CH623809A5 - Process for the preparation of pyrrolidones - Google Patents

Description

The present invention relates to a process for the preparation of new pyrrolidones of the formula I which are analogous to prostaglandins

N-CH -CH = CH- (CH

H = CH-CH-R

OH

in which

R1 is a straight, branched, saturated or unsaturated aliphatic hydrocarbon radical with up to 10 carbon atoms or a cycloaliphatic hydrocarbon radical with 3 to 7 carbon atoms, which can be substituted by a) a straight or branched alkoxy, alkylthio, alkenyloxy or alkenylthio radical with up to 5 carbon atoms;

b) a phenoxy radical, which in turn may be mono- or disubstituted by an optionally halogen-substituted alkyl group having 1 to 3 carbon atoms, halogen atoms, an optionally halogen-substituted phenoxy radical or an alkoxy radical having 1 to 4 carbon atoms;

c) a furyloxy, thienyloxy or benzyloxy radical, which in turn may be mono- or disubstituted by an optionally halogen-substituted alkyl group having 1 to 3 carbon atoms, halogen atoms or an alkoxy group having 1 to 4 carbon atoms;

d) a trifluoromethyl or pentafluoroethyl group;

e) a cycloalkyl radical having 3 to 7 carbon atoms;

f) a phenyl, thienyl or furyl radical, which in turn can be mono- or disubstituted by an optionally halogen-substituted alkyl group having 1 to 3 carbon atoms, halogen atoms or an alkoxy group having 1 to 4 carbon atoms;

R2 is hydrogen, a straight-chain or branched, saturated or unsaturated aliphatic or cycloaliphatic hydrocarbon radical having up to 6 carbon atoms or an araliphatic hydrocarbon radical having 7 or 8 carbon atoms; and

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n is the number 2, 3 or 4, and the physiologically tolerable metal or amine salts of the acids of the formula I.

The process according to the invention is characterized in that 5. In a compound of the formula XXVIII

N-CH2-CH0

(XVI)

n-ch "-ch = ch- (ch") -coor * 2 2 n

CH2-0R

10 arises,

b4) the aldehyde of the formula XVI obtained with a ylide of the formula XVII

CH = CH-C-R "

(xxviii), 15

(R7) 3P = CH (CH2) nCOOMe

(XVII),

0

wherein R1, R2 and n have the meaning given for the formula I, the ketone carbonyl is reduced and the compound of the formula I is optionally converted into a physiologically tolerable metal or amine salt. The acids obtained can be converted into their esters and the esters into the acids.

The compounds of formula XXVIII can be prepared by bj) in the pyrrolidone of formula II

(ii)

CH2-0H

introduces an alcohol protecting group R6 which can be easily split off under acidic conditions, the compound of the formula XIV

(xiv)

20th

25th

wherein n has the meaning given for the formula I, R7 is the same or different, straight-chain (C1-C4) alkyl radicals or phenyl radicals and Me is an alkali metal atom, to give a compound of the formula XVIII

N-CH2-CH = CH- (CH2) n-C00Me ch2-or

(xviii)

30th

and the corresponding acid of the formula XIX

35

n-ch0-ch = ch- (ch_.) -c00h 2 2 n ch2-or

(xix)

releases, wherein in the formulas XVIII and XIX n has the meaning given for the formula I, or

45 b4 ') the protected pyrrolidone of the formula XIV is deprotonated with a base on nitrogen and the resulting anion with a carboxylic acid derivative of the formula XII

CH2-0R

receives,

b2) the pyrrolidone of the formula XIV is deprotonated with a base on nitrogen and the anion formed with an allyl halide to give the pyrrolidone of the formula XV

N-CK2-CH = CH2

(XV)

CH2-0RU

implements.

b3) the pyrrolidone of the formula XV thus obtained is subjected to ozonolysis, an aldehyde of the formula XVI

50 Y-CH2-CH = CH- (CH2) n-COOR2 (XII),

in which R2 is hydrogen, and a compound of the formula XIX is formed,

bs) the compound of the formula XIX obtained in the corresponding 55 ester of the formula XX

N-CH2-CH = CH- (CH2) n-C00R '

60

65

CH2-0R

(XX),

wherein R2 and n have the meaning given for formula I, transferred, or

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4th

b5 ') the protected pyrrolidone of the formula XIV is deprotonated with a base on nitrogen and the resulting anion is reacted with a carboxylic acid derivative of the formula XII, a compound of the formula XX being formed directly,

b6) splitting off the protective group R6 in the compound of the formula XX obtained under acidic conditions, an alcohol of the formula XXI

arises, and from it the underlying acid of formula XXVI

N-CH2-CH = CH ~ (CH2) n-COOH

-CH2-CH = CH- (CHg) n-C00RÉ

CH20H

xxvi ch2-0h xxi in which R2 and n have the meaning given for the formula I, arises and then, if desired, releases the underlying acid, or b6 ') carries out the esterification of a compound of the formula XIX and the removal of the protective group R6 in one step, or b6 ") the pyrrolidone of the formula II is deprotonated on a nitrogen with a base and the anion formed is converted directly with a carboxylic acid derivative of the formula XII to a compound of the formula XXI, or b61) the pyrrolidone of the formula II is deprotonated on a nitrogen with a base and the anion formed is reacted with an allyl halide, a compound of the formula XXII

N-CH2-CH = CH2

releases and, if desired, converts this into an ester of the formula XXI, in compounds of the formulas XXV and XXVI n having the meaning given for the formula I, or 15 b63 ') deprotonating the pyrrolidone of the formula II with a base on nitrogen and the anion formed with a carboxylic acid derivative of the formula XII, in which R2 is hydrogen, or b63 ") splits off the protective group R6 from a compound of the formula XIX, a compound of the formula XXVI being formed,

b7) the alcohol of the formula XXI obtained is oxidized, an aldehyde of the formula XXVII

- 25th

30th

N-CH2-CH = CH- (CH2) nC00R £

(XXVII),

CHO

xxii ch20h emerges,

b62) the compound of formula XXIII thus obtained is subject to ozonolysis, a compound of formula XXIII, which can also be present in the tautomeric ring-closed form XXIV,

"ch2-ch0

ch2-oh in which R2 and n have the meaning given for the formula I, is obtained and, if desired, the underlying acid of the formula XXVII (R2 = H) is released therefrom,

b8) the aldehyde of the formula XXVII obtained with a phosphonate of the formula V

• 0

40 4 II 1

(R 0) 2-P-CH2-C-RX (V),

fi reacts, a compound of the formula XXVIII

N-CH2-CH = CH- (CH2) n-C00R

50

xxiii xxiv results, or b62 ') splits off the protective group R6 from a compound of the formula XVI, the compound of the formula XXIII (or XXIV) likewise being formed,

b63) the compound of the formula XXIII (or XXIV) is reacted with a ylide of the formula XVII, a compound of the formula XXV

N-CH2-CH = CH- (CHg) n ~ COOMe

55

\ 1

CH = CH-C-R

II

0

(XXVIII),

wherein R1, R2 and n have the meaning given for formula I, or b8 ') a compound of formula X

60

65

-NH

(X),

CH2-0H

xxv

CH = CH-C-R "

s

5

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deprotonated with a base on nitrogen and the anion formed is reacted directly with a carboxylic acid derivative of the formula XII to give a compound of the formula XXVIII,

b71) oxidizes a compound of the formula XXVI, an aldehyde of the formula XXVII, in which R2 is hydrogen, is formed and, if desired, converts it into the ester of the formula XXVII,

b8i) reacting an aldehyde of the formula XXVII, in which R2 is hydrogen, with a phosphonate of the formula V, a compound of the formula XXVIII (R2 = H) being formed and, if desired, converting it into an ester of the formula XXVIII, or b8i ') a compound of the formula X is deprotonated with a base on nitrogen and the anion formed is reacted directly with a carboxylic acid derivative of the formula XII (R2 = H) to give a compound of the formula XXVIII (R2 = H).

Among the meanings given for the substituents R1, R2 and n, the following are preferred:

For R1: a straight or branched, saturated or unsaturated aliphatic hydrocarbon residue with up to 7 carbon atoms or a cycloaliphatic hydrocarbon residue with 5 to 7 carbon atoms, which can be substituted by a) a straight or branched alkoxy, alkylthio, alkenyloxy or alkenylthio residue 1 to 4 carbon atoms,

b) a phenoxy radical, which in turn can be mono- or disubstituted by an alkyl group having 1 to 3 carbon atoms, the trifluoromethyl group, halogen atoms, an optionally halogen-substituted phenoxy radical or an alkoxy radical having 1 or 2 carbon atoms,

c) a thienyloxy or benzyloxy radical, which in turn can be mono- or disubstituted by an alkyl group having 1 to 3 carbon atoms, the trifluoromethyl group, halogen atoms or an alkoxy group having 1 or 2 carbon atoms,

d) a trifluoromethyl group e) a cycloalkyl radical with 5 to 7 carbon atoms,

f) a phenyl or thienyl radical, which in turn can be mono- or disubstituted by an alkyl group having 1 to 3 carbon atoms, the trifluoromethyl group, halogen atoms or an alkoxy group having 1 or 2 carbon atoms,

for R2: a straight-chain or branched alkyl radical with 1 to 6 carbon atoms, a straight-chain or branched alkenyl radical with 2 to 4 carbon atoms, a cycloalkyl radical with 5 or 6 or an aralkyl radical with 7 or 8 carbon atoms.

In particular, the following meanings are preferred: For R1: a straight or branched alkyl radical with 1 to 7 carbon atoms, a straight-chain or branched alkenyl radical with 3 to 5 carbon atoms or a cycloalkyl radical with 5 to 7 carbon atoms, which can be substituted by:

a) a straight or branched alkoxy, alkylthio, alkenyloxy or alkenylthio radical having 1 to 3 carbon atoms,

b) a phenoxy radical, which in turn may be mono- or disubstituted by a methyl, trifluoromethyl or methoxy group, chlorine, fluorine or a phenoxy radical optionally substituted by chlorine or fluorine,

c) a thienyloxy or benzyloxy radical, which may be mono- or disubstituted in the nucleus by a methyl, trifluoromethyl or methoxy group, chlorine or fluorine,

d) a trifluoromethyl group e) a cycloalkyl radical with 5 to 7 carbon atoms,

f) a phenyl or thienyl radical, which may be mono- or disubstituted by a methyl, trifluoromethyl or methoxy group, chlorine or fluorine, and for R2: a straight-chain alkyl radical with 1 to 6 carbon atoms, a branched alkyl radical with 3 to 5 carbon atoms , a straight-chain alkenyl radical with 2 to 4 carbon atoms, the cyclopentyl and cyclohexyl and the benzyl radical.

n is preferably the number 3.

The hydroxymethylpyrrolidone of formula II used as starting material for the preparation of the compounds of formula XXVIII can be prepared by methods known from the literature [J. Amer. Chem. Soc. 74, 851 (1952)].

The procedure is to reflux glutamic acid in the presence of an alcohol ROH and an acid catalyst for a few hours, the 5-alkoxycarbonyl-pyrrolidone-2 of the formula XXIX resulting coor

For this implementation, the use of conc. Sulfuric acid as a catalyst and n-butanol as an alcohol component, since the water of reaction can be separated off during the reaction by means of a water separator.

The conversion of XXIX into II by catalytic hydrogenation is also described in J. Amer. Chem. Soc. 74, 851 (1952). Numerous metals and noble metals such as e.g. B. Raney nickel, copper chromium oxide and ruthenium oxide can be used on carbon. The hydrogenations are carried out consistently at 100-250 ° C, preferably at 140-180 ° C, and 150-250 atü in a suitable solvent. Preferred solvents are alcohols such as methanol, ethanol or isopropanol or ethers such as tetrahydrofuran and dioxane.

The above-mentioned process for the preparation of the compound of the formula XXVIII starts from 5-hydroxymethylpyrrolidone-2 of the formula II. It begins with the introduction of the alcohol protecting group R6, whereby compounds of the formula XIV are formed.

Protecting group R6 for the hydroxymethylpyrrolidone are primarily those which can be split off again under mild reaction conditions, for example by acid hydrolysis or by hydrogenation. The allyl, benzyl, tert-butyl and chloromethyl radical and enol ether groups in particular meet this condition [J. Org. Chem. 38 (1973) 3224; Tetrah. Lett. (1972) 107].

The alcohol group can also be protected by acyl groups, the reaction with acetic anhydride in pyridine at -10 to + 20 ° C. having proven successful.

Preferred is the formation of acetals, which by reacting the alcohol of formula II with enol ethers, such as. B. 2,3-dihydropyran, ethyl vinyl ether or methyl isopropenyl ether, can be prepared in an aprotic solvent in the presence of a catalytic amount of a strong acid. As acids, mineral acids, such as. As hydrochloric acid, sulfuric acid or phosphorus oxychloride, Lewis acids, such as. B. boron trifluoride etherate, or organic acids such as p-toluenesulfonic acid or trifluoroacetic acid.

Aliphatic or aromatic hydrocarbons, such as. As pentane or benzene, or halogenated hydrocarbons, such as. B. chloroform, methylene chloride,

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6

Nitriles such as B. acetonitrile, or ether, such as. B. diethyl ether or dioxane, proven. The reaction is preferably carried out at -10 to + 60 ° C. The reaction times can range from 1 hour to about 24 hours. To isolate the compounds of formula XIV, the reaction mixture is shaken with a sufficient amount of an acid scavenger, preferably with saturated, aqueous sodium bicarbonate solution, or, if one wishes to work anhydrous, e.g. B. with triethylamine, the organic phase dries with sodium sulfate and cleans the product after removal of the solvent by high vacuum distillation or by means of column chromatography.

The subsequent alkylation of the pyrrolidones of the formula XIV with an allyl halide of the formula XV can be carried out by customary methods. The procedure is to use a suitable base, such as. B. sodium or potassium hydroxide, sodium or potassium amide, sodium hydride, potassium tert-butoxide, lithium diisopropylamide or lithium cyclo-hexyl-isopropylamide, the nitrogen deprotonated and then the alkylating agent, dissolved in bulk or the solvent in question, is added.

Allyl chloride or allyl bromide are the main allyl halides.

The reaction of the base with the compounds of the formula XIV is advantageously carried out with the exclusion of air and moisture because of the sensitivity to air and moisture of the bases and the carbanions formed. Aprotic polar liquids are particularly suitable as solvents which still have a sufficient solvent power even at low temperatures and which are inert under the reaction conditions. If necessary, mixtures of two or more solvents are used to lower the solidification point. Z are preferred. B. ether, such as dimethyl ether, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether, also dimethylformamide, dimethyl sulfoxide or toluene. The reaction temperatures are expediently between -30 and + 80 ° C, preferably between -10 and + 50 ° C, in particular between 0 ° C and room temperature. The reaction is generally carried out in such a way that, with stirring, a solution of the pyrrolidone of the formula XIV is added to a frozen solution of the base in one of the solvents mentioned in such a way that the temperature range desired for the reaction is maintained. The union of the components can also take place in the reverse order.

The allyl halide is then again generally added to the frozen solution thus obtained in such a way that the temperature range of the reaction mixture is not substantially exceeded by the exothermic reaction.

After the addition has ended, the mixture is generally stirred for a further 12 to 12 hours and then worked up.

Working up can be carried out, for example, by adding a certain amount of water to the reaction mixture, separating the organic phase, extracting the aqueous phase several times with an organic solvent and drying and concentrating the combined organic phases. In a few cases, the residue can be purified by high vacuum distillation, but in most cases by column chromatography. However, the products are often so pure that cleaning is not necessary.

The conversion of the olefins of the formula XV into the aldehydes of the formula XVI by ozonolysis can be carried out analogously to the literature [Chem. Rev. 58, 990 (1958), Tetrah. Lett. 36, 4273 (1966)] in the following manner.

The olefins are, optionally with the exclusion of moisture, in a certain amount of methanol, which may also contain a halogenated hydrocarbon such as. B. methylene chloride is added, dissolved. The equivalent amount of ozone is introduced into this solution at temperatures between -100 and -50 ° C, preferably at -70 ° C. A small excess of ozone has no influence on the yield. Then the excess ozone is displaced by an inert gas, dimethyl sulfide is added to reduce the ozonolysis products and the mixture is stirred at −10, 0 and 20 ° C. for about an hour.

To isolate the aldehydes, the solutions are concentrated in vacuo at the lowest possible temperatures, the residue is optionally treated with saturated sodium bicarbonate solution and the product is then extracted with a suitable solvent, preferably benzene, or the crude product is chromatographed directly.

The aldehydes are either directly or after prior purification, e.g. by column chromatography, used for the subsequent Wittig reaction.

The compounds of the formula XIX can be obtained by reacting a phosphonium ylide of the formula XVII, in which the radical R7 is preferably phenyl, with the aldehydes of the formula XVI in a suitable solvent. The phosphonium ylides and the phosphonium salts on which they are based are prepared according to analogous procedures described in the literature, [J. Amer. Chem. Soc. 91, 5675 (1969)].

For ylide production, inorganic bases, such as. As sodium hydride, sodium amide, lithium amide or potassium tert-butoxide, or organic bases, such as. B. alkali metal organic compounds such. As lithium butyl, lithium diisopropylamide or the sodium salt of dimethyl sulfoxide can be used.

Suitable solvents are, for example, ethers such as diethyl ether, tetrahydrofuran, diethylene glycol dimethyl ether, di-lower alkyl sulfoxides such as dimethyl sulfoxide or amides of carboxylic acids such as dimethylformamide, dimethylacetamide.

The preferred solvent is dimethyl sulfoxide. In particular, the sodium salt of dimethyl sulfoxide is used as the base. Under these conditions, cis-double bonds are preferably formed.

The preparation of the ylide and the subsequent reaction with the aldehyde is advantageously carried out in a one-pot reaction.

The procedure is as follows, for example:

The solution of the phosphonium salt is added at room temperature with the exclusion of moisture and under inert gas to an equivalent of a base which is also dissolved in an aprotic solvent, usually dimethyl sulfoxide. After stirring for about an hour, a solution of 0.30 to 0.95 equivalents of the aldehyde is added. The reaction is complete after 2-24 hours. It is acidified with a mineral acid at -5 to + 5 ° C, the acid extracted from the reaction mixture with a suitable solvent, such as. B. ether, methylene chloride or benzene, dries the organic phase and concentrates. In order to separate by-products and the phosphine oxide, the acid is converted back into its alkali metal salt and the aqueous phase is extracted with a suitable solvent. The carboxylic acids of the formula XIX are then isolated from the aqueous phase by renewed acidification and extraction with a suitable solvent.

To separate the triphenylphosphine oxide and the diphenyl-cj-hydroxycarbonylalkylphosphine oxide formed during the hydrolysis of the excess ylide, one can also proceed by dissolving the raw material in ether, preferably diethyl ether, and crystallizing the phosphine oxides at temperatures below -20 ° C. leaves. The desired reaction products remain dissolved under these conditions and are separated from the impurities with the solvent.

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The esters of the formulas XX and XXI can be prepared by analogous processes described in the literature. So you can z. B. esterify the acids with the alcohol in question in the presence of a strong acid such as sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid, etc., optionally 5 in the presence of a tractor for the water formed. The alcohol is used in excess. Under these conditions, the protective group R6 is simultaneously split off, and the compounds of the formula XXI are obtained directly. In contrast, the protective group R6 is not attacked in the presence of carbodiimides in an esterification with Al-10 alcohols. The reaction with diazoalkanes, preferably diazomethane, in an inert solvent also leads to the same result, as does the reaction of the sodium salt of the acid with an alkyl halide in a polar solvent, e.g. Dimethylformamide.

The elimination of the protective group R6 and the esterification can, as explained above, be carried out in one step. Otherwise the esters of formula XX are used in the presence of acidic catalysts in an alcohol such as methanol, ethanol or ch9-ch0 in order to remove the protective group

yn / 2

\ 3

. CH2-0ir xvi

Isopropanol heated to 50 to 80 ° C for about 30 minutes. Then neutralized and isolated the compound of formula XXI by extraction with a suitable solvent, such as. B. methylene chloride, chloroform or diethyl ether.

If the alcohol protecting group is removed from XIX in a mainly aqueous medium using the acidic catalysts mentioned above, the hydroxycarboxylic acids XXVI are obtained, which in turn can be esterified or can also be used for the further reaction steps.

The compounds XIX, XX, XXI and XXVI can also be obtained if the compounds XIV or II are subjected to an alkylation with a carboxylic ester derivative XII or a carboxylic acid derivative XII (R2 = H). The conditions specified for the alkylation of compounds of the formula XI are applied analogously to these reaction steps.

At room temperature, the aldehydes XVI can cyclize slowly to the lactols XXIV with elimination of the relevant protective group:

xxiv

In general, this cyclization in solvents such as 35 aliphatic or aromatic hydrocarbons such as. As pentane or toluene, halogenated hydrocarbons such. B. chloroform, ethers such. B. diethyl ether, dioxane, or alcohols such as. B. methanol or ethanol with or without an acid catalyst such. B. conc. Carry out sulfuric acid, p-toluenesulfonic acid or boron trifluoride etherate at temperatures between -10 ° C and the boiling point of the solvent.

Compound XXIII or XXIV can also be obtained if the 5-hydroxymethylpyrrolidone-2 (II) is subjected directly to an alkylation reaction with an allyl halide without the introduction of an alcohol protecting group R3. The conditions specified for the conversion of compounds of the formula XI into those of the formula XIII can also be used for the introduction of the allyl radical into (II), of the execution conditions mentioned preferably using potassium hydroxide as the base in dimethyl sulfoxide at temperatures between +10 and + 40 ° C comes into question.

The compound of the formula XXII resulting from this reaction is then accessible to an analogous ozonolysis as described for compounds of the formula XV, 55 giving the corresponding aldehyde XXIII, which, however, is only very little stable in the open form and generally already cyclized to XXIV on working up.

This cyclization can optionally be completed by applying the conditions specified for the conversion of XVI to XXIV. The compounds of the formula XXIII or XXIV are accessible to a corresponding Wittig reaction, as has already been described above for the compounds XVI. The compounds of the formula XXVI are then immediately reached. 65

The conditions already specified for the reaction sequence oxidation, Horner reaction, reduction of the ketone carbonyl to transfer the compound of the formula II or III

in compounds of the formula XIII can also be applied analogously to the reaction of the compounds of the formula XXI or XXVI to the compounds of the formula I. It is therefore irrelevant whether the ester XXI or the free acid XXVI is used or whether an acid is esterified or an ester is saponified to acid in the course of these three stages. However, it has proven useful to carry out a corresponding conversion into different derivatives only on the end product, provided that this is not caused by the reaction conditions used.

An esterification is generally carried out by the methods known from the literature, as have already been described, for example, for converting compounds of the formula XIX into compounds of the formulas XX and XXI.

The reduction of the keto group that can be introduced by the Horner reaction provides a mixture of a and β isomers with respect to the resulting secondary hydroxyl group. The separation into the two antipodes can take place either on the reaction product of the reduction step or after one of the subsequent reaction stages. This means that all reactions that follow the reduction of this ketocarbonyl, e.g. B. Conversion into the free acid or esterification or conversion into metal or amine salts, both on the pure a and β isomers and on a mixture of a and ^ isomers.

If the individual reaction products are not already obtained in pure form so that they can be used for the following reaction step, cleaning by means of e.g. B. column, thin layer or high pressure liquid chromatography.

The compounds of formula I have two asymmetric centers, namely the carbon atom, which is the

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secondary hydroxy group, and the carbon atom adjacent to the nitrogen in the five-membered ring, which corresponds to the 5-position in the pyrrolidone ring.

Since none of the specified reaction routes provides sterically uniform products, the formula I represents all compounds regardless of the steric arrangement on the different carbon atoms. In addition to the two optically isomeric carbon atoms already mentioned above, this also applies to the geometrically isomeric compounds with regard to the two double bonds. In general, however, it can be assumed that the Horner reaction, due to the way the reaction is carried out, mainly results in a trans-linkage and that the corresponding cis product which is formed only to a small extent is removed by chromatographic purification steps. Similarly, the corresponding cis-olefin is mainly formed in the Wittig reaction for the introduction of the carboxyl side chain. Here too, the trans-olefin occurring as a by-product can be separated off by appropriate cleaning operations.

The geometry of the double bond specified in the carboxylic acid derivatives XII is transferred to the later end products by the alkylation step. This means that when the corresponding trans derivative of XII is used, the later end product carries a trans double bond in the carboxyl side chain. The same applies analogously to the use of the cis derivative of XII.

Due to the possibilities for introducing the two double bonds, it can be assumed that the geometry of the two double bonds is uniform. The mixture of two diasteromers present due to the two optically isomeric carbon atoms can be obtained in the case of crystallizable derivatives by fractional crystallization or also with the aid of chromatographic methods, e.g. Separate column, gas, thin layer or medium or high pressure liquid chromatography into the two racemic diastereomers. The racemates are broken down into the optically active compounds by generally customary methods, such as Treatment of the compounds of formula I (R2 = H) with optically active bases such as e.g. Brucine.

In addition to those mentioned in the examples, the following compounds can also be prepared by the processes according to the invention:

l- [6-n-butoxycarbonyl- (Z) -2-hexen-l-yl] -5- [3-hydroxy-

(E) -l-octen-l -yl] pyrrolidone-2 l- [6-n-hexyloxycarbonyl- (Z) -2-hexen-l-yl] -5 - [- 3-hydroxy-

(E) -l-octen-l-yl] pyrrolidon-2 l- [5-ethoxycarbonyl- (Z) -2-penten-l-yl] -5- [3-hydroxy-

(E) -1 -octen-1 -yl] pyrrolidone-2 l- [7-ethoxycarbonyl- (Z) -2-hepten-l-yl] -5- [3-hydroxy-

(E) -1 -octen-1-yl] pyrrolidon-2 l- [6-methoxycarbonyl- (Z) -2-hexen-l-yl] -5- [3-hydroxy-

(E) -1-hexen-1 -yl] pyrrolidon-2 l- [6-methoxycarbonyl- (Z) -2-hexen-l-yl] -5- [3-hydroxy-

(E) -1 -undecen-1 -yl] -pyrrolidone-2 l- [6-methoxycarbonyl- (Z) -2-hexen-lyl -] - 5- [3-hydroxy-

(E, E, E) -1,4,6-octatrien-1-yl] pyrrolidon-2 l- [6-methoxycarbonyl- (Z) -2-hexen-l-yl] -5- [3-hydroxy -

4-methyl- (E) -1-penten-1-yl] -pyrrolidon-2 l- [6-carboxy- (Z) -2-hexen-l-yl] -5- [3-hydroxy-3-cyclo -

pentyl- (E) -1-buten-1-yl] -pyrrolidon-2 l- [6-carboxy- (Z) -2-hexen-l-yl] -5- [3-hydroxy-3-cyclo-

hexyl- (E) -l-buten-l-yl] pyrrolidon-2 l- [6-methoxycarbonyl- (Z) -2-hexen-l-yl] -5- [3-hydroxy-

5-ethoxy- (E) -1-pentene -1 -yl] pyrrolidone-2 l- [6-n-hexyloxycarbonyl- (Z) -2-hexen-l-yl] -5- [3-hydroxy-

6-methylmercapto- (E) -l-hexen-l-yl] pyrrolidon-2 l- [6-carboxy- (Z) -2-hexen-l-yl] -5- [3-hydroxy-5-isobutyl -oxy-4,4-dimethyl- (E) -1-penten-1-yl] -pyrrolidone-2

l- [6-carboxy- (Z) -2-hexen-l-yI] -5- [3-hydroxy-5-allyl-

mercapto-4,4-dimethyl- (E) -1-penten-1-yl] -pyrroldidon-2 l- [6-carboxy- (Z) -2-hexen-l-yl] -5- [3-hydroxy -4- (4-methylphenoxy) - (E) -1-buten-yl] pyrrolidone-2 5 1 - [6-methoxycarbonyl- (Z) -2-hexen-1-yl] -5 - [3 -hydroxy-4- (4-chlorophenoxy) - (E) -butene-l-yl] pyrrolidon-2 l- [5-methoxycarbonyl- (Z) -2-penten-l-yl] -5- [3- hydroxy

4- (4-methoxyphenoxy) - (E) - 1-buten-l-yl] pyrrolidon-2 1 - [6-methoxycarbonyl- (Z) -2-hexen-1-yl] -5- [3-hydroxy -io 4- (4-phenoxyphenoxy) - (E) -l-buten-l-yl] -pyrrolidon-2 l- [6-ethoxycarbonyl- (Z) -2-hexen-l-yl] -5- [3 -hydroxy-

4- (4-chlorophenoxy-phenoxy) -4-methyl- (E) -l-buten-l-yI] pyrrolidone-2

l- [6-ethoxycarbonyl- (Z) -2-hexen-l-yl] -5- [3-hydroxy-l s 4- (3-chlorophenoxy) - (E) -1-buten-1-yl] - pyrrolidon-2 l- [6-iso-propoxycarbonyl (Z) -2-hexen-l-yl] -5- [3-hydroxy-4- (2-chloro-4-methylphenoxy) - (E) - l-buten-l-yl] pyrrolidone-2

1- [6-methoxycarbonyl- (Z) -2-hexen-l-yI] -5- [3-hydroxy-20 4-benzyloxy- (E) -1-buten-1-yl] pyrrolidone-2

1 - [6-Ethoxycarbonyl- (Z) -2-hexen-1-yl] -5- [3-hydroxy-4- (5-methyl-3-thienyloxy) - (E) -l-buten-l-yl ] -pyrrolidone-2

l- [6-ethoxycarbonyl- (Z) -2-hexen-l-yl] -5- [3-hydroxy-25 4- (4,5-dimethyl-3-thienyloxy) - (E) -1-butene l-yl] pyrrolidone-2

l- [5-ethoxycarbonyl- (Z) -2-penten-l-yl] -5- [3-hydroxy-4- (4-fluorobenzyloxy) - (E) -l-buten-l-yl] pyrrolidone- 2 l- [6-carboxy- (Z) -2-hexen-l-yl] -5- [3-hydroxy-4- (3-tri-30 fluoromethylbenzyloxy) - (E) -1-buten-1-yl ] -pyrrolidon-2 l- [6-n-hexyloxy- (Z) -2-hexen-l-yl] -5- [3-hydroxy-4-

(4-methoxybenzyloxy) - (E) -l-buten-l-yl] pyrrolidon-2 l- [6-carboxy- (Z) -2-hexen-l-yl] -5- [3-hydroxy-4 - (2-chloro

4-methyl-benzyloxy) - (E) -1-buten-1-yl] pyrrolidone-2

3 s 1 - [6-carboxy- (Z) -2-hexen-1 -yl] -5- [3 -hydroxy-7-trifluoromethyl- (E) -1 -hepten-1 -yl] -pyrrolidone- 2 l- [6-methoxycarbonyl- (Z) -2-hexen-l-yl] -5- [3-hydroxy-

5-cyclopentyl- (E) -1-penten-1-yl] -pyrrolidon-2 l- [6-methoxycarbonyl- (Z) -2-hexen-l-yl] -5- [4-hydroxy-

40 4-cycloheptyl- (E) -l-buten-l-yl] pyrrolidon-2 l- [6-ethoxycarbonyl- (Z) -2-hexen-l-yl] -5- [3-hydroxy-

4- (4-chlorophenyl) - (E) -l-buten-l-yl] pyrrolidon-2 l- [6-n-butoxycarbonyl- (Z) -2-hexen-l-yl] -5- [3 -hydroxy-

5- (3,4-dichlorophenyl) - (E) -l-pentene-l-yI] pyrrolidon-2 45 l- [6-carboxy- (Z) -2-hexen-l-yl] -5- [ 3-hydroxy-5-

(4-toluyl) - (E) -1-penten-1-yl] -pyrrolidon-2 l- [6-methoxycarbonyl- (Z) -2-hexen-l-yl] -5- [3-hydroxy-

• 4- (5-methyl-3-thienyl) - (E) -l-buten-l-yl] pyrrolidon-2 l- [6-carboxy- (Z) -2-hexen-l-yl] -5 - [3-hydroxy-4,4-dimethyl-50 5- (4-methoxyphenyl) - (E) -l-penten-l-yl] pyrrolidone-2 1 - [6-n-butoxycarbonyl- (E) - 2-hexen-1 -yl] -5 - [3 -hydroxy-

(E) -l-octen-1-yl] pyrrolidon-2 l- [6-n-hexyloxycarbonyl- (E) -2-hexen-l-yl] -5- [3-hydroxy- (E) -l -octen-l -yl] -pyrrolidon-2 55 l- [5-ethoxycarbonyl- (E) -2-penten-l-yl] -5- [3-hydroxy- (E) -1 -octen-1 -yl ] -pyrrolidon-2 l- [7-ethoxycarbonyl- (E) -2-hepten-l-yl] -5- [3-hydroxy-

(E) -1 -octen-1 -yl] pyrrolidon-2 l- [6-methoxycarbonyl- (E) -2-hexen-l-yl] -5- [3-hydroxy-60 (E) -1 - hexen-1-yl] pyrrolidone-2

l- [6-methoxycarbonyl- (E) -2-hexen-l-yl] -5- [3-hydroxy-

(E) -1 -undecen-1-yl] pyrrolidone-2 l- [6-methoxycarbonyl- (E) -2-hexen-l-yl] -5- [3-hydroxy- (E, E, E) -l, 4,6-octatien-l-yl] pyrrolidone-2 65 l- [6-methoxycarbonyl- (E) -2-hexen-l-yl] -5- [3-hydroxy-4-methyl- ( E) -l-penten-l-yl] pyrrolidone-2 l- [6-carboxy- (E) -2-hexen-l-yl] -5- [3-hydroxy-3-cyclopentyl- (E ) -1-butene-1-butene-1 -yl] pyrrolidone-2

623 809

I - j 6-carboxy- (E) -2-hexen-1-yl] -5- [3-hydroxy-3-cyclo-

hexyl- (E) -1-buten-1 -yl 1-pyrrolidon-2 l- [6-methoxycarbonyl- (E) -2-hexen-l-yl] -5- [3-hydroxy-

5-ethoxy- (E) -1-penten-1-yl] -pyrrolidon-2 l- [6-n-hexyloxycarbonyl- (E) -2-hexen-l-yl] -5- [3-hydroxy-

6-methylmercapto- (E) -1-hexen-1-yl] pyrrolidon-2 l- [6-carboxy- (E) -2-hexen-l-yl] -5- [3-hydroxy-5-isobutyl -

oxy-4,4-dimethyl- (E) -1-penten-1-yl] -pyrrolidon-2 l- [6-carboxy- (E) -2-hexen-l-yl] -5- [3-hydroxy -5-aIlyl-

mercapto-4,4-dimethyl- (E) -l-penten-l-yl] pyrrolidone-2 l- [6-carboxy- (E) -2-hexen-l-yl] -5- [3-hydroxy -4-

(4-methylphenoxy) - (E) -l-buten-l-yl] pyrrolidon-2 l- [6-methoxycarbonyl- (E) -2-hexen-l-yl] -5- [3-hydroxy-4 - (4-chlorophenoxy) - (E) -1-buten-1-yl] -pyrrolidon-2 l- [5-methoxycarbonyl- (E) -2-pentene-l-yl] -5- [3-hydroxy-

4- (4-methoxyphenoxy) - (E) -1-buten-1-yl] pyrrolidone-2 l- [6-methoxycarbonyl- (E) -2-hexen-l-yI] -5- [3-hydroxy -

4- (4-phenoxyphenoxy) - (E) -1-buten-l-yl] pyrrolidon-2 l- [6-ethoxycarbonyl- (E) -2-hexen-l-yI] -5- [3-hydroxy -4- (4-chlorophenoxyphenoxy) -4-methyl- (E) -l-buten-l-yI] pyrrolidone-2

1 - [6-ethoxycarbonyl- (E) -2-hexen-1 -yl] -5- [3 -hydroxy-4- (3-chlorophenoxy) - (E) -l-buten-l-yl] pyrrolidone- 2 l- [6-iso-propoxycarbonyl- (E) -2-hexen-l-yl] -5- [3-hydroxy-4- (2-chloro-4-methylphenoxy) - (E) -1 - butene -1 -yl] pyrrolidone-2

l- [6-methoxycarbonyl- (E) -2-hexen-l-yl] -5- [3-hydroxy-

4-benzyloxy- (E) -l-buten-l-yl] pyrrolidon-2 l- [6-ethoxycarbonyl- (E) -2-hexen-l-yl] -5- [3-hydroxy-4- ( 5-methyl-3-thienyloxy) - (E) -1-buten-1-yl] pyrrolidone-2

l- [6-ethoxycarbonyl- (E) -2-hexen-l-yl] -5- [3-hydroxy-4- (4,5-dimethyl-3-thienyloxy) - (E) -l-buten-l -yI] -pyrrolidone-2

1 - [5-Ethoxycarbonyl- (E) -2-penten-1-yI] -5- [3 -hydroxy-4- (4-fluorobenzyloxy- (E) -1-buten-1-yl] pyrrolidone-2 l- [6-carboxy- (E) -2-hexen-l-yl] -5- [3-hydroxy-4- (3-tri-

fluoromethylbenzyloxy) - (E) -l-buten-l-yl] pyrrolidone-2 1 - [6-n-hexyloxy- (E) -2-hexen-1-yl] -5 - [3 -hydroxy- 4-

(4-methoxy-benzyloxy) - (E) -1-buten-1-yl] pyrrolidon-2 l- [6-carboxy- (E) -2-hexen-l-yl] -5- [3-hydroxy -4- (2-chloro-

4-methyl-benzyloxy) - (E) -1-buten-1-yl] -pyrrolidon-2 l- [6-carboxy- (E) -2-hexen-l-yl] -5- [3-hydroxy- 7-trifluoro

methyl- (E) -1 -hepten-1-yl] pyrrolidon-2 l- [6-methoxycarbonyl- (E) -2-hexen-l-yl] -5- [3-hydroxy-

5-cyclopentyl- (E) -l-penten-l-yl] pyrrolidon-2 l- [6-methoxycarbonyl- (E) -2-hexen-l-yl] -5- [3-hydroxy-

4-cycloheptyl- (E) -1-buten-1-yl] pyrrolidone-2 1 - [6-ethoxycarbonyl- (E) -2-hexen-1-yl] -5- [3-hydroxy-

4- (4-chlorophenyl) - (E) -l-buten-l-ylj-pyrrolidon-2 l- [6-n-butoxycarbonyl- (E) -2-hexen-l-yl] -5- [3- hydroxy

5- (3,4-dichlorophenyl) - (E) -l-penten-l-yl] -pyrrolidon-2 l- [6-carboxy- (E) -2-hexen-l-yI] -5- [3 -hydroxy-5-

(4-toluyl) - (E) -l-penten-l-yl] pyrrolidon-2 l- [6-methoxycarbonyl- (E) -2-hexen-l-yl] -5- [3-hydroxy-

4- (5-methyl-3-thienyl) - (E) -l-buten-l-yl] -pyrrolidon-2 l- [6-carboxy- (E) -2-hexen-l-yl] -5- [3-hydroxy-4,4-dimethyl-5- (4-methoxyphenyl) - (E) -l-penten-l-yl] pyrrolidone-2

The compounds produced according to the invention are characterized on the one hand by spasmogenic, on the other hand by spasmolytic, e.g. B. bronchodilator, further hypotensive, gastric secretion-inhibiting and abortive properties. They can therefore be used as medicines.

The compounds of formula 1 prepared according to the invention can be used as free acids, in the form of their physiologically acceptable inorganic or organic salts or as

Esters of aliphatic, cycloaliphatic or araliphatic alcohols are used.

Suitable organic salts are, for example, alkali metal, alkaline earth metal or ammonium salts, while those which are derived from primary, secondary or tertiary amines can be used for the formation of salts with organic bases, and further hydrophilic groups may also be present in the amine . There are, for example, salts with methyl, triethyl, benzyl, phenylethyl, allylamine or even with piperidine, pyrrolidine, morpholine or with ethanolamine, triethanolamine, tromethamine, and the esters of lower aliphatic alcohols such as methyl are preferred as esters -, Ethyl, propyl, butyl or hexyl esters and benzyl esters.

15 acids and salts or esters can be in the form of their aqueous solutions or suspensions or dissolved or suspended in pharmacologically acceptable organic solvents such as mono- or polyhydric alcohols such as. As ethanol, ethylene glycol or glycerin, oil such as. B. sun-20 flower oil or cod liver oil, ethers such. B. diethylene glycol di-methyl ether or polyethers such. B. polyethylene glycol or in the presence of other pharmacologically acceptable polymer carriers such. B. polyvinyl pyrrolidone are used.

25 The usual galenical infusion or injection solutions and tablets as well as locally applicable preparations such as creams, emulsions, suppositories, in particular also aerosols, can be considered as preparations.

The compounds prepared according to the invention are 30 for use in aerosol form with customary, physiologically acceptable, taste-irritating solvents such as. B. water or ethanol in solution or z. B. in lower alkyl esters of higher fatty acids such as myristinic acid, optionally with the addition of 35 surfactants as stabilizers, for. B. sorbitan or pentaerythritol fatty acid ester, suspended and filled together with a conventional inert propellant in aerosol containers. However, the preparations mentioned can also be applied with a conventional atomizing device using compressed air 40.

Another application of the new compounds is in the combination with other active ingredients. In addition to other suitable substances, these include:

Diuretics such as B. furosemide, antidiabetic agents, such as. B. 45 glycodiazine, tolbutamide, glibenclamide, phenformin, Bufor-min, metformin, or circulatory agents in the broadest sense, such as. B. coronary dilators such as chromonar or prenylamine, hypotensive substances such as reserpine, a-methyl-dopa or clonidines or antiarrhythmics, lipid-lowering agents or geriatrics and other metabolically active preparations, psychotropic drugs, such as. B. chlordiazepoxide, diazepam or meprobamate, as well as vitamins, or other prostablandins or prostaglandin-like compounds and also prostaglandin antagonists.

For the different possible indications, 55 following unit or daily doses can be considered:

60

Bronchodilator effect (as aerosol): unit dose: 0.3-3000 / ig 1 preferred: 3 - 600 fig j

Daily dose: 0.3-30 mg

(per spray)

Hypotensive effect:

65

orally

Unit dose:

prefers:

Daily dose:

Unit dose:

prefers:

Daily dose:

5-5000 fig 5- 500 fig 5- 50 mg

1-100 mg 1-50 mg 10-500 mg parenterally (IV)

orally

623 809

The doses when used against gastrointestinal disorders correspond to those mentioned for use as an antihypertensive agent.

Reference examples A, B and C relate to the production of starting materials and intermediate products.

Reference Example A Compounds of Formula XIX

ai) 5-tetrahydropyran-2-yl-oxy-methyl-pyrroli-don (XIV)

0.1 mol of 5-hydroxymethyl-pyrrolidone together with 0.15 mol of dihydropyran and 0.25 g of p-toluenesulfonic acid in 150 ml of dioxane are heated to reflux for 4 hours. The acid is then neutralized with triethylamine and the solvent is removed by vacuum distillation.

Chromatographic purification on silica gel with toluene / ethyl acetate / methanol 5: 4: 1 as eluent.

NMR: Ò = 6.5 ppm (broad singlet) NH 1 Prot.

ô = 4.6 ppm (broadened singlet) O-CH-O 1 Prot.

bj) 1-Allyl-5- (tetrahydropyran-2-yl-oxy-methyl) -pyrrolidon-2 (XV)

0.25 mol of 5- (tetrahydropyran-2-yl-oxy-methyl) -pyrroli-don-2 are dissolved in 150 ml of dried dimethyl sulfoxide and mixed with 0.3 mol of powdered potassium hydroxide. With ice cooling, 0.3 mol of allyl bromide is added dropwise within 30 minutes. The mixture is stirred for a further 2 hours, during which the reaction solution warms to room temperature. Water is added and the product is extracted with ether, dried, concentrated and distilled.

Chromatography on silica gel. Eluent: chloroform / acetone 8: 2. NMR: ò = 5.0-6.2 ppm (several multi-plates) CH = CH2 3 prot.

ò = 4.7 ppm (broadened singlet) O-CH-O 1 Prot. IR: 1680 cm-1 vC = 0

Ci) 1-Formylmethyl-5- (tetrahydropyran-2-yl-oxy-methyl) -pyrrolidon-2 (XVI)

0.02 mol of l-allyl-5- (tetrahydropyran-2-yloxymethyl) pyrrolidone-2 are dissolved in 100 ml of methylene chloride and mixed with 10 ml of methanol. The mixture is cooled to -78 ° C. and ozone is introduced at this temperature until the blue solution no longer discolors. The reaction mixture is warmed to -20 ° C. 0.2 mol of dimethyl sulfide is added dropwise at this temperature. The cooling bath is then removed and the reaction flask is left at room temperature for 2 hours. It is concentrated and then chromatographed.

(Silica gel, eluent chloroform / acetone 8: 2)

NMR: ò = 9.6 ppm (s) CHO 1 Prot.

à = 4.6 ppm (broadened sing.) O-CH-O 1 Prot.

d,) (XIX)

1. l- (5-Carboxy- (Z) -2-penten-l-yl) -5- (tetra-hydropyran-2-yl-oxy-methyl) -pyrrolidon-2

0.1 mol of sodium hydride are stirred in 45 ml of dimethyl sulfoxide at 60 ° C. until the evolution of hydrogen has ended. Then it is cooled to room temperature and 0.05 mol of 3-carboxy-butyl-triphenylphosphonium bromide dissolved in 40 ml of dimethyl sulfoxide is added. The mixture is stirred at room temperature for 30 minutes. Then 0.02 mol of l-formylmethyl-5- (tetrahydropyran-2-yl-oxymethyl) -pyrroli-don-2 dissolved in 25 ml of dimethyl sulfoxide is allowed to run in and the mixture is then heated to 50 ° C. At this temperature, the mixture is stirred for 3 hours.

After cooling to 10 ° C., 400 ml of water are added and the pH is adjusted to 2 using 5% aqueous sodium hydrogen sulfate solution. One breathes out again, dries and concentrates. The residue is purified chromatographically on silica gel. Eluent chloroform / methanol 95: 5. NMR: ò = 9.0 ppm (broad singlet) COOH 1 Prot. Ò = 5.2-5.7 ppm (m) CH = CH 2 Prot.

1

I.

ò = 4.62 ppm (broadened singlet) O — CH — O 1 Prot.

2. l- (6-Carboxy- (Z) -2-hexen-l-yl) -5- (tetra-hydropyran-2-yl-oxy-methyl) -pyrrolidon-2

Reaction analogous to the above-mentioned protocol from l-formylmethyl-5- (tetrahydropyran-2-yl-oxy-methyl) -pyrroli-don-2 and 4-carboxy-butyl-triphenylphosphonium bromide chromatography on silica gel. Elute with chloroform / methanol 95: 5.

NMR: ó = 9.1 ppm (broad singlet) COOH 1 prot. Ò = 5.2-5.7 ppm (m) ÇH = ÇH 2 prot.

ó = 4.64 ppm (broadened sing.) O-CH-O 1 Prot.

3. 1- (7-carboxy- (Z) -2-hepten-l-yl) -5- (tetra-hydropyran-2-yl-oxy-methyl) -pyrrolidon-2

From l-formyl-5- (tetrahydropyran-2-yl-oxy-methyl) -pyrro-lidon-2 and 5-carboxy-pentyl-triphenylphosphonium bromide analogous to the above-mentioned regulation Chromatography on silica gel. Solvent: chloroform / methanol 95: 5.

NMR: ò = 9.0 ppm (broad singlet) COOH 1 prot. (3 = 5.1-5.8 ppm (m) CH = CH 2 prot.

<3 = 4.60 ppm (s) -O-CH-O 1 Prot.

IR: 1680 cm-1 vC = 0 1700 cm-1 vC-O an) 1- (6-carboxy- (Z) -2-hexen-l-yl) -5- (tetra-hydropyran-2-yl-oxymethyl ) -pyrrolidone (XIX) From 5- (tetrahydropyran-2-yl-oxy-methyl) -pyrrolidon-2 by alkylation with 6-bromo-(Z) -4-hexen-l-carboxylic acid according to the one given in Example 1 bi) Regulation. See above for physical data.

Reference Example B Compounds of Formula XX

aj) l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- (tetra-hydropyran-2-yl-oxy-methyl) -pyrrolidon-2 (XX)

0.03 mol of l- (6-carboxy- (Z) -2-hexen-l-yl) -5- (tetrahydro-pyran-2-yl-oxy-methyl) -pyrrolidon-2 are dissolved in 75 ml of diethyl ether and mixed with ethereal diazomethane solution until the yellow color remains. Excess diazome-than is destroyed with a trace of glacial acetic acid. The mixture is concentrated and the pure end product is obtained after all solvents have been driven off.

Chromatography on silica gel. Solvent carbon tetrachloride / acetone 7: 3.

NMR: Ò = 5.15-5.70 ppm (m) CH = CH 2 Prot.

ô = 4.7 ppm (broad sing.) O-CH-O 1 Prot. IR: 1680 cm-1 vC = 0 1735 cm "1 vC = 0 an) l- (6-methoxycarbonyl- (Z) -2- hexen-1 -yl) -5- (tetra-hydropyran-2-yl-oxy-methyl) -pyrrolidon-2 (XX)

From 5- (tetrahydropyran-2-yl-oxy-methyl) -pyrrolidon-2 by alkylation with 6-bromo- (Z) -4-hexen-l-carboxylic acid methyl ester according to the procedure given in Example 1 fy). Physical data identical to that given above.

Reference Example C Compounds of Formula XXI

a ^ l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5-hydroxy-methyl-pyrrolidon-2 (XXI)

0.01 mol of l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- (te-trahydropyran-2-yl-oxy-methyl) -pyrrolidon-2 are dissolved in 50 ml of methanol and boiled together with a few granules of p-to-toluenesulfonic acid for 3 hours at reflux. A drop of triethylamine is added to neutralize the acid, the mixture is concentrated and chromatographed. (Silica gel, toluene / ethyl acetate / methanol 5: 4: 1).

NMR: ò = 5.2-5.8 ppm (m) CH = CH 2 Prot.

ò = 4.1 ppm ABX spectrum CH -.- OH ó = 3.7 ppm (s) COOCH,

10th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

623 809

IR:

vC = 0 vC = 0

1680 cm "

1735 cm "1 a": (XXI)

1. 1 - (6-methoxycarbonyl- (Z) -2-hexen-1-yl) -5-hydroxy-methyl-pyrrolidone-2

Treat l- (6-carboxy- (Z) -2-hexen-l-yl) -5- (tetra-hydropyran-2-yl-oxy-methyl) -pyrrolidon-2 in methanol with p-toluosulfonic acid as in Example 3 at). Chromatography and physical data see there.

2. 1 - (6-ethoxycarbonyl- (Z) -2-hexen-1 -yl) -

5-hydroxymethyl-pyrrolidone-2

Analogous to the above rule (ani.) Using ethanol instead of methanol. Chromatography: silica gel, toluene / ethyl acetate / ethanol 5: 4: 1.5.

NMR: Ó = 5.2-5.8 ppm (m) CH = CH 2 Prot.

IR: 1680 cm-1 vC = 0 1730 cm-1 vC = 0

3. l- (7-ethoxycarbonyl- (Z) -2-hepten-l-yl) -5-hydroxy-methyl-pyrrolidon-2

From l- (7-carboxy- (Z) -2-hepten-l-yl) -5- (tetrahydropy-ran-2-yl-oxy-methyl) -pyrrolidon-2 by treatment with ethanol in the presence of p-toluenesulfonic acid analogous to the above regulation (anl.). Chromatography on silica gel with toluene / ethyl acetate / ethanol 5: 4: 1.5 as eluent. NMR: Ò = 5.2-5.85 ppm (m) ÇH = ÇH 2 Prot.

Ò = 1.35 ppm (Z) O-CHo-CH, 3 prot.

IR: 1680 cm-1 vC = 0 1735 cm-1 vC = 0 on: (XXI)

1. 1 - (6-methoxycarbonyl- (Z) -2-hexen- 1-yl) hydroxymethyl-pyrrolidon-2

From 5-hydroxymethyl-pyrrolidone-2 by alkylation with

6-Bromo- (Z) -4-hexen-l-carboxylic acid methyl ester analogous to Example 1 bi).

For cleaning and physical data see above.

2. l- (6-methoxycarbonyl- (E) -2-hexen-l-yl) -

5-hydroxymethyl-pyrrolidone-2

From 5-hydroxymethyl-pyrrolidone-2 by alkylation with

6-bromo- (E) -4-hexen-l-carboxylic acid methyl ester analogous to Example 1 bi).

Chromatography on silica gel, solvent toluene / ethyl acetate / methanol 5: 4: 1.

NMR: ò = 5.2-5.9 ppm (m) CH = CH 2 Prot.

ò = 3.65 ppm (s) COOCH3 IR: 1738 cm "1 i> C = 0 1680 cm-1 vC = 0 aiv) l-allyl-5-hydroxymethyl-pyrrolidone-2 (XXII)

By alkylation of 5-hydroxymethyl-pyrrolidone-2 with allyl bromide analogously to Example 1 bj).

20th

25th

30th

35

40

K,

• p 0.3 mm

161 to 169 ° C

NMR: ó = 5.0-6.3 ppm (several multiplets) ÇH = CH-, 3 prot.IR: 1680 cm-1 vC = 0

bi v) 1-formylmethyl-5-hydroxymethyl-pyrrolidon-2-ó-lactoI (XXIV)

By ozonolysis of l-allyl-5-hydroxymethyl-pyrrole-55 don-2 analogously to the procedure in Example 3 c).

After concentrating the reaction mixture, the crystalline residue is recrystallized from ethanol.

Mp .: 152 to 154 ° C.

b | V) 1-formylmethyl-5-hydroxymethyl-pyrrolidone-60

2-ó-lactol (XXIV)

0.01 mol of I-formylmethyl-5- (tetrahydropyran-2-yl-oxy-methyl) -pyrrolidon-2 are boiled under reflux in 50 ml of ethanol for 7 hours. The reaction product crystallizes when concentrated. Mp .: 151 to 154 ° C. 65

c, v) (XXVI)

1. 1- (5-carboxy- (Z) -2-penten-l-yl) -5-hydroxy-methyl-pyrrolidon-2

From l-formylmethyl-5-hydroxy-methyl-pyrrolidone-2-ó-lactol and 3-carboxypropyl-triphenylphosphonium bromide analogously to the procedure in Example 1 d ^.

Chromatography on silica gel, solvent chloroform / methanol 8: 2.

NMR: Ò = 5.15-5.85 ppm (m) CH = CH 2 Prot.

IR: 1680 cm-1 vC = 0 1703 cm "1 vC = 0 2. 1- (6-carboxy- (Z) -2-hexen-l-yl) -5-hydroxy-methyl-pyrrolidon-2

From l-formylmethyl-5-hydroxymethyl-pyrrolidone-2- <3-lac-tol and 4-carboxy-butyl-triphenylphosphonium bromide analogously to Example 1 d [).

Chromatography on silica gel, eluent chloroform / methanol 85:15.

NMR: Ò = 5.2-5.8 ppm (m) ÇH = ÇH 2 Prot.

IR: 1700 cm-1 vC = 0 1680 cm-1 vC = 0 cIV ') 1- (6-carboxy- (Z) -2-hexen-l-yl) -5-hydroxy-methyl-pyrrolidon-2

From 5-hydroxymethyl-pyrrolidone by alkylation with 6-bromo (Z) -4-hexen-l-carboxylic acid according to the instructions in Example 1 bj) See above for physical data.

cIV ') 1- (5-carboxy- (Z) -2-penten-l-yl) -5-hydroxy-methyl-pyrrolidon-2

0.05 mol of 1- (5-carboxy- (Z) -2-penten-l-yl) -5- (tetrahydro-pyran-2-yl-oxymethyl) pyrrolidone-2 are mixed in a mixture of 100 ml of ethanol and 50 ml 6% aqueous oxalic acid was stirred for 4 hours at room temperature and then for 4 hours at 40 ° C. The acid is neutralized with triethylamine and the reaction mixture is concentrated. Chromatographic purification on silica gel with toluene / ethyl acetate / methanol 5: 4: 0.3.

See above for physical data. dIV) 1- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5-hydroxy-methyl-pyrrolidon-2

By esterification of l- (6-carboxy- (Z) -2-hexen-l-yl) -5-hydroxymethyl-pyrrolidon-2 with methanol. Implementation analogous to Example 3).

Physical data correspond to that of compound example 3 ai).

Example 1 Compounds of Formula I a,) (XXVII)

1. 1 - (6-methoxycarbonyl- (Z) -2-hexen-1-yl) -5-formyl-pyrrolidone-2

0.15 mol of pyridine in 160 ml of methylene chloride

0.075 mol of chromium (VI) oxide is added and the mixture is then stirred at room temperature for 15 minutes. It is cooled to 0 ° C. and 0.01 mol of 1- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5-hydroxymethyl-pyrrolidon-2, dissolved in 40 ml of methylene chloride, is added and the mixture is stirred Continue for 40 minutes under ice cooling. 0.3 mol of powdered sodium hydrogen sulfate monohydrate is added and the mixture is stirred for a further 30 minutes while cooling with ice. It is suctioned off, dried with sodium sulfate and at +5 to

+ 10 ° C concentrated under vacuum.

2. l- (6-ethoxycarbonyl- (Z) -2-hexen-l-yl) -5-formyl-pyrrolidon-2

By oxidation of l- (6-ethoxycarbonyl- (Z) -2-hexen-l-yl) -5-hydroxymethyl-pyrrolidon-2 analogously to Example 3 aj 1.

3. 1- (6-methoxycarbonyl- (E) -2-hexen-l-yI) -5-formyl-pyrrolidon-2

By oxidation of l- (6-methoxycarbonyl- (E) -2-he-xen-l-yl) -5-hydroxymethyl-pyrrolidon-2 analogously to Example 3a!

1.

4. l- (7-ethoxycarbonyl- (Z) -2-hepten-l-yl) -5-formyl-pyrrolidon-2

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By oxidation of l- (7-ethoxycarbonyl- (Z) -2-hepten-l-yl) -5-hydroxymethyl-pyrrolidon-2 analogously to Example 3 ai 1. The compounds of the formulas XXVII 1 to 4 thus prepared are because of their instability used as a raw product for the next stage without additional cleaning.

b,) (XXVIII)

1. l- (6-Methoxycarbonyl- (Z) -2-hexen-l-yl) -5- (3-oxo- (E) -1 -octen-1-yl) -pyrrolidone-2

0.03 mol of dimethyl 2-oxoheptyl phosphonate in 140 ml of absolute dimethoxyethane are mixed with 0.033 mol of sodium hydride and the suspension is stirred at room temperature for 1 V2 hours. Then 0.03 mol of 6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5-formyl-pyrrolidon-2 dissolved in 10 ml of dimethoxyethane is added and the mixture is stirred for 272 hours at room temperature. Neutralize with glacial acetic acid.

NMR: Ò = 5.2-5.8 ppm (m) £ H = £ H (ice) 2 prot.

ò = 6.05-7.0 ppm (m) CH = CH (trans) 2 prot. Ó = 3.7 ppm (s) COOÇH3

The following compounds are synthesized quite analogously:

2. 1- (6-methoxycarbonyl- (E) -2-hexen-l-yl) -5- (3-oxo- (E) -1 -octen-1-yl) pyrrolidone-2

From l- (6-methoxycarbonyl- (E) -2-hexen-l-yl) -5-formyl-pyrrolidon-2 and the dimethyl-2-oxo-heptyl-phosphonate.

Chromatography: toluene / ethyl acetate / methanol 5: 4: 0.3. NMR: ò = 5.1-5.9 ppm (m) CH = CH (trans, not conjugated) 2 prot.

Ò = 6.0-6.9 ppm (m) CH = CH (trans, conjugated) 2

Prot.

ò = 3.75 ppm (s) COOÇH3

3. l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- (3-oxo- (E) - 1-decen-l-yl) pyrrolidone-2

From 2- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5-formyl-pyrrolidon-2 and dimethyl-2-oxo-nonyl-phosphonate. Chromatography: toluene / ethyl acetate / methanol 5: 4: 0.1. NMR: <3 = 5.2-5.85 ppm (m) CH = CH (ice) 2 prot. <3 = 6.0-6.7 ppm (m) ÇH = ÇH (trans) 2 prot. <3 = 3.75 ppm (s) COOÇH3

4. 1- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- (3-oxo-5-ethoxy-4,4-dimethyI- (E) -l-penten-l-yl ) -pyrrolidone-2

From 1 - (6-methoxycarbonyl- (Z) -2-hexen-1-yl) -5-formyl-pyrrolidone-2 and dimethyl- (2-oxo-4-ethoxy-3,3-dimethylbutyl) phosphonate . Chromatography: toluene / ethyl acetate 5: 4. NMR: Ò = 1.0 ppm (s) C (CH3) 2 6 Prot.

ò = 3.7 ppm (s) COOÇH3 <3 = 5.2-5.8 ppm (m) CH = CH (ice) 2 prot.

5. 1- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- (3-oxo-5-allyl-oxy-4,4-dimethyl- (E) -1-penten-1 -yl) -pyrrolidone-2

From l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5-formyl-pyrrolidon-2 and dimethyl- (2-oxo-4-allyloxy-3,3-dimethyl-butyl) phosphonate . Chromatography: toluene / ethyl acetate 5: 4. NMR: ò = 5.0-7.0 ppm (m) all olefinic protons 6 prot.

Ò = 3.65 ppm (s) COOÇH3

6. 1- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- [3-oxo-4- (4-chlorophenoxy) phenoxy-4,4-dimethyl- (E) -l -butene-l-yl] pyrrolidone-2

From l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5-formyl-pyrrolidon-2 and dimethyl- [2-oxo-3- (4-chlorophenoxy) -phen-oxy-3, 3-dimethyl-propyl] -phosphonate. Chromatography: chloroform / ethyl acetate 4: 1.

NMR: <3 = 1.05 ppm (s) C (CH3) 2 6 Prot.

ó = 6.9-7.9 ppm (m) aromatic protons 8 prot. Ó = 3.7 ppm (s) COOCH3

7. 1- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- [3-oxo-4- (3-thienyloxy) - (E) -1-buten-1-yl] - pyrrolidone-2

From 2- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5-formyl-pyrrolidon-2 and dimethyl- [2-oxo-3- (3-thienyloxy) propyl | phosphonate. Chromatography: carbon tetrachloride / acetone 7: 3.

NMR: ò = 5.2-5.9 ppm (m) CH = CH (ice) 2 prot. Ò = 6.0-6.9 ppm (m) CH = CH (trans) 2 prot. Ó = 3, 7 ppm (s) COOCH3

8. l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- (3-oxo-

6-pentafluoroethyl- (E) -l-hexen-l-yl) -pyrrolidon-2

From l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5-formyl-pyrrolidon-2 and dimethyl- (2-oxo-5-pentafluoroethyl-pen-tyl) phosphonate. Chromatography: toluene / ethyl acetate / methanol 5: 4: 0.5.

NMR: <5 = 3.7 ppm (s) COOCH3

ó = 5.2-5.9 ppm (m) ÇH = Œ (cis) 2 prot.

ó = 6.0-6.7 ppm (ABX spec.) CH = CH (trans) 2 prot.

9. l- (6-methoxycarbonyl- (Z) -hexen-l-yl) -5- (3-oxo-cyclopentyl-4,4-dimethyl- (E) -l-penten-l-yI) -pyrrolidone- 2nd

From l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5-formyl-pyrrolidon-2 and dimethyl- (2-oxo-4-cyclopentyl-3,3-dimethyl-butyl) -phosphonate. Chromatography: toluene / ethyl acetate 5: 5.

NMR: Ò = 1.0 ppm (s) C (CH3) 2 6 Prot.

ò = 3.7 ppm (s) COOCH3 ó = 6.0-7.0 ppm (m) CH = CH (trans) 2 prot.

10. 1- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- (3-oxo-5-phenyl- (E) -1-p-enten-1-yl) pyrrolidon-2

From l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5-formyl-pyrrolidon-2 and dimethyl- (2-oxo-4-phenyl-butyl) phosphonate. Chromatography: carbon tetrachloride / acetone 7: 3. NMR: ò = 7.3 ppm (s) aromatic protons 5 prot. Ó = 3.7 ppm (s) COOCH3 ò = 5.15-5.75 ppm (m) CH — CH (ice) 2 prot.

11. 1- (6-methoxycarbonyl- (Z) -2-hexen-1-yl) -5- [3-oxo-5- (4-methyl-2-chlorophenyl) -4,4-dimethyl- ( E) -l-penten-l-yl] pyrrolidone-2

From l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5-formyl-pyrrolidon-2 and dimethyl- [2-oxo-4- (4-methyl-2-chlorophenyl) - 3,3-dimethylbutyl] phosphonate. Chromatography: toluene / ethyl acetate 5: 4.

NMR: <3 = 1.0 ppm (s) C (CH3) 2 6 Prot.

ò = 2.3 ppm (s) CH3_3 Prot.

ò = 6.1-6.9 ppm (m) CH = CH (trans) 2 prot.

12. l- (6-ethocycarbonyl- (Z) -2-hexen-l-yl) -5- (3-oxo-

7-methyl- (E) -l-octen-l-yl) pyrrolidone-2

From l- (6-ethoxycarbonyl- (Z) -2-hexen-l-yl) -5-formyl-pyrrolidon-2 and dimethyl- (2-oxo-6-methyl-heptyl) -phosphonate. Chromatography: chloroform / ethyl acetate 4: 1. NMR: (5 = 1.05 ppm (d) CH (CH3) 2 6 Prot.

ò = 1.3 ppm (t) COOCHtCH ^ 3 prot.

ó = 5.2-5.9 ppm (m) CH = CH (ice) 2 prot.

13. l- (6-ethoxycarbonyl- (Z) -2-hexen-l-yl) -5- (3-oxo-4,4-dimethyl- (E) -l-octen-l-yl) -pyrrolidone- 2nd

From 1 - (6-ethoxycarbonyl- (Z) -2-hexen-1-yl) -5-formyl-pyrrolidone-2 and dimethyl (2-oxo-3,3-dimethyl-heptyl) -phosphonate. Chromatography: toluene / ethyl acetate / ethanol 5: 4: 0.3.

NMR: ó = 0.95 ppm (s) C (CH ^), 6 prot.

ó = 1.25 ppm (t) COOCH2 £ H3 3 prot.

Ò = 5.15-5.95 ppm (m) CH = CH (ice) 2 prot. Ò = 6.0-7.05 ppm (m) CH = CH (trans) 2 prot.

14. l- (6-ethoxycarbonyl- (Z) -2-hexen-l-yl) -5- [3-oxo-4- (3-trifluoromethylphenoxy) - (E) -1-buten-1-yl] - pyrrolidone-2

From l- (6-ethoxycarbonyl- (Z) -2-hexen-l-yl) -5-formyl-pyrrolidon-2 and dimethyl- [2-oxo-3- (3-trifluoromethyl-pheno-

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xy) propyl | phosphonate. Chromatography: toluene / ethyl acetate 5: 4.

NMR: Ò = 1.2 ppm (t) COOCH2C% 3 prot.

Ó = 4.6 ppm (s) CH7-O 2 Prot.

ò = 6.0-6.95 ppm (m) CH = CH 2 Prot.

15. 1 - (6-Ethoxycarbonyl- (Z) -2-hexen-1-yl) -5- [3-oxo-4- (4-chlorobenzyloxy) - (E) -l-buten-l-ylj-pyrrolidone -2

From l- (6-ethoxycarbonyl- (Z) -2-hexen-l-yl) -5-formyl-pyrrolidon-2 and dimethyl- [2-oxo-3- (4-chlorobenzyloxy) propyl] phosphonate . Chromatography: carbon tetrachloride / acetone 7: 3.

NMR: ò = 4.4 ppm and 4.6 ppm (2 sing.) CH -, - 0 4 prot. Ò = 1.2 ppm (t) COOH2-CH3 3 prot.

ò = 7.0-7.5 ppm (m) aromatic Prot. 4 Prot.

16. l- (6-ethoxycarbonyl- (Z) -2-hexen-l-yl) -5- [3-oxo-

4- (2-thienyl) - (E) -l-buten-l-yl] pyrrolidone-2

From l- (6-ethoxycarbonyl- (Z) -2-hexen-l-yl) -5-formyl-pyrrolidon-2 and dimethyl- [2-oxo-3- (2-thienyl) propyl] phosphonate. Chromatography: toluene / ethyl acetate / ethanol 5: 4: 0.1.

NMR: ò = 3.9 ppm (s) -CH * 2 Prot.

ó = 7.1-7.3 ppm (m) thiophene protons 3 prot. ó = 6.0-6.90 ppm (m) ÇH = ÇH (trans) 2 prot.

17. l- (7-ethoxycarbonyl- (Z) -2-hepten-l-yl) -

5- (3-oxo-5-ethoxy-4,4-dimethyl- (E) -l-penten-l-yl) pyrrolidone-2

From 1 - (7-ethoxycarbonyl- (Z) -2-hepten-1-yl) -5-formyl-pyrrolidone-2 and dimethyl- (2-oxo-4-ethoxy-3,3-dimethyl-butyl) -phosphonate. Chromatography: toluene / ethyl acetate 5: 4. NMR: Ò = 1.0 ppm (s) C (CH3) 2 6 Prot.

Ó = 1.2 ppm (t) COOCH2CH3 3 prot.

Ò = 6.0-6.95 ppm (m) ÇH = ÇH (trans) 2 Prot, bj ') l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- (3- oxo- (E) -l -octen- l-yl) -pyrrolidon-2 (XXVIII)

By alkylation of 5- (3-oxo- (E) -l-octen-l-yl) -pyrro-lidone-2 with 6-bromo- (Z) -4-hexen-l-carboxylic acid methyl ester according to that given in Example 1 Regulation.

For physical data and chromatography see Example 3 to 1.

ci) (I)

The reduction of the a./? Unsaturated ketones (XXVIII) described above to the compounds of the formula I is carried out as described in the following example.

The following connections are made analogously:

1. 1- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- (3-hydroxy-1-octen-1-yl) pyrrolidone-2

0.2 mol of anhydrous zinc chloride are suspended in 300 ml of dimethoxyethane and 0.8 mol of sodium borohydride is carefully added. The mixture is then stirred at room temperature for 1 hour. It is filtered and 0.08 mol of 1- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- (3-oxo- (E) -l-octen-l-) is added dropwise to the solution thus obtained. yl) -pyrrolidon-2 in 50 ml of dimethoxyethane within 10 minutes and then stirred for 2 V2 hours at room temperature. You acidify with glacial acetic acid. Chromatographic purification on silica gel with toluene / ethyl acetate / methanol 5: 4: 0.3.

NMR: Ó = 5.3-5.8 ppm (m) ÇH = ÇH 4 Prot.

Ó = 3.7 ppm (s) COOÇH3 3 prot.

IR: 1680 cm "1 vC = 0 1735 cm" 1 vC = 0

2. 1- (6-methoxycarbonyl- (E) -2-hexen-1-yl) -5- (3-hydroxy-1-octene-1-yl) pyrrolidone-2

From l- (6-methoxycarbonyl- (E) -2-hexen-l-yl) -5- (3-oxo- (E) -l-octen-l-yl) -pyrrolidone-2.

NMR: Ò = 5.3-5.8 ppm (m) ÇH = ÇH4 Prot.

à = 3.7 ppm (s) COQ CHU 3 Prot.

IR: 1680 cm-1 vC = 0 1735 cm-1 vC = 0

3. 1- (6-methoxycarbonyl- (Z) -2-hexen-1-yl) -5- (3-hydroxy-1-decen-1-yl) pyrrolidone-2

From l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- (3-oxo- (E) -l-decen-l-yl) -pyrrolidone-2. Chromatography: toluene / ethyl acetate / methanol 5: 4: 0.5.

NMR: Ó = 5.2-5.85 ppm (m) CH = CH 4 Prot.

à = 3.75 ppm (s) COOC%

IR: 1680 cm-1 vC = 0 1735 cm "1 vC = 0

4. l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5-

(3-hydroxy-5-ethoxy-4,4-dimethyl- (E) -1-penten-1-yl) -pyrrolidon-2

Ausi - (6-methoxycarbonyl- (Z) -2-hexen-1-yl) -5 - (3-oxo-5-ethoxy-4,4-dimethyl- (E) -l-penten-l-yl) - pyrrolidone-2.

NMR: Ò = 0.9 ppm (s) C (CH3) 2 6 Prot.

ò = 3.7 ppm (s) COOCH, 6 prot.

IR: 1680 cm-1 vC = 0 1735 cm-1 vC = 0

5. 1- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- (3-hydroxy-5-allyloxy-4,4-dimethyl- (E) -l-penten-l-yl -pyrrolidone-2

From l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- (3 -oxo-5 -allyloxy-4,4-dimethyl- (E) -1-penten-1 -yl- pyrrolidone 2. Chromatography: toluene / ethyl acetate /

Methanol 5: 4: 1.

NMR: ô = 5.0-6.5 ppm (m) all olefinic prot. 6 prot.

ô = 3.65 ppm (s) COOCH ^

IR: 1680 cm-1 vC = 0 1735 cm "1 vC = 0

6. 1- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- [3-hydroxy-4- (4-chlorophenoxy) phenoxy-4,4-dimethyl- (E) -1 -buten-1 -yl] -pyrrolidone-2

From l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- [3-oxo-4- (4-chlorophenoxy) phenoxy-4,4-dimethyl- (E) -l- buten-l-yl] pyrrolidone. Chromatography: chloroform / ethyl acetate 4: 1.

NMR: ô = 1.05 ppm (s) C (CH3) 2 6 Prot.

ò = 6.9-7.9 pom (m) aromatic protons 8 Prot, ô = 3.7 ppm (s) COOCH3 IR: 1680 cm-1 vC = 0 1733 cm "1 vC = 0

7. 1 - (6-methoxycarbonyl- (Z) -2-hexen-1-yl) -5- [3-hydroxy-4- (3-thienyloxy) - (E) -l-buten-l-yl] - pyrrolidone-2

From 1 - (6-methoxycarbonyl- (Z) -2-hexen-1-yl) -5 - [3-oxo-4- (3-thienyloxy) - (E) -l-buten-l-yl] pyrrolidone -2. Chromatography: toluene / ethyl acetate / ethanol 6: 4: 0.2.

NMR: ô = 5.3-5.6 ppm (m) CH = CH 4 Prot.

Ò = 3.7 ppm (s) COOCH3 IR: 1680 cm-1 vC = 0 1738 cm-1 vC = 0

8. l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- (3-hydroxy-6-pentafluoroethyl- (E) -l-hexen-l-yl) -pyrrolidon-2

From 1 - (6-methoxycarbonyl- (Z) -2-hexen-1 -yl) ~ 5 - (3-oxo-6-pentafluoroethyl- (E) -l-hexen-l-yl) -pyrrolidon-2. Chromatography: toluene / ethyl acetate / methanol 5: 4: 0.5.

NMR: Ó = 3.7 ppm (s) COOCH3

ò = 5.2-5.6 ppm (m) CH = CH 4 Prot.

IR: 1680 cm-1 vC = 0 1730 cm "1 vC = 0

9. l- (6-methoxycarbonyl- (Z) -hexen-l-yl) -5- (3-hydroxy-5-cyclopentyl-4,4-dimethyl- (E) -l-penten-l-yl) - pyrrolidone-2

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From l- (6-methoxycarbonyl- (Z) -hexen-l-yI) -5- (3-oxo-5-cyclopentyl-4,4-dimethyl- (E) -l-penten-l-yl) pyrrolidone -2. Chromatography: toluene / ethyl acetate / methanol 5: 4: 0.3.

NMR: ò = 0.9 ppm (s) C (CH3) 2 6 Prot.

ó = 3.7 ppm (s) COOCHj Ó = 5.3-5.5 ppm (m) ÇH = ÇH 4 Prot.

IR: 1680 cm "1 vC = 0 1740 cm" 1 vC = 0

10. 1 - (6-methoxycarbonyl- (Z) -2-hexen-1-yl) -5 - (3-hydroxy-5-phenyl- (E) -l-penten-l-yl) pyrrolidone-2

Àus l- (6-methoxycarbonyl- (Z) -2-hexen-1-yl) -5- (3-oxo-5-phenyl- (E) - 1-pentene-l-yl) pyrrolidone-2. Chromatography: toluene / ethyl acetate / methanol 5: 4: 0.1.

NMR: ô = 7.3 ppm (s) aromatic protons 5 prot. Ó = 3.7 ppm (s) COOCH3 ò = 5.15-5.50 ppm (m) CH = CH 4 Prot.

IR: 1730 cm "1 vC = 0 1680 cm" 1 vC = 0

11. 1- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- [3-hydroxy-5- (4-methyl-2-chlorophenyl) -4,4-dimethyl- ( E) -1-penten-1 -yl] pyrrolidone-2

From l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- [3-oxo-5- (4-methyl-2-chlorophenyl) -4,4-dimethyl- (E ) -l-penten-l-yl] -pyrrolidone-2. Chromatography: toluene / ethyl acetate 5: 4.

NMR: Ò = 1.0 ppm (s) C (CH3) 2 6 Prot.

ö = 2.3 ppm (s) CH3 3 Prot.

Ò = 5.3-5.7 ppm ÇH = ÇH 4 Prot.

IR: 1740 cm "1 vC = 0 1680 cm" 1 vC = 0

12. l - (- ethoxycarbonyl- (Z) -2-hexen-l-yl) -5-

(3-hydroxy-7-methyl- (E) -1 -octen-l-yl) -pyrrolidon-2

From 1 - (6-ethoxycarbonyl- (Z) -2-hexen-1-yl) -5- (3-oxo-7-methyl- (E) -l-octen-l-yl) pyrrolidone-2. Chromatography: chloroform / ethyl acetate / ethanol 8: 2: 0.5. NMR: <5 = 1.0 ppm (d) CH (CH3) 2 6 Prot.

ò = 1.25 ppm (Z) COOCH2CH3 3 prot.

Ò = 5.2-5.5 ppm (m) ÇH = ÇH 4 Prot.

IR: 1730 cm "1 vC = 0 1675 cm" 1 vC = 0

13. 1 - (6-ethoxycarbonyl- (Z) -2-hexen-1-yl) -5- (3-hydroxy-4,4-dimethyl- (E) -1 -octen-1-yl) -pyrrolidone- 2nd

From l- (6-ethoxycarbonyl- (Z) -2-hexen-l-yl) -5- (3-0X0-4,4-dimethyl- (E) -l-octen-l-yl) pyrrolidone-2 .

NMR: Ò = 5.3-5.8 ppm (m) CH = CH 4 Prot.

ô = 0.9 ppm (s) C (CH3) 2 6 prot.

IR: 1680 cm "1 vC = 0 1740 cm" 1 vC = 0

14. l- (6-ethoxycarbonyl- (Z) -2-hexen-l-yl) -5- [3-hydroxy-4- (3-trifluoromethylphenoxy) - (E) -l-buten-l-yl] - pyrr ° lid ° n-2

From 1 - (6-ethoxycarbonyl- (Z) -2-hexen-1-yl) -5 - [3-oxo-4- (3-trifluoromethylphenoxy) - (E) -l-buten-l-yl] pyrrolidone -2.

NMR: Ò = 5.2-5.7 ppm CH = CH 4 Prot.

IR: 1680 cm "1 vC = 0 1730 cm" 1 i / C = 0

15. 1 - (6-ethoxycarbonyl- (Z) -2-hexen-1-yl) -5 - [3-hydroxy-4- (4-chlorobenzyloxy) - (E) -l-buten-l-yl] - pyrrolidone-2. Chromatography: carbon tetrachloride / acetone 7: 3.

NMR: ò = 5.1-5.4 ppm (m) CH = CH 4 Prot.

ó = 1.1 ppm (t) COOCH2-C% 3 prot.

ó = 7.0-7.5 ppm (m) aromatic Prot. 4 Prot. IR: 1735 cm "1 vC = 0 1680 cm" 1 vC = 0

16. l- (6-ethoxycarbonyl- (Z) -2-hexen-l-yl) -5- [3-hydroxy-4- (2-thienyl) - (E) -l-buten-l-yl] - pyrrolidone-2

From l- (6-ethoxycarbonyl- (Z) -2-hexen-l-yl) -5- [3-oxo-4- (2-thienyl) - (E) -l-buten-l-yl] pyrrolidone -2. Chromatography: toluene / ethyl acetate / ethanol 5: 4: 0.5. NMR: ô = 7.1-7.3 ppm (m) thiophene protons 3 prot.

ò = 5.2-5.6 ppm (m) CH = CH 2 Prot.

IR: 1740 cm "1 vC = 0 1680 cm" 1 vC = 0

17. l- (7-ethoxycarbonyl- (Z) -2-hepten-l-yl) -5- (3-hydroxy-5-ethoxy-4,4-dimethyl- (E) -l-penten-l-yl ) -pyrrolidone-2

From 1 - (7-ethoxycarbonyl- (Z) -2-hepten-1-yl) -5- (3-0X0-5-ethoxy-4,4-dimethyl- (E) -1-penten-1-yl) -pyrrolidone-2. Chromatography: toluene / ethyl acetate / ethanol 5: 4: 0.5.

NMR: ò = 0.9 ppm (s) C (CH3) 2 6 Prot.

Ò = 1.2 ppm (t) COOCH2CH3 3 prot.

ô = 5.15-5.5 ppm (m) ÇH = ÇH 4 Prot.

IR: 1738 cm "1 vC = 0 1680 cm-1 vC = 0

ClI) (I, R2 = H)

1. 1 - (5-Carboxy- (Z) -2-penten-1-yl) -5-formyl-pyrrolidone-2

By oxidation of l- (5-carboxy- (Z) -2-penten-l-yl) -5-hydroxymethyl-pyrrolidon-2 analogously to Example 3 a] 1.

2. 1 - (6-Carboxy- (Z) -2-hexen-1-yl) -5-formyl-pyrrolidone-2

By oxidation of l- (6-carboxy- (Z) -2-hexen-l-yl) -5-hydroxymethyl-pyrrolidon-2 analogously to Example 1 br).

The two aldehydes represented in this way are used as crude products for the next stage without further purification.

b „) (XXVIII, R2 = H)

1. 1 - (5-Carboxy- (Z) -2-penten-1-yl) -5- (3-oxo-4,4-dimethyl-5-ethoxy- (E) -1-penten-1-yl ) -pyrrolidone-2

0.03 mol of dimethyl- (2-oxo-3,3-dimethyl-4-ethoxy-butyl) -phosphonate in 140 ml of absolute dimethoxyethane is mixed with 0.033 mol of sodium hydride and the suspension is stirred for 1 1/2 hours at room temperature. Then 0.03 mol of l- (5-carboxy- (Z) -2-penten-l-yl) -5-formyl-pyrrolidon-2 dissolved in 10 ml of dimethoxyethane is added and the mixture is subsequently stirred at room temperature for 2 hours. Neutralize with glacial acetic acid and concentrate. The residue is chromatographed on silica gel with chloroform / ethyl acetate 4: 1 as the eluent. Chromatography: ethyl acetate / glacial acetic acid 98: 2.

NMR: Ò = 1.0 ppm (s) C (CH3) 2 6 Prot.

ò = 5.2-5.5 ppm (m) CH = CH (ice) 2 prot.

ò = 6.1-6.9 ppm (m) CH = CH (trans) 2 prot.

2. l- (6-carboxy- (Z) -2-hexen-l-yl) -5- (3-oxo- (E) -1 -octen-1-yl) pyrrolidone-2

From l- (6-carboxy- (Z) -2-hexen-l-yl) -5-formyl-pyrroli-don-2 and dimethyl-2-oxo-heptyl-phosphonate analogous to the example above. Chromatography: ethyl acetate / glacial acetic acid 98: 2. NMR: ò = 5.2-5.85 ppm (m) £ H == CH (ice) 2 prot. Ò = 6.0-6.95 ppm (m) CH = CH (trans) 2 prot.

bn ') l- (6-carboxy- (Z) -2-hexen-l-yl) -5- (3-oxo- (E) -l-octen-l-yl) -pyrrolidone-2 (XXVIII, R2 = H)

From 5- (3-oxo- (E) -l-octen-l-yl) -pyrrolidone-2 by alkylation with 6-bromo (Z) -4-hexen-l-carboxylic acid according to Example 1 bi). See above for physical data and cleaning.

c „) (1, R2 = H)

1. l- (5-carboxy- (Z) -2-penten-l-yl) -5- (3-hydroxy-4,4-dimethyl-5-ethoxy- (E) -l-penten-yl) - pyrrolidone-2

From l- (5-carboxy- (Z) -2-penten-l-yI) -5- (3-oxo-4,4-dimethyl-5-ethoxy- (E) - 1-penten-1 -yl) -pyrrolidone-2 analogous to Example 3 ^ 1. Chromatography: ethyl acetate / glacial acetic acid 98: 2.

14

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

NMR: ò = 1.0 ppm (s) C (CH3) 2 6 Prot.

Ò = 5.2-5.5 ppm (m) CH = CH 4 Prot.

1R: 1705 cm "1 vC = 0 1680 cm" 'vC = 0 2. 1- (6-carboxy- (Z) -2-hexen-l-yl) -5- (3-hydroxy- (E) -1 -octen-l-yl) -pyrrolidone-2

From I- (6-carboxy- (Z) -2-hexen-l-yl) -5- (3-oxo- (E) -1-octen-l-yl) -pyrrolidone-2 analogously to Example 1 d ^. Chromatography: ethyl acetate / glacial acetic acid 97.5: 2.5.

NMR: ò = 5.3-5.7 ppm (m) CH = CH 4 Prot.

IR: 1700 cm-1 vC = 0 1682 cm-1 vC = 0 am) (I, R2 = H)

1. l- (6-Carboxy- (Z) -2-hexen-l-yl) -5- (3-hydroxy- (E) -1 -decen-1-yl) pyrrolidone-2

0.01 mol of l- (6-methoxycarbonyl- (Z) -2-hexen ~ l-yl) ~ 5- (3-hydroxy- (E) -l-decen-l-yl) -pyrrolidone-2 become 30 ml of a 0.5 molar aqueous sodium hydroxide solution were added and the mixture was stirred at room temperature overnight. It is acidified with dilute hydrochloric acid and the aqueous phase is etherified several times. The residue remaining after drying and concentration of the solvent can be purified by chromatography as usual. Chromatography: ethyl acetate / glacial acetic acid 98: 2. NMR: ò = 5.2-5.65 ppm (m) CH = CH 4 Prot.

IR: 1680 cm-1 vC = 0 1705 cm "1 vC = 0

2. 1- (6-carboxy- (Z) -2-hexen-l-yl) -5- [3-hydroxy-4- (4-chlorophenoxy) phenoxy-4,4-dimethyl- (E) -1 -butene-l-yl] pyrrolidone-2

15 623 809

From l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- [3-hydroxy-4- (4-chlorophenoxy) phenoxy-4,4-dimethyl- (E) -1 - buten- 1-yl] pyrrolidone-2 analogous to the example above. Chromatography: cyclohexane / ethyl acetate / glacial acetic acid 6: 4: 0.1. s NMR: Ò = 1.05 ppm (s) C (CH3) 2 6 Prot.

ó = 6.9-7.9 ppm (m) aromatic protons 8 prot. IR: 1680 cm-1 vC = 0 1700 cm-1 vC = 0

3. l- (6-carboxy- (Z) -2-hexen-l-yl) -5- (3-hydroxy-6-10 pentafluoroethyl- (E) -1 -hexen-l-yl) pyrrolidone-2

From 1 - (6-methoxycarbonyl- (Z) -2-hexen-1 -yl) -5- (3-hydroxy-6-pentafluoroethyl- (E) -l-hexen-l-yl) -pyrrolidon-2 analogously to the example 3 ara 1. Chromatography: toluene / ethyl acetate / glacial acetic acid 5: 4: 0.1.

15 NMR: Ó = 5.2-5.45 ppm (m) CH = CH 4 Prot.

IR: 1685 cm-1 vC = 0 1705 cm-1 i> C = 0

4. 1- (6-carboxy- (Z) -2-hexen-l-yl) -5- [3-hydroxy-5- (4-methyl-2-chlorophenyl) -4,4-dimethyl- ( E) -

20 1-penten-1-yl] pyrrolidone-2

From l- (6-methoxycarbonyl- (Z) -2-hexen-l-yl) -5- [3-hydroxy-5- (4-methyl-2-chlorophenyl) -4,4-dimethyl- (E ) -l-penten-l-yl] -pyrrolidone-2. Chromatography: cyclohexane / ethyl acetate / glacial acetic acid 6: 4: 0.1.

25 NMR: ó = 0.9 ppm (s) C (CH3) 2 6 Prot.

ò = 2.3 ppm (s) CH ^ 3 Prot.

Ò = 5.3-5.7 ppm CH = CH 4 Prot.

IR: 1705 cm-1 vC = 0 1680 cm-1 vC = 0

Claims (3)

623 809 2. The method according to claim 1, characterized in that a compound of the formula I obtained, in which R2 is hydrogen, is correspondingly esterified. 2nd PATENT CLAIMS 1. Process for the preparation of new pyrrolidones of the formula I N-CH -CH = CH- (CH CH = CH-CH-R OH in which R1 is a straight, branched, saturated or unsaturated aliphatic hydrocarbon radical with up to 10 carbon atoms or a cycloaliphatic hydrocarbon radical with 3 to 7 carbon atoms, which can be substituted by a) a straight or branched alkoxy, alkylthio, alkenyloxy or alkenylthio radical with up to 5 carbon atoms; b) a phenoxy radical, which in turn may be mono- or disubstituted by an optionally halogen-substituted alkyl group having 1 to 3 carbon atoms, halogen atoms, an optionally halogen-substituted phenoxy radical or an alkoxy radical having 1 to 4 carbon atoms; c) a furyloxy, thienyloxy or benzyloxy radical, which in turn may be mono- or disubstituted by an optionally halogen-substituted alkyl group having 1 to 3 carbon atoms, halogen atoms or an alkoxy group having 1 to 4 carbon atoms; d) a trifluoromethyl or pentafluoroethyl group; e) a cycloalkyl radical having 3 to 7 carbon atoms; f) a phenyl, thienyl or furyl radical, which in turn can be mono- or disubstituted by an optionally halogen-substituted alkyl group "having 1 to 3 carbon atoms, halogen atoms or an alkoxy group having 1 to 4 carbon atoms; R2 is hydrogen, a straight-chain or branched, saturated or unsaturated aliphatic or cycloaliphatic hydrocarbon radical having up to 6 carbon atoms or an araliphatic hydrocarbon radical having 7 or 8 carbon atoms; and n denotes the number 2, 3 or 4, and of physiologically tolerable metal or amine salts of the acids of the formula I, characterized in that in a compound of the formula XXVIII N-CH0-CH = CH- (CH ") -C00R (XXVIII) CH = CH-C-R wherein R1, R2 and n have the meaning given for the formula I, the ketone carbonyl is reduced and the compound of the formula I is optionally converted into a physiologically compatible metal or amine salt. 3. The method according to claim 1, characterized in that a compound of the formula I obtained, in which -COOR2 stands for the ester group, is converted into the corresponding acid. Prostaglandins are a group of natural products that have been isolated from various animal tissues. They are responsible for a variety of physiological effects in mammals. The natural prostaglandins have a carbon skeleton of generally 20 carbon atoms and differ primarily in the higher or lower content of hydroxyl groups or double bonds in the cyclopentane ring [for the structure and action of prostaglandins see inter alia M.F. Cuthbert, "The Prostaglandins, Pharmacological and Therapeutic Advances", William Heinemann Medicai Books Ltd., London (1973)]. The synthesis of non-naturally occurring analogues of prostanoic acids, in which the multitude of pharmacological effects of natural prostanoic acids are differentiated, is becoming increasingly important.