HU188009B - Process for preparing new derivatives of 2,3,4-trinor-1,5-inter-m-phenylene-pgt down 2alpha - Google Patents

Abstract

The present invention relates to a novel 2,3,4-trinor-1,5-inter-m-phenylene-prostaglandin F2a derivative of the formula I, wherein a bicyclic lactol of formula II is formed from a phosphonium salt of formula III with a strong base phosphorane. reacting in a dipolar aprotic solvent followed by esterification of the resulting 2,3,4-trinor-1,5-inter-m-phenylene-PGF4 derivatives of formula I with an ester derivative of C1-C4 alkyl, where appropriate, and / or the resulting 2,3,4-trinor-1,5-inter-m-phenylene-PGF? -substitutes of formula I having the amino group Z and free amino groups, optionally substituted with C 1-4 alkanoylamino, benzoylamino, or substituted with halo; optionally acylating with C1-4 alkanoyl, benzoyl or tosyl to produce derivatives containing a tosylamino group; and / or the 2,3,4-trinor-1,5-inter-m-phenylene-PGF2o derivatives of formula I obtained, if desired, by saponification, salt formation, deacylation, as appropriate but also within the scope of the general formula I to form a compound. The compounds of the formula I according to the invention can be used as intermediates for the preparation of prostaglandin F2tt analogs, for the preparation of suitable PGI derivatives. -1-

Description

The present invention relates to a novel formula I

2,3,4-Trinor-1,5-interm-m-phenylene-prostaglandin F _2a- derivatives

R ^{1 is} hydrogen, C 1 -C 4 alkyl, an alkali metal cation or a primary, secondary, tertiary or quaternary ammonium cation,

R ² and R ³ each independently represents hydrogen, tetrahydropyranyl, ethoxyethyl or tri- (Cl-C4) alkylsilyl group, ·

^R4 is hydrogen or C1-4 alkyl ¹⁰ group,

^R5 is hexyl, heptyl, phenoxymethyl, m-trifluormetilfenoximetil- or a CH-R ⁶ radical general képle15 needle,

Z is (C 1 -C 4) alkanoylamino, (C 2 -C 5) alkoxycarbonylamino, benzoylamino or tosylamino, optionally substituted with halo;

R ^ö C4-6 alkyl, phenyl or benzyl.

The compounds of formula I are prostaglandin-F1 analogues, the significance of which is that other prostaglandin derivatives having substantially more selective pharmacological activity than the well-known natural PGI ₂ , and their use as novel compounds, for example the novel Also for the preparation of 2,3,4-trinor-1,5-interphenylene PGI ₂ . The preferred use of the compounds of the present invention as starting materials for the preparation of 2,3,4-trinor-1,5-interphenylene-PGI ₂ derivatives is described in 962 /

81 and 963/81.

The novel prostaglandins of formula III followed the procedures developed in the prostaglandin synthesis techniques [see, e.g., Bindra, IS and Bindra R. (1977): Prostaglandin Synthesis, Academic Press, New York], ⁴⁰ of which the most widely used of C ₅ -C ₆ double bond, in the final step, a constructive Wittig reaction.

According to the present invention are prepared by a II bicyclic formula lactol formula - wherein R ^2, R ^3, R *, R ^5, Z and R ⁶ are as previously MEG ⁴⁵ specific keys - one III phosphonium salt of the formula - wherein Ph is phenyl, And X represents a monovalent anion - by reacting with a strong base of phosphorane in an aprotic dipolar solvent, and the resulting 2,3,4-tri- ^50- nor-1,5-inter-m-phenylene-PGF 4 derivatives of formula I Represents ¹ hydrogen atom and R ² , R ³ , R ⁴ , R ⁵ ,

Z and R ⁶ are as defined above, but Z is other than trifluoroacetamido, optionally esterified to an ester ⁵⁵ having R ^{1 as a C} 1 -C 4 alkyl group and / or the resulting 2,3-free amino group of Formula 2,3. , 4-trinor-1,5-inter-m-phenylene-PGF _2a derivatives wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Z and R ⁶ are as defined above, optionally in one of the following cases ^: halogen atoms, - C 1-4 alkanoyl, benzoyl or tosyl group is acylated with an acylating agent, and / or the resultant of the formula I Z-R ^^ trinor-inter-m-phenylene PGF ^ general 20 - wherein R ', R ² , R ³ , R ⁴ , R ^J , Z and R ⁶ are as defined herein, if desired, by saponification, salt formation, deacylation to another compound of formula I.

The reaction results in the formation of 2,3,4-trinor-1,5-inter-m-phenylene-PGF ₂₀ derivatives of formula I and Z. The resulting products may be purified, hydrolyzed, deprotected, or otherwise protected as necessary.

The medium used in the Wittig reaction strongly influences the ratio of E and Z geometric isomers formed. Nonpolar solvents favor the formation of the E isomer. Since the biological activity of the Z isomer is better than that of the corresponding E isomers, the reaction is preferably carried out in a dipolar aprotic solvent such as dimethylsulfoxide. In addition, mixed solvents such as dimethylsulfoxide-tetrahydrofuran, dimethylsulfoxide-dimethoxyethane may also be used.

From the phosphonium salt of formula III, the preparation of phosphorane can be carried out with strong bases such as sodium amide, butyl lithium, preferably sodium methylsulfenyl ether (DIMSYL-Na). Purification of the products of the reaction can be easily carried out by column chromatography. Esters of the purified products can be prepared by known methods such as diazoalkanes. If the desired product is a carboxylic acid salt, salt formation from the acid formed in the reaction may also be carried out by known methods. For example, the alkali metal salts may be formed with an alkali metal hydroxide in an aqueous or alcoholic reaction mixture. When the desired product is an amine salt, the compound of formula I isolated in acid form is reacted with the corresponding primary, secondary or tertiary amine such as tris (hydroxymethyl) aminomethane, dicyclohexylamine or triethylamine. In the case of the quaternary ammonium salt, the desired derivative can be obtained from the quaternary ammonium hydroxide by, for example, tetrabutylammonium hydroxide.

The Wittig reaction may also be carried out when in the lactols of the formula II the substituents R ¹ and R ³ are hydrogen. The product thus obtained can be obtained by acylation, tetrahydropyranylation, ethoxyethylation or silylation to give the desired R * and R ³ substituents. Of course, the acylated, tetrahydropyranylated, ethoxyethylated or silylated derivatives can also be prepared directly from the appropriately substituted starting material.

Acetyl-containing derivatives can be converted to the corresponding dihydroxy compounds by conventional means, such as potassium carbonate in methanol. Derivatives containing tetrahydropyranyl, ethoxyethyl or silyl groups may be cleaved in acidic medium, for example, in a 3: 1: 1 mixture of acetic acid: tetrahydrofuran: water. In addition, the silyl protecting group may be cleaved with tetrabutylammonium fluoride under neutral conditions.

If Z is a free amino group, then the 16-amino derivatives are most easily prepared by removing the protecting group previously introduced on the amino group in the final step. Preferred C 1-4 alkanoyl, alkoxycarbonyl, benzoyl, tosyl, benzyloxycarbonyl, p-nitrophenoxycarbonyl optionally substituted with halogen, which can be readily cleaved by methods known per se. Alternatively, starting from lactol containing a free amino group.

When Z in the starting material of formula II is trifluoroacetylamino, it is cleaved by the base to give compounds of formula I which contain a free amino group.

The corresponding PGI ₂ derivatives of the 2,3,4-trinor-1,5-interphenylene-PGF _2a derivatives of formula I are prepared by optionally esterifying them into an ester having a C 1 -C 4 alkyl group at R ¹ and Z is a free amino group, for example, acylated with an acylating agent containing a trifluoroacetyl group, and the resulting prostaglandin F 4 derivatives of formula I having a substituent other than Z is a free amino group - wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is other than as defined in 1 for formula and Z is a free amino group - an EX reacted with an electrophilic reagent X being a halogen atom and a halogen atom, or N-szukcinimidocsoportot M in an organic solvent or a two-phase medium comprising water and a water-immiscible organic solvent - is reacted with if necessary, the presence of acid scavengers and then reacting the resulting halogenated PGI derivatives of formula V, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are other than Z in the formula I, with basic reagents, and finally the resulting compounds of formula IV

- wherein R ^1, R ^2, R ^3, R ^4, R ^s, R ⁶ and Z are as defined above

- if desired, by saponification, salt formation, acylation, deacylation to another compound of formula IV.

Example 1

2,3,4,17,18,19,20-Heptanor-1,5-inter-m-phenylene-1,15-bis (tetrahydropyran-2-yloxy) -16-phenoxy-PGF _2a -methyl ester

250 mg (10.41 mM) of sodium hydride was weighed into a round-bottomed flask with a dried three-necked magnetic stirrer, a plunger thermometer and a rubber stopper. The atmosphere is purged with nitrogen and 5 ml of dry dimethylsulfoxide is added. The device is connected to a nitrogen bottle and, using a slow stream of nitrogen, creates a slight nitrogen overpressure in the device using a mercury-bubble bubble. The temperature of the suspension was then slowly raised to 60 ° C. At this time gas evolution was observed. After completion (about 'A hour), the temperature of the reaction mixture was raised to 70 ° C and the mixture was stirred for an additional Vi hour. A dark gray solution is obtained to which 2.45 g (5.68 mM) of vacuum-dried (meta-carboxybenzyl) triphenylphosphonium chloride are added at 15 ° C.

The resulting red solution was stirred at room temperature for ^X hours and then 1.57 g (2.59 mM) 3,3ap, 4,5,6,6aP-hexahydro-2-hydroxy-43- [3- (tetrahydropyran-2 -yloxy) -4-phenoxy-butenyl] -5a- (tetrahydropyran-2-yloxy) -2H-cyclopenta [b] furan was added to the reaction mixture with 500 μΐ of dry dimethylsulfoxide. The reaction mixture was stirred at 60 ° C for 1 hour. The reaction mixture was then poured into a mixture of 20 g of ice and 50 ml of water. The solution was extracted with ether (2 x 10 mL), then the pH of the aqueous phase was adjusted to 4-5 with 2N aqueous sodium hydrogen sulfate solution, and this aqueous phase was extracted with ether (4 x 20 mL) and ethyl acetate (2 x 20 mL). The combined organic phases are dried over sodium sulfate, filtered and the solvent is distilled off under reduced pressure. It is convenient for attaching. The resulting crude product (2.5 g) was dissolved in ether (20 ml) and diazomethane ethereal solution was added dropwise at 0 ° C with stirring until the yellow color of diazomethane had disappeared. The methyl ester thus prepared was also subjected to layer chromatography on a silica gel .G layer plate with 20: 10: 1 benzene dioxane acetic acid. The acid obtained in the Wittig reaction has an R _f of 0.52 and the methyl ester prepared from it has an R _f of 0.73. (If the methyl ester is incomplete, an additional ethereal diazomethane solution is added.) After distilling off the ether, the crude methyl ester is chromatographed on a silica gel column with benzene-ethyl acetate (2: 1) and the benzene dioxane-acetic acid is 0.73 _Rf value appropriate fractions were collected and concentrated spots. The title compound thus obtained was 1.426 g (70%).

Analytical characteristic of the product: TLC on silica gel G analytical layer plate with benzene-dioxane-acetic acid 20: 10: 1.

_Rf value: 0.73.

Similarly, 2,3,4-trinor-1,5-interm-phenylene-11,15-bis (tetrahydropyran-2-yloxy) 20-methyl, -PGF _2a -methyl ester was prepared. [α] D = + 2 ° (c = 1, in ethanol).

Example 2

2,3,4,17,18,19,20-Heptanor-1,5-inter-m-phenylene-16-phenoxy-PGF _2a methyl ester

The procedure of Example 1 was followed except that 350 mg (1.29 mM) of 3,3aP, 4,5,6,6aP-hexahydro-2-hydroxy-4β- (3-hydroxy-4-phenoxy) A solution of 1-trans-butenyl) -5a-hydroxy-2H-cyclopenta [b] furan in 450 μΐ of dry dimethyl sulfoxide was added to the reaction mixture. This gave 401.9 mg (77.5%) of the title compound. NMR (CDCl3):

δ 6.85-7.5 (m, 7H, aromatic, 7.5-8.05 (m, 2H, aromatic, 5.25-6.75 (m, 4H, olefin protons)), 3.92 (s , 3H, OCH ₃ )

-3188 009.

In a similar way the 2,3,4,17,18,19,20-heptanor-l, 5-inter-m-lm fenilénló-trifluoromethyl phenoxy-PGF ^ -methyl ester NMR (CDC1 _3):

7.1-7.5 (m, 5H, aromatic protons), 7.5 to 8.05 ⁵ (m, 3H, aromatic protons), 2,3,4-trinor-5-inter-m- methylene-20-methyl-PGF _2a methyl ester

NMR (CDC1 _{3): '1n} δ 0.89 (t, 3H, _CH3 -), 3.90 (s, 3H, - OCH ₃₎ ¹⁰

5.23-6.7 (m, 4H, olefinic protons), Ί, ΊόΤ, 55 (m, 2H, aromatic protons), 7.6-8.05 (m, 2H, aromatic protons)

R _f : 0.34 (benzene-dioxane-acetic acid 20: 10: 1), and a

2,3,4-trinor-1,5-inter-m-phenylene-20-ethyl-PGF _2a methyl ester _Rf: 0.35 (benzene-dioxan-acetic acid 20: 10: 1);

Example 3

2,3,4,18,19,20-Hexancr-1,5-inter-m-phenylene} 1,15-bis (tetrahydropyran-2-oxo) -16-acelamido-17-phenyl-PGF _2a- methyl ester

The procedure of Example 1 was followed except that 1.37 g (2.59 mM) of 3,3aP, 4,5,6,6aP-hexahydro-2-hydroxy-4β- [3- (tetrahydropyran-2) -Yloxy) -4-acetamido-5-phenyl-1-transpentenyl] -5a- (tetrahydropyran-2-yloxy) -2H-cyclopentane [b] furan was added to 500 ml of anhydrous dimethylsulfoxide. 1.426 g (70%) of the title compound are obtained. R _f : 0.05 (20: 10: 1 benzene-dioxane-acetic acid on Merck G analytical silica gel plate). 35

Example 4

2,3,4-Trinor-1,5-inter-m-phenylene-16-amino-PGF _2a methyl ester ⁴⁰

a) Proceed as in Example 2, except that 0.497 g (1.29 mM) of 3,3aP, 4,5,6,6ap-hexahydro-2-hydroxy-4β- [3-hydroxy-4- (t -butoxycarbonylamino) -1-trans-octenyl] ^-45 [alpha] -hydroxy-2H-cyclopenta [b] furan in 400 μΐ of dry dimethylsulfoxide was added to the reaction mixture. 0.450 g (87%) of 2,3,4-trinor-1,5-inter-m-phenylene-16-tert-butoxycarbonylamino-PGF2a-methyl ester are obtained. Thin layer chromatography on silica gel ⁵⁰ analytical layer plate Rf: 0.31 ethyl acetate: benzene 4: 1.

Prepared as 2,3,4,17,18,19,20-heptanor-l, 5-inter-m-fenilén16-phenyl-1-O-butoxycarbonyl-rierc -propionic PGF ^ as described above, - ⁵ methyl ⁵ ( R _f : 0.35 ethyl acetate: benzene 4: 1) and 2,3,4,18,19,20-hexanor-1,5-inter-m-phenylene-16 (tert-butoxycarbonylamino) -17-. phenyl-PGF _2a- methyl ester.

R f: 0.36 (ethyl acetate: benzene 4: 1)

b) 0.450 g (0.87 mM) of 2,3,4-trinor-1,5-interphenylene-16- (tert-butoxycarbonylamino) -PGF _2a -methyl ester are dissolved in 5 ml of acetic acid and 1.05 equivalents of dry hydrogen chloride gas is introduced into the solution. The end of the reaction _{g5 is} indicated by the completion of the evolution of isobutylene gas. The reaction mixture was diluted with ethyl acetate (50 mL) and the pH was adjusted to 8-9 with 1 N sodium hydroxide with vigorous stirring. The aqueous phase was separated and the organic layer was dried over anhydrous sodium sulfate and evaporated. The crude product was chromatographed on a silica gel column using isopropanol: water 8: 1. R _f: 0.4 (isopropyl alcohol: water = 7: 2), fractions were collected and evaporated. 0.291 g of the expected product are obtained.

2,3,4,17,18,19,20-heptanor-1,5, inter-m-phenylene-16-amino-16-phenyl-PGF _2a -methyl ester (Rp 0.45 7: 2) was prepared as described above. i-propanol / water mixture) and a

2,3,4,18,19,20-hexanor-1,5-inter-m-phenylene-16-amino-17-phenyl-PGF _2a -methyl ester (R _p · 0.47, 7: 2 i-propanol- water in a mixture).

Example 5

2,3,4-Tinor-l, 5-meters is m-phenylene-16-acetamido '

PGF _2a methyl ester

2.5 g (5.92 mM) of methyl 16-amino-2,3,4-trinor-1,5-intermphenylene-PGF _{2a are} dissolved in 3 ml of anhydrous pyridine and the solution is cooled to 0 ° C. 12.9 mM acetyl chloride (0.98 g, 0.79 mL) was added dropwise.

The reaction mixture was stirred at 0 ° C for 30 min and then diluted with 50 mL of ethyl acetate. The organic layer was washed with 1N hydrochloric acid (10 mL), dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. Yield: 2.36 g (86%). (R _f : 0.7 isopropanol: water 7: 2.)

The 2,3,4-trinor-1,5-inter-m-phenylene-16-benzoylaminoPGF _2a methyl ester (R _{p =} 0.67 in isopropanol: water 7: 2) and the 2,3 , 4-trinor-5-inter-m-fenilén16-tosylamino-PGF ^ -methyl ester _(Rf 0.61 isopropanol: water = 7: 2)

Example 6

2,3,4-Trinor-1,5-inter-m-phenylene-16- (trifluoroacetamido) -PGF _2a- methyl ester

2,3,4-Trinor-1,5-inter-m-phenylene-16-amino-PGF-4-methyl ester (460 mg, 1.1 mM) was dissolved in 3 ml of anhydrous triethylamine and cooled to 0 ° C. Anhydrous trifluoroacetic acid (160 μΐ, 1.15 mM) was then added. The reaction mixture was stirred at 0 ° C for 30 min and then diluted with ethyl acetate (50 mL). The organic layer was washed with 1 N oxalic acid (2 x 10 mL), dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. This gives 2,3,4-trinor-1,5-inter-m-phenylene-16- (trifluoroacetamido) -PGF _2a- methyl ester. Yield: 87.8%; R _f : 0.3 (2: 1 ethyl acetate-benzene)

188,009

Example 7

2,3,4-Trinor-1,5-inter-m-phenylene-11,15-bis (tetrahydropyran-2-yloxy) -15,20-dimethyl-PGF _2a -methyl ester

The procedure of Example 1 was followed, except that 1.21 g (2.59 mM) of 3.3aP, 4,5,6,6afl-hexahydro-2-hydroxy-4P- [3- (tetrahydropyran-2) -yloxy) -3-methyl-non-1-en-yl] -5a- (tetrahydropyran-2-yloxy) -2H-cyclopenta [b] furan is added with 500 µl of anhydrous dimethylsulfoxide. 1.12 g (72%) of the title compound are obtained. R _f : 0.4 (2: 1 benzene-ethyl acetate).

Example 8

2,3,4-Trinor-1,5-inter-m-phenylene-1,115-bis (1-ethoxyethoxy) -15,20-dimethyl-PGF _2a -methyl ester

The procedure of Example 1 was followed except that 1.14 g (2.59 mM)

3,3aB, 4,5,6,6aP-Hexahydro-2-hydroxy-4B- [3- (letoxyethoxy) -3-methyl-non-1-enyl] -5d- (1-ethoxyethoxy) 2H-cyclopenta [ A solution of b] furan in 500 µl of anhydrous dimethyl sulfoxide was added to the reaction mixture. 1.09 g (73%) of the title compound are obtained. _Rf 0.35 (2: 1 mixture of benzene and ethyl acetate).

Example 9

2,3,4-Trinor-1,5-inter-m-phenylene-1,115-bis (dimethyl-tert-butylsilyloxy) -15,20-dimethyl-PGF _2a- methyl ester

Example 1 except that 1.36 g (2.59 mM) of 3,3ap, 4,5,6,6ap-hexahydro-2-hydroxy-4β- [3- (dimethyl-tert- butylsilyloxy) 3-methyl-non-1-enyl] -5α- (dimethyl-tert-butylsilyloxy) 2H-cyclopenta [b] furan is added with 500 µl of anhydrous dimethylsulfoxide. 1.2 g (71%) of the title compound are obtained. _Rf 0.43 (2: 1 mixture of benzene and ethyl acetate).

Example 10

2,3,4-Trinor-1,5-inter-m-phenylene-20-methyl-PGF _2il sodium salt

To a solution of 402 mg (1 mM) of 2,3,4-trinor-1,5-inter-m-phenylene20-methyl-PGF _{20 in} 1 ml of anhydrous methanol was added 1 ml of 1 mM sodium hydroxide in methanol, followed by evaporate the solution to dryness in vacuo. 420 mg of the title salt are obtained in the form of a white powder. Mass Spectrum: M ⁺ / e = 402; typical fragmentation: M ⁺ - 18 / e = 384.

Example 11

2,3,4-Trinor-1,5-inter-m-phenylene-20-ethyl-PGF _2a tromethamine salt

In all cases, Example 10 was repeated except that 415 mg of 2,3,4-trinor-1,5-interphenylene-20-ethyl-PGF _2a and 1 ml of 1 mM methanolic tromethamine were used. reaction solution. This gave 520 mg of the title salt as a white powder.

Mass Spectrum: M ⁺ / e = 415; typical fragmentation: M ⁺ - 18 / e = 397.

Example 72

2,3,4,17,18,19,20-Heptanor-1,5-inter-m-phenylene-16-phenoxy-PGF _2a -dicyclohexylamine salt

In each case, the procedure of Example 10 was followed except that 424 mg of 2,3,4,17,18,19,20-heptanorl, 5-inter-m-phenylene-16-phenoxy-PGF ₂₀ and 1 ml of A 1 mM solution of dicyclohexylamine in methanol was reacted. The residue was 605 mg of the title salt.

Mass Spectrum: M ⁺ / e = 424; typical fragmentation: M ⁺ - 18 / e = 406.

Claims (16)

A process for the preparation of novel 2,3,4-trinorl, 5-inter-m-phenylene-prostaglandin-F _2a- derivatives of formula I - wherein R ^{1 is} hydrogen, C 1 -C 4 alkyl, an alkali metal cation or a primary, secondary, tertiary or quaternary ammonium cation, R ² and R ³ are each independently hydrogen, tetrahydropyranyl, ethoxyethyl or tri (C 1 -C 4) alkylsilyl; R ^{4 is} hydrogen or C 1-4 alkyl, R ^{5 is} hexyl, heptyl, phenoxymethyl, m-trifluoromethylphenoxymethyl or an -CH-R ⁶ I z a group of the general formula Z is (C 1 -C 4) alkanoylamino, (C 2 -C 7) alkoxycarbonylamino, benzoylamino or tosylamino, optionally substituted by halogen; R ^{6 is C} 4 -C ⁶ alkyl, phenyl or benzyl for the preparation of a bicyclic lactol of formula II - wherein R ² , R ³ , R ⁴ , R ⁵ , Z and R ⁶ are as defined in the present specification - from a phosphonium salt of Formula III wherein Ph is a phenyl group and X is a monovalent anion with a strong base phosphorane in a dipolar aprotic solvent and the resulting 2,3,4-trinor-1,5-inter-m-phenylene derivatives wherein R ^{1 is} hydrogen and R ² , R ³ , R ⁴ , R ⁵ , Z and R ⁶ are as defined in the present specification but Z is other than trifluoroacetamido, optionally wherein R ¹ is a C 1-4 alkyl group; and / or the resulting 2,3,4-trinorl, 5-inter-m-phenylene-PGF, _a derivatives of formula I, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ meaning in the subject circle 1881 specified - where Z is optionally substituted halo, today substituted C1-4 alkanoylamino, benzoylamino, or containing tozilaminocsoportot derivatives optionally acylated halosubstituted C1-4 alkano ^5-yl, benzoyl, or tosyl, with an acylating agent, and / or formula I thus obtained 2,3,4-trinor1,5-inter-m-phenylene PGF ^ derivatives of formula - wherein R ^1, R ^2, R ^3, R, R ^3, Z and R are as ^his material ¹⁰ as defined above - if desired, saponification, salt formation by treatment with an appropriate deacylation, but also includes those belonging to the formula I compound. 2. The method of claim 1, namely ^15-way, characterized in that dimethyl sulfoxide is used as dipolar aprotic solvent. 3. A process according to claim 1 or 2, wherein the strong base is dimethyl sulfoxide sodium derivative ^2C . The process according to any one of the preceding claims, which is 2,3,4,17,18,19,20-heptanor-1,5-inter-m-phenylene-11,15-bis (tetrahydropyran-2-yloxy) -16-phenoxy. For the preparation of -PGF _2a- methyl ester, ^2E, characterized in that 3.3aP, 4,5,6,6aP-hexahydro-2-hydroxy-4β- [3- (tetrahydropyran-2-yloxy) -4-phenoxy-1-trans-butenyl] Starting from -5a- (tetrahydropyran-2-yloxy) -2H-cyclopenta [b] furan. 5. Process for the preparation of ^3C according to any one of claims 1 to 4 for the preparation of 2,3,4-trinor-1,5-interphenylene-11,15-bis (tetrahydropyran-2-yloxy) -20-methyl-PGF _2a- methyl ester, characterized in that 3,3a3,4,5,6,6a3-hexahydro-2-hydroxy-4β- [3- (tetrahydropyran-2-yloxy) -1-trans-nonenyl] 5α-tetrahydropyran-2-yloxy) -2H-cyclopenta [b ] we start from furan. 6. A method according to any preceding mode of implementation of 2,3,4,17,18,19,20-heptanor-l, 5-inter-m-phenylene-16-phenoxy _PGF2 -metilész- ^c space preparation, characterized in that We start from 3,3aP, 4,5,6,6aP-hexahydro-2-hydroxy-4β- (3-hydroxy-4-phenoxy-1-trans-butenyl) -5α-hydroxy-2H-cyclopentafiburfuran. 7. ^4E Rás procedure according to any preceding mode of implementation of 2,3,4,17,18,19,20-heptanor-l, 5-inter-m-phenylene-16- (m-trifluoromethyl phenoxy-PGF ^ -methyl preparing wherein 3,3ap, 4,5,6,6aP-hexahydro-2-4P [3-hydroxy-4- (m-trifluoromethylphenoxy) -l-trans- ^c butenyl] -5-hydroxy- Starting from 2H-cyclopenta [b] furan. 8. A method according to any preceding mode of implementation of 2,3,4-trinor-5-inter-mfenilén-20-methyl-PGF ^ -methyl preparation of ⁵⁵ wherein said 3,3aP, 4,5,6,6ap-hexahydro- Starting from 2-hydroxy-4β- (3-hydroxy-1-trans-nonenyl) -5α-hydroxy-2H-cyclopenta [b] furan. 9. Method as claimed in any one mode of implementation, ^{2,3,4-trinor-5-inter-m-phenylene-60-ethyl-PGF} 20, _the methyl ester thereof, characterized in that 3,3ap, 4,5,6- 6α-hexahydro-2-hydroxy-4β- (3-hydroxy-1-trans-decenyl) -5α-hydroxy-2H-cyclopenta [b] furan. 10. A process according to any one of claims 1 to 4, 2,3,4,18,19,20-hexanor-1,5-inter-m-phenylene-11,15-bis (tetrahydropyran-2-yloxy) -16-acetamido-17-phenyl-PGF ₂₀ - methyl ester, characterized in that 3,3ap, 4,5,6,6aphexahydro-2-hydroxy-4P- [3- (tetrahydropyran-2yloxy) -4-acetamido-5-phenyl-1-transpentenyl] -5a Starting from (tetrahydropyran-2-yloxy) -2H-cyclopenta [b] furan. 11. A process for the preparation of a process according to any one of claims 1 to 4 for the preparation of 2,3,4-trinor-1,5-interphenylene-1-tert-butoxycarbonylamino-PGF-4-methyl ester, characterized in Starting from 6α-3-hexahydro-2-hydroxy-4β- [3-hydroxy-4- (tert-butoxycarbonylamino) -1-trans-octenyl] -5α-hydroxy-2H-cyclopenta [b] furan. 12. The process according to any one of claims 1 to 4, 2,3,4,17,18,19,20-heptanor-1,5-interm-m-phenylene-16-phenyl-16- (tert-butoxycarbonylamino) -PGF _2a -methyl ester. characterized in that 3,3ap, 4,5,6,6aP-hexahydro-2-hydroxy-4P- [3-hydroxy-4-phenyl-4- (tert-butoxycarbonylamino) -1-trans-butenyl] -5a starting from hydroxy-2H-cyclopenta [b] furan. 13. Process for the preparation of a process according to any one of claims 1 to 4 for the preparation of 2,3,4,18,19,20-hexanoro-1,5-inter-m-phenylene-16- (tert-butoxycarbonylamino) -17-phenyl-PGF _20- methyl ester, , 3aP, 4,5,6,6aP-Hexahydro-2-hydroxy-43- [3-hydroxy-5-phenyl-4- (tert-butoxycarbonylamino) -1-trans-pertyl] -5a-hydroxy-2H- starting from cyclopenta [b] furan. 14. Process for the preparation of a process according to any one of claims 1 to 3 for the preparation of 2,3,4-trinor-1,5-interphenylene-11,15-bis (tetrahydropyran-2-yloxy) -15,20-dimethyl-PGF-4-methyl ester, characterized in that 3aP, 4,5,6,6aP-Hexahydro-2-hydroxy-4β- [3-] - (tetrahydropyran-2-yloxy) -3-methyl-1-trans-transnonyl] -5α- (tetrahydropyran-2-yloxy) -2H starting from cyclopenta [b] furan. 15. Process for the preparation of a process according to any one of claims 1 to 3 for the preparation of 2,3,4-trinor-1,5-interphenylene-11,15-bis (1-ethoxyethoxy) -15,20-dimethylPGF 4 -methyl ester, characterized in that 3.3aP , 4,5,6,6aP-Hexahydro-2-hydroxy-4β- [3- (1-ethoxyethoxy) -3-methyl-1-trans-nonenyl] -5α- (1-ethoxyethoxy) -2H-cyclopenta [b] furan let's start. 16. Process for the preparation of a process according to any one of claims 1 to 5 for the preparation of 2,3,4-trinor-1,5-interphenylene-11,15-bis (dimethyl-tert-butylsilyloxy) 15,20-dimethyl-PGF-4-methyl ester, characterized in that 3.3aP, 4,5,6,6aP-hexahydro-2-hydroxy-4β- (3- (dimethyl-tert-butylsilyloxy) -3-methyl-trans-nonenyl) -5α-dimethyl-tert-butyl -Silyloxy) 2H-cyclopenta [b] furan. 1 figure