pressure is carried out over 5% palladium on calcium carbonate in a lower alkanol, such as an alkanol with 1-3 carbon atoms, especially ethanol.

3. Hydrogenation at a temperature of 20 to 25°C and at atmospheric pressure is carried out over platinum oxide in ethyl acetate.

4. Hydrogenation at a temperature of 2b to 25 °C and at atmospheric pressure is carried out over 10% palladium on carbon in ethyl acetate.

Preparation of 6a[2-(8'P-2-(S)-aethylbutyryloxy-2'β ,6 a .dimethyl-1', 2', 3', 4', 6', 8', 8'a-octahydronaphthyl-1)ethyl] -4p-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one III&

A mixture of 50 mg (0.1236 mmol) of the compound of formula III _B and an equivalent molar amount (114.35 mg, 0.1236 mmol) of tris-(triphenylphosphine)chlororhodium in 10 ml of anhydrous toluene was hydrogenated at room temperature for 6 days, consuming a total of 14.6 ml of hydrogen.

The mixture was evaporated to dryness in vacuo, the red residue was chromatographed on a thin layer of silver nitrate impregnated silica gel and the plates were developed twice with 10% ethyl acetate in ether. The yield of the compound of formula III _b was 22.3 mg.

Mass spectrum (m/e) 406 (M ⁺ )

304 (M-,02)

286 (m-102-18)

MMR (CDC lp 300 MHz) δ

4.37 (m, ,H) 4.60 (m, ,H)

4

5.34 (d, t, J = 2.5 Hz, 1H) 5.41 (m, 1H).

Preparation of 6α [2-(8'β-2-(S)-methylbutyryloxy-2% 6α-diethyl-1',23 *, 5',6', 7',8 *, 8'α-octahydronaphthyl-1)ethyl]-4β-hydroxy-3,4,5,6-tatrahydro-2H-pyran-2-one, III _C

A solution of 80.91 mg (0.2 mmol) of the compound of formula III in 10 ml of absolute ethanol is hydrogenated in the presence of an equal weight of 5% Pd on CaCO^ at a pressure of 0.1 MPa until 1 molar equivalent of hydrogen is consumed. The catalyst is then filtered off and the filtrate is evaporated to dryness (81 mg). After purification by preparative thin layer chromatography, a small amount of by-product, the tetrahydro compound, is removed and 72 mg of the product of formula III, which is formed by 1,4-reduction, are obtained.

Mass spectrum (m/e)

NMR ( _C12Cl3 , 300 MHz)8

406 (M ⁺ ) 304 (M-102) 286 (304- _H2O ). 4.38 (m, 1H) 4.64 (m, 1H) 5.28 (d, t _ř J 5.48 (m, 1H).

Preparation of 6α- [2-(8'β-2-(S)-methylbutyryloxy-2 *u ,ό'β-dimethyl-l *,2',3',4',4' aa,5',6',7',

8',8'a-decahydronaphthyl-1-)ethyl]-4P-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, III*

A solution of 80.91 mg (0.2 mmol) of the compound of formula III _a in 10 ml of ethyl acetate is hydrogenated in the presence of the same weight of platinum dioxide at a pressure of 0.1 MPa. 2 molar equivalents of hydrogen are consumed within one hour. The catalyst is filtered off, the filtrate is concentrated to dryness and an oily residue is obtained. The cis- and trans-isomers are separated by preparative chromatography on silica gel plates (10% ethyl acetate in ether) and the bands are detected by spraying with water. The trans-isomer of formula III* ae occurs as a more polar spot compared to the cis-isomer. 60 mg of product is isolated.

Mass spectrum (m/e) 408 (M ⁺ )

323 (M-85)

306 (M-102).

NMR (CDCl ₃ , 300 MHz) 6 4.36 (broad singlet, 1H)

4.59 (m, 1H)

5.19 (d, t, J = 2.5 Hz, 1H).

The invention is further illustrated in the following examples, which, however, do not limit it in any way:

Example 1

6(R)~[2-(8'(S)-2,2-dimethylpropanoyloxy-2'(S)-6'(R)-dimethyl-1',2',6',7',8',8'a(R)-hexahydronaphthyl-1'(S))ethyl]-4(R)-hydroxy-»3,4,5,6-tetrahydro-2H-pyran-2-oa

Step A: Preparation of 6(R)-[2-(8'(S)hydroxy-2'(S)—6'(R)-dimethyl-1',2',6',7',8',8'a(R)-hexahydronaphthyl-1'(S))ethyl]-4(R)-(dimethyl-tert-butylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one ^V a

A mixture of alcohol of formula IV* (18.3 g, 57.1 mmol), 21.5 g (142.8 mmol) tert-butyldimethylchlorosilane and 19.4 g (265.6 mmol) imidazole in 200 ml of N,N-dimethylformamide was stirred for 18 hours at 20 °C under nitrogen. The reaction mixture was then diluted with 1500 ml of ether and washed successively with water, 2% aqueous hydrochloric acid, water and saturated sodium bicarbonate. The ethereal solution was dried over magnesium sulfate, filtered and concentrated to a volume of 1 liter. The volume was reduced to 600 ml by distillation from a steam bath by adding 600 ml of hexane. The product crystallized at room temperature and after isolation and air drying, 13.7 g of a white, viscous solid was obtained. The mother liquors were concentrated to 250 ml and a second crop of crystalline product was isolated after standing the solution overnight at 0 °C. The combined yields were 17.13 g (69.56%) of the title compound as a white, viscous solid, mp 142-144 °C. NMR (CDCl3) δ 0.10 (s, 6, (CH3) _2Si ), 0.90 (s, 9, (CH3CSi)

1.19 (d, 3, <J ³ 7 Hz, CH-^), 2.58 (d, 2, J = 4 Hz, pyran protons), 4.3 (m, 2, pyran, and naphthalene CgH), 4.70 (m, 1, pyran CgH), 5.57 (m, 1, naphthalene C^H), 5.58 (dd, 1, J = 6.10 Hz, naphthalene C^H), 6.03 (d, 1, J = 10 Hz, naphthalene C^H).

Analysis for ^C25H42 ° ^4Si: calculated: C69.08K>, H9.74%, found: C69.4656, H9.83% ^.

Step B: Preparation of 6(R)-[2-(8'(S)-2,2”-dimethylpropanoyloxy-2'(S),6'(R)-dimethyl-1',2*,6', 7 *,8 *,8*a(R)-hexahydronaphthyl-1*(S))ethyl]-4 (R)-(dimethyl-tert.butylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one, VI&

A solution of 6.0 g (13.8 mmol) of the alcohol of formula from step A and 200 mg of 4-dimethylaminopyridine in 50 ml of pyridine was cooled to 0°C under nitrogen. 6.8 ml (6.65 g, 55.2 mmol) of pivaloyl chloride was added to this stirred solution over 15 minutes. The reaction mixture was stirred for one hour at 0°C and then for 4 days at 20°C. The reaction mixture was diluted with 750 ml of ether and washed with 2% hydrochloric acid until the washing solution was acidic, followed by washing with saturated sodium bicarbonate. After drying over magnesium sulfate, the solution was filtered and evaporated to give 7.81 g of the title compound as a pale orange oil.

NMR (CDCl1) 6 0.09 (s, 6 (CH^Si), 0.88 (s, 9, (CH ₃ ) ₃ CSi), 1.28 (s, 9, (CH-j^CCC^-),

2.57 (d, 2, J = 4 Hz, pyran C ₃ protons), 4.32 (m, 1, pyran C^H), 4.63 (m, 1, pyran CgH), 5.34 (m, 1, naphthalene ΟθΗ), 5.54 (m, 1, naphthalene C^H), 5.78 (dd, 1, J =

6.10 Hz, naphthalene C ₃ H), 6.03 (d, 1, J = 10 Hz, naphthalene C 3 H).

Using the procedure described in Example 1, Step B, but replacing the pivaloyl chloride used therein with an equimolar amount of the acid chloride of structure R-COCl described in Table II, the esters of formula VI* described in Table II are prepared.

Table II

R - C - O

CH,

MNR (CDCl ₃ .8)

7.10 (t, 2, J = 8 Hz, p-FPh-) 8.03 (dd, 2, J = 5.8 Hz, p-FPh)

_2.02 (s, 3, _CH3CO2- )

1.19 (d, J = 7 Hz, e-CH ₃ ester), 1.21 (d, J = 7 Hz, ^a -CH ₃ ester) total 3H

Ιό (CH ₃ ) ₂ CHCH2C0 ₂ (CH ₃ ) ₂ CHCO ₂ CHýCHjPjCC^tj3_co ₂ 0.83 (a, 6, J = 6 Hz, (CH ₃ ) ₂ CH-)

1.13 (d, 6, J => 6 Hz (CH ₃ ) ₂ CH) 0.95 (t, 3, J = 7 Hz, CH ₃ -(CH ₂ ) ₃ ·

1.00-2.08 (m, 15, adamantyl)

0^H3(^θΗ2)6002^C6^H11^WHAT2 0¾ = CH-CO2

CP ₃ (CH2) ₂ C0 ₂ 4-ClC ₆ H ₄ CO ₂ 2,4-F ₂ ^c 6 ^H 3 ^C ° ₂ CP ₃

Ch/h-C^COjj.

CH ch ₃

CHj

CH,

A>°2ch ₃ (ch ₂ ) ₈ co ₂ “CC

_HCH3

Step C: Preparation* of 6(R)-[2-(8'(S)-2,2-dimethylpropanoyloxy-2'(S),6'(R)-dimethyl-1',2',',8',8 *a(R)-hexahydronaphthyl-1'(S) )-ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyren-2-one,

To a solution of 10.0 g (31.7 mmol) of Bu^N+F ^- . 3 HgO and 2.4 ml (2.5 g, 42.3 mmol) of acetic acid in 50 ml of tetrahydrofuran was added 7.81 g (13.8 mmol) of the allyl ether of formula VI _from step B in 50 ml of tetrahydrofuran. This mixture was stirred for 18 hours under nitrogen at 20 °C. The reaction mixture was diluted with 700 ml of ether and washed successively with 2% aqueous hydrochloric acid, water and saturated sodium bicarbonate solution. The organic saturated solution was dried (MgSO^) and filtered. Evaporation of the solvent gave 6.45 g of an off-white solid. This material was crystallized from 100 ml of butyl chloride and the isolated crystals were stirred for 4 hours at 35 °C/1.3 Pa. Yield 4.0 g (72%) of the title compound as off-white needles: mp 167.5-170.5 °C, MIR (CDCl-j) δ 0.88 (d, 3, J - 7 Hz, CHy, 1.08 (d, 3, J = 7 Hz, CH ₃ ), 1.19 (a, 9, (CH ₃ ) ₃ C), 2.67 (d, 2, J * 4 Hz. pyranic C ₃ protons), 4.39 (m, 1, pyranic C^H),

4.65 (m, .1, pyranic C _g H), 5.36 (m, 1, naphthalene C ₀ H), 5.55 (m, 1, naphthalene C^H),

5.80 (dd, 1, J » 6 Hz, naphthalene C ₃ H), 6.04 (d, 1, J » 10 Hz, naphthalene C^H), high-pressure liquid chromatography (4.6 mm x 25 cm Partie11 10 PAC, 10% isopropyl alcohol/hexane, 4 ml/min) retention time 4.4 min.

Analysis for:

calculated: C 71.25%, H 8.97%, found: C 71.40%, H 8.93%·

Using the procedure of Example 1, Step C, but substituting the 2,2-dimethylpropanoyloxysilyl ether of the compound of formula VI& for an equivalent amount of the other esters of formula VI _& , described in Table II, the esters of formula I _& described in Table III are prepared.

Table III _ftC0 ₂ ~_ formula tt (°C)

^G 24 ^H 36°5

139 - 148 ch ₃

^G 26 ^T 31 ^MON 5

119.5 - 120.5 (CH ₃ ) ₂ CHCH ₂ CO ₂ (CH ₃ ) ₂ CHCO ₂ CH ₃ (CH ₂ ) ₃ CO ₂ CH ₃ CO ₂ CH ₃ (CH ₂ ) ₆ CO ₂ C ₆ H _n CO ₂ CH ₂ =CH-CO ₂ CP ₃ (CH ₂ ) ₂ C0 ₂ 4-ClC ₆ H ₄ CO ₂ 2,4-F ₂ C _ó H ₃ CO ₂ cp ₃

CH^H-CHgCOg ^C 24 ^H 36°5 ^C 23 ^K 34°5 ^C 24 ^H 36°5 ^C 21 ^H 30°5· ⁰ ' ^{1 C} 4 ^H 9 ^C 3O ^H 42°5- °' ^{05 G} 6 ^H 12

126 - 128

144 - 147

153 - 156

155 - 158 formula

tt (°C) rco ₂ CH,

CH r~ ch ₃ ch,

X/ ^C °2CH ₃ (CH ₂ ) ₈ CO ₂ CHfX ^{2_ 3} H CH ₃

Example 2 '6(R)-[2-(8'(S)-phenylacetoxy-2*(S), 6'(R)-dimethyl-1',2',6',7',8',8'a(R)-hexahydronaphthyl-1'(S)ethyl]-4-(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one

Step A: Preparation of 6(R)-[2-(8'(S)-phenylethoxy-2'(S)-6'(R)-dimethyl-1',2',6',7',8',8'a(R)-hexahydronaphthyl-1'(S))ethyl]-4(R)-dimethyl-tert-butylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one, VI _and

A solution of 434 mg (0.1 mmol) of the alcohol of formula V _and from Example 1, Step A, 204 mg (1.5 mmol) of phenylacetic acid and 309 mg (1.5 mmol) of N,N'-dicyclohexylcarbodiimide in 10 ml of dichloromethane was treated with 22 mg (0.15 mmol) of 4-pyrrolidinopyridine and the reaction mixture was stirred at 20°C under nitrogen. After 3 days, the solvent was evaporated in vacuo and the residue was suspended in 25 ml of ether and filtered. Evaporation of the filtrate gave a viscous oil which was chromatographed on a 3 x 15 cm column of silica gel (230-400 mesh). Elution (under atmospheric pressure) with ether/hexane (1:1 v/v) afforded 460 mg (83%) of the title compound as a viscous oil. NMR (COCl2) δ 0.10 (s, 6, (CH2IgSi), 0.90 (s, 9, ( _CH3 ) _3CSi ), 3.58 ( _s , 2, PhCH2-), 5.34 (m, 1, naphthalene CgH), 7.30 (s, 5, Ph).

Using the procedure of Example 2, Step A, but replacing the phenylacetic acid used with an equimolar amount of an organic acid of formula RCOOH described in Table IV, the esters of formula VI _and described in Table IV are obtained.

I a b u 1 k a IV

NMR (CDCl ₃ , S) [>-co ₂ 0.78-1.02 (m, 4, cyclopropane)

NMR (CDCl-p S ) ^3

CH,CH-<

CI^CH-CHgC^- 1.04 (a, 3, J = 7 Hz, ch ₃ chcf. 1.88 (e, 3, CH ₃ C=C) Γ 2.17 (a, 3, j = 2 Hz, CH ₃ C=C) ch ₃ 5.68 (Broad, β, 1, C=CH-) ch ₂ 1.80 (s, 3, CH ₃ C=C) Jk/CO ₂ - 4.86, , 4.92 (s, 2, 0^=0 CH ₃ CH ₃ (CH ₂ ) co ₂ - 0.87 (m, 3» CH ₃ (CH ₂ ) ₈ CO ₂ ~)

1.25 (a, 14, CH ₃ (CH ₂ 5 ₇ CH2CO ₂ -S

C0 ₅ -

(CH^gCHCHgCOg(CH ₃ ) ₂ CHCO ₂ CH ₃ (CH 2 ) ₃ C0 ₂ -

2337’β

II

R - C - O

NMR (CPC1 ₃ , 6 )

C-COj— —c-co ₂ CH ₃ (CH ₂ ) ₆ CO ₂ c ₆ h,,co ₂ CHjXJH-COg ^CF 3 ^(CH 2 )2 ^C0 24-cic ₆ h ₄ co ₂ 2,4-F ₂ ^c 6 ^h 3C° ₂ - .

Step 3: Preparation of 6(R)-[2-(8*(S)-phenylacetoxy-2'(S),6*(R)-rdimethyl-1 ',2',6',7',8*,8'a(R)-hexahydronaphthyl-1'(S))ethyl]-4(R)-hydroxy-3, 4,5,6-tetrahydro-2H-pyran-2-one, I _and

Using the procedure described in Example 1, Step C, replacing the propanoyloxy compound with an equimolar amount of the phenylacetoxy compound from Example 2, Step A, affords the title compound, mp 109-112°C.

Using the other esters of formula VI _and described in Example 2, step A (Table IV) and following the procedure of Example 2, step 3, ee prepares the esters of formula I _& described in Table V.

Table V

RCO, · formula. m.p. (°C)

J^co ₂ - ” ⁶ -” ⁹ j ^F 3

CHjCHCHgCOg ^C 24 ^K 33 ^F 3°5

110 - 113

2337.8

HCO~ formula

(m.p. <°C)

CH ^C 24 ^H 34°5

113 - 118

CH,

CH

CH,

X—

CojHo ,0 _c

34 5

116 - 119

CH ₃ (CH ₂ ) ₈ C0 ₂ °29 ^H 46°5 (wax)

^C 24 ^H 36°5

126 - 129 ch ₃ co ₂ en< γ Ό—

CH„ <CH ₃ ) ₂ CHCH ₂ CO ₂ » (CH ₃ ) ₂ CHCO ₂ CH ₃ (CH ₂ ) ₃ CO ₂ —— CO2—

-COoV-c-co ₂ 233718

BCOg formula tt (°C) ~1 —c-co ₂ CH^CHglgCOgC ₆ H _n CO ₂ ch ₂ =ch-co ₂ CF ₃ (CH ₂ ) ₂ CO ₂ 4-C1C _ï H ₄ CO ₂ 2,4-K ₂ ^c 6 ^h 3 ^c ° ₂ Example3

6(R)-[2-(8'(S)-2-methylbutyryloxy-2*(S)-6'(R)-dimethyl-1*,2*,6',7*,8*,8'a(R)-hexahydronaphthyl-1'(S)ethyl]-4(R)-hydroxy-3>4,5,6-tetrahydro-2H-pyran-2-one

Step A: Preparation of 6(R)-[2-(8'(S)-2-ethyl-2-methylbutyryloxy-2*(S)-6'(R)-dimethyl-1',2',6*,7',8',8'a(R)-hexahydronaphthyl-1'(S))ethyl]-4(R)-(dimethyl-tert.butyleyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one, VI*

3.0 g of 2-ethyl-2-methylbutyryl chloride (20 mmol) was added to a magnetically stirred solution of 2.17 g (5 mmol) of the alcohol of formula V* and 74 mg of 4-pyrrolidinopyridine in 20 ml of pyridine. This reaction mixture was stirred for 9 hours at 100 °C under nitrogen. The reaction mixture was diluted with 500 ml of ether, washed with 1 N hydrochloric acid until the washings were acidic and then with brine (3x50 ml). After drying over magnesium sulfate, the solution was filtered and evaporated to give 4.2 g of a brown oil. This oil was chromatographed on a 6 x .5 cm silica gel column (230 to 400 mesh). Elution (under air pressure) with ether/hexane (1:1, v/v) afforded 2.6 g (95%) of the title compound as a white oil.

NMR (CDC1 ₃ ) δ 0.08 (a, 6, (CH ₃ ) ₂ Si), 0.9 (a, 9, (CH^CSi), 2.57 (d, 2, J » 4 Hz, pyran C ₃ protons), 4>30 (m, 1, pyran C^H), 4.63 (m, 1, pyran CgH), §.42 (m, 1, naphthalene CgH), 5.53 (m, 1, naphthalene C^H), 5.78 (dd, k, J = 6 Hz, naphthalene C ₃ H), 6.03 (d, 1, J 10 Hz, naphthalene C^H).

Using the procedure described in Example 3, Step A, but substituting an equimolar amount of the acid chloride of formula RCOC1 described in Table VI for 2-ethyl-2-methyl-butyryl chloride, the esters of formula VI* described in Table VI are obtained.

Table VI

R-CO

co ₂ NMR (CPC1 ₃ , δ )

0.87 (m, 9, CHjCHgCH^CI^CHpgCCOg)

3

O

II

R-CO_NMR (CflCl ₃ , )

c-co ₂ —c-co ₂ 0.78 (t, 9, J = 7 Hz, (CH ₃ CH ₂ ) ₃ CCO ₂ ) 1.48 (q, 6, J = 7 Hz, (ΟΗ^Η^ΟΟΟ^

1.28 (β, 6, (CH ₃ ) ₂ CCO ₂ )

2.20 (β, 3, _CH3 -C= _CH2 )

3.86 Cm, 2, CHg = C)

1.12 (s, 6, ( _CH3 ) _{2CO2 )}

0.83 (t, 3, (CH2CH3CCO3)

Step B: Preparation of 6(R)-[2-(8'(S)-2-ethyl-2-methylbutyryloxy-2 '(S)-6'(R)-dimethyl-1 ', , 6',7 ^# ,8 *,8*a(R)-hexahydronaphthyl-1 *(S))ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one

Using the procedure described in Example 1, Step C, or Example 2, Step B, but using the silyl ether of the compound from Example 3, Step A, as the starting material, the title compound is prepared, mp 111-113 °C θή26^40°5^’

Similarly, esters of structure I* described in Table VII are prepared using the other esters of formula VI* described in Table VI as starting materials.

Table VII

RCOg ^- formula tt (°C)

3-00,=^co ₂ >—C—COj— —fA' ^C 28 ^H 44°5 ^C 27 ^H 42°5 ^C 26 ^H 38°5 ^c 25 ^H 38°5

83

129 - 132

- 78

135 - 138

Using the procedures of Example 1, Step A and the following Example 1, Steps B and C or Examples 2 or 3, Steps A and B and replacing the diol of Formula IV* in Example 1, Step A, with the corresponding diols of Formula IV _be or *, the silyl ethers of Formulas V * and new esters of Formula I are formed in sequence in accordance with Scheme A, where H - CO in the 8'-alkamoyl group is:

CH ₃ CO ₂ 4-ClC ₆ H ₄ C0 ₂ 2,4-F ₂ ^c ďH ₃ CO ₂ -

(CH ₃ ) ₂ CHCú ₂ CH.j(CH ₂ ) ₃ CO ₂ $Lco ₂ CH ₃ (CH ₂ )gCO ₂ °6 ^H 11 ^C0 2ch ₂ =ch-co ₂ CF ₃ (CH ₂ ) ₂ CO ₂ -

C-COjI ^3 —-co ₂ CH ₃ (CH ₂ ) ₈ CO ₂ CH ₃ CH-CH ₂ CO ₂ -

CHj co ₂ 'ch ₃

Example 4

Preparation of 6(B)-{2-[8(S)-(2-ethyl-2-methylbutyryloxy)-2'(S) ,6'(S)-<Jitnet,hyl-1',2',3',4*,4'a (S) ,5*,6*,7*,8',8*a(S)-decahydronaphthyl-1*(S)-J ethyl}-4(H)-hydroxy-3,4,5, 6-tetrahydro-2H-pyran-2-one, I _# itupen A: Preparation of o(R)-[2-(8 ^/ (S)-hydroxy-2*(S) ,6'(S)-dimethyl-1',2',34',4*a(S),5',6',8',8'a(S)-decahydronaphthyl-1 *(S))ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one,

A solution of 2.0 g (6.2 mmol) of the alcohol of formula IV _in 100 ml of ethyl acetate was hydrogenated in the presence of platinum dioxide (1 g) at 0.3 MPa until two molar equivalents of hydrogen were consumed. The catalyst was then filtered off and the filtrate was evaporated to dryness to give a white solid (1.9 g) which was chromatographed on a 6 x 20 cm column of silica gel (230 to 400 mesh). Elution (under air pressure) with a mixture of acetone and methylene chloride (3:7, v/v) gave 1.0 g (50%) of the title compound as a colourless solid.

An analytical sample was prepared by crystallizing a portion of the material from chloroform to give a white, cottony solid, mp 166-168 °C.

, <

Step B: Preparation of 6(R)-[2-(8'(S)-hydroxy-2'(S),6'(S)-dimethyl-1 ^2^3^4^4^(8), 5',6', η',8',8'a(S)-decahydronaphthyl-1 '(S)-ethyl]-4(R)-(dimethyl-tert.butylsilyloxy)^3,4,5,6•tetrahydro-2H-pyran-2-one, V _#

A solution of the alcohol of formula IV _e (1.0 g, 3.1 mmol), imidazole (1.05 g, 15.4 mmol) and tert. butyldimethylchlorosilane (1.16 g, 7.7 mmol) in 20 ml of N,N-dimethylformamide was stirred for 18 hours under nitrogen at 20 °C. The reaction solution was diluted with 200 ml of ether and washed successively with water, 2% aqueous hydrochloric acid and sodium chloride solution. The ethereal solution was dried over magnesium sulfate and evaporated to give a white solid (1.8 g), which was chromatographed on a 6 x 20 cm column of silica gel (230 to 400 mesh). Elution under air pressure with acetone:methylene chloride (1:19, v/v) gave 1.0 g (74%) of the title compound as a white solid, mp 136-138°C.

Step C: Preparation of 6(R)-(2 [e'(S)-(2-ethyl-2-methylbutyryloxy)-2'(S),6'(S)-dimethyl-1', ',3 ',4',4'e(S), 5',6',7 ',8',8'a(S)-decahydronaphthyl-1 '(S)-ethyl}-4(R)-dimethyl-tert.butylsil· yl-oxy)-3,4,5,6-tetrahydro-2H-pyren-2-one, VI _e

Substituting an equimolar amount of the alcohol of formula V _# for the alcohol of formula V* in Step A, Example 3 and following the procedure for Step A, gave the corresponding amount of the title compound of formula VI _# as a yellow oil. NMR (CDCl^) 0.08 (s, 6, _CH3 ) _2Si ), 0.90 (s, 9, (CH^jyJSi), 1.13 (s, 6, (CH^COg), 2.63 (m, 2, pyran _C3 proton), 4.33 (m, 1, pyran C^H), 4.60 (m, 1, pyran CgH), 5.23 (m, 1, naphthalene ΟθH).

Step D: Preparation of 6(R)-{2-[8'(S)-(2”-ethyl-2-methylbutyryloxy)-2'(S), 6'(S)-dimethyl-1',2'',4',4'a(S), 5',6',7»,8',8'a(S)-decahydronaphthyl-1'(S)]ethyl}-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, Ιθ

Substituting an equimolar amount of the silyl ether of formula VI _e from Example 4, Step C with the silyl ether from Step C, Example 1, following the procedure of Step C of Example 1, afforded the corresponding amount of the title compound as a solid.

An analytical sample was prepared by recrystallization of the material from hexane to give white needles, mp 146-147 °C.

Example 5

5(R)-{2-[8'(S)-(2-ethyl-2-methylbutyryloxy)-2'(S),6'(R)-dimethyl-1',2',3',4',6*,7',8'a(S)-octahydronaphthyl-1'(S)] ethylJ-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, 1θ

Step A: Preparation of 6(R)-[2-(8'(S)-hydroxy-2'(S),6'(R)-dimethyl-1',2',3',4',6',7',8'a(S),-octahydronaphthyl-1'(S)]ethyl-4(R)-hydroxy-3,4,5 _l 6-tetrahydro-2H-pyran-2-one, IV.

Using the procedure described for the preparation of starting material of formula IV* hydrolyzed

MK-803 by heating with aqueous LiOH.HgO for 56 hours, but replacing MK-803 with an equimolar amount of compound of formula _IIIb gives the title compound of formula IV^ in comparable yield, mp 136-139 °C.

By proceeding as in Example 4, Steps B, C and D, but substituting the compound of formula IV* used in Step B for an equimolar amount of the compound of formula _IVb from Step A of this Example, comparable yields as in Example 4 are obtained of the following compounds.

Step B: (R)- 2-(8'(S)-hydroxy-2'(S),6'(R)-dimethyl-1',2',3',4',6',1',8'a(S)-octahydronaphthyl-1'(S)-ethyl]-4(H)-(dimethyl^tert-butylsilyloxy)-3,4,5 ₎ 6-tetrahydro^áH-pyran-2-one, V _b , mp 140 to 142 °C

Step C: 6(R)-{2-[(8*(S)-(2-ethyl-2 ^M -methylbutyryloxy)-2'(S),6'(R)-dimethyl-1 *,2',3',4*, 6',7',8'a(S)-octahydronaphthyl-1'(S)]-ethyl}-4(8)-(dimethyl-tert.butylellyloxy)-3,4,5*6-tetrahydro-2H-pyran-2-one, VI^ _b j, where

Step D: 6(R)-{2-[8'(S)-(2-ethyl-2-methylbutyryloxy)-2'(S),6'(R)-dimethyl-1',2*,3*,4*,6',7',8*a(S)-octahydronaphthyl-1'(S)]-ethyl}-4(H)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, I _b , mp 129 to 131 °C, where

Example

Typical formulations for filling size 0 hard gelatin capsules contain 3.125 mg, 6.25 mg, 12.5 mg, 25 mg or 50 mg of one of the novel compounds of the invention such as the products of Example 3, Step B, Example 1, Step C, or Example 2, Step B and sufficient finely divided lactose in an amount to provide a capsule content of about 580 to 590 mg.

Claims (4)

SUBJECT V V R & L E Z U A process for the preparation of acyloxypolyhydronaphthyl derivatives of 2H-pyran-2-one of the general formula I wherein K is optionally branched C 1 -C 10 alkyl, except for 2- (S) -butyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkenyl 10 carbon atoms, C 1 -C 10 substituted alkyl of 1 to 10 carbon atoms, halophenyl, the symbols X, Ϊ and Z represent possible double bonds, and if these double bonds are present then they are either 3 in the combination of X and Z or X alone, Ϊ or Z and the corresponding dihydroxy acids of the formula II wherein R, X, Y and Z are as defined above or pharmaceutically acceptable salts of these acids, C 1 -C 4 alkyl esters or phenyldimethylamino- or acetylamino-substituted C 1 -C 4 alkyl esters characterized in that the compound of formula III wherein X, X and Z are as defined above, is heated with an alkali metal hydroxide in a protic form. a solvent, followed by acidification and lactonisation to give a compound of formula IV (IV), 233713 2b wherein X, Ϊ and Z are as defined above, which are reacted with tert-butyldimethylchlorosubstituted in an inert atmosphere at room temperature in the presence of an acid acceptor, to form the 4-tert-butyldimethylsilyl oxy compound acylated with a corresponding R- The slyl group is removed at room temperature in tetrahydrofuran in the presence of 3 equivalents of tetrabutylammonium fluoride and 4 equivalents of acetic acid per equivalent of the silyl compound, and optionally converted to the corresponding dihydroxy acids, salts or alkyl esters. 2. The process of claim 1, wherein the corresponding starting materials are those wherein R is a branched alkyl having from 3 to 10 carbon atoms, with the exception of 2- (S) -butyl and X, X and Z have the meaning given in point 1. ' 3. A process according to claim 1, wherein the corresponding starting compounds are reacted, wherein the aubatituent R-C = O is C = O or ^ _ _{c = 0} and X, Ϊ and Z are as defined in 1. 4. A process according to any one of claims 1 to 3, wherein the corresponding starting compounds are reacted, wherein none of X, X or Z represents a double bond and R is as defined in point 1.,