HU180273B - Process for producing 1,5-disubstituted-2-pyrrolidone derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of novel 1,5-substituted 2-pyrrolidones, which in their. chemical structure and its biological character to prostaglandins. The novel compounds are characterized by a particularly selective biological activity. For the preparation of 50- (tetrahydropyran-2'-oxyloxyethyl) -2-pyrrolidone 1 (as for example a compound), 5-D-hydroxy-methylene-2-pyrrolidone is treated under a nitrogen atmosphere with methylene chloride, dihydropyrane and p-toluenesulfonic acid (tosic). acid. The reaction mixture is diluted with ethyl acetate and extracted with saturated sodium bicarbonate solution and saturated brine. Compounds which can be prepared by the process according to the invention are, for example, 1- (6'-carboxyhexyl) -5ß- {3 "-a-hydroxy-4 · * -phenylbut-1" -enyl) -2-pyrrolidone and the Sa epimer thereof. or 1- (6'-carboxyhex-2'-enyl) ~ 5l ~~ (3''-a-hydroxy-4'-phenoxybut-1'-enyl) -2-pyrrolidone and the 5a-epimer thereof.

Description

The present invention relates to a process for the preparation of 1-5-disubstituted-2-pyrrolidones having a prostaglandin-like chemical structure and biological properties.

Twenty carbon atoms, unsaturated fatty acids known as prostaglandins, are a large group of naturally occurring compounds. These molecules can contain at least five asymmetric centers and are present in a large number of biological tissues and can produce biological activity. The brain compound of prostaglandin group E / PGE ₂ / brain is represented by formula (I).

According to the generally accepted term for the stereochemistry of prostaglandins, the bold drawn valence denotes the / * configuration - this is the chemical bond that rises up from the plane of the paper toward the reader. Thus, the configuration of prostaglandin E ₂ in Formula I is at C 8 and C 12 carbon atoms (Berkstrom et al., Acta Chem. Scand., 16, 501 (1962)).

According to similar nomenclature, the dashed line valence represents a mixture of the cO and a / 3 positions. Thus, 2-pyrrolidone having the structure shown in formula II is a mixture of epimers consisting of compounds having the structure shown in formulas III and IV.

The structure of the pyrrolidone represented by Formula IV and the prostaglandin ® _{2 represented by} Formula I can be compared stereochemically. The positions of C 12 and C 15 are stereochemically identical in both compounds, and C 8 is different. This means that the bond between the 8 and 7 carbon atoms is a

-1180.273 Prostaglandin E has an o-C-configuration, but the chemical bond between the N-8 and the 7 ~ θ ³ carbon atoms is located in the plane of the paper as shown in the drawing. It is also possible to mark this configuration difference in the drawing in other ways. Thus, for example, the configuration of prostaglandin E is the. V, and the pyrrolidone configuration may be designated as in Formula VI; A and B in the drawings represent the side chains described in the examples. The illustrative figures in this case indicate the chemical bond between the carbon atoms A and C8 and the carbon atoms 12 and the hydrogen to which they are attached * and the carbon atoms 12 and B, respectively, and the corresponding the relative position of the hydrogen bond at prostaglandin E; however, in Figure VI, the position of the bond between A and N atoms relative to the chemical bond between the carbon atoms B, 12 and the hydrogen atom at the dihedral angle can be observed for pyrrolidone. The difference in conformation described above is due to a change in the amide group of pyrrolidone (Roberts, Caserio, & Benjamin, New York, 1965, p. 674).

The systematic name for 1,5-disubstituted-2-pyrrolidone represented by Formula VIII is 1- (6'-carboxy-hexyl) -5β, 3β-C-hydroxyoct-1′-enyl / -2-pyrrolidone, but we can call it

Also the E 4 derivative of 11-deoxy-prostaglandin, i.e. 8-aza-11-deoxy-PGE 4 -.

The corresponding 8-aza-II-deoxy-PGE ₂ has the structure shown in Formula VIII, wherein the single chemical bond between the 2 'and 3' carbon atoms is replaced by a double chemical bond.

The aforementioned e-aza-II-deoxy-PGEg has the structure shown in Formula IX, which is replaced by a single chemical bond between the 1 'and 2' * carbon atoms.

The pyrrolidones described above have multiple centers of asymmetry, may exist as racemic mixtures (optically inactive), but may also exist in the two enantiomers (optically active), i.e. dextro (D) and levorotatory (1). As will be apparent from the foregoing, each formula representing the pyrrolidone structure represents each of the optically active forms or enantiomers which may otherwise be derived in part from D-glutamic acid. The mirror images or optical antipodes of the above structures represent another enantiomeric pair of the corresponding pyrrolidones and are derived in part from L-glutamic acid. _Λ For example, the optical antipode of 1- (6'-carboxyhexyl) -5 / 2- / 3 '* -O-hydroxyoct-1' * -enyl / -2-pyrrolidone can be described by the structure given in X and It can be called '-carboxy-hexyl / -5 / 3- / 3' -C-hydroxyoct-1 '* -enyl / -2-pyrrolidone.

The racemic forms of the above pyrrolidones contain the same amount of one of the enantiomeric forms and have a mirror image thereof. Compounds from. As used herein, the term "rac" is used herein to refer to the racemic moiety before the compound names. This abbreviation means that the D and L, i.e. the enantiomeric forms are present in equimolar amounts.

The optical isomeric pairs that exist as optical antipodes or enantiomeric modifications are linked by

-2180.273 The absolute configuration of all asymmetry centers is reversed. In contrast, if the absolute configuration is reversed at one or more but not all asymmetric centers, then the isomeric pairs are epimers or diastereomers. For example, 1- (6 * -carboxyhexyl) -5- [4- (3 ') -NH-hydroxyoct-1 *' -enyl] -2-pyrrolidone and 1- (6 * -carboxyhexyl) -5- (3'-carboxyhexyl) -2- / 3 * ¹ * 1 * β--hidroxiokt -enll / -2-pyrrolidone · polyvinylpyrrolidone diastereomers, whereas, as shown in the XI and XII, formulas 5 to reverse the two carbon atom compounds.

In fact, any chemical modification on one or a mixture of the enantiomeric pairs will produce similar and identical results.

As stated previously, the substitution of a carbon atom with a nitrogen atom causes a significant change in the three-dimensional conformation of the resulting prostaglandin. Because chemical structure and biological activity are related, and often conformational change has a significant effect on biological activity, this type of molecular alteration of prostaglandins, i.e. the introduction of heteroatoms into the molecule, is often studied today. Most experiments have involved the replacement of carbon atoms 9 and 11 of the prostaglandin molecule with a heteroatom, for example, 9-oxapro-prostaglandins [Vlattas, Tetrahedron Letters, 4455, 1974; 11-oxa-prostaglandins Fougerousae, Tetrahedron Letters, 398J, 197 ^{Z |} i θθ Hanessian et al., Tetrahedron Letters, 3983, 197'Q and 9-thiaprostaglandins [Vlattas, Tetrahedron Letters, 4459. 197 ^z O ·

We have found in the literature two 8-aza-11-deoxy-prostaglandin E derivatives having two natural O-side chains, where the aza group is instead of 11-deoxy-prostaglandin and E ₂ -8 (Jolliger and Muchowski, Tetrahedron Let., 2931). 1975I and Bruin et al., Tetrahedron Let., 4599, 1975J. The above-described pyrrolidine derivatives are not within the scope of the present invention, for the preparation of compounds having higher complexity and molecular variations on the first carbon atom of the prostaglandin molecule and on the? . Relatively small amounts of biological activity data are available for these literature examples and are comparable with the molecular complexity of the novel compounds of the present invention.

Natural prostaglandins and their numerous derivatives, such as esters, acylated derivatives and pharmacologically acceptable salts thereof, are particularly effective inducers of various biological responses / Willson. Arch.Intern. Med., 133, 29, 1974, particularly for smooth muscle tissues such as cardiovascular, pulmonary, gastrointestinal and reproductive systems, cellular tissues such as the central nervous system, haematological, reproductive, gastrointestinal, pulmonary, nephritic, epidermal, and they act as mediators in the homeostasis process. Compounds such as prostaglandins that act on a wide scale obviously play a fundamental role in cellular biological processes. Indeed, the essential role of prostaglandins is supported by the fact that they are found in the cellular tissues of all animal organisms.

At this cellular level, _{t is} structurally related naturally

-3180.273 The effect of prostaglandins may be the opposite. For example, PG-Eg increases the aggregation of human blood cells, while PGE4 inhibits this aggregation.

Such adverse effects can also be observed at tissue level, for example, PG®2 ^ - ^{n V} I ^VO exerts its effect on ^the mammalian cardovascular system by lowering blood pressure while causing PGFg in vivo to increase blood pressure j / Iee, Arch. Intern. Med., 133, 56 (1974).

At present, the biological activity of these compounds of each prostaglandin class cannot be predicted. For example, as stated above, the effects of PGEg and PGFg on the cardiovascular system are counter-productive, both in vivo and in vitro, similar to mammalian uterine smooth muscle, i.e., stimulating / causing muscle contraction // Behrman et al., Arch. Intern. Med., 133 »

77. A974j.

When synthesizing therapeutically active compounds after synthesis, basic requirements include the search for compounds which are highly selective in their pharmacological activity and longer-acting than naturally occurring congeners. The increased selectivity of one of the compounds in the group of compounds that are naturally occurring protazaglandins usually results in an enhancement of one of the prostaglandin-like physiological effects, while in the others. By increasing selectivity, some of the side effects observed with the administration of natural prostaglandins can be eliminated; for example, gastrointestinal side effects in diarrhea or emesic or cardiovascular side effects of compounds administered to induce a bronchodilatory effect. The present research is being conducted to increase biological selectivity, such as 11-deoxy-prostaglandins (Anderson, Arch. Intern. Medl, 133, 30, 1974, (2-decarboxy-2-tetrazol-5-yl) -II-deoxy-15-substituted-β-pentanor-prostaglandins / Johnson et al., U.S. Pat. No. 3,932,389. U.S. Pat. No. 4,192,123, which has some effects on selective vasodilation, anti-gastric ulcer, anti-fertility, bronchodilation and antihypertensive effects; 16-phenoxyl-16-Gú-tetranor-prostaglandins are known for their antifertility activity (British Patent No. 1,350,971); it also includes 1-imide and 1-sulfonimide-prostaglandins (U.S. Pat. No. 3,954,741).

The present invention relates to a novel, selective and highly biologically active prostaglandin-like compound represented by the formula XIII and to a 05-epimer signal wherein Q is a carboxyl-tetrazol-5-yl group, -COOR or -CONHR. group where

B is C1-C5 alkyl, phenyl or p-biphenylyl,

R is -COR or -SOgR * '*, wherein

R '' is phenyl or C 1 -C 5 alkyl, W is a single or cis double bond,

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Z single bond or trans double bond,

M is a group LVII or LVIII, and

R * 0 is phenyl or phenoxy substituted with -thienyl, phenyl, phenoxy or chloro or fluoro, phenyl, methoxy, trifluoromethyl or C 1-3 alkyl.

The present invention also relates to carboxylate derivatives or tetrazol-5-yl derivatives thereof.

According to the present invention, a compound of formula XIV wherein Q, W, Z and R * are as defined above is reduced, preferably and optionally, the resulting compound of formula XIII wherein Q is C 2-6 alkoxycarbonyl, and / or optionally esterifying the resulting compound of formula XIII, wherein Q is a carboxylic acid, with an alcohol as defined above for R.

The structure of pyrrolidone derivatives having selective prostaglandin-like biological activity produced by the process of the present invention is represented by Formula XVII, wherein W, Z, M, R * and R are as defined above; the invention also relates to the C5 oligomers of these compounds.

Also of interest for their biological activity are the pyrrolidones produced by the process of the invention and their C5 epimer signal, the structure of which is shown in formulas XVIII and XIX; in formulas XVIII and XIX, W, Z, M, R * and R 'have the meanings given above.

Particularly valuable are those compounds within the scope of the invention and their C5-epimer signal, the structure of which is represented by formula XX; in the general formula W, Z, M and R 'have the meanings given above.

Another group of compounds of particular interest to the present invention include compounds having selective biological activity, the structure of which is represented by Formula XIX; also includes the C5 epimer signal of these compounds. In Formula XIX, W, Z, M and R 'have the meanings given above.

Particularly preferred compounds for their selective biological activity according to the invention are:

1- (6 * -carboxyhexyl) -5 / 5- (3 * * PC-hydroxy-4 * '- phenylbut-1 * -enyl] -2-pyrrolidone, its methyl ester and 5 (X-epimer;

1- (6'-carboxy-hexyl-2 '-enyl) -5- (3'0G) -hydroxy-4' * -phenylbut-1 '* -enyl / -2-pyrrolidone and its 5o-epimer;

1- [6 * -carboxy-hexyl] -5- [3- [3-c] -hydroxy-4 * '-phenyl-butanyl] -2-pyrrolidone and its 5C epimer;

1- (6 * -carboxy-hexyl) -5 / 5- (3 * *) -C-hydroxy-4 ** -phenoxybut-1 '* -enyl] -2-pyrrolidone and its 5o6-epimer;

l- / karboxihöx 6'-enyl-2 * / -5p- / 3 * 'oC-hydroxy-4-phenoxy-but-1 ^,, "enyl / -2-pyrrolidone polyvinylpyrrolidone and its epimer ö'K je ;

1- (6'-carboxy-hexyl) -5 / - (3 '') -C-hydroxy-4 '* -phenoxybutane] -1,2-pyrrolidone and its 5 (X-epimer;

those compounds in which the 6 * - (tetrazol-5-yl) group is substituted for the 6 * -carboxylate are particularly preferred compounds;

-5180.273 • compounds in which a 3 '* / ^ - hydroxy-1 option is substituted for the 3' * c <-hydroxyl group of the 6'-carboxy and 6 * - / tetrazole-5- described above. i1-derivatives also have very advantageous properties.

According to the present invention, optically active compounds having prostaglandin-like activity are prepared by a six-step reaction sequence in which the two side chains, i.e., the (X- or the top side) and the CO- or the lower side chain, are attached to the pyrrolidone ring. , D- or L-glutamic acid as the starting compound. Obviously, the absolute conformation of the carbon atom of the 2-pyrrolidone ring is decided by whether we start from D- or L-glutamic acid and the same The following examples and explanations illustrate the process for D-configurator: Compounds with L-configurator are prepared by similar reactions starting from 'L-glutamic acid.

Reaction equation A shows the binding of the liζ-o Ida lian to the 2-pyrrolidone ring. It should be noted that the pyrrolidone intermediates of formula XXIV prepared by these methods differ only in the chemical bond between the 2 * and 3 * carbon atoms. The final products of the invention are prepared according to the reaction equations B, C and D starting from the intermediates of formula XXIV.

A brief summary of reaction equation A is described below: In the first step, a-a-α-D-glutamic acid is cyclized to methyl D-pyroglutamate and the pyroglutamate is reduced to 5 µl-hydroxy-2-pyrrolidone (Bruckner et al., Acta Chim. Hung. Tomus, 21, 106, 1959 / A / b /, in the second reaction step, the hydroxymethyl group is protected with the protective compound T; T represents any group that protects the hydroxyl group from alkylation. Examples of such groups are benzyl. dimethyl tert-butylsilyl, acetyl, 1-ethoxyethyl or preferably tetrahydropyranyl. In Steps (c) and (e), the sodium or lithium salt of pyrrolidone XXV is alkylated with an alkylating Bzer XXVI or an XCHgCH / OY ^; in the general formulas X is chlorine, iodine or preferably bromine; Q is an N- (acyloxymethyl) -tetrazol-5-yl group containing N-acyloxymethyl-tetrazol-5-yl, or a N- (phthalidyl) -tetrazol-5-yl, N- tetrahydropyran-2-yl-tetrazol-5-yl or tetrazol-5-yl; Y is C 1-3 alkyl. and wherein W is cleaving the T group during the A / d / reaction step of the above meaning, the cleavage is performed in a manner depending on the quality of _: T. In step (f), the pyrrolidone derivative (XXII) is converted into the 1- (ethane-2 * -al) -5-hydroxymethyl-2-pyrrolidone (XXIII) in the reaction mixture itself, which is converted to the hemiacetal derivative (XXIII) compound / exists in equilibrium. The step / g / step is actually a Wittin reaction of a balanced mixture of bicyclic D, 4, OJ nonan-5 on a phosphonate of the formula Ph ^ P ^ CH / CH ^ / ^ Q, wherein the Q is as defined above. the protecting group to give the corresponding 2-pyrrolidone derivative XXIV, wherein A is a double chemical bond.

-6180.273

The reactions are carried out in such a way that epimerization on carbon 5, which is an optically active center, does not occur. Thus, starting from either of the two enantiomers glutamic acids, centers of asymmetry of the same configuration will be present in the product. Of course, when starting from racemic glutamic acid, a racemic or rac product is obtained.

In describing the process of the present invention, the 5-carbon position of the intermediates and the products is given by the γ-configuration, but the 5-carbon configuration is also provided, provided that the starting glutamic acid is suitably configured.

Condensation and esterification of D-glutamic acid. in the first two reaction steps to yield the corresponding D-methylpyroglutamate of Formula XXVII Qlardegger et al., Helv. Chem. Acta, 38, 312, 1955; and Segel, J. Am. Chem. Soc., 74, 851, 1952].

The third and known reaction step, according to equation A, is the reduction of the 5-carboxymethyl group of D-methylpyroglutamate to give 5-D-hydroxymethyl-2-pyrrolidone. The reaction is preferably carried out according to the method of Bruckner et al., Acta, Chem. Hung. Volume 21, 106, 1959] ·

The reaction is carried out by reacting the D-methylpyroglutamate with lithium borohydride in anhydrous tetrahydrofuran or an ethereal solution of rh, and stirring is continued until the reduction is substantially complete. According to the disclosed method, after isolation of the product, it has the structure shown in formula XXVIII

5-D-hydroxymethyl-2-pyrrolidone is obtained.

In order to alkylate the amide nitrogen atom of 5-D-hydroxymethyl-2-pyrrolidone, the hydrogen atom of the 5-hydroxymethyl group is protected by the known tetrahydropyranyl group. This reaction (reaction equation A, reaction step b) is preferably carried out in the presence of 5-D-hydroxymethyl-2-pyrrolidone in the presence of an organic acid such as para-toluenesulfonic acid in a non-reactive organic solvent such as methylene chloride, chloroform, tetrahydrofuran or diethoxy. in ethane with dihydropyran. The reaction is preferably carried out at a temperature in the range of 0 ° C to the reflux temperature of the reaction mixture, most preferably at room temperature. After the reactants are completely converted to 5-D &apos; -tetrahydropyran-2'-yloxymethyl / -2-pyrrolidone XXV The reaction is usually carried out overnight. The product is isolated after basic extraction to remove the organic acid, removal of the solvent and excess dihydropyran under reduced pressure. The product is then generally purified by column chromatography.

Other protecting groups which are capable of protecting the hydroxyl groups from alkylation may also be used in the reaction. Examples of such groups are benzyl, acetyl, dimethyl tert-butylsilyl and 1-ethoxyethyl. These protective opiates may be readily formed on the 5-hydroxymethyl group by known methods. Their selection for synthetic reactions depends on the protecting group on carbon number 7 *. For example, if the acidic hydrogen of the 7-carbon tetrazol-5-yl group (Q) is to be protected with an N-tetrahydropyran-2-yl group, the hydroxy group substituted on the 3-carbon group is acetyl or dimethyl tert-butyl. silyl group (T).

-7180.273

Shown in Formulas XXI and XXII l- / alkylated / -2-pirrol.idon derivatives prepared by two reactions, emelyeket 5-D / ^{tetrahydro-pyran-2-yloxy-methyl} / -2-pyrrolidone any T group. The first step is to prepare the sodium or lithium salt of pyrrolidone XXV by reacting a compound of formula XXV with a base such as n-butyllithium, phenyl lithium in an inert organic solvent such as tetrahydrofuran, diethoxyethane or dioxane. , or preferably with sodium hydride. The salt formation is carried out at room temperature to the boiling point of the reaction mixture, preferably at room temperature. All bases must react before starting the alkylation reaction, which usually requires 1-4 hours. Subsequently, the 1- (alkyl) -2-pyrrolidone derivatives represented by formulas XXI and XXII are prepared by reacting the 2-pyrrolidone lithium or sodium salt of the above formula with a structure represented by the formula XXVI or With an alkylating agent of the formula XCH ₂ OH / 0Y / ₂ , wherein

X is chlorine, iodine or preferably bromine;

W and Q are as defined above, and wherein

Y is C 1-3 alkyl.

This second part of the alkylation reaction is generally carried out by adding a solution of the alkylating agent in a previously defined non-reactive organic solvent, or preferably a polar aprotic organic solvent such as dimethylformamide or dimethylacetamide, to form pyrrolidone XXV. a solution of the sodium or lithium salt thereof prepared in a non-reactive organic solvent as described above and then reacting the sodium or lithium salt of 2-pyrrolidone with the reaction mixture at room temperature and the reflux temperature until the alkylation reaction is substantially complete ; the reaction time is usually 16 hours.

2-alkylated pyrrolidones obtained after XCH ₂ CH / 0Y / alkylating agent ₂ can be prepared by reaction of the formula with an alkylating agent of the formula XCH ₂ C0 ₂ Et in such a manner that, after the alkylation of the resulting l- / ² ethyl acetate-5- The ester group of the (substituted) -2-pyrrolidone is converted to the aldehyde group by selective conversion.

When an acidic hydrogen atom is present in the Q group, the alkylation reaction is most conveniently carried out by protecting or removing this acidic hydrogen atom. For example, when R is hydrogen, it is most preferred to use an ester derivative which can be cleaved by alkali hydrolysis after completion of the synthetic reaction. In the case where Q is a tetrazol-5-yl group, the acid hydrogen atom is replaced by an acyloxymethyl group as described above, but can be replaced by a phthalidyl group. Daehne, J. Med. Chem. 607, 1970; Isaka et al., Chem. Pharm. Bull., 24, 102, 1967J, desire also with tetrahydropyran-2-yl. The first two groups used to protect the tetrazole-5-11-moiety are utilized by hydrolysis at the end of the synthesis / reaction equation /

-8180.273, however, the tetrahydropyranyl group is cleaved from the molecule under acidic conditions. In the following, unless; Unless otherwise stated, the acidic hydrogen atom of group W is protected. The nature of the chemical bonds between the 2 * and 3 'carbon atoms of the 2-pyrrolidone derivatives represented by the formula XXI is the nature of the A group of the formula XXVI and the alkylating agent used in the reaction Define. Depending on what kind of A synthesis end product the? 4 side chain is unsaturated or saturated; that is, it determines whether the final product is 8-aza-11-deoxy-PGE or an 8-aza-deoxy-pge ₂ .

It will be appreciated that the chemical bond W determines the nature of the chemical bond between the 2 'and 3 * carbon atoms of the O &apos; side chain and the pyrrolidone derivative wherein W is a double bond, to a pyrrolidone where W represents a single chemical bond. For example, the 2-pyrrolidone derivative of formula XXI in which A represents a double chemical bond is reacted with a metal catalyst such as palladium on carbon at room temperature / adsorption of one equivalent of hydrogen to give a 2-pyrrolidone of formula XXI wherein means a single chemical bond. For the foregoing, see Compound XXIX, wherein W represents a double chemical bond, which, upon hydrogen uptake, is converted to compounds of Formula XXX, in which the chemical bond between the 2 'and 3' carbon atoms is single.

In both cases, the following procedure is followed by cleavage of the T group by known methods (reaction equation A, reaction step d). The thus prepared 2-pyrrolidone derivative of general formula XXIV, wherein W and A are synthesized by the above-described syntheses described in Reaction B, C and D to form a novel end product of the invention.

The 2-pyrrolidone derivatives of Formula XXIV may also be prepared by hydrolyzing a 2-pyrrolidone of Formula XXII (Y and T in Formula XXII, as defined above) to a Ph 2 -PsCH / CH 2 wherein Q is as defined above and is not protected, such as a carboxyl group or a tetrazol-5-yl group. See U.S. Patent No. 3,953,466 for the synthesis of tetrazol-5-yl-phosphorane.

This reaction, illustrated in steps f and g of reaction equation A, can be carried out as follows. In the case where the T protecting group, the preferred tetrahydropyran-2-yl group in the compounds of formula XXII, is acidic hydrolysis of this compound with acetic acid commonly used to cleave the acetal group in an aqueous mixture at 40 ° C. the tetrahydropyran-2-yl group and the acetal group are cleaved to give 1- (ethan-2 * -al) -5,3-hydroxymethyl-5H-pyrrplidone, which is 4-aza-2-hydroxy-1-yl. oxabicyclo [4,3,3] nonanan-5-one (XXIII) is in equilibrium.

The equilibrium mixture containing the hemiacetal shown in Formula XXIII can then be reacted with two equivalents of phosphorane as described above for a polar,

-9180.273 in an aprotic solvent such as dlmethylsulfoxide or a mixture of a polar aprotic solvent and an ether such as dimethylsulfoxide and tetrahydrofuran at a temperature between 0 ° C and 60 ° C, usually overnight to give a compound of formula XXIV, where A is a double bond. Note that the acidic hydrogen atom or Q group can then be protected as an ester in the case of a carboxylic acid, or in the case of a tetraalol-5-yl group as an N-acyloxymethyl, N-phthalidyl or N-tetrahydropyran-2-yl. 2-pyrrolidone of general formula (A) wherein A represents a double chemical bond and may, if desired, be converted to the 2-pyrrolidone of general formula XXIV by hydrogenation as described above wherein A represents a single chemical bond,

The following describes the preparation of the 2-pyrrolidone derivatives of Formulas XXXIII and XXXIV by oxidation of the 5/3 hydroxymethyl group of 2-pyrrolidones of Formula XXIV to give the 5'-formyl-2-pyrrolidone derivatives of Formula XXXI. Horner-Wittig's reaction with the sodium or lithium salts of the phosphonates of the formula (MeO ^ POCI ^ COCHg) (where R 'has the meaning given above) and the 2-pyrrolidones of formula XXXII thus obtained are 5- / 4' '- by reduction of a substituted -but-1 ** -en-J''-onyl.

The reaction sequence outlined above, i.e. the bonding of the to side chain to the molecule, is illustrated in Reaction B,

To produce the aldehyde XXXI, 5/9-hydroxymethyl-1-2-pyrrolidone XXIV is subjected to modified Pfitzner-Moffatt oxidation by PPfitzner and Moffatt, J. Am. Chem. Soc., 87, 5661 (1961). wherein the 5/4-boiling 1-derivative of formula XXXI is not contacted with water * By using 1 - [(methoxycarbonyl) hexyl] -5, 4-hydroxymethyl-2-pyrrolidone or other suitable 5 -? a suspension of hydroxymethyl-2-pyrrole in a non-reactive organic solvent, such as toluene, xylene or preferably a mixture of benzene and dimethylsulfoxide with a weak acid such as acetic acid or preferably pyridinium trifluoroacetate and a water-soluble, such as diethylcarbodiimide, or preferably dimethylaminopropylethylcarbodiimide, if necessary, with their hydrochloride salts, at 0 ° C to room temperature for 1 to 4 hours. In each case, the primary alcohols XXIV are oxidized to the aldehydes XXXI. The oxidation may be carried out using the conventional Pfitzner-Moffatt reaction or the chromium trioxide-pyridine complex [Ratcliffe et al., J. Org. Chem., 35, 4000, 17703, but preferably the reaction described in more detail above. «

For the preparation of the 5 '- (4'')-butyl-1'<-en-3'-onyl / -2-pyrrolidone derivatives of Formula XXXII, a 5-O-formyl-2-pyrrolidone compound of Formula XXXI is prepared using XXXV a phosphonate of the formula wherein R 'is reacted with its sodium or lithium salt as defined above. The reaction, which in solution or suspension removing _r week, an ether such as tetrahydrofuran, dimethoxyethane or dioxane is prepared, the reaction temperature was adjusted to 0 C and 50 0 C, the reaction is carried out until the analytical test of the complete did not change. On this

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The product of the Horner-Wittlg reaction is isolated by chromatography known to those skilled in the art. Isolation may also be effected by other means, such as high performance liquid chromatography or, in some cases, by fractional crystallization. See U.S. Patent No. 3,932,389 for the preparation of phosphonates.

Reduction and optionally alkaline or acidic hydrolysis of the compounds represented by formula XXXII yields several end products of the invention, wherein Q is R ^{0 -C} &^gt; ^-tetrazol -5-yl. The reduction is preferably lithium triethyl. but other selective reagents, such as zinc borohydride or sodium borohydride, which do not reduce other groups than the ketone group may be used. The reaction mixture is preferably prepared with an ether such as tetrahydrofuran or diethyl ether. The reaction is carried out at a temperature dependent on the activity of the reducing agent, and in most cases is kept in a bath of a suspension of dry ice and acetone.

Under normal reaction conditions, the reduction of the but-1 * '- en-3' '- onyl group of the pyrrolidones of formula XXXII gives rise to two 2-pyrrolidone derivatives which are diastereoisomers in stereochemistry. These two compounds are the 3 * &gt; -OH-hydroxy derivatives represented by the formula XXXVI and the 3 * '/ 3-hydroxy derivatives represented by the formula XXXVII. These two compounds, which can be separated by known methods, such as high performance liquid chromatography, are obtained in each case by the above method; both are present even if only the presence of the azo-isomer is indicated. In the absence of separation of the two diastereomers. to give a mixture of the two compounds, designated as XXXVIII; the structure means that both 0ζ and β epimer are present in the mixture.

After isolation of the products of the above reduction reaction in a conventional manner, it is possible to cleave the

A protecting group for Q substituted with 7 carbon atoms; cleavage is carried out by a known reaction to remove such types of groups. For example, when Q is an alkyl ester and the acid is to be prepared, alkaline hydrolysis is carried out with an equivalent amount of base present at room temperature and the reflux temperature of the solvent, usually overnight; after neutralization, the carboxylic acid is obtained. Similarly, the phthalidyl and acyloxymethyl groups may be cleaved using an acid such as aqueous acetic acid or methanolic p-toluenesulfonic acid to cleave the tetrahydropyran-2-yl group (THP) at room temperature and 5 ° C to 0 ° C. and usually overnight.

Compounds of Formulas XL and XLI which are within the scope of the invention, wherein W and Z are a single bond, are 3 * * -tetrahydropyran-2 * * * -yloxy derivatives of XXXIX, wherein XXXIX in the general formula W is a single chemical bond prepared by catalytic reduction. The reaction sequence is illustrated in Reaction C.

Compounds of formula XXXIX wherein W is a single bond, tetrahydropyran-2 * * '-yloxy; the general formulas of XXV! 5-D- / tetrahydropyran-211 shown

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prepared by repeating the procedure described for the preparation of -1-oxy-methyl--2-pyrrolidones. The reaction is carried out by hydrogenation of a reagent in the presence of a noble metal catalyst such as palladium on carbon or platinum oxide in a reaction mixture with a solvent such as ethyl acetate, methanol or ethanol at a temperature ranging from room temperature to the boiling point of the reaction mixture; then removing the tetrahydropyran-2 ** -yl group and optionally the W protecting group, whereby the 8-aza-11-deoxy-prostaglandin Εθ derivatives of structure XLIII can be prepared,

Compounds within the scope of the invention wherein Q is R''HNOC are prepared from tetrahydropyran-2 '' '- yloxy derivatives of the compounds represented by formulas XXXIX and XLIII; W in the general formulas represents a carboxyl group. The reaction sequence is shown in Reaction D, where R * 'has the meaning given above. Acid derivatives XLIV and XLV are prepared by reactions well known in the preparation of imide and sulfonimide derivatives of carboxylic acids. Preferably, the process described by Speziale and Hurd is carried out according to the process, whereby the above derivatives of the compounds of formula XLIII are prepared in a solvent mixture, for example ether or tetrahydrofuran, at room temperature to the reflux temperature of the reaction mixture, usually overnight. isocyanate. See Speziale et al., J. Org. Chem., 30, 4306, 1965; Hurd es Prap, J. Org. Chem., 24, 388, 19> 9; Survey of Organic Synthesis, Beuhler, Perason, Wiley Interscience, New York, 1970; Reactions of isocyanates with carboxylic acids; March, Advenced Organic Chamistry; Reactions, Mechanism and Structure, McGraw-Hill, New York, 1968, p. 340, N-acylation of amides and imides.

There are several other methods for preparing the starting compound of the process of the invention, wherein Q is a R''HNOC group. In one such embodiment, the 5- / 4 * '- substituted-but-1' '- en-3 *' - onyl / -2-pyrrolidone of Formula XXXII, wherein W is carboxyl, is the Speziale-Hurd method. Reaction with acyl or sulfonyl 1 isocyanate.

In another preferred embodiment, the nonanone of Formula XXIII is condensed with a phosphorane of Ph 2 P 2 OH / GHg / µCONHR * ', as described for the preparation of a compound of Formula XXXIV from a nonanone of Formula XXIII. After reduction by hydrogenation, 5 and

A double bond, having a carbon atom of 6, gives the pyrrolidone intermediate of structure XLII.

The above pyrrolidone-carboxamide intermediate is analogous to the pyrrolidone derivative of formula XXI1 and can be converted according to Reaction Equation B into compounds of the invention wherein Q is an R 1 'HNOC group ₀

Esters wherein Q is carboalkoxy, carbophenoxy or carbo-para-biphenoxy are prepared from the corresponding carboxylic acid derivative by reactions known in the art, C 1 -C 5 diazoalkanes, phenols or para-biphonones, or dicyclohexylcarbodiimide esters. trainers.

-12180,273

The novel prostaglandin derivatives of the present invention have a greater selectivity, potency and prolonged physiological activity than natural prostaglandins according to numerous in vivo and in vitro assays. These studies included effects on smooth muscle isolated from guinea pig uterus, inhibition of histamine-induced bronchospasm in guinea pigs, effects on canine blood pressure, inhibition of stress-induced ulcer formation in rats, diarrheal effects in mice and rats, and inhibition of secretion.

Physiological responses obtained in these studies may be used; and the cost of treating the test compound with various natural and pathological conditions. Thus, it can be determined whether the test compound has vasodilatory, antihypertensive, bronchodilatory, anti-fertility and anti-gastric ulcer activity,

The 8-aza-II-deoxy-prostaglandins produced by the process of the present invention exhibit significant selective activity over their corresponding naturally occurring prostaglandins, but in most cases have a prolonged action. For example, the prostamimetric pyrrolidones containing aryl (phenyl, substituted phenyl and o-thienium 1) and Q at the carbamyl, ester or tetrazol-5-yl group of the invention may be used with vasodilatory activity. They have. The following pyrrolidone derivatives are of particular therapeutic interest: 1- (6'-carboxyhexyl) -5β- [3 * '-hydroxy-4''- phenyl-bat-1 * * -enyl] -2-pyrrolidone and l- (6'-carboxy-hexyl) -? -? - (3 '') -hydroxy-4 · '* -phenylbut-1''- enyl] -2-pyrrolidone, which is disclosed in U.S. Patent No. 3,956,284. administered intravenously to anesthetized dogs as described above, exhibiting the same antihypertensive activity as PGE ₂ . When the bronchodilatory and antiulcerating or other effects are investigated according to U.S. Patent No. 395θ 284, they are found to be greatly reduced with respect to PGE 4.

Another class of pyrrolidones produced by the process of the present invention is of outstanding therapeutic importance because of its selective anti-ulcer activity. These compounds contain R ₂ at aryloxy group (including phenoxy-substituted phenoxy group), while Q at carboxy group contains a carboxylic ester or an imide group, a tetrazol-5-yl group or a sulfonyl group. 1- (6'-Carboxy-hexyl) -5 / 3- / 3 '' -hydroxy-4 '' -phenoxybut-1 '' -enyl / -2-pyrrolidone, for example, has outstanding and selective antisecretory activity in dogs. .

The novel compounds of the present invention may be used as pharmaceutical compositions containing the active compound or a pharmaceutically acceptable salt thereof. The compositions may be administered in various ways, depending on the condition and condition of the subject being treated.

The 8-aza-11-deoxy-16-aryl-CO-tetranor prostaglandin derivatives of the present invention and their

-13180.273 eplmer signal vasodilators useful in practice. For the treatment of hypertension, the compounds are preferably administered by intravenous injection at a dose of 0.005-0.5 mg / day, preferably in the form of capsules or tablets, of 0.5 to 10 mg / day, preferably in the form of capsules or tablets.

The 8-aza-11-deoxy-16-aryloxy-O-tetranor-prostaglandin derivatives of the present invention and their epimers are advantageously used as anti-gastric agents. For the treatment of peptic gastric ulcer, the compounds are preferably in the form of capsules or tablets, daily and body weight. Between 0.005 mg and 0.5 mg,

For the above purposes, pharmaceutically acceptable salts useful for this purpose are prepared with pharmaceutically acceptable metal ions, ammonium lipids, amines or quaternary ammonium cations.

Preferred metal cations are cations of alkali metals such as lithium, sodium or potassium, calcium cations of alkaline earth metals such as magnesium, although other metals such as aluminum, zinc or iron may also be used; these compounds would fall within the scope of the invention.

Pharmaceutically acceptable amine salts are prepared with primary, secondary or tertiary amines. Examples of amines are methylamine, dimethylamine, triethylamine, ethylamine. dibutylamine, triisopropylamine, N-methylhexylamine, decllamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, phenylethylamine, phenylethylamine, ethylenediamine, diethylenediamine, diethylenediamine, cycloaliphatic or araliphatic amines having up to 18 carbon atoms, but also heterocyclic amines such as piperidine, morpholine, pyrrolidine, piperazine and lower alkyl derivatives such as 1-methylpyrrolidone, 1,4-dimethyl-1 methylpiperidine and others; salts of amines which promote water solubility or hydrophilic groups may be prepared, for example, mono-, di- and triethanolamine, ethyl-diethanolamine, N-butyl-1-ethanolamine, 2-amino-1-butanol, -1, N-propanediol, 2-amino-2-methyl-1-propanol, tris-hydroxymethyl-1-aminomethane, N-phenyl-1-ethanolamine, N-p-tert-amine 1-phenyl N-diethanolamine, galactamine, N-methylglucamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine and the like.

Preferred pharmaceutically acceptable quaternary ammonium salts are prepared, for example, with tetramethylammonium, tetraethylammonium1, benzyltrimethylammonium, phenyl 1-triethylammonium or the like.

The compounds of the present invention are administered in a variety of pharmaceutical formulations, and may contain various inert diluents, exoipients, or excipients. These materials include, for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, cholesterol, and other known pharmaceutical carriers. If necessary, excipients such as preservatives, wetting agents may be added to these pharmaceutical compositions. stabilizers, or other therapeutically active substances such as antibiotics.

The invention is further illustrated by the following examples. The examples are illustrative only and are not intended to limit the scope of the invention.

-1418C.273

The spectra were determined on a Varian T-60 or A-60 nuclear magnetic resonance spectrometer, a Perkin-Elmer infrared spectrometer and a LKB-9000 mass spectrometer. Infrared spectral data are in reciprocal centimeters, and nuclear magnetic resonance spectral data are expressed in parts per million against TMS standard material.

The reactions set forth in the Examples, unless otherwise stated, are carried out at room temperature, which is from 15 ° C to 30 ° C.

Unless otherwise stated, the time required for the reactions given in the Examples is determined by thin layer chromatography. Silica gel coated on a glass plate (Merek Silica Gel Sheets, Merek, Darmstadt, Germany) was used as a thin layer chromatography system, eluting with a mixture of benzene and ether or methanol and chloroform, eluting with ethanol vanillin or iodine. Van Nostrand-Reinhold, New York, 196. As a general rule, the reaction in question is considered to be substantially complete when the thin layer chromatography spot corresponding to that starting material has disappeared or changed.

Preparation of O - (Tetrahydro-pyran-1'-yloxymethyl) -2-pyrrolidone (XXV)

In a flame-dried flask under nitrogen

2.55 g (22.1 mmol), Btruckner et al., Acta Ghom. Hung. 5-D-Hydroxymethylene-2-pyrrolidone (Tomus, 21, 106, 1959) and methylene chloride (50 ml) were poured. Cool the solution to 0 ° to 5 ° C and then

3.72 g (44.2 mmol) of redistilled dihydropyran and 0.2 g of para-toluenesulfonic acid are added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with ethyl acetate (20 mL), extracted with saturated aqueous sodium bicarbonate (2 x 5 mL), and then extracted with saturated aqueous sodium chloride (1 x 10 mL). The organic solvent phase was dried over magnesium sulfate, filtered to remove magnesium sulfate, and then distilled under reduced weeds to remove the solvent; 4.1 g of product are obtained in the form of a yellow oil.

The oily material was chromatographed on a 50 g Merek silica gel column in chloroform. Elution with one liter of chloroform removes less polar impurities. Elution with 2% chloroform in methanol was continued and 10 ml fractions were separated to isolate and purify the product. The product-containing fractions were combined and the solvent removed by distillation under reduced pressure to give 3,95 - (tetrahydropyran-2 * -yloxymethyl) -2-pyrrolidone as a pale yellow oil: Yield: 90% Nuclear Magnetic Resonance Spectrum of the prepared compound (T-60) / DCC1, J: 6.60 ppm, broad singlet, (1H); 4.60 ppni, multiplet, -¼ H /; 4.05-3.25 ppm, multiplet, (5H); 2 ^ 50-2.10 ppm, multiplet; 2.00-1.40 ppm, multiplet, 1 OH.

The infrared absorption spectrum of the compound in chloroform shows absorption at the following wavelengths! maximum: 3425, 2980, 2930, 2850, 1680, 1250-1200, and 1025 cm ^-1 :

-15Ιθθ.273

Alternatively, the dimethyl-tert-butylsilyl protecting group may be used in place of the tetrahydropyren-2-yl group, in which case Corey et al., J. Am. Chem. Soc. D-hydroxymethylene-2-pyrrolidone,

Example 2

Preparation of 1- (ethoxycarbonylhexyl) -5, 5 '- (tetrahydropyran-2' * -yloxymethyl) -2-pyrrolidone

A flame-dried reaction vessel containing nitrogen was charged with 0.725 g / 18.7 mmol / 62% sodium hydride in mineral oil and 10 ml of anhydrous tetrahydrofuran. Stir the mixture and stir slowly (3.74 g / 18.7 mmol). 5-D- (Tetrahydropyran-2-yloxymethyl) -2-pyrrolidone in 10 ml of anhydrous tetrahydrofuran was added. After the addition is complete, the slurry is stirred for 50 minutes, during which time hydrogen evolution ceases. Then, the sodium salt is subcloned.

Ethyl 7-bromoheptanoate (5.34 g, 22.5 mmol) in anhydrous dimethylformamide (15 mL) was added dropwise to the room temperature suspension. The addition is complete after about 15 minutes, by which time the suspension is dissolved and the sodium bromide slowly precipitates out of solution. After stirring overnight, the reaction mixture was filtered, and the solvent was removed from the filtrate by distillation under reduced pressure. Ethyl acetate (100 mL) was added to the distillation residue and the solution was extracted with water (2 x 20 mL). The organic solvent phase was dried over anhydrous magnesium sulfate, filtered to remove the salt, and then distilled under reduced pressure to remove the solvent; The residue was obtained by distillation to a yellow oily product * which was chromatographed on a column of 120 g Merek with silica gel using chloroform. Elution is carried out with 250 ml of chloroform, 500 ml of 5% ethyl acetate in chloroform and 1000 ml of 10% ethyl acetate in chloroform is added to 10 ml of fractions which allows the product to be isolated and purified. The product-containing fractions were combined and the solvent was removed by distillation to give 1.39 g of 1- (ethoxycarbonyl) -hexyl-5,3-tetrahydro-pyran-2 * '-yloxymethyl--2- as a colorless oil. obtaining pyrrolidone; yield 51% «

Magnetic resonance spectrum of the product obtained

quintet; Jp 8Hz; 4.00 - 2.70 ppm, multiplet, (9H); 2.6-1.4 ppm, multiplet; 1.3 ppm: triplet; J8: 8Hz, / 25H /.

The infrared absorption spectrum of the prepared compound in chloroform solution exhibits absorption maxima at the following wavelengths: 2975, 2915, 2840, 1720, 1665, 1450, 1250-1200, 1125, 1025 οι ¹ , '

M / e%: 356-1%, 355-3%, 310-17%, 240-100%, 194-83%.

The above procedure also provides pyrrolidones of the formula XLVI by using the appropriate alkylating agent in place of ethyl 7-bromoheptanoate, and preferably pyrrolidone XXV, dinethyl milk; analog is used. THE

-16180,273

In formula XLVI, X ^H 5 ° ^C 6 ° ^C 2 'CH 2 O 8 C-, N- (tetrahydropropran-2-yl) -tetrazol-5-H- · N- (aoethyloxymethyl) -tetrazol-5-yl- A represents a single or double bond at the O-position and finally T represents tetrahydropyranyl or dimethyl tert-butylsilyl.

As stated, 1- (azubstituted) -5- [4- (tetrahydropyran-2-yl) oxymethyl or dimethyl-tert-butylsiloxylmethyl] -2-pyrrolidones can be prepared by reacting ethyl Instead of -7-bromoheptanoate, the appropriate alkylating agent is used. Thus, for example, if 1- (6 * -carboxymethylhex-2 * -enyl) -5- [4- (tetrahydro] pyrran-2 ** -yloxymethyl] -2-pyrrolidone is prepared, methyl-7- bromohept-5-enoate is used as the alkylating agent. In the case that 1- [6 * -1 * '* - aoethyloxymethyltetrazol-5' * '- ylhexyl] -5 - [(tetrahydropyran-2' ') yloxymethyl] -2- Pyrrolidone was prepared using 6-bromo-1- (1'-acetyloxymethyl) -tetrazol-5'-yl] -n-hexane as alkylating agent.

1- (2,2-Diethoxyethyl) -5H-tetrahydropyran-2'-yloxymethyl-2-pyrrolidone can be prepared by a similar procedure using 2-bromo-ao-etaldehyde-diethyl-ethyl as the alkylating agent.

6-Bromo-1-tetraBol-5'-yl-n-hexane was prepared as follows using ² x 98 g / 23.5 mmol / 7-hydroxy-heptane nitrile. 1 ^ 60 g / 30.0 mmol / ammonium chloride, 0.032 g / 0.76 mmol / 11thium chloride, 1.91 g / 29.3 mmol / sodium azide / 50 ml of dimethylformamide were added and then at 120 ° C under nitrogen for 18 hours. , or stir the reaction mixture until the reaction is complete. By distillation under reduced pressure, the dimethylformamide is removed and the distillation residue is purified by known methods such as chromatography or extraction. The pure product, 6-hydroxy-1- (tetrazol-5-yl) -hexane, is reacted with phosphorus tribromide under appropriate reaction conditions to give 6-bromo-1- (tetrazol-5-yl) -hexane. The N'-acetyloxymethyl moiety of the compound was coupled to the compound following the procedure of Example 1, following the method of Daehne et al., Supra.

In the case where the 7- (tetrahydropyran-2 * -yloxy) -hept> -5-indonitrile is reacted as described above, the 6- (tetrahydropyran-2'-yloxy) -1-yl- tetrazol-5 * -yl / -hex-4-int is obtained. This compound is disclosed in U.S. Patent No. 2,121,361, which is incorporated herein by reference. A. 7θ → 24,712 <Γ] can be converted to 6-bromo-1- (tetrazol-5'-yl) -hex-4-ene. Of course, the starting compound, hept-5-indonitrile, can also be converted to azolefin by hydrogenation. before converting the nitrile to tetrazole by a substantially similar process. The acidic hydrogen protecting groups of the tetrazol-5-yl group are attached to the molecule as described above.

Example 3

Preparation of 1- (methoxycarbonylhexyl) -5, N - (hydroxymethyl) -2-pyrrolidone

In methanol (200 mL), 3 x 99 g of tetrahydropyranpyrrolidone prepared in Example 2 were dissolved and 79 mg of para-toluenesulfonic acid was added. The reaction mixture is refluxed overnight. After isolation of the product (see below), the compound is examined by nuclear magnetic resonance spectroscopy. According to the study, the amount of climax starts17

-17180.273 of the ethyl ester is present. Therefore, the reaction mixture is redissolved in 160 ml of methanol, 0.080 g of para-toluenesulfonic acid is added and the mixture is refluxed overnight. The solvent was removed by distillation under reduced pressure to give a yellow oil. It was dissolved in ethyl acetate and extracted with 10 ml of a 1: 2 mixture of saturated aqueous sodium bicarbonate and semi-saturated RocheHe brine. The organic solvent phase was dried over magnesium sulfonate, filtered and the solvent was distilled off. Distillation residue gave 2.528 g (88%) of 1- (megoxycarbonylhexyl) -5 Z 3 - (hydroxymethyl) -2-pyrrolidone as a clear yellow oil.

In the nuclear magnetic resonance spectrum of the prepared compound (A-60 / DCCI), the peaks at 3.86 ppm, singlet 4.00-3.33 ppm, multiplet; 3.20-270 ppm, multiplet, (13H); 2.50 - 2.00 ppm, multiplet; 1.90-1.20 ppm, multiplet, (10H); partial spectrum.

The infrared absorption spectrum of the prepared compound in the chloroform solution shows absorption maxima at the following wavelengths: 355θ ”, 3180, 2980, -2910, 2840, 1720, 1650, 1450, 1425, 1410, 1250-1190 cm-1.

Mass Spec for LKB 9000 Mass Spectroscopy: Input / w / w% / 70 eV: 226-26%, 194-19.8%, 74-100%, 13 eV 257-3.3%, 226-100%. , 168-24.6%.

A 65:35 mixture of glacial acetic acid and water may also be used to hydrolyze the tetrahydropyran-2 * ♦ * -yl group. The procedure was carried out essentially as in Example 14 for about 18 hours.

In this case, the diethyl ester of the tetrahydroplanylpyrrolidone prepared in Example 2 remains intact.

The following hydrolysis with aqueous acetic acid may also be used to cleave the tetrahydropyranyl protecting group of other pyrrolidone derivatives prepared as in Example 2 to give the corresponding 1-substituted / -5 / 3-hydroxymethyl-2-pyrrolidones. In the case where the tetrazol-5-yl protecting group is tetrahydropyran-2-yl, the preferred T group is dimethyl tert-butylsilyl. This silyl group may be selectively cleaved from the molecule using n-butylammonium fluoride according to Corey's method described above.

The acetic acid reaction was carried out by cleaving the tetrahydropyranyl group using 1- (2,2-dlethoxyethyl) -5- (tetrahydropyran-2 * 1'-yloxymethyl) -2-pyrrolidone prepared as in Example 2. interacts with the cleavage and cyclization of the acetal group to give a product of the equilibrium mixture of 4-aza-2-hydroxy-1-oxabicyclo [alpha] 5,4, nonan-5-one of formula XXIII and the compound containing the opened ring.

The equilibrium mixture containing the closed cyclic compound according to equation XXIII is converted to the 1- (substituted) -4-hydroxymethyl-2-pyrrolidones as follows.

23.4 g (52.0 mmol) of triphenyl- (4-carboxybutyl) -phosphanium bromide in 46 ml of anhydrous dimethylsulfoxide are treated dropwise with 2.0 N sodium methylsulphinyl methide in 49.3 ml (98.6 mmol) of dimethylsulphoxide solution. To the resulting red solution is then added, over a period of one hour, 3.27 g (20.8 mmol) of 4-aza-2-hydroxy-1-oxabicyl chloro [5,4,15] nonan-5-one in 63 ml of anhydrous dimethylsulfoxide. . More for half an hour

The reaction mixture was stirred at -18180.273, then poured into 600 ml of ice water and extracted with ethyl acetate (2 x 300 ml). Ethyl acetate was poured into the cold aqueous phase and H was added with 10% hydrochloric acid.

After adjusting to 3, the aqueous phase was extracted with ethyl acetate (2 x 200 mL). The organic extracts were combined, washed with water, brine, and dried over anhydrous sodium sulfate. The filtered organic solvent solution is then concentrated to give crude 1- (6'-carboxyhex-2'-enyl) -5 / 3-hydroxymethyl-2-pyrrolidone. The product was purified by chromatography. The resulting pure acid is esterified with diazomethane.

The process described above can also be used to prepare the 1- (substituted) -5- [N-hydroxymethyl-2-pyrrolidones of formula XLVII, wherein X is as defined in Example 2. The reaction is carried out by using the appropriate phosphonium salt instead of the triphenyl- (4-carboxybutyl) -phosphonium salt and protecting the acidic hydrogen atom with an N-acyloxymethyl group as described previously by Daehne et al. The acidic hydrogen atom can also be protected by N-tetrahydropyran-2-yl as described in Example 1 or, in the case of carboxylic acid, by esterification.

Example 4

Preparation of 1-methoxycarbonyl-1-hexyl-5H-formyl-2-pyrrolidone

In a flame-dried nitrogen flask was added 0.1286 g (0.5 mmol) of 1-methoxycarbonylhexyl / -5Z, 4-hydroxymethyl-2-pyrrolidone dissolved in 5 ml of anhydrous benzene. 0.1286 g (1.5 mmol) of dimethylaminopropylethylcarbodiimide hydrochloride (DAPC), 0.142 ml (2 mmol) of dimethylsulfoxide and then, after about 5 minutes, 0.108 g (0.55 mmol) of pyridinium trifluoroacetate are added to the solution. . The reaction mixture was stirred at room temperature under nitrogen for 1.75 hours, then the benzene was decanted off and the viscous second phase was washed with 3 x 5 mL benzene. Combine the benzene solutions and remove the solvent by distillation under reduced pressure to give 0.152 g of 1- (methoxycarbonylhexyl) -5Z, 4-formyl-2-pyrrolidone as a clear, yellow oil. The crude product was used without further purification in the following reaction.

Nuclear Magnetic Resonance Spectrum of the prepared compound (T-60) / DCCl2, t doublet, 9.72 ppm, Jp 3 Hz, 1H. multiplet, 4, 37-4.07 ppm, (1H); singlet, 3.70 ppm, (3H). / Partial spectrum./

The following procedure is used to oxidize other 1- (substituted) -5Z3-hydroxymethyl-2-pyrrolidones prepared as described in Example 3 to the corresponding 1- (substituted) -5, 6-formyl-2-pyrrolidones. - - .... ...........

5 »example

Preparation of 1- (methoxycarbonylhexyl) -5 [t] - [4 '' - phenylbut-1 * '- en-3 *' - onyl] -5-pyrrolidones

Into a flame-dried nitrogen flask was added 0.1188 g (2.97 mmol) of mineral oil, 60% sodium hydride and 5 ml of tetrahydrofuran. To the suspension thus prepared, 0.7815 g of methyl 3 - [(3-phenylpropan-2-one) phosphonate dissolved in 5 ml of tetrahydrofuran was added.

-19180.273. After the evolution of white hidi'ogéngáz suspending boarding ⁷ is formed which is stirred for 15 minutes. Subsequently, 0.6894 g (2.70 mmol) of 1 - [(methoxycarbonylhexyl) -5 / 2] -2-formyl-2-pyrrolidone in 10 ml of tetrahydrofuran is added to the suspension over a period of about one minute. Within 5 minutes, the reaction mixture turned to a clear yellow solution, followed by stirring for an additional 2 hours. The reaction mixture was adjusted to pH 5 with glacial acetic acid and quenched. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in 100 ml of ethyl acetate. Extract the organic solution with 2 x 10 mL of saturated aqueous sodium bicarbonate, 100 mL of water, and 1 x 10 mL of saturated aqueous brine. It was then dried over magnesium sulfate, filtered, and the solvent removed by distillation under reduced pressure. The residue was distilled to give 1.141 g of a yellow oily substance. This crude product was chromatographed on a column of 35 g Merek silica gel with ethyl acetate. Elution was carried out with ethyl acetate and 10 ml fractions were collected. The product containing fractions were combined and the organic solvent was distilled under reduced pressure to now remove Juk ^1, yielding a colorless oily substance from 0.614 g / yield: 61% based on the starting alcohol / l / methoxycarbonyl-hexyl / -5 / 3- / 4 ♦ ♦ -. phenyl-but-1 * * -en-3 * '-onyl--2-pyrrolidone is obtained.

Nuclear Magnetic Resonance Spectrum of the prepared compound (T-60) / DCCl3 / tJ: singlet, 733 ppm, (5H); 6.73 ppm, J 4: 7 Hz, Jg 16 Hz; doublet 6.60 ppm, Jg: 16 Hz, (2H); multiplet, 4.27 ppm, (1H); singlet, 3.93, (2H); singlet 3.73 ppm, (3H) (partial spectrum).

The infrared absorption spectrum of the prepared compound in the chloroform solution exhibits the following wavelength absorption maxima: 2980, 2900, 2840, 1725, 1685 / shade /, 1675, 1625, 1250-1200 cin · ¹ .

Mass spectrum (LKB 9000, m / e%). 70 eV 372-20%. 371-82%, 252-96%, 226-24%, 194-35%, 12 eV 372-18 371-100%, 252-24%, 226-39%.

Numerous other 1- (substituted) -5- (3-formyl-2-pyrrolidone derivatives of the related compounds of Example 4 can be used in the following procedure instead of 1- (7 * -methyl-heptanato) -5, N-formyl-2-pyrrolidone. for the preparation of the corresponding 1- (substituted) -5-3- (4'-phenyl-1-but-1'-en-3 * * -onyl) -2-pyrrolidone derivatives. In addition, instead of dimethyl- / 3-phenyl-propan-2-onyl / phosphonate may be used in / MeO / gPOCHgCOCHgZ the corresponding phosphonates of formula l- / substituted / -5 / ^ - / 4 * ⁱ -szubszti- substituted / for the preparation of -but-1''-en-3 * '-yl-2-pyrrolidone derivatives wherein Z 1 -C 3 -C 1 -C 2 -, (1 -C 2 -C 1 - 2) - Cg-H ^ Cg or ClH ^ C ^.

All pyrrolidone derivatives are listed below. including the 4 '* -phenyl derivatives are referred to as 1- (substituted) -5Z (4) *-substituted-but-1 *' -en-3 * '-onyl / -2-pyrrolidones, example

Preparation of 1- (methoxycarbonylhexyl) -5 / 3- (3 '' -hydroxy-4 '»-phenyl-but-1' * -enyl) -2-pyrrolidone

Flame-dried lom20 equipped with magnetic stirrer

-20 • 80.273 put a thermometer in the bik and then introduce nitrogen. 0.5784 g (1.56 mmol) of l-t-motoxycarbonylhexyl 1 -5-3- (4 '' -phenyl-but-1 '* -en-3' * -one) in 20 ml of anhydrous tetrahydrofuran. Pour -2-pyrrolidone into the flask. Cool the clear, colorless solution to -78 ° C and per osepsis. With the aid of an injection, 1.56 ml / 1.56 mmol / lithium triethylborohydride is added over 15 minutes. After one hour, thin layer chromatography showed that the initial enone concentrator was reduced to zero, so the reaction was stopped by adjusting the pH to 5 with glacial acetic acid. The solvent is then removed under reduced pressure. The distillation residue was dissolved in ethyl acetate (50 mL) and the organic solvent was extracted with half-saturated sodium bicarbonate (1 x 10 mL), water (4 x 10 mL), and brine (10 mL). The organic solvent phase was filtered off with soda-magnesium sulfate, filtered and the solvent removed by distillation under reduced pressure. 700 mg of crude product are obtained as a distillation residue. This was chromatographed on a column of silica gel (9 g) suspended in ethyl acetate. Elution with ethyl acetate. and collecting 5 ml fractions to isolate the product from impurities. The product-containing fractions were combined and the solvent was removed by distillation under reduced pressure to give 0.298 g of 1- (methoxycarbonyl-1-hexyl) -5 / 3/3 * -hydroxy-4 * '-phenyl-bub-1 * as a colorless oil. 1-ene-2-pyrrolidone is obtained; Yield 51%.

Magnetic Resonance Magnetic Resonance Spectrum of the compound prepared was (T-60) / DCO11 - / - cT singlet, 7.37 ppm, δ H / doublet, 5.72 ppm, J7 Hz; doublet, 5.6? ppm, J1: 7 Hz, (2H); tnu

4.67-4.3.3 ppm; multiplet, 4, JO-3.83 ppm, / 2H / singlet,

3.73 ppm, (3H); doublet, 2.90 ppm, J ₂ t 6Hz, (2H), (partial spectrum).

It is produced; the infrared absorption spectrum of the compound in chloroform solution exhibits absorption maxima at the following wavelengths; 3450-3200, 2975, 2900,

2830, 1725, 1665, 1250-1200 cm ^-1 .

Other 1- (substituted) -5 / 3- / 4 '' - substituted-but-1 * ^, -en-3-onyl / -2-pyrrolidone derivatives prepared by the method of Example 5o may also be used in the same manner as described above. in the preparation of the corresponding 1-substituted / -5 / 3- / 4 "A-substituted-3 * '-hydroxybub-1 * * -enyl / pyrroldon derivatives.

Example 7

The 1/6 '-karboxihexi 1 / -5 / ^ - / 3 * * * -hydroxy-4' phenyl-but-l ^M K. -eni1 / mL solution of 2-pyrrolidone. 69 mg (0.185 mmol) of 1- (6-methoxycarbonone) in methanol are added to 1-hexyl-5- [3- (3-hydroxy) -4-phenylbut-1-enyl] -2-pyrrolidone, 0.185 ml / 0.185 ml. milliequivalents per liter of sodium hydroxide. The reaction mixture is refluxed overnight and then adjusted to pH 4 with ice-water. The solvent is removed under reduced pressure and the oily product obtained as a distillation residue is dissolved in 15 ml of ethyl acetate. The organic solution was extracted with water (2 x 2 mL) and brine (2 mL), dried over magnesium sulfate and filtered. Under reduced pressure distillation, © 1 <1ό | 5256 / Φ, amlksr

-21180.273 59.4 mg (yield: 89%) of 1- (8'-carboxyhexyl) -5? - (3 * '-hydroxy-A *' -phenyl-but-1 * * -enyl) as a yellow oil. 2-Pyrrolidone is obtained. '

Nuclear Magnetic Resonance Spectrum of the prepared compound (T-60) / DCCl3: δ: singlet, 7.53 ppm, (5H), broad, azingulet, 6.30 ppm, (1H); doublet, 5.73 ppm, J 7: 7 Hz; doublet,

5.6 ppm, 7 Hz (2 H); multiplet, 4.6-3.2 ppm, (4H); doublet, 2.93 ppm,: 7 Hz, (2H); / partial spectrum.

The infrared absorption spectrum of the compound prepared in chloroform shows absorption maxima at the following wavelengths: 3500-5100, 2980, 2920, 1700, 1600, 1250-1200 cm ^-1 .

In the case where, instead of the pyrrolidone derivative used in this example, other 1- (substituted) -5Z3-hydroxybutene-1-pyrrolidone derivatives obtained by the procedure of Example 6 are used, the methyl ester or the acyloxymethyl protecting groups are cleaved to yield the following δ-aza-11-deoxy-prostaglandin and E2 derivatives. When the compound contains an N-tetrahydropyran-2-yl protecting group, it can be cleaved

As in Example 3 or 14. The following compounds are obtained: XLVIII and XLIX wherein X is carboxyl or tetrazole-5-yl; Z is a H ^ GH ^ Cg-, O-thienyl, Η ^ ΟΟΗ ^ Οθ-, Η ^ Οθ-Η ^ Οθ-, FjCH ^ Cg- or H ^ Cg-drip.

Example 8

Preparation of 1- [6 * -methoxycarbonylhexyl] -5-oxo-4 * '-phenoxybut-1 *' -en-3 '' - onyl] -2-pyrrolidone

To a flame-dried reaction vessel containing nitrogen gas was added 22 mg (0.55 mmol) of sodium hydride dispersed in mineral oil and 5 ml of tetrahydrofuran. Dissolve 0.1549 g (0.6 mmol) of dimethyl (3-phenoxypropan-2-onyl) phosphonate in 5 ml of tetrahydrofuran and add the solution to the above sodium hydride suspension. After the evolution of hydrogen gas had ceased, a clear, pale yellow solution was obtained, which was stirred for 15 minutes. Then, 0.1277 g (0.5 mmol) of 1- (6'-methoxycarbonyl-1-hexyl-5H) -butyl 1-pyrrolidone in 5 ml of tetrahydrofuran is added over about 1 hour. Within 5 minutes, the reaction mixture turned to a sharp yellow solution, which was stirred for an additional 2 hours. Adjust the pH of the reaction mixture to 5 with glacial acetic acid when the reaction is stopped. The solvent was removed by distillation under reduced pressure and ethyl acetate (50 ml) was added to the residue. 2x5 ml saturated aqueous sodium bicarbonate solution. Extract the organic solvent with 2x5 mL of water and finally with 5 mL of saturated brine. After dehydration with magnesium sulfate, the organic solvent solution was filtered and the solvent removed under reduced pressure to give 0.231 g of a yellow oily product as a distillation residue. This was chromatographed on a column of 25 g Merek silica gel and cyclohexane 1. Elution was carried out with 50% chloroform in cyclohexane and 10 mL fractions were collected to separate the product.

-22180,273 were collected and the solvent was removed with distillation under reduced pressure, yielding a residue comprising 53 »θ 1- / 6« -metoxikarbon 1 hexi1 / -5 / ^ - / 4 ¹ '* -fenoxibut-1' -en-3 '* -onyl' -2-pyrrolidone is obtained; yield: 28% based on the starting alcohol.

Nuclear Magnetic Resonance Spectrum of the prepared compound (T-60) (DCCl 3): J: multiplet, 7.40-6.70 ppm, (5H); multiplet, 6.7-6.33 ppm * (2H), singlet, 4.67 ppm, (2H); multiplet, 4.40-3.97 ppm, (1H); singlet, 3.67 ppm, (3H), partial spectrum.

In the case where, instead of the pyrrolidone derivative given in this example, the process described in this example is different,

The 1- (New) -substituted / -5 '*' - formyl-2-pyrrolidone derivatives described in Example 4 are used to give the corresponding 1- (substituted) -5 ', 4' '- phenoxybut-1 ** ** -3 - onyl / -2-pyrrolidones. For the preparation of the corresponding 2-pyrrolidone derivatives, the phosphonates of the formula (Me0 / p-POCH 2 CO 2 CH 2 O-V) can be used instead of the dimethyl (3-phenoxypropan-2-one) phosphonates, where V is a egy ^ Η ^ Οθ-, FjCH ^ Cg-, Η ^ Οθ-Η ^ Οθ-, HjCOH ^ Cg-, Cl-Η ^ Οθ- or H ^.

9 «Example

Preparation of 1- (6'-methoxycarbonylhexyl) -5 ₍ Z - (3 * '-hydroxy-4''-phenoxybut-1-enyl) -2-pyrrolidone)

A flame-dried reaction vessel equipped with a magnetic stirrer and thermometer, containing 0.1046 g (0.27 mmol) of 1- / 6'-meboxycarbonylhexyl / -5 / 3- / 4 '' -phenoxy dissolved in 5 ml of anhydrous tetrahydrofuran ^but-1-en-1 * 3 * 'onyl / 2-pyrrolidone was added. The crude colorless solution was cooled to -78 ° C and 0.27 mL / 0.27 mmol / lithium tritylborohydride was added dropwise with an injection needle for approximately 15 minutes. After 1 hour, thin layer chromatography indicated that the starting enone was converted to pH 5 with glacial acetic acid. The solvent was removed by distillation under reduced pressure, the residue was dissolved in ethyl acetate (25 ml), extracted with half-saturated aqueous sodium bicarbonate (1 x 5 ml), water (1 x 10 ml), and saturated brine (1 x 10 ml). The organic solvent phase was dried over magnesium sulfate and then filtered under reduced pressure; 101 mg of crude product are obtained as a distillation residue. This was chromatographed on a column of 25 g of silica and benzene. The product was eluted with ethyl acetate, and fractions of 5 ml were burned; when the contaminants are separated from the product but the two epimeric forms do not separate. The product fractions were collected and the solvent was removed under reduced pressure, a residue of 85 g of θ / 82% / l / ^6, -raetoxikarbonil-hexyl / -5, z9- / 3 ** - * hydroxy-4 '- phenoxy-but-1-enyl / -2-pyrrolidone is obtained.

Nuclear Magnetic Resonance Spectrum (T-60) / (DCClx): 3 ^! multiplet, 7.54-6.82 ppm, 5H multiplet, 5.94-5.73 ppm, 2H; multiplet, 4.79-4.4? ppm, (1H); multiplet, 4.33-3-94 ppm, (3 E); s, _t 7 O 3 ppm / 3 H /; partial spectrum.

In the infrared absorption spectrum of the prepared compound in chloroform solution, the following wavelengths

Absorption maxima can be observed along -23180.273; 3600-3100, 2980, 2920, 1730, 1670, 1600, 1200-1250 cm ^-1 .

Using the 1- (substituted) -5- (3-phenoxy-butenoyl) -2-pyrrolidone derivatives of the pyrrolidone used in this example instead of the pyrrolidone derivative used in the above example gives the corresponding 1 - (substituted) - (N -) - (4 '* -phenoxy-3 *' -hydroxybut-1 * '- enyl) -2-pyrrolidone derivatives.

Example 10

Preparation of 1- (6 * -carboxyhexyl) -5 / 3- (3 * * -hydroxy-4'-phenoxybut-1 '' -enyl) -2-pyrrolidone in ml methanol 50 mg / 0.128 mmol / l- / 6-Methoxycarbonylhexyl-5-β- (3 * * -hydroxy-4 * '-phenoxybut-1 *' -enyl) -2-pyrrolidone was added and 0.128 mL / 0.128 mmol / l sodium hydroxide was added. The reaction mixture is refluxed overnight, then adjusted to pH 4 with glacial acetic acid. The solvent was removed by distillation under reduced pressure and the oily residue was dissolved in Ί5 ml of ethyl acetate. The organic solvent was extracted with water (2 x 2 mL) and brine (1 x 2 mL), dried over magnesium sulfate and filtered. The filtrate was removed under reduced pressure to give a yellow solid

1- [6 * -carboxy-hexyl] -5 / 3- [3 * * -hydroxy-4'-phenoxy-but-1 * '-enyl] -2-pyrrolidone is obtained.

Nuclear Magnetic Resonance Spectrum of the prepared compound (T-60) / DCCiy: J: multiplet, 7.40-6.82 ppm, (5H); multiplet, 6.73-6.17 ppm, (2H); multiplet, 5.87-5.70 ppm, 2H / l multiplet, 4.7-4.4 ppm, 1H; multiplet, 4.23-3.88 ppm, '(3H); partial spectrum.

The infrared absorption spectrum of the prepared compound in the chloroform solution exhibits absorption at the following wavelengths, 3600-2900, 2920, 1700, 1670, 1600, 1200 and 1250 cm ^-1 .

In the case where, in the procedure described in this example, 1- (7 * -methyl-heptanoate) -5P- (3 ** -hydroxy-4 ** -phenoxybut-1 * * -enyl / -2-pyrrolidone instead of another 1- (substituted) -5- (3-hydroxy-phenoxy-butenyl) -2-pyrrolidone prepared in the same manner as in Example 9, the methyl ester or aoyloxy-rethyl group is cleaved and L or the glazes of 8-aza-11-dehydroxy-prostaglandin E ·-és and E £-s in the formulas LI. The N-tetrahydropyranyl protecting group can be cleaved from the molecule as described in Example 14. In formulas L and LI, X is carboxyl or tetrazol-5-yl; VH ^ CH ^ CG, ϊ ^ ΟΗ θ- ^, θ ^ Η Η-θ- ^ H ₃ C0h ₄ C ₆ -, C 1 -C ₆ H ₄ - or -C ₆ H ₅ group, i

Example 11

Preparation of 1- [6 * -methoxycarbonyl-1-hexyl] -5 / 3- [3 * '- tetrahydropyran-2 *' * -yloxy-4 * * -phenyl-but-1-enyl] -2-pyrrolidone

In a flame-dried reaction vessel containing nitrogen gas, 1- (6'-methoxycarbonylhexyl) -5 / 3- (3 '') -hydroxy-4 * * -phenyl-128 mg (0.342 mmol) dissolved in 5 ml of methylene chloride

-24180,273

-1 '* -enyl / -2-pyrrolidone is added. The solution is cooled to 0 ° C to 50 ° C and 0.062 ml (0.684 mmol) of redistilled dihydropyran and 3 mg of para-toluenesulfonic acid are added. The reaction mixture was allowed to warm to room temperature and stirred overnight. 10 ml of ethyl acetate were then added. Extract with 2 x 2 mL of saturated aqueous sodium bicarbonate solution and 5 mL of saturated aqueous brine. The organic solvent phase was dried over magnesium sulfate, filtered and the solvent removed by distillation under reduced pressure. Yield: 0.135 g of product as a yellow oil. This was chromatographed on a column filtered through 15 g of Merek silica gel and chloroform. First, elute less polar pollutants with one liter of chloroform. Elution was continued with 2% methanol in chloroform to separate 10 mL fractions. when the pure product is separated. The product-containing fractions were combined and the solvent removed under reduced pressure to give 0.1756 g of 1- (6 * -methoxycarbonylhexyl) -5? -phenyl-but-1'-enyl-2-pyrrolidone is obtained.

Nuclear Magnetic Resonance Spectrum of the prepared compound: (T-60) / DCCl 2 / s ≤ 6 s singlet, 6.34 ppm, / 5H, multiplet, 5.77-5.37 ppm, (2H); multiplet, 5.13-4.80 ppm, 1H; singlet, 3.7 ppm, / 3 H / t partial spectrum.

The procedure for the preparation of the corresponding tetrahydropyranyl derivatives in the example is prepared by the method of Examples 6, 7, 9, or 10 prepared by the method of Examples 6, 7, 9, or 10, 3-hydroxy-but-1-substituted. * * -enyl / -2-pyrrolidone derivatives are used.

Example 12

Preparation of 1- (6 * -methoxycarbonyl-1-hexyl) -5 / 3- (3 '' -tetrahydropyran-2 * * '-yloxy-4 * * -phenyl-butyl) -2-pyrrolidone in ml of ethyl acetate 156.5 g / 0.34 mmol (1- [6 * -methoxycarbonylhexyl] -5β- [3 * *] - tetrahydropyran-2 '* * -yloxy-4 *' -phenyl-but-1 * * -enyl) -2 Dissolve '-plrrolidone. 31 mg of activated carbon composition containing 10% palladium was added to the solution, the whole reaction mixture was poured into a Parr hydrogen reduction apparatus and shaken under a hydrogen atmosphere of about 25 atmospheres for 4 hours. After addition of a gellite filter aid, the suspension was filtered to remove the catalyst, and the solvent was removed from the filtrate, followed by 158.2 g of 1- [6 * -ethoxycarbonylhexyl] -5 / 2 - / 3 * * -tetrahydropyran-2 * * *. yielding -yloxy-4'-phenyl-t-butanyl / -2-pyrrolidone.

Nuclear Magnetic Resonance Spectrum of the prepared compound: (T-60) / DCCl3: d: singlet, 7.33 ppm (5H); multiplet, 5.13-4.67 ppm, (1H); multiplet, 4.57-4.33 ppm, (1H); singlet, 3 * 73 ppm, [3 H] {partial spectrum.

The process described in Example 12 may also be used to prepare the corresponding hydrogenated derivatives using the tetrahydropyranyl derivatives prepared in Example 11 wherein A is a single bond.

Example 13

Preparation of 1- (6 * -carboxy-hexyl) -5β, 3β-tetrahydropyran-2 *** -yloxyphenyl-2-pyrrolide, on

-25dU.273 ml of methanol 1582 mg (0.342 mmol) of 1- (6'-methoxycarbonylhexyl) -5- [3 * '- tetrahydropyran-R' '' - yloxy-4 '* - phenylbutanyl] -R Pyrrolidone is dissolved and 0.342 ml / 0.342 mmol / l sodium hydroxide is added. The reaction mixture is refluxed overnight and then adjusted to pH 4 with glacial acetic acid. The solvent was removed by distillation under reduced pressure, and the oily residue was dissolved in 15 ml of ethyl acetate. The organic solvent was extracted with 2 x 2 mL of water, then with 1 x 2 mL of saturated aqueous brine, then dried over magnesium sulfate and filtered. The solvent was removed by distillation under reduced pressure to give a yellow oil. The product weighs 134.2 mg (89% yield) and is identical to 1- (6 * -carboxy-hexyl) -5 / 6- (3 * * -tetrahydropyran-2 * * ') -yloxyphenyl-butanyl / -R-pyrrolidone .

The compound obtained by nuclear magnetic resonance spectrum of A / T-60 / / DCClj / <T: singlet, 7.57 _ppm> / _5-H /; m.

4.4-3.2 ppm; multiplet, 2.92, (2H); partial spectrum.

Other hydrogenated derivatives prepared in the same manner as in Example 12 may also be used to prepare the corresponding 6 * carboxylic acids and 6 * -trazol-5-yl derivatives.

Example 14

1- (6 * -Carboxyhexyl) -1,5-dichloro-3 '' -hydroxy-4 * '-phenyl-butyl--2-pyrrolidone, also known as 8-aza-11-deoxy-16-phenyl -16 - Preparation of tetranor PGEq

Eoetsav and water 65: 35 mixture of 5 ml of a 134.2 mg / 0.3 mmol / l / 6 »-kárboxihexil / -5y5- / 3 ^t» -Jtetrahidropiran-2 · * -iloxi.-phenyl -6-butyl-2-pyrrolidone was dissolved and the solution was stirred under nitrogen at room temperature overnight. The solvent was removed by distillation under reduced pressure in a vacuum pump, the distillation residue was further distilled in the presence of an azeotropic mixture / benzene, and the resulting crude product was purified by column chromatography on 15 g of ARCC7 silica gel. Removal of the solvent afforded 82 mg of 8-aza-11-dehydroxy-16-phenyl-16-tetranor ΡΟΕθ.

Nuclear Magnetic Resonance Spectrum of the prepared compound (T-60): d: singlet, 7.17 ppm, (5H); m.

3.2-4.0 ppm, (3H); doublet, 2.77 ppm, J _H : 7 Hz, (2 H); partial spectrum.

The infrared absorption spectrum of a chloroform solution of the test compound obtained shown in the following wavelength absorption maxima: 3600-3100, 2930, 2860, 1700 "1660, 1250, 1200 and 710 cm in ^{the first}

The procedure described in the present example can be used to: a

The 6'-carboxylic acid and 6'-tetrazol-5-yl derivatives prepared in Example 13 and the hydrogenated derivatives of Example 12 were also cleaved with tetrahydropyranyl protecting groups.

Example 15

1- / 6'-N-feni1-1midohexi1 / -5 / ^ - / 3 '' - hydroxy-4 »/ _z phenyl-but-1 * * enyl / -2-pyrrolidone Preparation.

-26180.273 ml of 1- (6 * -carboxyhexyl) -5 / 3- (4 * ^1- phenyl) -3,3'-tetrahydropyran-2 * * (64 mg, 0.171 mmol) in dry tetrahydrofuran. -yloxybut-1'-enyl-2-pyrrolidone is dissolved. To the solution was added 25.16 mg (0.171 mmol) in 5 mL of anhydrous tetrahydrofuran and Speziale / J. Chem., 27, 3742, 1962). The reaction mixture is refluxed overnight, the solvent is removed by distillation under reduced pressure and the tetrahydropyranyl group is cleaved from the compound as in Example 14. There is thus obtained 1- [6'-N-phenyl-indnidohexyl] -5- [3 ', 3'-hydroxy-4''-phenyl-but-1''-enyl] -2-pyrrolidone.

By repeating the above procedure with appropriately protected carboxylic acids prepared as described in Examples 7, 10 or 14, the imide derivatives of formula L.TI or Lili can also be prepared. In formulas LII and Lili, lm represents NHOCPh or NHOCCH 1; Z in Example 7, V in Example 10? report; A represents a single or cis double bond, and B represents a single or trans double bond.

Example 16

Preparation of 1- (6'-N-methylsulfonimido-hexyl) -5, 5 '- (3' ') -hydroxy-4' -phenyl-but-1'-enyl] -2-pyrrolidone in ml anhydrous benzene (0.171 mmol) of N- (6 * -carboxyhexyl), N-5 / 3- (4 * * -phenyl-3 **) -tetrahydropyran-2 * '' -yloxybut-1 prepared as in Example 11. Dissolve '-enyl' -2-pyrrolidone. To the solution was added at room temperature 20.7 mg (0.171 mmol) of Speziale method (see Example 15) and 5 ml of anhydrous benzene dissolved in ethyl benzyl isocyanate. The reaction mixture was refluxed overnight and the solvent was removed by distillation under reduced pressure. The product obtained as the distillation residue was treated according to the procedure of Example 14 to give the product which was no longer containing the tetrahydrofuranyl group, i.e. 1- (6 * -N-methylsulfonimido-hexyl) -5 / 1 - / 3 '' - hydroxy. -4 '' - phenyl-but-1 '' - enyl / -2-pyrrolidone.

When this procedure is carried out with phenylsulfone 1-isocyanate instead of methylsulfonyl isocyanate, the corresponding phenyl azulfoximide derivatives are obtained.

In addition, the sulfonimide derivatives of the formulas LIV and LV can be prepared by the above procedure using the appropriately protected carboxylic acids prepared by the procedures of Examples 7, 10 and 14 as starting materials. In the formulas LIV and LV, Suf is -NHSO ₂ CH ₃ or -NHSOgPh; V has the meaning given in Example 10 and Z has the meaning given in Example 7 »A is a single or cis double bond and B is a single or trans position double bond.

Claims (1)

A process for the preparation of 1,5-disubstituted-2-pyrrolidone derivatives of formula XIII and C5 epimers thereof, wherein Q is a carboxyl, tetrazol-5-yl, -COOR or -CONHR "osopo'r, where ... -27180,273 R is C 1-5 alkyl, phenyl or p-biphenylyl, R is -COR "'or -SOgR" *, wherein R '' is phenyl or C 1-5 alkyl, W represents a single or cis double bond, Z single bond or trans double bond, M is LVII or LVIII, and R * c -thienyl, phenyl, phenoxy or chlorine or fluorine, phenyl, raethoxy, trifluoromethyl or C 1-3 alkyl. substituted phenyl or phenoxy, characterized in that a compound of formula XIV, wherein Q, W, Z and R 'are as defined above, is reduced, preferably with borohydride, and optionally a resulting compound of formula XIII wherein Q is C 2-6 alkoxycarbonyl , hydrolyzing and / or, if desired, esterifying the resulting compound of formula XIII, wherein Q is a carboxylic acid, with an alcohol as defined above for R.