NO763490L - - Google Patents

Description

In our widely available patent application 75.1358, it is described, among other things, a method for the preparation of optically active sulfoxides.with the general formula

where R. means a carboxyl group or a carbolic oxy group with 2 to 7 carbon atoms, and it is characterized by the fact that a racemate of a thioether with the general formula

where, as stated above, is oxidized, and then one of the two racemates is separated into its optically active antipodes. In this way, it has so far only been possible to separate [1-(2,-fluoro-4-biphenylyl)ethylsulfinyl acetic acid with a melting point of 164-165°C (decomposition)*

It has now surprisingly been found that all four theoretically possible antipodes with the above general formula I, which possess valuable pharmacological properties, in particular antithrombotic effects and a lowering effect on the cholesterol and triglyceride level, can be obtained with good yield and with high purity. hot as a result

Oxidation of an optically active thioether of the general formula II and subsequent splitting of the obtained diastereomeric mixture of the compounds of formula I into the optically active antipodes.

The oxidation is preferably carried out in a solvent, e.g. in methanol, water, water/methanol, ethanol, water/pyridine, acetone, glacial acetic acid or trifluoroacetic acid, depending on the oxidizing agent used, suitably at temperatures between -80 and 60°C. Thus, e.g. the oxidation with hydrogen peroxide.in glacial acetic acid at 0 to 20°C or in acetone at 0 to 60°C, with sodium metaperiodate 1 aqueous methanol or ethanol at 15 to 25°C, with tert.butyl hypochlorite in methanol at -80 to -30 °C, with iodobenzene dichloride in aqueous pyrldine at 0 to 5°C, with nitric acid in glacial acetic acid at 0 to 20°G, with chromic acid in glacial acetic acid or 1 acetone at 0 to 20°C and with

sulfuryl chloride in methylene chloride at -70°C, the thioether/chlorine complex thus obtained being hydrolysed with aqueous ethanol.

The obtained diastereomeric mixture of the sulfinyl acetic acids is then separated on the basis of their different solubility, e.g. by fractional crystallization in glacial acetic acid, or the esters thereof. by column chromatography, e.g. on silica gel with cyclohexane-ethyl acetate.

The free acid with the general formula I produced according to the present invention can be reacted with a corresponding alcohol in the presence of an acid activating agent such as carbonyldiimidazole or N-dicyclohexylcarbodiimide or with an alkyl halide such as methyl iodide in the presence of potassium carbonate in dimethylsulfoxide, optionally is transferred to the corresponding ester.

The optically active thioethers of the general formula II used as starting materials are obtained by racemate cleavage of the corresponding compounds in a manner known per se. As mentioned at the outset, the antipodes of the general formula I exhibit valuable pharmacological properties, in particular antithrombotic effects.

As an example, the following compounds were investigated with regard to their biological properties:

High-reducing II-(2,-fluoro-4-biphenylyl)~ethylsulfinyl]-acetic acid methyl ester with toJD+ 217.8 and B » Benstredrelehde" El-(2'-fluoro-4-bphenylyl)-ethylsulfinyl]~00 f\ acetic acid methyl ester with taJD - 220.5 . 1. Determination of platelet aggregation according to Bora and Cross (J. Physiol. I70. 397 (1964)): Platelet aggregation was measured in platelet-rich plasma from healthy subjects. Below is the course of the change in the optical density after the addition of commercially available collagen from the company Hormonchemie, Munich, which contains 1 mg of collagen fibrils per ml, measured photometrically and recorded. The rate of aggregation (Vmax) was deduced from the slope angle of the density curve. The point on the curve where the greatest light transmission was present was used to calculate the "optical density" (O.D.). The collagen doses were chosen as low as possible,

but however such that an irreversible aggregation appeared. To achieve maximum aggregation release, approx. 0.01 ml of collagen solution to 1 ml of platelet-rich plasma.

The numbers in the table mean percentage reduction of the aggregation rate (Vmax) and percentage change in optical density (O.D.) in relation to the comparison sample without addition of substance.

The following table contains the values found:

2» Effect on platelet thrombi in rats

Method:

Literature: H. Poliwoda, J. Lilli, G. Hagemann, D.. Schyma:

Z. ges. exp. With. 145, 252, 1968

Male rats (weight between 70 and 90 g) received an intraperitoneal nembutal anesthesia (dose: 50-60 mg/kg). To avoid hypothermia, they were placed on a heated experimental table (approx. 37°C). In order to keep the airways free, a tracheal cannula was inserted. After making an incision across the abdomen, a tarcn loop was exposed which was fixed, and a vein was found with a transverse measurement of approx. 300p.. in this vein, a monopolar platinum electrode with a cross-section of 100 µm, which was embedded in glass, was arranged as an irritation cathode. The indifferent electrode was in the same vessel opposite the cathode. The irritation occurred with 150 volts direct current for a time of 100 msec. After the irritation, the observation area became

flushed continuously with warm (37°C) physiological saline solution. Formation and growth of the thrombus was followed under a binocular microscope for a period of 20 minutes.

During the entire observation period, it was felt within the individual time periods how many percent of the carver plume was closed by the thrombus. 5 male rats weighing between 70 and 90 g served as the control group.

Additional groups, consisting of 5 animals, received the test compounds administered orally in tylose suspension. The dose was 10 mg/kg. The influence of the test compounds on the thrombus size 1 hour after administration of the test compounds was investigated:

The investigations with regard to significance were carried out by the method according to Gebeleln (Lit.: Die Naturwissenschaften, Jabhgang 3_9, Heft 20, pp. 457-461, 1952).

The prepared compounds of the general formula I and their physiologically compatible salts with inorganic or organic bases, if meaning a carboxyl group, are thus particularly suitable for the prevention of arterial thromboembolism and arterial to-,

constipation disorders.

For pharmaceutical use, the prepared compounds with the general formula I and their physiologically compatible salts with inorganic or organic bases, if R. means a carboxyl group, possibly in combination with other active substances, can be incorporated into usual pharmaceutical preparation forms such as dragées, tablets, suppositories, suspensions or solutions; and the single dose is suitably 10 to 50 mg.

The following examples shall serve to further illustrate the invention: Note: For co-ion chromatography, silica gel from the company Woelm, grain size: 0.05 to 0.2 mm, was used, and for thin-layer chromatography silica gel-finished plates F 254 from the company Merck.

■ Example A

(-)-[1-(2«-fluoro-4-blphenylyl)-ethylthioacetic acid

Solutions of 100.0 g (0.345 mol) racemic [1-(2 *-fluoro-<;>4-biphenylyl)-ethylthio]acetic acid In 500 ral methanol and of 102.0 g (0.345 mol) (-)- zinkonldin 1,700 ml of methanol are mixed, filtered and evaporated. The evaporation residue, a glassy foam, is boiled for 20 minutes with acetone, whereby it is converted into a thick crystal slurry. After cooling and extraction, you get 157 g of salt with a melting point of 142-151°C. Crystallization four times from the 50- to 80-fold volume amount of acetone gives 29.2 g of salt with melting point

169-171°C. By acidification with hydrochloric acid, extraction and recrystallization from cyclohexane-petroleum ether a 4/i, one isolates 12.4 g (24.8% of the theoretical) (-)-II-(2,-fluoro-4- biphenylyl)-ethylthio]-acetic acid.

Melting point: 66-68°C.

IolD° ~275° (methanol, c 0.5)

Example B

dextrorotatory thi-(2'-fluoro-4-biphenylyl)-ethylthio]acetic acid

290.4 g (1 mol) of racemic [1-(2'-fluoro-4-biphenylyl)-ethylthio)-acetic acid are suspended in 2.9 1 of dry tetrahydrofuran and 178.0 g (1.1 mol) of carbyldilmidazole are added. During C02 evolution

a clear solution of the imidazolide is formed. /After 1 hour, 580 g (1*5 mol) of cholesterol (ta]^° » -30.2°, c = 0.5 in ethyl acetate) are added and boiled for 16 hours while excluding moisture. The solvent is evaporated in a vacuum, the residue is taken up in water and washed several times with dilute soda solution, dilute hydrochloric acid and finally with saturated sodium chloride solution.

The evaporation residue (719 g) is dried, evaporated and filtered

to remove by-products on a column of 13 kg silica gel with cyclohexane-ethyl acetate « 9/1 as eluent. The fractions with an R^ value of 0.6 are collected and evaporated. 578 g (87^8% of the theoretical) residue is obtained as a beech-yellow oil.

The evaporation residue is dissolved in 2,3 1 n-butanol. During

of 3 days, 230.7 g of crystals with a melting point of 98-100°G crystallize out. By recrystallization from n-propanol, n-butanol and

isopropanol gives 460.6 g (49.6% of the theoretical) (+)~tl~(2*-flubr-4-bIfen<y>l<y>l)-et<y>ltio]acetic >re-choleether<y>ester with melting point 116-118°C and [o]^° +160.5° (chloroform-ethanol - 3/1, c »0.5)

C43H59F02S (659.01)

Calculated; C 78.37, H 9.02, S 4.87

Found 78.70 9.10, 5.04

For hydrolysis, the ester (144.3 g) is boiled in 1 liter of ethanol with 18.7 g of powdered potassium hydroxide for 30 minutes. You evaporate, add water and extract the cholesterol with ether. The dextrorotatory 11-(2'-fluoro-4-biphenylyl)-ethylthio]acetic acid is obtained from the aqueous-alkaline base by acidification, extraction and recrystallization from cyclohexane-petroleum ether 1/1.

Yield: 59.3 g

Melting point: 67-69°C.

[o]^Q +280.8° (chlorophora-ethanol 3/1, c 0.5).

Example C

left-handed II-(2'-fluoro-4-biphenylyl)-ethyltip] acetic acid

The butanol filtrate described in example B, which contains the left-handed ester enriched, is evaporated and saponified with potassium hydroxide. You thereby get enriched left-handed acid

City ■ /*\

[aJD . * -151.5 . This acid (134.5 g) is dissolved in 4.7 liters of acetone, and while boiling, 137.0 g of (-)-cinconidine is added. On standing overnight, the salt of the levorotatory acid separates with cinchonidine (205.4 g), which is recrystallized from 18 liters of acetone.

After cleavage with hydrochloric acid and after usual work-up, the left-handed [1-(2'-fluoro-4-biphenylyl)-ethylthio]acetic acid is obtained. Yield: 68.0 g, melting point: 66-68°C.

[α]p° -281° (chloroform-ethanol = 3/1, c <= 0.5).

Example 1

Dextrorotatory diastereomers [ 1-(21-fluoro-4-biphenylyl)-ethylsulfinvH-acetic acids a) Sparingly soluble Isomer 29.0 g (0.1 mol) dextrorotatory [1-(2'~fluoro-4-biphenylyl)-ethylthio]acetic acid with ta]^°» +280.8° (chloroform-ethanol 3/1,

c «= 0.5) is dissolved in 100 ml of glacial acetic acid and 9.9 g of 36% perhydrol is added at 15 to 20°C. Stir for 2.5 hours, cool to 10°C and suction off the precipitate. Wash with cold glacial acetic acid and then with petroleum ether, dry and recrystallize from 100 ml of glacial acetic acid. Yield: 15.5 g {50.7% of the theoretical) Melting point: 171^173°C (decomposition).

OA *t

UJD.«+216.5 (chloroform-ethanol 3/1, c 0.5) ;

C16H15F03S (306.37)

Calculated: C 62.73, H 4.94, S 10.47

Found: 62.50, 4.97, 10.57 b) Easily soluble isomer The glacial acetic filtrate of the sparingly soluble isomer is evaporated. The residue contains the easily soluble isomer in an enriched state and is esterified without further purification (see example 4).

Example 2

left-handed diastereomers [1-(2t-fluoro-4-biphenyl)-ethyl-. sulfiny1] acetic acids

a) Heavy solvent isomer

Produced analogously to example la) from left-handers

II-(2•-fluoro-4-biphenylyl)-ethylthio]acetic acid with Ia]^° « -281°

(chloroform-ethanol = 3/1, c = 0.5) by oxidation with hydrogen peroxide in glacial acetic acid.

Yield: 47.8% of the theoretical,

Melting point: 170-172°C (dec.) (from glacial acetic acid).

[a]*G -215.4° (chloroform-ethanol 3/1, c =0.5)

b) Easily soluble isomer Prepared analogously to example lb) as evaporation residue (see example 6).

Example 3.

Dextrorotatory [ 1^( 3»- fluoro- 4- biphenylyl)- ethylsulflnyI] acetic acid methyl ester

12.5 g (+)-II-(2<*->fluoro-4-biphenylyl)-ethylsulfinyl acetic acid

(heavily<q>soluble isomer, melting point: 171-173°C, Ia]<20>= +216.5°)

7.3 g of carbonyldiimidazole are added to 60 ml of dry tetrahydrofuran,

and after the CGj evolution has ceased, 1.45 g of methanol» After a further 1 hour, the mixture is evaporated and the residue distributed between ether and water. The organic phase is extracted with 1N soda solution, then with 1N hydrochloric acid and washed with water. After drying and evaporation, 13.2 g of an oil remain which solidifies crystalline, and this is recrystallized from cyclohexane-ethyl acetate =« 6/1. ; ,'• ,'

Yield: 9.5 g (72.5% of the theoretical)

Melting point: 50-52°C.

la]22» +217.8° (chloroform-ethanol = 3/1, c 0.5)

NMR spectrum (in deuterochloroform):

CH3: doublet at 1.75 ppm (J » 7.2 Hz)

CH: quartet at ;4.2 ppm (J « 7.2 Hz)

CH^:doublet at 3.48 ppm (J 14 Hz)

C17H17F03S (320.36)

Calculated: C 63.73, H 5.34, S 10.01

Found: 63.50, H 5.49, S 9.94

By column chromatography of the mother liquor on silica gel with cyclohexane-ethyl acetate <■ 1/2, a further 2.3 g are recovered with the same physical properties.

Example 4

Dextrorotatory 11-(2*-fluoro-4-bphenylyl)-ethylsulf^inyl]acetic acid methyl ester

8.8 g of the enriched easily soluble isomer of the dextrorotatory II-(2*-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid described in example 1 is dissolved in 45 ml of dry tetrahydrofuran and 5.12 g of carbonyldiimidazole is added and after a half an hour 1.1 g methanol. After

for a further 1 hour, evaporate, take up the residue in ether, wash with dilute sodium carbonate solution, with dilute hydrochloric acid and with

saturated sodium chloride solution. After drying and evaporation, 8.6 g of an oily residue remain, which is then chromatographed on the 200-fold amount of silica gel with cyclohexane-ethyl acetate »l/2.

The fractions with an R^ value of 0.6 are collected and evaporated. Yield 5.7 g, R^-value: 0.6 (cyclohexane-ethyl acetate 1/2)

Species •

[o)D + 41,<2>(chloroform-ethanol * 3/1, c « 0.5)

NMR spectrum (in deuterochloroform):

CHy doublet at 1.8 ppm (J » 7.2Ha)

CH: quartet at 4.1 ppm (J 7.2 Ha)

. CHj j singlet at 3.3 ppm C17H17P03S <320<36>

Calculated: C 63.73, H 5.34, S 10.01

Found: 63.60, 5.56, 10.20

The fractions obtained by column chromatography with an R^ value of 0.5 contain the diastereomeric ester with melting point

50 to 52°C <see example 3).

Example 5

Levorotatory [ 1-( 2'- fluoro- 4- bphenylyl)- ethylsulfinyl] acetic acid methyl ester

Prepared analogously to example 3 from (-)-[l-(2,-fluoro-4-biphenylyl)~ethyisulfinyl]acetic acid (hardly soluble isomer, . melting point 170-172°C, [a]2)<0>33 -215 .4°) by esterification with methanol using carbonyldimidazole. Yield: 60.8% of the theoretical. Melting point: 50-52°C (cyclohexane-ethyl acetate = 6/1).

(aj20 » -220.5° (chloroform-ethanol 3/1, c »

NMR spectrum (in deuterochloroform):

CH3: doublet at 1.75 ppm (J « 7.2 Hz)

CH: quartet at 4.2 ppm (J = 7.2 Hz)

CH2: -doublet at 3.45 ppm (J 14Hz) C17H17F03S <320'36)

Calculated: C 63.73, H 5.34, S 10.01 Found: 63.50, 5.46, 9.90

Example 6

Left-handed [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]acetic acid methyl ester Prepare analogously to example 4 from the enriched, easily soluble isomer of left-handed {1-(2*-fluoro-4-biphenylyl)-ethylsulfinyl]acetic acid , methanol and carbonyldimidazole. Isolation by column chromatography on the 200-fold quantity -

silica gel with cyclohexane-ethyl acetate 1/2.

Oil, Rf value: 0.6 (cyclohexane-ethyl acetate 1/2). Yield: 41.5% of the theoretical

la)21*-41.8° (chloroform-ethanol * 3/1, c0.5) 33MR spectrum (in deuterochloroform):

GH3: doublet at 1.8 ppm (J *» 7.2 Hz)

CH: quartet at 4.1 ppm (J 7.2Hz)

CH28 singlet at 3.3 ppmC17<H>17F03S*320'36*

Calculated: C 63.73, H 5.34, S 10.01

Found: 63.70 5.54 9.72

Claims (4)

1. Process for the production of optically active sulfoxides with the general formula where R^. means a carboxyl group or a carbolic oxy group with 2 to 7 carbon atoms, characterized in that an optically active thioether of the general formula where R4 is as indicated above, is oxidized in a solvent, . the obtained diastereomeric mixture of the compounds with the general formula I is separated into its optically active antipodes, and optionally, a sulfinic acid obtained with the general formula I is transferred to an ester thereof. 2. Method as stated in claim 1, characterized in that the oxidation is carried out by temperatures between -70 and 60°C. 3. Method as stated in claim 1, characterized in that the obtained diastereomeric mixture is separated by fractional crystallization or by column chromatography. 4. Process as stated in claim 1, characterized in that the esterification is carried out in the presence of an acid activating agent or with an alkyl halide.