FI78083C - Process for 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. - Google Patents

Description

78083

Method (+) - (4R, 6S) - (E) -6- [T- (4'-fluoro-3,3 ', 5-trimethyl- [T, 1'-biphenyl-2-yl) ethenyl] The invention relates to a process for the preparation of hypocholesterolemic and hypolipemic (+) - (4R, 6S) - (E) -6-one-6-tetrahydro-4Hydro-2H-pyran-2-one. N- (4'-fluoro-3,3 ', 5-trimethyl-N'-biphenyl-2-yl) ethenyl] -3,3,4,5,6-tetrahydro-4-hydroxy-2H-pyran- For the preparation of 2-one of formula (III)

10 H

CH3 SC0! T ^ H F * 15 r il i I CH, (m) / 3 20 CH3

The total synthesis of the 4 (R) -trans-lactone of formula III is shown in the following synthetic scheme. The number of each step of the synthetic scheme corresponds to the numbering of the description and example of the method shown after the scheme. Steps 5-9 represent a new production method according to the invention.

O

CHO jL

1 CH-. I

Cv ^ 3 / L. ^ CH3 \] Step Y | 1 Step 2 35 'li CH- 1 CH3 2 78083 CH3 CH0

5 AcQ ^, Step 3 <, i I

XP <£ I CH, - ^

/ Y Y I

'ks X ch,

/ -7 I

7 CH0 10 - 3 J 2

Step 4

V

Y'C ° 2CH! CH3 CHO

15 CH3 J> H

i 'f CH, UJLAv ^ H3 ^ 3 j ^ ij CH3 CH3

I Phase 6 ST

25 HO - H0V ^ / °

OO-CH- I

? "> X ^«? V FI 1., 7 F \ yk, J Step X Γ Step 8 IL / Cii3 'CH3 H3 i <35 3 78083 CH3. / Ho *. ^ --1 Step 9 H0 \, U 1 'J3 J * j 5 ri! F' CH L o ^.; 'VCH3 \ I i T Ox / Cch3 tH3 1 y io iH3 111

Steps in Reaction Scheme 1. Reaction with aniline in boiling toluene.

2. Reaction with palladium (II) acetate in boiling acetic acid.

3. Reaction with substituted Grignard reagent CH 3 F - (/ γ-MgBr 2 O in a suitable solvent such as benzene or toluene in the presence of triphenylphosphine, followed by hydrolysis with 6 N HCl at ambient temperature.

4. Aldol reaction a) Conventional Aldol synthesis in which acetaldehyde is condensed with benzaldehyde, the resulting β-hydroxy aldehyde is acetylated with acetic anhydride and the acetic acid is thermally removed to give the corresponding cinnamic aldehyde.

b) Modified Aldol condensation in which the anion of an appropriately N-substituted ethylidenylimine, such as ethylenedicyclohexylimine, is condensed with benzaldehyde at room temperature or in a cooler aprotic solvent such as THF to give p-hydroxy phenylpropylidenylimine, which upon simultaneous dehydration and hydrolysis of the imine under acidic conditions in dilute HCl, forms the corresponding cinnamon aldehyde.

c) Use of a nucleophilic reagent corresponding to acetaldehyde, in which cis-2-ethoxyvinyllithium obtained from cis-1-ethoxy-2-tri-n-butylstannylethylene is condensed with benzaldehyde to give an allyl alcohol which is modified in suitable under acidic conditions, to the corresponding cinnamon aldehyde.

10 5. Dianion step. Reaction with the diacione of acetic acid ester in a suitable solvent such as THF or dioxane.

6. Reduction of NaBH 4 in a suitable solvent such as ethanol at room temperature or cooler.

7. Lactone formation. Saponification with a base (e.g. NaOH) in aqueous alcoholic solution, followed by acid formation and ring-closing dehydration by heating in toluene, followed by chromatographic separation of the cis and trans isomers on silica gel or crystallization.

8. Decomposition of the trans racemate into its enantiomers by treatment of (+) - trans-lactone with either D - (+) - or L - (-) - X-methylbenzylamine to form diastereomeric dihydroxyamines which are separated by chromatography or crystallization.

9. Hydrolysis of each pure diastereomeric amide under basic conditions, such as in ethanol-NaOH, to give the corresponding pure dihydroxy acid enantiomer, which is obtained by formation of the lactone in boiling toluene, the pure (+) - trans enantiomer. The stereochemical structure depends on the absolute stereochemical structure of the diastereomeric amide starting material.

35 i 5 78083

The compound prepared according to the invention belongs to the group of compounds having structure (I) v

E

I (I) 10 6 7i2 R1— "Τ '- * 2 15 and the corresponding dihydroxy acid formed by hydrolytic opening of the lactone ring, and pharmaceutically acceptable salts of said acid.

Recently, Endo et al. (U.S. Patent Nos. 4,049,495, 4,137,322 and 3,989,140) describe the preparation of a fermentation product which is effective in inhibiting cholesterol biosynthesis. This natural product, now called compactin, is described by Brown et al. (J. Med. Soc. Perkin I (1976) 1165).

Recent U.S. Patent Nos. 4,198,425 and 4,255,444 contain a number of synthetic compounds of general formula (II), such as T 1111 R 33 35 J- * 2 6 78083 wherein A is -CH 2 or hydrogen, E is a direct bond, The β-alkene bond or the vinylene bond and the Rs are different substituents.

EP 0 024 348 (Merck & Co., Inc.) 5 contains a similar group of synthetic compounds in which A is hydrogen and the lactone ring configuration is (4R) -trans, which isomer has all the antihypercholesterol content of the inseparable cis-trans-lactone mixture. impact.

The (+) - (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 has an unexpectedly high potency compared to other members of the group mentioned in the above-mentioned EP-A-0 024 348 and is is an unexpectedly potent cholesterol inhibitor with better inhibitory ability than compactin.

The aforementioned U.S. Patent Nos. 4,198,425 and 4,255,444 do not provide stereochemical data for the compound of formula (II), only the assumption that an unexpectedly large potentiation of the effect may be due to the resolution of the cis- and trans-racemates and the latter resolution, especially when when the phenyl ring is preferably 2,4,6-trisubstituted. However, EP-A-0 024 348 discloses that the 4 (R) -enantiomers of the trans-racemates of formula (I) are particularly effective against the 3-hydroxy-3-methyl-glutaryl-coenzyme A-reductase, which is known to be involved in the rate-limiting step of cholesterol biosynthesis, inhibitors.

The compound of formula (III) prepared according to the invention is the most potent compound of the latter group. The cholesterol biosynthesis inhibitory effect of these compounds has been measured by two methods. Method A according to U.S. Patent No. 4,198,425 was H.J. Knaussin et al. (J. Biol.Chem. 234 (1959) 2835) in vitro I: 7 78083 ro method and activity was expressed as the molar concentration IC 50 (M) which causes 50% inhibition of the enzyme activity. Method B of U.S. Patent No. 4,198,425 was A.A. Kandutschin et al.

5 (J. Biol. Chem. 248 (1973) 8403) a method for measuring C-cholesterol biosynthesis from C-acetic acid in mouse L cells. Activity is expressed as the amount that inhibits 50% of cholesterol biosynthesis.

The results obtained by these two methods for the compounds of formula (II) described in the US--4-6 pantheets give IC 50 values of 10 to 10 in both experiments. The lowest amount mentioned for 50% inhibition is about 4 x 10, while the value obtained for the compactin in the same experiment is about 0.8-10. EP-A-0 024 348 shows that the inhibitory potency increases greatly when the isomers are separated, in particular when the optimal 2,4,6 order of R 1, 1 * 2 and R 2 in the phenyl ring of the compound of formula (II) is additionally selected, and in particular when A is hydrogen and E is trans-CH = CH-. Thus 6- [3 "(2,4-dichloro-6- (phenylmethoxy) phenyl) ethyl] -3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one The (+) - trans isomer has an IC 2 value of 6.8 x 10 ® in the experiment of Method A. An even more potent compound is (E) -6- / T- (3,5-dichloro-4'-fluoro-25). (2'-Biphenyl-2-yl) ethenyl] -3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (+) - trans isomer, and a compound of this invention, ( E) -6- [2- (4'-fluoro-3,31,5-trimethyl- [1 ', 1'-biphenyl-2-yl) ethenyl] -3,4,5,6-tetrahydro- The (+) - trans isomer 30 of 4-hydroxy-2H-pyran-2-one is many times more potent.

The compounds were tested as sodium salts of the corresponding dihydroxy acids. A further advantage of the compound of the invention is that it has no chlorine substituents. Although the metabolism of the compound is not fully known, it is not preferable to use a compound that may form polychlorophenyl (PCB), a group of substances known to be carcinogenic.

The compound of the invention may be used in pharmaceutical preparations in combination with pharmaceutically acceptable carriers or diluents. The pharmaceutical preparations can be formulated conventionally using solid or liquid carriers or diluents, as well as pharmaceutical excipients, according to the desired route of administration. The compounds may be administered orally, for example, as tablets, capsules, granules or powders, or parenterally as injections. The dose to be administered depends on the total dose, the symptoms and the age and weight of the patient. The dose to be administered to adults is preferably 200 to 2000 mg / day, which may be administered in a single dose or in 1 to 4 single doses per day.

A typical oral capsule contains the active substance (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is screened through a 60 mesh screen and packaged in gelatin capsule no. 1.

A typical preparation for injection is prepared by aseptically packing 250 mg of sterile active substance in a vial, aseptically lyophilisating and sealing the vial. For use, the contents of the flask are mixed with physiological saline (2 ml) to give a thiol solution for injection.

The compound of the invention is also useful as an antifungal agent. It can be used, for example, against Penicillum sp., Aspergillus niger, Cladosporium sp., Cochliobolus miyabeonus-30 and Milminthosporium cynodnotis. For this purpose, it is mixed with suitable formulation agents, powders, emulsifiers or solvents, such as an ethanol-water mixture, and sprayed and applied to the plants to be treated as a powder.

The invention is illustrated by the following examples in which the solution; 9 78083 tin ratios are given in volumes and percentages, unless otherwise indicated, or in weights.

Example (+) - (4R, 6S) - (E) -6- [7- (4'-fluoro-3,31,5-trimethyl-1,1-bi-5-phenyl-2-yl)] ethenyl.7-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one

Step 1: Preparation of N-Z (2,4-dimethylphenyl) methylene [7] benzamine 2,4-dimethylbenzaldehyde (53.7 g, 0.4 mol), freshly distilled aniline (37.5 g, 0.4 mol) and toluene (150 ml) ) the mixture was refluxed using a Dean-Stark trap (azeotropic water separator) for 2 h. The solution was cooled and concentrated in vacuo. The residue was distilled at 0.2 mmHg to give a yellow oily product (83.3 g, 97% yield), b.p. 122-130 ° C, which solidified on cooling.

Step 2: Preparation of bis (N- (acetano-0: 0)) bis (3,5-dimethyl-2- (phenylimino) methyl) phenyl-C, B7-dipalladium N- (1,2,4-dimethylphenyl) methylene] a mixture of benzamine (58.7 g, 0.28 mol) and palladium (II) acetate (62.9 g, 0.28 mol) was refluxed in acetic acid (1 L) with stirring for 1 hour. Cooled to 50 ° C, filtered and the filtrate was poured into water (4 L). The aqueous mixture was stirred overnight and filtered. The solid residue was washed several times with cold water and dried for several hours with suction and dried in a vacuum oven (45 ° C) for 2 days to give the desired product as a yellow-orange solid (101.3 g, 97% yield).

Step 3: Preparation of 4'-fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-carboxaldehyde To a three-necked flask (1 L) equipped with a magnetic rod, a tube for conducting nitrogen, a dropping funnel (250 ml) and refluxed with a drying tube, 4.5 g (0.185 mol) of magnesium crystals were placed. The apparatus was heated under nitrogen and then allowed to cool to room temperature. 5-Bromo-2-78083 fluorotoluene (35.0 g, 0.185 mol) was dissolved in ether (300 mL) and 40 mL of this solution was added over Mg crystals. The mixture was warmed slightly to initiate the reaction and the remaining ether solution was added at such a rate that the solution boiled all the time (1 h). The mixture was refluxed with stirring for another 30 min and cooled to room temperature.

At this time, the Pd complex (45.2 g, 0.06 mol) obtained in Step 2 was added to toluene (1 L) in a 3 L three-necked flask. The mixture thus obtained was stirred vigorously and refluxed (1 h) using a Dean-Stark trap to remove residual water. The mixture was cooled to room temperature under nitrogen, triphenylphosphine (64.0 g, 0.24 mol) was added and stirred for 30 min. The Grignard reagent was added slowly and evenly via addition funnel, and the reaction mixture was stirred for 1 h. 200 mL of 6 N HCl was added, stirred for an additional 1 h and filtered. The solid residue was washed several times with toluene. The filtrate and washings were combined and the layers were separated. The toluene-ether solution was washed twice with 200 ml of sat. brine and dried over MgSO 4. Filtration and evaporation gave a black oil (70 g) which was purified by chromatography on a 120 mm column (1.5 kg of 230-400 mesh silica gel) eluting with 40% v / v CH 2 Cl 2 / hexane. 2 1000 ml fractions and 20 500 ml fractions were collected, 25 pure products were in fractions 5-14. Fractions 14-17 contained the desired aldehyde and 2,4-dimethylbenzaldehyde. A total of 19-21 g of product was obtained as a pale yellow solid (70% yield); the product appeared as a single spot on a TLC plate (Rf = 0.30 on a Silica Gel GF plate 40% v / v CH 2 Cl 2 -hexane mixture as eluent), m.p. 75-78 ° C. The m.p. of the pure sublimed product is 78-80 ° C.

Step 4: Preparation of 3- (4'-fluoro-3,31,5-trimethyl-1,1'-biphenyl] -2-yl-2-propenal

To a dry four-necked flask (1 L) equipped with 35 magnetic rods, a tube for nitrogen conduction, a thermometer, a dropping funnel sealed with a drying tube, and a septum cap were added 78083 of (Z) -1-ethoxy-2-tributylstannyl in dry THF (200 mL). 68.5 g, 0.19 mol) and then cooled in a dry ice-acetone bath. n-Butyllithium (1.48 M hexane solution, 130 mL, 0.19 mol) was added via syringe over 25 min. 41-Fluoro-3,3 ', 5-trimethyl-1,1'-biphenyl-2-carboxaldehyde (40.7 g, 0.168 mol) dissolved in THF (150 ml) was stirred at 5-75 ° C for 1 h. ) was added dropwise over 1 hour at -75 ° C. After stirring for 10 min, the cold bath was removed and the reaction mixture was stirred at ambient temperature for 1.5 h. Slowly added 10 mL and evenly sat. NaHCO 3 solution (150 mL), ether (500 mL) and water (500 mL) were added and the layers were separated. The aqueous layer was extracted with ether twice. The ether extracts were combined, washed with cold water and sat. in brine and dried over MgSO 4. Filtered and evaporated to give a tan oil (120 g) which was purified by chromatography on silica gel (2.6 kg, 230-400 mesh, 140 mm column). Eluted with Cl 2 Cl 2 -hexane (3: 1 by volume) 21 fractions (1 L each), most of the product was in fractions 11-19. After evaporation, the oil was dissolved in warm hexane (60 mL); crystallization centers were added and cooled to room temperature to give a white crystalline precipitate (20.6 g), m.p. 82-85 ° C. Fractions 9 and 10 were treated separately to recrystallize from hexane to give an additional 3.6 g of product; the total amount obtained was 24.2 g (yield 54%).

Step 5: Methyl- (E) -7- (4'-fluoro-3,3 ', 5-trimethyl-1,1-bi-phenyl [7-2-yl) -5-hydroxy-3-oxo- Preparation of 6-heptenoate Methyl acetoacetate (12.31 g, 0.106 mol) was added dropwise with stirring to dry tetrahydrofuran (180 ml) suspended in sodium hydride (50% oil suspension, 5.09 g, 0.0106 mol) at 0 ° C ( below the surface, keeping the temperature below 10 ° C) and nitrogen as shielding gas. The resulting solution was stirred at 0 ° C for 15 min and then treated with a 1.40 M solution of butyllithium in hexane (78.7 mL, 0.106 mol), which was added dropwise over 20 min via syringe. After stirring at 0 ° C for 20 min, the bath was changed to an ice-acetone bath and stirred for another 5 min. 3- (4'-Fluoro-3,3 ', 5-trimethyl-1,1-biphenyl-2-yl-2-propenal (26.5 g, 0.099) dissolved in dry THF was added to 178083 (150 mL). mol) dropwise over 15 min, maintaining the temperature at 10. The reaction mixture was stirred at 0 for 30 min and 45 mL of 6 N HCl was added again, diluted with water (300 mL) and The ether extracts were combined, washed with cold water and brine, dried over MgSO 4, filtered and evaporated to give a yellow oil (38 g), which appeared as a single spot on a TLC plate (Silica Gel GP), R .49 (5% v / v acetone-ch2Cl2).

Step 6: Preparation of methyl (E) - (4'-fluoro-3,3'5-trimethyl-1,1-bi-phenyl / -2-yl) 3,5-dihydroxy-6-heptenoate

Sodium borohydride (1.92 g, 0.0507 mol) was added portionwise over 10 minutes with stirring to a cold (0 ° C) solution of methyl (E) -7- (4'-fluoro-3,3 ', 5- trimethyl (11,11-biphenyl-2-yl) -5-hydroxy-3-oxo-6-heptenoate (37.5 g) in methanol (400 ml). The clear reaction mixture was stirred for 15 min and then diluted with water (300 mL). Keeping the temperature below 10 ° C with an ice bath, the mixture was acidified with 12 N HCl (22 mL). Extracted three times with ether (250 ml at a time), the ether extracts were combined, washed with cold water and sat. brine, dried over MgSO 4 and evaporated to a viscous oil (38 g). The product appeared as a single spot on a TLC plate (Silica Gel GF), Rf = 0.21 (10% v / v acetone-CH2Cl2).

Step 7; (+) - trans- (E) -2- (2- (4'-fluoro-3,3 ', 5-trimethyl- (1,1'-biphenyl) -2-yl) ethenyl) -3,4, Preparation of 5,6-tetrahydro-4-hydroxy-2H-pyran-2-one Methyl (E) -7- (3'-fluoro-3,3 ', 5-trimethyl-4'-dissolved) in methanol (150 ml) A mixture of 1,1'-biphenyl-2-yl) -3,5-dihydroxy-6-heptenoate (37.7 g, 0.0976 mol) and 1N sodium hydroxide (100 ml, 0.10 mol) was stirred at room temperature. at 15 min. The methanol was removed by evaporation at 35 (30 ° C), the reaction mixture was diluted with water (600 mL), acidified with concentrated HCl and extracted with ether (3 x 300 mL). The ether extracts were combined, washed with cold water and sat. brine, dried over MgSO 4 and evaporated to give a yellow-orange oil (37 g).

The crude oily diol acid dissolved in toluene (300 mL) was refluxed under a Dean-Stark seal for 1 h.

Evaporation gave a yellow oil (37 g) which was a mixture of cis- and trans-lactones. The product was purified by chromatography on a 140 mm column (230-400 mesh silica gel), eluting with 10% v / v acetone-CH 2 Cl 2.

After collecting 3 1 L fractions and 25 10 500 ml fractions, elution was continued with 20% v / v acetone-CH2-Cl2 and 6 1 L fractions containing mainly cis-racemate were collected ( 84%). Fractions 12-15 of 500 ml were combined and evaporated to give the trans racemate as a pale yellow oil (90% pure by HPLC analysis). This was crystallized from Et 2 O-hexane to give a solid product (5 g), m.p. 115-117 ° C. Fractions 16-25 were combined and evaporated to give a pale yellow oil (12 g) which was a 6: 4 mixture of trans and cis racemates.

This mixture (12 g) was rechromatographed twice on a Waters Prep LC500, using two preparative PAK-500 silica cartridges in series and eluting with acetone-CH 2 Cl 2 (1: 9, v / v). 5 g of the trans isomer and 4 g of the cis isomer were obtained. The trans-rase-25 countries collected from both chromatographic separations were combined to give a white crystalline solid (10 g), m.p. 115-117 ° C. All cis fractions obtained by chromatography and Waters separation were combined to give 9 g of product which crystallized on standing.

Step 8: (3R, 5S) -N - ((S) -c (methylbenzyl) -7- (4'-fluoro-3,3 ', 5-trimethyl-11,11-biphenyl-2-yl) Preparation of -3,5-dihydroxy-6-heptenoic acid amide dissolved in THF (35 ml) (-) - trans- (E) -6- [T- (4'-fluoro-3,3 ', 5-trimethyl, 1'- biphen-2-yl) ethenyl] -35,4,5,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (10 g, 28.2 mmol) and (S) - (-) - o (methylmethylbenzylamine (36.35 mL, 24.17 g, 282 mmol) was gently stirred at reflux under nitrogen for 14,780 8 3 16 h. The reaction mixture was cooled, diluted with South (400 mL) and washed with water (2 x 200 mL), 3 N HCl (2 x 300 mL) and brine (2 x 200 mL), dried over MgSO 4 and filtered, and the filtrate was evaporated to give a mixture of diastereomeric amides as a pale yellow gum.

The residue was dissolved in Et 2 O (100 mL) and treated with hexane until the solution was cloudy. Crystallization centers were added and cooled to 0 ° C. Solid, 1.5 g, 10 m.p. 110-12 ° C, collected by filtration. The filtrate was evaporated to give a gummy product (12 g).

This mixture of diastereomeric amides was purified by chromatography on a Waters Prep LC500. The mixture was separated using two preparative PAK-500 / silica cartridges in series eluting with methylene chloride-acetone (80:20, v / v). The mixture was divided and eluted in two portions. Two diastereomers (1) (4.5 g, m.p. 110-12 ° C) and (2) (3.5 g, 52.6% of theory) were obtained, m.p. 86-9 ° C. Compound (2), which is 99% pure by HPLC analysis, is the desired diastereomer. The mother liquors from the crystallizations of (2) were combined (1.9 g, 75% (2)).

Step 9: (+) - (4R, 6S) - (E) -6- [2-4'-fluoro-3,3 ', 5-trimethyl- [3 ”, 1'-biphenyl] -2-yl ) ethenyl / -3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one 25 Solution of N - ((S) -o <-methylbenzyl) -7- (4 ' - fluoro-3,31,5-trimethyl-1,1'-biphenyl-2-yl-3,5-dihydroxy-6-heptenoic acid amide (3.5 g, 7.35 mmol), diastereomer (2) from the above step 8.1 N NaOH (44 mL, 44 mmol) and H 2 O (44 mL) in EtOH (300 mL) were refluxed under nitrogen for 14 h.

The solvent was evaporated under reduced pressure (40 ° C). The residue was dissolved in ice water (300 mL) and Etis (500 mL), cooled and slowly added with stirring and 3 N HCl (50 mL). The organic layer was separated and washed with ice-cold 1 N HCl (200 mL) and sat. brine (2 x 200 mL), dried over MgSO 4 and filtered. The solvent was evaporated under reduced pressure and the residue was dissolved in toluene (500 ml) and refluxed in toluene under a Dean-Stark seal for 2 h.

15 78083

Evaporation gave a yellow oil which was purified by chromatography on a 50 mm column (230-400 mesh silica gel) eluting with acetone-methylene chloride (10:90 by volume) and collecting 10 ml fractions. Product 5 was in fractions 19-31, followed by elution of fractions slightly contaminated with cis-lactone. The less pure fractions were combined and, after evaporation, enriched by crystallization from Et 2 O-hexane. The combined yield was 1.6 g, 61%. The product was 99% pure by HPLC analysis, m.p. 87-9 ° C.

[.Alpha.] D @ 20 + 40.56 DEG (c = 1.075, CHCl3).

Claims (7)

Method (+) - (4R, 6S) - (E) -6- [2- (4'-fluoro-3,3 ', 5-trimethyl- [1,1'-biphenyl] -2-yl)] ethenyl, / - 3 / 4,5,6-tetra-5 hydro-4-hydroxy-2H-pyran-2-one of formula (III) H 10 FH 3 f * HF 1 J III 15 l | v characterized in that a) the dianion of the acetic acid ester is condensed with an aldehyde of the formula CH-, CHO J x '30 to give a compound of the formula li 78083 ° = f ^ CO-CH- 1 OH CH- ^ 5 j) f ^ j) CH 3 X b) reducing the keto group to hydroxyl to give a compound of formula 15 H °. co2ch3 ^ OH ch3 ^ FsA 20 | X 25 c) saponifying the ester, forming the lactone and separating the cis and trans racemates to give the lactone of formula 18 78083 HO ‘O O D) formation of diastereomeric C 1-4 methylbenzylamides from the trans-racemate by treatment of (±) -trans-lactone with either d- (+) - or 1- (-) - n-methylbenzylamine to give compound of formula CH3xX \ 20. J »CH3 1 Tlf b ^ 3 and separating the diastereomeric dihydroxyamides by chromatography or crystallization, and 30 e) hydrolyzing the diastereomer containing the (+) - trans enantiomer of the product with a base and converting the resulting compound to the lactone by heating it in toluene under reflux . i, i9 78083 For the preparation of (+) - (4R, 6S) - (E) -6-Cl- (4'-fluoro-3,3 ', S-trimethyl-1,1-biphenyl) -2- yl) ethenyl / -3,4,5,6,6-tetrahydro-4-hydroxy-2H-pyran-2-one, with formula (III) H 10 l? H 3 H III F Jv J Ml f 15 T 1 Th3 kännetecknat därav, att man 20 a) condensed dianion of acetoacetic acid ester with aldehyde with the formula CHO CH3 I 25 mJL jt ^ VVCli3 V CH3 30 for heat recovery with the formula 20 78083 o = r ^ co2cH3 L OH 5 CH3 J txx 10 ch3 b) reduction of ketogroups to a hydroxyl group for a mixture of 15 H0 L OH ch3 20 FTil f 25 <^ 3 c) förvälar estern, bildar lactonet och separerar cis- och transracematen för erhällande av en förening med formeln