DE2612114A1 - PROSTAGLANDIN DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND THE PHARMACEUTICAL OR VETERINARY MEDICAL COMPOSITIONS THEREOF - Google Patents

Description

Dipi.-lng. P. WIRTH Dr. V. SCH MI ED- KOWARZl K Dipl.-Ing. G. DANNENBERG Dr. P. WEINHOLD Dr. D. GUDEL

^{281134 6 FRANKFURTAM MAIN}

287014 GR. ESCHEtJHCIMEn STREET 30

Case: Br 169

L a "b a z

Avenue Pierre 1er de Ser "bie, 39

F - 75008 Paris, France

Prostaglandin derivatives. Process for their preparation and pharmaceutical or veterinary compositions containing them

6 0 9 8 41/0989

2617 1 14

The present invention relates to prostaglandins, and in particular to new compounds which are related in their structure to the prostaglandin E ,, which the Structural formulaϊ

has, sorie on a method of making this new one Links.

The prostaglandin E ₁ is usually abbreviated as "PGE ₁ " «It is common practice to also write _{the formula of PGE 1} as follows:

COOH

The compounds with which the present invention is concerned have the following general formula:

CH.

O ii

.C-OK

CH, CIL

^ CHX- ² ^ CK

CK-, 'J

OH

where R = hydrogen, methyl or ethyl.

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The compounds of the formula I have isomeric centers and can therefore be in the form of optical isomers, positional isomers or mixtures of these isomers are prepared. The mixtures of these isomers can optionally be used in suitable Steps, separated according to known methods, to the corresponding to obtain individual isomers.

These isomers, as well as mixtures of these, are a matter of course encompassed by the present invention.

The compound of the formula I in which R - is hydrogen, can be prepared by adding a DL-ci> -carboalkyloxy ~ 1-hexyl-5- (3'-hydroxy-1'-octen-(E) -yl) -2-pyrrolidinone the general formula:

II

wherein FL means a linear or branched alkyl group with about 1-7 carbon atoms,

is saponified in an alcoholic medium, such as methanol, the saponification with the aid of an alkali, e.g. Sodium hydroxide is made, and the resulting alkali metal salt of the compound of formula II is hydrolyzed using a strong acid, for example hydrochloric acid, to obtain the desired compound of formula I.

The other compounds of the formula I, namely those in which R = methyl or ethyl, can be prepared by adding a DL-cu-carbomethoxy- or -carboethoxy-1-h.exyl-5- (3'-oxo-1 ' -octen- (E) -yl) -2-pyrrolidinone of the formula:

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where Rp = methyl or ethyl,

is reduced with a suitable reducing agent such as sodium borohydride in an inert medium such as dimethoxyethane.

This reduction can be at a temperature between about 0 and +5 ⁰ C, preferably at ⁰ ° C, are carried out.

The compounds of formula III can in one process can be produced in which a known and easily available compound is used as the starting product, namely DL-pyroglutamic acid of the formula:

By esterification of the compound of formula IV with ethanol in the presence of an acid, e.g. p-toluenesulfonic acid one ethyl DL-pyrοglutamate of the formula:

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which, after reduction with sodium borohydride in a solvent, e.g. methanol, DL-5-hydroxymethyl-2-pyrrolidinone the formula:

VI

receives. The compounds of the formulas V and VI are known products which are described in J. Am. Chem. Soc. 70, 3121-3125 (1948) have been described.

The alcohol function of the compound of the formula VI is then blocked in an inert medium, for example methylene chloride, and in the presence of an acid, for example p-toluenesulfonic acid, with 2,3-dihydropyran, whereby DL-2 ¹ -tetrahydropyranyl-5-oxymethyl-2 -pyrrolidinone of the formula:

VII

CH ₀ O

receives, which then with methyl or ethyl 7-bromoheptanoate the formula:

VIII

wherein R _{2 has} the same meaning as in formula III,

in a solvent, preferably toluene, and in the presence Treated by sodium amide to form a compound of the general formula:

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where Rp has the same meaning as in formula III, to obtain.

The DL-to-carbomethoxy- or -Carboäthoxy-i-hexyl-2 ¹ -tetrahydro ■ pyranyl-5-oxymethyl-2-pyrrolidone of the formula IX is then in an acid medium, e.g. hydrochloric acid, and in the presence of a solvent, e.g. methanol, hydrolyzed to restore the alcohol function and thereby the corresponding DL-Csj-carbomethoxy- or -carboethoxy-1-hexyl-5-hydroxymethyl-2-pyrrolidinone of the formula:

CHpOH

wherein R _{2 has} the same meaning as in formula III,

after which the primary alcohol group is then placed in an inert medium, e.g. benzene, under the combined action of dimethyl sulfoxide, dicyclohexylcarbodiimide and dichloroacetic acid is oxidized to an aldehyde function to form a DL-cu-carbomethoxy- or -carboethoxy-i-hexyl-5-carboxaldehyde-2-pyrrolidinone the formula:

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where Rp has the same meaning as in formula III,

to obtain. The aldehyde function in the compound of the formula XI then undergoes a Wittig reaction using i-triphenylphocphoranylidene-2-heptanone of the formula:

= CH-CC ₅ H ₁ -J

subject,; im the corresponding DL-OJ-carbomethoxy- or -Carboethoxy-1-hexyl-5- (5'-oxo-1'-octen- (E) -yl) -2-pyrrolidinone of formula III to form.

The methyl or ethyl -? - bromoheptanoate of the formula VIII can be obtained from Sub er insäur e, ie from octanedioic acid, by first adding the methyl or ethyl monoester of suberic acid according to the method described in HeI ^r .. Chim. Acta. _12_, page 466, and this compound is then exposed to the action of silver nitrate, whereby methyl or ethyl silver suberate is obtained, and finally the silver salt formed in this way in an inert medium, for example carbon tetrachloride, is reacted with bromine, which in Org.Synth. Coil., Volume J3, page 578, is used.

The compound of formula VIII in which Rp is methyl is a known product which, together with the process for its manufacture, is described in Chemical Reports, 75B, pages 291 297 (1942) has been described.

The compound of formula VIII wherein Ro is ethyl is also a known product which together with the process for its preparation in J. Chem. Soc. 1950, page 174 has been. The latter product can also be prepared according to the above-mentioned, in Chemical Reports 75B, pages 291-297 (1942) described method.

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As for the phosphorus-containing compound of formula XII, it can be obtained by first using of n-pentyl magnesium bromide and cadmium chloride according to the in Chem. Lett. 2, 197-200 (1973) described method prepared di-n-pentylcadmium and then caused that ' the cadmium derivative formed in this way with monochloroacetyl chloride reacted. The i-chloro-2-heptanone obtained in this way is then treated with triphenylphosphine to give the triphenyl-2-oxo-heptylphosphonium chloride the formula:

to form, and this compound then becomes a treatment subjected to potassium carbonate in an aqueous medium, to obtain the desired compound of Formula XII. The compound of formula XIII is and will be a known product mentioned in Tetrahedron Letters, 773-774 (1972).

As an alternative method, the compound of the formula XII can also be used according to that described in J. Org. Chem. Volume 37, No. 11 (1972) Process are produced.

Of the starting compounds of the formula II, those in which R ₁ = methyl or ethyl are also included in the formula I, for the preparation of which a process is described above. The other esters of the formula II can all be prepared by the process described above for preparing the methyl and ethyl esters of the formulas I and II.

It has been found that the compounds according to the invention have valuable pharmacological properties. Most of these properties are generally characteristic of the natural prostaglandins and in particular of the prostaglandin E ^, also known as PGE ₁ , characteristic. Try that with

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the compounds according to the invention have been carried out, have shown that these compounds - depending on the administered Dose - a contraction effect on the smooth intestinal and Exercise uterine muscles, a vasodilatory effect and an inhibitory effect on gastric secretion. In addition, A <tired found that the connections of the Formula I, in addition to its other properties, also have a bronchodilator-like effectiveness, in particular can be used in the treatment of asthma and pathological conditions affecting the respiratory system »

The compounds according to the invention can therefore be used to treat the various disorders in human and animal organisms which are _{advantageously influenced by the action of PGE 1} , in particular asthma or pathological conditions which impair the respiratory system, at least one compound of the formula I is administered in the form of a mixture of isomers or in the form of an active isomer, advantageously as a pharmaceutical or veterinary composition.

Another object of the present invention is therefore to provide a pharmaceutical or veterinary one Composition which as the essential active ingredient at least one compound of formula I in the form of a mixture comprised of isomers or in the form of an active isomer in association with a non-toxic carrier.

In addition, the present invention also relates to a process for the preparation of pharmaceutical and veterinary Compositions which consist in that at least one compound of the formula I in the form of a mixture of isomers or of an active isomer combined with a non-toxic carrier.

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Prostaglandins have been of particular interest for several years awakened in the pharmacological and therapeutic field. These are natural compounds which are very common in mammalian tissues, and several of which are from human seminal fluids have been separated.

The prostaglandins have a very wide range of action, which seems to result from theira influence on the production of 3 ¹ »5'-cyclic adenosine monophosphate (cyclic AMP).

According to their chemical structure, they have different pharmacological effects, such as hypertensive or hypotensive or anti-ulcerogenic activity, or - depending on the part of the body affected - a stimulating one or relaxing effects on smooth muscles, all of these effects being observed at very similar doses can.

This lack of a specific action on the part of the natural prostaglandins is also responsible for most of the side effects that are caused by them.

Of the natural prostaglandins, the one mentioned above appears under the name PGE. known prostaglandin to be the most effective, as pointed out in Chimie Therapeutique Λ_, 34 (1969). For example, PGE .. is able to stimulate the smooth intestinal and uterine muscles, induce vasodilation and bronchodilation, reduce gastric secretion and inhibit the aggregation of blood platelets when administered in infinitely small doses on the order of nanograms.

However, PGE .. has certain disadvantages due to its lack are associated with a specific effectiveness with natural prostaglandins. For example, PGE .. calls through his spasmogenic effect on the digestive tract causes certain side effects such as nausea, vomiting and diarrhea.

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It is therefore desirable to have a synthetic prostaglandin which has a greater specificity with regard to the therapeutic effectiveness, whereby certain disadvantages of PGE., in particular those mentioned above, can be eliminated.

The compounds according to the invention solve this problem. Pharmacological. Try that with these compounds as well for comparison purposes with PGE ,, have shown that the compounds of the formula I, like PGE. the smooth muscles of the intestine and uterus contract, dilate the blood vessels and bronchi and inhibit gastric secretion. The compounds according to the invention however, act in a much more specific way than PGE. in the Bronchi and, to a much lesser extent, in the vessels.

It has been found, for example, that the compound of the formula I in which R = a hydrogen atom, namely f! L-8-aza-11-deoxy-PGE., Has a bronchodilator activity which is practically that of PGE. equivalent, while it is 10-100 times less effective than a vasodilator

PGE., As a spasmogenic agent in the intestinal and uterine area, 200 times weaker than PGE. and is 30 times less effective than PGE ₁ in reducing the volume of gastric secretions.

The compounds according to the invention are therefore suitable for therapeutic use in the treatment of pathological conditions which impair the respiratory system, particularly of asthma, with virtually none of the above pertaining to PGE. side effects mentioned occur.

Irrespective of their pharmacological effectiveness, the 2-pyrrolidinone derivatives according to the invention also have certain advantages over PGE ₁ , in particular with regard to their production. PGE., Which is a natural product, can be obtained, for example, by extraction from natural materials,

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in particular of the vesicle glands of sheep, pig lungs or also from human seminal plasma will. It is evident that with such sources this product is only available in limited amounts and with use is available from expensive devices, which makes the product much more expensive.

In addition, the production of PGE ^ on synthetic Path due to several asymmetric centers present in the molecule cannot be done without major difficulties. These ' Difficulties cause the number of steps in making the connection to increase, thereby increasing it the manufacturing cost is effected.

In the preparation of the compounds according to the invention Formula I these difficulties are practically avoided.

Their simpler chemical structure, which eliminates the asymmetry in the 8 and 11 positions of the carbon atoms in PGE ₁ , simplifies chemical production. In addition, the starting materials required for the production of the compounds according to the invention are readily available, and it is therefore possible to produce the compounds according to the invention in much larger quantities than if - as in the case of PGE ₁ - natural tissues are used as the starting material.

These significant advantages with the manufacture of the invention Compounds connected contribute to their preference over PGE ^.

The results of a series of pharmacological experiments with a compound according to the invention, namely DL-8-aza-11-deoxy-PGE ^, are listed below. These tests show the clearly specific nature of the effectiveness this connection on the bronchi and their much less specific effect on the vessels. In each of these

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Tests were carried out on the compound to be investigated and also the PGE used for comparison purposes. in the form of ethanol Solutions diluted with distilled water are used.

I. SpasjDogenic effect on isolated intestines or uterus . _{t i} ^

The Magnus / Arch. Gees. Physiol.,, 102, 123 (1904) 7 applied.

It was found that the compound according to the invention, when administered at a dose of 0.2 × 10 g / ml bath, causes a strong and reproducible spasm in the ileum of a guinea pig, whereas when PGE is used. a dose of 0.1 10 "^ g / ml is sufficient to produce a spasm of the same intensity .

When applied to the uterus of a rat which had been blocked with stilboestrol prior to the estral cycle , it was found that this organ was caused by PGE ,, at a dose of

-5 0.3 x 10 g / ml was strongly and regularly contracted, while to achieve an equivalent spasm it was necessary to give the bath a dose that is 200 times greater, i.e. 0.6 10 g / ml to add the compound according to the invention.

The administration of an inactive dose of the compound of the invention on the order of 10 "g / ml, 30 seconds before the administration of a dose of PGE, in an amount of 10 g / ml in contact with the ileum or uterus is brought does not modify the effect of the latter compound on the examined organ.

II. Cardiovascular effect

The effect of different doses of the invention Connection and from PGE ,. on the systolic arterial pressure, the diastolic arterial pressure, the electrocardiogram, the

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Heart rate and the flow velocity in the thigh has been tested in the conventional manner in dogs.

When administered intravenously at a dose of 0.5-1 pg / kg causes PGE. Immediate systemic arterial hypotension, which affects both systolic and diastolic pressures. The mean pressure is reduced by 5 to 21 % of the initial value, depending on the animal, while the C 3 velocity of the arterial flow is increased to a considerable extent, namely 34 to 100 % of the initial value. On the other hand, a moderate sinus tachycardia is evident. These results indicate that PGE. is a very powerful vasodilator.

With respect to the compound of the invention, it has been observed that intravenous administration of doses between 5 and 50 pg / kg has the same cardiovascular system effects as PGE. Has.

These results show that the vasodilating effect of the compound of the invention occurs at doses that are around 10 to 50 times larger than in the case of PGE, ..

To get an analogous effect with papaverine, it is necessary to use a dose that is 50-100 times is as large as the dose of the compound according to the invention.

When the compound of the present invention is administered into the femoral artery, arterial flow becomes much less Volume increased than with administration of PGE, ..

For example, the compound according to the invention in a dose of 1 μg / kg causes a change of + 100 % in the initial flow in the thigh, while PGE. causes a change of + 173% at a dose of 0.01 μg / kg. These results show that the compound of the invention, when administered intra-arterially, is more than 100 times less effective than PGE, ..

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III. Bronchodilatory activity in the guinea pig.

For this purpose, the KONZETT & RÖSSLER (Arch. Exp. Path. Pharmakol., 1940, 1_ £ 5> 71 - 74) applied the developed procedures; Acetylcholine was used as a spasm-inducing agent used.

The results show that the compound of the present invention has a significant bronchodilator efficacy of 48 % and about 2 minutes after intravenous administration of a dose of 2.5 µg / kg. At a dose of 5 jig / kg, the reduction of the bronchospasm is 2 minutes after intravenous administration of the present compound 77% _t wherein the duration is 10 minutes. PGE ₁ is a very powerful bronchodilator because, at a dose of 2 µg / kg administered intravenously, it inhibits 74% of bronchospasm 2 minutes after administration.

If one considers the two parameters, intensity and duration of action, the compound of the invention is as effective as PGE ₁ , since both compounds at a dose of 5 ng / kg, which is administered intravenously, over a period of 10 minutes, an average of 45 % of the through Inhibit acetylcholine induced bronchospasm.

IV. Effect on rat gastric secretion.

Conventionally, the effect of the compound of the present invention on gastric secretion and gastric acidity has been demonstrated of female rats previously on a water diet for 24 hours and complete for the subsequent 24 hours Have been exposed to starvation.

The results show that the compound according to the invention at a dose of 10 mg / kg reduces the volume of gastric secretions to a great extent, ie by about 58%. Also will

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the total acid is reduced by 72% , while the pH value is increased from 1.9 in the comparison animals to 4.0 in the treated animals.

Under conditions similar to those described above, the volume of gastric secretions is reduced by 50% _{by administration of PGE 1} at a dose of 0.3 mg / kg (Gastroenterology, 1968, vol. 55, no. 4, pages 481-487), from which it can be seen that the compound according to the invention is about 30 times less effective than PGE in this experiment.

The pharmaceutical and veterinary compositions according to the invention can be prepared in any form which is suitable for administration in human or veterinary therapy. For easier administration, the composition is normally in dosage units vox " ⁴ , which are suitable for the desired type of administration, for example as compressed tablets for perlingual administration, as a pill, powder, capsule or syrup for oral administration, as a suspension for oral or oral administration Aerosol administration, as a suppository for rectal administration, as a cream or ointment for external or topical administration and as a sterile solution or suspension for parenteral administration.

The therapeutic compositions of the invention are prepared by known methods by at least one compound according to the invention with a suitable diluent or excipients combined and optionally the resulting mixture into the desired dosage unit form is brought. Examples of suitable diluents and excipients are distilled Water, ethanol, talc, magnesium stearate, starch and cocoa butter.

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The amount of active ingredient used can be, for example, 0.5 to 3000 µg daily in 1 to 60 aerosol inhalations in asthma or other ailments of the respiratory system or 0.1 to 1 μg per Minutes and per kg of body weight for intravenous administration to have a va & odilatory effect or an effect to achieve a smooth muscle.

In the following. Examples are the preparation of the invention Connections described.

In these examples, the analytical results obtained by infrared spectra (IR) and nuclear magnetic resonance spectra (KM ₀ R.) contain the following abbreviations, which have the following meanings:

l.R. spectrum

f = weak absorption
m = mean absorption

F = strong absorption

N.M.R. spectrum

δ or chemical shift indicates the difference between the field forces at which signals for nuclei of the of the same type as the proton, but which are in different molecular environments.

TPM = parts per million
T = triplet
M = multifunction
Q = quadruplet
S = singlet

CDCl, = Deuterium-containing chloroform, which for comparison and used as a solvent.

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example 1

Production of DL-a ^ -Carbomethoxy-i-hexyl-5 · - (3 * -hydroxy-1 ' octen- (B) -yl) -2-pyrrolidinone or DL-8-Aza-H-deoxy-PGE.-m e thyl e s t he _____ ",

a) Silver and methyl sub-era t

In a 3-neck spherical flask of 4 liters capacity equipped with a mechanical stirrer and a dropping funnel, 1.4 liters of water was poured, and then 27 g (0.48 kol) of potassium in tablet form was added. After the potassium was dissolved, 91 'J (Ο, Λδ mol) methyl monosuberate was added, and then a solution of 81.5 g (0.48 mol) silver nitrate in 900 ml V gas was added dropwise with vigorous stirring. The mixture was then filtered off with suction, and the precipitate obtained was washed with a little methanol and then dried under vacuum until a constant weight was reached (36 hours at 100 ^° C.).

In this way, 111 g of silver and methyl suberate were obtained, which corresponds to a yield of 78 % .

b) methyl 7-bromoheptanoate

In a spherical three-neck flask with a capacity of 500 ml, the one fitted with a dropping funnel, mechanical stirrer and one with a calcium chloride trap Was equipped with a water cooler, 170 ml were drier Cast carbon tetrachloride. Thereafter, the 111 g (about 0.38 mol) of silver and methyl suberate prepared according to a) were obtained added, the whole was cooled with ice water and 20 ml (0.365 mol) of dry bromine was slowly added. the The reaction was strongly exothermic. After the addition was complete, the reaction mixture was placed in an oil bath for 90 minutes Heated to reflux, then allowed to cool, filtered,

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and then the obtained precipitate was washed with 100 ml of hot carbon tetrachloride. The obtained organic Phase was then washed with a 10% aqueous solution of potassium carbonate, then dried, and the Solvents have been removed.

The remaining oil was distilled under vacuum, and the fraction which passed at a temperature of 100-107 ° C / 4 mmHg was collected. 27 g of a crude product were obtained, obtained by chromatography on a silica gel column (420 g Silicon oxide) using the following eluents in succession: two times 500 ml of hexane, four times 500 ml of a mixture of benzene and hexane in a ratio of 1: 4 and then once 500 ml of ether.

18.3 g of methyl 7-bromoheptanoate were obtained in the form of a colorless; clear liquid, which corresponds to a yield of 17% * Boiling point: 115 ° C / 8 mm Hg *

IR spectrum: -CO (ester) at 1740 cm " ¹ (F)

-CO (ester) at 1200 cm " ¹ (m) -C-Br at 640 cm" ¹ (f)

B - Preparation of the i-triphenylphosphorane-2-heptanone

a) 1-chloro-2-heptanone

In a spherical three-necked flask with a capacity of 1 liter, which is equipped with a water cooler, a dropping funnel and equipped with a mechanical stirrer, 330 ml of dry ether was poured, followed by 16.3 g (0.66 g-atom) magnesium shavings added. The resulting mixture was refluxed, and then - during the Ether was further refluxed - 101 g (0.66 mol) of n-pentyl bromide was added dropwise. Once the whole Magnesium had disappeared, the solution was diluted with an equal volume of ether, and then were taken Stirring 96 g of dry cadmium chloride were added. The resulting mixture was left in an oil bath for 1 hour, its temperature

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was kept at about 40 ⁰ C (reflux temperature of the ether), heated. The ether was then distilled off, where it was gradually replaced by 350 ml of anhydrous benzene, and after a temperature of 70 C was reached, the distillation was stopped. The reaction mixture was then cooled in an ice water bath and a solution of 78 g (0.66 mol) of ilonochloii ^ .cetyl chloride in 150 ml of dry benzene was added dropwise. During this addition, the temperature of the reaction mixture was adjusted so that it did not exceed 40 ⁰ C. The reaction was allowed to take place for 1 hour, after which the reaction mixture was heated ^{to 40 ° C. in an oil bath for 21/2 hours.}

After cooling, the reaction mixture was placed in 250 g of ice poured, and 750 ml of n-sulfuric acid were added. The aqueous phase was taken up with benzene and the organic phase was successively washed with an aqueous solution treated with sodium bicarbonate, water and a saturated aqueous solution of sodium chloride. The obtained organic Fraction was dried, solvents removed, and distillation with a Nester Faust column was performed made after a first rectification with a Vigreux column had been carried out. The faction that at 86.5 to 87 ° C / 20 mm Hg was collected.

In this way, 27 g of 1-chloro-2-heptanone were obtained in the form of a colorless, clear liquid, which corresponds to a yield of 28 % .

NMR Spectrum (CDCl ₃ ): δ = 0.9 ppm (T) 3P (CH ₃ )

= 1.4 ppm (M) 6P (CH ₂ )

= 2.6 ppm (T) 2P (COCH ₂ ).

= 4.2 ppm (S) 2P (CH ₂ Cl)

b) 2-oxo-heptyl-triphenylphosphonium chloride

In a spherical three-neck flask of 250 ml capacity, which was equipped with a water cooler

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12.25 g of the 1-chloro-2-heptanone prepared under a) were poured, and then a solution of 26.7 g of triphenylphosphine in 100 ml of chloroform was added. The reaction mixture was heated for 3 hours in an oil bath at 70 ⁰ C (reflux of chloroform). After cooling, the solvent was removed, the remaining oil was taken up in 80 ml of acetone, and the resulting solution was placed in a refrigerator for 12 hours. The crystals obtained were filtered off with suction, washed with eti. ^f washed as ice-cold acetone and then dried under vacuum,

In this way, 24 g of 2-oxo-heptyltriphenylphoniumchloride were obtained in the form of a crystalline, hygroscopic white powder, which corresponded to a yield of about 72 % .

Thin layer chromatography of the obtained product revealed one major spot with an Rf value of 0.8 and three secondary spots with Rf fourths of 0.85, 0.90 and 1.00, respectively, using a mixture of hexane, chloroform, Ethanol and ammonia in a ratio of 40: 40: 19: 1 was used.

c) 1-triphenylphosphoranylidene-2-heptanone

A solution of 30 g of the previously prepared 2-0xo-heptyltriphenylphosphonium chloride in 300 ml of chloroform was placed in a spherical flask. This solution was initially with an aqueous potassium carbonate solution and then treated with a saturated sodium chloride solution. The reaction mixture was dried, the solvent removed and the remaining oil obtained was taken up with about 30 parts by volume of hexane

In this way, 17 g of 1-triphenylphosphoranylidene-2-heptanone were obtained in the form of white crystals, which corresponds to a yield of about 62 % . Thin layer chromatography of the product obtained revealed one major spot with a

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Rf value of 0.2 and a secondary l ^? licking with an Rf-Vfert of 0.5, a mixture of benzene, dioxane and acetic acid in the ratio of 90: 25: 4 being used as the solvent.

C - Production of DL-ct> -Carbomethoxy-1-h.pxyl-5- (3 ^l -hyc.roxy- 1 * -o et e n-Q ¹ Q-Vl) 2- pyrrol idinqn "__" ___

900 ml of absolute ethanol were poured into a spherical Drai-neck flask of 2 l capacity, which was equipped with a mechanical stirrer and a water condenser, over which a calcium chloride trap was located, and then 100 g of DL-pyroglutamic acid and 10 gp ~ toluenesulfonic acid added. The reaction medium was heated ^{to 100 °} C. in an oil bath for 16 hours. After cooling, about 800 ml of alcohol were removed and the remainder was taken up with 200 ml of methylene chloride. The organic phase was washed with a 20% strength aqueous solution of potassium carbonate and then with a saturated aqueous sodium chloride solution. Thereafter, it was dried, the solvents were removed, and the residue was distilled, collecting the fraction which passed over at 138 ° C / 0.3 mmHg.

This gave 90.2 g of ethyl DL-pyroglutamate in the form of agglomerated white crystals, which corresponds to a yield of about 74 % .

IR spectrum (KBr): - NH at 3200 cm " ¹ (m)

- CO (ester) at 1735 cm " ¹ (F)

- CO-NH at 1700 cm " ¹ (F)

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): £ = 1.2 ppm (T) 3P (CH ₃ )

= 2.3 ppm (M) 4P (CH ₂ CH ₂ ) = 4.2 ppm (Q) 3P (CH ₂ -CH ₃ +

tertiary CH) = 7.2 T.p.M. (S) 1P (NH)

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440 ml of methanol and 330 ml of water were placed in a spherical three-neck flask with a capacity of 1 liter, which was equipped with a mechanical stirrer. The solution was cooled to 0 ° C. with the aid of a cryostat, and 15.7 g of the previously prepared ethyl] -DL-py.foglutamate were added. Dcnach were sodium borohydride in small portions 22.8? And the temperature was maintained for 90 minutes to ⁰ ° C. Then the reaction mixture was allowed to return to normal temperature and allowed to stand for 24 hours. Thereafter, continuous extraction with methylene chloride was carried out for 44 hours. The solvents were removed and the resulting oil was taken up in 2 volumes of acetone.

In this way, 9 g of DL-5-hydroxymethyl-2-pyrrolidinone were obtained in the form of a pale yellow crystalline powder, which corresponded to a yield of 81 % . Melting point: 65.5 ⁰ CIR spectrum (IiBr): NH, OH at 3260 cm " ¹ (m)

3210 cm " ¹ (m) CO at 1670 cm" ¹ (F)

c) DL-2 '-Tetrahvdropvranyl ^ -oxymethyl ^ -pyrrolidinone

In a spherical three-necked flask with a capacity of 1 liter, which is fitted with a calcium chloride trap and a mechanical one Stirrer was equipped, 450 ml of methylene chloride, which had been dried on a 4-A sieve, was poured, and thereafter 23 g of the previously prepared DL-5-hydroxymethyl-2-pyrrolidinone and 26 g of freshly distilled 2,3-dihydropyran were obtained admitted. This was followed by a solution of 600 mg of p-toluenesulfonic acid in 120 ml of anhydrous tetrahydrofuran added dropwise. The reaction was allowed to continue for 90 minutes take place at normal temperature, after which the mixture is then neutralized to a pH of 6 to 7 with 10 ml of pyridine and then the reaction medium was diluted to 1 liter with methylene chloride. The organic phase was with

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Water and then washed with a saturated sodium chloride aqueous solution. The organic fraction was dried, the solvents were removed and the oil obtained was taken up in an equal volume of isopropyl ether. In this way, 30 g of DL-2'-texrahydropyranyl-5-oxymethyl-2-pyrrolidinone Ln in the form of a white powder were obtained, which corresponds to a yield of 75 % .

Melting point: first melting at about 50 ⁰ C,

second melt at 82-95

^r C.

By observation of melting under a microscope, it was possible to distinguish two allotropic Fornen, of which the one at about 45 - 46 ° C and the other at about 88 - 90 ⁰ C melted. Partial separation of these two forms was achieved by recrystallizing the initial mixture in parts by volume of isopropyl ether. In this.7 you get
melt.

the first crop you get is crystals, which at about 88 -

d) DL-eu-carbomethoxy-1-hexyl-2 '-tetrahydropyranyl-5-oxy methoxy-2-pyrrolidinone

In a 1 liter spherical three-Kals flask equipped with a nitrogen supply, a mechanical stirrer and a water condenser fitted with a calcium chloride trap, 100 ml of dry toluene, 3.9 g (0.1 mol ) Sodium amide and then a solution of 20 g of the previously prepared DL-2 ¹ -tetrahydropyranyl-5-oxymethyl-2-pyrrolidinone in 300 ml of toluene added dropwise. The reaction medium was heated under reflux for 1 hour and, after cooling, a solution of 23 g (0.1 mol) of methyl 7-bromoheptanoate, which had been prepared according to A (b), in 500 ml of dry toluene was added dropwise. The mixture was heated for 24 hours under reflux in an oil bath at 120 ⁰ C. After cooling, the reaction mixture was poured into 100 μl of ice water, decanted off, and the organic phase was washed with water

609841/0989 ..- .. ·

and then again with an aqueous sodium chloride solution washed. Then it was dried and the solvents removed.

Was obtained in this way 32 g of DL-co-carbomethoxy-1-hexyl-2 ^{I-tetrahydropyranyl-oxymethyl-5} - 2-pyrrolidinone in Forin day of a yellow oil, sufficiently pure to be used directly in order to then.

Yield: 94 r-j.

I.R. spectrum (film): absence of OH band

CO (ester) at 1740 cm " ¹ (F) CO (amide) at 1690 cm" ¹ (F)

e) DL- u> -Carbomethoxy-1-hexyl - ^ - hydroxym ethyl - ^ - pyrrolidin on

130 ml of methanol and then 32 g of the previously prepared DL- * j -Carbomethoxy-i-hexyl ^ '- tetrahydropyranyl-5-oxymethyl were placed in a spherical three-necked flask with a capacity of 250 ml, which was equipped with a mechanical stirrer -2-pyrrolidinones poured. The resulting solution was cooled with an ice water bath, and then 50 ml of an n-hydrochloric acid solution was added. The reaction was allowed to take place for 21/2 hours at room temperature, then the methanol was removed and 100 ml of methylene chloride was added. The resulting mixture was decanted off and the organic phase was washed first with a 10% aqueous potassium carbonate solution and then with a saturated aqueous sodium chloride solution. It was then dried and the solvents removed to give an oil which was allowed to crystallize in a refrigerator.

In this way, 11.6 g of DL-ui-carbomethoxy-1-hexyl-5-hydroxymethyl-2-pyyrolidinone were obtained in the form of an almost white powder, which corresponds to a yield of 48 % .

609841/0989

" ²⁶ -" 261 ?! 14th

The purity of the product obtained is generally satisfactory. If necessary, however, the product can be purified by chromatography on an oil gel column, using the following eluents in sequence be: methylene chloride, a mixture of methylene chloride and acetone in the ratio of 2: 1, a mixture of methylene chloride and acetone in the ratio of 1: 1 and a mixture of methylene chloride and acetone in a ratio of 1: 2.

Thin layer chromatography of the product gave three Spots with an Rf value of 0.4, 0.45 and 0.50, respectively, with a Mixture of benzene, methanol and acetic acid in the ratio 79: 14: 7 was used.

IR spectrum (CCl ₄ , 5 %): OH at 3350 cm " ¹

CO (ester) at 1740 cm ~ ¹ (F) CO-N at I67O cm " ¹ (F)

f) DL-cu -Carbomethoxv-1 -hexyl-5-carboxaldehyde-2-PA ^? "rrolidinone

In a spherical three-necked flask, with a capacity of 250 ml, fitted with a mechanical stirrer, a calcium chloride trap and a nitrogen supply x-. ^r ar, 60 ml of anhydrous dimethyl sulfoxide and 120 ml of dry benzene were added. Then 5.15 g (0.02 mol) of DL-C 1 -C -arbomethoxy-1-hexynahydroxymethyl-2-pyrrolidinone, which had been prepared by the method described above, and 12.4 g (0.06 mol) of dicyclohexylcarboaiimide were added . The obtained mixture was cooled with an ice-salt 3ad to 0 ⁰ C, and then 1.06 ml (0.02 mol) dichloroacetic acid was added. A white precipitate of dicyclohexylurea quickly formed. The reaction medium was allowed to return to room temperature, at which it was then held with stirring for 6 1/2 hours. At this stage, the aldehyde formed can then be separated off using one of the following two different methods:

609841/098 9.

1) 4.4 g of oxalic acid are added, and the reaction is allowed to take place for about 30 minutes at ⁰ ° C., after which the substance formed is filtered off and the precipitate is washed with benzene and then with chloroform to a volume of 300 The solution obtained is neutralized, for example with pyridine, and the reaction medium is treated with water and then with a saturated aqueous sodium chloride solution, after which it is dried and the solvents are removed under vacuum, and finally 3 g are obtained DL-co-carbomethoxy-1-hexyl-5-carboxaldehyde-2-pyrrolidinone in the form of an oil, which can be used directly or purified by chromatography on a silica gel column.

2) 5 g of ice are added and the reaction is allowed to take place

Take place for 15 minutes, after which the obtained substance is filtered off, the precipitate obtained is washed with a little benzene and the solvents under vacuum removed. The remaining oil is taken up with a few milliliters of ether, and the resulting solution is placed in a refrigerator. Then the solution is filtered, washed with ether, the ether removed and the residue obtained was taken up with 150 ml of chloroform. The organic phase is mixed with water and then with a saturated aqueous sodium chloride solution and then dried. The solvents are removed, and 12 g of an oil are obtained which contains about 3 g of dimethyl sulfoxide, 4 g of dicyclohexyl carbodiimide and 5 g of the desired Contains aldehyde.

This oil can be used directly or purified by chromatography on a silica gel column, with the following Eluants used are: methylene chloride, a mixture of methylene chloride and acetone in proportion 3: 1 and a mixture of methylene chloride and acetone in a ratio of 1: 1.

6 0 9 841/0989

26121 H.

IR spectrum (CHCl ₃ ): CO (ketone) at 1670 cm " ¹ (F)

CO (ester) at 1730 cm " ¹ (F)

NMR Spectrum (CDCl ₃ ): Aldehyde peak at 9.7 ppm

Ester peak at 3.7 T.p.M.

g) DL-uj-carbomethoxy-1-hexyl-5- (3'-o ^ o-1'-octen- (E) ~ yl) ~ 2-pyrrolidinone

Into a 500 ml three-necked spherical flask equipped with a water condenser, a dropping funnel and a nitrogen supply was poured 120 ml of anhydrous dioxane, and then 5 g (about 0.02 mol) of DL-i - Added carbomethoxy-1-hexyl-5-carboxaldehyde-2-pyrrolidinone, which had been prepared as described above. A solution of 11 g (about 0.03 mol) of i-triphenylphosphoranylidene-2-heptanone, which had been prepared according to B (c), dissolved in 240 ml of dry benzene, was then added dropwise. The reaction mixture was 8 1/2 hours an oil bath heated to reflux at 90 ⁰ C with the aid of, and after cooling, the solvents were removed under vacuum. The oil obtained was taken up with a few milliliters of ether and the solution obtained was placed in the refrigerator for a few days. The precipitated triphenylphosphine oxide was then filtered off, filtered off with suction and washed with ether. The resulting solution was collected and the ether removed. 18.5 g of an oil were obtained which was purified by chromatography on a silica gel column (700 g of silicon oxide), the following eluents being used in succession (800 ml portions each)

were: once methylene chloride, three times methylene chloride and 5 % ethyl acetate, five times methylene chloride and 10 % ethyl acetate and 18 times methylene chloride and 20 % ethyl acetate. In this way, 5.5 g of DL-t ^ -Carbomethoxy-1-hexyl-5- (3'-oxo-1'-octen- (E) -yl) -2-pyrrolidinone were obtained in the form of a brown oil, which corresponds to a yield of about 79 %. * "ie Ί subset, 3 subsets etc.

60 9841/098 9

261211A

IR spectrum (CHCl ₃ 10 %) : CO (ester) at 1730 cm " ¹ (F)

CO (ketone) at 1675 cm " ¹ (F)

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ): S = 3.6 ppm (S) 3P (CCOCH ,,)

= 6 T.p.M. - 7.3 BPM (M) 2P

(HC = CH)

h) DL - ^ - Carfoometho: xy-1-hexyl-5- (3'-hydroxy-1 ^f -ccten- (E) - yl) ~ 2-pyrro li dinon

In a spherical three-neck flask with a capacity of 1 liter, which was equipped with a mechanical stirrer and a calcium chloride trap, 400 ml of dry dimethoxyethane were added, and then 5 g (0.014 mol) of the above-prepared DL-t ^ -Carbomethoxy-1-hexyl-5 ~ (3 ^t -oxo-1'-octen- (E) -yl) -2-pyrrolidinones added. ^{The solution was cooled to 0} ° C. with the aid of a cryostat, and 1.09 g (0.028 mol) of sodium borohydride were added in small portions. The reaction was allowed to take place for 45 minutes at ⁰ ° C., after which 50 ml v / water and then 100 ml of a 2% aqueous tartaric acid solution (the final pH of the solution was about 4) were carefully added. The reaction medium obtained was extracted several times with methylene chloride, the organic phases were combined and washed with water and then again with a saturated aqueous sodium chloride solution. The organic fraction was dried and the solvents were removed. 5 g of an oil were obtained which was purified by chromatography on a silica gel column (320 g of silicon oxide) using the following eluents in succession (320 ml portions each): eight times methylene chloride and 20% ethyl acetate and ten times methylene chloride and 50% ethyl acetate.

In this way, 2.7 g of DL-α-carbomethoxy-1-hexyl-5- (3'-hydroxy-1'-octen-(E) -yl) -2-pyrrolidinone were obtained in the form of a colorless oil, which corresponds to a yield of about 54 %.

609841/0989

This connection shows in thin-layer chrociatography on silica gel using a mixture of λ ^ οιι chloroform and ethyl acetate in a ratio of 1: 1 as the eluent only a single point (kidney-shaped).

Rf value "about 0.35.

IR spectrum (CHCl-,): broad OH at 3430 er »" ¹ (m) and

at 3600 cm " ¹ (f)

COO- at 1730 cm " ¹ (F)

-CO-N at 1670 cn: " ¹ (F)

IJ.MR spectrum (CDCl ₃ ): δ = 0.9 ppm (T) 3P ₃

= 2.3 T.p.M. (S) 1P (OH interchangeable with trifluoroacetic acid)

= 3.6 ppm (S) 3P (COOCH ₃ )

Example 2

Preparation of DL-oJ-Carboxy-1-hexyl-5- (3'-hydroxy-1'-octen- (E) -yl) -2-pyrrolidinone or DL-8-Aza-ii-deoxy-PGE ^

In a spherical three-neck flask with a capacity of 250 ml, equipped with a mechanical stirrer, 100 ml of methanol and then 2.6 g of the above prepared DL-6J-carbomethoxy-1-hexyl-5- (3'-hydroxy-1'-octen-(E) -yl) -2-pyrrolidinone given. The resulting solution was cooled to 0 C with the aid of an ice-water bath, and then were slowly added 40 ml of a 0.5N sodium hydroxide solution. The reaction was allowed to take place for 2 1/2 hours at room temperature, after which time 20 ml of water was added and the obtained aqueous solution was with a 25 / C 'aqueous Hydrochloric acid solution washed to a pH of 2, after which it was extracted several times with ethyl acetate. The organic phases obtained were combined and then washed with a saturated aqueous sodium chloride solution, after which they were dried and the solvents removed.

609841/0989

In this way, 2.1 g of the desired DL-oi-carboxy-1-hexyl-5- (3 ^f -hydroxy-1'-octen (E) -yl) -2-pyrrolidinone or DL-8-aza were obtained -H-deoxy-PGE .. in the form of a partially crystallized hygroscopic gel, which corresponds to a yield of about 85 / 'ο.

Chromatography with a thin layer of silica gel using a "mixture of benzene, dioxane and acetic acid in the ratio of 90: 25: 4 as the eluent gave a main spot with an Rf value of 0.33 and two secondary spots with Rf values \" ^r on 0.39 or 1st IR spectrum (CHCl,): CO (acid) at 1710 cm " ¹ (F)

CO-N at 1665 cm " ¹ (F)

NMR spectrum (DMS0d6): corresponding spectrum. Example 3

Preparation of DL-i *> - Carboethoxy-1-hexyl-5- (3 ^t -hydroxy-1'- octen- (E) -yl) -2-pyrrolidinone

A - manufacture; of Ethyl-7-bromoheptanoate

a) Ethyl (5-acetoxv-pentvl) malonate

A suspension of 4.8 g (0.2 mol) of sodium hydride in 150 ml of anhydrous benzene was cooled in an ice bath. While stirring, 32.03 g (0.2 mol) of ethyl malonate in 150 ml of dimethylformamide were added dropwise. The mixture was then stirred for a further 12 hours at room temperature, and 0.4 g of potassium iodide and 32.9 g of 5-acetoxypentyl chloride (prepared according to the process described in J. Am. Chem. Soc, 1947, 69, 2581 ) admitted. The mixture was ^{heated to 125 °} C. for 24 hours and then concentrated under vacuum. The residue obtained was taken up in 100 ml of 5 5% sulfuric acid. 1 g of ammonium chloride and 500 ml of ether were then added to this solution. After this

".6 09841/0989

Filtration, the precipitate was washed with ether and the filtrate was washed with sodium chloride-saturated water. The aqueous phase was extracted again with 100 ml of methylene chloride. The organic fractions were dried over sodium sulfate and concentrated, and 35 g of ethyl (5-acetoxy-püiityl) malonate were obtained in the form of an oil. Yield: about 60 %.

k) h Ät yl -7-bromo heptanoate

A mixture of 57.6 g (0.2 mol) of the ethyl (5-acetoxy-pentyl) malonate prepared above and 100 ml of a 48% aqueous solution of hydrobromic acid was refluxed for 20 hours and then added by distillation an internal temperature of 120 ⁰ C concentrated. The cooled residue was taken up with ether. The ethereal solution was washed with water saturated with sodium chloride and then dried. The ether was removed and 38 g of a dark, viscous liquid was obtained (yield about 93 %) which consisted of crude 7-bromoheptanoic acid. To this crude product, 31 ml of absolute ethanol, 72 ml of anhydrous benzene and 3 drops of concentrated sulfuric acid were then added. The reaction medium was refluxed with a Dean-Stark system for 24 hours and then 100 ml of benzene was added. The mixture was washed with a 10% sodium bicarbonate solution and then with water until neutral. The solution was dried, concentrated and the oily residue was distilled.

This gave 35 g of ethyl 7-bromoheptanoate, which was found to be homogeneous in thin-layer chromatography. Boiling point: 98 ⁰ C (below 1 mm Hg).

Yield: about 82 %.

NMR spectrum (CDCl ₅ ): S = 1.25 Τ.ρ, Μ. (T) (CH ₅ )

= 4.15 ppm (Q) (CH ₂ OCH)

= 2.3 ppm (T) (CH ₂ -CO-O)

= 3.4 ppm (T) (CH ₂ -Br)

609841/0989

B ~ Preparation of 1- triohenylphosphorus anylidene-2-heptanone

a) ethyl-3-οxo-capr yla t

48 g (2 mol) of sodium hydride were 250 ml of dry ether and ' 236 g (2 ^ mol) of ethyl carbonate were added. Under Rüokflu3 were 11 <· 'dropwise over the course of 7 hours. g (1 mole) of 2-heptanone added in 250 ml of ether. The mixture was heated for 12 hours, then the reaction medium was placed in an ice bath cooled down. Thereafter, 125 ml of glacial acetic acid were added dropwise under gentle reflux, followed by the addition of water to completely dissolve the precipitate. The organic phase was decanted off with a sodium bicarbonate solution

until and then washed again with water to neutrality. The ethereal solution was dried, concentrated and distilled.

In this way, 145.5 g of ethyl 3-oxo-caprylate were obtained a boiling point of 122 - 124 ° C below 20 mm Hg.

Yield: about 78 %.

ⁿ D ^{2 = 1} » ⁴⁵²⁰

NMR Spectrum: S = 3.4 ppm (-CO-CH ₂ -CO-)

b) 1-chloro-2-heptanone

To 93 g (0.5 mol) of the ethyl 3-oxo-caprylate prepared above, which was cooled in an ice bath, 200 ml of sodium hydroxide were added dropwise. The mixture was stirred at room temperature until the supernatant oil disappeared (after about 7 hours). The solution was then extracted with ether and the aqueous phase was acidified with 10% hydrochloric acid to give a white precipitate. This precipitate was filtered off, washed twice with cold water and recrystallized from petroleum ether to give 70 g (yield: 86%) of 3-oxo-caprylic acid (m.p. 73-74 ⁰ C) received in the form of white flakes. A solution of 90 g (0.57 mol) of this acid in 36O ml of methylene chloride at 25 ⁰ C was added dropwise 82.3 g of thionyl chloride dissolved in 45 ml methylene HO 9841/0989

26121 IA

chloride, added * The mixture was stirred for 7 hours, then left to stand at room temperature for 65 hours.

The solvent is removed and the residue is distilled.

In this way, 81 g of 1-chloro-2-heptanone were obtained in the form of a pale yellow GI, which appears in thin layer chromatography proved to be homogeneous.

Boiling point: 86 - 87 ° C (below 20 mm Hg) njp = 1.4400

Nuclear Magnetic Resonance Spectrum: (CDCl ₃ ): S = 4.1 ppm (ClCH ₉ -CO-)

= 2.5 ppm (-CO-CH ₂ -)

^c ) 2-Oxo - heptyl-triphenylphosphonium chlora -d

This compound is prepared according to the method described in Example 1 under B, b).

d) 1-triphenylphosphoranylidene-2-heptanone

This compound was prepared according to the method described in Example 1 under B, c).

C - Production of DL-cu-Carboethoxy-i-hexyl-S - ^ '- hydroxy- 1 ^l -octen- (E) -yl) -2-pyrrolidinone

a) DL- u> -Carboethoxy-1-hexyl-2'-tetrahydropyranyl-5-oxymethyl- 2-pyrrolidinone

A mixture of 19.9 g (0.1 mol) of DL-2 ^f -tetrahydropyranyl-5-oxymethyl-2-pyrrolidinone, which had been prepared according to the method described in Example 1 under C, c), and 3.9 g Sodium amide (0.1 mol) and 400 ml of dry toluene were heated for 1 hour. After cooling, a solution of 23.7 g (0.1 mol) of the ethyl 7-bromoheptanoate prepared above in 50 ml of dry toluene was added dropwise. The reaction medium was refluxed for 24 hours and then poured into 500 ml of ice water. The organic phase was washed with water saturated with sodium bicarbonate and then with pure water until neutral.

609841/0989

After drying, the solvents were removed.

In this way, 32 g of DL-uo-carboethoxy-1-hexyl-2 ' -tetrahydropyranyl ^ -oxyniethyl ^ -pyrrolidinone in the form of a almost pure oil.

Yield: 90 %.

A further purification was carried out by chromatography on a oilika column made. The first elution was with hexane carried out to remove the unreacted ethyl 7 ~ bromoheptanoate, and a second elution was carried out with benzene as Eluent made, whereby you get the desired product j η received a very high degree of purity.

Rf value = 0.55 (thin layer chromatography with acetone and Methylene chloride in a ratio of 20:80 as solvent)

IR spectrum (film): CO (ester) at 1735 cm " ¹

CO (amide) at 1690 cm " ¹ COC at 1030 cm" ¹

NMR Spectrum (CDCl ₃ ): S = 1.25 ppm (CH ^ ₃ -CH ₂ -O)

= 4.1 ppm (-CH ₂ -O) = 4.6 ppm (0-CH-O)

b) DL- tu -Carboethoxy-1-hexyl ^ -hydroxymethyl ^ -pyrrolidinone

A solution of 17.75 g (0.05 mol) of the above prepared DL-to -carboethoxy-1-hexyl-2 ¹ -tetrahydropyranyl-5-oxymethyl-2-pyrrolidinone, 100 ml of ethanol and 50 ml of 1N-hydrochloric acid was 3 Stirred for hours at room temperature. Then the ethanol was removed under vacuum. The residue was washed with water saturated with sodium bicarbonate and then washed again with 200 ml of pure water. After drying, the solvents were removed and 10 g of an oil were obtained. The oil was purified by chromatography on a silica gel column and the impurities removed with chloroform as the eluent. A further elution was then carried out with a mixture of acetone and methylene chloride in a ratio of 20:80 as the solvent.

6Ü9841 / Ü989

In this manner, there was obtained 9.2 g of DL ~ u> -Carboäthoxy-1-hexyl-5-hydroxymetiryl i ^{n-2-pyrrolidinone} as an oil, which turned out in thin layer chromatography to be homogeneous.

Yield: 67 %.

Rf-Wart = 0.8 (thin-layer chromatography with benzene, methanol and acetic acid in the ratio 79: 14: 7 as solvent).

IR spectrum (film): OH at 3380 cm "" ¹

CO (ester) at 1730 cm " ¹ CO (amide) at 1650 cm" ¹

NMR Spectrum (CDCl ₃ ): £ = 1.25 ₂

= 4.1 (CH ₂ O) = 4.3 (OH)

c) DL- i ^ -Carboethoxy-1-hexyl ^ -carboxaldehyde ^ -pyrrolidinone

A mixture of 1.42 g (0.02 mol) of the above prepared DL-c ^ -Carboarhoxy-i-hexyl ^ -hydroxymethyl- ^ - pyrrolidinone, 12.4 g of dicyclohexylcarbodiimide, 120 ml of anhydrous benzene and 60 ml of anhydrous dimethyl sulfoxide was cooled to 0 ^{0 C.} To this mixture was added 1.06 mol of dichloroacetic acid dropwise. The reaction medium was then stirred for 7 hours at room temperature, and 4.4 g of oxalic acid were added in small portions at ⁰ ° C. The mixture was allowed to react at the same temperature for 30 minutes and then filtered. The precipitate was washed with toluene and the filtrate was taken up with 300 ml of chloroform. The chloroform solution was washed with water saturated with sodium bicarbonate and then again with distilled water until neutral. After drying, the solvents were removed under vacuum. The oil obtained was taken up with 50 ml of ether. After filtering, the filtrate was chromatographed on a silica gel column.

A first elution was carried out with methylene chloride, to remove impurities (dicyclohexylcarbodiimide, dimethyl sulfoxide etc.) to remove; afterwards a second elution was carried out with

609841/0989

" ³⁷ " 26121 ΊΑ

a mixture of acetone and methylene chloride in proportion 8:80 pm.

In this way, 5 g of DL-co-carboethoxy-1-hexyl-5-carboxaldehyde-2-pyrrolidinone were obtained in the form of a brown oil which, as determined by titration, had a degree of purity of 94.1 % .

Yield: 92 %.

IR spectrum (CHCl ₇ ): CO (ester) at 1730 cm " ¹

CO (amide) at 1670 cm " ¹

NM, R. Spectrum (CDCl ₃ ): S = 1.1 ppm ₃

= 4.1 ppm (CH ₂ O) = 4.9 ppm (OH-enol) = 9.65 ppm (CHO)

d) DL-cJ-Carboethoxy-1-hexyl-5- (3 '-oxo-1' -octen- (E) -yl) -2- pyrrolidinone

A mixture of 5.38 g (0.02 mol) of the above prepared DL- L j -carboethoxy-1-hexyl-S-carboxaldehyde ^ -pyrrolidinone, 7.08 g (0.02 mol) of the above prepared 1-triphenyiphosphoranylidene -2-heptanones, 120 ml of anhydrous dioxane and 240 ml of anhydrous benzene were refluxed for 12 hours. The solvents were then removed in vacuo and the remaining oil was taken up in 20 ml of ether. After filtration, 7 g of an oil was obtained as a filtrate, which oil partially crystallized out after allowing it to stand at room temperature. After performing two chromatographies on a silica gel column, an oil was obtained which still contained aromatic impurities. These impurities were removed by chromatography on silica gel plates using a 20:80 acetone-methylene chloride mixture as the eluent (Rf = 0.8).

609841/0989

In this way, 6.5 g of DL-co-carboathoxy-i-hexyl-5- (3'-οχο-1 ^I -octen- (E) ~ yl) -2-pyrrolidinone (degree of purity = 99 %) were obtained.

Yield:. 89 ^.

IR spectrum (CHCl ₃ ): CO (ester) at 1725 cm " ¹

CO (amide and -CH = CH-CO) at 1675 cm " ¹ C = C at 1630 cm" * ¹

NMR Spectrum (CDCl ₅ ): & = 0.9 ppm (CH ₃ )

= 1.25 ppm (CH ₃ -ESter)

= 1.4 ppm (C ₁₁ N ₂ )

- 4.2 ppm (CH ₂ -O)

= 6.2 and 6.7 BPM (-CH = CH-CO)

e) DL-i ^ -Carboethoxy-1-hexyl-5- (3'-hydroxy-1'-octen- (E) -yl) -2-pyrrolidinone or DL-8-aza-11-deoxy-PGE ₁ - ethyl ester

A solution of 3.65 g (0.01 mol) of the above prepared DL- u: · -Carboethoxy-1-hexyl-5- (3 '-oxo-1 ^f -octen- (E) -yl) -2- pyrrolidinones in 150 ml of anhydrous dirnethoxyethane was cooled to ^{0 ° C.} To this solution, 0.700 g of sodium borohydride was added in small portions, and the resulting mixture was allowed to react at 3 ° C. for 2 hours. Then 10 ml of ice water and then 20 ml of a 2% tartaric acid solution were added. The mixture was extracted with methylene chloride and the organic phase was washed several times with pure water to remove the traces of dimethoxyethane and then washed again with water saturated with sodium chloride. After drying, the solvents were removed in vacuo to give an oily residue which contained the desired product in a purity of 98.8 % .

In this way, DL-α-carboethoxy-1-hexyl-5- (3'-hydroxy-1'-octen-(E) -yl) -2-pyrrolidinone was obtained.

609841/0989

Rf value = 0.33 (thin layer chromatography with acetone and methylene chloride in a ratio of 20:80 as solvent)

IR spectrum (CHCl ₃ ): OH at 3420 cm " ¹

CO (ester) at 1730 cm " ¹ CO (amide) at ί670 cm" ¹

NMR Spectrum (CDCl ₇ ): S = 4.15 ppm (0-CH ₂ )

= 5.65 ppm (jPC = CC ^H )

= 0.9 ppm (CH ₃ ) = 2.3 ppm (OH)

Example 4

For the treatment of ailments of the respiratory tract "an aerosol was produced according to known methods, which contains 2 mg DL-cJ-carboxy-i-hexyl-5- (3'-hydroxy-1 ^f -octen- (E) -yl) - 2-pyrrolidinone together with an inert propellant and 10 g of ethanol.

809841 / Ü389

Claims (1)

where R = hydrogen, methyl or ethyl, in the form of a mixture of isomers or of individual isomers. 2. DL-u; -carboxy-1-hexyl-5- (3'-hydroxy-1'-octen-(E) -yl) -2-pyrrolidinone in the form of a mixture of isomers or of individual isomers. 3. DL-ov-carbomethoxy-i-hexyl-5- (3'-hydroxy-1'-octen-(E) -yl) -2-pyrrolidinone in the form of a mixture of isomers or of individual isomers. 4. DL-w-Carboethoxy-i-hexyl-5- (3 * -hydroxy-1'-octen-(E) -yl) -2-pyrrolidinone in the form of a mixture of isomers or of individual isomers. 5. Process for the preparation of a prostaglandin derivative of Formula: 609841/0989 26121 H. OH characterized in that an ester of the general formula: wherein R ^ is a linear or branched alkyl group with means about 1-7 carbon atoms, is saponified in an alcoholic medium with the aid of an alkali and the resulting alkali metal salt of the compound of formula II is hydrolyzed with the aid of a strong acid. 6. The method according to claim 5, characterized in that methanol is used as the alcoholic medium. 7. The method according to claim 5-6, characterized in that sodium hydroxide is used as the alkali. 8. The method according to claim 5-7, characterized in that hydrochloric acid is used as the strong acid. 9- The method according to claim 5-8, characterized in that as an ester of the general formula II, the methyl or ethyl ester is used. ... 6 0 9841/0989 2612 1 U 10. Process for the preparation of prostaglandin derivatives the general formula: where Rp = methyl or ethyl, characterized in that a ketone of the general Formula: where Rp has the meaning given above, is reduced in an inert medium with a suitable reducing agent. 11. The method according to claim 10, characterized in that sodium borohydride is used as the reducing agent. 12. The method according to claim 10-11, characterized in that dimethoxyethane is used as the inert medium. 13. The method according to claim 10-12, characterized in that the reduction at a temperature of about 0-5 ⁰ C, preferably at about 0 ⁰ C, is carried out. Bü98A1 / 0ü89 ⁴³ - 26121H Pharmaceutical or veterinary composition, characterized in that it is at least as active ingredient a prostaglandin derivative of the general formula: Ic-OR where R = hydrogen, methyl or ethyl, in the form of a mixture of isomers or an active isomer together with a non-toxic excipient. 15. The composition according to claim 14, characterized in that it comprises as active ingredient DL-cu-carboxy-1-hexyl-5- (3'-hydroxy-1 ^! -Octen- (E) ~ yl) -2-pyrrolidinone. 16. The composition according to claim 14, characterized in that it comprises as active ingredient DL- u; -Car'bomethoxy-1-hexyl-5- (3 ^t hydroxy-1'-octen (E) -yl) -2-pyrrolidinone . 17. The composition according to claim 14, characterized in that it is DL-u) -carboethoxy-1-hexyl-5- (3'-hydroxy-1'-octen (E) -yl) -2-pyrrolidinone as the active ingredient includes. 609841/0989