CS219922B4 - Thyl-l,1 biphenyl-2-yl/ethenyl/-3,4,5,6-tetrahydro-4-hydroxy-2h-pyraan-2-one - Google Patents

Description

The present invention relates to a hypocholesterolemic and hypolipemically active compound which belongs to a class of compounds whose structure corresponds to the general formula I

and which also includes the corresponding dihydroxy acids formed by the hydrolytic opening of the lactone ring and the pharmaceutically acceptable salts of these acids. Specifically, the invention relates to a compound of formula I wherein E is trans-CH = GH, R1 is 6- (4‘-fluoro-3‘-methyl), R2 is 2-methyl, and R3 is 4-methyl.

Recently, Endo et al. (U.S. Pat. Nos. 4,049,435, 4,137,312, and 3,983,149) have found a fermentation product that is sufficiently active to inhibit cholesterol biosynthesis. This natural product, now called compactin, has been published in Brown et al. (J. Chem. Soc. Porkin I., 1165 (1976) and has the structure of a substituted mevalonic acid lactone derivative. However, low production of this compound from the fermentation medium limits the natural product.

Recent US Patents 4198,425 and 4,255,444 disclose a group of synthetic compounds of Formula II

(ID where

A is methyl or hydrogen,

E represents a direct bond, a C1 to C8 alkylene bridge or a vinylene bridge and

R 1, R 5 and R 3 represent various substituents.

Published European Patent Application by Merck & Co. Inc. No. 0 024 348 discloses a similar series of synthetic compounds wherein A represents hydrogen and in which the lactone ring has the (4R) -trans configuration, an isomer that exhibits all the aintihypercholesterlolemic activity of the uncleaved cis-trans lactone mixture.

The invention relates to one compound falling within the class of compounds disclosed in Czechoslovak Patent No. 219,921 and also disclosed in the aforementioned European Patent Application. 0 024 348, which has an unexpectedly higher order of effectiveness compared to other members of the same class. This compound is ('+) - (4R, 6S) - (E) -6- (2- (3,3', 5-trimethyl-4'-fluoro (1,1'-biphenyl) -2-yl) Ethenyl] -3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one.

Said hypocholesterolemically and hypollpemically active compound has a structure corresponding to formula III

and the invention also relates to the corresponding dihydroxy acid formed therefrom by hydrolytic opening of the lactone ring and a pharmaceutically acceptable salt thereof. Said compound is an enantiomer with the 4- (R) -configuration in tetrahydropyran, the wound residue of the trans-racemate represented by the general formulas (I) and

III.

The designation 4 (R) in the compound indicates that the absolute configuration in the carbon atom space at position 4 of the tetrahydropyran ring is true (Reictus-RJ, and dextrorotatory), which is an unexpectedly potent inhibitor of cholesterol biosynthesis that exceeds inhibitory activity compactinu.

U.S. Patents 4,198,425 and 4,255,444 do not disclose the stereiochemistry of compounds of formula II, let alone the unexpectedly great improvement in potency by separating cis and trans racemates and resolving the resulting products, particularly in this. however, when the phenyl ring is preferably substituted with three substituents at the 2, 4 and 6 positions. Published European Patent Application No. 0 004 348 discloses, however, that the 4 (R) enantiomers of the transacetates of the compounds of Formula I specifically inhibit 3- activity with high efficiency. hydroxy-3-methylglutaryl coenzyme A reductase, an enzyme known to be involved in the rate limiting rate of cholesterol biosynthesis.

The compound of formula (III) to which the invention relates is the most potent member of the above series. The inhibitory activity of these compounds for cholesterol biosynthesis was measured by two methods. Experimental Method A (see U.S. Patent No. 4,198,405) was performed in vitro by the method of HJ Knauss et al., J. Blol, Chem. 234, 2835 (1959) and the activity was expressed as the molar concentration of IC 50 (M) required to inhibit 50% of the enzymatic activity. The second experimental method B is the method of AA Kandutsch et al., J. Blol. Chem. 248, 8403 (1973), which measures the quantity of ¹⁴ C-cholesterol biosynthesized from ¹⁴ C-acetic acid in L-cells of mice. Activity was expressed as inhibition of 50% cholesterol biosynthesis.

The results obtained in these two tests for the compounds of formula II shown in the cited US patents show that IC 50 values ranged from 10 ⁴ to 10 ^-6 . The lowest 50% effective dose is about 4 X X10 ^-6 , while the values for compactin in the same tests are 0.8 Χ Ϊ0 ^-8 .

As shown in European Patent Application Publication No. 0024 348, the inhibitory effect is considerably higher for the resolved isomers, especially if these isoinery have an optimal choice of 2,4,6 arrangements of R1, R2 and R3 substituents on the phenyl ring in the structure of formula II, and in particular in which case A represents hydrogen and E represents a trans-CH = = C'H-group. Thus, the (+) trans enantiomer of 6- {2- [2,4-dichloro-6- (phenylmethoxy) phenyl] ethyl; 3,4,4,6-tetrahydro-4-hydroxy-1H-pyran-2-one has an IC50 of 6.8XT0 ^-8 in Test A. An even stronger compound is the (+) -trans enantiomer of (E) -6- {2- (3,5-dichloro-4'-fluoro- [1,1'-biphenyl] -2-yl) ethenyl} -3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one and the compound of the invention, i.e. the (+ J trans enantiomer (EJ -6- {2- ( 4'-Fluoro-3,3 ', 5-trimethyl- [ΐ, Γ-biphenyl] -2-yl] -ethenyl-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one is several times stronger.

The compounds were tested in the form of the sodium salts of the corresponding dihydroxy acids. The compound of the invention has the additional advantage that it contains no chlorine substituents. Although the metabolism of these substances is not fully elucidated, it is preferred that the compound cannot be metaholicized to polychlorobiphenyl (PCBJ), a class of substances known to cause cancer.

The synthesis of the 4 (R) tranf lactone of the invention is shown in the following scheme.

The number of each step of the reaction shown in the scheme corresponds to the paragraph number describing this Reaction and the number of the corresponding step in Example 1. Steps 5 to 9 represent a novel process of the invention.

CHO

Grade 9 ch ₃

Reactions in the scheme:

1. Reaction with aniline in boiling toluene under reflux.

2. Reaction with palladium acetate in acetic acid at reflux.

3. Reaction with a substituted Grignard reagent of formula ₃ in a suitable solvent such as benzene or toluene in the presence of triphenylphosphine, followed by hydrolysis with · 6 · hydrochloric acid at room temperature.

4. Aldol condensation

a) A classical aldol synthesis in which acetaldehyde is condensed with the starting benzaldehyde, the resulting β-hydroxyaldehyde is acetylated with acetic anhydride and acetic acid is eliminated by heat to form the corresponding cinnumylaldehyde.

b) Direct aldol condensation in which an anion of a suitably N-substituted ethylidenylimine such as ethylidenecyclohexylimine and the like is condensed with the starting benzaldehyde at room temperature or lower in an aprotic solvent such as tetrahydrofuran and the like to form β-hydroxy-4-phenylpropylidenylimine, which, after simultaneous dehydration and hydrolysis of the imine in an acidic environment such as dilute scientific hydrochloric acid, provides a corresponding reaction and 1 de hy d.

c) Use of a nucleophilic equivalent of acetaldehyde. wherein the cis-2-ethoxyvinyllithium produced from cis-1-ethoxy-2-tri-n-butylstannylethylene is condensed with the starting benzaldehyde to form an allyl alcohol, which is then converted into the allyl alcohol. appropriate acidic conditions, switches to the corresponding cinnamaldehyde.

5. Dianion stage

Reaction with an acetic acid ester dianic in a suitable aprotic solvent such as tetrahydrofuran, dioxane and the like.

6. Reduction with sodium borohydride in a suitable solvent such as methanol, ethanol and the like at or below room temperature.

7. Lactonization. Base saponification, for example with sodium hydroxide in aqueous alcohol, followed by acidification and cyclodehydration by heating in toluene, followed by separation of the cis and trans isomeric mixtures by silica gel chromatography or crystallization.

8. Resolution of the trans racemate to its enantiomers, which is carried out by treating either (-) - or - (. Alpha.-alpha-methylbenzylamine) with (+) - trans lactone to form diastereometric dihydroxyamides which are separated by chromatography or crystallization.

9. Hydrolysis of each pure diastereometric amide under basic conditions, such as in the presence of ethanolic sodium hydroxide, and the like, to give the corresponding enantiomerically pure dihydroxy acid which, upon lactonization, for example in refluxing toluene, affords the pure (+) -trans enantiomer. Stereochemistry depends on the absolute stereochemistry of the diastereometric amide from which it is derived.

The present invention also relates to pharmaceutical compositions comprising at least one compound of formula III in association with a pharmaceutical carrier or diluent. The pharmaceutical composition may be formulated in a conventional manner using a solid or liquid carrier or diluent and pharmaceutical excipients suitable for the product in question. application. The compounds may be administered orally, for example in the form of tablets, capsules, granules or powders, or may be administered parenterally in the form of injectables. The dose to be administered depends on the unit dose, symptoms, age and weight of the patients. The doses for adults are preferably between 200 and 21090 milligrams per day, and can be administered at one time or in several divided doses of 1X to 4X per day.

Typical capsules for oral administration contain the active ingredient (2 | 50 mg), lactose (75 milligrams) and magnesium stearate (15 mg). The mixture is sieved through a sieve of about 210 millimeters and filled into No. 1 gelatin capsules.

Typical injectable formulations are prepared by aseptically placing 250 mg of the sterile component into a vial, freeze-drying under aseptic conditions to dry the formulation and then sealing the vial. In use, the contents of the vial are mixed with 2 ml of physiological saline to obtain an injectable preparation.

The compounds of the invention also have an advantageous antifungal effect. For example, they can be used to suppress strains of Penicillium sp., Aspergillus niger, Cladosporium sp., Cochlioflbelus miyabeonus, and Hilminthosporium isynodnotls. For these uses, they are mixed with suitable formulating agents, powders, emulsifying agents or solvents, such as suitable ethanol, and the resulting compositions are applied to the plants to be treated, such as spraying or dusting.

The invention is illustrated by the following examples. The examples are illustrative only, but do not limit the scope of the invention in any way. The ratios of the amounts of solvents are by volume and percentages are by weight unless otherwise stated.

Example i (+) - 1 (4R, SS) - (E) -6- {2- (4'-fluoro-3,3 ', 5-trimethyl / 1,1'-biphenyl / -2-yl) ethenyl ) -3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one

Stage 1:

Preparation of N- [(2,4-dimethylphenyl) methylene] benzenamine

A mixture of 2,4-dimethylbenzaldehyde (53.7 g, 0.4 mol), freshly distilled aniline (37.5 g, 0.4 mol) and toluene (150 ml) was heated to reflux using Dean-Stark. water separators for 2 'hours. The solution was cooled and concentrated under reduced pressure. Distillation of the residue under a pressure of 27 P'a give the product as a yellow oil (81.3 g, 97% yield], b.p. 122 to 130 ^Q C, which solidified upon cooling.

Stage 2:

Preparation of bis (N - (acetato-O: O)) bis-3,5-dimethyl-2 - [(phenylamino) methyl] phenyl-C, N '} dipaladium

A mixture of N - [(2,4-dimethylphenyl (methylene) benzenamine (58.7 g, 0.28 mol) and palladium acetate (62.9 g, 0.28 mol) in acetic acid (1 liter) is heated to reflux. After cooling to 50 ° C, the reaction mixture was filtered by gravity filtration and the filtrate was poured into water (4 liters) .The aqueous mixture was stirred overnight and then filtered. of water, air dried for several hours with suction and then dried in a vacuum oven (2 days at 45 ° C) to give the desired product as a yellow-orange solid (101.3 g, 97% yield).

Stage 3:

Preparation 4 ^<-fluoro-3,3 ', 5-trimethyl-l-biphenyl-2-carboxaldehyde

In a 1 liter three-necked flask equipped with a magnetic stir bar, nitrogen inlet, dropping funnel (250 mL) and a condenser closed with a drying tube was placed magnesium shavings (4.5 g, 0.185 mol).

The apparatus, which is kept under nitrogen, is heated with a temperature tube and then allowed to cool to room temperature. 5-Bromo-2-fluorotoluene (35.0 g, 0.185 mol) was dissolved in 300 mL of ether and 40 mL of the resulting solution was added to the magnesium shavings. After gentle warming with a thermometer to initiate the reaction, the remainder of the ether solution was added at a rate to maintain reflux (1 hour). The mixture was stirred an additional 30 minutes under reflux and then cooled to room temperature.

Meanwhile, the palladium complex (45.2 g, 0.06 mol) from step 2 was added to 1 liter of toluene in a 3 L three neck flask. The resulting mixture was stirred vigorously and refluxed for 1 hour using a Dean-Stark water trap to separate traces of water. The mixture was cooled to room temperature under nitrogen, triphenylphosphine (64.0 g, 0.24 mol) was added and stirred for an additional 30 minutes. The Grgnard reagent was added from the dropping funnel in a slow steady stream and the reaction mixture was stirred for 1 hour. After addition of 200 ml of 6 N hydrochloric acid, the mixture is stirred for an additional hour and then filtered. The separated solid was washed with several portions of toluene. The filtrate and washings were combined and subjected to separation. The toluene-ether solution was washed with 2X 20C · ml solution of common salt in water and dried over magnesium sulfate. After filtration and evaporation of the filtrate, a black oil (70 g) is obtained which is chromatographed on a 120 mm 'Slili' column (1.5 kg of silica gel with a particle size of 38 to 63 μπι) using a mixture of 40% methylene chloride in hexane ( Two fractions of 1000 ml each and 20 fractions of 500 ml each are collected The pure product is contained in fractions 5 to 14. Fractions 14 to 17 contain a mixture of the desired aldehyde and 2,4-dimethylbenzaldehyde to obtain 9 to 21. g of the coupled product as a light yellow solid (70% yield); chromatoigramu one spot on TLC (R _f = 0.30 on a silica gel GF plate using a mixture of 40 vol.% methylene chloride in hexane), m.p. 75-78 ^Q C. The melting point of the over-sublimed product is 78-80 ° C.

Stage 4:

Preparation of 3- (4‘-fluoro-3,3,5,5-trimethyl / 1,1'-biphenyl-2-yl) -2-propenal

A (1) -1-ethoxy-2-tributylstannylethylene solution (68.5 grams, 0.19 mol) was placed in a dry one liter four-necked flask equipped with a magnetic stir bar, nitrogen inlet tube, thermometer, dropping funnel (closed drying tube) and septum. n-butyllithium (1.48 molar solution in hexane, 130 mL, 0.19 mol) was added via syringe to the solution over a period of 25 minutes using a dry ice / acetone bath. The resulting mixture was stirred under nitrogen at -75 ° C for one hour, then a solution of 4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-carboxaldehyde was added dropwise over one hour. (40.7 g, 0.108 mol) in tetrahydrofuran (150 mL) at -75 [deg.] C. The reaction mixture was stirred for 10 minutes, then the cooling bath was removed and the reaction mixture was stirred at room temperature for 1 L. 2 hours Saturated aqueous sodium bicarbonate solution was added The reaction mixture was partitioned between ether (5.00 ml) and water (500 ml). After separation of the layers, the aqueous phase is extracted with 2X ether. The ether extracts were combined, washed with cold water and brine, dried (MgSO 4) and evaporated.

The residual oil was taken up in tetrahydrofuran (2010 mL), 6 N hydrochloric acid (25 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hour. Dilute the mixture with cold water and extract with ether (3.X). The ether extracts were combined, washed with cold water and brine, and dried over magnesium sulfate. Filtration of the extract and evaporation gave a tan oil (120 g) which was chromatographed using 2.6 kg of silica gel (particle size 38-63 / un) placed in a “Still” column. Elution was carried out with a mixture of methylene chloride and hexane (3: 1 by volume) and collected with 21 fractions, each having a volume of 1 liter. The major part of the product is contained in fractions 11 to 19. After evaporation, the oil is taken up in warm hexane (60 ml), seed crystals are added to the solution and cooled to room temperature. A white crystalline solid (20.6 g) is obtained, m.p. 82-85 ° C. Fractions 9 and 1d were treated separately and afforded an additional 3.6 grams of product after recrystallization from hexane. The total amount is therefore

24.2 g (54% yield).

Stage 5:

Preparation of methyl- (E-7- [4'-fluoro-3,3 ', 5-trimethyl (1,1'-biphenyl) -2-yl) -5-hydroxy-3-oxo-6-hept enoát u

Methyl acetoacetate (12.31 g. 0.106 mol) was added dropwise to a stirred suspension of sodium hydride (50% w / o oil suspension) (5.09 g, 0.106 mol) in dry tetrahydrofuran (180 mL at 0 ° C (internal temperature, temperature). maintained 'at 10 ° C ja under nitrogen. the resulting solution was mixed at ¹ ° C JPO for 15 minutes and then treated via syringe dropwise over 20 minutes 1.40 M solution of n-butyllithium in hexane (78.7 ml The mixture is stirred for 20 minutes at 0 ° C, the bath is replaced with a dry ice / acetone bath and stirring is continued for a further 5 minutes before the solution of 3- [4'-fluoro-3,3 ', 5-trimethyl (1,1'-biphenyl) -2-yl] -2-propylphenol (26.5 g, 0.099 mol) in dry tetrahydrofuran (150 ml) for 15 minutes at such a rate to maintain the temperature at 10 ° C. ^Q C. the reaction mixture was stirred for 30 · minutes at 0 ° C and then quenched by the slow addition of 6 N hydrochloric acid (45 mL). the mixture was diluted with water (300 m The ether extracts were combined, washed with cold water and brine, dried (MgSO 4), filtered and evaporated. The product was a yellow oil (38 g); one major spot on thin layer chromatogram (silica gel GFj at _Rf = 0.419 (5% acetone in methylene chloride).

Stage 6

Preparation of methyl (E) -7- [4'-fluoro-3,3,5,5-trimethyl (1,1'-biphenyl) -2-yl] -3,5-dihydraxy-6-heptenoate

Sodium tetraborohydride (1.92 g, 0.0507 mol) was added portionwise over 10 minutes to a cold (0 ° C) methyl (E) -7- [4'-fluoro-3,3 ', 5- trimethyl (1,1'-biphenyl} -2-yl) -5-hydroxy-3-oxo-6-heptenoate (37.5 gj in methanol (400 ml). The clear reaction mixture was stirred at 0 ° for 15 min. The mixture was then acidified with 1.2 N hydrochloric acid (22 mL), maintaining the temperature of the mixture below 10 ° C by cooling in an ice bath, and extracted with ether (3 X 230 mL). ), the ether extracts were combined, washed with cold water and brine ·, dried over magnesium sulfate and evaporated to a viscous oil (38 g j. the product showed one major spot on thin layer chromatogram (silica gel GFj, R _f = 0.21 (10% acetone in methylene chloride).

Stage 7:

Preparation of (+) trans (E) -6- (2- [4'-fluoro-3,3 ', 5-trimethyl. (1,1'-biphenyl) -2-yl] ethenyl} -3,4 5,6-tetrahydro-4-hydroxy-2H-pyran-2-one

A solution of methyl (E) -7- (3'-fluoro-3,3 ', 5-trimethyl (1,1'-biphenyl) -2-yl] -3,5-dihydroxy-6-heptenoate (37.7 g) (0.0376 mol) and 1 N sodium hydroxide (100 ml, 0.10 mol) in methanol (150 ml) was stirred at room temperature for 15 minutes. After removal of the methanol by evaporation (30 ° C), the reaction mixture was diluted with water. The organic extracts were combined, washed with cold water, brine, dried over magnesium sulfate, filtered and evaporated to give a yellow-orange oil (37 g).

A solution of the crude oily diacid in toluene (300 mL) was refluxed for one hour using a Dean-Stark water separator. Evaporation gave a yellow oil (37 gj, a mixture of cis and trans lactone. The crude product was chromatographed on a 140 millimeter column. “Still” (silica gel, particle size 38 to 63, μπι) using 10% acetone in methylene chloride (v / v) as the eluent, collecting three fractions of 1 liter and 25 fractions of 5ΌΟ ml and then eluting with A 20% acetone in methylene chloride solution was collected to yield B 1 liter fractions containing predominantly cis racemate (84%). Fractions 12-15 (500 mL each) were combined and evaporated to give a pale yellow oil (£0% purity by The oil was recrystallized from diethyl ether-hexane to give a solid (5 g), m.p. 115 DEG-117 DEG C. Fractions 16-25 were combined and evaporated to give a pale yellow oil (m.p. 12 g), which is a 6: 4 mixture of trans and cis racemate.

This mixture (12 g) was rechromatographed in two batches (using a Waters Prep LC500). Splitting is performed on two columns (prep PAK-5TO) connected in series. Elution was carried out with a 1 ^: 9 v / v mixture of acetone-methylene chloride. Using the recycling technique, the trans isomer (5 g) and the cis racemate (4 g) were obtained. The samples of the trans racemate obtained in the two chromatographic separations were combined to give a white crystalline solid (10 grams), mp 115-117 ° C. All cis fractions from chromatography and separation (Waters) were combined. 9 g of product are obtained, which crystallizes on standing.

Stage 8:

Preparation of (3R, 5S) -N - [(S) -alpha-methylhenzyl) -7- (4'-fluoro-3,3 ', 5-trimethyl (11,1'-biphenyl) -2-yl] - 3,5-dihydroxy-6-heptenamide

(+) -Trans- (E) - 6- (2- [4'-Fluoro-3,3 ', 5-trimethyl (1,1'-biphenyl) -2-yl) ethenyl) -3,4 solution 5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (10 g, 23.2 mol) and (S) - (-) - α-methylbenzylamine (36.35 ml, 34.17 g, 282 mmol) in tetrahydrofuran (35 ml) was stirred under gentle reflux under nitrogen for 16 hours. The reaction mixture was cooled, diluted with diethyl ether (4010 mL) and washed sequentially with water (2X200 mL), 3 N hydrochloric acid (2X300 mL) and brine (2X200 mL), dried over magnesium sulfate and filtered. The filtrate was evaporated to give a mixture of intermediate diastereomeric amides as a light amber resin as a residue.

The resin obtained as a residue was digested in diethyl ether (100 ml) and hexane was added until the solution became cloudy. Seed crystals were then added to the solution and the mixture was cooled to 0 ° C. A solid (1.5 g) having a melting point of 110-112 ° C was collected by filtration. The filtrate was evaporated to a resin (12 g).

This mixture of diastereometric amides was chromatographed (on Waters prep LC 500).

Separation of the mixture is performed on two columns (prep PAK 500 / silica) connected in series. Elution is carried out with a mixture of methylene chloride and acetone (80: 20 v / v). The mixture is separated and the separation is carried out in two separate separations. Using the recycling technique, two diastereoisomers 1) (4.5 g, mp 110-112 ^and C) and 2) (3.5 g, 62.6% of theory, mp 86-89 ° C) were obtained. Compound 2), which is 99% pure by HPLC (HPLC), is the desired diastereoisomer. The mother liquors from recrystallization of compound 2) were combined (1.9 g, 85% of compound 2)).

Stage 9:

Preparation of (+) - (4R, 6S) - (E) -6- (2- (4'-fluoro-3,3 ', 5-trimethyl (1,1'-biphenyl) -2-yl) -ethenyl) -3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one

A solution of N - [(S) -? - methylhenzyl] -7- [4'-fluoro-3 ₍ 3 ' ₁ 5-trimethyl (1,1'-biphenyl) -2-yl] -3,5-dihydroxy- 6-heptenamide (3.5 g, 7.35 mmol), i.e. diastereoisomer 2) from step 8 above, in diethyl ether (300 ml) containing 1 N sodium hydroxide, (44 ml, 44 mmol) and water ( 44 ml) was refluxed under nitrogen for 14 hours. Then the solvent was removed under vacuum (4iO ^Q C). The residue was dissolved in ice water (300 mL) and diethyl ether (500 mL), and then 3 N hydrochloric acid (50 mL) was slowly added to the resulting solution while stirring and cooling to 0 ° C. The organic layer was separated and washed successively with ice-cold 1 N hydrochloric acid (200 ml) and brine (2 X 200 ml), dried over magnesium sulfate and filtered. After evaporation of the solvent in vacuo, the residue was dissolved in toluene (500 ml) and refluxed using a Dean-Stark water trap for 2 hours. Evaporation gave a yellow oil which was chromatographed on a 50 mm silica gel column with a particle size of 38-63 µπι in a "StilT" column. A mixture of acetone and methylene chloride (:0: Ϊ0, v / v) was used as eluent and 10 ml fractions were collected. The product is contained in fractions 19 to 311. The following fractions are slightly contaminated with cis lactone. The fractions that are not completely pure are combined after evaporation and enriched by crystallization from diethyl ether / hexane. Total yield 1.6 g, 01%. The product was pure by 99CL (99.99%) and had a melting point of 87-89 degrees Celsius. [Α] D + 40.56 ° (0 = 1.075,

CHCh).

Claims (1)

SUBJECT A method for preparing (+] - (4R, 6S) - (Ej-6- {2- [4'-fluoro-3,3 ', 5-trimethyl- (Ι, Γ-biphenyl) -2-yl] ethenes (1) -3,4,6,6-tetrahydro-4-hydroxy-2H-pyrah-2-one according to Patent No. 2119 921, characterized in that the dianion of the acetic acid ester is condensed with an aldehyde of the formula to form of the compound of the invention keto is reduced to a hydroxy group, the ester group is saponified, lactanisated and the cis and trans racemates are separated, diastereometric .alpha.-methylenylamides of the trans racemate are prepared and diastereomers are separated and hydrolyzed diastereomer containing the (+) - traris enantiomer with lactonization.