FI68614C - FRAMEWORK FOR THE PREPARATION OF THERAPEUTIC THERAPEUTIC ANVAENDBARA 17-ATSA-PGF2ALFA-DERIVAT - Google Patents

Description

NOTICE OF PUBLICATION (11) UTLÄGG Nl NGSSKRIFT 6 861 4 C (45) Patent granted 10 10 1935 Potent ceddolat * (51) Ky.lk. * / Lnt.Cl. * C 07 C 177/00 (21) Patent application - Patenttnsöknlng 780162 ( 22) Date of application - Ansöknlngsdag 1 8.0 1.78 (F ») (23) Starting date - Giltighetsdag 1 8.01. 78 (41) Become Public - Blivit offentlig 19-07.79

National Board of Patents and Registration Date of publication | -

Patent- och registerstyrelsen '' Ansökan utlagd och utl.skriften publicerad 28.O6.85 (32) (33) (31) Pyydetty etuoikeus — Begärd priority (71) CHINOIN Gygyszer is Vegy6szeti Termdkek Gyära RT, To u. 1 to 5,

Budapest IV, Hungary-Hungary (HU) (72) Istvän Szekely, Szentendre, Gäbor Kovacs, Budapest, Sändor Virag, Budapest, Mätyäs Szentivanyi, Budapest,

Hungary-Hungary (HU) (7 * 0 Oy Kolster Ab (5 * 0 Process for the preparation of new therapeutically useful 17-aza-PGF2oC "derivatives - For the preparation of new therapeutically useful 17-aza-PGF2oC derivatives)

The invention relates to a process for the preparation of new optically active and racemic 17-aza-PGF derivatives of the formula

is OH

^ ^ Ns' ^^ XC00Q

; "Xii R ** ° M 2 wherein R 1 is hydrogen, lower alkanoyl, trihaloalkanoyl, benzyloxycarbonyl or a phenoxycarbonyl group which may be substituted by nitro, methoxy or chlorine is Alkyl having 1 to 4 carbon atoms, R 1 is hydrogen or a protecting group and Q is hydrogen, alkyl of 1 to 4 carbon atoms, or a pharmaceutically acceptable, non-toxic cation.

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Natural prostaglandins are derivatives of prostanoic acid Prostanoic acid is a fatty acid of 20 carbon atoms containing a cyclopentane ring. These compounds are known to have a very potent effect on various biological functions and are therefore useful for pharmacological purposes (Pharmacol. Rev. 20, 1 (1968)). The compound PGFβ can achieve very good results in gynecology (BE patent 738,177).

Several publications have discussed prostagalandine analogs, i.e., compounds having a prostaglandin-like structure. For example, NL Patent 7,206,361 describes PGFβ and PGE analogs containing an oxygen atom or a sulfinyl or alkylimino group at position 17 and a lower side chain terminus with an aryl, benzyl or furfuryl group which may be substituted, and fertilized compounds of these compounds. preventive and hypotensive spasmolytic effect. NL Patent Publication No. 7,313,322 relates to prostaglandin analogs of the above type in which the lower side chain of the prostaglandin terminates in a monovalent heterocyclic group.

It has now been found that the new 17-αΐοα-Ρ6ΐ2. ^ Derivatives of formula (XII) are much more potent than the natural PGF? .A "compounds and have a d-adrenergic stimulating effect in addition to the typical properties of prostaglandins.

This invention relates not only to optically active isomers of the compounds in question but also to racemates, the term "alkanoyl" used in the definition of the substituents of formula XII denoting a straight-chain branched aliphatic acid radical having 1 to 4 carbon atoms (e.g. acetyl, propinoyl, n-butanoyl, etc.). ). The term "trihaloalkanoyl" preferably means a trifluoroacetyl group.

3,68614

Alkyl groups R 2 and, Q are straight-chain or branched, such as methyl, ethyl, n-propyl, isopropyl or n-butyl.

Suitable pharmaceutically acceptable, non-toxic cations include, for example, sodium, potassium, calcium or ammonium ions.

A compound of formula XII having acetyl, n-propyl and Q is hydrogen is preferred.

17-Aza-PGF 2 derivatives of formula XII can be prepared by reacting a compound of formula (α 2)

/B

p- \ <X ^ V V R.

wherein R 1 and R 2 are as defined above and are hydrogen or a protecting group commonly used in prostaglandin chemistry, is reacted with phosphorane prepared from a triphenyl (4-carboxybutyl) phosphonium salt, or (a 2> compound of the formula 0 ° Λ V r 40 r ± wherein R 1, R 2 and R 2 are as defined above are reduced with a complex metal hydride, followed by the compound of formula 68614 λοη

is

Wherein R 2 and are as defined above are reacted with a phosphorane prepared from a triphenyl- (4-carboxybutyl) -phosphonium salt, or a compound of formula (a,) n

A

O 'R 6 -R 2 VI' 0 Ra wherein R 1, R 2 and R 2 have the same meaning as above are reduced with complex borohydride to give the obtained compound of formula

. »R

p Γ 1 N - - R X

R4 ° RÖI ^

4U R

wherein R 1, R 2 and R 2 have the same meaning as above, are reduced with a complex metal hydride and the resulting compound of formula

v OH

A

Wherein R 1, R 2 and R 2 are as defined above are reacted with phosphorane prepared from a triphenyl- (4-carboxybutyl) -phosphonium salt; and optionally 5 68614 1) deprotection of a compound of formula XII, and / or 2) conversion of a compound of formula XII having a trihaloalkanoyl, benzyloxycarbonyl or phenoxycarbonyl group which may be substituted with nitro, nitro or chloro to a compound of formula XII wherein is hydrogen, by hydrolysis in an acidic medium, and / or 3) a compound of formula XII wherein R 1 is hydrogen is converted to a compound of formula XII having a lower alkanoyl, a lower alkanoyl group in the molecule, and / or 4) a compound of formula XII wherein Q is hydrogen is converted to a compound of formula XII wherein Q is alkyl of 1 to 4 carbon atoms, and / or 5) a compound of formula XII wherein Q is hydrogen is converted to a pharmaceutically acceptable, non-toxic salt.

In the starting materials of formulas (VIII), (X) and (XI), R 1 represents hydrogen or a protecting group. As the protecting group, any protecting group commonly used in prostaglandin chemistry can be used. Thus, R 2 may be a protecting group which is resistant to base treatment but can be easily removed in an acidic medium. Suitable protecting groups include, for example, tetrahydropyranyl and trialkylsilyl (e.g., trimethylsilyl or triethylsilyl, etc.). R 1 may also be p-phenylbenzoyl.

The protecting groups are attached to the molecule by known methods. For example, a tetrahydropyranyl group can be attached to a compound containing a free hydroxyl group by reacting it with 3,4-dihydro-2H-pryan. The reaction is carried out in a solvent or without a solvent in the presence of a small amount of acid catalyst. Suitable solvents for the reaction include chlorinated hydrocarbons (e.g., dichloromethane) and small amounts of phosphorus oxychloride or p-toluenesulfochloride can be used as the acid catalyst.

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The trialkylsilyl protecting group can be attached to the molecule using trialkylsilyl chloride. The reaction is preferably carried out in the presence of an acid scavenger such as pyridine.

The p-phenylbenzoyl protecting group can be derived from p-phenylbenzoyl chloride. This protecting group can be attached to compounds of formulas (X) and (XI).

The tetrahydropyranyl and trialkylsilyl protecting group can be removed by acid treatment after the desired reaction is completed. For this purpose, it is preferable to use an aqueous solution of acetic acid.

If the group is a p-phenylbenzoyl group, it is automatically removed under Wittig reaction conditions. If the p-phenylbenzoyl group is to be eliminated at an earlier stage of the process (e.g. from compounds of formula (IX)), this can be done with potassium carbonate in methanol solution.

Compounds of formula (XI) may be converted to the corresponding compounds of formula (XII) by a Wittig reaction in a known manner. Phosphorane prepared from the triphenyl- (4-carboxybutyl) phosphonium salt is used as the Wittig reagent. A preferred embodiment is one in which a dimethyl sulfoxide solution of dimsyl sodium is prepared by reacting dimethyl sulfoxide and sodium hydride, followed by the addition of triphenyl- (M-carboxybutyl) phosphonium bromide and then a compound of formula (XI). The prepared compound of formula (XII) can be isolated by any known method, preferably by column chromatography (e.g. silica gel).

Compounds of formula (XI) may be prepared by reduction of the corresponding compounds of formula (X). The reduction takes place by methods commonly used in prostaglandin chemistry. The reduction is preferably carried out with diisobutylaluminum hydride in an aprotic solvent (e.g. toluene) at a temperature between 0 ° C and -100 ° C, preferably between -70 ° C and -B ° C.

If R 1 + in the compounds of formula (X) is hydrogen, alternatively both hydroxyls may be protected with a suitable protecting group (e.g. tetrahydropuranyl). The reaction proceeds as described above.

Compounds of formula (X) are prepared by reduction of the corresponding compounds of formula (VIII). Complex borohydrides are used as reducing agents. For example, zinc borohydride and sodium borohydride in an ethereal medium are suitable for this purpose. Depending on the configuration of the 15-hydroxyl group, (S) or (R) isomers can be obtained from this reduction. When the reduction is carried out with zinc borohydride, the (S) -isomer corresponding to the structure of natural prostaglandin and the (R) -isomer in a ratio of 1: 1 are obtained.

In a preferred embodiment, the reduction is performed with lithium tri- (sec-butyl) borohydride, in which case about BO% of the product contains the desired (S) -isomer and only about 20% of the (R) -isomer. The reduction is carried out in an ethereal medium, preferably a mixture of tetrahydrofuran and ether, and preferably at a temperature below -100 ° C. A temperature of about -130 ° C is very suitable and can be obtained by using a methylcyclohexane nitrogen cooling bath. The (S) and (R) isomers of formula (IX),

J

0 \

cw,

'; , '' R9 IX

R 10 OH 1 1 R 1 can, if desired, be separated by conventional methods, usually by column chromatography. However, this step can be omitted - especially if the reduction is carried out with lithium tri (sec-butyl) borohydride - since the final product is in any case isolated by column chromatography, and at the same time it is possible to separate the small amount of undesired isomer present.

In the compounds of general formula (IX) or (X), the p-phenylbenzoyl protecting group R 1 may be removed by base treatment, preferably with potassium carbonate.

Compounds of formula (XII) wherein R 1 is trihaloalkanoyl, benzyloxycarbonyl or a phenoxycarbonyl group which may be substituted by nitro, nitro or chloro may be converted to the corresponding compounds of formula (XII) containing hydrogen. The acid treatment is preferably carried out in a mixture of hydrogen bromide and glacial acetic acid.

Compounds of formula (XII) wherein R is hydrogen may be canoylated using reagents to attach a lower alkanoyl group to the molecule. Suitable reagents are, for example, acetyl chloride or acetic anhydride.

The resulting compounds of formula (XII) wherein Q is hydrogen can be converted to the corresponding esters wherein Q is lower alkyl. The esterification is carried out in a known manner, e.g. with diazomethane.

Compounds of formula XII wherein Q is hydrogen are converted to the corresponding salts by conventional methods, such as by reacting the acid and the required base.

The starting materials of formula (VIII) are novel compounds which can be prepared by acylation of an amine of formula R 2 NH 2 (I) with an acid chloride of formula R 1 Cl (II) in the presence of an acid-binding reagent using a known method. In formula (II) R 1 is alkanoyl or trihaloalkanoyl. If compounds of the formula HNR 1 R 2 (III) in which R 1 is a benzyloxycarbonyl or a phenoxycarbonyl group which may be substituted by nitro, nitro or chlorine are desired, the amine of the formula (I) is reacted with an aryl ester of chloroformic acid.

The acid proton of the compound of formula (III) is replaced by an alkali metal atom using a strong base such as alkyllithium, preferably butyllithium, or an alkali metal hydride to give a compound of formula Φ &

MeN-R2 (IV) wherein He is an alkali metal and R1 and R2 are as defined above. This compound is then reacted with phosphorane of the formula Hgg-CO-CH = P (CgH ^) 3 (V), where Hlg is halogen. The reaction is carried out in a known manner. The compound thus obtained of the formula (C 9 H 8) 3 P = CH-CO-CH 2 NR 1 R 2 (VI), in which R 1 and R 2 have the same meaning as above, is reacted in a known manner with a Corey aldehyde of the formula 9,661 4 ° C

\ 1 VII

V "^ CH = O R40 wherein is as defined above. Due to its unstable nature, the Corey aldehyde of formula (VII) is preferably prepared in situ by oxidation of the corresponding alcohol of formula 0

A

Ci ch2-oh

V

The obtained compound of formula (VIII) is separated from triphenylphosphine oxide as described in the Wittig reaction (by column chromatography).

The compounds of formula (XII) have valuable pharmaceutical properties. After biochemical experiments in rat uterus in Krebs-Ringer bicarbonate solution, it has been found that the compounds of formula XII have approximately the same activity as PGF2oi. They cause a stronger supsituent in the presence of adrenergic blockers.

They enhance the breakdown of rat epidermal adipose tissue. In this respect, their effect is stronger than that of natural catecholamines.

In light of the results described above, the compounds have two types of activity. They can act as either catecholamine or prostaglandin, depending on the organ and method of treatment being treated. The prostaglandin nature is predominant if catecholamine inhibitors are used. From a therapeutic point of view, the effects on adipose tissue and smooth muscle, especially the uterus, are quite important.

The compounds of formula XII are useful regulators of gastric fluid secretion and disperse platelet aggregations which are the cause of vascular thrombosis.

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It is preferred that the compounds of formula XII be administered in infusion form at a dosage level of between 0.1 and 5 ug / kg / min. This same dosage can also be used to regulate fatty acid metabolism.

The smooth muscle stimulating effect of the compounds can be used to potentiate known smooth muscle stimulating agents at a dose level of 0.001 to 25 μg / kg. On the other hand, these compounds are useful in mammals, including humans, if it is desired to induce an abortion, initiate labor or regulate menstrual bleeding, or dilate the cervix, and then intravaginal, intramondal, or intravaginal administration are suitable routes of administration. For the above purposes, the new compounds may be administered in unit doses ranging from 1 μg to 20 mg, or intracellularly. at an infusion rate of 5-50 mg / kg / h. The well-defined dose depends on the age, condition and weight of the person being treated.

The compounds of formula (XII) and their pharmaceutically acceptable, non-toxic salts may be incorporated into pharmaceutical compositions prepared by methods commonly used in the pharmaceutical industry. The pharmaceutical compositions may be in solid (capsule, tablet), semi-solid (e.g. cream) or liquid (e.g. solution, suspension, emulsion) form. The compositions are preferably administered parenterally or intravaginally. The compositions contain a conventional solid or liquid pharmaceutical carrier or diluent (e.g., water, aqueous sodium acetate, physiological saline).

The invention is illustrated by the following examples.

Preparation of starting materials Example I

1? g of sodium hydride suspension (0.1 mol, 20% suspension in paraffin oil) are weighed under a nitrogen atmosphere into a 1 liter 4-neck round-bottomed clown equipped with a condenser, stirrer, thermometer and dropping funnel. 358 ml of dry dimethoxyethane are then added and a solution of 10.1 g (0.1 mol) of N-propylacetamide and 50 ml of dry dimethoxyethane is poured into the suspension thus obtained at room temperature. After refluxing for 2 hours and then cooling to room temperature, the sodium salt of the amide is obtained as a gel-like precipitate. To the reaction mixture is added 35.3 g (0.1 mol) of triphenylchloroacetonylphosphorane suspended in 50 ml of 68614 dry dimethoxyethane. The resulting mixture is stirred slowly for 2 hours so that the amide salt precipitate dissolves. The dimethoxyethane is distilled off, the residue is dissolved in ethyl acetate, washed first with water and then with brine, dried over sodium sulfate and evaporated. 44-46 g of crude triphenyl- (N-propylacetylamino) -acetonylphosphorane are thus obtained. Melting point (recrystallized from a mixture of tetrahydrofuran and ether) 147-148 ° C. Yield 34.7 g (83%).

IR: 3080, 1640, 750, 720, 695 cm -1 NMR (CDCl 3) δ 7.4-8.0 (m, 15H, aromatic), 3.65-4.25 (m.p. 3H, PCH + COCH, N), 3.52 (t, 2II, NCH 2, J = 7Hz), 2.17 (s, 3H, COCH 3), 1.1-2.0 (m, 2H, CH 2 CH 3), 0.9 ( t, 3H, CH 2 CH 3).

Example II

290 ml of a solution of 0.049 g of chlorine in 1 ml of carbon tetrachloride (0.2 mol) are weighed into a 2-liter 4-neck round-bottomed flask equipped with a dropping funnel, a stirrer, a thermometer and a drying tube filled with calcium chloride. The solution is cooled to -10 ° C with a chloroform / dry ice bath and then 24.8 g (0.2 mol) of thioanisole in 200 ml of dry dichloromethane are added at this temperature. The mixture is stirred for 30 minutes, then cooled to -25 ° C and 35.2 g (0.1 mol) of (-) - 3, 3a /? , 4,5,6,6a /? -hexahydro-4β -hydroxymethyl-5β - (4-phenyl-benzoyloxy) -2-oxocyclopenta [fb] f uranium. After the addition, the reaction mixture is stirred at the same temperature for 2 hours.

40.4 g (0.4 mol) of triethylamine in 200 ml of dichloromethane are then added dropwise and the temperature is allowed to rise to room temperature. The reaction mixture is then poured into 1 liter of 1N aqueous hydrochloric acid. The aqueous layer is separated off and the organic layer is washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The solidified crude product is suspended in cold ether and the white crystals formed are filtered off. 26.4 g of (-) - 3, 3a / 3,4,5,6, 6a /? -hexahydro-4β-formyl-5X- (4-phenyl-benzoyloxy) -2-oxo-2H-cyclopenta [2,7] uranium.

The compound of formula (VII) obtained is added to a solution of 34.2 g (0.082 mol) of triphenyl- (N-propylacetylamino) acetonylphosphorane in 100 ml of dichloromethane in a 250 ml round-bottomed flask. If desired, 0.01 moles of butyric acid can be added to the reaction mixture as a catalyst. The solution is allowed to stand overnight and then diluted with 200 ml of dichloromethane and washed first with 200 ml of 0 ° C aqueous hydrochloric acid and then with 100 ml of water. The organic phase is dried and evaporated. This gives 63 g of (-) - 3,3a β, 4,5,6,6a tert-hexahydro-4 β-ZT3-oxo-4- (N-propylacetylamino) -1-trans-butenyl17-5- x- (4-Phenylbenzoyloxy) -β-oxo-2H-cyclopenta [b] Furan as a yellow oil. Yield 23.9 g (59.2%).

R ^. = 0.3 (5% methanol / ethyl acetate). IR (due to tef): 3U80, 2900, 1780, 1720, 1700, 1650, 975, 755, 695 cm-1.

NMR (CDCl 3): h - 7.2-8.2 (m, 9H, aromatic protons), 6.2-7.2 (d + dd, 2H, trans-olefin protons, J r 36 (Hz), 4, 9-5.5 (m, 2H, OCH), 4.3 (c, 2H, COCH N), 3.0-3.4 (m, 2H, O 2), 2.13 (s, 3H, COCH 3), 0.9 (t, 3H, CH 2 CH 3).

Example III

To a 250 ml dry 4-neck round-bottomed flask equipped with a stirrer, a resistance thermometer, a gas tail, a tetrahydrofuran trap through which the gas can bubble, and a sylon stopper are placed 30 ml (0.03 moles) of Li-selectide / lithium tri- (sec-butyl) borohydride in tetrahydrofuran (1 mole) 7, 160 ml of dry ether and 20 ml of dry tetrahydrofuran. The solution is cooled to -130 ° C under a slow stream of argon (methylcyclohexane or ether / petroleum ether and liquid nitrogen). A solution of 4.9 g (0.01 mol) of (-) 3,3a β, 4,5,6,6aβ-hexahydro-4 β - / j3- is added to the Li-electride solution via silicone rubber stopper over 30 minutes with vigorous stirring. oxo-4- (N-propylacetylamino) -1-trans-butenyl-1H-5- (4-phenylbenzyloxy) -2-oxo-2H-cyclopentane / 1H-uranium in 20 ml of dry tetrahydrofuran. The reaction mixture is stirred for 1 hour at a temperature between -127 and -130 ° C. The progress of the reaction is monitored by thin layer chromatography (5% ethyl acetate in methanol). Rf value of the compound of formula (VIII) = 0.3, Rf value of the compound of formula (IX) = 0.27.

The excess reducing agent is decomposed by adding 5 ml of methanol and then the reaction mixture is poured into 500 ml of 1 M aqueous sodium bicarbonate solution while cooling. The organic phase is separated and shaken with ethyl acetate (3 x 100 mL). The organic phases are combined, washed with brine, dried over sodium sulfate, concentrated in vacuo to 100 ml, diluted with 200 ml of petroleum ether and the resulting solution is chromatographed on silica gel (200 g, grain size 0.063-0.2 mm). The precious metal boranes are washed with a mixture of petroleum ether and ethyl acetate (2: 1) and (-) - 3,3a -, (4,5,6,6a, 4-hexahydro-2-oxo-4 '- (iT3S) -3-hydroxy-4- (N-propylacetylan) -10-trans-1-butenyl--5α- (4-phenylbenzoyloxy) -N-cyclopenta [b] uranium is eluted with a 5% solution of methanol in ethyl acetate. The fractions with an Rf value of 0.27 (5% ethyl acetate in methanol) are combined and evaporated. Yield 3.1 g (63.3%), yellow oil. In another development, 0.4 g (8.15%) of the transition fraction is obtained.

Total yield: 3.5 g (71.5%).

= 0.27 (5% ethyl acetate in methanol) IR (liquid film): 34 50, 3080, 2950, 2980, 1770, 1725, 750, 700 cm NMR (CDCl 3): δ - 7.4-8.3 ( m, 9H, aromatic protons), 5.8 (m, 2H, olefin protons), 5-5.5 (m, 2H, OCH), 4.45 (m, 1H, OCH, allyl), 3-3.6 (m, 4H, NCH 2), 2.13 (s, 3H, COCH 3), 0.9 (t, 3H, J = 6Hz, CH 2 CH 3).

Example IV

In a 250 ml round-bottomed flask, dissolve 4.9 g (0.01 mol) of (-) - 3, 3a / 9, 4,5, 6,6a? -Hexahydro-2-oxo-4 β - / T3S) -3- hydroxy-4- (N-propylacetylamino) -trans-1-butenyl-5- (4-phenylbenzoyloxy) -2H-cyclopenta [b] furan to 50 ml of nice methanol and then 1.5 g (0.11 mol) of burnt are added, ground potassium carbonate. The flask is fitted with a drying tube filled with calcium chloride and the suspension is stirred with a magnetic stirrer at room temperature. The progress of the reaction is monitored by thin layer chromatography (5% ethyl acetate in methanol). Analysis shows that the reaction is complete after one hour. The compound of formula (IX) R 1. = 0.27, R 1 of the compound of formula (X) = 0.05 and R 4 of the methyl ester of 4-phenylbenzoic acid. = 0.95.

The pH of the reaction mixture is adjusted to 6 with 1M methanolic hydrochloric acid and then the methanol is distilled off in vacuo. The residue, which contains several liquid and solid components, is mixed with 100 ml of a mixture of petroleum ether and ethyl acetate (2: 1) and poured onto a silica gel column. 4-Phenylbenzoic acid methyl ester is eluted with a mixture of petroleum ether and ethyl acetate (2: 1) and (-) - 3, 3a / 3, 4,5,6,6a β-hexahydro-2-oxo-5''-hydroxy- [3-Z * (3S) -3-Hydroxy-4- (N-propylacetylamino) -trans-1-butenyl] -2H-cyclopentaAh7f varan is eluted with 10% methanol in ethyl acetate.

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Yield 2.93 g (93.4%), yellow oil.

R ^. = 0.33 (10% ethyl acetate in methanol) IR (liquid film): 3450, 2950, 2980, 1775, 1635 cm -1.

NMR (CDCl 3): δ = 5.65 (m, 2H, olefin protons), 5.0 (m, 1H, OCH lactone), 4.35 (m, 1H, OCH allyl proton), 4.10 (m, 1H , OCH), interchangeable OH protons 2H, 3.1-3.5 (m, 4H, NCH 2), 2.13 (ε, 3H, COCH 3), 0.9 (t, 3H, CH CH 3, J = 7 Hz).

Example V

2 Pour a solution of 3.1 g (0.01 mol) of (-) - 3 into a 50 ml dry 4-neck rotary flask equipped with a stirrer, thermometer, gas connection, dropping funnel and dry tetrahydrofuran trap through which the gas can bubble. , 3α, β, 4,5,6,6aβ-hexahydro-2-oxo-5β-hydroxy-4β- (3S) -3-hydroxy-4- (N-propylacetylamino) -trans- 1-Butenyl-2H-cyclopenta [b] -furan in 70 ml of dry tetrahydrofuran, the flask is purged with dry argon and cooled to -78 ° C in a dry ice-acetone bath under a slow stream of argon. To the cooled solution is added 6.4 g over 30 minutes with vigorous stirring. (0.046 mol) of diisobutylaluminum hydride in 70 ml of dry toluene Gas evolution is complete before the addition is complete, after which the reaction mixture is stirred for one hour at -78 [deg.] C. The reaction is monitored by thin layer chromatography (ethyl acetate / ammonium chloride microforming) and can be the reaction is complete when s eco-above manit-tu hour. The reaction mixture is decomposed by adding 10 ml of 2N aqueous sodium hydrogen sulfate solution. The cooling bath is then removed and the temperature is allowed to rise to 0 ° C. The pH of the mixture is adjusted to 3-4 with 2M sodium hydrogen sulfate solution. The organic phase is separated in a separatory funnel. The aqueous phase is shaken six times with 50 ml of ethyl acetate, the organic phases are combined, dried over sodium sulfate and evaporated under reduced pressure. This gives 3 g (97%) of impure (-) - 3.3a /? , 4,5,6,6a β-hexahydro-2,5 cl · -dihydroxy-4 β - ε (3S) -3-hydroxy-4- (N-propylacetylamino) -trans-1-butenyl] -2H-cyclopentane .7f uranium as a yellow oil.

For analysis, prepare on a silica gel column using a 20% solution of methanol in methanol as eluent, collecting the fractions corresponding to an Rf value of 0.095 (ethyl acetate / acetic acid 20: 4).

IR (liquid film): 3400, 2950, 2975, 1630, 1010, 1060, 1070, 10 cm -1. NMR (CDCl 3): δ = 5.65 (m, 3H, 2 olefin protons + OCHO), 4- 4.7 (m, 3H, OCH allyl, OCH 5/3, OCH 6a / 3, interchangeable protons 3H, 3.1-3.65 (m, 4H, NCH 2), 2.13 (s, 3H, COCH 3 > 0.9 (5, 3H, CH 2 CH 3).

Example VI

Following the procedure of Example I, but substituting 19.3 g (0.1 mol) of N-propylbenzylurethane for N-propylacetamide, 39.7 g (78%) of triphenyl- (N-propylbenzyloxycarbonylamino) acetone are obtained. ifosforaania.

Melting point: 111-112 ° C

IR (KBr): 1705, 1520, 1390, 1230, 1100, 740, 705, 695 cm -1.

NMR (CDCl 3): δ = 7.1-8 (m, 20H, aromatic protons), 5.2 (s, OCH 2, 2H), 3.9-4.8 (m, 3H, PCH + COCH 2 N).

Example VII

Following the procedure of Example I, but substituting 13.1 g (0.1 mol) of N-propylethylurethane for N-propylacetamide, 35.1 g (78.3%) of triphenyl- (N-propylethoxycarbonylamino) acetonylphosphorane are obtained.

Melting point: 92-94 ° C

IR (KBr): 1695, 1580, 1390, 1240, 1100, 750, 715 and 695 cm -1.

NMR (CDCl 3): δ = 7-7.9 (m, 15H, aromatic protons), 3.9-4.6 (m, 5H, PCH + COCH 2 N + OCH 2, quartet 4.1, J = 8 Hz) .

Example VIII

Following the procedure of Example II, but substituting 41.8 g (0.082 moles) of triphenyl- (N-propylbenzyloxycarbonylamino) acetone phosphorane for triphenyl- (N-propylacetylamino) acetonylphosphorane, 35.9 g (63%) of (-) - 3, 3a β, 4,5,6,6a β-hexahydro-2-oxo-4 β - β-oxo-4- (N-propylbenzyloxycarbonylamino) -. trans-butenyl-5- [1- (4-phenylbenzyloxy) -2H-cyclopenta [b] furan.

R ^. = 0.3 (petroleum ether / ethyl acetate 1: 1) and 0.85 (ethyl acetate) NMR (CDCl 3): δ = 7.4-8.3 (m, 14H, aromatic protons, 6.15-7.2 (d + dd, 2H, trans-olefin protons, J = 36 Hz), 5.0-5.5 (m, 4H, 5/5 and 6α-proton and benzyl-CH2), 4.25 (s, 2H , COCH 2 N), 3.3 (t, 2H, NCH 2, J = 7 Hz), 0.9 (t, 3H, aliphatic methyl protons).

i6 6861 4

Example IX

The procedure of Example III is followed, but (-) - 3,3a, 4,5,6, -6a-hexahydro-4-β-Z3-oxo-4- (N-propylacetylamino) -1-transbutenyl? In place of 5 o- (4-phenylbenzoyloxy) -2-oxo-2H-cyclopenta [h] -furan, 5.7 g (0.01 mol) of (-) - 3,3a, 4,5,6,6a / - hexahydro-2-oxo-4H-Z3-oxo-4- (N-propylbenzyloxycarbonylamino) -1-trans-butenyl - -5 - ((- (4-phenylbenzoyloxy)) - 2 H-cycle open (B7-furan) to give 4.4 g (76.5%) of (-) - 3,3a, 4,5,6,6a / 3-hexahydro-2-oxo-4 / - "(3S) -3-Hydroxy-4- (N-propylbenzyloxycarbonylamino) -1-trans-1-butenyl] -506- (4-phenylbenzoyloxy) -2H-cyclopentafluorofuran. Rf = 0.39 (ethyl acetate / petroleum ether 3: 2), a compound of formula (IX) having the (R) configuration, Rf = 0.31 (ethyl acetate / petroleum ether 3: 2).

NMR (00012): (δ = 7.3-8.2 (m, 14H, aromatic protons, 5.7 (m, 2H, olefin protons)), 4.9-5.45 (m, 4H, 5 / - and 6α and benzyl-CH 2 protons), 4.35 (m, 1H, CHOH), 3-3.5 (m, 4H, CH 2 N).

Example X

Following the procedure of Example V, but (-) - 3,3a A, 4,5, -6,6a-hexahydro-2-oxo-5H-hydroxy-4H-3S) -3-hydroxy- In place of 4- (N-propylacetylamino) -trans-1-butenyl) -2H-cyclopentan-7-furan, 3.0 g (0.01 mol) of (-) - 3,3a (4,5,5,6a) / -hexa-hydro-2-oxo-5 ° C-hydroxy-4β-3S) -3-hydroxy-4- (N-propylbenzyl oxycarbonylamino) trans-1-butenyl-2H- cyclopenta [b] furan, 2.9 g (97%) of (-) - 3,3a, 4,5,6,6a) -hexahydro-2, beC-dihydroxy-4 β - / '(3S) -3 are obtained -hydroxy-4- (N-propylbenzyl-1-oxycarbonylamino) -trans-1-butyl-2H-cyclopenta [f] uranium.

R f = 0.09 (ethyl acetate / petroleum ether 2: 1).

NMR (CDCl 3: δ 5.75 (m, 3H, olefin protons + OCHO protons), 5.2 (s, 2H, CH 2 proton of benzyl and), 4.25-4.8 (m, 3H , 5β, 6α and allyl CHOH proton), 3-3.5 (m, 4H, Cl 2 N).

Example XI

In the same manner as described in Example I, but using N-propyltrifluoroacetamide as a starting material instead of N-propylacetamide, triphenyl- (N-propyl-trifluoroacetylamino) -acetonyl-phosphorane is obtained.

Characteristic values:

Sp. 166-167 ° C

17 6861 4 IR (KBj?): 1740, 1545, 738, 705, 700 cm -1, max NMR (CDCl 3): δ = 7.2-7.8 (m, 15H aromatic) 3.55-4 .30 (comp. 3H, PCH + COCH2N).

3.65 (t, 2H, NCH 2), 0.9 (t, 3H, CH 2 CH 3).

Example XII

In the same manner as described in Example I, but starting from N-propylnitrophenylurethane instead of N-propylacetamide, triphenyl- (N-propyl-p-nitrophenoxycarbonylamino) -acetonyl-phosphorane is obtained.

Characteristic values:

Sp. 130-131 ° C.

IR (KBr): 1715, 1510, 1225, 1100, 740, 710, 700 cm -1.

NMR (CDCl 3): δ = 7-8.2 (m, 19H, aromatic protons), 3.85-4.9 (m, 3H, PCH + COCH 3 N).

Example XIII

In the same manner as described in Example II, but starting from triphenyl- (N-propyl-trifluoroacetylamino) -acetonylphosphorane instead of triphenyl- (N-propyl-acetylamino) -acetonyl-phosphorane, (-) - 3,3a /? , 1+, 5,6,6a-N-hexahydro-2-oxo-4 '- [3-oxo-5- (N-propyl-trifluoroacetylamino) -1-transbutenyl] -5 ° C - (4-phenylbenzyloxy) - 2H-cyclopenta / k7furaani.

Characteristic values: Rf: 0.36 (5% methanol: ethyl acetate) NMR (CDCl3) δ c 7.3-8.2 (m, 9H, aromatic protons) 6.1-7.1 (d + dd, 2H, trans-olefin protons), 5.0-5.5 (m, 2H, and 6a / 3 protons), 4.3 (s, 2H, -COCH 2 N), 3.2 (t, 2H, NCH 2).

Example XIV

In the same manner as described in Example VIII, but starting from triphenyl- (N-propyl-p-nitrophenyloxycarbonylamino) -acetonyl-phosphorane instead of triphenyl- (N-propyl-benzyloxycarbonylamino) -acetonyl-phosphorane, , 3α, 4, 5,6,6a / S-Hexahydro-2-oxo-4H-Z3-oxo-4- (N-propyl-p-nitrophenoxycarbonylamino) -1-trans-butenyl_7-5c - (4-phenyl-benzoyloxy) -2H-cyclopenta [h] furan.

Characteristic values: Rf: 0.16 (petroleum ether: ethyl acetate 1: 1) 0.45 (ethyl acetate), NMR (CDCl3): 7.4-8.6 (m, 13H, aromatic protons) 18 6861 4 6, 2-7.2 (d + dd, 2H, trans-olefin protons), 5.1-5.7 (5 /) and 6a β-protons and), 4.4 (s, 2H, COCHIN).

Example XV

In the same manner as described in Example III, but starting from (-) - 3,3a / 3,3 ', 5,6,6a // 3-hexahydro-2-oxo-4 / ®-Z.3-oxo-4- (N-propyl-trifluoroacetylamino) -1-transbutenyl--5 ° C- (4-phenyl-benzoyloxy) -2H-cyclopenta [b] furan gives (-) - 3, -3a and jb, 4,5,6, 6α-Hexahydro-2-oxo-N - [(3S) -3-hydroxy-4- (N-propyl-trifluoroacetylamino) -1-trans-butenyl] -5 ° C - (4-phenyl-benzoyloxy) -2H -syklopentaZh7furaani.

Characteristic values: Rf: 0.33 (5% methanol / ethyl acetate).

Example XVI

In the same manner as described in Example V, but using as starting material (-) - 3,3a / 0,4,5,6,6a / 3-hexahydro-2-oxo-4 '- (73S) -3-hydroxy-4- ( N-propyl-trifluoroacetylamino) -1-trans-butenyl-17H-cyclopenta [b] furan is obtained with (-) - 3,3a (2,3,4,6,6a) -hexahydro-2,5,6-dihydroxide-4 [3-Z7 3S) -3-Hydroxy-4- (N-propyl-trifluoroacetylamino) -1-trans-butenyl] -2H-cyclopenta [b] furan.

Characteristic values:

Rf: 0.14 (ethyl acetate-acetic acid 20: 4).

Example XVII

4.25 g (0.01 mol) of (-) - 3,3a f, 4,5,6,6a / ®-hexahydro-2-oxo-πβ-α 3S) -3-hydroxy-4- (N- propylacetylamino) -trans-1-butenyl] -5- (6-hydroxy-2H-cyclopenta [2H] furan) is dissolved in 60 ml of dry dimethylformamide. To this solution is added 1.70 g (0.025 moles) of imidazole and then 2.26 g (0.015 moles) of dimethyl tert-butylsilyl chloride. The homogeneous solution thus obtained is stirred at room temperature for 16 hours. The solution is diluted with 500 ml of ether and shaken with 2 x 20 ml of water, 2 x 30 ml of 0.01 N hydrochloric acid and 20 ml of saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. 5.525 g of (-) - 3.3a /? , 4,5,6,6a-Hexahydro-2-oxo-4H-Z- (3S) -3- (dimethyl-tert-butylsilyloxy) -4- (N-propylacetylamide) -trans-1-butenyl7 -5 - [(dimethyl-tert-butylsilyloxy) -2H-cyclopentai] uranium.

Yield: 97%.

19 6861 4 Rf: 0.12 (1: 2 ethyl acetate-petroleum ether) NMR (CDCl 3): δ 5.6 (m, 2H, olefin protons), 5.02 (m, 1H, OCH, "lacon" - protons), 3.1-3.5 (m, 4H, NCH 2), 2.11 (s, 3H, COCH 3), 0.86 (s, 2 x 9H, "SiC (CH 3) 3"), 0.04 (s, 2 χ 6H, "SiC (CH 3) 2").

Manufacture of finished products

Example 1 To a 500 ml 4-neck round bottom flask equipped with a magnetic stirrer, gas connection, silicone rubber stopper, vacuum connection and ground glass stopper, purge with argon and add 10.8 g (0.09 moles) of a 20% paraffin suspension of sodium hydride. The suspension is then injected with 10 ml of dry petroleum ether. The mixture is stirred with a magnetic stirrer, allowed to settle and the oily petroleum ether phase is sucked off with a syringe. This procedure is repeated twice more and the remaining petroleum ether is removed in vacuo. 150 ml of dry dimethyl sulphoxide are added to the oil-liberated sodium hydride and the flask is fitted with a thermometer and a dimethyl sulphoxide trap through which the gas can bubble and purge with argon. The suspension is then slowly heated to 75 ° C in an oil bath. At 60 ° C, an ever-increasing release of hydrogen begins, which ceases within about 30 minutes. A pale yellow solution is obtained, which is stirred at 70-75 ° C for about 60 minutes, cooled to 15-20 ° C and a total of 20 g (0.045 moles) of triphenyl- (4-carboxybutyl) phosphonium boride in four portions and a measuring vessel are added. washed with 50 ml of dry dimethyl sulfoxide. The color red indicates the formation of phosphorane. The solution is stirred at room temperature for 30 minutes and then a solution of 3.12 g (0.01 mol) of (-) - 3,3a / 2, 4,5,6,6a-5-hexahydro-2,5 ° C is added. dihdyroxy-4/3 - [(3S) -3-hydroxy-4- (N-propylacetylamino) -trans-1-butenyl] -2H-cyclo-penta] bfuran in 100 ml of dry dimethyl sulfoxide. The mixture is stirred at room temperature. Thin layer chromatographic analysis shows (a sample of the reaction mixture was decomposed with ethyl acetate and sodium hydrogen sulfate) that the reaction was complete after 18 hours. Compound of formula (XII) Rf = 0.23 and compound of formula (XI) = 0.09 (ethyl acetate / acetic acid 20: 4).

The reaction mixture is poured into a mixture of 400 ml of 2M sodium hydrogen sulphate, 100 ml of ice water and 150 ml of ethyl acetate. The mixture is shaken in a separatory funnel, the organic phase is separated off and the aqueous phase (CpH = 1) is shaken six times with 100 ml of ethyl acetate. The organic phases are combined, cooled and washed three times with 50 ml of sodium hydroxide solution at 0 ° C. The basic extracts are combined, 100 ml of ethyl acetate are added and the pH of the solution is adjusted to 3 by careful addition of 2 M sodium hydrogen sulphate at 0 ° C. When the organic phase is dried over sodium sulfate and evaporated, 3.7 crude products are obtained in the form of a dark brown oil. The crude product is chromatographed on 300 g of silica gel using a mixture of ethyl acetate and acetic acid (20: 4) as eluent. The products with Rf = 0.62 (methanol / ethyl acetate / acetic acid 5: 20: 4) are collected.

Yield: 2.2 g (62.5%).

The obtained (+) -9ού, 11 c> C, 15 (S) -trihydroxy-16- (N-propylacetylamino) -17,18,19,20 tetranor-5-cis-13-trans-prostadienoic acid has a slight impurity (N-acetyl-7-aza-PGF2) acetic acid. Purification is further carried out by column chromatography (100 g of silica gel, acetone as eluent). 1.73 g (78% of the chromatographed impure product) of a yellow viscous oil are obtained as the main fraction.

= 0.62 (methanol / ethyl acetate / acetic acid 5: 20: 4) NMR (CDCl 3): (±) = 5.6 and 5.4 (m, 2H + 2H, trans and cis-olefin protons) , 3.9, 4.15 and 4.3 (1-im, 3H, 9-OCH, 11-OCH and 15-allyl OCH protons), interchangeable protons, 3.15-3.6 (m, 4H , NCH 2), 2.13 (s, 3H, COCH 3), 0.95 (t, 3H, CH 2 CH 3, J = 7 Hz).

IR (liquid film): 3400, 1730, 1630, 1445, 1260, 1025, 960 cm -1 Specific rotation: LocJ = +19 (-2) (c = 1.2, tetrahydrofuran).

Example 2

Following the procedure of Example 1, but with the addition of (-) - 3,3a, 4,5,5 -6,6a, N-hexahydro-2, 6-dihydroxy-4R - [(S) -3-hydroxy- 4- (N-propylacetylamino) -trans-1-butenyl] -2H-cyclopenta / Ti7-furan is replaced by 3.0 g (0.01 mol) of (-) - 3,3,3,3,5 , 6,6α, β-Hexahydro-2,5α-dihydroxy-4β- [* (3S) -3-hydroxy-4- (N-propylbenzyloxycarbonylamino) -1-trans-butenyl] -2H-cyclopenta 3.17 g (65%) of (+) - 9,11,11,15 (S) -trihydroxy-16- (N-propylbenzyloxycarbonylamino) -17,18,19,20- tetranor-5-cis-13-trans-prostadieenihappoa.

= 0.28 (benzene / dioxane / acetic acid 20: 20: 1) NMR (CDCl 3): δ = 5.6 and 5.4 (m, 2H + 2H, trans and cis-olefin protons), δ, 15 (s, 2H, CH 2 protons of benzyl), 3.95, 4.1 and 4.3 2 6868 4 (1-im, 3H, 9-OCH, 11-OCH and 15-allyl OCH), 3- 3.5 (m, KH, CH, N>, 0.85 (t, 3H, terminal methyl protons)).

Example 3

In the same manner as described in Example 1, but starting from (-) - 3,3a β, 4,5,6,6a / 3-hexahydro-2,5-dihydroxy-4β-Z- (3S) -3-hydroxy -4- (N-propyl-trifluoroacetylamino) -1-trans-buten-yl] -2H-cyclopenta [7,7] furan gives (+) 9 <x, 11 <* 15 (S) -trihydroxy-16- (N-propyl -trifluoriasetyyliamino) -l7,18,19,20-tetranor-5-cis-13-trans-prostadieenihappo.

Characteristic values: Rf .: 0.67 (methanol-ethyl acetate-acetic acid 5: 20: 4).

Example 4

In a manner similar to that described in Example 1, using the appropriate starting materials, the following compounds of general formula (XII) with hydrogen are obtained: (+) - 9c>, Ilot, 15 (S) -trihydroxy-16- (N-propyl- p-nitrophenoxy-carbonylamino) -17,18,19,20-tetranor-5-cis-13-trans-prostadieenihappo. R f: 0.21 (20: 20: 1 benzene-dioxane-acetic acid mixture NMR (CDCl 3): δ 7.4-8.1 (m, 4H, aromatic protons), 5.5 and 5.7 (m , 2H + 2H, trans and cis olefin protons) (+) -9v *, ii <x, 15 (S) -trihydroxy-16 - (N-propyl-p-chlorophenoxycarbonylamino) -17 , 18,19,20-tetranor-5-cis-13-trans-prostadieenihappo.

R f: 0.28 (20: 20: 1 benzene-dioxane-acetic acid) NMR (CDCl 3): δ 7.1-7.8 (m, 4H, aromatic protons) 5.4 and 5.65 (m, 2H + 2H, trans and cis olefin protons) 3-3.45 (m, 4H, CH 2 N).

(+) - 9oi, 11 ot, 15 (S) -Trihydroxy-16- (N-propyl-p-methoxyphenoxy-carbonylamino) -17,18,19,20-tetranor-5-cis-13-trans -prostadieenihappo.

Rf: 0.31 (20: 20: 1 benzene-dioxane-acetic acid) NMR (CDCl3): / 7.1-7.7 (m, 4H, aromatic protons) 5.4 and 5.65 (m, 2H + 2H, trans and cis olefin protons) 3.5 (s, 3H, OCH 3), 3-3.45 (m, 4H, CH 2 N).

Example 5

In the same manner as described in Example 1, using the appropriate starting materials, the following compounds of general formula (XII) having a protecting group are obtained: (+) - 9β-hydroxy-11 cL, 15 (S) -bis (dimethyl-tert- butylsilyloxy) -16- (N-propylacetamide) -17,18,19,20-tetranor-5-cis-13-trans-22 68 61 4 prostadienoic acid.

Rf: 0.81 (20: 20: 1 benzene-dioxane-acetic acid) NMR (CDCl 3): δ 5.6 and 5.4 (m, 2H + 2H, cis and trans olefin protons) 3.10-3, 16 (m, 4H, NCH 2), 2.15 (s, 3H, COCH 3), 0.86 (s, 2 x 9H, "SiC (CH 3) 3", 0.02 (s, 2 x 6H, "Si (CH 3) 2 N).

(+) - 9 cis-hydroxy-11 cc, 15 (S) -bis (tetrahydropyranyloxy) -16- (N-propylacetamide) -17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid .

R f: 0.78 (20: 20: 1 benzene-d.-oxane-acetic acid) NMR (CDCl 3): δ 5.75-5.20 (m, 6H, cis and trans olefin proteins and 2 OCHO - protons) 3.12-355 (m, 4H, NCH 2), 2.15 (s, 3H, COCH 3).

(+) - 9 ot, 15 (S) -dihydroxy-11- (dimethyl-tert-butylsilyloxy) -16- (N-propylacetamide) -17,18,19,20-tetranor-5 cis-13-trans-prostadieenihappo.

Rf: 0.76 (20: 20: 1 benzene-dioxane-acetic acid) NMR (CDCl3): <5.6 and 5.4 (m, 2H + 2H, cis and trans olefin protons and) 3.12 - 3.6 (m, 4H, NCH 2), 2.13 (s, 3H, COCH 6), 0.85 (s, 9H, "SiC (CH 3) 3") 0.03 (s, 6H, "Si ( CH 3) 2 ").

(+) - 9 *, 15 (S) -dihydroxy-11α-tetrahydropyranyloxy-16- (N-propylacetamide) -17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid.

Rf: 0.48 (20: 20: 1 benzene-dioxane-acetic acid) NMR (CDCl3): δ 5.75-5.20 (m, 5H, 2x2 cis and trans olefin protons and), 3, 14-3.5 (m, 4H, NCH 2), 2.15 (s, 3H, COCH 2).

The R 1 values given above and elsewhere in the specification were measured on silica gel plates No. "Art. 5719" nitrogen "CD-Fert: igplatten, Kieselgel 60 ^ 254" 'preparedFanut Merck.

Example 6 (+) - 9,11 °, 15 (S) -trihydroxy-16- (N-propylacetylamino) -1,7,18,20,20-tetranor-5-cis-13-trans-prostadienoic acid is reacted with a molar equivalent of sodium hydrogen carbonate. with aqueous solution to give (+) -9: x, 11 <x, 15 (S) -trihydroxy-16- (N-propylacetylamino) -17,18,19,20-tetranor-5-cis-13- sodium salt of trans-prostadienoic acid in 90% yield.

Rf: 0.28 (methanol-ethyl acetate-acetic acid, 5: 20: 4).

6861 4 23

Example 7 (+) - 9ot, ilot-, 15 (S) -Trihydroxy-16- (N-propyltrifluoroacetylamino) -17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid, obtained according to Example 3 is hydrolysed with a mixture of hydrogen bromide and glacial acetic acid and the (+) - 9 oi, 11 06.15 (S) -trihydroxy-16- (N-propylamino) -17,18,19,20-tetranor 5-cis-13-trans-prostadienoic acid is reacted with acetyl chloride in acetic anhydride medium. (+) -9 = * ·, 11 <*, 15 (S) -trihydroxy-16- (N-propylacetylamino) -17,18,19,2-tetranor-5-cis-13-trans enoic acid.

Rf: 0.62 (methanol-ethyl acetate-acetic acid, 5: 20: 4).

Example 8 (+) - 9,11,11-, 15 (S) -trihydroxy-16- (N-propylacetylamino) -17,18,19,2-tetranor-5-cis-13-trans-prostadiene. the acid is reacted at 0 ° C in methylene chloride solution with diazomethane. The reaction mixture is evaporated to give in an almost calculated yield (+) -90 ° (11 °, 15 (S) -trihydroxy-16- (N-propylacetylamino) -17,18,19,20-tetranor-5-cis-13 trans-prostadieenihappo methyl ester.

Rf: 0.40 (methanol-ethyl acetate-acetic acid, 5: 20: 4).

Example 9

(+) - 9α, 11,15 (S) -bis- (dimethyltert-butylsilyloxy) -16- (N-propylacetylamino) -17,18,19,20-tetranor-5-cis- 13-Trans-prostadienoic acid is treated with aqueous acetic acid. The (+) -9,11 <, 15 (S) -trihydroxy-16- (N-propylacetylamino) -17,18,19,20-tetranor-5-cis-13-trans-prostadienoic acid thus obtained is similar to the compound obtained according to Example 7.

Claims (5)

6861 4 24 A process for the preparation of therapeutically useful optically active or racemic N-aza-PGF 1, 4 derivatives of the formula 0Π XII to R 0: Γ I 2 VV R 1 wherein R 1 is hydrogen, lower alkanoyl, trihaloalkanoyl, benzyloxycarbonyl or phenoxycarbonyl group which may be substituted by nitro, nitro or chloro, R 4 is alkyl of 1 to 4 carbon atoms, R 1 is hydrogen or a protecting group and Q is hydrogen, alkyl of 1 to 4 carbon atoms or a pharmaceutically acceptable, non-toxic cation, known that (a ^) a compound of formula OH οΛ I / _R2 XI. IV R40 R1 wherein R1 and R2 are as defined above and R1 is hydrogen or a protecting group commonly used in prostaglandin chemistry is reacted with a phosphorane prepared from a triphenyl- (4-carboxybutyl) -phosphonium salt, or (a2) a compound of formula C Cl V ^ s ^ X ^ NR X RO R b R 25 6861 4 wherein R 1, R 2 and R 2 are as defined above is reduced with a complex metal hydride, followed by the resulting compound of formula OH P> -R XI R 4 Wherein wherein, R 2 and R 2 are as defined above, is reacted with a phosphorane prepared from a triphenyl- (> 4-carboxybutyl) -phosphonium salt, or (a ^) a compound of the formula, ° R2 A · '' -R 2 R 1 wherein , R 2 and R 2 are as defined above are reduced with complex borohydride, followed by reduction of the resulting compound of formula 0 CW.-5 VR 2 wherein R 1, R 2 and R 4 are as defined above with complex metal hydride and is -ΛΗ CL · Rj Ö ii 2 R „° R, wherein R 1, R 2 and R 2 are as defined above, is reacted with a phosphorane prepared from a triphenyl- (4-carboxybutyl) phosphonium salt; 26 6861 4 and optionally 1. the protecting group R 1 is removed from a compound of formula XII, and / or 2. a compound of formula XII wherein R 1 is trihaloalkanoyl, benzyloxycarbonyl or a phenoxycarbonyl group which may be substituted by nitro, nitro or chlorine, is converted to a compound of formula XII wherein R 1 is hydrogen by hydrolysis in an acidic medium, and / or 3. a compound of formula XII wherein R 1 is hydrogen is converted to a compound of formula XII wherein R 1 is lower alkanoyl by attaching a lower alkanoyl group to the molecule, and / or 4. converting a compound of formula XII wherein Q is hydrogen to a compound of formula XII wherein Q is alkyl of 1 to 4 carbon atoms, and / or 5. converting a compound of formula XII wherein Q is hydrogen to be pharmaceutically acceptable, not -toxic salt. Process according to Claim 1, characterized in that the starting materials used are compounds of the formulas (VIII), (X) and (XI) which have a protecting group which is stable to alkali but is readily removed in an acidic medium. Process according to Claim 2, characterized in that the starting materials used are compounds of the formulas (VIII), (X) and (XI) in which R 1 is a tetrahydropyranyl group or a trialkylsilyl group. 27 6861 4 A process for the preparation of a therapeutically active compound with an active and racemic 17-aza-PGF2 <A derivative with a pH of __ XI1 R4 ° R4Ö Ra2 for R1, a alkanoyl, trihaloalkanoyl, benzyloxycarbonyl or phenoxycarbonyl group, which may be substituted with nitro, methoxy or chloro, R2 is alkyl with 1-4 cholatomers, R1 is alkyl with a ring group and Q is a plant, alkyl with 1-4 cholaters or a pharmaceutical moiety, non-toxic cation, känneteck-n at därav, att (a.) en förening med formeln OH 0 ^ Ct N - R2 XI:! R 2 and R 2 are selected from the group consisting of the same or a prostaglandic compound and a preferred group of compounds having the same triphenyl- (4-carboxybutyl) -phosphonium salt as phosphorus, or (a 2) with the form f - r2 x I 1 VR „0 R1 28 6861 4 of R ^, R2 and R ^ betecnar samma som ovan, reducing with a complex metal hydride, varferter den ehällna, föreningen med formeln OH, ° Λ V ^^ n- R2 XI V \ b Ra is a mixture of R1, R2 and R2 which is selected from the group consisting of triphenyl- (4-carboxybutyl) -phosphonium salt and phosphorus, or (a3) is formed with a form of 0, ° · "'N Ru0 Y | R2 VI11 is a mixture of R1, R2 and R4 which are similar, reducing with a complex of borohydrides, varying with a particular form of med At - R2 XVR, 0' of R1, R2 and R1 including the same metal, reducers with a complex metal hydride and the formation of a compound