CH629772A5 - Process for the preparation of optically active 8-azaprostanoic acid derivatives - Google Patents

Description

The invention relates to a process for the preparation of new optically active 8-azaprostanoic acid derivatives of the formula 10OH

1

14

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13

OH

wherein R is methyl or ethyl, and their and pharmaceutically acceptable salts.

Prostaglandins are known to have widely spread interesting biological effects (see, e.g., Advances in the Biosciences Vol. 9, International Conference on Prostaglandins, Ed. Pergamon Press, Vieweg, 1973), and eight different series of prostaglandins (A, B, C , D, E, Fa, G & F) have been isolated from various sources such as seminal fluid, the kidney, the lung, the central nervous system, etc. The synthesis of heterocyclic derivatives of prostaglandins and their pharmacological properties have also recently been reported. For example, Himizu et al made 10-oxaprostanoic acid derivatives such as 15 (S) -hydroxy-9-oxo-13,14- (trans) -didehydro-10-oxaprostanoic acid, and at the same time found that these compounds are useful for the treatment of gastrointestinal disorders or to stimulate the birth process (US Pat. No. 3,787,448). RM Scriber reports that 8,12-diazaprostanoic acid derivatives such as sodium 7- [3'-oxo-l '- (3'-hydroxy-n-octyl) pyrazolidin-2-yl] heptanoate and ethyl 7- [3'-oxo-2 '- (3'-hydroxy-n-octyl) pyrazolidin-l'-yl] -heptanoate show prostaglandin-like properties or antagonistic effects against prostaglandins JPA 61164/1974). Furthermore, the synthesis of 9- or 11-oxa-prostaglandins and 9-thia-prostaglandins by I. Vlattas et al in "Tetrahedron Letters", No. 48, p. 4267 (1974) and "ibid.", No. 51 / 52, pp. 4451-4462 (1974).

It has now been found that the aforementioned compounds of the formula I have various biological properties similar to prostaglandin and are suitable for treatment where prostanglandins were previously indicated. For example, compound I is a good bronchodilator

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because it shows bronchodilator activity over long periods of time. If the bronchodilatory effect is determined by the preventive effect against a histamine-induced bronchoconstriction after the intravenous injection (test animal: guinea pig) has ^ -20-methyl-15a-hydroxy-13,14- (trans) -dehydro-9- oxo-8-azapro-stanoic acid at a dose of 10 [ig / kg (iv) a maximum bronchodilation for about an hour or longer and i-20-ethyl-15a-hydroxy-13,14- (trans) -didehydro-9 -oxo - 8-azaprostanoic acid for more than three hours, while prostaglandin Ej has only a temporary bronchodilatory activity. In addition, prostaglandin Ej has no bronchodilatory effect when administered intraduodenally even in doses of 1 mg / kg, while ^ -20-methyl-15 a-hydroxy-13,14- (trans) -idehydro-9-oxo -8-azapro-stanoic acid and ^ -20-ethyl-15a-hydroxy-13,14- (trans) -dide-hydro-9-oxo-8-azaprostanoic acid has a potent bronchodilatory effect at an introduodenal dosage of 10 pg / kg . The compound of formula I may also be useful as an antihypertensive or labor inducing agent. For example, if ^ -20-methyl-- 15a-hydroxy-13,14- (trans) -didehydro-9-oxo-8-azaprostanoic acid and ^ -20-ethyl-15a-hydroxy-13,14- (trans) -didehydro - 9-oxo-8-azaprostanoic acid orally administered to rats, they show a moderate decrease in blood pressure. Compound I can also cause a spontaneous increase in uterine contraction.

Furthermore, the compound of formula I can be advantageous for the treatment of gastrointestinal diseases or gastric ulcers. For example, it shows an increasing effect on the instinct motility and further reduces or controls the excessive secretion of gastric acid and increases the spontaneous motility of the stomach. '

The toxicity of compound I is low. If i-20 - methyl-15a-hydroxy-13,14- (trans) -didehydro-9-oxo-8-aza-prostanoic acid and i-20-ethyl-15a-hydroxy-13,14- (trans) - dide-hydro-9-oxo-8-azaprostanoic acid mice are injected orally at a dose of 10 mg / kg X day, no mouse died within the period of 10 days.

Compound I can be used for pharmaceutical purposes either as a free acid or as a salt. Pharmaceutically acceptable salts of Compound I include, for example, alkali or alkaline earth metal salts (e.g. sodium, potassium or calcium), quaternary ammonium salts (e.g. ammonium or tetramethylammonium salts) and organic amine salts (e.g. cyclopentylamine, benzylamine, triethanolamine and monoethanolamine salts). Compound I can be administered in the form of a pharmaceutical preparation for enteral or parenteral administration or inhalation in the case of bronchodilators. The pharmaceutical preparation can be in solid form (e.g. tablets, pills, capsules or powder) or as a liquid dosage form (as a solution, suspension or emulsion). Compound I can also be used in combination or in admixture with a pharmaceutical excipient suitable for enteral or parenteral administration or for inhalation. Suitable excipients are, for example, gelatin, lactose, glucose, starch, vegetable oils and others.

The process according to the invention for the preparation of the compound of formula I mentioned above is characterized by the following process steps:

i) condensing an optically active 1-alkoxycarbonyl-hexyl-5-formyl-2-pyrrolidone of the formula

629772

O

CHO

wherein R 'is lower alkyl with a compound of the formula

Y —CO - (CH2) 5 —R

wherein Y is a group of the formula (R "0) 20PCH2 or (CeH5) 3P = CH- and R" lower alkyl,

ii) reducing the optically active pyrrolidone of the formula obtained

COOR '

O

with a metal borohydride, wherein an optically active 15P - hydroxy-8-azaprostanoate derivative of the formula

O

• COOR

OH

is obtained, and iii) hydrolysis of the optically active 15-hydroxy-8-azaprostanoate derivative obtained.

The 5-formyl-2-pyrrolidone derivative II has an asymmetric carbon atom in the 5-position and can exist in the form of two stereoisomers, i.e. as the d or ^ isomer. Each of the two optically active isomers can be used in the process according to the invention, and all reactions can be carried out without racemization.

The condensation of the optically active 1-alkoxycarbonyl-hexyl-5-formyl-2-pyrrolidone II with the Wittig reagent can be carried out in a solvent. Dimeth-oxyethane is a suitable solvent. It is preferred to carry out the reaction at a temperature of 0-30 ° C in an inert gas such as nitrogen. The reaction can be carried out either in the presence or absence of an alkali metal hydride. Preferred hydrides are lithium hydride, sodium hydride or potassium hydride.

The reduction of compound III is carried out in a simple manner by treating compound III with a metal borohydride in a solvent. Lithium borohydride, sodium borohydride, potassium borohydride and zinc borohydride are preferably used. Methanol, ethanol and isopropanol are suitable solvents. It is preferred to carry out the reaction at a temperature of -30 to 25 ° C, especially at -15 to 5 ° C.

The optically active compound IV obtained in this way is composed of stereoisomers which3

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visually differentiate the steric configuration of the hydroxy group at the 15-position, and these isomers can be easily separated into the components by silica gel chromatography using ethyl acetate / benzene / methanol or ethyl acetate / benzene as a solvent. In this specification and claims, the more polar isomer or component (ie, the one that is more strongly absorbed by silica gel) is referred to as “15a isomer” and the less polar isomer or the component (ie, the one that is less strong on silica gel is absorbed) as a "15ß-isomer" in analogy to the chromatographic behavior of the esters of natural prostaglandins. When performing silica gel chromatography, due to the difference in polarity between these components, the 15ß isomer is always eluted in the earlier fractions and the 15a isomer in the later fractions. If desired, one of these components (i.e., the 15a and 15ß isomers) of compound IV can be converted to compound III if the latter is to be used as a starting material in the synthesis of the other component. The conversion of the compound IV into the compound III can be carried out by conventional oxidation, for example by treatment with anhydrous chromic acid pyridine complex at room temperature in a solvent.

The hydrolysis of the compound IV can be carried out by treatment with an alkali metal hydroxide. It is preferred to carry out the reaction at a temperature of 0-30 ° C in a solvent. Preferred examples of the alkali metal hydroxides are sodium and potassium hydroxide. Lower alcohols (i.e. methanol, ethanol) or aqueous mixtures thereof can be suitable as solvents. The 15a or 15β isomer of compound IV can be used in the above-mentioned hydrolysis, and the optically active compound I is used as the corresponding 15a or 15ß isomer of the corresponding isomer (ie the 15a or 15ß isomer) the optically active compound IV obtained.

The starting compound II of the process according to the invention, i.e. the optically active (either d- or £ -) 1-alk-oxycarbonylhexyl-5-formyl-2-pyrrolidone is a new compound. It can be prepared by condensing an optically active 5-hydroxymethyl-2-pyrrolidone with vinyl ethyl ether in the presence of a small amount of an acid (ie hydrochloric acid, hydrobromic acid, trichloroacetic acid) in a solvent (eg chloroform), with optically active 5- [l - (Ethoxy) -ethoxymethyl] -2-pyrrolidone is obtained, condensing an alkali metal salt (eg sodium salt) of the pyrrolidone with a lower alkyl 7-bromo-n-heptanoate in the presence of potassium iodide in an inert gas (nitrogen gas) at 50 ° C. in a solvent (ie dimethylformamide), treating the optically active 5- [l - (ethoxy) -ethoxymethyl] -l- (6-lower alkoxycarbonylhexyl) -2 - pyrrolidone with a strong acid (ie p-toluenesulfonic acid) Room temperature in a solvent (ie methanol) to give an optically active 1- (6-lower alkoxycarbonylhexyl) -5-hydroxymethyl-2-pyrrolidone, and then treating the 5-hydroxymethyl-2-pyrrolidone with an oxidizing agent (ie dimethy Isulfoxide-dicyclohexyl-carbodiimide, anhydrous chromic acid-pyridine complex) under nitrogen gas at room temperature or with ice cooling.

Practical and preferred embodiments of the present invention are shown in the following examples. Throughout the description and claims, the term "lower alkyl" refers to alkyl groups with 1-5 carbon atoms.

example 1

1) 17 g of i-5-hydroxymethyl-2-pyrrolidone are dissolved in 99 ml of chloroform and then 0.43 g of trichloroacetic acid and 71 ml of vinyl ethyl ether are added. The solution is stirred at room temperature for 3.5 hours. The solution obtained is cooled in ice water and washed with an aqueous sodium bicarbonate solution. The wash water is extracted with chloroform. Then the organic layer and the chloroform extract are combined and washed with a saturated aqueous ammonium sulfate solution, dried and evaporated to remove the solvent. The residue obtained is distilled under reduced pressure. There is obtained f-5- [l- (ethoxy) ethoxymethyl] -2-pyrrolidone as a light yellow oil.

Yield: 24.5 g, K.P. 152-154 ° C / 4 mm Hg, [a] D25-22.6 ° (C = 2, ethanol).

2) A solution of 21.0 gi -5 - [1 - (ethoxy) ethoxy methyl] -2-pyrrolidone in 20 ml dimethylformamide was gradually added to a mixture of 50 ml dimethylformamide, 4.47 g 65% sodium hydride ( Oil dispersion, washed with n-hexane) and 22.46 g of potassium iodide added. The addition was carried out under nitrogen, ice cooling and with stirring. The mixture was stirred at room temperature for 1 h and then again at 50 ° C. for 20 min. After the mixture had cooled to room temperature, 30.3 g of methyl 7-bromo-n-heptanoate were added and the mixture was stirred at 50 ° C. for 2 days. The mixture was evaporated at 60-75 ° C under reduced pressure (4 mm Hg) to remove the solvent. The residue obtained was mixed with ether and an aqueous saturated ammonium sulfate solution and the mixture was shaken. Then the organic layer was separated from the mixture and the aqueous layer was extracted with ether. The organic solvent layer and ether extract were combined, washed with water saturated with ammonium sulfate, dried, and then evaporated to remove the solvent. The residue obtained was purified by silica gel chromatography [solvent: ethyl acetate / methanol (20: 1)]. f-5- [l- (Ethoxy) -ethoxymethyl] -l - (6-methoxycarbonylhexyl) -2-pyrrolidone was obtained as a colorless oil.

3) A solution of i -5- [1 - (ethoxy) ethoxy methyl] -1 - (6-methoxycarbonylhexyl) -2-pyrrolidone obtained as above and 1.5 g of p-toluenesulfonic acid in 150 ml of methanol were 17 hours stirred at room temperature. The solution was evaporated to remove the solvent. The residue was dissolved in ethyl acetate and the ethyl acetate solution was washed successively with an aqueous sodium bicarbonate solution and an aqueous saturated ammonium sulfate solution. The solution was then dried and evaporated to remove the solvent. The residue obtained was distilled under reduced pressure. f-l- (6 - methoxycarbonylhexyl) -5-hydroxymethyl-2-pyrrolidone was obtained as a colorless oil.

Yield: 22.0 g, K.P. 200-203 ° C / 0.1 mm Hg, [a] D27'5-9.4 ° (C = 2, ethanol).

4) 7.0 g of chromium trioxide was added to a mixture of 11.3 ml of pyridine and 165 ml of dichloromethane at 25 ° C. under nitrogen. The mixture was stirred at room temperature for 15 minutes. A solution of 2.88 g of i-l- (6-methoxycarbonylhexyl) -5-hydroxymethyl-2-pyrrolidone in 10 ml of dichloromethane was added to the mixture at room temperature. Then the mixture was stirred at room temperature for 20 minutes and 4 ml of isopropanol were added and the mixture was stirred for a further 20 minutes at room temperature. After the reaction, the dichloromethane layer was separated by decantation. The residue was washed with 200 ml dichloromethane with vigorous stirring.

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see and then the dichloromethane layer separated again by decantation. The residue was then washed twice with 100 ml of water and the ether layer was separated off by decantation. After the dichloromethane and ether layers had been combined, 10 g of silica gel were added and the mixture was evaporated to remove the solvent. The silica gel powder obtained was placed in a column of 55 g of silica gel and eluted with ethyl acetate / methanol (9: 1). ^ -l- (6-Methoxycarbonylhexyl) -5-formyl-2-pyrrolidone was obtained as a pale yellow oil.

Yield: 1.54 g, [a] D22 -2.3 ° (C = 2.04, ethanol).

Example 2

1) 3.65 g of d-5-hydroxymethyl-2-pyrrolidone, 0.1 g of trichloroacetic acid and 16 ml of vinyl ethyl ether were treated in the same manner as described in Example 1- (1), d-5 - [l- (Ethoxy) ethoxymethyl] -2-pyrrolidone was obtained as a light yellow oil.

Yield: 5.45 g, K.P. 119-121 ° C / 0.2 mm Hg, [a] D24> 5 + 20.8 ° (C = 2, ethanol).

2) 2.0 g d-5- [l- (ethoxy) ethoxymethyl] -2-pyrrolidone, 0.42 g 65% sodium hydride, 2.13 g potassium iodide and 2.87 g methyl-7-bromo-n -heptanoate was treated in the same manner as described in Example 1- (2). d-5- [l- (Ethoxy) - ethoxymethyl] - l- (6-methoxycarbonylhexyl) -2-pyrrolidone was obtained.

Yield: 5.65 g (crude product).

3) 5.65 g of d-5- [l- (ethoxy) ethoxymethyl] -1- (6-methoxycarbonylhexyl) -2-pyrrolidone and 0.3 g of p-toluenesulfonic acid were prepared in the same manner as in Example 1- (3) treated, d-1 - (6-methoxycarbonylhexyl) -5-hydroxymethyl - 2-pyrrolidone was obtained as a colorless oil.

Yield: 1.42 g, [a] D24 + 8.9 ° (C = 2.12, ethanol).

4) 3.20 g of d-1- (6-methoxycarbonylhexyl) -5-hydroxy-methyl-2-pyrrolidone, 7.75 g of chromium trioxide and 12.5 ml of pyridine were treated in the same manner as described in Example 1- (4). d-1- (6-Methoxycarbonylhexyl) -5-formyl-2-pyrrolidone was obtained as a pale yellow oil.

Yield: 2.07 g, [a] D24-5 + 2.2 ° (C = 2.25, ethanol).

Example 3

1) 205 mg of 65% sodium hydride in mineral oil were suspended in 33 ml of dimethoxyethane under nitrogen gas. A solution of 1.52 g of dimethyl 2-oxo-octylphosphonate in 6 ml of dimethoxyethane was added to the suspension with ice cooling. The mixture was stirred at the same temperature for 10 minutes and at room temperature for 15 minutes. After cooling the mixture in an ice bath, a solution of 1.49 g of il- (6-methoxycarbonylhexyl) -5-formyl-2-pyrrolidone in 6 ml of dimethoxyethane was added dropwise and the mixture was then added at the same temperature for 1 hour and at room temperature 1 , 5 h stirred. 50 ml of ether was added to the mixture. The mixture was then washed with an aqueous saturated ammonium sulfate solution, dried and evaporated to remove the solvent. The residue obtained was purified by thin layer chromatography [silica gel, solvent: ethyl acetate / benzene (6: 1)]. ^ -20-Methyl-9,15-dioxo-13,14- (trans) -di-dehydro-8-azaprostanoic acid methyl ester was obtained as a light yellow oil.

Yield: 1.49 g (71.6%).

IR spectrum: v (cm-1): 1735, 1700, 1690, 1635.

Nuclear Magnetic Resonance Spectrum: ppm (CDC13): 0.8-2.6 (27H), 2.85-4.40

H

(3H), 3.69 (3H, s, 0-CH3), 6.30 (1H, d, J = 16.2,)>

O

6.67 (1H, d of d, J = 16.2 and 7.4, ().

H O

5

Mass analysis: m / e: 365 (M +).

2) 0.24 g of sodium borohydride gradually became a solution of 60 ml of methanol and 1.45 g of ^ -20-methyl-9,15-dioxo-13,14- (trans) -didehydro-8-azaprostanoic acid methyl-io added ester. The addition was carried out under nitrogen gas and cooling with chloroform / dry ice. The mixture was stirred for 50 minutes at the same temperature.

After the reaction was completed, the mixture was poured into 180 ml of ice water. Then the mixture was saturated with ammonium 15 sulfate and extracted with ethyl acetate. The extract was washed with an aqueous saturated ammonium sulfate solution, dried and evaporated to remove the solvent. I-20-methyl-15 ^ -hydroxy-13,14 - (trans) -didehydro-9-oxo-8-azaprostanoic acid methyl ester was obtained-20 de.

Yield: 1.35 g.

The 8-azaprostanoate thus obtained was purified by thin layer chromatography [silica gel, solvent: ethyl acetate / benzene / methanol (8: 1: 1)], whereby 25 f-20-methyl-15a-hydroxy-13,14- (trans) -didehydro-9-oxo-8 - aza-prostanoic acid methyl ester (591 mg) and ^ -20-methyl - 15ß-hydroxy-13,14- (trans) -didehydro-9-oxo-8-azaprostanoic acid methyl ester (661 mg) were obtained as colorless oils. The IR and NMR spectra and the mass analysis of these 30 compounds were identical.

IR spectrum: v (cm4): 3440, 1735, 1665.

Nuclear Magnetic Resonance Spectrum: ppm (CDC13): 0.8-2.6 (27H), 2.7-4.3

35 (4H), 3.67 (3H, s, -0-CH3), 5.53-5.72 (2H,

H

Mass analysis: m / e: 367 (M +).

3) 5 ml of an aqueous 20% sodium hydroxide solution were added to a solution of 7.5 ml of methanol and 555 mg of f-20-methyl-15a-hydroxy-13,14- (trans) -idehydro-9-oxo -8-Azaprostanoic acid methyl ester added. The addition was carried out under nitrogen gas and under ice cooling. The mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the mixture was evaporated to remove the solvent. The residue was acidified with concentrated hydrochloric acid while cooling with ice, and the resulting precipitate was separated off by filtration. The precipitate was washed with water, dried and then recrystallized from ethyl acetate. i-20-Methyl-15a-hydroxy-13,14- (trans) -didehydro-9-oxo-8-azaprostanoic acid was obtained as colorless needles.

Yield: 400 mg (75%), M 114-116 ° C, [a] D25 -5.6 ° (C = 1.0, ethanol).

55 IR spectrum: v max. ' (cm-1): 3150-2500, 1725, 1660.

Nuclear Magnetic Resonance Spectrum: ppm (CDC13): 0.8-2.5 (27H), 2.8-4.3

(4H), 5.55-5.74 (2H,

60

H

Mass analysis: m / e: 353 (M-).

4) 5.5 ml of an aqueous 20% sodium hydroxide solution, 598 mg of i-20-methyl-15β-hydroxy-13,14- (trans) -di-65 dehydro-9-oxo-8-azaprostanoic acid methyl ester and 8.5 ml of methanol was treated in the same manner as described in paragraph 3). After the reaction was completed, the mixture was concentrated to remove the solvent

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steams. The residue was acidified with concentrated hydrochloric acid while cooling with ice and extracted with chloroform. The extract was dried and evaporated to remove the solvent. Then the residue obtained was recrystallized from ethyl acetate. I-20-methyl-15β-hydroxy-13,14- (trans) -didehydro-9-oxo-8-azaprostanoic acid was obtained. Yield 280 mg (48.7%), F 82-83 ° C, [a] D27 -28.0 ° (C = 0.5, ethanol).

The IR and NMR spectra and the mass analysis of the product were identical to those of the ^ -15a-hydroxy compound obtained according to paragraph 3).

Example 4

1) 138 mg of 65% sodium hydride, 1.02 g of dimethyl 2-oxo-octylphosphonate, 1.0 g of dl- (6-methoxycarbonylhexyl) -5-formyl-2-pyrrolideone and 30 ml of dimethoxyethane were prepared in the same manner treated as described in Example 3- (l). D-20-methyl-9,15-dioxo-13,14- (trans) -didehydro-8-azaprostanoic acid methyl ester was obtained as a pale yellow oil. Yield: 1.05 g (73.2%). The IR and NMR spectra and the mass analysis of the product were identical to those of the corresponding ^ isomer, prepared according to Example 3- (1).

2) 955 mg of d-20-methyl-9,15-dioxo-13,14- (trans) -dide-hydro-8-azaprostanoic acid methyl ester, 160 mg of sodium borohydride and 40 ml of methanol were prepared in the same manner as in Example 3- ( 2) described. D-20-methyl-15; -hydroxy-13,14- (trans) -didehydro-9-oxo-8-azaprostanoic acid methyl ester was obtained. Yield: 950 mg.

The 8-azaprostanoate thus obtained was purified by thin layer chromatography [silica gel, solvent: ethyl acetate / benzene / methanol (8: 1: 1)], whereby d-20 - methyl-15a-hydroxy-13,14- (trans) -didehydro-9-oxo-8-aza-prostanoic acid methyl ester (386 mg) and d-20-methyl-15ß-hydroxy-13,14- (trans) -didehydro-9-oxo-8-azaprostanoic acid methyl ester (426 mg) were obtained as a yellow oil. The IR and NMR spectra and the mass analysis of these products were identical to those of the corresponding ^ isomers obtained according to Example 3- (2).

3) 348 mg of d-20-methyl-15a-hydroxy-13,14- (trans) -dide-hydro-9-oxo-8-azaprostanoic acid methyl ester, 3 ml of an aqueous 20% sodium hydroxide solution and 4.5 ml of methanol treated in the same manner as described in Example 3- (3). d-20-Methyl-15a-hydroxy-13,14- (trans) -9-oxo-8-azaprostanoic acid was obtained in the form of crystals. Yield: 231 mg (69%), M 115-117 ° C, [a] D25 + 5.6 ° (C = 1.0, ethanol). The IR and NMR spectra and the mass analysis of the product were identical to those of the £ -15a-hydroxy compound, prepared according to Example 3- (3).

4) 364 mg of d-20-methyl-15β-hydroxy-13,14- (trans) -dide-hydro-9-oxo-8-azaprostanoic acid methyl ester, 3 ml of an aqueous 20% sodium hydroxide solution and 4.5 ml Methanol was treated in the same manner as described in Example 3- (3). d-20-Methyl-15ß-hydroxy-13,14- (trans) -dide-hydro-9-oxo-8-azaprostanoic acid was obtained in the form of crystals 5. Yield: 192 mg (55%), F 82-84 ° C, [a] D27 + 27.5 ° (C = 0.51, ethanol).

Example 5

1) 297.1 mg 65% sodium hydride, 2.33 g dimethyl-io -2-oxo-nonylphosphonate, 2.16 g f-l- (6-methoxycarbonyl-

Hexyl) -5-formyl-2-pyrrolidone and 64 ml of dimethoxyethane were treated in the same manner as described in Example 3- (1). ^ -20-ethyl-9,15-dioxo-13,14- (trans) -didehydro-8-azaprostanoic acid methyl ester was obtained as a colorless oil. 15 Yield: 2.275 g (70.9%, mass analysis: m / e: 379 (M +).

2) 2.275 g ^ -20-ethyl-9,15-dioxo-13,14- (trans) -didehy-dro-8-azaprostanoic acid methyl ester, 364 mg sodium borohydride and 180 ml methanol were prepared in the same manner as in Example 3- ( 2) described. i-20-ethyl-15 £ -hy-

20 methyl droxy-13,14- (trans) -dehydro-9-oxo-8-azaprostanoate was obtained as a light yellow oil. Yield 2.20 g.

The 8-azaprostanoate thus obtained was purified by thin layer chromatography [silica gel, solvent: ethyl acetate / benzene (2: 1)], whereby f-20-ethyl-25 -15a-hydroxy-l 3,14- (trans) -dehydehydro -9-oxo-8-azaprostanoic acid methyl ester (957 mg) and f-20-ethyl-15 ß-hydroxy - 13,14- (trans) -didehydro-9-oxo-8-azaprostanoic acid methyl ester (965 mg) when crystals were obtained. F 51-52 ° C (15a isomer) and 40-41 ° C (15ß isomer). The mass analysis of these 30 compounds was identical.

Mass analysis: m / e: 381 (M +).

3) 415 g ^ -20-ethyl-15a-hydroxy-13,14- (trans) -didehy-dro-9-oxo-8-azaprostanoic acid methyl ester, 3 ml of an aqueous 20% sodium hydroxide solution and 6 ml of methanol

35 were treated in the same manner as described in Example 3- (3). £ -20-Ethy 1-15a-hydroxy-13,14- (trans) -didehydro - 9-oxo-8-azaprostanoic acid was obtained in the form of colorless, transparent prisms. Yield: 336 mg (84%), F 76-77 ° C (recrystallized from a mixture of ethyl acetate 40 and petroleum ether). [a] D30 -4.4 ° (C = 1, ethanol).

Mass analysis: m / e: 367 (M +).

4) 440 mg of i-20-ethyl 1-15β-hydroxy-13,14- (trans) -didehy-dro-9-oxo-8-azaprostanoic acid methyl ester, 3 ml of an aqueous 20% sodium hydroxide solution and 6 ml Methanol

45 were treated in the same manner as described in Example 3- (3). i-20-ethyl-15β-hydroxy-13,14- (trans) -didehydro - 9-oxo-8-azaprostanoic acid was obtained in the form of colorless, transparent prisms. Yield 342 mg, F 60-61 ° C (recrystallized from a mixture of ethyl acetate and petroleum 50 ether). [a] D30 -27.4 ° (C = 1, ethanol).

Mass analysis: m / e: 367 (M +).

v

Claims (9)

629772 2. The method according to claim 1, characterized in that the 8-azaprostanoate derivative of the formula IV is subjected to silica gel chromatography, the compound being separated into the corresponding 15a and 15β-hydroxy compounds. 2nd PATENT CLAIMS 1. Process for the preparation of optically active 8-aza-prostanoic acid derivatives of the formula O COOH OH wherein R is methyl or ethyl, and their pharmaceutically acceptable salts, characterized by the following process steps: i) condensing an optically active 1-alkoxycarbonylhexyl-5-formyl-2-pyrrolidone of the formula CHO wherein R 'is lower alkyl with a compound of the formula Y —CO - (CH2) 5 —R where Y is a group of the formula (R "0) 20PCH2- or (C6H-) 3P = CH-, where R" is lower alkyl, ii) reducing the optically active pyrròlidone of the formula obtained O COOR1 0 with a metal borohydride, wherein an optically active 15 £ - hydroxy-8-azaprostanoate derivative of the formula O COOR ' OH is obtained, and iii) hydrolysis of the optically active 15-hydroxy-8-azaprostanoate derivative obtained. 3. The method according to claim 1, characterized in that the condensation stage i) at 0-30 ° C in an inert atmosphere, the reduction stage ii) at -30 to 25 ° C and the hydrolysis iii) by treatment with an alkali metal hydroxide at - 5 to 30 ° C is carried out. 4. The method according to claim 2 for the preparation of i-20 - methyl-15 a-hydroxy-13,14- (trans) -didehydro-9-oxo-8-aza-prostanoic acid. 5. The method according to claim 2 for the preparation of d-20 - methyl-15a-hydroxy-13,14- (trans) -didehydro-9-oxo-8-aza-prostanoic acid. 6. The method according to claim 2 for the preparation of i-20 - methyl-15 ß-hydroxy-13,14- (trans) -didehydro-9-oxo-8-aza-prostanoic acid. 7. The method according to claim 2 for the preparation of d-20 - methyl-15ß-hydroxy-13,14- (trans) -didehydro-9-oxo-8-aza-prostanoic acid. 8. The method according to claim 2 for the preparation of f-20 - ethyl-15a-hydroxy-13,14- (trans) -didehydro-9-oxo-8-aza-prostanoic acid. 9. The method according to claim 2 for the preparation of i-20-ethyl-15ß-hydroxy-13,14- (trans) -didehydro-9-oxo-8-aza-prostanoic acid.