Processing of 6(r)-(2-(s(s)-(2,2-dimethylbutyryloxy)-2(s),6(s)-dimethyl-1,2,3,4,4a(s),5,6,7,8,8a(s)-decahydronaphtyl-1(s),(ethyl)-4-(r)-hydroxy-3,4,5,6,-tetrahydro-2h-pyran-2-pyranon

Compounds having a structure and biological effects similar to the compound of formula I are known in the literature. U.S. Pat. No. 3,983,140 describes the fermentation preparation of a compound known as ML-236B and compactin. U.S. Pat. No. 4,231,938 and U.S. Pat. No. 4,294,846 disclose, using another organism, the fermentation preparation of mevinoline and 4α, 5-dihydromevinoline and Japanese published application (Kokai) no. No. 55009-024 discloses tetrahydrocompactin wherein the polyhydronaphthyl moiety is decalin.

The present invention provides a novel compound of formula I derived from mevinoline, which has a trans-decalin moiety in place of the hexahydronaphthyl group and an 8 (S) - (2,2-dimethylbutyryloxy) group instead of the natural 8 (S) - (2 (S) -methylbutyryl) -groups. _γ

The present invention provides a process for the preparation of a compound of formula I or Ia

Λ

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(I) or

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or a pharmaceutically acceptable magnesium or ammonium salt of an ethyl or ω-monoglyceride salt of a compound of formula Ia, such as sodium, potassium, calcium, and the like, or an alkyl ester of a compound of formula Ia, such as methyl,

The following synthetic schemes I and II illustrate the preparation of a compound of the invention.

Synthetic scheme

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Synthetic Schemes I and II illustrate 3 different methods for preparing the intermediate of formula V, starting from an identical starting material, followed by the preparation of a new compound of formula I according to the invention in two steps. Procedures under these steps include:

Stage 1

Compound iaK-603 (mevinoline) or the corresponding 4α, 5-dihydroderivative is reacted with an excess of lithium hydroxide in aqueous solution at 50-100 ° C (reflux temperature) for 2-4 days, after which the reaction mixture is cooled, The mixture is acidified, extracted with a solvent, and lactonisized by heating the toluene solution.

Stage 2

The diol of formula III or VII with niono silyl is reacted with tert-butyldimethylsilyl chloride and imidazole in an aprotic solvent such as dimethylformamide at room temperature for 12 to about 24 hours to give 4-silyl ether.

Stage 3

The double bonds of the polyhydronaphthyl moiety of the molecule are reduced with hydrogen using a noble metal catalyst such as platinum oxide in an organic solvent such as ethyl acetate at a pressure of 10 to 10 bar at room temperature for 10 to 20 hours.

After isolation, the resulting decalin product is chromatographed, preferably on silica gel, and only the trans-decalin of formula V is isolated.

Stage 4

The 8-hydroxyl group in the compound of formula V is esterified by reaction with 2,2-dimethylbutyryl chloride in pyridine with or without an acylation catalyst such as 4-pyrrolidinopyridine, 4-dimethylaminopyridine or 4-hydroxybenztriazole at a temperature of about 100 to 140 ° C for about 4 to 10 hours.

Stage 5

The 4-O-silyl group is removed by reacting the compound of Formula VI with about 4 equivalents of glacial acetic acid and about 3 equivalents of tetrabutylaminium fluoride trlhydrate in an ether solvent such as tetrahydrofuran, ether, 1,2-dimethoxyethane and the like in an inert atmosphere at 15-30 ° C for 1 to 3 days.

The compound of the invention is useful as an antihypercholesterolemic agent for the treatment of atherosclerosis, hyperlipaemia and the like. It can be administered orally or parenterally in the form of capsules, tablets or injectable preparations and the like. Usually oral administration is desirable. The dosages may vary depending on the age, severity of the disease, body weight and other conditions of the patient. Daily doses of adult humans range from about 2 to 2000 mg (preferably from 10 to 100 mg) and are administered in three or four individual doses. If necessary, higher doses may be administered.

The compound of the invention also exhibits antifungal properties. For example, it can be used to control strains of Penicillium sp., Aspergillus niger, Cladosporium sp., Cochliobolus miyabeanus, and Helminthosporium cynodnotis. For these uses, the compound is mixed with suitable agents, powders, emulsion agents or solvents such as ethanol and sprayed or dusted onto the plants to be protected from fungi.

Example, ^L

Stage 1

Preparation 6 (R) - [2- (8 (S) -Hydroxy-2 (S), 6 (R) -Dimethyl-1,2,6,7,8,8a (R) -hexahydronaphthyl-1 (S)) ethyl] -4 (H) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (2).

A mixture of mevinoline (50.2 g, 0.124 mol) and LiOH. HgO (52.0 g, 1.24 mol) in water (3 L) was magnetically stirred and heated to reflux under nitrogen for 72 hours. The stirred mixture was cooled to 0 ° C (ice-acetone bath) and 12 N HCl (120 mL, 1.44 mol) was added at a rate such that the temperature did not exceed 3 ° C. This mixture was saturated with solid NaCl and extracted with ether (4 x 500 mL). The combined extracts were washed with brine (2 x 250 mL), dried over magnesium sulfate and evaporated to give an orange oil (31.7 g).

This oil was dissolved in toluene (250 mL) and the solution was refluxed for 4 hours under a nitrogen atmosphere while removing water in a Dean-Stark apparatus to relactonize. Evaporation of toluene gave an oily residue which was dissolved in ether (1.5 L). This solution was washed with saturated sodium bicarbonate solution (250 mL), water (250 mL) and brine (250 mL), dried and evaporated to give a solid. Trituration of this solid in hexane (200 mL) afforded the title compound as a cream solid (29.7 g,

%), which does not require further purification for synthetic purposes. An analytical sample was prepared by recrystallization of a portion of the above prepared solid from n-butyl chloride to give colorless drus t, t, 128-131 ° C.

and

Stage 2

Preparation 6 (R) - [2- (8 (S) -Hydroxy-2 (S), 6 (R) -Dimethyl-1,2,6,7,8,8a (R) -hexahydronaphthyl-1 (S)) ethyl-3-4 (R) -tert-butyldimethylsilyloxy-3,4,5,6, -tetrahydro-2H-pyran-2-one (3)

A solution of the alcohol of formula III (18.3 g 0.057 mol), tert-butyldimethylsilyl chloride (10.3 g 0.068 mol) and imidazole (9.3 g 0.137 mol) in dimethylformamide (200 mol) was stirred magnetically at room temperature for 18 hours . The reaction mixture was diluted with ether (1500 mL) and washed successively with water (200 mL), 2% aqueous hydrochloric acid (200 mL), water (200 mL), saturated sodium bicarbonate solution (200 mL), and water (2 mL). 200 ml) and dried over magnesium sulfate. The filtered ether solution was concentrated to 1 liter, diluted with 600 mL of hexane and concentrated to 600 mL to give a white solid (13.7 g). A second crop of crystals (3.4 g) was obtained by evaporating the mother liquors to a volume of 250 ml and standing overnight at 0 ° C. Total yield, 7.1 g (69%) of product m.p. 142-44 ° C.

Stage 3

Preparation 6 (r) -? 2- (8 (S) -hydroxy-2 (S), 6 (S) -dimethyl-1,2,3,4,4a (S), 5,6,7,8, 8a (S) -Decahydro-naphthyl-1 (S) -ethyl-4- (R) -tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one (4).

A mixture of the silyl ether of formula IV (5.0 g, 0.011 5 mol) and PtOg (1.0 g) in ethyl acetate (200 mL) was hydrogenated in a Paar apparatus overnight. The catalyst was filtered off, the filtrate was concentrated to dryness to give a white solid. This product is chromatographed on a 80 mm column containing 17.5 cm silica gel 230-400 mesh. Elution was carried out under air pressure using a mixture of methylene chloride and acetone (98; 2 v / v, 1.5 L). The residue was poured and further eluting with the same solvent (2 L) to give the title compound as a solid

white solids (3.4 g, 67%) mp 146-47 ° C.

Stage 4

Preparation 6 (R) -? - Cs (S) - (2,2-dimethylbutyryloxy) -2 (S), 6 (S) -dimethyl-1,2,3,4,4a (S), 5,6, 7,8,8a (S) -Decahydro-naphthyl-1 (S) 3-ethyl 11-4 (R) -tert-butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one (5)

2,2-Dimethylbutyryl chloride (0.067 g, 0.000 5 mol) was added to a magnetically stirred solution of the alcohol of formula V (0.11 g 0.000 25 mol) and 4-pyrrolidinopyridine (0.007 4 g 0.000 05 mol) in pyridine (2 ml). The solution was heated at 100 ° C for three hours under a nitrogen atmosphere, then 0.033 5 g of 2,2-dimethylbutyryl chloride and 0.003 g of 4-pyrrolidinopyridine were added and the reaction mixture was heated for an additional three hours.

The reaction mixture was cooled, diluted with ether (50 mL), washed with 3 H hydrochloric acid (2 x 5 mL) and brine (2 mL, 0 mL). The ethereal solution was dried over magnesium sulfate, filtered, and evaporated to a yellow oil (0.136 g).

233743 6

This oil is chromatographed on a 30 mm 15 cm silica gel column (230-400 mesh).

The column was eluted under air pressure with dichloromethane (300 mL) and then with dichloromethane / acetone (98: 2, v / v, 100 mL). The front thus obtained is discarded. Further elution with dichloromethane and acetone (98: 2, v / v, 50 mL) gave the desired product as a pale yellow oil (0.081 g, 60%).

Stage 5

Preparation 6 (R) - [2-C8 (3) - (2,2-Dimethylbutyryloxy) -2 (3), (S) -dimethyl-1,2,3,4,4a (S), 5,6 7,8,8a (3) -decahydro-phenyl-1 (S) 3-ethyl-4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.

»

The silyl ether of formula VI (0.5 g, 0.000 93 mol) was added to a solution of tetrahydrofuran (30 mL) containing glacial acetic acid (0.224 g, 0.003 72 mol) and tetrabutylammonium fluoride trihydrate (0.88 g, 0.002 79 mol). This solution was magnetically stirred under nitrogen for 48 hours. The reaction solution was diluted with ether (150 mL) and washed with water (25 mL), brine (2 x 75 mL). The ether solution was dried over magnesium sulfate, filtered and evaporated to give a viscous oil (0.45 g). This oil is chromatographed on a 40 mm column containing 15 cm of silica gel (230-400 mesh).

The column was eluted with a mixture of dichloromethane and acetone (85:15, v / v) under air pressure and collected with 20 ml fractions. Fractions 21-37 were combined and concentrated to dryness to afford the title compound as a solid (0.37 g, 94%). An analytical sample was prepared by recrystallization from ether-hexane to give colorless plates.

159 to 160 ° C.

Example 2

Ethyl-3 (K), 5 (R) -dihydroxy-7-E8 (S) - (2,2-dimethylbutyryloxy) -2 (S), 6 (S) -dimethyl-1,2,3,4,4a (S), 5,6,7,8,8a (S) -decahydronaphthyl-1 (3) 7 sodium heptanoate liethoxide (30 mg) was added to a stirred suspension of the compound of formula 1 (3.0 g) in ethanol (50 g). ml) under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 30 minutes and then diluted with ether (300 mL). The ethereal solution was washed with water (3 x 50 mL), dried over magnesium sulfate and then filtered. The filtrate was evaporated in vacuo to give an oil which was chromatographed on a 60 mm column containing 15 cm silica gel (230-400 mesh). Elution with methylene chloride / ethanol (96: 4, v / v, 250 mL) under air pressure gave the title compound as a solid.

Example 3

2,3-dihydroxypropyl-3 (R), 5 (R) -dihydroxy-7- [8 (S) - (2,2-dimethylbutyryloxy) -2 (S), 6 (S) -dimethyl-1,2, 3,4,4a (S), 5,6,7,8,8a (S) -decahydronaphthyl-1 (S) 7-heptanoate.

The sodium salt of the compound of formula Ia is prepared by adding 1 N NaOH (0.55 ml) to a solution of the compound of formula I in 0.22 g of diraethylformamide (2 ml). The solution was stirred for 15 minutes, 1-iodo-2,3-dihydroxypropane (0.2 g) was added and the stirred solution was heated at 80 ° C (oil bath) for 6 hours. After cooling to room temperature, the real solution was poured into ether (100 mL). This ethereal solution was washed with brine (2 x 25 mL), dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo to give an oil which was chromatographed on a 20 mm column containing 15 cm silica gel (230-400 mesh).

Elution with acetone / methylene chloride (60:40, v / v) under air pressure gave the title compound as an oil which solidified overnight upon freezing.