HU187296B - Process for the preparation of new 2-bracket-8-acyloxy-2,6-dimethyl-polyhydroxynaphthyl-1-bracket closed-ethane derivatives - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to novel 2- (8-acyloxy-2,6-dimethylpolihydronaphthyl-1) -ethane derivatives of the formula (I): wherein R is a straight or branched alkyl group having from 1 to 10 carbon atoms, except for 2- (S). ) butyl, C 3-6 cycloalkyl, C 3-5 alkenyl, C 1-3 alkyl substituted with trifluoromethyl, halophenyl, or C 1-3 alkylalkyl in the alkyl moiety, X and Z dashed lines represent a possible double bond, and if such a double bond is present at all in the molecule, then X and Z represent either alone and Q is a group of formula (15) and the corresponding Q is (16). and pharmaceutically acceptable salts thereof. The compounds of the invention have antihypercholesterolemic activity. -1-

Description

The present invention relates to novel 2- (8-acyloxy-2,6-dimethyl-polyhydronaphthyl-1-) - ethane derivatives of the general formula (I):

R is C 1 -C 10 straight or branched alkyl, except for 2- (S) -butyl, C 3 -C 10 cycloalkyl, C 3 -C 5 alkenyl, C 1 -C 3 alkyl substituted by trifluoromethyl, halophenyl, or a C 1-3 phenylalkyl group in the alkyl moiety. The dashed lines X and Z represent one of the possible double bonds, and if such a double bond is present at all in the molecule, it is represented by X and Z together or X alone, and Q is a group of formula (15) ) for the preparation of pharmaceutically acceptable salts thereof.

The intermediates used in the preparation of the 8-acyloxy derivatives of the invention, namely: a

6 (R) - [2- (8'-hydroxy-2 ', 6'-dimethyl-polihidronaftilr) ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one derivatives are also new compounds.

Some mevalonate derivatives are known to inhibit cholesterol biosynthesis (see F. M. Singer et al., Proc. Soc. Biol. Med., 102, 370 (1959) and F.H. Hulcher, Arch. Biochem. Biophys. 146, 422 (1971)]. However, these compounds have not been shown to be sufficiently effective, i.e., practicable.

Recently, Endo et al., U.S. Patent Nos. 4,049,495, 4,137,322 and 3,983,140, describe a fermentation process whose products have been found to be quite active in inhibiting cholesterol biosynthesis. The most active member of this group of natural products is called compactin and according to Brown et al. Chem. Soc. Perkin 1,1165 (1976)] has the mevalonolactone structure of formula (VII).

Recently, an inhibitor has been described by Monaghan et al. (U.S. Patent No. 4,231,938). This inhibitor is designated as ΜΚ-803, has the structure shown in Table I (Formula IIIJ [Q = Group 15)], and is prepared by a completely different fermentation process from Albers-Schonberg et al., A dihydro-MK803- (see, United States Patent No. 154,157, filed May 28, 1980). The dihydro-MK-03 derivative has the formula (III _d ) in Table I (Q = 15). Patchett et al. Describe the dihydro and tetrahydro derivatives of MK-803 of various structures [which are shown in Table I (IIIJ, (IIIJ and (IIIJ)). of formula (Q '* (15))] and are prepared by

MK-803 is catalytically hydrogenated.

The tetrahydro analogue of compactin VIII is disclosed in Japanese Patent Publication No. 5509-024 (Kokai).

According to Gullo et al., U.S. Patent Application No. 207,508, filed Nov. 17, 1980, the dihydrogen analogue of Compactin IX has recently been isolated from a fermentation culture of compactin.

The (ΙΙΙ ') and (III _d) materials of formula (O - (15) R) is produced by a fermentation process conducted as Aspergillus terreus strain. The ATCC number of this strain is 20 542. In the collection of Merck and Co., Inc., Rahway, New Jersey, this strain is MF-4845.

Synthesis of _(III) and (Illj) Compounds of formula (Q '(15) R)

A) Fermentation

A tube of lyophilized MF-4845 culture tube was opened aseptically and suspended in a 250 ml open Erlenmeyer flask (inoculum). The flask contained 10 ml of medium of the following composition:

Medium

Corn soaking juice 5g tomato Paste 40g Oatmeal 10g glucose 10g Trace Element Solution 10g Distilled water 1000 ml pH adjusted to 6.8 with NaOH Trace Element Solution • FeSO ₄ 7H ₂ O 1000 mg MnSO ₄ · 4H ₂ O 1000 mg CuCl ₂ 2H ₂ O 25 mg CaCl ₂ · 2H ₂ O 100 mg h ₃ bo ₃ 56 mg (NH ₄ ) ₆ Mo ₇ O ₂₄ · 4H ₂ O 19 mg ZnS0 ₄ · 7H ₂ O 200 mg

Deionized Distilled Water 1000 ml In a 220 rpm shaker (about 5 cm swing), the inoculated flask was incubated for 24 hours at 28 ° C. An open 2-liter Erlenmeyer flask containing 500 ml of the above medium was inoculated with 10 ml of inoculum produced during the first fermentation step. The mixture was shaken again for 24 hours at 28 ° C.

A 200 gallon (about 908 liter) stainless steel fermentation vessel was filled with 485 liters of medium:

Cerelose 4.5 v%

Peptonized milk 2.5 v%

Autolysed yeast 0,25 v%

Polyglycol P 2000 0.25 vol%

The pH of the medium was adjusted to 7.0. The medium was sterilized for 15 minutes at 121 ° C. One liter of inoculum produced in the second stage was added and the mixture at 85 rpm for 12 hours, followed by

187 296

At 130 rpm, it was incubated for 84 hours at 28 ° C, with approx. 141 liters / minute, while in the second 84 hours approx. A flow rate of 282 liters / minute was maintained.

B) Isolation

1. Extraction

Two portions of 100 gallons (about 454 liters) of total medium were combined, acidified to pH 4.1 with 800 ml of concentrated hydrochloric acid, extracted with 75 gallons (about 340 liters) of ethyl acetate and and stirred for an hour.

Thereafter, about 25 pounds (about 11.2 kg) of silicate-containing filter aid was added and the entire slurry was passed through a 24-inch (about 61 cm) filter press. An additional 75 gallons (about 340 liters) of ethyl acetate was used to wash the nucleus, and the extraction was continued by changing the flow direction four times. All washing solvents were then removed from the press and combined with the first filtrate. The biphasic filtrate was allowed to settle and the aqueous layer was removed. The ethyl acetate phase was washed with 10 gallons (about 45.4 liters) of deionized water, allowed to separate, and the ethyl acetate extracts concentrated under reduced pressure to give a residue of about 10 gallons (about 45.4 liters).

2. Lactonization

Another ethyl acetate extract from another 300 gallon (about 1360 L) medium was added to the above extract and the volume of the extracts was reduced to about one third by vacuum distillation. About 50 gallons (about 227 liters) of toluene were added and then concentrated under reduced pressure to about 32 gallons (about 145 liters); this step was repeated; then enough toluene was added to make the mixture a volume of 75 gallons (about 340 liters). The mixture was refluxed for 2 hours without pressure reduction while the temperature was above 106 ° C.

The solution was then concentrated under reduced pressure to a small volume, and then concentrated by evaporation in a rotary evaporator under vacuum to give an oily residue.

3. Chromatography on silica gel

The extract obtained above was freed from all solvents by washing with 2 gallons (about 9.1 liters) of methylene chloride and evaporating again to an oily product.

The oily residue was dissolved in about 5 gallons of ethyl acetate / methylene chloride (30/70 by volume) and a slurry of 2.8 kg of silica gel was prepared.

The suspension was applied to a 12 x 15 inch (about 30.5 x 38 cm) silica gel column packed with the same solvent mixture.

Elution was carried out with ethyl acetate / methylene chloride (40/60 by volume) at 800 mL / min. After a 10 gallon (ca. 45.4 liters) pre-fraction, 4 gallons (ca. 18.1 liters) were collected.

6-10. The combined fractions were concentrated under reduced pressure, and the resulting oily residue was dissolved in hot ethyl acetate, clarified with charcoal, filtered hot and cooled. The crystals of (IIIJ (Q = 15)) were filtered off and the mother liquors were concentrated to an oil for further chromatography. The pure product (IIIJ) had a melting point of 170-171 ° C.

4. Repeat chromatography on silica gel

The above mother liquor residue was combined in methylene chloride solution with additional mother liquor obtained from similar processing of the products of another gallon of 600 gallons (about 2725 liters). Half of the solution was further chromatographed on silica gel. The solids content was found to be 325 g in a small aliquot. The solution was clarified with 40 g of activated carbon, filtered and the residue was washed with methylene chloride. The combined washings and filtrates were evaporated under reduced pressure to give an oily residue. The residue was dissolved in 800 mL of ethyl acetate / methylene chloride (30/70 by volume) and suspended in 225 g of silica gel. The suspension was loaded onto a 14 x 36 cm silica gel column packed with the same solvent mixture. Elution was carried out with ethyl acetate / methylene chloride (40/60 by volume). A 3 L pre-fraction was set aside and 800 mL fractions were collected.

Chromatography on opposite phase charge

40 ml of fraction 12 of the above chromatography was concentrated to 500 mg of oil and the oil was redissolved in 5 ml of acetonitrile. The acetonitrile solution was loaded onto a 5/8 inch (about 1.6 cm) diameter 6 foot (about 1.83 cm) stainless steel chromatographic column called "Bondapak C18 / Porasil B" preparative reverse phase liquid chromatography. The column contained a filler (manufactured by Waters Associates, Inc., Milford, Mass. 01757). The column was eluted with a mixture of 55% v / v acetonitrile and 45% v / v 0.05m ammonium phosphate (pH 3). The volume of eluate between 1360 and 1700 ml was pooled based on the detection of the refractive index. The organic solvent was evaporated under reduced pressure and the resulting aqueous solution was extracted with ethyl acetate. The ethyl acetate was evaporated in vacuo and the residue (120 mg) was recrystallized from concentrated acetonitrile solution. This gave the product of the formula Hij (group Q = 15), m.p.

187 296

129-131 ° C.

Preparation of compounds of formula (III,) and (III) (Q-group (15))

(Production IIIj, (III _C) and (III _C) formulation of the materials (Q = (15) R) in Scheme 1 and the following a), b) and c) is done according to examples.

The desmethyl analogues (II-Q, -15); the 6-methyl group of formula (IIa-e) is hydrogen) derivative of the compounds of formula (IIIJ, (III)) and (IIIJ) are essentially as described by Patchett et al. in each case it may be prepared starting from the desmethyl analogue derived from the compound of formula (HI _a ) (Q = group 15).

Reduction of compound (IIIJ (group Q = 15)) may be advantageous if the trans-position of the hydronaphthalene ring present in the starting material is retained in the final product and if avoided formation of various isomers.

Reaction and Reagents:

(1) Hydrogenation: at about 20-75 ° C, from atmospheric to 4 atmospheric pressure, over tris (triphenylphosphine) -chloroform, in an aromatic solvent such as benzene, toluene or xylene, preferably toluene. Preferred conditions: about 40 'C, 2-7 atm in toluene.

(2) Hydrogenation: at 20-25 ° C, at about atmospheric pressure, 5% palladium calcium carbonate, lower alkanol such as C 1-3 alkanol, especially ethanol.

(3) Hydrogenation: at about 20-25 'C, at atmospheric pressure, over platinum oxide in ethyl acetate.

(4) Hydrogenation: at 20-25 ° C, at atmospheric pressure, 10% palladium on charcoal in ethyl acetate.

Example a)

6a- [2- [8'p- (2- (S) -methyl-butyryloxy) -2'P, 6'a l'-dimethyl-2 ', - 3', 4 ', 6', 7 ', 8', 8'a-octahydro-naphthyl-1] -ethyl] -4P-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one [(IIII; Q = Preparation of a mixture of mg (0.1236 mmol) of Compound IIIJ (Q-15) and equimolar amount (114.35 mg, 01236 mmol) of tris (triphenylphosphine) -chlorodium in 10 mL Hydrogenated in anhydrous toluene for 6 days at room temperature while hydrogenation consumed a total of 14.6 ml of hydrogen, then evaporated to dryness in vacuo. ethyl acetate system, 22.3 mg of (III J (Q 15)) was obtained.

Mass Spectrum: (M / e)

406 (m ⁺ )

304 (m-102)

286 (m-102-18)

Nuclear Magnetic Resonance Spectrum (CDCl3, 300 MHz) δ 4.37 (m, 1H)

4.60 (m, 1H)

5.34 (doublet of triplets, 1 = 2.5 Hz, 1H)

5.41 (m, 1H)

Example b)

6a 2- {[8'P- (2- (S) -methyl-butyryloxy) -2'P, 6'a-dimethyl-l ', 2', 3 ', - 5', 6 ', 7 ', 8'8'a-octahydro-naphthyl-1] -ethyl} -4P-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one [(Compound IIIJ; (Q = ( 15)

A solution of 80.91 mg (0.2 mmol) of the compound IIIJ (Q = 15) in 10 ml of absolute ethanol was hydrogenated at 5 atmospheres of 5% palladium on calcium carbonate. The hydrogenation was carried out in one molar equivalent. The catalyst was removed by filtration and the filtrate was evaporated to dryness (81 mg). mass spectrum: (M / e).

406 (m ⁺ )

304 (m-102)

286 (304-H ₂ O)

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz) δ 4.38 (m, 1H)

4.64 (m, 1H)

5.28 (doublet of triplets, J = 3.5 Hz, 1H)

5.48 (m, 1H)

Example c)

6a- {2- [8'B- (2- (S) -methyl-butyryloxy) -2'P, 6'a-dimethyl-1 ', 2', 3 ', 4'aa, 5', 6 ', 7', 8 ', 8'-decahydro-naphthyl-1] ethyl} -4P-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one [(IIII; (Q - A solution of 80.91 mg (0.2 mmol) of compound IIIJ (Q = 15) in 10 ml of ethyl acetate was hydrogenated in the presence of an equal weight of platinum oxide at 1 atmosphere. Exactly two molar equivalents of hydrogen were consumed in 1 hour, and the catalyst was removed by filtration.

187,296 was fired and the filtrate was evaporated to dryness to give an oil. The cis and trans isomers were separated by preparative thin layer chromatography on silica gel plates (10% ethyl acetate-ether system; detection of bands by aqueous spraying). The trans isomer of compound 111.0 (Q = group 15) appeared to be a more polar spot (relative to the cis isomer), and 60 mg of the trans isomer was isolated.

Mass Spectrum · (M / e)

408 (m ⁺ )

323 (m-85)

306 (m-102)

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz)

54.36 (broad singlet, IH)

4.59 (m, 1H)

5.19 (doublet of triplets, J = 2.5 Hz, 1H)

Oatmeal 10 g

Cerelose 10 g

Trace element mixture 10 ml ® Distilled water 1000 ml pH 6.8

Trace Element Mixture:

FeSO ₄ · 7H ₂ O 1 g

MnSO ₄ · 4H ₂ O lg

CuCl ₂ 2H ₂ O 25 mg

CaCl ₂ 100 mg

H ₃ BO ₃ 56 mg (NH ₄ ) ₆ Mo ₇ O ₂₄ · 4H ₂ O 19 mg 15 ZnSO ₄ · 7H ₂ O 200 mg

Distilled water 1000 ml

LM medium without malt extract:

dextrose 20g 20 Glycerol 20 ml Development of pH 10g The compound of formula (III _d) (Q = (15) wherein CoCl ₂ · 6H ₂ O 8g Preparation of the 6-desmethyl analog of group 2) Polyglycol p 2000 0.25 fermentation Distilled water 1000 ml A) Fermentation 25 pH 7.0

LM medium without modification:

A natural isolate of Penicillium citrinum (NRRL 8082) was used to prepare the yeast-malt extract (YME). The extract was incubated for 2 weeks at 28 ° C.

One portion (1 / 5th) of the extract was inoculated into five open 250 ml seed flasks containing 44 ml of KF inoculum with CaCl ₂ . The flasks were incubated for 3 days at 28 ° C and 220 rpm. Approximately 1.5 ml of inoculum was added to each of 100 100 ml flasks of culture medium without LM malt extract (open, 250 ml). The culture flasks were incubated for 4 days at 25 ° C.

Another set of culture flasks (140) containing 40 ml each of LM medium without modification was inoculated and incubated under font size and conditions. The media of both fermentations were combined.

The following media were used in these fermentations:

Dextrose Glycerol Ardamine pH Malt extract CoCl ₂ · 6H ₂ O Polyglycol p 2000 Distilled water pH g 20 ml 10 g 20 g mg 0.25%

1000 ml 7.0

YME:

dextrose

Malt Extract Yeast Extract Agar

PH of distilled water

KF inoculum with CaCl3: CaCl3

Corn Soaking Juice Tomato Paste g / 1 10 g / 1 4 g / 1 20 g / 1 liter 7.0 g

5g 40g

B) Isolation

The combined media (10.3 L) was filtered and the mycelial cake was washed with 2.5 L of deionized water. The combined filtrates and washings were adjusted to pH 4.0 with 1N hydrochloric acid. The aqueous solution was extracted with ethyl acetate (7 L) and the extracts were back-extracted with aqueous sodium hydroxide solution (3 x 2 L). The combined sodium hydroxide extract was adjusted to pH 3.8 with 1N hydrochloric acid and extracted with ethyl acetate (2 L, 1 L). The combined ethyl acetate solutions were dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The oily residue was dissolved in toluene and refluxed for one hour. The toluene solution was evaporated to dryness and the residue was dissolved in n-hexane / toluene / methanol (4: 1: 1 v / v). This solution was applied to a Sephadex 1H-20 column, 30 cm internal diameter, 40 cm long, equilibrated with the same solvent mixture. Elution with 300 ml of solvent gave a 10 ml fraction which was evaporated to an oil. ES Industries on Chromega * Column (9mm x 50cm)

Liquid chromatography (HPLC) of 187.296 (60:40 v / v acetonitrile) gave 45 mg of dihydrocompactin (6-desmethyl derivative of compound IIIJ (Q-15)).

392.2560 (calculated for C ₂₃ H ₃₆ O ₃ : 392.2558).

Major peaks of the IR spectrum recorded in KBr (Fourier Transform - IR (FTIR, Nicolet, Model 7199)): 1724, 1704, 1258, and 1070 cm @ -1. Substantial peak at 3005 cm⁻¹ in and ^_l 3030 cm - _is living in the absence peak.

The nuclear magnetic resonance spectrum was recorded in CDCl ₃ (about 1 mg / 0.5 mL) on a Varian SC-300 NMR spectrometer. Below we give the location of the peaks in ppm (δ). The measured values are referenced to tetramethylsilane (TMS) as an internal standard.

δ Which group is attributable to it 5.62d, d, d (2.17, 4.5 10.0) H ₃ , (or 4 ') 5.43 d (10) H ₄ , (or 3 ') 5.20 m h ₈ , 4.63 m h ₆ 4.39 m h ₄ 2.75 d, d (17.5, 5.5) 3CH ₂ = ₂ 2.63 d, d, d (17.5, 4.0 1.5) 3 — CH ₂ 2.39 m ch ₃ c // c = o 2.29m h _4b + h ₂ , 1.14 d c // ₃ chc = o 0.90 t CH ₃ CH ₂ - 0.84 d 2'— CH ₃ -

d: doublet; m: multiplet; t: triplet

These data prove that the compound is of formula (1).

It has now been found that the a-methylbutyryl group of the compound (IIIJ (Q = 15)) can be readily removed to give 6 (R) - [2- (8-hydroxy-2,6-dimethyl-polyhydronaphthyl) -1) -ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one derivatives which are hypocholesterolemic agents in themselves and which are extremely useful intermediates in this field esters.

According to the invention, the preparation of new alcohols is carried out by heating the esters (III-J) (group Q = 15) in a protic solvent such as water or alcohol with an alkali metal hydroxide such as lithium hydroxide, potassium hydroxide or sodium hydroxide. Preferably, the reaction is carried out in water under reflux with lithium hydroxide, for a reaction time of 50-72 hours, at a higher pressure and at 120-180 ° C for a shorter reaction time of about 8-24 hours.

The pyrarion ring opens easily, but the removal of the acyl side chain is no longer so easy. Heating should be continued and / or pressure applied. It may be advisable to work in an intimate atmosphere. It is quite unexpected that molecules with so many sensitive functional centers can withstand the powerful reaction conditions required to remove the highly inhibited α-methylbutyryl ester group. The high yields obtained by the process are particularly unexpected.

Trihidroxisav-forms of _(IV _J compound (Q = (15) R) can be isolated by acidification and extraction with organic solvents, these trihídroxisavak again laktonizálhatók such that the acid with a suitable organic solvent. - such as toluene or benzene - of the solution is heated in an apparatus for continuous removal of the water formed.

These trihídroxisavak from alcohols, or of the lactone ring-opening the case (IV represented by _the general formula _J (O - (15) or (16) R).

Alternatively, the compounds of Formula (II), (Formula II) and (Formula II) may be prepared by hydrolyzing the compound (Formula IHJ) to form a compound (Formula II), and then hydrogenating the resulting compound (Formula II). using reaction conditions such as those already described for the preparation of the compounds of formula IIIJ, (IIIJ and (IIIJ.). Hydrogenation results in the preparation of compounds of formula (IIJ, (IIJ) or (IIJ).

Preparation of compounds of formula (IV _a _ _e)

The starting materials for the esterification step of the present invention, 8'a-hydroxy compounds described by Willard (U.S. Patent No. 118,049), can be prepared by preparing the various 8'-esters, as described by Monaghan et al., (IIIJ; (Q - 15), Albers-Schonberg et al. ((IIIJ; Q = 15)) and Patchett et al. (IIIb _<: J; (Q == 15)). - heating over a longer period of time with lithium hydroxide solution. The pyranone ring opens easily, but removal of the acyl side chain is no longer easy. Heating should be continued for longer periods and / or pressure applied.

The 8'-hydroxy products can be isolated by acidification and extraction with an organic solvent to give the hydroxy acid form in which the pyranone ring is still open. These hydroxy acids can be lactonized again. This can be accomplished by -61 with an organic solvent suitable for the acid

187.296, such as benzene or toluene, is heated in an apparatus for continuous removal of water formed.

These alcohols (in the form of an acton) correspond to Table I (Formula IV, J (Q = 15)) and may be prepared by the procedures of Examples d), e) and f) below.

Example d)

6 (R) - [(8 '- (S) -hydroxy-2' (S), 6 '(R) -dimetill', 2 ', 6', 7 ', 8', - 8'A (R) -hexahydro-naphthyl-1 '(S) -ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one [(IV); (Q = group 15) dodllitnsd

A mixture of 8.0 g (19.78 mmol) of MK-803 (IIIJ, Q = 15) and 8.31 g (197.8 mmol) of LiOH · H ₂ O in 600 mL of water was added. After stirring for 56 hours at reflux under nitrogen, the reaction mixture was cooled to 0 ° C, then concentrated hydrochloric acid (20 mL) was added, the mixture was extracted with ether (3 x 250 mL), and the combined extracts were washed with water (3 x 200 mL). After drying over magnesium sulfate, the organic solution was filtered to give an oily residue by evaporation of the solvent under reduced pressure, which was dissolved in toluene (200 mL) and continuously re-lactonized to remove water. the solution was refluxed under nitrogen for 2 hours. Trituration gave 5.15 g (81%) of the title compound of formula (Q = 15) as a white solid. The product obtained did not require further purification.

An analytical sample was prepared by recrystallization of a portion of the resulting product from butyl chloride. The white crystals melted at 128-131 ° C (in vacuo).

NMR (in _CDCl3): §0,87 (d, 3, J = 7Hz, -CH _3), l, 16 (d, 3, J = 7Hz, _CH3), 2.64 ( m, 2, pyran C ₃ H), 4.27 (brm, 1, naphthalene C ₈ H), 4.37 (m, 1, pyran C ₄ H) 4.71 (m, 1, pyran C ₆ H) 5.56 (m, 1, naphthalene C _s H), 5.79 (dd, 1, J = 6, 10Hz, naphthalene C ₃ H), 6.03 (d, 1, J = 10Hz, naphthalene C ₄ H).

IR (CHCl ₃ ) 3400 (-OH), 1725

I (C-O), 1240, 1120 and 1080 cm @ -1.

I

Analysis for C ₉ H ₂₈ O ₄ O ₁ C ₄ H ₉ Cl: C (%) H (%) Calculated: 70.6 / 8.84 Toll: 70.77 8.75

Example e)

6 (R) - [2- (8 '(S) -Hydroxy-2' (S), 6 '(R) -dimethyl-1', 2 ', 6', 7 ', 8', - 8'a (R) -Hexahydronaphthyl-1 '(S)) -ethyl-4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one [(Compound of Formula VII; Q = (15) )

A suspension of MK-803 (Compound IIIJ, Q = 15) (188 mg, 0.463 mmol) in 5 mL of 1 N aqueous LiOH was shaken for 12 hours at 135 ° C in a stainless steel pressure vessel. The cooled reaction mixture was acidified with 1 m H ₃ PO ₄ and extracted with ethyl acetate, the ethyl acetate solution was dried over magnesium sulfate, filtered, and the solvent was evaporated, and the residue was dissolved in 20 mL of toluene. solution was refluxed in a Dean-Stark apparatus _y 4 hours to újralaktonizálás. The toluene was evaporated to afford the product of the title compound.

f) Example (IVa, (IVc), (IV _d) Preparation of and (IVa alcohols of formula (Q = (15) R)

Essentially, any one of the methods described above is used, only the equivalent of (IIIJ, (IIIJ, (IIIJ, or IIIJ) (Q = 15)) instead of (IIIJ, Q - 15)). This yields the appropriate alcohols (EMI, (EMI, (EMI) and (EMI) (Q = (15))).

It has now been found that compounds of formula (IV) can be acylated to provide a new class of 8-acyloxy compounds of structure (megfelelő). These new compounds inhibit cholesterol synthesis in vivo,

The absolute configuration of these compounds can be determined by X-ray diffraction studies. The structure and stereochemistry of the compounds are shown in Table I below. The reference numbers of the various compounds, including those referring to polyhydronaphthyl structures, remain the same throughout the specification. Each of the alcohol moieties of formula I, J (group Q = 15) contains seven or eight chiral centers. The relative and absolute configurations of these asymmetry centers are shown in Table I, in formula (V) (or in formula IJ). esters (Q = group of formula (15)) - the absolute configuration of Cahn, Ingold, Prelog is as follows: 4 (R), 6 (R), 1 '(S), 2' (S), 6 '( R), 8 '(S) and 8a' (R) (RS cahn, C. Ingold and V. Prelog, Angew. Chem. Int. Ed. 5, 385 (1966)). Compounds of Formula I (Q-15) contain the same spaced groups on each chiral carbon atom, such that the same stereochemical soro-72

They belong to 187,296. Besides this marking is possible due to certain details of the sequence rules used for determining that the markings given asymmetric centers RS differ from (I _a) ester of the formula (O - (15) R) from findings. The compound (I _d) and (I _c esters of the formula - having a deficiency of the ester of formula (I), an additional chiral center 4a 'hydrogens oriented downwards (or α-helyzetűj- see Table I -, which trans results in ring attachment.

The 8'-acyloxy derivatives of the present invention are useful as antihypercholesterolemic agents in the treatment of atherosclerosis, hyperlipaemia and the like in human medicine. They may be administered orally or parenterally in the form of capsules, tablets, injectable preparations and the like. Oral administration is generally preferred. Dosages may be varied from 2 to 2000 mg per day, preferably from 10 to 100 mg, depending on the age, severity of the condition, body weight and other conditions of the individual being treated. This dose is administered in three or four divided doses. Higher doses may be used if desired.

The compounds of the present invention also have a fungal effect. Thus, they can be used, for example, against strains of Penicillium sp., Aspergillus niger, Cladosporium sp., Cochliobolus miyabeanus and Helminthosporium cynodnotis. When used as such, the compounds may be admixed with suitable formulation agents, powders, emulsifiers or solvents such as aqueous ethanol. They can be applied to the plants to be protected by spraying or dusting.

Scheme 2 illustrates the process of the invention. The substituents X, Z, R and Q in the reaction scheme have the same meanings as described herein, and the sequence a-e has the same meaning as in Table I. And Q 'is a group of formula (15) without OH. Reactions in Scheme 2:

“1. Lithium hydroxide, heating, acidification and lactonization.

2. t-Butyldimethylchlorosilane and imidazole in dimethylformamide at room temperature and in an inert atmosphere.

3. Treatment in pyridine solution with RCOCl, where R is as defined above, and 4-dimethylaminopyridine, preferably in an inert atmosphere.

4. Treatment with dichloromethane with RCOOH, wherein R is as defined above, with N, N'-dicyclohexylcarbodiimide, preferably in an inert atmosphere.

5. In tetrahydrofuran, one equivalent of ester contains three equivalents of tetrabutylammonium fluoride and four equivalents of acetic acid, preferably under inert atmosphere.

6. Wet lye, then carefully acidify with dilute acid.

7. See Scheme, Reactions and Reagents for the Synthesis of Compounds of Formula III _bce .

In the novel process of the present invention, the 4-hydroxy group on the pyranone ring of the alcohols (IV,,,) is first protected with a t-butyldimethylsilyl group. This is done with t-butyldimethylchlorosilane at room temperature, at room temperature and in the presence of an acid acceptor such as imidazole, to give the protected alcohols (V, 4). In one method, a solution of the desired acyl group in acid chloride with pyridine is used as reagent and

It is carried out in the presence of 4-dimethylaminopyridine catalyst. Alternatively, 8'-polyhydronaphthalene is treated with the free acid corresponding to the desired acyl group and a carbodiimide, such as N, N1-dicyclohexylcarbodiimide, using 4-pyrrolidinopyridine as the catalyst. To give the protected ester of formula (VI _c), these procedures. Then, removal of the silyl protecting group with the piranongyürű 4-hydroxy-csopórtjáról per equivalent of (VI _a _ _{e) the} ester of formula is carried out in three equivalents of tetrabutylammonium fluoride and four equivalents of acetic acid to thereby obtain _a desired _ _(Y ) (Q = group 15). In the latter reaction, the ratio of reagents is critical for yield and purity of the product.

Of the acyl groups which may be attached to the 8'-hydroxyl group, 1,1-dimethylpropyl, 1,1-diethylpropyl or 1-ethyl-1-methylpropyl is preferred. Furthermore, it is particularly preferred that X and Z are other than double bonds.

The compounds of formula (I _a _e) (Q = (15) R) bases such as sodium hydroxide to be hydrolyzed. If another base providing a pharmaceutically acceptable cation is used, the corresponding salts are obtained. The salts careful acidification to yield (1, -) of formula hydroxy acids (Q = (16) a group of Formula) which revert to acid pH η of Formula (la _the _e) a compound of formula I, wherein Q is (15) the formula group.

Pharmaceutically acceptable salts of the present invention include salts with the following cations and amines: sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium hydroxide, as well as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, chlorine, Ν, Ν'-dibenzylethylenediamine, chloro-procaine, diethanolamine, procaine, N-benzylphenethylamine, 1- (chlorobenzyl) -2- (pyrrolidine-1 ') -ylmethyl) benzimidazole, diethylamine, piperazine and tris (hydroxymethyl) aminomethane.

Example I

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6 (R) - {2- (8 '(S) - (2' ', 2-dimethyl-propanoyl) -2' (S), 6 '(R) -dimethyl-r, 2', 6 ' Preparation of 7 ', 8'8'a (R) -hexahydro-naphthyl-r (S)] -ethyl} -4- (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 5

The step:

6 (R) - [2- (8 '(S) -hydroxy-2' (S) -6 '(R) -dimetilr, 2', 6 ', 7', 8 ', 8'A (R) - hexahydro-naphthyl-1 '(S) -ethyl] -4 (R) - (dimethyl-tert-butylsilyloxy) -3,4,5,6-tetrahydro-2H-pyran-2-one [(V) Compound _a );

Alcohol (18.3 g, 57.1 mmol), _(IV) Formula (Q = radical of formula (15)), 21.5 g (142.8 mmol) of tert-butyl dimethyl chlorosilane and 19.4 g A mixture of imidazole (285.6 mmol) in ml, Ν-dimethylformamide (200 mL) was stirred at 20 ° C for 18 h under a nitrogen atmosphere. The reaction mixture was diluted with ether (1500 mL) and washed with water, 2% aqueous hydrochloric acid, water and saturated sodium bicarbonate solution. The ethereal solution was dried over magnesium sulfate, filtered and evaporated to 1 L (2 L). After adding 600 mL of hexane, the volume was reduced to 600 mL on a steam bath.

The product crystallized at room temperature; isolation and air drying gave 13.7 g of a white fluffy solid. Further evaporation of the mother liquor to 2 250 ml and subsequent recrystallization from the solution kept at 0 ° C overnight. A total of 17.13 g (69% yield) was obtained from the white fluffy solid. Mp 142-144 ° C (in vacuo). Nuclear Magnetic Resonance Spectrum (in CDCl 3): δ 0.10 (s, 6, - (CH ₃ ) ₂ Si), 0.90 (s,

I 'ί

9, (CH ₃ ) ₃ CS 1), 1.19 (d, 3, J = 7, Hz, -CH ₃ ), 2.58 (d, 2, J = 4Hz, pyran C ₃ H), 4.3 (m, 2, pyran C ₄ H and naphthalene C ₈ H), 4.70 (m, 1, pyran C ₆ H), 5.57 (m,

1, naphthalene C ₅ H), 5.58 (dd, 1, J = 6 and 10 Hz, naphthalene C ₃ H) and 6.03 (d, 1, J = 10 Hz, naphthalene C ₄ H). _the

Analysis for C _{2 J} H ₄₂ O ₄ Si:

Calculated: C 69.08 9.74 Found: 69.46 9.83

Step B:,

6 (R) - {2- [8 '(S) -2,2-dimethylpropanoyloxy) 2' (S), 6 (R) -dimethyl-1 ', 2', 6 ', 7', 8 ', - 8'a (R) -Hexahydro-naphthyl-1' (S)] -ethyl} -4 (R) - (dimethyl-tert-butylsilyl, oxy) 3,4,5,6- tetrahydro-2H-pyran-2-one [(Preparation of VIJ)

A solution of 6.0 g (13.8 mmol) of the alcohol from Step A (Q = 15) and 200 mg of 4-dimethylaminopyridine in 50 mL of pyridine was cooled to 0 ° C under nitrogen. To this stirred solution was added pivaloyl chloride (6.8 mL, 6.65 g, 6.65 g, 55.2 mmol) over a period of 15 minutes, and the reaction mixture was added over 1 hour. After stirring at 0 ° C and then for 4 days at 20 ° C, the reaction mixture was diluted with ethers (750 ml) and washed with 2% aqueous hydrochloric acid until saturated with sodium bicarbonate solution. After drying, the solution was filtered and evaporated to give the title product (7.81 g) as a light orange oil.

Nuclear Magnetic Resonance Spectrum (in CDCl ₃ ): δ 0.09 (s, 6, (CH ₃ ) ₂ Si), 0.88 (s, 9, (CH ₃ ) _{3 C 5} ), 1.28 (s) , 9, (Ch ₃ ) ₃ CC _{2 - 2} ), 2.57 (d, 2, J = 4 Hz, pyran C ₃ H), 1.32 (m, 1, pyran C ₄ H), 4.63 ( m, 1, pyran (C _Ö H), 5.34 (m, 1, naphthalene C ₈ H), 5.54 (m, 1, naphthalene C _s H);

5.78 (dd, 1, J = 6 and 10 Hz, naphthalene C ₃ H) and 6.03 (d, 1, J = 10 Hz, naphthalene C ₄ H).

By proceeding essentially as in Example 1, Step B, only an equimolar amount of pivaloyl chloride was used instead of pivaloyl chloride. using the acid chloride of formula R-COC1 listed in Table II. was prepared as described in Table _(VI) esters thereof.

II. spreadsheet

0 II R-C-O NMR spectrum (in _CDCl3, δ) Yield: A group of formula (2) 7.10 (t, 2, J = 8Hz, p-FPh ·) 8.03 (dd, 2, J = 5 and 8 Hz, p-FPh-) 86% CH ₃ CO ₂ 2.02 (s, 3, CH ₃ CO ₂ -) not isolated A group of formula (3) 1.19 (d, J = 7 Hz, a-CH ₃ ester) 1.21 (d, J = 7 Hz, a-CH ₃ ester) 83% (CH ₃ ) ₂ CHCH ₂ CO ₂ - (CH ₃ ) ₂ CHCO ₂ - Total 3H, 0.83 (d, 6H, J = 6Hz, (CH _{3) 2} CH-) 89% 1.13 (d, 6H, J = 6 Hz _{(CH3) 2} CH-) 100% CH ₃ (Ch ₂ ) ₃ Co ₂ - 0.95 (t, 3, J = 7Hz, Ch ₃ - (Ch ₂ ) ₃ - 70% A group of formula (4) 1.60-2.08 (m, 15, adamantyl) 79%

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Step C:

6 (R) - {2- [8 '(S) - (2,2-dimethylpropanoyl-oxy) -2' (S), 6 '(R) -dimethyl-l', 2 ', 6', 7 ', 8', - 8'a (R) -Hexahydronaphthyl-1 '(S)] -ethyl} -4 (R) -hydroxy-3,4,5,6-tetrahydro-

2H-pyran-2-one [(IJ;

(Q = 15)

To a solution of Bu ₄ N ⁺ F - 3 H ₂ O (10.0 g, 31.7 mmol) in acetic acid (2.4 mL, 2.5 g, 42.3 mmol) in tetrahydrofuran (50 mL) was added 10 ( A solution of 7.81 g (13.8 mmol) of silyl ether of formula VIJ in 50 ml of tetrahydrofuran was stirred for 18 hours at 20 [deg.] C. The reaction mixture was diluted with 700 ml of ether and then 2%. The organic solution was dried over magnesium sulfate and filtered to give 6.45 g of an off-white solid which was removed by evaporation of the solvent. After recrystallization from 20 chlorides, the crystals were collected and dried for 4 hours at 35 ° C / 0.01 mm to give 4.0 g (72% yield) of the title product as off-white needle crystals, m.p. 170.5 ° C (vacuum). 25 NMR spectrum _(CDCl3 -b an): δ 0.88 (d, 3, J = 7 Hz, -CH _3), 1.08 (d, 3, J = 7Hz, -CH _3), 1.19 (s, 9, _(CH3 ) ₃ C), 2.67 (d, 2, J = 4Hz, pyran C ₃ H), 4.39 (in, 1, pyran C ₄ H), 4.65 (m, 1, pyran C _Ö H ), 5.36 (m, 1, naphthalene C ₈ H), 5.55 (m, 1, naphthalene C _s H), 5.80 (dd, 1, J = 6 and 10 Hz, naphthalene C ₃ H) and 6.04 (d, 1, J = 10 Hz, naphthalene C ₄ H). HPLC (4.6mm x 25cm Paratisil 10, 10% isopropanol / hexane, 4ml / min) retention time: 4.4min.

Analysis for the compound of the formula C ₂₄ H _3e O ₅ :

C H C calculated: 71.25 8.97 found: 71.40 8.93

Following the procedure of Example 1, step C), only the (Vij equivalent amount given in Table III. (VI instead _of 2,2-dimethyl-propanoyl-oxy-silyl ether of the formula) using the esters of the formula described in Table III. ( Esters of Formula I (Q == 15) were prepared.

///. spreadsheet

Melting point _v ·. ,, bay Extraction

Rászámított

Elemental analysis received a formula

A group of formula (8) C: 71.25 C ₂₄ H ₃₆ O ₅ C: 70.70 139-148 49% H: 8.97 H: 9.00 A group of formula (2) C: 10.51 c ₂₆ h _3I fo ₂ C: 10.62 119.5-120.5 84% H: 7.06 H: 7.12 (vacuum) (CH ₃ ) ₂ CHCH ₂ - C: 71.25 C ₂₄ H ₃₆ O ₅ C: 70.93 126-128 79% CO ₂ - H: 8.97 H: 9.02 (CH ₃ ) ₂ CHCO ₂ - C: 70.74 C ₂₃ H ₃₄ O ₅ C: 70.48 144-147 86% H: 8.18 H: 8.88 CH ₃ (CH ₂ ) ₃ CO ₂ - C: 71.25 C ₂₄ H _{3 <s} O ₅ C: 71.19 64% H: 8.97 H: 9.21 ch ₃ co ₂ - C: 69.14 c ₂ , h ₃₀ o ₅ oic ₄ h ₉ C: 68.95 153-156 65% H: 8.37 H: 8.53 (vacuum) A group of formula (4) C: 14.75 C ₃₀ H ₄₂ O _s OO5C ₆ H ₁₂ C: 15:13 155-158 79% H: 8.82 H: 8.90.

Example 2

6 (R> [2- (8 '(S) phenylacetoxyacetate 2' (S), 6 '(R) -dimethyl-l', 2 ', 6', 7 ', 8-hexahydro ^ to (R) Preparation of naphthyl-1 '(S) -ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one

The step:

6 (R) - [2- (8 '(S) phenylacetoxyacetate 2' (S), 6 '(R) -dimethyl-l', 2 ', 6', 7 ', 8', 8'A ( R) hexahydro-riaftil-l '(S)) - ethyl] -4 (R) N-tert-butyl-silyl-oxy) -3,4,5,6-tetrahydro-2H-pyran-2- on [(compound of formula VIJ;])

434 mg (1.0 mmol) of the alcohol (VJ (Q) 15) of Example 1 Step A and 309 mg (1.5 mmol) of N, N-dicyclohexyl, carbodiimide were prepared in 10 mL of dichloromethane. oldatáéhoz stirring to 20 ° C and nitrogénatmoszfé ^OU tree was added (0.15 mmol) of 4-pirrolidi10 22mg

-102

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In the same manner as in Example 2, Step A, only equimolar amounts of phenylacetic acid were used instead of phenylacetic acid. using the organic acid of formula R-COOH in Table IV. The esters of the formula (VIJ) are prepared as described in Table II.

amino-pyridine. After 3 days, the solvent was evaporated in vacuo and the residue was slurried in 25 mL of ether and filtered. Evaporation of the filtrate gave a viscous oil which was chromatographed on a 5 3 x 15 cm silica gel column (230-400 mesh). Elution with atmospheric pressure and ether / hexane (1: 1 by volume) gave the title product as a viscous oil. 10

Nuclear Magnetic Resonance Spectrum (in CDCl ₃ ): δ 0.10 (s, 6,

II (CH ₃ ) ₂ Si), 0.90 s, 9, (CH ₃ ) ₃ CSi), 3.58 (s, 2, 15).

PhCH ₂ -, 5.34 (m, 1, naphthalene C ₈ H) and 7.30 (s,

5, Ph).

ARC. spreadsheet

0 II R-C-O NMR spectrum (in _CDCl3, δ) Yield: A group of formula (9) 0.78-1.02 (m, 4, cyclopropane) 99% cf ₃ í ch ₃ ch— ch ₂ —CO ₂ - 1.04 (d, 3, J = 7Hz, CH ₃ CHCF ₃ ) (not isolated) A group of formula (5) 1 1.88 (s, 3, CH ₃ C = C), I I 1 2.17 (d, 3, J = 2 Hz, _CH3 C = C) 31% 1 5.68 (brs, 1, C = CH--) 1 A group of formula (6) 1 1 1.80 (s, 3, _CH3 C = C) 1 (not isolated) 1 4.86, 4.92 (s, 2, CH ₂ = C) 1 CH ₃ (CH ₂ ) ₈ CO ₂ - 0.87 (m, 3, CH _y (CH ₂ ) ₈ CO ₂ -) 78% 1.25 (m, 14, CH ₃ (C H ₂ ) ₇ CH ₂ CO ₂ -)

Step B:

h (R) - (2- (8 '(S) phenylacetoxyacetate 2' (S), 6 '(R) -dimethyl-l', 2 ', 6', 8 ', 8'A (R) - hexahydro-naphthyl-1 '(S) -ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (Compound of Formula IJ; Q - (15) of formula IIa]

By proceeding essentially as in Example 1, Step C, only the propanoyloxy compound used therein was replaced by an equimolar amount of the phenylacetoxy compound prepared in Example 2, Step A, to afford the title compound. Melting point:

⁶⁰ 109-112 ° C.

-11il

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Yield: 30%.

H, 7.81 Found: C, 74.29; H, 7.99. 5

Using additional esters of formula VIJ as described in Example 2, Step A (Table IV), the esters of formula IJ (group Q = 15) described in Table V were prepared.

Table V.

RCOj - calculated Analysis Molecular formula got melting point [° C] Yield: A group of formula (9) C: H: 71.10 8.30 c ₂₃ h ₃₂ 0 ₅ C: 70.95 H: 8.42 116-119 75% cf ₃ I CH ₃ CH CH ₂ CO ₂ - C: H: 62.86 7.25 c _I4 h ₃₃ f ₃ 0 ₅ C, 62.74; H, 7.23 110-113 70% A group of formula (5) 0 ₂ 4 ^ 34θ5 113-118 33% A group of formula (6) C24H34OJ 116-119 32% CH ₃ (CH ₂ ) ₈ CO ₂ - C ₂₉ H _4e O _s (wax) 43% (7) ^ 24Η ₃ 6θϊ 126-129 25%

Example 3

6 (R) - {2- [8 '(S) - (2' '- ethyl-2' '- methylbutyryloxy) -2' (S), 6 '(R) -dimethyl-1', 2 ', 6', 7 ', 8', 8'a (R) -Hexahydro-naphthyl-1 '(S)] -ethyl} -4 (R) -hydroxy-3,4,5,6-tetrahydro- Preparation of 2H-pyran-2-one / step 4)

6 (R) - {2- [8 '(S) - (2 "-ethyl-oxy-2-methyl-butyryl) -2' (S), 6 '(R) -dimethyl-l', 2 ', 6 ', 7', 8 ', - 8'a (R) -hexahydro-naphthyl-1' (S)] -ethyl} -4 (R) - (dimethyl-tert-butylsilyloxy) -3, 4,5,6-tetrahydro-2H-pyran-2-one [(VI _l) compound] Preparation of

2-ethyl-2-methyl-butyryl chloride (3.0 g, 20 mmol) was added 2.17 g (5 mmol) of _(V) alcohol and 74 mg of 4-pyrrolidinopyridine were added 20 ml of pyridine formula. The resulting reaction mixture was stirred at 100 ° C for 9 hours under nitrogen. The reaction mixture was then diluted with ether (50 mL) and washed with 1N hydrochloric acid and then with 3 x 50 mL of brine until the acid was acidic. After drying over magnesium sulfate, filtration and concentration of the solution, 4.2 g of a brown oil are obtained. The resulting oil was chromatographed on a 6 x 15 cm silica gel column (230-400 mesh). Elution under atmospheric pressure with ether / hexane (1: 1 by volume) gave the title product as a viscous yellow oil.

Nuclear Magnetic Resonance Spectrum (in CDCl ₃ ): δ 0.08 (s, 6, (CH ₃ Cl ₂ ), 0.9 (s, 9, (CH ₃ ) ₃ Cl ₂ ), 2.57 (d, 2, J Hz, pyran C _S H), 4.30 (m, 1, pyran C ₄ H), 4.63 (m, 1, pyran C ₆ H), 5.42 (m, 1, naphthalene (C _e H) 5.53 (m, 1, naphthalene C _s H), 5.78 (dd, 1, J = 6 and 10 Hz, naphthalene C ₃ H), and 6.03 (d, 1, J - 10 Hz, naphthalene C ₄ H).

By essentially following the procedure of Example 3, only the equilibrium amount of 2-ethyl-2-methylbutyryl chloride used therein is the same as that of Example VI. using the acid chloride of formula R-COCl in Table VI. The esters of the formula (VIJ) are prepared as described in Table II.

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VI. spreadsheet

R-CO ₂ - (10) group (11) group (12) group (13)

NMR spectrum (in _CDCl3, δ)

0.87 (m, 9H, C // ₃ CH ₂ CH ₂ (C // JCH _{2) 2} CCO ₂ -), 0.78 (t, 9, J = 7Hz, (CTF ₃ CH _{2) 3} CCO ₂ -)

1.48 (q, 6, J = 7Hz, (CH ₃ CH ₂ ) ₃ CCO ₂ -)

I

1.28 (2, 6, (CH _{3) 2} CCO ₂ -)

I

2.20 (s, 3, Ctf _{3 -} C = CH ₂ )

I

3.86 (m, 2, CH ₂ = C)

I

11.12 (s, 6, (CH ₃ ) ₂ CCO ₂ -)

Yield (%) (not isolated)

0.83 (t, 3, (C // ₃ CH ₂ CCO ₂ -)

Step B:

6 (R) - {2- [8 '(S) -2-ethyl-2-methyl-butyryl) 2' (S), 6 '(R) -dimethyl-l', 2 ', 6', Preparation of 7 ', 8'-8'a (R) -Hexahydronaphthyl-1' (S)] -ethyl} -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one

Substantially following the procedure of Example 1, Step C or Example 2, Step 35, B, using only the silyl ether obtained in Example 3, Step A as starting material, the title compound was prepared.

Melting point: 111-113 ° C. Yield: 26%.

Elemental analysis for C ₂₆ H ₄₀ O ₅ :

Calculated: C, 72.18; H, 9.32 Found: C, 72.24; H, 9.57.

Similarly prepared in Example VII. indicated in Table (I _a) esters of general formula, but starting with other _(VI) of formula VII. The esters given in Table II were used.

Table VIL

rco ₂ - calculated Analysis Molecular formula got melting point rq Yield: 17J Is a group of formula (10) C: 73,00 C: 72.77 81-83 77 H: 9.26 H: 9.78 is a group of formula (II) C: 72.61 c _2I H ₄₂ o _s C: 72.45 129-132 68 H: 9.48 H: 9.68 Is a group of formula (12) C: 72.52 CídHjgOj C: 72.33 75-78 62 H: 8.89 H: 9.08 Is a group of formula (13) C: 71.73 c _2J h ₃₈ o ₅ C: 79.90 135-138 48 H: 9.15 H: 9.54

Example 4, 6 (R) - {2- [8 (S) - (2-Ethyl-2-methyl-butyryloxy) 2 '(S), 6' (S) -dimethyl, 2 ', 3' , 4 ', 4'a (S), 5', 6 ', 7', 8 ', 8'a (S) -decahydro-naphthyl, -1' (S)] - ethyl} -4 (R) - hydroxy-3,4,5,6-tetrahydro-2, _Preparation of [compound (Q = (15) θθ a radical of formula (ζ)] pyran-2-one

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The step:

6 (R) - [2- (8 '(S) -hydroxy-2' (S), 6 '- (S) -dimetill', 2 ', 3', 4 ', 4'a (S), 5 ', 6', 7 ', 8', - 8'A (S) decahydro-naphthalenyl '(S)) - ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2Hpirán- 2-one (IVJ; Q = 15)

2.0 g (6.2 mmol) of alcohol IV (Q = 15) dissolved in 100 mL of ethyl acetate in the presence of platinum oxide (1 g) at about 2.7 atm up to two molar equivalents of hydrogen hydrogenated. The catalyst was removed by filtration and the filtrate was evaporated to dryness to give 1.9 g of a white solid which was chromatographed on a 6 x 20 cm silica gel column (230-400 mesh). Elution under atmospheric pressure with acetone / methylene chloride (3: 7 v / v) afforded 1.0 g (50%) of the title product as a colorless solid.

An analytical sample was prepared from the resulting material by recrystallization from a small amount of chloroform to give a white fluffy solid. Melting point: 166-168'C.

Elemental analysis for C ₁₉ H ₃₂ O ₄ :

Found: C, 70.33; H, 9.94; Found: C, 69.92; H, 10.05.

Step B: 6 (R) - [2- (8 '/ S) -Hydroxy-2' (S), 6 '(S) -Dimethyl-1', 2 ', 3', 4 ', 4'a (S), 5 ', 6', 7 ', 8', 8'a (S) -Decahydro-naphthyl-1 '(S)) -ethyl] -4 (R) - (dimethyl-tert-butylsilyl) oxy) -3,4,5,6-tetrahydro-2H-pyran-2-one (VJ)

1.0 g (3.1 mmol) of alcohol (II), 1.05 g (15.4 mmol) of imidazole and 1.16 g (7.7 mmol) of tert-butyl chlorosilane in 20 mL of N, N-dimethyl formamide solution was stirred for 18 hours at 20 DEG C. under nitrogen, and the reaction mixture was diluted with ether (200 mL), washed with water, 2% aqueous hydrochloric acid, and brine, dried over anhydrous magnesium sulfate, and concentrated. This gave 1.8 g of a white solid, which was chromatographed on a 6 x 20 cm silica gel column (230-400 mesh) eluting with atmospheric pressure and eluting with a mixture of acetone / methylene chloride (1: 19 by volume) to give 1.0 g of the title compound. The product was isolated as a white solid, m.p. 147-148 ° C.

Elemental analysis for C _{2 J} H ₄₆ SiO ₄ :

Found: C, 68.44; H, 10.57; Found: C, 68.64; H, 10.81.

Step C:

6 (R) - {2- [8 '(S) - (2-oxy-methyl-2-ethyl-butyryl) -2' (S), 6 '(S) -dimethyl-l', 2 ', 3' , 4 ', 4'a (S), - 5', 6 ', 7', 8 ', 8'a (S) decahydro-naphthyl-1' (S)] - ethyl} -4 (R) - ( Preparation of dimethyl tert-butylsilyloxy) -3,4,5,6-tetrahydro-2H-pyran-2-one (VIJ)

Using equimolar amounts of the alcohol (VJ) used in Example 3 (A) instead of the alcohol (VJ) and following the procedure of Example 3 (A), an appropriate amount of the title product (VIJ) was obtained as a yellow oil.

Nuclear Magnetic Resonance Spectrum (CDCl _{3 in} δ 0.08 (s, 6, (CH ₃ ) _{2 s} )), 0.90 (s, 9, (CH ₃ ) ₃ C 5 -), 2.63 (m, 2 , pyran C ₃ H), 4.33 (m, 1, pyran C ₄ H), 4.60 (m, 1, pyran C _e H) and 5.23 (m, 1, naphthalene C _g H). : 66%.

Similarly, the corresponding 8 '(S); (2,2-dimethylbutyryloxy) derivative was prepared in 60% yield. The compound is an oily substance.

Step D:

6 (R) - {2- [8 '(S) - (2-ethyl-2-meti1-butyryloxy) 2' (S), 6 '(S) -dimethyl-l', 2 ', 3', 4 ', 4'a (S), 5', 6 ', 7', 8 ', 8'A (S) decahydronaphthyl-l' (S)] - ethyl} -4 (R) -hydroxy-3,4 , 5,6-Tetrahydro-2H-pyran-2-one [(IJ; Q = 15)]

The silyl ether used in Example 1 (C) was replaced by an equimolar amount of the silyl ether (VIJ) from Example 4 (C) and Example 1.

Following the procedure of step C), the title compound is prepared in the form of a solid cap.

An analytical sample of the resulting product was recrystallized from hexane to give white needle-like crystals. Melting point: 146-147 ° C.

Elemental analysis for C ₂₆ H ₄₄ O ₅ :

H, 10.16 Found: C, 71.61; H, 10.48.

In substantially the same manner as in Example 4, Step D, 6 (R) -} 2- [8 '(S) - (2,2-dimethylbutyryloxy) -2' (S), 6 '(S) dimethyl, 2' , 3 ', 4', 4'a (S), 5 ', 6', 7 ', 8', 8'A (S) -decahydro-naftilr (S)] - ethyl} -4 (R) -hydroxy -3,4,5,6-Tetrahydro-2H-pyran-2-one was prepared.

Yield: 94%, m.p. 159-160 ° C.

Elemental analysis for C ₂₅ H ₄₂ O ₅ :

date; C, 71.05; H, 10.02 Found: C, 70.88; H, 10.36.

Example 5

6 (R) - {2- [8 '(S) - (2-ethyl-2' '- methylbutyryloxy) 2' (S), 6 '(R) -dimethyl-1', 2 ', 3 ', 4', 6 ', 7', 8'a (S) -octahydronaphthyl-1 '(S)] -ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro- Preparation of 2H-pyran-2-one (IJ; Q = 15)

The step:

6 (R) - [2- (8 '(S) -hydroxy-2' (S), 6 '(R) -dimetill', 2 ', 3', 4 ', 6', 7 ', 8'A (S) -octahydronaphthyl-1 '(S) -ethyl] 4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one [(Compound of Formula IV; Q' - 15)]

Essentially, the starting material (Formula II)

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Following described 187,296 (Q = (15) R) preparation process - in which the ΜΚ-803 at Aqueous LiOH H ₂ O for 56 hours at reflux hydrolyzed only MK-803 in an equimolar amount of (III _b) wherein the compound (Q = (15) R) title product in similar yields formula (IV _b) (Q = (15) R) was prepared. Melting point; 136-139'C.

Elemental analysis for C, $ H ₃₀ O ₄ :

Calculated: C, 70.77; H, 9.38; Found: C, 70.43; H, 9.79.

Following the procedure of Example 4, B), C) and D) steps, for equimolar amounts of the former instead of the compound used in step B) (IV _e)) obtained in step (IV _b) using the compound of Example 4 in similar yields to those obtained:

Step B:

6 (R) - [2- (8 '(S) -hydroxy-2' (S), 6 '(R) -dimetill', 2 ', 3', 4 ', 6', 7 ', 8'A (S) -octahydro-naphthyl-r (S) -ethyl] -4 (R) - (dimethyl-tert-butylsilyloxy) -3,4,5,6-tetrahydro-2H-pyran-2-one [ Compound ₍ Vb): mp 140-142 ° C; Elemental analysis for C ₂₅ H ₄₄ SiO ₄ :

Found: C, 68.76; H, 10.16; Found: C, 68.59; H, 10.63.

Step C:

6 (R) - {2- [8 '(S) - (2-ethyl-2-methylbutyryloxy) 2' (S), 6 '(R) -dimethyl-1', 2 ', 3', 4 ', 6', 7 ', 8'a (S) -octahydronaphthyl-1' (S)] -ethyl} -4 (R) - (dimethyl-tert-butylsilyloxy) -3,4,5, 6-tetrahydro-2H-pyran-2-one; [(VI _b) a compound of formula R-COO-represents a group of formula (14)]; Yield: 100% (crude product)

Step D:

6 (R) - {2- [8 '(S) - (2-ethyl-2-methyl-butyryloxy) 2' (S), 6 '(R) -dimethyl-l', 2 ', 3' , 4 ', 6', 7 ', 8'a (S) -octahydronaphthyl-1' (SO) -ethyl} -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran -2-one [formula (I _b) a compound of the formula Q = (15) R, R-COO- is (14) R], mp 129-131 ° C;

Yield: 36%.

Analysis for C _2o H ₄₂ 0J Calculated compound:

Found: C, 71.85; H, 9.74; Found: C, 71.86; H, 10.15.

Example 6

6 (R) - {2- [8 '(S) - (2,2-Dimethylbutyryloxy) 2' (S), 6 '(S) -dimethyl-1' 2 ', 3', 4 ' , 4'a (S), 5 ', 6', 7 ', 8', 8'a (S) decahydro-naphthyl-1 '(S)] -ethyl} -4 (R) -hydroxy-3,4 , 5,6-tetrahydro-2H-pyran-2-one

The step:

6 (R) - [2- (8 '(S) -Hydroxy-2' (S), 6 '(R) -dimethyl), 2', 6 ', 7', 8 ', 8'a (R) Preparation of -hexahydro-naphthyl-1 '(S) -ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one

50.2 g (0.124 mol) of MK-803 (mevinoline, see formula I in Table I, group Q = 15) in 3 L of water 52.0 g (1.24 mol) of LiOH · H ₂ O was heated to reflux for 72 hours under stirring with a magnetic stirrer under nitrogen. The mixture was cooled to 0 ° C with stirring and diluted with 120 ml (1.44 mol) of 12N hydrochloric acid so that the temperature remained below +3 ° C. The solution was saturated with solid NaCl and extracted with ether (4 * 500 mL). The collected extracts were washed with 2 x 250 mL of saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and the solvent removed in vacuo. The resulting yellow oil (31.7 g) was dissolved in toluene (250 mL), refluxed under nitrogen for 4 h, and the water was continuously separated in a Dean Stark apparatus. The toluene was then distilled off and the residual oil was dissolved in ether (1500 mL). The solution was washed with NaHCO ₃ solution, then water, and evaporated to dryness. The residue was taken up in 200 mL of hexane to remove the solvent to give 29.7 g (75%) of a cream product. No further purification was necessary. For analytical purposes, colorless crystals were obtained from n-butyl chloride, m.p. 128-131 ° C.

Step B:

6 (R) - [2- (8 '(S) -hydroxy-2 (S) -hydroxy-2' (S) ,. 6 '(R) dimethyl-r, 2', 6 ', 7', 8 ', 8'a (R) -Hexahydro-naphthyl-1 (S)) ethyl] -4 (R) - (tert-butyldimethylsilyloxy) · 3,4,5,6-tetrahydro-2H-pyran- 2-on.

From the alcohol derivatives obtained in Step A, 18.3 g (0.057 mol) and 10.3 g (0.068 mol) of tert-butyldimethylsilyl chloride and 9.3 g (0.137 mol) of imidazole in 200 ml of dimethyl formamide and stirred for 18 hours at room temperature with a magnetic stirrer. The reaction mixture was then diluted with 1500 mL of ether and washed several times in the following order: 200 mL water, 200 mL 2% aqueous hydrochloric acid, 200 mL water, 200 mL saturated NaHCO ₃ solution, 200 mL water. The resulting solution was dried over magnesium sulfate and concentrated in vacuo to one liter. The mixture was diluted with 600 mL of hexane and the solution was concentrated to 600 mL to give 13.7 g of a white solid. Concentration from the mother liquor to 250 ml and standing overnight at 0 ° C gave an additional 3.4 g of product. The total product thus obtained was 17.1 g (69%), m.p. 142-144 ° C.

Step C:

6 (R) -j2 might - / (8 ') (S) -hydroxy-2' (S), 6 '(R) -dimetilS', 2 ', 3', 4 ', 4a' (S) -5 ' , 6 ', 7', 8 ', 8a -' (S) -decahydro-nafUll '(S)) - ethyl] -4 (R) - (tert-butyl-dimethylsilyl) 3,4,5 Preparation of 6-tetrahydro-2H-pyran-2-one

5.0 g (0.0155 mole) of the silyl ether obtained in Step B was hydrogenated in 200 ml of ethyl acetate in the presence of 1.0 g of Pt dioxide in a Paar low pressure hydrogenator overnight. The catalyst was removed by filtration and the filtrate was evaporated

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187,296 rolls. The residue was chromatographed on a 80 cm diameter 15 cm silica gel column (230-240 mesh). Elution under pressure was carried out with 1.5 liters of a 98: 2 by volume mixture of methylene chloride and acetone. The eluents gave 3.4 g (67%) of the title compound, mp 146-147 ° C.

Step D:

6 (R) - [2 - / (8 ') of (S) -2,2-dimethyl-butyryloxy) 2' (S), 6 '(R) -dimethyl-l', 2 ', 3', 4 ', 4a' (S), 5 ', 6', 7 ', 8', 8a '(S) decahydro-naphthyl-l' (S) / - ethyl] -4 (R) - (tert-butyl Preparation of dimethylsilyloxy) -3,4,5,6-tetrahydro-2H-pyran-2-one

0.11 g (0.00025 mol) of the alcohol obtained in Step C is dissolved in 2 ml of pyridine and 0.0074 g (0.00005 mol) of 4-pyrrolidine-pyridine, while stirring with magnetic stirrer, 0.067 g (0.0005 mol). 2,2-Dimethylbutyryl chloride was added. After heating for 3 hours at 100 ° C under nitrogen, an additional 0.0335 g of 2,2-dimethylbutyryl chloride and 0.0039 g of 4-pyrrolidine-pyridine were added and the reaction mixture was heated for an additional 3 hours.

The reaction mixture was cooled, diluted with ether (50 mL) and washed with 3N HCl (2 x 5 mL) and brine (2 x 10 mL). The ethereal solution was dried over magnesium sulfate and evaporated. The resulting yellow oil (0.136 g) was chromatographed on a 30 cm diameter silica gel column (230-400 mesh). It was eluted under pressure with 300 mL dichloroethane followed by 100 mL 98: 2 dichloroethane / acetone. Elution was continued with dichloroethane / acetone (98: 2, 50 mL) to give 0.081 g (60%) of the desired product as a pale yellow oil.

Step E:

6 (R) - [2- / 8 '(S) - (2,2-dimethyl-butyryl) -2' (S), 6 '(S) -dimethyl-l', 2 ', 3', 4 ', 4a' - (S), 5 ', 6', 7 ', 8', 8a '(S) decahydro-naphthyl-l' (S) / - ethyl] -4 (R) -hydroxy-3,4 , 5,6-tetrahydro-2H-pyran-2-one

A solution of 0.5 g (0.00093 mol) of the silyl ether obtained in Step D in 30 ml of tetrahydrofuran was treated with 0.224 g (0.00372 mol) of acetic acid and 0.88 g (0.00279 mol) of tetrabutylammonium fluoride. trihydrate. The mixture was stirred with a magnetic stirrer under nitrogen for 48 hours. The mixture was diluted with ether (150 mL) and washed with water (25 mL) and brine (2 x 75 mL). The ethereal solution was dried over magnesium sulfate, filtered and evaporated. The resulting viscous oil (0.45 g) was chromatographed on a 40 cm diameter 13 cm silica gel column (230-400 mesh). Elution was carried out under pressure with 85:15 v / v dichloroethane / acetone and 20 ml fractions were collected. 21-37. fractions were collected and the solution was evaporated to dryness. The product obtained was 0.37 g (94%). Recrystallization from ether / hexane gave analytical colorless crystals, m.p. 159-160 ° C.

Example 7

Ammonium-3 (R), 5 (R) -dihydroxy-7- [8 '(S) - (2,2-dimethylbutyryloxy) -2' (S) -6 '(S) -dimethyl, 2', 3 ', 4', 4a '(S), 5', 6 ', 7', 8 ', 8a- (S) -Decahydro-naphthyl' (S) -j-heptonate].

300 g of lactone were suspended in 2.1 ml of methanol and then 1.47 ml of sodium hydroxide solution and 2.1 ml of water were added. After stirring for 1 hour at room temperature, the methanol was evaporated in vacuo. The resulting mixture was cooled in an ice / acetone bath, ether (4 mL) was added, and the reaction mixture was acidified with 3N hydrochloric acid with stirring. The ether layer was separated, dried over magnesium sulfate, filtered and bubbled with anhydrous ammonia at room temperature for 2 minutes. The resulting solid was collected to give the title compound, m.p. 143-145 'C.

Elemental analysis: based on C ₂₅ H ₄₇ NO ₆ :

Found: C, 65.61; H, 10.35; N, 3.06 Found: C, 65.34; H, 10.64; N, 3.14.

Example 8

Typical pharmaceutical compositions having a total content of 580-590 mg were prepared by filling size 0 hard shell gelatin capsules with the novel compounds of the present invention, such as in Example 3 (B), Example 1 (C) or Example 2. 3.125, 6.25, 12.5, 25 or 50 mg of the compound obtained and a suitable amount of finely divided lactose.

Claims (10)

A process for the preparation of new 2- (8-acyloxy-2,6-dimethyl-polyhydronaphthyl-1) -ethane derivatives of the formula I R is C 1 -C 10 straight or branched alkyl, except for 2- (S) -butyl, C 3 -C 10 cycloalkyl, C 3 -C 5 alkenyl, C 1 -C 3 alkyl substituted by trifluoromethyl, halophenyl, or the alkyl moiety in the alkyl moiety is C 1-3 phenylalkyl, the dotted lines X and Z represent one of the possible double bonds and if such a double bond is present at all in the molecule then X and Z together or X alone represent and Q is a compound of formula (15), or a pharmaceutically acceptable salt thereof, wherein X and Z are as defined herein, and the corresponding pharmaceutically acceptable salts thereof. Q is a group of formula (15) - heated in a protic solvent with an alkali metal hydroxide followed by acidification and heating and lactonization with -162 After 187,296, the resulting compound of formula (VIII), (VIII) or (II), wherein X and Z are as defined above and Q is (15), is reacted with tert-butyldimethylchlorosilane under inert atmosphere at room temperature. and reacting the resulting 4- (tert-butyldimethylsilyloxy) derivative in pyridine solution with an acid chloride of formula RCOCI in the presence of an acylation catalyst under inert atmosphere, or with an acid of formula RCOOH in the formula R is acylated by stirring with 3 equivalents of 4 eq. mixing in the presence of an acid to remove the silyl group and, if desired, a compound of formula I wherein R, X and Z are as defined above and Q is group (15) with a base having a group of formula (16) The compound of formula (I) wherein R, X and Z are as defined herein is converted into a pharmaceutically acceptable salt thereof. (Priority: 08.08.1980) 2. Process for the preparation of new 2- (8-acyloxy-2,6-dimethyl-polyhydronaphthyl-1-) -ethane derivatives of the formula I R is C 1 -C 8 straight or C 3 -C 10 branched alkyl, except for 2- (S) -butyl, C 3 -C 10 cycloalkyl, C 3 -C 5 alkenyl, C 1 -C 3 alkyl substituted by trifluoromethyl, halogen phenyl or C 1-3 phenylalkyl in the alkyl moiety, the dotted lines X and Z represent one of the possible double bonds and if such a double bond is present at all in the molecule, then X and Z together or X and Q is selected from the group consisting of (15) and pharmaceutically acceptable salts of the corresponding compounds wherein Q is represented by the formula (16), characterized in that one of the compounds of formula (IV), (II) or (II) is X and Z are as defined in the present specification, and Q is a group of formula (15) - in an inert atmosphere at room temperature in the presence of an acid scavenger reaction with tert-butyldimethylchlorosilane and the resulting 4- (tert-butyldimethylsilyloxy) derivative in pyridine solution under inert atmosphere and in the presence of an acylation catalyst, with an acid chloride of the formula RCOCI, wherein R is as defined herein. acylated with or mixed with an acid of formula RCOOH, wherein R is as defined above, and N, N-dicyclohexylcarbodiimide in solution at room temperature and in the presence of an acylation catalyst, and the resulting silyl derivative is mixed with ammonium fluoride and 4 equivalents of acetic acid to remove the silyl group and, if desired, the compound of formula (I) wherein R, X and Z are as defined above and Q is a compound of formula (15). port is converted to a pharmaceutically acceptable salt of a compound of formula I wherein Q, wherein R, X and Z are as defined herein. (Priority 02/02/1980) 3. A process as claimed in claim 1 wherein R is a RCOCI or RCOOH containing a branched alkyl group having from 3 to 10 carbon atoms, except the 2- (S) -butyl group. (Priority: 08.08.1980) 4. A process according to claim 1 wherein the starting compound is a compound of formula III wherein the RCOO group is a compound of formula (11), (13) or (14); Z and Q are as defined in claim 1. (Priority: 08.08.1980) 5. A process according to claim 1, 3 or 4 wherein the starting compound is a compound of formula III wherein X and / or other than double bond and R and Q are as defined in claim 1. specified. (Priority: 08.08.1980) 6. A process according to claim 2, wherein R is a C 3 -C 10 branched alkyl group, except for RCOCI or RCOOH having 2- (S) -butyl. (Priority 02/02/1980) 7. A process according to claim 2 wherein ROC is a compound of formula RCOCI or RCOOH containing 1,1-dimethylpropyl, 1-ethyl-1-methylpropyl or 1,1-diethylpropyl. . (Priority 02/02/1980) 8. A process according to claim 2, 6 or 7 wherein the starting compound is a compound of formula IV wherein X and Z are other than double bonds and Q is as defined in claim 1. (Priority 02/02/1980) 9. A process for the preparation of a pharmaceutical composition having an antihypercholesterolemic effect, comprising the preparation of a compound of formula (I) according to claim 1, wherein R, X, Z and Q are as defined in claim 1, into a pharmaceutical composition. We converted. (Priority: -172 187,296 to a compound of formula (I) R, X, Z and Q are as defined in claim 2 - transforming it into a pharmaceutical composition with auxiliaries customary in the manufacture of pharmaceuticals. 05/08/1980.) 10. A process for the preparation of a pharmaceutical composition having an antihypercholesterolemic effect, comprising the steps of: