HU184918B - Process for producing simultaneously pgf-2 down alpha derivatives substituted at the 4 or 7 position - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to novel substituted PGF? Derivatives of the general formula I and II, wherein R is hydrogen, an alkali metal cation, optionally one to four identical or different C 1-4 alkyl substituted ammonium cations or a C 1 -C 4 alkyl group, R 1. * hydrogen atom or C 1-4 alkanoyl, R 2 and R 3 are hydrogen, C 1-4 alkanoyl, tetrahydropyranyl, benzoyl, or tri- (C 1 -C 4 alkyl) silyl, R 4 hydroxyl, halogen, methanesulphonyloxy or toluenesulphonyloxy or R 1 and R 4 together may represent a -C (C 1 -C 4 alkyl) 2 -O group, R 5 a hydroxyl group, a halogen atom, a methanesulphonyloxy group or a toluenesulphonyloxy group, and 2 a? According to the present invention, a PGF2a derivative of formula III is optionally hydroxylated with a selenium compound 5 of +4 in the presence of hydrogen peroxide, followed by the novel substituted PGF2a isomers of formula I and II, wherein R4 is hydrogen. and R5 represents a hydroxyl group 10, if desired, by hydrolysis, acylation, acetylation or salt formation to form another compound of formula I and II and / or, if desired, isolating the isomers I and II. Compounds of formulas I and II exhibit a therapeutic effect similar to PGF2a and are useful, for example, for the synthesis of prostacycline derivatives as starting materials. 184 918

Description

The present invention relates to novel substituted PGF _2a derivatives of the formulas I and II wherein R is hydrogen, an alkali metal cation, optionally substituted with 1 to 4 identical or different C 1 -C 4 alkyl groups or a C 1 -C 4 alkyl group,

R 'is hydrogen or a C 1-4 alkanoyl group,

R ² and R ^{3 are} hydrogen, C 1-4 alkanoyl, tetrahydropyranyl, benzoyl or tri (C 1-4 alkyl) silyl,

R ^{4 is} hydroxy, halogen, methanesulfonyloxy or toluenesulfonyloxy, or

R ¹ and R ⁴ together may form a -C (C 1 -C 4 alkyl) ₂ -O- group,

^R5 is a hydroxyl group, a halogen atom, a toluenesulfonyloxy group and the metánszulfoniloxivagy kötésvQnal ~ a- or β-position space refers to - preparing juxtaposed.

Although the compounds of formulas I and II of the present invention, which themselves have significant smooth muscle stimulant and gastric acid secretion inhibitory activity, their main uses are as intermediates in the preparation of various PGI derivatives.

According to the invention, the novel substituted PGF _2a derivatives of formulas I and II are prepared by reacting a prostaglandin F _2i derivative of formula III wherein R, R ¹ , R ² and R ³ are as defined above, with H 4 hydroxylation with selenium oxidation compounds, optionally in the presence of hydrogen peroxide, followed by the resulting isomeric mixture of a new substituted PGF _2a derivative of formula I and II - wherein R, R ¹ , R ² and R ³ are as defined above, R ⁴ and R ⁵ represents a hydroxy group, optionally by hydrolysis, acylation, re-acetalation or salt formation to another compound of the formulas I and II and / or the isomers of the formulas I and II if desired.

PGF _{2a is a} known endogenous substance with significant biological effects (e.g., Synthesis of Prostaglandins, Cs. Szántay and L. Novák, Akadémiai Kiadó, Budapest, 1978, pp. 9-12). Among other things, its smooth muscle stimulating effect is routinely used in the gynecological field to induce therapeutic abortion. The cytoprotective activity against the ulcer in the gastrointestinal tract is also significant.

However, therapeutic use of PGF _{2a is} hampered by a number of unpleasant side effects, most notably diarrhea induced by stimulation of intestinal smooth muscle. The main purpose of the preparation of PGF _2a analogues is to produce selective analogues that exhibit either a main activity at a lower dose or a higher dose of side effects, possibly in the order of magnitude.

PGF _2a derivatives substituted at the 4 or 7 position according to the prostaglandin nomenclature show a difference in their activity spectrum with that of PGF _2a , so that the molecules are physiologically significant.

According to the invention, the preparation of the PGF _2a derivatives substituted at the 4 or 7 position is preferably carried out by oxidizing the PGF _Za derivatives of formula III (where the substituents have the same meanings as defined above) with selenium dioxide and optionally submitting the resulting hydroxy compounds to a substitution reaction. applied. Suitable solvents are acetic acid, tert-butanol, benzene, tetrahydrofuran, dimethoxyethane, dioxane, diethylene glycol dimethyl ether alcohols, carbon tetrachloride. The reaction can be carried out at 40-120 ° C.

The various derivatives for the production of the starting materials are available as follows: The oxidation with selenium dioxide may be carried out with or PGF _2ot esters. The product thus obtained is tetrahydroxy or tetraacyloxy-1 or II.

If the starting material is 9,11,15-triacyl (acyl group hereinafter referred to as C 1-4 alkanoyl or benzoyl group), tristetrahydropyranyl, tris [tri- (C 1-4) alkylsilyl] -PGF _2a esters which are prepared by acylation, silylation, tetrahydropyranylation of PGF _{2 (t} esters) by known reactions, the corresponding 4- and 7-hydroxy-9,11,15-trialyl, tris [(C 1-4 alkyl) silyl] , tristyreehydropyranyl products.

9-Hydroxy-11,15-diacetyl-PGF ₂₀ (Chem. Lett. 1979, 661-664), 9-hydroxy-11, 15-bis-tetrahydropyranyl (JACS 1971, 93, 1491-) or 9-hydroxy-11. , For 15-bis-tri- (C 1-4 alkyl) silyl-PGF _2a methyl esters,

4- and 7-hydroxy-9-hydroxy-11,15-diacetyl or -11,15-bistetrahydropyranyl or -11,15-bis [tri (C 1-4 alkyl) silyl] -1 and II product.

Using monoacetyl, tetrahydropyranyl or tri- (C 1-4 alkyl) silyl-PGF _2ol esters or acids [JACS 1977 (99), 7738] as starting materials, the corresponding 4- and 7-hydroxy monoacetyl, tetrahydropyranyl or afford _{2 (x} derivatives tri- (Ci-C4 alkyl) silyl-PGF. of course, any combination of protecting groups can be achieved. For example. the 11,15-diacetyl-PGF _2a methyl ester of 9-hydroxy group of tetrahydropyranylable or tri- (C 1-4 alkyl) silylated and then further carried out on selenium dioxide oxidation to give 4- and 7-hydroxy-9-tetrahydropyranyl or tri- (C 1-4 alkyl) silyl-11,15 -diacetyl-PGF _2a -methyl ester is formed.

The 4- and 7-hydroxy compounds can be further converted by substitution of these hydroxyl groups to the corresponding halogen, mesyl, tosyl and the like. derivatives. In addition, the resulting mesyl or tosyl groups can also be further substituted as activated groups, e.g. to halogen.

In the present invention, 4- and 7-substituted PGF _2a derivatives are formed side by side. They are generally separated by column chromatography.

In the case of a mixture of the 7,9-dihydroxy and 4,9-dihydroxy-PGF _2a derivatives, it is also possible to carry out the reaction of e.g. dimethoxypropane with an acidic catalyst e.g. p-szulfonsavvíl! selectively forming the 7,9-0,0-isopropylidene derivative which can also be much more easily separated by column chromatography

4,9-dihydroxy compound. The ratio of the 4-hydroxy and 7-hydroxy products of the product mixtures can be influenced by the substituent of the 9-hydroxy group. In the case of the 9-hydroxyl group, the ratio of the 7: 4 hydroxy product is 4: 5-1, e.g. 7-acetyl starting material 1: 2.

Further details of the invention are, without limitation, illustrated by the following embodiments,

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Example 1

9,11,15-Triacetyl-4- and 7-hydroxy-PGF _2a -methyl ester

4.67 g (9.41 mM) of 9,11,15-triacetyl PGF _2a methyl ester are dissolved in 1.5 ml of dry tert-butanol. The solution was heated to reflux and then 2,436 g (18.9 mM) of selenic acid was added. The reaction mixture was refluxed for 1 hour and 3 ml of 5% aqueous sodium bicarbonate solution was added and stirred for 30 minutes. The mixture was extracted with ether (4 x 30 mL), the ether layers were combined, extracted with brine and dried over magnesium sulfate, filtered and evaporated. The crude product (470 mg, weight) was chromatographed on a silica gel column in a 2: 1 mixture of benzene: ethyl acetate. The above solvents are suitable for the value 0.2 to 0.15 _Rf fractions were collected.

Candidates The 0.2 _Rf value of 9, ll, 15-triacetyl-7-hydroxy-PGF _2a methyl ester weight: 685.7 mg (14.3%).

Candidates of _Rf value 0.15 9, ll, 15-triacetyl-4-hydroxy-PGF _{2 O,} methyl ester weighing 1.73 g (36.4%).

Analytical data:

R _f : Benzene: ethyl acetate 2: 1 on silica gel G: 0.2 and 0.15 (benzene: dioxane: acetic acid 3: 10: 1 on silica gel G) 0.51.

NMR (δ): 5.5-5.75 (m, 4H, olefin protons), 5.2 (q, 14) CHOHc), 4.95 (m, 1H, CHOHc), 4-4.5 (m , 2H, CHOH), 3.65 (s, 3H, CH ₃ O), 2.05 (s, 6H, CH ₃ CO), 0.95 (t, 3H, CH ₂ CH ₃ ).

Example 2

4- and 7-Hydroxy-ll, 15-diacetyl-PGF _2ot -melilés2ter

6.18 g (12 mM) of 11,15-diacetyl-PGF _{2 = 1-} methyl ester are dissolved in 50 ml of dry dioxane. To the solution was added 2.66 g (24 mM) of selenium dioxide. After suspending the mixture in a bath at 100-101 ° C for 20 minutes, the reaction mixture is cooled, 20 ml of 5% aqueous sodium bicarbonate solution are added and the mixture is stirred for an additional 30 minutes. The mixture was extracted with ether (6 x 30 mL), and the ether layer was dried over magnesium sulfate, filtered and evaporated. The crude product obtained is chromatographed on a silica gel column with a 1: 1 mixture of benzene: ethyl acetate.

The ethyl acetate-benzene 2: 1 mixture of 0.43 and 0.35 corresponding _Rf fractions were collected and concentrated.

The corresponding value _Rf 0.43 fraction of 7-hydroxy-11,15-diacetyl, methyl-PGF _2l, which weighed 2.01 g (30.1%).

The _Rf value of 0.35 corresponding fraction of the 4-hydroxy-ll, 15-diacetyl-PGF _2a methyl ester weight: 678 mg (10.4%).

Analytical data:

NMR (CDCl 3, δ) 5.5-5.8 (m, 4H, olefin protons),

4.85-5.15 (m, 1H, CHOAc), 5.2-5.45 (m, 1H, CHOAc), 4.0-4.5 (m, 2H, CHOH), 3.65 (s , 3H, OC 2 H 2.05 (s, 6H, CH ₃ CO), 0.95 (t, 3H, CH ₂ CH ₃ ).

TLC: ethyl acetate: benzene 2: 1 Merck silica gel Kieselgel G laponta _Rf = 0.35 and 0.43.

Example 3

4- and 7-Hydroxy-PGF _{2t (} methyl ester

507.5 mg (1.4 mM) of PGR1-methyl ester are dissolved in 5 ml of dry dioxane. The solution was heated in a 100 ° C bath, 311 mg (2.8 mM) selenium dioxide was added and the suspension was stirred for 1 hour.

The reaction mixture was then cooled and stirred with 5 ml of 2.5% sodium bicarbonate solution for 30 minutes. The reaction mixture was extracted with ethyl acetate (6 x 20 mL). The organic layers were combined and dried over magnesium sulfate, filtered and evaporated.

The crude product was chromatographed on a silica gel column with acetone: ethyl acetate 1: 4.

Acetone: ethyl acetate TLC showed _Rf value of 0.42 candidate fractions were collected analytical silica plate. This fraction contains the 7-hydroxy-PGF 4-methyl ester.

Weight: 250 mg (46.7%).

The above analytical system candidates 0.31 _Rf value fractions were also collected. This product is a

Corresponds to 4-hydroxy-PGF _2x methyl ester. After evaporation, weight: 166.3 mg (30.9%).

Analytical data:

TLC (Merck silica gel G plate), benzene: dioxan: acetic acid 20: 20: 1 _Rf = runtime system 495 and 0,485.

Acetone: ethyl acetate 1: 4 running system _Rf = 0.42 and 0.3.

NMR (CDCl ₃ ; δ): 5.45-5.7 (m, 4H, olefin protons), 4.0-4.8 (m, 4H, CHOH protons), 3.65 (s, 3H, CH _3). SHE).

Example 4

The procedure described in Example 2 was followed except that 1,15,15-dibenzoyl-PGF _2a- methyl ester was replaced with 11,15-dibenzoyl-PGF _2x methyl ester to give 1.753 g (34%) of 7-hydroxy 11,15-dibenzoyl-PGF _21- methyl ester and 0.528 g (10.1%) of 4-hydroxy-11,15-dibenzoyl-PGF _2x methyl ester are obtained. _Rf = 0.41 and 0.36 (1: 1 mixture of benzene and ethyl acetate).

Example 5

4- and 7-Hydroxy-11,15-bistetrahydropyranyl-PGF _2x- methyl ester

Each was as in Example 2 except that the starting material was 12 mM

11,15-Bistetrahydropyranyl-PGF-4-methyl ester was obtained, yielding 1.566 g (27.1%) of 7-hydroxy-11,15-bistetrahydropyranyl-PGF-4-methyl ester and 0.508 g of 4-hydroxy-11,15-bistetrahydropyranyl-PGF _2x. we get a methyl ester.

R _f = 0.61 and 0.60 (2: 1 ethyl acetate / benzene).

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Example 5a

4- and 7-hydroxy-11,15-bis (dimethyl-tert-butylsilyl) -PGF _2l methyl ester

All of the procedures described in Example 2 were repeated except that 12 mM 11,15-bis (dimethyl-tert-butylsilyl) -PGF _2a- methyl ester was used as starting material. Thus 1.535 g (26.6%) of 7-hydroxy-11,15-bis (dimethyl-tert-butylsil) -PGF _2a -methyl ester and 0.530 g (9.2%)

4-Hydroxy-11,15-bis (dimethyl-tert-butylsilyl) -PGF2sl-methyl _{ester is} obtained.

R _f = 0.63 and 0.62 (2: 1 ethyl acetate-benzene).

Example 6

7-Hydroxy-7,9a-0,0-isopropylidene-1 1,15-diacetyl-PGF _2a -methyl ester

740 mg of 7-hydroxy-11,15-diacetyl-PGF _2a -methyl ester are dissolved in 5 ml of anhydrous benzene. 821.8 μΐ 2,2-dimethoxypropane was added followed by 2 drops of 10% p-toluenesulfonic acid in tetrahydrofuran and the solution was stirred at room temperature for 30 minutes. The catalyst was neutralized with 2 drops of pyridine and the reaction mixture was evaporated. The crude product (1.1 g) on silica gel, benzene: ethyl acetate 2: 1 yields chromatography, the product was a benzene: ethyl acetate 2: 1 equivalent in analytical Kieselgel spot 0.5 _Rf fractions were collected and concentrated.

Chromatography: 596.5 mg (76%).

Analytical characteristics:

_Rf: benzene: ethyl acetate 2: 1 solvent of 0.71 and 0.62.

NMR (CDCl 3): 5.4 - 5.7 (m, 4H, olefin protons), 5.25 (m, 1H, CH 2 OH), 4.9 (q, 1H, CHO), 4.4, 45 (m, 2H, C-7 and C-9 CHO), 3.65 (s, 3H, OCH ₃ ), 2.05 (s, 6H, CH ₃ CO), 0.95 (t, 3H, CH ₂ CH ₃ ).

Example 7

4-and 7-Hydroxy-PGF _2l

A mixture of 470 mg (0.92 mM) of 9.1 l, 15-triacetyl-4- or 7-hydroxy-PGF _2e -methyl ester was dissolved in 0.5 ml of methanol and added with stirring to 18.5 ml (11.06 mM). Potassium hydroxide in 0.6 M 50: 1 methanol / water.

After stirring at room temperature for 4 hours, the reaction mixture was adjusted to pH 5-6 with 1 M oxalic acid while cooling with ice. The solution was diluted with saturated brine and extracted with ethyl acetate (6 x 20 mL), the organic layers were combined, dried over magnesium sulfate, filtered and evaporated.

The crude product is chromatographed on a silica gel column with ethyl acetate: methanol 3: 1.

Dioxane: benzene: acetic acid 20: 20: 1 analytical system running thin layer chromatography Fractions with _Rf of 0.31 and 0.25 were separately collected and concentrated.

The _Rf = 0.31 fraction of the corresponding 7-hydroxy-PGF _{2 O (weight} of 92.9 mg (26%).

The fraction corresponding to R _f = 0.25 is 4-hydroxy-PGF _{2c (} ; weight: 157 mg (45.5%)).

Analytical characteristics:

TLC:

benzene: dioxan: acetic acid 20: 20: 1 system, the _Rf value = 0.25 and 0.31.

NMR (acetone-d ₆ ): 5.35-5.75 (m, 4H, olefin protons), 3.8-4.35 (m, 8H, CHOH protons), 0.95 (t, 3H, CH ₂ CH ₃ ).

Example 8

7-Chloro-9,11,15-triacetyl-PGF _2a- methyl ester

Triphenylphosphine (400 mg, 1.55 mM) is dissolved in 5 ml of anhydrous carbon tetrachloride distilled from phosphorus pentoxide. The resulting solution is dissolved in 520 mg (1.02 mM) of 7-hydroxy-9,11,15-triacetyl-PGF _2a -methyl ester with stirring.

The reaction mixture was refluxed for 4 hours, then cooled to room temperature, diluted with ether (50 mL), the precipitated triphenylphosphinoxide filtered off and the filtrate evaporated. The crude product thus obtained was chromatographed with benzene: ethyl acetate (4: 1).

Benzene: ethyl acetate = 2: 1 running candidate Kieselgel twice the R _f value of 0.68 were collected fractions analytical silica gel plate (Merck) and evaporated. The title compound obtained was 232 mg (44%).

Analytical characteristics:

TLC: Merck silica gel plate benzene: dioxan: acetic acid 20: 20: 1 mixture of the R _f value of 0.8 benzene: ethyl acetate twice run system with an R _f value of 0.68. '

Example 9

7-Methanesulfonyloxy-9,11,15-triacetyl-PGF _{2 (1-} methyl ester mg (0.098 mM) 7-hydroxy-9,11,15-triacetyl-PGF 4-methyl ester is dissolved in 2 ml of dry methylene chloride and then 58.6 triethylamine (0.588 mM) was added and the mixture was cooled to -20 ° C.

Distilled methanesulfonyl chloride (67.3 mg, 44 mL, 0.588 mM) was added over 5 minutes.

The reaction mixture is stirred for 1 hour at -20 ° C and for 1 hour at 0 ° C. The reaction mixture was then diluted with 30 ml of 0 ° C ether and extracted with 3 x 5 ml of ice-water, 0.1 N hydrochloric acid, the organic phase dried over magnesium sulfate, filtered and evaporated.

The crude product was chromatographed on a silica gel column using benzene: ethyl acetate 3: 1 as eluent.

Fractions in the benzene: ethyl acetate 2: 1 analytical run were collected on a silica gel plate at 0.23 R _f and evaporated. 23.4 mg (46.8%) of the title compound are obtained.

Analytical characteristics:

NMR (CDCl ₃ ; δ), 5.35-5.75 (m, 4H, olefin protons), 5.15-5.3 (m, 2H, CHOAc), 4.95-5.1 (m, 1H , CHOAc), 3.65 (s, 3H, CH ₃ C), 3.0 and 3.5 (s + s, 3H, C 77 ₃ SO ₂ ).

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Example 10

4- and 7-Hydroxy-PGF 4 -methyl ester

15.9 mg of selenium dioxide are dissolved in 4.10 ml of 30% hydrogen peroxide and 1.18 g of PGF-4-methyl ester in 1 ml of tetrahydropyran are added.

The resulting solution was refluxed for 4 hours. The reaction mixture was then diluted with ethyl acetate (100 mL), washed with brine (15 mL), dried over magnesium sulfate, filtered, and evaporated. The crude product is chromatographed on a silica gel column with ethyl acetate / acetone (4: 1).

There was thus obtained 430 mg (34.2%) of 7-hydroxy-PGF _2a- methyl ester and 129 mg (16.3%) of 4-hydroxy-PGF _2a -methyl ester. The physical constants of the products are the same as in Example 3.

Example 11

7-Hydroxy PGF ^ sulfosuccinate

85.2 mg (0.24 mM) of 7-hydroxy-PGF _2a was dissolved in 500 μΐ of anhydrous methanol and 240 μΐ (0.24 mM) of 1 mM methanolic sodium hydroxide solution was added. The reaction mixture was evaporated. 94.1 mg (100%) of the title salt are obtained in the form of a white powder. _Rf = 0.31 (20: 20: 1 benzene-dioxan-acetic acid).

Example 12

4-Hydroxy-PGF _2s sodium salt

The amount given in Example 11 is the same

Repeat with 4-hydroxy-PGF ₂₀ . 94.1 mg (100 mg)

The sodium salt of 4-hydroxy-PGF _{2a is} obtained. _Rf = 0.25 (20: 20: 1 benzene-dioxan-acetic acid).

Example 13

7-Hydroxy PGF ^ -ammóninmsó

95.2 mg (0.25 mM) of 7-hydroxy-PGF 4 are dissolved in 1 ml of methanol and 0.25 moles of ammonia gas are added at + 5 to 0 ° C. The solution was then concentrated. The title salt was obtained as a white residue (96.8 mg, 100%). _Rf = 0.31 (20: 20: 1 benzene-dioxan-acetic acid).

Example 14

Ammonium salt of 4-hydroxy-PGF _2a 60

Example 13 was repeated with the same amount of 4-hydroxy-PGF _2a . 96.8 mg (100%) of the title salt are obtained. R f = -0.25 (20: 20: 1 benzene-dioxane-acetic acid). 65

Example 15

7-Hydroxy-PGF _2a -tetrabutylammonium salt

All. The procedure described in Example 1B was followed, except that 240 μΐ of 1 mM methanolic tetrabutylammonium hydroxide solution was used in place of methanolic sodium hydroxide solution. 146.8 mg (100%) of the title salt are obtained. R _f = 0.31 (20:20: 1

With an IC ratio of benzene dioxane / acetic acid).

Example 16

4-Hydroxy-PGF ^ -tetrabutil salt

The amount given in Example 15 is the same

_Repeat with 4-hydroxy-PGF _2tt . 146.8 mg (100%) of the title salt are obtained. R _f = 0.25 (20: 20: 1)

2C benzene dioxane-acetic acid).

Claims (12)

Patent claims 1. Procedure for the new substituted I and, PGF 4 derivatives - where R is hydrogen, an alkali metal cation, an ammonium cation optionally substituted with 1 to 4 identical or different (C 1 -C 4) alkyl groups, or C 3 -C 4 alkyl, ^R1 is hydrogen or a C1-4 alkanoyl _t, R ² and R ^{8 are} hydrogen, C 1-4 alkanoyl, tetrahydropyranyl, benzoyl or 35 is a tri- (C 1 -C 4) alkylsilyl group, R ^{4 is} hydroxy, halogen, methanesulfonyloxy or toluenesulfonyloxy, or R 'and R ^{4 taken} together may form a -C (C 1 -C 4 alkyl) ₂ -O group, 4C ^R5 is hydroxy, halo, metánszulfoniloxivagy toluenesulfonyloxy group and the ~ bond represents a or β-space position refers to - prepare next to one another, characterized in that a III prostaglandin F Formula _2a -származé45 derivative - wherein R, R ^1, R ² and R ³ are as defined above - (- 4 with selenium compounds of oxidation number 4, optionally in the presence of hydrogen peroxide), and the resulting new substituted PGF 4 isomeric mixture of formula I and II - wherein R, R ¹ , R ² and R ³ are as defined above, and R ⁴ and R ⁵ are hydroxy - optionally, by halogenation, hydrolysis, acylation, re-acetalation or salt formation, to a corresponding compound of formula I and és and / or isomers of formula (I) are optionally separated. 2. A process according to claim 1 wherein the hydroxylation is carried out in the presence of hydrogen peroxide. 3. The process of claim 1 wherein the hydroxylation is carried out without the use of hydrogen peroxide. Process according to any one of the preceding claims, characterized in that the hydroxylation is carried out in a medium containing from 1 to 4 carbon atoms. 5. A process according to any one of claims 1 to 6, wherein the hydroxylation is carried out in the presence of an organic solvent containing an ether linkage. 6. The process of claim 5, wherein the ethereal organic solvent is dioxane. A process for the preparation of substituted PGF 4 derivatives of formula I and II having R ⁴ and R ⁵ in which R ⁴ and R ^{5 are} hydroxy, wherein R, R ¹ , R ² and R ³ are as defined above, characterized in that an isomeric mixture of PGF 4 derivatives of formula I and II obtained after hydroxylation, wherein R, R ¹ , R ² and R ³ are as defined in claim 1 and R ⁴ and R ^{5 are} hydroxy, optionally by hydrolysis or salt formation in I and II; and / or, if desired, separating the isomers of formulas I and II from one another. 8. Figures 1-6. A process according to any one of claims 1 to ^{4 for the preparation of} substituted PGF 4 derivatives of formula I and II having R ⁴ and R ³ other than hydroxy, wherein R ¹ , R ^2, and R ³ are as defined in claim 1, that the PGF _2a derivative of formula I and II obtained after hydroxylation, wherein R, R ¹ , R ² and R ³ are as defined in claim 1 and R ⁴ and R ^{3 are} hydroxy, is acylated, re-acetated and optionally hydrolyzed and / or salt formation to form a suitable compound of Formula I and Formula II and optionally separating the isomers of Formula I and Formula II. 9. A process for the preparation of a process according to claim 8, wherein the substituted PGF 4 derivatives of formula I and II containing halogen atoms R ⁴ and R ⁵ - wherein R, R ¹ , R ² and R ³ are as defined in claim 1, characterized in that after hydroxylation the PGF 4 isomeric mixture of the formulas I and II - wherein R, R ¹ , R ² and R ³ are halogen as defined in claim 1 and R ⁴ and R ^{5 are} hydroxy. The process of claim 8 for the preparation of substituted PGF 4 derivatives of Formulas I and II wherein R ⁴ and R ^{5 are} methanesulfonyloxy, wherein R ¹ , R ¹ , R ² and R ³ are as defined in Claim 1. characterized in that the mixture of PGF _2a isomers of formula I and II obtained after hydroxylation, wherein R, R ¹ , R ² and R ³ are as defined in claim 1, is methanesulfonylated. 11. A process according to claim 8, wherein the post-hydroxylation reactions are carried out after separation of the PGF _2a isomeric mixture of formulas I and II into isomers. A process for the preparation of a process according to claims 8 and 11 wherein R ¹ and R ^{4 are} a substituted PCF 4 derivative of formula I having C (C 1 -C 4 alkyl) 2-O - wherein R 1, R ² , R ³ is as defined in claim 1, characterized in that a PGF ² derivative of the Formula I containing R ¹ is hydrogen and R ⁴ is hydroxy, wherein R, R ² and R ³ are as defined in Claim 1 is -C 4 -C 4 alkyl) _-2- C (C 1 -C 4 alkoxy) ₂ with acetal. Process for the preparation of a process according to any one of the preceding claims for the preparation of PGF2a derivatives of the general formula I and II having R ² and R ^{3 having a C} 1-4 alkanoyl group, wherein R, R ¹ , R ⁴ and R ³ are as defined in claim characterized in that the formula III PGF2iszármazékokból ^R2 and ^R3 represents C1-4 alkanoyl group - starting material - wherein R and R ¹ are as defined in claim 1. 1 page drawing