Processing of 2h-pyran-2 acyloxypolyhydronaphtylderivative

The invention relates to the group 6 (R) - [2- (8'-Aeylocy-2'-methyl-6'-methyl (or hydrogen) -polyhydronaphthyl-1 ') - ethyl] -4 (R) -hydroxy-3, 4,5,6-tetrahydro-2H-pyren-2-ones and the hydroxy acid forms of these pyranones and the 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 the compounds of formula I shown in Table I, wherein the dashed lines X, Y and Z represent possible double bonds, wherein the double bonds when present are either X and Z together or X, X or Z alone , R is a straight or branched alkyl of 1 to 10 carbon atoms (except for (S) -2-butyl), cycloalkyl and 3 to 10 carbon atoms, alkenyl of 2 to 10 carbon atoms, a CF 1 group substituted with 1 to 10 carbon atoms, halophenyl, and the 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'-dimethylpolyhydroaaphthyl-1') -ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro- 2H-pyran-2-ones as intermediates for the above described 8'-acyloxy compounds.

Certain mevalonic acid derivatives are known to inhibit cholesterol biosynthesis. See FM Singer et al., Proc. Soc. Exper. Biol. Med., 102, 370 (1959) and FH Hulcher, Arch. Biochem. Biophys., 146, 422 (1971). While the activity of these known compounds is not always sufficient, these compounds have practical applications.

U.S. Pat. Nos. 4,049,495, 4,137,322 and 3,983,140 disclose the preparation of fermentation products that are fully active in inhibiting cholesterol bioeynesis. The most active member of this group of natural substances now called Compactin (IIIa) has been mentioned by Brom et al. [J; Chem. Soc. Perkin I, 1165 (1976)] and this compound has the structure of a mevalolactone derivative,

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

Disclosed herein are dihydro MK-803 represented by Formula IIl_and in Table I, which has the same effect as. MK-803 isolated from the same fermentation as MK-803. In addition, dihydro- and tetrahydroderivatives of MK-803 structures III are known_b θ (Table I) prepared by catalytic hydrogenation of MK-803.

It has now been found that the N-methyl-butyryl group in the compound of formula III_and In hydrogenated derivatives of formula III_b__E and e can readily cleave to form Group 6 (R) - [2- (8-hydroxy-2,6-dimethylpolydyhronaphthyl) -1-ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H pyran-2-ones, which are such hypocholesteremic agents, and which are useful as intermediates for the preparation of novel esters which are even more effective in this use.

It has been found that the 8'-hydroxy compounds of structural formula IV can be acylated to give a new group of 8-acyloxyalealanines of formulas I and II of the definitions below. These novel compounds are inhibitors of cholesterol eynthesis in vivo.

The present invention provides a process for the preparation of the acyloxypolyhydronaphthyl derivatives of the 2H-pyran-2-one of formula I

<img file="CS233718B2_D0001.tif" />

wherein S is optionally branched alkyl of 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, CF 1 substituted alkyl of 1 to 10 carbon atoms , halophenyl, X, X, and Z are possible double bonds, and if present, they are either a combination of X and Z or X, X or Z alone and the corresponding dihydroxy cyanines of formula II

<img file="CS233718B2_D0002.tif" />

wherein R, X, X and Z are as defined above or pharmaceutically acceptable salts of these acids, alkyl esters and 1 to 4 carbon atoms of these acids, or phenyldimethylemino or acetylamino and substituted alkyl esters and 1 to 4 carbon atoms of these acids, carried out by: The compound of formula III is heated

<img file="CS233718B2_D0003.tif" />

wherein X, X * Z are as defined above, and an alkali metal hydroxide in a protic solvent, followed by acidification and lactonisation to give a compound of formula IV

<img file="CS233718B2_D0004.tif" />

wherein X, X and Z are as defined above, which are reacted with tert-butyldimethylchlorailane in an inert atmosphere at room temperature in the presence of an acid acceptor; 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 etereochemical relationships. The reference numbers of the various compounds, including the compounds of different series of polyhydronaphthyl structures, remain the same throughout the description and are used as such. Each of the esters of Formula I_and__Eof the present invention contains seven to eight chiral centers. The relative and absolute configuration of these asymmetric centers is shown in Table X. More specifically for the ester of formula X_and, Cahn, Xngold, Prelog absolute designation is 4 (R), 6 (R), 1 * (S), 2 * (S), 6 * (R), 8 * (S), and 8a '(R) fs .WITH. Cahn, C. Ingold, and V. Prelog, Angew. Chem. Int. Ed., 5, 385 (1966)].

<img file="CS233718B2_D0005.tif" />

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 thus belong to the same stereochemical series. The RS designation for each center need not be identical to the designation found for the ester of formula X_and having regard to the details of the sequence rule used to determine this label.

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

Table I,

<img file="CS233718B2_D0006.tif" />

Stereochemistry of hydronaphthyl series

Pří tomná

<td></td><td>double bond</td><td>Structure</td>

<td>and</td><td>X and Z</td><td>po * ** »** * ch₃AX /</td>

<td>b</td><td>X</td><td>CH3</td>

<td>C</td><td>Y</td><td>f ***** T *^Vol*^Ml ch / - ^</td>

<td>d</td><td>OF</td><td>CHj _with</td>

H none

<img file="CS233718B2_D0007.tif" />

The 8'-acyloxy compounds of the invention are useful as antlhypercholesterolemic agents useful in the treatment of atherosclerosis, hyperlipaemia and the like in humans. They can be administered orally or parenterally in the form of capsules, tablets, injectable preparations, and the like. The doses may vary and depend on the age, severity of the disease, body weight and other conditions of the patient, but the daily dose for an adult is in the range of 2 to 2000 mg (preferably 10 to 100 mg) in three to four divided doses. If desired, higher doses may also be administered.

The compounds of the invention may also be used as antifungal agents. For example, they can be used to control the growth of Fenicillium sp., Aspergillus nger, Cladosporium sp., Cochliobolus miyabeanus and Helminthosporlum cynodnotis. For such use, it is mixed with a suitable formulation agent such as dusts, emulsifying agents or solvents (for example aqueous ethanol) and sprayed or sprayed on the plants to be protected.

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

Scheme A

III —iv - * ae ae ch₃ch₃

<img file="CS233718B2_D0008.tif" />

<img file="CS233718B2_D0009.tif" />

ae ae.

ae

VI ©

II

AND

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

Reaction - 1)

Lithium hydroxide, heating, acidification and lactonisation.

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 under an inert atmosphere.

4) Reaction with RCOCH and β, Κ'-dicyclohexylkerbodiimide and 4-pyrrolidinopyridine in dichloromethane, preferably under an inert atmosphere.

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

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

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

D | b | β

The preparation of the novel alcohols according to the invention is carried out by heating the esters of the formula HI_and__Ewith 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 higher temperatures of 120 to 180 ° C for a period of 8 to 24 hours .

The pyranone ring is easy to open, but the removal of the underside acyl group is not easy. Heating must be carried out for a long time and / or pressure must be applied. It is also preferred to use an inert atmosphere. It is quite unexpected that a molecule with so many sensitive functional centers can withstand the conditions necessary to remove the highly hindered cr-methylbutyryleater. It is quite 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 relactonized 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 resulting water.

The alcohols that form part of the present invention include the structures of formulas IV._Eas well as trihydroxy acids formed by the opening of lactone rings.

Alternative synthetic route to compounds of formulas IV_Bc * includes the steps of hydrolyzing compounds of Formulas 1X1 * to IV * as described above and following hydrogenation of a compound of Formula XV * from the conditions previously described for the preparation of compounds of Formula III_{b 0} *, to form compounds of formulas IV_b, IV * or IV *, depending on the reaction conditions.

Preparation of Compounds of Formulas IV * _ *

Starting materials, 8o-hydroxy compounds of formulas IV_and__E described by Willard are prepared from the 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 an extended period. The pyran ring is easy to open, but removing the side group is not easy. Heating must be carried out for an extended period of time and / or pressure applied. The use of an inert atmosphere is also suitable.

2337,8

In the case of compounds of the formulas III_and__E The saponification of the 8'-esters is easier to carry out and within about 20 hours the saponification is complete.

The 8'-hydroxy products are isolated by acidification and extraction with organic solvents to give compounds in the form of a hydroxy acid 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 resulting water.

In the form of lectone, these alcohols are compounds of formula IV_and__E listed in Table I and, are prepared according to the following preparations:

Preparation 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 of O97 *, 8 mmol) of LiOH. The HgO in 600 ml of water was stirred and heated to boiling under nitrogen atmosphere for 56 hours. The reaction mixture is cooled to 0 ° C and treated with 20 ml of concentrated hydrochloric acid with stirring. 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 200 ml 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 is redissolved in 200 ml of toluene and heated to boiling for two hours with continuous separation to allow re-rectonization. Evaporation of toluene and trituration of the residue in hexane afforded 5.15 g (81%) of the title compound of formula IV., (R '= CH3) as a white solid which does not require further purification.

An analytical sample is prepared by recrystallization of a portion of this material from butyl chloride to give drus tt 128-131 ° C, HwLR (CDCl 3) δ 0.87 (d, 3, J = 7 Hz, CH 2), 1.16 (d, 3,

J = 7 Hz, 2.64 (m, 2, pyran C 1 H 5), 4.27 (brm, 1, naphthalene C 8 H), 4.37 (m, 1, pyran C 1 H 5), 4, 71 (m, 1, pyran C 1 H), 5.56 (m, 1, naphthalene C 1 H), 5.79 (dd, 1, J = 6.10 Hz, naphthalene, C 1 ')₃H), 6.03 (d, J, 10 Hz, naphthalene C)₄H). IR (CHCl3) 3400 (OH), 1725 (.dbd.O), 1240, 1120, 1080 cm @ -1.

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-1,2', 6 ', 7', 8 ', 8 * and (R) -Hexahydronaphthyl-1 '(S) -ethyl] -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, IV_and

Suspension 188 mg (0.463 mmol) MK-803 (III_and(5) in 5 ml (5 mmol) of aqueous 1 N lithium hydroxide solution are 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 washed with 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, and relactonization was performed. Evaporation of toluene gave the title compound.

In the novel process of the invention, the 4-hydroxyl group of the pyranone ring, the alcohols of formula IV_and__E it first protects the tert-butyldimethylsilyl group by reaction with tert-butyldimethylchlorosilane under an inert atmosphere at room temperature in the presence of acid acceptors such as imidazole to give protected alcohols of formula V_and__EThe 8-hydroxyl on the polyhydronaphthyl ring is then acylated in one of two ways. The first involves reaction with an acid chloride of the desired acyl group in pyridine in the presence of 4-dimethylaminopyridine as a catalyst. The second involves reacting 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 procedure provides protected esters of formula^VIand__E·

Removal of the silyl protecting group from the 4-hydroxyl pyranone ring and then carried out using three equivalents of tetrabutylammonium fluoride and four equivalents of acetic acid per equivalent of esters of formula VI_and__# to give the desired compounds of formula I_and__EThe ratio of reagents 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 formulas I 'are:

“•“ β

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

2) C 3 -C 10 cycloalkyl;

3) alkenyl of 2 to 10 carbon atoms,

4) CF 1 substituted alkyl and 1 to 10 carbon atoms,

5) hylogenphenyl wherein the halogen atom is a chlorine, fluorine, bromine or iodine atom.

Preferred R substituents are:

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

Compounds of formula I_and__E may be hydrolyzed with bases such as NaOH to form salts such as sodium salt of compounds of formula H_and__EBy using bases with other pharmaceutically acceptable cations, salts of these cations are obtained. By careful acidification of the salts, the hydroxy acids of the formula ΙΙ are obtained_#__βwhich are converted at acidic pH to the compounds of formula I_and__EReaction of compounds of formula I_and__E with acidic or basic catalysts with methanol, ethanol, propanol or butanol or with phenyl, dimethylamino-, or acetylaminoalkanols, and e to obtain the corresponding esters of the 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 amine-derived salts such as ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, Ν, Ν'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine, piperazine and tria- ) aminomethane.

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

Preparation of Compounds of Formulas III_and *

A. Fermentation

<td>Test tube of lyophilized culture MF-4845 in a 250 ml Erlenmeyer flask (seed flask)</td><td>aseptically opens containing about 10</td><td>and the contents are suspended in ml of the medium following</td>

<td>Medium:</td><td></td><td></td>

<td>corn extracts</td><td>5 g</td><td></td>

<td>tomato paste</td><td>40 g</td><td></td>

<td>oatmeal</td><td>10 g</td><td></td>

<td>glucose</td><td>10 g</td><td></td>

<td>trace element solution</td><td>10 g</td><td></td>

<td>Distilled water</td><td>1000 ml</td><td></td>

<td>pH 6.8 adjusted with HaOH</td><td></td><td></td>

<td>Trace element solution</td><td></td><td></td>

<td>FeSO₄.7 H₂0</td><td>1000 mg</td><td></td>

<td>MnSO4.4H₂0</td><td>1000 mg</td><td></td>

<td>CuC1₂.2 H₂0</td><td>25 mg</td><td></td>

<td>CaCl₂.2 H₂0</td><td>100 mg</td><td></td>

<td>^h3bo₃</td><td>56 mg</td><td></td>

<td>(ΝΗ₄)₆Μο_γ0₂₄.4 H₂0</td><td>19 mg</td><td></td>

<td>ZnS0₄.7 HgO</td><td>200 mg</td><td></td>

<td>distilled water deionized</td><td>1000 ml</td><td></td>

<td colspan="2">The inoculated flask was incubated for 24 hours at 28 ° C on a rotary flask</td><td>shaker with 220 turns</td>

per minute (5.4 cm shift). A 2 liter septum-free Erlenmeyer flask containing 500 ml of medium is inoculated with 10 ml of fermentation medium and grown to seed. Shake flasks at 28 ° C for 24 hours.

910 liters stainless steel fermentation tank filled with 485 liters of cerelose containing medium peptoned 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 was adjusted to 7.0. The medium is aged for 15 minutes at 121 ° C. Add one liter of the above prepared second stage and mix and incubate&gt; 2 hours at 85 rpm and then 84 hours at 28 ° C and 130 rpm, at an air flow rate of 0.14 m 2 / 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 were combined, acidified with stirring to pH 4.1 by carefully adding 800 mL of concentrated hydrochloric acid, and extracted by adding 341 liters of ethyl acetate and mixing and stirring for an additional two hours.

About 11.3 kg of silica filter aid is then added and the total suapenae is pumped through a 61 cm filter press. An additional 341 liters of ethyl acetate was used to wash the compressed cake and its extraction was performed four times by pumping in reverse directions. Then, all of the wash solvent is removed from the cake and combined with the first filtrate. The biphasic filtrate was allowed to settle and the aqueous phase was 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

Ethyl acetate extracts from additional ci. 1340 liters of fermentation medium are added to the extract prepared above and the volume is reduced to about 136 liters by vacuum distillation. 227 liters of toluene are added and the batch is concentrated to 145 liters under vacuum. This step is repeated and then sufficient fresh toluene is added to obtain a volume of 341 liters. Without vacuum, the mixture was then heated to reflux for two hours while maintaining the temperature 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. Sillkagel chromatography

The extract obtained above was freed of other solvents by addition of 9.1 liters of methylene chloride and concentration 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 sillcagel and applied to the top of a 30.5 x 127 cm column packed with silica gel in the same mixture solvents.

Elution was performed with ethyl acetate-methylene chloride (40:60 v / v) at a rate of 800 mL / min. A front of 45 liters is collected and then a fraction of 18 liters is collected.

Fractions 6 to 10 inclusive were concentrated in vacuo and the oily residue was dissolved in hot ethyl acetate, treated with charcoal, filtered hot and cooled. Crystals of the compound of formula ΙΙΙ_# The mother liquors are concentrated to an oil which is rechromatographed. Pure compound of formula III_and mp 170-171 ° C.

4. Rechromatography on sillkagel

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

5. The reverse phase chromatography (ml) from fraction 22 of the above chromatography is concentrated to an oil of 500 mg with oil and redissolved in 5 ml of acetonitrile. The acetonitrile solution is applied to a 1.5 x 180 cm stainless steel column packed with preparative reverse 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 the refractive index detection. The organic solvent was removed in vacuo and the remaining aqueous solution was extracted with ethyl acetate. Removal of the ethyl acetate in vacuo gave 120 mg of a compound which crystallized from a concentrated acetonitrile solution to give crystals of the compound of formula III_andmp, 29-31 ° C.

Preparation of compounds of formulas IIIa. .

u, c, e

Starting materials of formulas III, III₀^{and Se} P ^ IP^ravAlso according to the following scheme and the above-mentioned prepaative methods.

For the preparation of a compound of formula (θ), it is preferable to reduce the compound of formula (III) if the desired trans linkage of the perhydronaphthalene ring present in the starting materials is maintained in the final product. There is no need to separate iaomers.

<img file="CS233718B2_D0010.tif" />

(1)

<img file="CS233718B2_D0011.tif" />

ch₃

III,

III .o ch₃'

<img file="CS233718B2_D0012.tif" />

III c

2337,8

<img file="CS233718B2_D0013.tif" />

from U (i)

CH 3 -CH 3 -CH-C 1

*

<img file="CS233718B2_D0014.tif" />

H

III

<img file="CS233718B2_D0015.tif" />

^IIJd

Reactions and reagents

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

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

3. Hydrogenation at 20-25 ° C and atmospheric pressure is carried out on platinum oxide in ethyl acetate.

4. Hydrogenation at 2b to 25 ° C and atmospheric pressure was carried out on 10% palladium on carbon in ethyl acetate.

Preparation 6a [2- (8'P-2- (S) -ethylbutyryloxy-2'β, 6a. Dimethyl-1 ', 2', 3 ', 4', 6 ', 8', 8'a-octahydronaphthyl -1) ethyl] -4β-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one III &amp; amp;

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) chloro-rhodium 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. Yield of the compound of formula III_b is 22.3 mg.

Mass spectrum (m / e) 406 (M &amp; lt; + &amp; gt;)⁺)

304 (M-, 02)

286 (m-102-18)

MMR (CDCl3 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-diaethyl-1 ', 23 *, 5', 6 ', 7', 8 *, 8'a-octahydronaphthyl- 1) ethyl] -4β-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, III_C

A solution of 80.91 mg (0.2 mmol) of the compound of formula (IIj) in 10 ml of absolute ethanol was hydrogenated in the presence of the same weight of 5% Pd to CaCO 3 at 1 atm until 1 molar equivalent of hydrogen was consumed. The catalyst was then filtered off and the filtrate was evaporated to dryness (81 mg). After purification by preparative thin layer chromatography, a small amount of the by-product, the tetrahydrofuran compound, was removed to give 72 mg of the product of formula ΙΙΙθ, which was formed by 1,4-reduction.

Mass Spectrum (m / e)

NMR (CH 2 Cl 2)₃, 300 MHz) 8

<td> 406</td><td>(M⁺)</td><td></td>

<td> 304</td><td colspan="2">M-102</td>

<td> 286</td><td colspan="2">304-H₂O).</td>

<td> 4,38</td><td>(m,</td><td>1H)</td>

<td> 4,64</td><td>(m,</td><td>1H)</td>

<td> 5,28</td><td>(d,</td><td>t_Ř J</td>

<td> 5,48</td><td>(m,</td><td>1H).</td>

Preparation of 6α- [2- (8'β-2- (S) -methylbutyryloxy-2 *), ό'β-dimethyl-1 *, 2 ', 3', 4 ', 4' aa, 5 ', 6' '7',

8 ', 8'a-decahydro-naphthyl-1-) ethyl] -4β-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_and in 10 ml of ethyl acetate is hydrogenated in the presence of the same weight of platinum oxide under 1 bar. 2 molar equivalents of hydrogen are consumed in one hour. The catalyst was filtered off, the filtrate was concentrated to dryness to give an oily residue. The cis- and trans-isomers were separated by preparative chromatography on silica gel plates (10% ethyl acetate in ether and the bands were detected by spraying with water. The trans-isomer of formula III * ae appears as a more polar spot compared to the cis-isomer. Isolate 60 mg of product.

Mass spectrum (m / e) 408 (M &amp; lt; + &amp; gt;)⁺)

323 (M-85)

306 (M-102).

NMR (CDCl3)₃, 300 MHz) δ 4.36 (broad singlet, 1H)

4.59 (m, IH)

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

The invention is illustrated by the following non-limiting examples.

Example 1

6 (R) - [2- (8 '(S) -2,2-dimethyl-propanoyloxy-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) and (R) -hexahydronaphthyl-1 '(S) ethyl-4 (R) - (dimethyl-tert-butylsilyloxy) -3,4,5,6-tetrahydro-2H-pyran-2-one ^INand

A mixture of alcohol of formula IV * (18.3 g, 57.1 mmol), 21.5 g (142.8 mmol) of t-butyldimethylchlorosilane and 19.4 g (265.6 mmol) of imidazole in 200 ml of Ν, Ν-dimethylformamide The mixture was stirred for 18 hours at 20 ° C under a nitrogen atmosphere. 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 solution. The ether solution was dried over magnesium sulfate, filtered, and concentrated to a volume of 1 liter. After addition of 600 ml hexane, the volume is reduced to 600 ml by steam bath distillation. The product crystallized at room temperature and after isolation and air drying, 13.7 g of a white, pale-white solid was obtained. The mother liquors were concentrated to 250 ml and a second crop of crystalline product was isolated after standing overnight at 0 ° C. Combined yields 17.13 g (69.56) of the title compound as a white waxy solid mp 142-144 ° C. NMR (CDCl3) δ 0.10 (s, 6, (CH3))₂Si), 0.90 (s, 9, (CH 2 CS 1))

1.19 (d, 3, J) ³ 7 Hz, CH 2, 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 1 H), 5.58 (dd, 1, J = 6.10 Hz, naphthalene C 1 H), 6.03 (d, 1, J = 10 Hz, naphthalene (CH3).

Analysa pro ^C25^H42°4^Si: calculated: C 69.08 K, H 9.74%, found: C 69.46 56, H 9.83%.

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

A solution of 6.0 g (13.8 mmol) of the alcohol of Step A and 200 mg of 4-dimethylaminopyridine in 50 mL of pyridine was cooled to 0 DEG C. under nitrogen. To this stirred solution was added 6.8 mL (6 mL) over 15 minutes. (65 g, 55.2 mmol) of pivaloyl chloride. The reaction mixture was stirred at 0 ° C for one hour, then at 20 ° C for 4 days. The reaction mixture was diluted with ether (750 mL) and washed with 2% hydrochloric acid until the wash was acidic, followed by washing with saturated sodium bicarbonate solution. 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 (CDCl 3) δ 0.09 (s, 6 (CH 2 Si), 0.88 (s, 9, (CH₃)₃CSi), 1.28 (s, 9, (CH-1 - CCl 2 -),

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, 6H, 5.78 (dd, J, J =

6.10 Hz, naphthalene C₃H), 6.03 (d, 1, J = 10 Hz, naphthalene C 14 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 the structure R-COC1 described in Table II, ee prepared the esters of Formula VI * described in Table II.

Table II

R - C - O

<img file="CS233718B2_D0016.tif" />

CH,

MNR (CDCl 3₃,8)

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

2.02 (s, 3, CH₃WHAT₂-)

1.19 (d, J = 7Hz, e-CH)₃ ester), 1.21 (d, J = 7Hz, ^and-CH₃ ester) total 3H

(Ό (CH₃)₂CHCH2C0₂(CH₃)₂CHCO₂CH3CH3P3CO4, ie₂0.83 (a, 6, J = 6 Hz, (CH₃)₂CH-)

1.13 (d, 6, J = 6 Hz (CH₃)₂CH) 0.95 (t, 3, J = 7Hz, CH)₃- (CH₂)₃·

1.00-2.08 (m, 15, adamantyl)

0^Η3(^θΗ2)6002^C6^H11^WHAT20¾ = CH-CO2

CP₃(CH2)₂C0₂4-ClC₆H₄WHAT₂2,4-F₂^C6^H3^C°₂CP₃

Ch / hCl 2 CO 3.

CH ch₃

CHj

CH,

A&gt; ° 2ch₃(ch₂)₈what₂“CC

H CH₃

Step C: Preparation of * 6 (R) - [2- (8 '(S) -2,2-dimethylpropanoyloxy-2' (S), 6 '(R) -dimethyl-1', 2 ',', 8 ' 8 * and (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 2 N + F^-. HgO and 2.4 ml (2.5 g, 42.3 mmol) of acetic acid in 50 ml of tetrahydrofuran and add 7.81 g (13.8 mmol) of the allyl ether of formula VI_and from Step B in 50 mL of tetrahydrofuran. The mixture was stirred under nitrogen at 20 ° C for 18 hours. The reaction mixture was diluted with ether (700 mL) and washed successively with 2% aqueous hydrochloric acid, water, and saturated sodium bicarbonate solution. The organic saturated solution was filtered (MgSO 4) and filtered. Evaporation of the solvent gave ee 6.45 g of an off-white solid. This material was crystallized from 100 ml of butyl chloride and the isolated crystals were allowed to stand at 35 ° C / 1.3 Pa for 4 hours. Yield 4.0 g (72%) of the title compound as almost white needles: mp 167.5-170.5 ° C; CH 1, 1.08 (d, 3, J = 7 Hz, CH₃), 1.19 (a, 9, (CH₃)₃C, 2.67 (d, 2, J * 4 Hz. Pyran₃ protons), 4.39 (m, 1, pyran C 4 H),

4.65 (m, 1, pyran C)_GH), 5.36 (m, 1, naphthalene C)₀H), 5.55 (m, 1, naphthalene C 4 H),

5.80 (dd, 1, J 6 Hz, naphthalene C)₃H), 6.04 (d, 1, J 10 Hz, naphthalene C 4 H), high pressure liquid chromatography (4.6 mm x 25 cm lot 11 10 PAC, 10% isopropyl alcohol / he17 xane, 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 equivalent amounts of the other esters of Formula VI_andThe esters of formula I are prepared as described in Table II_and described in Table III.

Table III _ftCO₂~ _ formula tt (° C)

<img file="CS233718B2_D0017.tif" />

^G24^H36°5

139 - 148 ch₃

<img file="CS233718B2_D0018.tif" />

^G26^H31^AFTER5

119.5 - 120.5 (CH₃)₂CHCH₂WHAT₂(CH₃)₂CHCO₂CH₃(CH₂)₃WHAT₂CH₃WHAT₂CH₃(CH₂)₆WHAT₂C₆H_nWHAT₂CH₂= CH-CO₂CP₃(CH₂)₂C0₂4-ClC₆H₄WHAT₂2,4-F₂C_OH₃WHAT₂cp₃

CH 2 H-CH 2 CO 3^C24^H36°5 ^C23^TO34°5 ^C24^H36°5 ^C21^H30°5·⁰’^{1 C}4^H9 ^C3O^H42°5- °’^{05 / G}6^H12

126 - 128

144 - 147

153 - 156

155 - 158 formula

mp (° C) rco₂CH,

CH r ~ ch₃ ch,

X /^C° 2CH₃(CH₂)₈WHAT₂CHfX ^2_³ H CH₃

Example 2 '6 (R) - [2- (8' (S) -phenylacetoxy-2 * (S), 6 '(R) -dimethyl-1', 2 ', 6', 7 ', 8', 8 and (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) -phenylaethoxy-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-tetrehydro-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 Ν, Ν'-dicyclohexylcarbodiimide in 10 ml of dichloromethane were treated with 22 mg (0.15 mmol) of 4- pyrrolidinopyridine and the reaction mixture was stirred at 20 ° C under a nitrogen atmosphere. After 3 days the solvent was removed 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 silica gel column (230-400 mesh). Elution (under air pressure) with ether / hexane (1: 1 v / v) gave 460 mg (83%) of the title compound as a viscous oil. NMR (COCl 4) δ 0.10 (s, 6, (CH 2 Ig 2 Si), 0.90 (s, 9, (CH₃)₃CSi), 3.58 (s, 2, PhCH₂5.34 (m, 1, naphthalene C 8 H), 7.30 (s, 5, Ph).

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

I abu 1 ka IV

<img file="CS233718B2_D0019.tif" />

NMR (CDCl3)₃, S) [&gt; -co₂0.78-1.02 (m, 4, cyclopropane)

NMR (CDCl 3? S)?

CH, CH-

<td>Cl 2 CH-CH 2 Cl 2 -</td><td> 1,04</td><td>(α, 3, J = 7 Hz, ch₃chcf.</td>

<td></td><td> 1,88</td><td>(e, 3, CH₃C = C)</td>

<td>Γ</td><td> 2,17</td><td>(α, 3, j = 2 Hz, CH₃C = C)</td>

<td>ch₃</td><td> 5,68</td><td>(Wide, β, 1, C = CH-)</td>

<td>ch₂</td><td> 1,80</td><td>(s, 3, CH₃C = C)</td>

<td>Jk / CO₂-</td><td> 4,86,</td><td>4.92 (s, 2, .delta. = 0)</td>

<td>CH₃</td><td></td><td></td>

<td>CH₃(CH₂) co₂-</td><td> 0,87</td><td>(m, 3 CH)₃ (CH₂)₈WHAT₂~)</td>

1.25 (a, 14, CH₃(CH₂5₇CH2CO₂-WITH

<img file="CS233718B2_D0020.tif" />

C0₅-

<img file="CS233718B2_D0021.tif" />

(CH 2 CH 2 CH 2 CO 3 (CH₃)₂CHCO₂CH₃(CH2)₃C0₂-

<img file="CS233718B2_D0022.tif" />

2337'β

<img file="CS233718B2_D0023.tif" />

II

R - C - O

NMR (CPCl)₃, 6 )

C-CO 3 -c-co₂CH₃(CH₂)₆WHAT₂C₆h ,, co₂CH3XJH-COg^CF3^(CH2)2^C024-cic₆h₄what₂2,4-F₂^C6^h3C °₂- .

Step 3: Preparation of 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;_and

Using the procedure described in Example 1, Step C, substituting propanoyloxy compounds for an equimolar amount of the phenylacetoxy compound of Example 2, Step A, the title compound was obtained, mp 109-112 ° C.

Using other esters of formula VI_and described in Example 2, Step A (Table IV) and following the procedure of Example 2, Step 3, ee to prepare esters of Formula I_&amp; described in Table V.

Table V

RCO, · formula. tt (° C)

J ^ co₂- ”⁶-”⁹ j^F3

CHjCHCHgCOg^C24^TO33^F3°5

110 - 113

2337,8

HCO ~ ​​formula

tt &lt;° C)

CH ^C24^H34°5

113 - 118

CH,

CH

CH,

X—

CojHo, 0_C

34 5

116 - 119

CH₃(CH₂)₈C0₂°29^H46 ° 5 (wax)

<img file="CS233718B2_D0024.tif" />

^C24^H36°5

126 - 129 ch₃what₂en &lt;γ Ό—

CH &lt;CH₃)₂CHCH₂WHAT₂»(CH₃)₂CHCO₂CH₃(CH₂)₃WHAT₂—— CO2—

-COoV-c-co₂233718

BCOg formula tt (° C) ~ 1 — c-co₂CH ^CHglgCOCOC₆H_nWHAT₂ch₂= ch-co₂CF₃(CH₂)₂WHAT₂4-C1C_ïH₄WHAT₂2,4-K₂^C6^h3^C°₂Example3

6 (R) - [2- (8 '(S) -2-Methylbutyryloxy-2 * (S) -6' (R) -dimethyl-1 *, 2 *, 6 ', 7 *, 8 *, 8') and (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) -haxahydronaphthyl-1 '(S) -ethyl] -4 (R) - (dimethyl-tert-butylilyloxy) -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. The reaction mixture was stirred at 100 ° C for 9 hours under nitrogen atmosphere. The reaction mixture was diluted with 500 mL of ether, washed with 1 N hydrochloric acid until the wash solution was acidic and then with brine (3 x 50 mL). After drying over magnesium sulfate, the solution was filtered and evaporated to give 4.2 g of a brown oil. This oil aa is chromatographed on a 6 cm, 5 cm silica gel column (230-400 mesh). Elution (under air pressure) with ether / hexane (1: 1, v / v) gave 2.6 g (95%) of the title compound as a brownish yellow oil.

NMR (CDCl3)₃) δ 0.08 (a, 6, (CH₃)₂Si), 0.9 (a, 9, (CH 2 CS 1)), 2.57 (d, 2, J 4 Hz, pyran C₃ protons), 4&gt; 30 (m, 1, pyran C 4 H), 4.63 (m, 1, pyran CgH), δ, 42 (m, 1, naphthalene CgH), 5.53 (m, 1, naphthalene C, 6 H, 5.78 (dd, k, J = 6 Hz, naphthalene₃H, 6.03 (d, 1, J 10 Hz, naphthalene C 14 H).

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

Table VI

R-CO

<img file="CS233718B2_D0025.tif" />

what₂NMR (CPCl)₃, δ)

0.87 (m, 9, CH 3 CH 2 CH 2 Cl 2 CHClCOCO)

3

O

II

R-CO_NMR (CflCl₃, )

<img file="CS233718B2_D0026.tif" />

c-co₂ —C-co₂0.78 (t, 9, J = 7Hz, (CH₃CH₂)₃CCO₂) 1.48 (q, 6, J = 7Hz, (.delta.)

1.28 (β, 6, (CH₃)₂CCO₂)

2.20 (β, 3, CH₃-C = CH₂)

3.86 Cm, 2, CHg = C)

1.12 (s, 6, (CH₃)₂CCO₂)

0.83 (t, 3, (CH 3 CH 3 CCO 3))

Step B: Preparation of 6 (R) - [2- (8 '(S) -2-ethyl-2-methylbutyryloxy-2' (S) -6 '(R) -dimethyl-1', 6 ', 7 ^#, 8 *, 8 * and (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 of Example 3, Step A, as the starting material, the title compound was prepared, mp 111-113 ° C; ^ '

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

Table VII

RCOg^- formula tt (° C)

3-00, = ^ co₂&gt; —C — COj— —fA ' ^C28^H44°5 ^C27^H42°5 ^C26^H38°5 ^C25^H38°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 substituting the diol of formula IV * in Example 1, step A, the corresponding diols of formula IV are prepared._be or *, the silyl ethers of formulas V * are gradually formed by new esters of formulas I in accordance with Scheme A, wherein H-CO in the 8'-alkamoyl group is:

<img file="CS233718B2_D0027.tif" />

CH₃WHAT₂4-ClC₆H₄C0₂2,4-F₂^CdH₃WHAT₂-

<img file="CS233718B2_D0028.tif" />

(CH₃)₂They want₂CH.j (CH₂)₃WHAT₂$ Lco₂CH₃(CH₂) gCO₂°6^H11^C02ch₂= ch-co₂CF₃(CH₂)₂WHAT₂-

<img file="CS233718B2_D0029.tif" />

C-CO 3 -CH 3 -₂CH₃(CH₂)₈WHAT₂CH₃CH-CH₂WHAT₂-

<img file="CS233718B2_D0030.tif" />

CHj co₂'ch₃

Example 4

Prepare 6 (B) - {2- [8 (S) - (2-ethyl-2-methylbutyryloxy) -2 '(S), 6' (W) - &lt;Jitnet, hyl-1 ', 2', 3 ' 4 *, 4'a (S), 5 *, 6 *, 7 *, 8 ', 8 * and (S) -decahydronaphthyl-1 * (S) -ethyl} -4 (H) -hydroxy-3 4,5,5-tetrahydro-2H-pyran-2-one;_# step A: Preparation of (R) - [2- (8^/(S) -hydroxy-2 * (S), 6 '(S) -dimethyl-1', 2 ', 34', 4 * and (S), 5 ', 6', 8 ', 8' and (S) 1-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_and in 100 ml of ethyl acetate was hydrogenated in the presence of platinum oxide (1 g) at 50 psi 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 silica gel column (230-400 mesh). Elution (under air pressure) with acetone / methylene chloride (3: 7, v / v) gave 1.0 g (50%) of the title compound as a colorless solid.

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

, &lt;

Step B: Preparation of 6 (R) - [2- (8 '(S) -Hyroxy-2' (S), 6 '(S) -dimethyl-1', 2 ', 3', 4 ', 4' (8), 5) ', 6', '', 8 ', 8'a (S) -decahydro-naphthyl-1' (S) -ethyl] -4 (R) - (dimethyl-tert-butylsilyloxy) ^ 3,4,5,6 • tetrahydro-2H-pyran-2-one;_#

Alcohol solution of formula IV_E (1.0 g, 3.1 mmol), imidazole (1.05 g, 15.4 mmol) and tert. Jutyldimethylchlorosilane (1.16 g, 7.7 mmol) in 20 mL of Ν, Ν-dimethylformamide was stirred for 18 hours under a nitrogen atmosphere at 20 ° C. The reaction solution was diluted with 200 mL of ether and washed successively with water, 2% aqueous hydrochloric acid and brine. 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 silica gel column (230-400 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) -dehydronaphthyl-1' (S) ethyl} -4 (R) -dimethyl-tert-butyl yloxy) -3,4,5,6-tetrahydro-2H-pyren-2-one VI_E

By exchanging an equimolar amount of an alcohol of formula V_# with the alcohol of formula V * in step A, example 3 and carrying out the process for step A, the corresponding amount of the compound of formula VI is obtained_# in the form of a yellow oil. NMR (CDCl 3) 0.08 (s, 6, CH₃)₂Si), 0.90 (S, 9, (CH 2 J 3) Si), 1.13 (S, 6, (CH 2 CO 3), 2.63 (m, 2, pyran C₃ protoy), 4.33 (m, 1, pyran C ^H), 4.60 (m, 1, pyran CgH), 5.23 (m, 1, naphthalene ΟθΗ).

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

By exchanging an equimolar amount of the silyl ether of formula VI_E from Example 4, Step C with the silylther of Step C, Example 1, following the procedure for Step C of Example 1, gave 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)] ethyl-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_l6-tetrahydro-2H-pyran-2-one; IV.

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

MK-803 by heating with aqueous LiOH. HgO for 56 hours but by substituting MK-803 from an equimolar amount of the compound of formula III_b the title compound of formula (IV), mp 136-139 ° C, is obtained in comparable yield.

Following the procedure of Example 4, steps B, C and D, but substituting the compound of formula IV * used in step B to an equimolar amount of the compound of formula IV_b from step A of this example, comparable yields were obtained as in Example 4 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-4 H -pyran-2-one, V_bmp 140-142 ° C

Step C: 6 (R) - {2 - [(8 * (S) -) - (2-ethyl-2)^M-methylbutyryioxy) -2 '(S), 6' (R) -dimethyl-1 *, 2 ', 3', 4 *, 6 ', 7', 8 'and (S) -octahydronaphthyl-1' (S) N-ethyl} -4 (8) - (dimethyl-tert-butylellyloxy) -3,4,5,6-tetrahydro-2H-pyran-2-one, VI_bj, where

<img file="CS233718B2_D0031.tif" />

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

<img file="CS233718B2_D0032.tif" />

Example

Typical compositions 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 a sufficient amount of finely divided lactose in an amount to supplement the capsule content of not about 580 to 590 mg.