NO174927B - Analogous Process for the Preparation of Therapeutically Active Benzopyrans - Google Patents

Description

The present invention relates to a process for the production of new, substituted benzopyrans with the general formula I

there

R 1 means C 1-4 alkyl,

I?2 means C1-4alkyl,

alk means C 1-7 alkylene,

R3 means polyfluoro-C8-y-alkyl with at least 5 fluorine atoms, and

R 4 means carboxy or C 1-4 alkoxycarbonyl,

and salts thereof.

Most compounds of formula I can, depending on individual character, also exist in the form of salts. Those of them having a sufficient acidity such as especially those with carboxyl, tetrazolyl or sulfamoyl groups can form salts with bases such as especially inorganic bases, preferably physiologically acceptable alkali metal salts and above all sodium and potassium salts. Also taken into account are ammonium salts with ammonia or physiologically acceptable organic amines such as mono-, di- or trilower alkylamines, for example diethylamine, mono-, di- or tri(hydroxyalkyl) amines such as tris(hydroxymethyl)methylamine or D-glucosamine.

The compounds of formula I and their salts exhibit advantageous pharmacological properties, in particular a pronounced leukotriene antagonism.

Thus, for example, they inhibit in vitro and within the concentration range approx. 0.001 to 1.0 jjmol/1, that of leukotriene-D4(LTD4) induced the contraction of a smooth muscle. This so-called LTD4 antagonism is established experimentally, for example as follows: In segments taken from the ileum of a 300 to 400 g guinea pig and incubated in an organ bath in Tyrode's solution at 38°C and under gas treatment with a mixture of 95 $ oxygen and 5$ carbon dioxide at a load of 1 g, contractions are triggered with synthetic leukotriene-D4 (as potassium salt) and these are recorded isotonically. The degree of inhibition due to the test substance is determined after a pre-incubation of 2 minutes and is indicated as IC50, ie the concentration which reduces the test contraction by 50%. The compounds of formula I are also active in vivo. In addition to the specific and therapeutically very significant advantage, they also have a relatively long working life. Thus, in vivo bronchoconstriction standard tests on guinea pigs by aerosol administration of a solution containing 0.0001 to 1 weight-56 of the test substance, a clear LTD4-antagonizing effect could be demonstrated.

Surprisingly, several compounds of formula I also exert a pronounced inhibitory effect on other physiologically important enzyme systems. Thus, inhibition of phospholipase A2 from human leukocytes has been observed in tested concentration ranges of approx. 0.5 to 50 pmol/1. Likewise, inhibition of phospholipase C from human platelets has been observed in tested concentration ranges of approx. 1 to 100 jjmol/1.

Thanks to these valuable pharmacological properties, the compounds of formula I can find therapeutic application wherever the action of leukotrienes leads to morbid conditions, and alleviate or remove them. According to this, they can, for example, be used for the treatment of allergic conditions and diseases such as asthma in particular, but also high fever and obstructive lung diseases including cystic fibrosis. Likewise, due to the anti-inflammatory effect, they are useful as an anti-inflammatory agent, especially as an external (topical) skin phlogistic for the treatment of bettennel-sesdermatoses of any genesis, for example light skin irritations, contact dermatitis, exanthems and burns, as well as as a mucosal phlogistic for the treatment of inflammations of the mucosa, for example in the eyes, nose, lips, mouth and genitals, respectively the anal area. Furthermore, they can be used as a sun protection agent.

The invention relates in particular to the preparation of the compounds of formula I mentioned in the examples and their salts, especially pharmaceutically acceptable salts.

The method of the invention for the preparation of compounds of formula I and their salts is based on methods known per se and is characterized by the fact that an epoxide of formula II

where R 1 , R 2 , alk and R 3 have the meaning given above, is reacted with a thiol of formula III

where R4 has the above meaning, or a salt thereof, and optionally converts a compound obtained according to the invention into another compound with formula I, separates a stereoisomer mixture obtained according to the invention into the individual

components and/or transfers a free compound obtained according to the invention to a salt or a salt obtained according to the invention to the free compound or another salt.

The reaction of the epoxide II with the thiol III takes place during configuration inversion on the C atom participating in the bond with the thio group and during configuration maintenance on the C atom carrying the hydroxy group. In order to arrive at the preferred compounds with the opposite configuration on the two C atoms, the starting point is preferably the corresponding trans-epoxides II. Thereby, by starting from R,R-epoxides II, compounds I with S(C-S-),R(C-OE) configuration are obtained, respectively by starting from S,S-epoxides II, compounds I with R(C-S )-S(C-OH ) configuration. The conversion takes place under known conditions at temperatures from approx. -20 to approx. +50°C, preferably at room temperature, that is 18 to 25°C, and preferably in a basic medium, for example in the presence of an amine and in particular a tertiary aliphatic, aryl-aliphatic or saturated heterocyclic amine such as trialkylamine (for for example triethylamine or ethyl-diisopropylamine), dialkylbenzyl (for example N,N-dimethylbenzylamine), N,N-dialkylaniline (for example N,N-dimethylaniline) respectively N-methyl- or N-ethylpiperidine or N,N'-dimethylpiperazine. Usually, the reaction is carried out in an indifferent organic solvent such as a lower alkanol, for example methanol or ethanol.

In a preferred embodiment, one starts from components II and III where R4 means esterified carboxy or tetrazolyl and R3 has the stated meaning, hydrolyzes R4 (possibly selectively) to carboxy and transfers this, if desired, to amidated carboxy.

Starting materials for the method of the invention are either known per se or can be obtained by known analogical methods in a manner known per se.

The epoxide with the above-defined formula II used as starting material can in particular be produced by means of the same method as is used in the synthesis of leukotrienes. In a typical general method of synthesis for compound II, where n means 1, one starts, for example, from an aldehyde with the formula

where A and R 3 have the above meaning, whereby an optionally present free carboxyl group R 3 is present in a form protected as an ester, for example as a lower alkyl ester. This compound is condensed with formylmethylene-triphenylphosphorane (or an equivalent reagent), whereby the corresponding trans-3-R3-prop-2-enal of formula is formed. This compound is then epoxidized in a manner known per se, preferably under slightly alkaline conditions (for example in the presence of alkali carbonates) with aqueous hydrogen peroxide, whereby a trans, i.e. 2(RS ),3(RS )-epoxy is formed -3-R3-propanal with the formula

The epoxy aldehyde VI can then by condensation with a phosphonium halide

where Ri, R2 and alk have the above meaning and Hal means a halogen atom and preferably bromine, and a base, for example sodium amide, in tetrahydrofuran, is converted to the corresponding epoxide II where R4 means esterified carboxy and n means 1. Compounds VII are prepared in particular by conversion of a corresponding compound of formula

with triphenylphosphine in the usual way.

Another method for preparing compounds of formula II consists in trans-3-R3~prop-2-enol of the formula

where R3 has the meaning given above, for example epoxidized with tert-butyl hydroperoxide in the presence of titanium tetraisopropanolate and a D- or L-tartaric acid dilave alkyl ester, by using a D-tartaric acid ester one thereby obtains predominantly 2R,3R-epoxy-3- R3~propanol Xlla respectively by using an L-tartaric acid ester predominantly the corresponding 2S,3S-epoxy-3-R3-propanol Xllb

This is then oxidized by treatment with oxalyl chloride/dimethylsulfoxide and then with triethylamine to the corresponding epoxyaldehyde VI which can then be reacted with the corresponding phosphonium salt VII to the corresponding epoxide II where R3 means esterified carboxy.

Thereby, one mainly obtains epoxide II in which the double bond has the preferred cis-stereotaxy. If you use a D-tartaric acid ester, you obtain, as mentioned, predominantly compounds II where the epoxy group exhibits R,R configuration or S,S enantiomers when the reaction takes place in the presence of L-tartaric acid esters.

Compounds obtained according to the method can, if desired, be transferred to other compounds of formula I.

For example, esterified or amidated carboxy groups can be hydrolyzed to free carboxy, preferably under basic conditions, for example in the presence of caustic soda, and preferably in a water-miscible organic solvent such as tetrahydrofuran, dioxane or a lower alkanol such as methanol or ethanol. Conversely, carboxy R4 can be esterified in the usual way.

Free or esterified carboxy R4 can further be amidated in the usual way, for example by treatment with ammonia or a mono- or di-alkylamine. For example, carboxy R4 can be transferred in the usual way, for example in the presence of a carbodiimide salt, for example in the presence of N-ethyl-N-(3-dimethylaminopropyl)-carbodiimide hydrochloride and 4-dimethylaminopyridine, transferred with an optionally substituted benzenesulfamide to the corresponding N-benzenesulfamidoylcarbamyl group.

Of course, the obtained diastereomer mixtures can be separated due to different physical properties of the components into the individual components and/or separate obtained enantiomeric mixtures according to common racemate separation methods into the individual enantiomers.

When individual diastereomers are desired, one can preferably use an individual diastereomer of a starting material at any step in the process or from a starting material present in the form of diastereomers preferably form a diastereomer by stereoselective reaction conditions or optically active reagents or separate racemic diastereomer mixtures by physical separation , possibly using optically active excipients.

In stereochemical terms, however, both the invention's condensation of components II and III as well as the preparation of the starting materials are carried out so that stereotactically uniform starting materials are always used, and the reactions are carried out stereoselectively as far as possible, i.e. by using stereotactically uniform, optically active reagents and/or auxiliaries and isolates stereotactically uniform products from the reaction mixtures immediately after the reaction.

Thus, for example, the cis- and trans-isomers possibly formed during the production of the unsaturated starting materials are separated at once, whereby normal physical separation methods such as chromatography in particular are suitable. In the main reaction, the stereomeric epoxide II is preferably used with the stereotaxic preferred in the final product for the double bonds present and this in racemic form (as is often formed in the variant with epoxidation of compound V with hydrogen peroxide) or preferably as an individual diastereomer with the relative to the final the product's preferred configuration on the (C-S-)-C atom opposite configuration on the oxirane C atom participating in the bond with the S atom.

Similarly, obtained salts can be transferred to the free acids or the obtained free acids to salts by acid treatment or by base treatment.

Due to the close connection between the new compounds in free form and in the form of salts, above and in the following, free compounds and salts naturally also mean the corresponding salts and free compounds respectively.

Preferably, such starting materials and such reaction conditions are used that the compounds specified as particularly preferred are arrived at.

The following examples shall illustrate the invention in more detail. All temperatures are given in °C.

Example 1; 7 - f ( 6R. 7S)- 15-( 4- acetyl- 3- hydroxy- 2- propyl-phenoxy )- l. 1. 1. 2 , 2- pentafluoro- 6- hvdroxy- pentadeca- 8( E) . 10(Z1-diene-7-vlthiol-4-oxo-4H-l-benzopyran-2-carboxylic acid nrethyl ester

A solution of 1.49 g of (6R,7S)-15-(4-acetyl-3-hydroxy-2-propylphenoxy)-6,7-epoksy-1,1,1,2,2,2- pentafluoro-pentadeca-8(E),10(Z)-diene in 100 ml of absolute methanol is stirred for 20 hours at room temperature with 3.3 ml of triethylamine and 1.05 g of 7-mercaptochromone-2-carboxylic acid methyl ester under argon and then evaporated . The residue is dissolved in ethyl acetate and filtered over silica gel. The filtrate is washed with 25 ml IN hydrochloric acid and with 4 x 25 ml of saturated sodium chloride solution, dried over sodium sulphate and evaporated. Purification of the residue by chromatography on silica gel with hexane:acetic acid ester (2:1) as eluent gives the title compound as a pale yellow foam with a melting point of 48-49°C;

Rf (hexane:acetic ester 3:2); = 0.33;

[α]D 2 O(CHCl 3 , 0.230$) = 67.4 ± 4.3°;

UV spectrum (CHC13): X max (c) = 271 (25120), 285 (22080),

324 (14000)

The starting materials are produced as follows:

a) 5, 5, 4, 4, 4-pentafluoro-l-pentene

Method A: At 20°C for 20 minutes, 39.5 g (160 mmol) of gaseous pentafluoroethyl iodide in a suspension of 20.2 g (180 mmol) of activated cadmium powder in 100 ml of dry dimethylformamide. After a 5-minute induction period, a strong exothermic reaction occurs. The reaction mixture is stirred for one hour at room temperature and then filtered under nitrogen under filter bags. The light green organic cadmium solution is then transmetalated at 0°C with 17.2 g (120 mmol) of copper (I) bromide in 100 ml of dry hexamethylphosphoric acid triamide. After stirring for 10 minutes at 0°C, 12.1 g (100 mmol) of allyl bromide are added dropwise over the course of 15 minutes and the whole is stirred for 2 hours at 25°C. Then 250 ml of cold N-hydrochloric acid is added to the cloudy reaction solution. The product is distilled directly over a Vigreux column from the reaction flask. At the boiling point 42-44°C, the title compound passes as a colorless liquid.

<1->H-NMR spectrum (CDCl 3 ; 300 MHz): 5.33 (br. s, 1E); 5.28

(m, 1H); 5.81 (t x d x q, J 16.1, 7.0, sl, 1H); 2.89 (t x d x q, J 17.2, 7.0, x 0.5, 2H).

Method B:

As described under A), under inert conditions, 39.5 g (160 mmol) of pentafluoroethyl iodide are introduced during 20 minutes at room temperature into a suspension of 11.8 g

(180 mmol) activated zinc dust and 160 ml of dimethoxyethane. After approx. After 5 minutes, a strong exothermic reaction occurs and a yellow-green suspension is formed. The reaction mixture is stirred for one hour at 25°C and then filtered under inert conditions. To the light green filtrate, 18.6 g (160 mmol) of N,N,N',N'-tetramethylethylenediamine are first added and at 0'C then 17.2 g (120 mmol) of copper (I) bromide and finally 12 .1 g (100 mmol) allyl bromide. After 5 hours

stirring at 50°C, the reaction mixture is mixed at room temperature with 250 ml of N-hydrochloric acid and the product is distilled directly from the reaction vessel. At the boiling point 51-45°C, the title compound passes as a colorless liquid.

b ) 6. 6. 6. 5. 5-pentafluoro-hexane-l-al

In a pressure autoclave, under inert conditions, 1.3 g (3.8 mmol) of dicobalt octacarbonyl is dissolved in 50 ml of absolute benzene. To this is added at -50°C 29.0 g (180 mmol) of 5,5,5,4,4-pentafluoro-1-pentene and at 60 bar until saturation, also carbon monoxide and hydrogen. The reaction mixture is heated to 100°C and held for 5 hours at this temperature and a pressure of 160 bar. The whole is then cooled and 10 ml (~20 mmol) of the violet solution is fractionally distilled. The boiling point of the thermolabile and air-sensitive aldehyde is 92-93°C (120 mbar),

<1>H-NMR spectrum (CDCl 3 ; 300 MEz): 9.77 (s, 1H); 2.61 (h,

J 7.0, 2H); 2.19 (m, 2H); 1.91 (quint, J 7.0, 2H).

c) 8, 8, 8, 7, 7- pentafluoro- 2( El- octenoic acid ethyl ester

To 40 ml (60 mmol) of the benzene solution of 6,6,6,5,5-pentafluorohexan-1-al (the reaction solution from the previous step) is added 17.4 g (50 mmol) of ethoxycarbonylmethylenetriphenylphosphorane and the whole kept for 14 hours under reflux. The benzene is then distilled off over a rotary evaporator and the residue separated from triphenylphosphine oxide by flash chromatography over a silica gel column with petroleum ether as eluent. The product obtained is fractionally distilled. At the boiling point equal to 103-105°C (28 mbar), the trans-ester passes over as a colorless liquid (the first fraction contains small amounts of cis-ester; E:Z ratio before the distillation: 93:7).

<1>H-NMR spectrum, E compound (CDC13, 60 MHz): 6.70

(d x h, J 15.5, 7, 1H); 5.67 (d, J 15.5, 1H); 4.07

(q, J7, 2H), 2.2 (m, 2H), 1.8 (m, 4H), 1.24 (t, J7).

<1>H-NMR spectrum, Z compound (CDCl 3 , 60 MHz): 6.73

(d x h, J 12, 7, 1H); 5.85 (d, J 12, 1H); 4.06 (q, J 7, 2H); 2.6 (m, 2H); 1.9 (m, 4H), 1.12 (t, J 7, 3H).

d) 7.7,8,8.8-pentafluoro-oct-2(E)-enol

To a solution of 40.0 g of 7,7,8,8,8-pentafluorooct-2(E)ene-carboxylic acid ethyl ester in 300 ml of ether, 380 ml of diisobutylaluminum hydride (1 molar in hexane) is added dropwise over the course of 2 hours at 0- 5<0>C. The obtained solution is poured onto a mixture of 480 ml of ice/water and 95 ml of concentrated hydrochloric acid (cooling, exothermic!). The whole thing is stirred vigorously until two phases have formed. The organic phase is washed three times with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The remaining pale yellow oil is distilled under water jet vacuum. The title compound is obtained with a boiling point of 81-86 °C at (14 mm Hg);

Rf (hexane:acetic ester 3:2) = 0.52;

IR spectrum (CH2C12): 3600, 2950, 2860, 1450, 1380, 1200,

1130, 1030, 970, 650 cm-<1>.

e) ( 2R. 3R)- 2. 3- epoxyv- 7. 7. 8. 8. 8- pentafluoro- octanol

Under absolutely anhydrous conditions and under argon becomes

the solution of 13.3 ml of tetraisopropyl orthotitanate in 100 ml of dichloromethane cooled to -80°C, 9.1 ml of D(-)-tartaric acid diethyl ester and 14.0 g of 7,7,8,8,8-pentafluoro-oct-2 (E)-enol in a little dichloromethane. After stirring for 10 minutes at -80°C, 61.7 ml of a 2.7 molar tert-butyl hydroperoxide solution in toluene is added, whereby the temperature rises to -68°C. Now the temperature is allowed to rise to 0°C over the course of 2 hours, the resulting yellow solution is slowly poured into a solution of 41.5 g of iron(II)-

sulfate and 16.0 g of L( + )-tartaric acid in 150 ml of water (cooling, exothermic!) and stir for 30 minutes at 5-10°C.

The aqueous phase is separated and extracted with 4 x 100 ml of ether. The combined organic extracts are dried over sodium sulfate and evaporated. The residue is dissolved in 100 ml of ether, cooled to 0-5°C, a suspension of 7.0 g of sodium hydroxide in 250 ml of saturated sodium chloride solution is added and the whole is stirred for one hour at 0-5°C. The aqueous phase is separated and extracted with 4 x 150 ml of ether. The combined ether phases are dried over sodium sulphate and evaporated. The residue is purified chromatographically on silica gel with hexane:acetic ester (1:1) as eluent. The title compound is obtained as pale yellow oil: [oc]D 2 o (CHC 13 , 0.49$) = +15.312.0°; Rf (hexane:acetic ester 1:1): = 0.36; IR spectrum (CH 2 Cl 2 ): 3550, 2900, 1440, 1370, 1180, 1130, 1010, 870, 635 cm-<1>. f) ( 4R. 5R)- 4. 5- epoxy- 9, 9. 10. 10. 10- pentafluoro- dec- 2( E)-enal To a solution of 11.0 g of (2R, 3R)-2, 3-epoxy-7,7,8,8,8-pentafluoro-octanol in 200 ml of dimethylsulfoxide is placed under argon, 5.6 ml of pyridine, 2.3 ml of trifluoroacetic acid and 37.0 g of N,N-dicyclohexylcarbodiimide and the whole is stirred for 3 hours at room temperature. After adding 23.6 g of formyl-methylenetriphenylphosphorane, the mixture is stirred for a further 18 hours at room temperature, 500 ml of acetic acid are added and after 10 minutes the whole is poured into 1 liter of saturated sodium chloride solution. The resulting suspension is stirred for 15 minutes and filtered through a P4 frit. In the filtrate, the aqueous phase is extracted with 3 x 100 ml of acetic acid. The combined organic phases are washed 3 times with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is filtered over silica gel with ether:hexane (4:1 + \10 triethylamine) as eluent. The filtrate is evaporated and the residue is first filtered over a column filled with 2 kg of silica gel, then over a column filled with 500 g of silica gel with hexane:acetic ester (3:2) as eluent. The title compound is thus obtained as a yellow oil; Rf (hexane:acetic ester 1:1) = 0.61; [oc]<D>20(0.21$ in CDC13) = +19.5 ± 4.8° g) ( 6R , 7S)- 15-( 4- acetyl- 3- hydroxy- 2- propylphenoxy)- 6 . 7-epoxy- 1, 1. 1. 2. 2- pentafluoro- pentadeca- 8( E). 10(Z)-diene The suspension of 4.0 g of 5-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-pentyl-triphenylphosphonium bromide in 150 ml of absolute tetrahydrofuran is stirred with 1.0 g of (4R,5R)- 4,5-epoxy-9,9,10,10,10-pentafluoro-dec-2(E)-enal o 0.54 g of sodium amide under argon for 2V2 hours at room temperature. The resulting suspension is poured onto 400 ml of phosphate buffer (pH 7) and extracted with 4 x 25 ml of ether. The combined ether extracts are washed with 2 x 25 ml of phosphate buffer (pH 7) and once with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residue is taken up with hexane:acetic ester (1:1 + 1$ triethylamine) and filtered over a silica gel column previously washed with this solvent. The filtrate is evaporated and the residue is purified by chromatography over silica gel with hexane:acetic ester (7:3 + 1% triethylamine). The title compound is thus obtained as a yellow oil; Rf (hexane:acetic ester 1:1) = 0.50; [a]D20(CHCl3, 0.20$) = + 15 ± 5° Example 2: 7 - f ( 6R. 7S)- 15-( 4- acetyl- 3- hydroxy- 2- propvl- f enoxy)-!, 1. 1. 2, 2- pentafluoro- 6- hydroxyz-pentadeca- 8( E). 10(Z)-diene-7-vlthiol-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt 1.3 g of the corresponding methyl ester according to example 1 is dissolved under argon in 40 ml of tetrahydrofuran, 9.4 ml of 0, 2N caustic soda at 0°C and the whole thing is stirred for one hour at room temperature. Evaporation and purification of the residue over a 240 g Merck Lichroprep® RP-8 column with methanol:water (7:3) as eluent gave the title compound of the formula:

with melting point 155-158°C;

[α]D20(0.12$, MeOH) = 44.2 ± 8.3°;

UV spectrum (MeOH): Xmax= 221 (c = 48080), 231/sh, 267 (c=

24720), 285 (c = 22080), 325/sh;

IR spectrum (CH2C12): 3480, 2920, 1630, 1450, 1420, 1360,

1200, 1120, 810 cm-<1>;

R f (MeOH:H 2 O = 3:1): = 0.20.

Example 3: 7- f( 6R. 7S)- 14-( 4- acetyl- 3- hydroxy- 2- propyl-phenoxy)- 1. 1. 2, 2- pentafluoro- 6- hydroxyz-tetradeca- 8 ( E). 10(Z)-dien-7-ylthiol-4-oxo-4H-1-benzopyran-2-carboxylic acid enrethyl ester

A solution of 0.53 g of (6R,7S)-14-(4-acetyl-3-hydroxy-2-propylphenoxy)-6,7-epoxy-1,1,1,2,2-pentafluoro-tetradeca- The 8(E),10(Z)-diene in 50 ml of absolute methanol is stirred under argon with 1.3 ml of triethylamine and 0.4 g of 7-mercaptochromone-2-carboxylic acid methyl ester for 20 hours at room temperature and then evaporated. The residue is dissolved in ethyl acetate and filtered over silica gel. The filtrate is washed once with 25 ml IN hydrochloric acid and then with 4 x 25 ml saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residue is purified by chromatography on silica gel with hexane:acetic ester (7:3). The title compound is obtained as a yellow oil with Rf (hexane:acetic ester 3:2) = 0.25.

The starting material can be prepared as follows:

a) ( 6R . 7S )- 14-( 4- acetvl- 3- hydroxy- 2- propvlphenoxy)- 6. 7-epoxy- 1. 1. 1, 2, 2- pentafluoro- tetradeca- 8( E) , 10 ( Z )- diene

0.4 g (4R, 5R )-4,5-epoxy-9,9,10,10,10-pentafluoro-dec-2 (E )-enal in 10 ml of tetrahydrofuran, 0.156 g of sodium amide and approx. 50 mg potassium tert-butanolate. The whole thing is then allowed to warm to room temperature for 2% hour. The resulting suspension is poured onto 200 ml of phosphate buffer (pH 7) and extracted with ether. The combined ether phases are washed once with phosphate buffer (pH 7) and twice with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residue is taken up in hexane:acetic ester (3:2 + -1% triethylamine) and filtered over a silica gel column previously washed with this solvent. The filtrate is evaporated and the residue is purified by chromatography on silica gel with hexane:acetic ester (7:3 + 1% triethylamine) as eluent. The title compound is obtained as a pale yellow oil.

Rf (hexane:acetic ester 3:2) = 0.50;

[α]D 2 O(CHCl 3 , 0.0955$) = 8.4 ± 10.5°;

UV spectrum (CHCl3); Xmax = 287 (c 20920), 330/sh.

Example 4: 7- f ( 6R. 7S)- 14-( 4- acetyl- 3- hydroxy- 2- propvi-phenoxy)- 1. 1. 2. 2- pentafluoro- 6- hydroxy- tetradec- 8( ). 10( Z )-diene- 7- valthiol- 4- oxo- 4H- 1-benzopyran- 2- carboxylic acid sodium salt

The title connection with the formula

is obtained analogously to example 2 from the corresponding methyl ester according to example 3. Melting point 159-160°C;

[cx]<D>2o (methanol, 0.087$) = +65.5 ± 11.5°;

UV spectrum (methanol): Xmax»(c)>221 (44480), 231/sh, 267

(22960), 285 (20400), 330/sh;

IR spectrum (CH2C12): 3380, 2950, 1630, 1500, 1420, 1360,

1270, 1200, 1120, 810 cm-<1>.

Example 5: 7-f(6R.7S)-15-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-l.1,1.2,2-pentafluoro-6-hydroxy-pentadeca-8( E ), 10( Z )-dien-7-ylthio1-4-oxo-4H-1-benzopyran-2-carboxylic acid

0.87 g of the corresponding methyl ester according to example 1 is dissolved under argon in 30 ml of tetrahydrofuran, 6.3 ml of 0.2N caustic soda is added at 0°C and the whole is stirred for one hour at 0-5°C. The reaction mixture is freed from tetrahydrofuran on a rotary evaporator and taken up in 20 ml of water and 50 ml of methylene chloride. The whole is acidified to pH 1 with 2N hydrochloric acid and extracted with 3 x 50 ml of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. The residue is purified over a silica gel column with methylene chloride:methanol (4:1) and the title compound is obtained as a tough resin.

Claims (3)

1. Analogous process for the preparation of therapeutically active benzopyrans of the general formula (I): there R 1 means C 1-4 alkyl, R 2 means C 1-4 alkyl, alk means C1_7<a>alkylene, R3 means polyfluoro-C2-7-alkyl with at least 5 fluorine atoms, and R4 means carboxy or C1-4 alkoxycarbonyl, and salts thereof, characterized in that an epoxide of formula (II): where R 1 , R 2 , alk and R 3 have the meaning given above, is reacted with a thiol of formula (III): where R4 has the above meaning, or a salt thereof; and if desired, converts a compound obtained according to the invention into another compound of formula (I), separates a stereoisomer mixture obtained according to the invention into the separate components, and/or transfers a free compound obtainable according to the invention to a salt or a salt obtained according to the invention to a free compound or to another salt. 2. Process according to claim 1 for the preparation of 7-[(6R,7S)-15-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-1,1,1,2,2-penta-fluoro-6 -hydroxy-pentadeca-8(E ), 10(Z )-dien-7-ylthio]-4-oxo-4H-i-benzopyran-2-carboxylic acid, or a salt thereof, characterized by starting from the corresponding starting compounds . 3. Process according to claim 1 for the production of 7-[(6R,7S)-14-(4-acetyl-3-hydroxy-2-propyl-phenoxy)-1,1,1,2,2-penta-fluoro- 6-hydroxy-tetradeca-8(E), 10 (Z )-dien-7-ylthio]-4-oxo-4H-1-benzopyran-2-carboxylic acid, or a salt thereof, characterized by starting from the corresponding output connections.