CS233718B2 - Processing of 2h-pyran-2 acyloxypolyhydronaphtylderivative - Google Patents

Abstract

Process for preparing acyloxypolyhydronyl derivatives 2H-pyran-2-one of formula I and the corresponding dihydroxy cyanamine of formula II wherein the compound is heated of formula III with alkali hydroxide metal in the protic solvent, whereupon with acidification and lactone to formula IV which is reacted and tert-butyldimethylchlorailane under an inert atmosphere at room temperature in the presence of an acid acceptor formed 4-tert-butyldlmethylsilyloxy compound is acylated with the corresponding acylating agent containing a residue in the meaning of R 1 in the alumina is removed at room temperature room temperature in tetrahydrofuran in the presence 3 equivalents of tetrabutylammonium fluoride and 4 equivalents of acetic acid per equivalent of silylslousenin. The compounds of the invention are potent cholesterol blosynthesis inhibitors.

Description

The present 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 F.M. Singer et al., Proc. Soc. Exper. Biol. Med., 102, 370 (1959) and F.H. 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.

Further disclosed are dihydro MK-803, designated by Formula II _and in Table I, which has the same effect as. MK-803 isolated from the same fermentation as MK-803. Furthermore, the dihydro and tetrahydro derivatives of the known MK-803 III structures θ _b (Table I) which was prepared by catalytic hydrogenation of the MK-803rd

It has now been found that "-methyl-butyrylekupina the compound of formula III _and · the hydrogenated derivative of Formula III _{b e} _ e can be easily cleaved to form a group of 6 (R) - [2- (8-hydroxy-2,6-dimethylpolydyhronaftyl) -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 still 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

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

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

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

wherein X, X and Z are as defined above, which is reacted with tert-butyldimethylchlorailane in an inert atmosphere at room temperature in the presence of an acid acceptor, the resulting 4-tert-butyldimethylailyloxyxysyl is acylated with The resulting silyl group was 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 formulas I _{and e of 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 _a , Cahn, Xngold, the Prelog absolute designation is 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 thus belong to the same stereochemical series. The RS label for each center need not be identical to the label found for the ester of formula X _and given the details of the sequence rule used to determine this label.

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

Table I,

Stereochemistry of hydronaphthyl series

Pří tomná

double bond Structure and X and Z · after ** »**» * · »· * ^ _CH3 AX / b X CH3 C Y f ***** T * ^zv * ^M l ch / - ^ d OF CHj _s

H none

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 ch ₃ ch ₃

a-e and-e.

a-e

VI ©

II

AND

The designations - X, ϊ, 2 and H have the meanings given in the description and series a-e 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 esters of the 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 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 * _e as well as the trihydroxy acids formed by opening the lactone rings.

An alternative synthetic route to compounds of formulas IV _bc * includes the steps of hydrolyzing compounds of formulas 1X1 * to IV * as described above and subsequently hydrogenating the compound of formula XV * from the conditions previously described for preparing 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 * _ *

The 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 solution sodium hydroxide for an extended period of time. 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 formulas III _{and e, the} saponification of the 8'-esters is easier to perform, 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 which allows continuous separation of the resulting water.

In the form of lectone, these alcohols are represented by the compounds of formula (IV) _{and (e)} in Table IA 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 was prepared by recrystallization of a portion of this material from butyl chloride to give drus m.p. 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 ₃ H), 6 03 (d, 1, J = 10 Hz, naphthalene C ₄ H). 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

A suspension of 188 mg (0.463 mmol) of MK-803 _(III) in 5 ml (5 mmol) of aqueous 1N lithium hydroxide solution was shaken for 12 hours at 135 ° C in a 30 ml pressure vessel made of stainless steel. 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, is} first protected with tert-butyldimethylsilyl by reaction with tert-butyldimethylchlorosilane under inert atmosphere at room temperature in the presence of acid acceptors such as imidazole. _V _ _e and 8-hydroxyl on polyhydronaftylovém 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 the catalyst in dichloromethane. This process provides protected esters of formula ^{VI a -} _e ·

Removal of the silyl protecting group of 4-hydroxy pyranone ring ae then performed using three equivalents of tetrabutylammonium fluoride and four equivalents of acetic acid per equivalent of esters VI _a _ _# and receive e desired compounds of formula I _and _ _e · The ratio of reagents in this reaction is not critical to process yield and product purity.

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 chain 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 the sodium salt of compounds of formula (H) _{and (e)} . Using bases with other pharmaceutically acceptable cations yields salts of these cations. Careful acidification of the salts affords the hydroxy acid of formula ΙΙ _# _ _β, which are converted at an acidic pH to compounds of formula I _and _ _e · Reaction of compounds of formula I _and _ _e under acidic or basic katalyay with methanol, ethanol, propanol or butanol or with phenyl- , dimethylamino-, or acetylaminoalkanols, and e give the corresponding esters of the compounds of formula H _{and e} , which are also within the scope of the 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 & Inc., Rahway, New Jersey.

Preparation of compounds of formulas III _and *

A. Fermentation

Test tube of lyophilized culture MF-4845 in a 250 ml Erlenmeyer flask (seed flask) aseptically opens containing about 10 and the contents are suspended in ml of the medium following Medium: corn extracts 5 g tomato paste 40 g oatmeal 10 g glucose 10 g trace element solution 10 g Distilled water 1000 ml pH 6.8 adjusted with HaOH Trace element solution FeSO ₄ .7 H ₂ 0 1000 mg MnSO ^ .4 H ₂ 0 1000 mg CuC1 ₂ .2 H ₂ 0 25 mg CaCl ₂ .2 H ₂ 0 100 mg ^h 3bo ₃ 56 mg (ΝΗ _{4) 6 Μο} γ 0 ₂₄ .4 H ₂ 0 19 mg ZnSO ₄ .7 HgO 200 mg distilled water deionized 1000 ml The inoculated flask was incubated for 24 hours at 28 ° C on a rotary flask shaker with 220 turns

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.

A 910 liter stainless steel fermentation tank fills 485 liters of cerelose-containing medium with peptoned milk of 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 prepared second stage and mix and incubate> 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 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

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. Chromatography on sillkagel

The extract obtained above was freed of other solvents by addition of 9.1 liters of methylene chloride and concentration to an oily residue.

Dissolve the residue in 22.7 liters of ethyl acetate-methylene chloride (30/70 v / v) and add 2.8 kg of sillkagel to prepare a suspension which is 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. The crystals of the compound of formula (a) _{and (} e) are filtered off and the mother liquors are concentrated to an oil which is rechromatographed. Pure compound of formula III _and has 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).

5. The reverse phase chromatography (ml) from fraction 22 of the above chromatography was 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 compound which crystallized from a concentrated acetonitrile solution to give the crystals of compound _III, tt, 29 to, 31 ° C.

Preparation of compounds of formulas III. .

u, c, e

Starting materials of formula 111 ^, ₀ ^{and Se} III P ^ IP ^rav according to the following scheme and said prepaaativních 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.

(1)

ch ₃

III,

III, .o ch ₃ '

III c

2337.8

from U (i)

CH 3 -CH 3 -CH-C 1

*

H

III

^IIJ d

Reactions and reagents

Hydrogenation at 20 to 75 ° C at atmospheric pressure to about 0.4 MPa and carried out to tris- (triphenylphosphine) chlorrhodium 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 performed on 10% palladium on carbon in ethyl acetate.

Preparation of 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 &

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 for a total of consumes 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: compound of formula III _b is 22.3 mg.

Mass Spectrum (m / e) 406 (M ^& lt ^{; +} & 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 ₃ Cl ₃ , 300 MHz) δ

406 (M ⁺ ) 304 M-102 286 (304-H ₂ O). 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 *), 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 10 ml of ethyl acetate was hydrogenated in the presence of the same weight of platinum oxide under 1 bar. 2 molar equivalents of hydrogen were 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 appeared as a more polar spot compared to the cis-isomer. .

Mass spectrum (m / e) 408 (M ^& lt ^{; +} & gt ^; )

323 M-85

306 (M-102).

NMR (CDCl 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) -hexahydronaftyl-1' (S)) ethyl-4 (R) - (dimethyl-t-butylsilyloxy) -3,4,5,6-tetrahydro-2H-pyran-2-one ^V and

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 (CDCl 3) δ 0.10 (s, 6, (CH 3) ₂ Si), 0.90 (s, 9, (CH 2 Cl 2))

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 C 8 H), 5.57 (m, 1, naphthalene C 4 H), 5.58 (dd, 1, J = 6.10 Hz, naphthalene C 4 H), 6, O 3 (d, 1, J = 10 Hz, naphthalene C 4 H).

Analysis for ^C 25 ^H 42 ° 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 &

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) 6 0.09 (s, 6 (CH ^ Si), 0.88 (s, 9, (CH3) 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 4 H), 4.63 (m, 1, pyran C 8 H), 5.34 (m , 1, naphthalene ^θΗ), 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 4 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-COC1 described in Table II, ee prepared the esters of Formula VI * described in Table II.

Table II

R - C - O

CH,

HNMR (CDC1 _3, 8)

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

2.02 (s, 3, CH ₃ CO ₂ -)

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

Ιό _{(CH3) 2} CHCH2C0 _{2 (CH3) 2} CHCO ₂ CHýCHjPjCC tj3_co ^ ₂ 0.83 (a, 6, J = 6Hz, (CH _{3) 2} CH-)

1.13 (d, 6, J => 6 Hz _{(CH3) 2} CH), 0.95 (t, 3, J = 7Hz, CH ₃ - (CH _{2) 3} ·

1.00-2.08 (m, 15, adamantyl)

0^Η3 (^θΗ2) 6002^C6^H11^WHAT2 0¾ = CH-CO2

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

Ch / h-CH 2 CO 3.

CH ch ₃

CHj

CH,

A> ° 2ch ₃ (ch ₂ ) ₈ co ₂ 'CC

H CH ₃

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 ^- . 3 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 ailyl 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 off-white needles: mp 167.5-170.5 ° C, IR (CDCl 3) δ 0.88 (d, 3, J = 7 Hz, CH 2, 1.08 (d, 3, J = 7 Hz, CH ₃ ), 1.19 (a, 9, (CH ₃ ) ₃ C), 2.67 (d, 2, J * 4 Hz. Pyran C) ₃ protons), 4.39 (m, 1, pyran C ^ H),

4.65 (m, .1, pyran 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 4 H), high pressure liquid chromatography (4.6 mm x 25 cm) 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 2,2-dimethylpropanoyloxysilyletheru compound of formula VI & equivalent amounts of other esters of formula _{VI, and} described in Table II are prepared the esters of formula I _and described in Table III.

Table III _ftCO ₂ ~ _ formula tt (° C)

^G 24 ^H 5 36 °

139 - 148 hp ₃

^G 26 ^H 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 CO ₂ 4-ClC ₆ H ₄ CO ₂ 2,4-F ₂ C ₆ 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 3} O ^H 42 ° 5- °' ^{05 G} 6 ^H 12

126-128

144-147

153-156

155 - 158 formula

mp (° C) rco ₂ CH,

CH r ~ ch ₃ ch,

X / ^C 2 CH ₃ (CH ₂ ) ₈ CO ₂ CH ₂ X ^{2 - 3} H CH ₃

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 of 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 is added. was treated with 22 mg (0.15 mmol) of 4-pyrrolidinopyridine and the reaction mixture was stirred at 20 ° C under 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 2) δ 0.10 (s, 6, (CH 2 Ig 3 Si), 0.90 (s, 9, (CH ₃ ) ₃ CSi), 3.58 (s, 2, PhCH ₂ -), δ 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 the formula RCOOH described in Table IV, the esters of Formula VI _and described in Table IV are obtained.

I and b u 1 k and IV

NMR (CDC1 ₃ S) [> _-CO2 0.78 to 1.02 (m, 4, cyclopropane)

NMR (CDCl 3? S)?

CH, CH-

Cl 2 CH-CH 2 Cl 2 - 1.04 (α, 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 (Wide, β, 1, C = CH-) ch ₂ 1.80 (s, 3, CH ₃ C = C) Jk / CO ₂ - 4,86, 4.92 (s, 2, .delta. = 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 CH ₂ CO ₂ -S

C0 ₅ -

(CH ₂ CHCH ₂ CO ₃ (CH ₃ ) ₂ CHCO ₂ CH ₃ (CH 2) ₃ CO ₂ -

2337’β

II

R - C - O

NMR (CPCl ₃ , 6)

C-COj- -C-CO ₂ CH ₃ (CH _{2) 6} CO ₂ C ₆ H ,, _CO2 CHjXJH ^COG-CF 3 ^(CH 2) ^C0 2 24-CIC ₆ H ₄ co ₂ 2,4-F ₂ ^c 6 ^h ₃ ° C -.

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

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, m.p. 109 DEG-112 DEG.

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 prepared the esters of Formula I _&

Table V

RCO, · formula. m.p. (° C)

J ^ co ₂ - " ^6- " ⁹ j ^F 3

CH 2 CHCH 2 CO 3 ^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 ° ^C ₂ ° 29 ^H 46 ° 5 (wax)

^C 24 ^H 36 ° 5

126 - 129 ch ₃ co ₂ en <γ Ό—

CH _{"<CH3) 2} CHCH ₂ CO _{2» (CH3) 2} CHCO ₂ CH ₃ (CH _{2) 3} CO ₂ - CO2-

-COoV-c-co ₂ 233718

BCOg formula tt (° C) ~ 1 — c-CO ₂ CH3 CHg1gCOgC ₆ H _n CO ₂ ch ₂ = ch-CO ₂ CF ₃ (CH ₂ ) ₂ CO ₂ 4-C1C _d H ₄ CO ₂ 2,4- K ₂ ^c 6 ^h 3 ^c ° ₂ Example 3

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 (CDC1 ₃₎ δ 0.08 (a, 6, _{(CH3) 2} Si), 0.9 (a, 9, (CH ^ CSi), 2.57 (d, 2, J »4Hz, pyran C ₃ protons), 4> 30 (m, 1, pyran C 4 H), 4.63 (m, 1, pyran C 8 H), δ, 42 (m, 1, naphthalene C 8 H), 5.53 (m, 1 , naphthalene C 4 H), 5.78 (dd, k, J = 6 Hz, naphthalene C ₃ H), 6.03 (d, 1, J 10 Hz, naphthalene C 4 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

co ₂ NMR (CPCl ₃ , δ)

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

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, CH ₃ -C = CH ₂ )

3.86 Cm, 2, CHg = C)

1.12 (s, 6, (CH _{3) 2} CCO ₂₎

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, m.p. 111 to 113 ° C 26θ26 ^ 40 ° 5 ^ ’

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, = ^ 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, Stage 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, Stage A, the corresponding diols of formula IV _be or * successively silyl ethers of formulas V * new esters of formulas I in accordance with Scheme A, wherein H - CO in the 8'-alkamoyl group is:

CH ₃ CO ₂ 4-ClC ₆ H ₄ CO ₂ 2,4-F ₂ ^{c d} H ₃ CO ₂ -

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

C-CO 3 -CH ₂ CH ₃ (CH ₂ ) ₈ CO ₂ CH ₃ CH-CH ₂ CO ₂ -

CH ₂ co ₂ 'ch ₃

Example 4

Prepare 6 (B) - {2- [8 (S) - (2-ethyl-2-methylbutyryloxy) -2 '(S), 6' (W) - <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, O-tetrahydro-2H-pyran-2-one, I _# itupeň A: Preparation of (R) - [2- (8 ^/ (S) -hydroxy-2 * (S), 6 '(S 1-Dimethyl-1 ', 2', 34 ', 4 * a (S), 5', 6 ', 8', 8 'and (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 _and 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 a portion of the material from chloroform to give an off-white solid, m.p. Mp 166-168 ° C.

, <

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 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. 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 yl-oxy) -3,4,5,6-tetrahydro-2H-pyrene-2-one, VI _e

Replacing an equimolar amount of the alcohol of formula V _# with an alcohol of formula V * in Step A, Example 3 and following the procedure for Step A yields the corresponding amount of the title compound of formula VI _# as a yellow oil. NMR (CDCl 3) 0.08 (s, 6, CH ₃ ) ₂ Si), 0.90 (S, 9, (CH 2 J ₃ ) Si), 1.13 (S, 6, (CH 2 CO 3), 2, 63 (m, 2, pyran C ₃ protozoa), 4.33 (m, 1, pyran C 4 H), 4.60 (m, 1, pyran C 8 H), 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 substituting an equimolar amount of the silyl ether of formula VI _e of Example 4, Step C for silylther from Step C, Example 1, the procedure of Step C of Example 1, afforded corresponding or quantity of the title compound as a solid.

An analytical sample was prepared by recrystallization of the material from hexane to give white needles of m.p. 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-l 3,4,5 6-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 substituting MK-803 equimolar amount of compound III _b formed in comparable yield the title compound of formula IV-tt 136 to 139 ° C.

Following the procedure of Example 4, Step B, C and D, but replacing the compound of Formula IV used in step B equimolar amount of a compound of formula IV _b from Step A of this example, similar yields were obtained as in Example 4, the following compounds.

Step B: (R) -2- (8 '(S) -hydroxy-2' (S), 6 '(R) -dimethyl-1', 2 ', 3', 4 ', 6', 1 ', 8'a (S) -oktahydronaftyl-1 '(S) ethyl] -4 (H) - (dimethyl-t-butylsilyloxy) _-3,4,5) 6-tetrahydro-aH-pyran-2-one, In _b, mp 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'a (S) -octahydronaphthyl-1' (S) J-ethyl} -4 (8) - (dimethyl-tert-butylellyloxy) -3,4,5 * 6-tetrahydro-2H-pyran-2-one, VI _b ^ j, wherein

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-one, I _b, mp 129-131 ° C wherein

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.

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.,