HU182583B - Process for preparing prostacyclin and analogues thereof - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to prostacyclin derivatives of formula I wherein R1 is hydrogen or C1-4alkyl, R3 is hydrogen or C1-4alkyl, R4 is hydrogen or C1-4alkanoyl, R5 is straight or branched 3-9. C 1 -C 4 -alkyl-2-alkanoyl-containing prostacycline derivatives of Formula I wherein R 3 and R 5 are as defined above, optionally saponified and, if desired, R 1 is hydrogen, wherein R 3, R 4 and R 5 are as defined above. - converting to ammonium or alkali metal salt. The compounds of the formula I according to the invention have valuable antiaggregatory activity and can therefore be used as active ingredients in pharmaceutical compositions for the treatment of blood clotting disorders. and for the preparation of their ammonium and alkali metal salts by the preparation of a 5-halo-prostacycline derivative of formula III wherein R3, R4 and R5 are as defined above, X is bromo or iodo, Re is hydrogen or C1-C4 alkyl; by restriction, that when R 3 and R 4 are hydrogen and R 5 is n-pentyl, then Re can only represent hydrogen - subjected to a elimination reaction with a base followed by R 1 to C 1-4 alkyl and / or R 1 —4 carbon 25-1-

Description

The mechanism that regulates the process of coagulation in mammalian organisms has recently become known in the study of the biological role of prostaglandins (Chemical and Engineering News, December 20, 1976, p. 17).

Accordingly, prostaglandins occurring mammalian tissues biosynthesis common precursor of prostaglandin endoperoxide one hand causes an enzyme produced by the platelets (thrombocytes), the highly active blood clotting substance, called thromboxane _-VE, on the other hand by means of an enzyme found in the aorta-wall of an equally very it is converted to an active anticoagulant substance. Anti-clotting latter substance, which proved to be 5 (Z) ^{-9-deoxy-6,9a-oxido-5} The -PGFja does in their chemical structure determination, was named prostacyclin. PGX designation is also used in the literature. It is a compound of formula I wherein R ¹ , R ³ and R ^{4 are} hydrogen, R ^{2 is} hydroxy and R ^{5 is} n-pentyl.

Prostacyclin has been biochemically produced by an enzyme system derived from prostaglandin endoperoxide in mammalian aortic tissue, and its biological activity has been demonstrated in vitro. During the experiment, the compound suspended adenosine diphosphate-induced aggregation of thromboytes. [Prostaglandins, VoJ. 12, No. 5, 685 (1976)].

The present invention relates to a process for the preparation of prostacyclin derivatives of the formula I wherein:

R ¹ H alkyl, obsession 14 -C R ³ H alkyl, obsession 1-4 -C R ⁴ H obsession 1-4 -C

alkanoyl

R ^{5 is a} linear or branched C 3 -C 9 alkyl group and its ammonium and alkali metal salts.

According to the present invention, the prostaglandin derivatives of formula I are prepared by reacting the 5-halo-prostacyclin derivatives of formula III wherein

R ³ , R ⁴ and R ⁵ are as defined above,

X is bromine or iodine,

R ^{e is} hydrogen or C 1-4 alkyl, with the proviso that when R ³ and R ^{4 are} hydrogen and R ^{5 is} n-pentyl then R ^e is hydrogen only - then subjected to the elimination reaction with the base and in the case of R ¹ , the prostacyclin derivatives of formula I wherein R ³ is C 1 -C 4 alkyl and / or R ⁴ is C 1 -C 4 alkanoyl, where R ³ and R ⁵ are as defined above, are optionally saponified and optionally R ¹ is hydrogen. The prostacyclin derivatives of the formula I wherein R ³ , R ⁴ and R ⁵ are as defined above are converted to an ammonium or alkali metal salt.

The starting compounds of formula III are readily available substances. It can be prepared by means of commercially available prostaglandin F ₂ (PGF ₂₎ or derivatives halogenation.

The halogenation is carried out with or without a solvent. The halogenating agent may be any brominating or iodinating agent known in the art. Thus, the halogenating agent can be the elemental bromine or iodine alone or in a complexed form, preferably pyridine-iodine complex, halogen compounds such as iodine monochloride or iodine monobromide, various known N-bromine and N-iodine reagents, for example, reagent systems providing N, N-dibromodimethylhydantoin, N-bromoacetamide, N-bromosuccinimide, N-iodosuccinimide or triiodide (J ₃ ) and tribromide (Br ₃ ) ions. The halogenation can be carried out in both acidic and basic media. Suitable solvents are all inert aprotic and aprotic solvents commonly used in organic chemistry. Examples of the former include water, alkanols, organic acids, while the latter include, for example, acetonitrile, dinethylformamide, dimethylsulfoxide, various chlorinated hydrocarbons and ether-type solvents. The reaction may also be carried out in a mixture of the above solvents. Depending on the reactivity of the reagent used, the halogenation may be carried out at temperatures between -78 ° C and + 100 ° C, preferably at room temperature. The progress of the reaction can be well monitored by thin layer chromatography.

These electrophilic reagents, mentioned above, regioselectively attack the Δ ⁵ cis-geometry of prostaglandin F ₂ a and its derivatives to form the corresponding bromonium or iodonium ions. In all cases, the formation of positively charged ions is stabilized by the presence of the 9-position hydroxyl group to form compounds of formula III.

By reaction of II PGF ₂ in the aforesaid formula halogenating the compounds types of two isomers compound of formula III is formed, which are epimers with respect hydrogen spacing of six carbon atoms in the conventional numbering of the prostanoic acid (endo-exo isomerism). For example, the use of various halogenating agents results in a mixture of exo III compounds and endo III compounds in a ratio of 1: 1 to 1:10, depending on the nature of the reagent used and the reaction conditions, to the benefit of the endo products. If desired, these isomers may be separated, for example, by column chromatography on silica gel. For chromatographic separation, it is preferred that the esters of the compounds of formula III be chromatographed, i.e., when R ⁶ is C 1-4 alkyl.

When the prostaglandin F ₂ acid is used as a chemical compound of formula II and halogenated by reaction with halogenating agents, it is possible to obtain the corresponding corresponding acid or salt of formula III obtained by R ³ and / or R ⁴

-2182583. The ethyl esters of formula III (R @ 3 in formula III) are most readily prepared by reaction with ether in diazomethane and the 11a, 15a-diacetates can be obtained by acylation with acetic anhydrides.

The compounds of formula (I) according to the invention are prepared from the compounds of formula (III) by an elimination reaction. Accordingly, compounds of formula III are treated with a base. If desired, heating may also be used to effect the elimination reaction. A preferred embodiment of the reaction is by reacting the compounds of formula III in alkanols with alkali metal alcoholates in the presence of either tertiary aliphatic or aromatic nitrogen bases such as pyridine, collidine, picoline or triethylamine. In addition, other reagents commonly used to effect elimination, such as diazabicycloundecene (DBU) or diazabicyclononene (DBN) in conventional solvents, may be used as bases in the reaction.

It has been found that an inferior base, such as potassium carbonate, in alkanols, as a solvent, is a particularly advantageous way of avoiding side reactions in order to avoid elimination of side reactions. The elimination reaction is preferably carried out at room temperature to 200 ° C.

Elimination of the epimeric compound ΓΙΙ from the endo isomer is much faster than that of the exo isomer, but the elimination product of both isomers is the 5 (Z) -isomer of formula I.

The isolation of the compounds of formula I from the reaction mixture is carried out in the usual manner. Since the compounds of the formula I have an extremely acid-sensitive enol ether structure, they are preferably stored at low temperature with the addition of a small amount of base, preferably sodium carbonate.

The compounds of Formula I of the present invention are capable of arresting or dissolving human platelets, such as adenosine diphosphate, at concentrations of 0.2 to 20 ng / ml.

The compound of formula I according to the invention having an anti-aggregation or thrombolytic activity of the compounds of formula I wherein R ³ and R ^{4 are} hydrogen, R ¹ is sodium and R ⁵ is n-pentyl (PGI ₂ - sodium salt) and a compound of formula III wherein X is iodine, wherein R ³ and R ^{4 are} hydrogen and R ^{5 is} n-pentyl, are prepared.

Investigation of anti-aggregation and thrombus dissolving effects

The assays were performed on human platelet rich plasma (PRP). One ml of plasma was assayed in a modified Born aggregometer.

1. The control sample 1X10- aggregation was induced by ⁵ M adenosine diphosphate (ADP). The measured aggregation (in scale) as a function of time is shown in Figure I. -.-. .

From about 2. 5 to 20 ng of PGI ₂ sodium salt dissolved in 0.05 M pH 7.5 Tris-HCl buffer ml PRP was incubated at room temperature for 1.5 minutes then placed ΙχΙΟ- aggregometer by addition ^{of 5} M ADP induced aggregation. Inhibition of aggregation was observed. The curve x-x-x shows the change in aggregation over time in Figure I.

3. 50-200 ng of the above general formula III

The 5-halo-prostacyclin derivative, when used under the conditions described in section 2, did not cause inhibition of aggregation. The measured data are plotted in Figure I, o-o-o-o-o.

4. ADP-induced aggregation in the presence of 200 ng of the above 5-halo-prostacyclin derivative of formula III was reversible by the addition of 20 ng of PGI ₂ sodium salt. The result of this latter test is shown in the curve x..x..x..x..x in Figure I.

Further details of the process of the invention are illustrated by the following non-limiting examples.

Example 1

To PGF _2? 398 mg (1.12 mmol), 32 mL of water and 8 mL

99.5% acetic acid was added. A solution of potassium iodate (80.1 mg, 0.37 mmol) in water (3 mL) was added dropwise to the resulting solution with stirring at room temperature (500 mg, 3 mmol). A brick-red solution is formed which almost colorless in 2-3 hours.

At this time, 20 ml of ether are added to the reaction mixture, the phases are separated after shaking, the ether solution is washed with 0.5 ml of 10% sodium thiosulphate solution, 4 x 5 ml of water and dried over magnesium sulphate at 0 ° C. . After filtration and evaporation, the residue is acetic acid-free at a pressure of 1 mmHg to constant weight. 486 mg (90%) of the title compound is obtained, mainly from the structure of Formula III, which according to TLC is a 5: 1 mixture of endo and exo stereoisomers with very small amounts of minor and higher polarity impurities.

This product is chemically pure and stereochemically pure 6-endo-6,9a-oxido-5a-iodo-11a, 15a-dihydroxy-13 (E) -prostenoic acid by column chromatography (silica gel, 20: 10: 1 chloroform: dioxane: acetic acid as eluent). and 6-exo-6,9a-oxido-5β-iodo-11α, 15α-dihydroxy-13 (E) -prostenoic acid, respectively, with an Rf of 0.25 and a latter of 0.30.

Thin layer chromatography on silica gel with 20: 10: 1 benzene dioxane / acetic acid.

The pure isomers can be converted to methyl ester by nearly quantitative yield with ethereal diazomethane at 0 ° C, at about 3182583. Thin layer chromatography under the above conditions gave endo III (methyl ester)

R _f = 0.40, while the exo III Compound 5 (methyl ester) Rf value = 0.43, where stain.

Example 2

To a solution of 290 mg (0.82 mmol) of PGF. In 2 mL of acetonitrile was added 140 mg (0.52 mmol) of mm, Ν-dibromodimethylhydantoin at 0 ° C. The reaction is complete within 5 minutes. The resulting 6-endo-6,9aoxido-5α-bromo-11α, 15α-dihydroxy-13 (E) -prostenoic acid 15 and 6-exo-6,9a-oxido-5β-bromo-11β, 15α-dihydroxy-13 (E) Proteinic acid ratio of about 5: 1 with minimal amounts of minor and higher polarity impurities. Thin layer chromatography as described in Example 1 yields a spot at Rf = 0.22 for endo III and Rf at 0.27 for exo III.

After removal of the solvent, the crude product (430 mg) was purified by column chromatography (silica gel, chloroform-dioxane-acetic acid 20: 5: 1) to give pure exo III (31.1 mg), exo-endo III. The mixture was separated into a mixture of compounds of formula (94.5 mg) and pure endo compound of formula III (102 mg). The pure isomers can be esterified with diazomethane in the same manner as in Example 1. The methyl esters in TLC - that given in Example 1 carrying out - is given in the following Rf values: endo compound of formula III Rf 0.35 Exo III compound R _f = 0.41. 35

Example 3

20.5 mg (0.0579 mmol) of PGF _{2 are} dissolved in 1 ml of anhydrous pyridine. A solution of 22.06 mg (0.0868 mmol) of iodine in 0.5 ml of pyridine is added with stirring at room temperature. The reaction mixture was stirred under a stream of nitrogen at room temperature for 24 hours. Water (3 mL) was added and the mixture was extracted with ether (3 x 2 mL) and the combined extracts were treated with 1 mL of 10% aqueous sodium thiosulfate, 4 mL of 0.5N HCl, and 1 mL of saturated brine. solution. The ethereal solution was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. The residue was 26 mg of a slightly yellow, dense oil.

The product was chromatographed on 3 g of acid-activated silica gel, eluting with 9: 1 ethyl acetate: methanol, 6-endo and 6-exo-6,9a-oxido-5-iodo-15,15-dihydroxy-13 (E). 23 mg of a 4: 1 mixture of prostenoic acids.

Example 4

35.4 mg (0.1 mmol) of PGF. ₂ were dissolved in acetonitrile at 2 mL acetonitrile. To the solution was added 17.87 mg (0.11 mol) of iodine monochloride with stirring, then stirred at room temperature for 1 hour. The reaction mixture was cooled to + 5 ° C and after dilution with water (2 ml), extracted with ether (3x2 m). Wash with 1 mL of 1% sodium bisulfite solution, then with 1 mL of brine, dry the washed ether solution over anhydrous sodium sulfate, filter, and evaporate the solvent.

43 mg of a yellow oil are obtained. This crude product was chromatographed as described in Example 3 to give 6-endo and 6-exo-6,9x-oxido-5-iodo-15α-dihydroxy-13 (E) -prostenoic acids in a ratio of about 2: 1. A mixture of 36 mg (74.8%) was obtained.

Example 5

To a solution of PGF ₂ (175 mg, 0.49 mmol) in dichloromethane (5 mL) was added N-bromo-camphorimide (141 mg, 0.55 mmol) at room temperature with stirring. The reaction is complete within 3 hours. The resulting 6-endo-6,9a-oxido-5a-bromo-11a, 15a-dihydroxy-13 (E) -prostenoic acid and 6-exo-6,9a-oxido-5a-bromo-11a, 15a-dihydroxy-13 (E) ) -prostenoic acid ratio of about 2: 1. After removal of the solvent, the crude product (320 mg) was purified by column chromatography. The procedure is the same as in Example 2. 45 mg of exo, 60 mg of endo isomer and 62 mg of exo-endo isomer are obtained.

Example 6

To a solution of PGF ₂ (973 mg) in dichloromethane (10 mL) was added N-bromosuccinimide (535 mg) and dichloromethane (5 mL). The reaction is complete within 80-90 minutes. The resulting bromine derivative of Formula III contains the endo and exo isomers in a ratio of 4: 1.

The crude product was chromatographically separated into its components as in Example 2. 131 mg of exo, 293 mg of endo isomer and 578 mg of exo-endo isomer are obtained.

Example 7

Dissolve 251 mg of PGF ₂ in a mixture of 10 ml of water and 10 ml of glacial acetic acid and add a solution of 1 g of potassium bromide in 5 ml of water and then 50 mg of potassium bromate in 5 ml of water. The reaction is complete within 3-4 hours. The reaction mixture was worked up as in Example 2. The crude product weighed 342 mg. Chromatographic purification yielded 65 mg of exo, 72 mg of endo isomer and 103 mg of exo-endo isomer.

-4182583

Example 8

450 mg (1.18 mmol) of 15 (S) -methyl-PGF ₂ α-methyl ester are dissolved in 15 ml of acetonitrile and 6 ml of a saturated sodium bicarbonate solution are added. Subsequently, 872 mg (3.44 mmol) of iodine was added over 2 hours with stirring. 10 minutes after the last injection, the reaction was complete. Ether (50 ml) was added and the mixture was partitioned between 15 ml of 10% sodium thiosulphate solution. The separated aqueous layers were extracted with ether (50 mL), the organic layers (reaction mixture and ether extract) were combined, washed with water (2 x 10 mL) and brine (1x), dried over magnesium sulfate. From the resulting anhydrous solution, the following compounds were isolated by column chromatography (eluent: 3: 1 methylene chloride / acetone / 1% triethylamine):

mg of 6-exo-6,9a-oxido-5-iodo-15 (S) -methyl-11a, 15adihydroxy-13 (E) -prostenoic acid methyl ester (R _f = 0.39)

333 mg 6-endo-6,9a-oxido-5-iodo-15 (S) -methyl-11a, 15a-dihydroxy-13 (E) -prostenoic acid methyl ester (R _f = 0.35) 150 mg isomeric mixture . Yield 86.0%.

6.9 mg (0.18 mmol) of methyl 6,9a-oxido-5-iodo-15 (S) -methyl-11a, 15a-dihydroxy-13 (E) -prostenoic acid are dissolved in 1 ml of methanol under argon, followed by 0.4 ml of 2 A 2M solution of sodium methoxide in methanol was added. The reaction was complete at 40 ° C for 3 hours. At this time, the reaction mixture was evaporated, ether (50 mL) was added to the residue, and the solution was partitioned between water (5 mL) and brine (5 mL) and dried over potassium carbonate. Evaporation of the ether 41 mg 15 (S) -methyl-5 (Z) -9-deoxy-6,9a-oxido-A ⁵ -PGF _1, methyl ester. R f = 0.49 (with 1: 1 hexane-acetone in triethylamine).

If given in Example 15. saponification step is carried out with sodium hydroxide solution, then the resultant 15 (S) -methyl-5 (Z) ^{-9-deoxy-6,9a-oxido-5} PGFjf The sodium salt white crystals precipitated from the solution. Mp: 165-168 ° C (block).

Example 9

16.16-Dimethyl-PGF ₂ α-methyl ester (551 mg, 1.39 mmol) was dissolved in ether (10 mL) and saturated sodium bicarbonate solution (16.5 mL) was added. The reaction mixture was cooled to 0 ° C and a solution of 0.48 g of iodine in 19 ml of ether was added with stirring over 15 minutes. After stirring at room temperature for 2 hours, the reaction mixture was worked up as in Example 8. 650 mg (89%) of methyl 6,9a-oxido-5-iodo-16,16-dimethyl-11,15a-dihydroxy-13 (E) -prostenoic acid were obtained as a slightly yellow oil.

The above product (262 mg, 0.5 mmol) was reacted with sodium methoxide as in Example 8. 145 mg (80%) of 16,16-dimethyl-5 (Z) -9-deoxy-6,9a-oxidoA ^s -PGFja acid methyl ester as a colorless oil. Rf = 0.55 (with 1: 1 hexane-acetone in triethylamine).

Example 10

363 mg (0.74 mmol) of the methyl ester of 9-deoxy-6,9a-oxido-5-iodo, 15a-dihydroxy-13 (E) -prostenoic acid obtained in Example 1 are dissolved in 5 ml of benzene, 5 ml of pyridine and Acetic anhydride (0.3 mL, 3.18 mmol) was added. The reaction is complete within a day. The reaction mixture was purified by column chromatography (silica gel, 30 g, 2: 1 hexane: ethyl acetate). The reaction yield was 92%. The Rf values of the isolated isomers of 9-deoxy-6,9a-oxido-5-iodo-15,15-diacetoxy-13 (E) -prostenoic acid in the former eluent were 0.23 and 0.31. 280 mg of the "exo", 38 mg of the "endo" isomer and 73 mg of the isomer mixture 15 are obtained in two.

Example 11

0.5 g (0.84 mmol) of the methyl ester of 9-deoxy-6,9a-oxido-5-iodo, 15a-diacetoxy-13 (E) -prostenoic acid obtained in Example 10 is dissolved in 10 ml of benzene and 2 ml of 8-Diazabicyclo [5.4.0] undec-7-ene is added. The reaction time is one day. The reaction mixture was purified by column chromatography. (50 g silica gel, 3: 1 v / v triethylamine in hexane / ethyl acetate). Yield: 316 mg (81%). The Rf of 5 (Z) -9-deoxy-6,9a-oxido [alpha] ⁵ -PGF] [beta] -methyl ester-11,15-diacetate was obtained using Merck "Kieselgel G" as a 2: 1 mixture of hexane-ethyl acetate: 0 , 35th

Example 12

900 mg (2.27 mmol) of a-methyl ester of 16,16-dimethyl-PGF _{2 are} dissolved in 25 ml of ether and 25 ml of a saturated aqueous solution of sodium bicarbonate are added and the reaction mixture is cooled to 0 ° C. To the reaction mixture was added a solution of 0.68 g (2.68 mmol) of iodine in 27 mL of ether at 0 ° C with stirring for 1 hour. The reaction mixture was stirred at room temperature for 6 hours. The two phases are separated, the ether layer is washed with 5% sodium thiosulfate solution, water, and finally with brine, dried over sodium sulfate, filtered and the solvent is distilled off. The crude residue was chromatographed on silica gel (60 g) with ethyl acetate-hexane (2: 1). 1.12 g (95%) of 6-endo and exo-9-deoxy-5-iodo-6,9a-oxido-16,16-dimethyl-PGF and 50 methyl ester are obtained as a colorless oil. Rf: 0.63 and 0.61 with ethyl acetate.

Example 13

9-Deoxy-5-iodo-6,9a-oxido-16,16-dimethyl-PGF? -Methyl ester (855 mg, 1.63 mmol) was dissolved in pyridine (5 mL), and then acetic anhydride (2 mL) was stirred at room temperature for 4 hours.

The reaction mixture was diluted with 20 ml of water and 3 x 25 ml of ethyl acetate

The combined organic extracts were washed with water, 3 x 10 mL of 1 N hydrochloric acid, 10 mL of saturated aqueous sodium bicarbonate, and finally with saturated brine, dried over sodium sulfate, filtered, and the solvent was evaporated. 913 mg (92%) of 5-iodo-9-deoxy-6,9a-oxido-16,16-dimethyl-PGF] -ethyl ester-11,15-diacetate are obtained in the form of a colorless oil. Rf: 0.51 with hexane-ethyl acetate (2: 1).

. <E

Example 14

891 mg (1.47 mmol) of 5-iodo-9-desoxy-6,9a-oxido-16,16-dimethyl-PGF a-methyl ester-11,15-diacetate are dissolved in 8.5 ml of anhydrous benzene and 1.66 ml of After addition of 8-diazabicyclo [5.4.0] undec-7-ene, the reaction mixture was stirred for 20 hours at room temperature. After the addition of benzene (20 ml), the organic layer was washed with water (6 X 5 ml) and finally with saturated aqueous sodium chloride solution (5 ml). After drying over sodium sulfate, the filtrate was evaporated in vacuo to give

163,6-Dimethyl-PGI _2- methyl ester-11,15-diacetate (632.5 mg, 90%) was obtained as a slightly yellow oil. Rf: 0.54 with hexane-ethyl acetate-triethylamine (2: 1: 0.1).

1 H-NMR (CDCl ₃ ): 5.5 (2H, m CH = CH),

5.3-5.1 (2H, m, CH-OAc),

4.5-4.1 (2H, m, CH-0),

4.19 (1H, t, O-C = CH),

3.67 (3H, s, COOCH ₃ ).

Example 15

300 g (0.50 mmol) of the methyl ester of 9-deoxy-6,9a-oxido-5-iodo, 15a-diacetoxy-13 (E) -prostenoic acid obtained in Example 10 are dissolved in 2.5 ml of 2N methanolic sodium methoxide. solution (50 mmol). Reaction time is 12 hours. The reaction was followed by TLC on silica gel (pre-run on triethyl ether ether) with 1: 1 acetone / ethyl acetate. Rf = 0.58. To the reaction mixture was added 1 ml of 1N sodium hydroxide solution and the mixture was stirred at room temperature for a further 2 hours. The methanol was evaporated and the sodium salt of PG1 ₂ crystallized from the distillate at 0 ° C. The precipitate was filtered. Wash with 2 ml of 1 N sodium hydroxide solution and dry for 20-24 hours.

Yield: 70%,

Ή NMR (DMSO-d _e -CDCl ₃₎ 4.18 (C = C = CH)

IRmax (KB _r ): 1725, 1678 cm ^-1; mp 116-118 ° C

Example 16

1 g (2.08 mmol) of 6,9a-oxido-5-iodo-15α-dihydroxy-13 (E) -prostenoic acid obtained in Example 1 is dissolved in 10 mL of 2N methanolic sodium methoxide solution (25 mmol). Reaction time is 12 hours. The reaction can be followed by thin layer chromatography. The disappearance of the starting material indicates the end of the reaction. The reaction mixture was concentrated and water (4 ml) was added. The recovery of the PGI ₂ sodium salt is carried out as described in Example 15 below. Yield: 65%. The physical constants of the product are the same as in Example 15.

Example 17

610 mg of the isomeric mixture of 6-endo- and 6-exo-6,9aoxido-5-iodo-11,15a-dihydroxy-13 (E) -prostenoic acid prepared in Example 3 are dissolved in 2 ml of anhydrous tert-butanol and 10 equivalents of a 5 molar solution of tert-butanol in sodium tert-butoxide. The resulting mixture was then stirred under nitrogen at 40 ° C for 1 hour. The tert-butanol was then evaporated in vacuo, water (3 ml) was added and the mixture was stirred at 0 ° C for 3 hours. The precipitated crystals of PGI ₂ sodium salt are filtered off, washed with 0.5 ml of 1 N sodium hydroxide solution and dried in vacuo. This gives 470 mg of PGI ₂ sodium salt.

IR (KBr pellet): 1694 ^cm-1 wavenumber characteristic absorption band of the enol ether.

Example 18

The procedure of Example 17 was repeated except that 23 mg of a mixture of isomers were used and the reaction was carried out in anhydrous methanol with 2.1 equivalents of 1 M methanolic tetrabutylammonium hydroxide solution. PGI ₂ -tetrabutylammonium salt is obtained. Rf = 0.51 (80:20 v / v on silica gel).

Claims (8)

1. A process for the preparation of a prostacyclin derivative of formula I blades - - where R ¹ hydrogen or C 1-4 alkyl, R ³ hydrogen or (1-4C) alkyl, R ⁴ hydrogen or C 1-4 alkanoyl, R ⁵ straight or branched chain 3-9 a C 5 -alkyl group, and their ammonium and alkali metal salts, characterized in that a 5-halo-prostacyclin derivative of formula III - wherein R ³ , R ⁴ and R ⁵ are as defined above, X is bromine or iodine, -6182583 R @ 3 is hydrogen or C1 -C4 alkyl, with the proviso that when R @ ³ and R @ ^{4 are} hydrogen and R @ ^{5 is} n-pentyl, R @ 3 is hydrogen only - and the resulting and optionally R ¹ is C 1-4 alkyl and / or R ⁴ is C 1-4 alkyl. Prostacyclin derivatives of the Formula I containing an acryl group - where R ³ and R ⁵ are as defined above - if desired, saponified and optionally I prostacyclin derivatives of the general formula are hydrogen, R ¹ is - in which R ^3, R ⁴ and R ^s are as defined above - converting it to an ammonium or alkali metal salt. 2. The method of claim 1, embodiment, wherein the 5-halo-prosztaciklinszármazékokból general Formula Ill where X represents iodine - starting material - wherein R ^3, R ^4, R ^s and R® as defined in claim 1. Process according to any one of the preceding claims, characterized in that the elimination reaction is carried out with an alkali metal alcoholate. 4. The method of claim 3, wherein the alkali metal alcoholate is sodium methylate or sodium tert-butylate. 5. A process according to claim 1 or 2, characterized in that it is eliminated Reactions were performed with cyclic nitrogen bases. 6. A process according to claim 5 wherein the cyclic nitrogen base is 1,8-diazabicyclo [5.4.0] undec-7. 7. Process 10 according to any one of claims 1 to 3, characterized in that the elimination reaction is carried out in a C 1-6 alkanol. 8. The process according to claim 6, wherein the elimination reaction is carried out in an apolar organic solvent. 9. A process for the preparation of a pharmaceutical composition having an anti-aggregation effect, characterized in that a composition according to any one of claims 1-8. A prostacyclin derivative of the Formula I prepared according to any one of claims ¹ to ³ , wherein R ¹ , R ³ , R ⁴ , R ⁵ are as defined in claim 1. 20, or an ammonium or alkali metal salt thereof, with the proviso that when R ³ , R ^{4 are} hydrogen and. R ^{5 is} n-pentyl then R ^{1 is} different from sodium - a filler, diluent, conventionally used in the preparation of pharmaceuticals, 25 are formulated into a pharmaceutical composition using stabilizing and formulation auxiliaries.