DD143768A5 - PROCESS FOR PREPARING PYRROLIDONE COMPOUNDS - 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

-a-

13,369

Field of application of the invention:

The invention relates to the preparation of novel 1,5-disubstituted-2-pyrrolidones, which are similar in their chemical structure and the biological character of the prostaglandins.

Characteristic of the known technical solutions ;

The C ₂ Q-unsaturated fatty acids known as prostaglandins form a large family of naturally occurring compounds. These molecules may even have five asymmetric centers and are present in, or may cause a reaction in, the most versatile biological tissues. An example of a particular type of prostaglandin generation Ξ is shown below

H OH prostaglandin

According to the formula drawing normally used to describe the stereochemistry of prostaglandins, a thick line represents the / 3 configuration, which is defined as the bond that stands out from the plane of the paper to the viewer. In a similar way, a dashed line represents

13 3.

or broken line represents the oi configuration, which is defined as binding that extends past the plane of the paper and away from the viewer. Thus, the prostaglandin E ₂ shown above has the δ (configuration at carbon atom 8 and the / 3 configuration at carbon atom 12 / Bergström, et al., Acta. Chem. Scand., 1_6, 501 (1962) 7.

Using the same terminology, a wavy line represents a mixture of the two forms d and / 3. Thus, a 2-pyrrolidone of the structure represents:

a mixture τοη epimers

With reference to the pyrrolidone of structure B and the prostaglandin E ~ shown above, a stereochemical comparison can be made between the two groups of compounds. The stereochemistry at positions 12 and 15 is the same for both species but that at position 8 is different. That is, the configuration of the C8-C7 bond of the prostaglandin E is ex j, on the other hand, that of the N8-C7 bond is as shown in the above drawing in the paper plane. Another way of representing the two examples above, which will provide a better understanding of this difference in configuration, is the above-standing drawing shown below:

OH

B H

Prostaglandin E

wherein A and B are the two side chains of the examples. The illustration here shows the occlusion of the A-C8 bond by the C12-H bond and the occlusion of the C12-H bond by the C8-H bond in the case of the prostaglandin E and the bisecting position of the A-N8 Bond with respect to the surface angle formed by B-C12-H in the case of the pyrrolidone. This difference in the conformation is the consequence of the surface area created by the amide component of the pyrrolidone. / "" Basic Principles of Organic Chemistry ", J.D. Roberts and M.C. Caserio, W.A.> Benjamin, New York, 1965, pp. 6747.

213 3

A systematic name for a 1,5-disubstituted-2-pyrrolidone of the structure:

OH

is 1- (6'-CarT3oxylyl) -5β- (3 "G / -hydroxyoct-1" -enyl) -2-pyrrolidone and it may also be referred to as a derivative of Λ "1-deoxyprostaglandin E, ie 8- aza ~ 11-deoxy-PGE ,.

The corresponding e-aza-H-desox-y-PGE ^ compound has the following structure:

OH

wherein the simple bond between C2 ^T and C3 ^{1 has been} replaced by a double bond. The corresponding 8-aza-11-deoxy-PGE _n compound has the following structure:

213 36

wherein the double bond between C1 "and C2" has been replaced by a simple bond.

The pyrrolidones mentioned above have different centers of asymmetry and can exist in the racemic (optically inactive) form and in one of the two enantiomorphic (optically active) forms, i. H. in the dextrorotatory (D) and the counterclockwise (L) form. As indicated above, each pyrrolidone structure shows the subject optically active form or enantiomer, which can be partially derived from D-gflutamic acid. The mirror image or optical antipode of each of the structures listed above represents the other enantiomer of that pyrrolidone and is in part derivable from! - glutamic acid.

For example, the p-type antipode of 1- (6'-carboxyhexyl) -5β- (3'-o-hydroxy-oct-1'-enyl) -2-pyrrolidone can be plotted as follows:.

and is referred to as 1- (6- ^l- carboxyhexyl) -5-o- (3 "/ 3-hydroxyoct-1-enyl) -2-pyrrolidone.

The racemic form of the above pyrrolidone contains the same number of a particular enantiomer and its mirror image. When referring to the racemic form of a compound listed here, the name of the compound is represented by the symbol "raz". This term should then be one

213 3

mean equimolar mixture of the D and the L or the enantiomorphic form and is represented exactly by it.

A pair of optical isomers, which are optical antipodes or enantiomers, are related by the inversion of the absolute configuration at all their asymmetric centers. In contrast, when the relationship is an inverse of the absolute configuration at one or more, but not all, asymmetric centers, the pair of isomers means epimers or diastereomers. For example, 1- (6'-carboxyhexyl) -5β- (3 "-ol-hydroxy-1'-enyl) -2-pyrrolidone and 1- (6'-carboxyhexyl) -5c / - (3" -ol-hydroxyoct-1 ⁿ -enyl) -pyrrolidone diastereomers, which are related by an inversion of the configuration of the C5 atom and are each represented as follows:

CO ₀ H

CO ₀ H

It is a fact that by chemical experimentation the same and identical results can be obtained on each member of an enantiomorphic pair or on a mixture of the two.

As already mentioned, the substitution of a nitrogen atom s for the carbon atom at C8 leads to a dramatic change in the three-dimensional conformation of the resulting

prostaglandins. Since the structure is related to biological activity and a subtle change in structure such as a conformational change often has a profound effect on biological activity, such a molecule modification of prostaglandins by substitution of heteroatoms has recently been studied. Most compounds are attempts in the study of heterotome substitutions at the C9 and C11 prostaglandin position, and include examples such as 9-0xaprostaglandins / I. Vlattas, Tetrahedron Let., 4455 (197417, 11-Oxaprostaglandine / Α. Fougerousse, Tetrahedron Let., 3983 (1974); and S. Hanessian et al., Tetrahedron Let., 3983 (1974) / and 9-thiaprostaglandins / I. Vlattas, Tetrahedron Let., 4459 (1974) 7.

Two types of 8-aza-ii-deoxy prostaglandins E, with the natural CO side chain, ie compounds having the aza-substitution at C8 of 11-deoxy prostaglandin E, and E ₂ have also been mentioned in the literature. G. Bolliger and J.M. Muchowski, Tetrahedron Let., 2931 (1975) (Aug. 1975); and ΰ. W. Bruin, et al. Tetrahedron Let., 4599 (1975) /. These examples of pyrrolidone compounds are outside the scope of the invention, which represents a complexity and molecular alteration at the C-1 prostaglandin position and in the CO side chain at a higher level. In these examples cited in the literature, relatively little biological activity is reported, and they can be compared in shape and molecular complexity with the novel compounds of the invention.

The natural prostaglandins and many of their derivatives such as the esters, acylates and pharmacologically acceptable salts are extremely strong inducers of various biological reactions / Ϊ). E. V / ilson, Arch. Intern. Med. 133, (29) (1974) / in smooth muscle tissues such as those of the circular muscle

and pulmonary, gastrointestinal and reproductive systems, in \ cellular tissues such as the central nervous, liver, reproductive, gastrointestinal, lung, kidney, epidermis, circulatory and adipose systems, and they also act as mediators at the homeostasis process. Because of this large range of reactions, it is clear that prostaglandins are involved in the basic biological processes of the cell. This basic involvement of prostaglandins is corroborated by the fact that they are found in the cell tissues of almost all animal organisms.

At such a cellular level, the effects of closely related natural prostaglandins can often be opposite. For example, the effect of PGE ₉ on human platelets is to increase aggregation while that of PGE. is the inhibition of aggregation.

These opposite effects are also observed in tissues. For example, the in vivo effect of PGE ₂ on the circulatory system of mammals is demonstrated in the generation of hypotension, whereas the effect of YGF ^ in vivo hypertension is £ S. B. Lee, Arch. Intern. Med., 133 , 56 (1974). However, the possibility of predicting the biological effect of prostaglandin classes on the basis of such observations is currently very illusory. For example, while the cardiovascular effects of PGEp and ^ GFp are opposite ^as described above, their in vivo or in vitro effect on uterine smooth muscle is at Equals and stimulates mammals (causes contraction) / HR Behrman, et al., Arch. Intern. Med., 131 77 (1974) /.

In the production of synthetic pharmaceutical agents, one of the main tasks is the development of compounds,

which are highly selective in their pharmacological mode of action and have a longer duration of activity compared to their naturally occurring relatives. In a number of compounds similar to the naturally occurring prostaglandins, increasing the selectivity of a single compound tends to enhance prostaglandin-like activity and reduce the other. By increasing the selectivity, one could alleviate the severe side effects that often occur after administration of the natural prostaglandins; for example, those side effects of the gastrointestinal tract such as diarrhea and vomiting, or cardiovascular tissue effects when bronchodilator effects are desired. Recent developments aimed at increasing biological selectivity include the 11-deoxyprostaglandins /%, H. Anderson, Arch. Intern. Med., 132, 30 (1974) Review /, 2-descarboxy-2- (tetrazol-5-yl) -ii-deoxy-15-substituted-CO-pentanor prostaglandin β1. R. Johnson et al, US-PS 3.932.389J ^7, where certain codifications are given which produce selective properties with regard to vasodilatation, prevention of ulcer formation and conception, extension of the bronchi and blood pressure reduction, 16-phenoxy-1o cc tetranorprostaglandine with contraceptive properties (GB 1,350,971) and 1-imide and 1-sulfonimide prostaglandins (US Pat. No. 3,954,741).

Object of the invention:

The invention relates to a process for the preparation of a pyrrolidone compound of the formula:

and the C5 epimer therein, in which

Q is a group of the formula -COOR ¹ ; Tetrazol-5-yl; N- (acyloxymethyl) tetrazol-5-yl having two to five carbon atoms in the acyloxy group; N- (phthalidyl) tetrazol-5-yl; N- (t-hydropyran-2-yl) -tetrazol-5-yl or a group of the formula -C (MHR ";

W is a single or a cis double bond;

Z is a single or a trans double bond;

_o 0H ß-

M = °> N. ^or \ ^is >

OH

R 10 is -thienyl, phenyl, phenoxy, monosubstituted phenyl or monosubstituted phenoxy wherein the substituent is chloro, fluoro, phenyl, methoxy, trifluoromethyl or alkyl of 1 to 3 carbon atoms; R ^{1 is} hydrogen, alkyl of -f to 5 carbon atoms, phenyl or p-biphenyl; and R "-COR ¹¹¹ * or -SO ₂ R"', wherein R " ^{f is} phenyl or alkyl of 1 to 5 carbon atoms; and the alkali metal, alkali metal, alkaline earth and ammonium salts of those compounds in which Q is a carboxylate; or tetrazol-5-yl group.

Explanation of the essence of inventions:

The invention is characterized in that a pyrrolidone of the following formula:

CH ₂ OT II

wherein T is a hydroxy-protecting group, either (a) with a compound of the formula:

III

wherein X is chlorine, bromine or iodine and W and Q have the meaning described above, or (b) with a compound of the formula XCH ₂ CH (OY) ₂ , wherein X has the abovementioned meaning and Y is alkyl having 1 to 3 carbon atoms is reacted, and when the reaction with a compound of formula III has been carried out, the protecting group T is removed and the resulting alcohol is oxidized to the aldehyde, and then the second side chain by reacting the aldehyde with a phosphonate of the formula:

(alk-O) _p POCH ₂ COCH ₂ R IV

wherein alk is an alkyl group having 1 to 3 carbon atoms; and when the first reaction with a compound of the formula XCH ₂ CH (OX) _{2 has taken place} in any order, (c) removing the protective group Y to liberate the aldehyde and replacing it with Ph, P = C (CHp), Q is implemented to add the upper side chain; and (d) removing the protecting group T and oxidizing the resulting compound to convert the formed alcohol to the corresponding aldehyde, and reacting the resulting aldehyde with a compound of formula IV above or the lithium, sodium or potassium salt thereof, to add the lower side chain; and when required, subjecting the resulting compound of formula I to subsequent reactions known as such for the preparation of other desirable products of formula I.

The novel pyrollidone compounds of the above formula I,

,H

where M

or

- 12

is, are Prostaglandin-like Ver-

compounds that have selective and strong biological activity. Those compounds of formula I wherein M = O are useful intermediates useful for forming the 15-hydroxy compounds of the invention and the present invention. Claims in the application Hr. 200468 can be hydrogenated.

The invention also relates to a process as described above for the preparation of a pyrrolidone compound of the formula:

3 4

and the C5 spider thereof, wherein Q, W, Z and R are as defined above, and the alkali metal, alkaline earth metal and ammonium salts of those compounds wherein Q is a carboxylate or tetrazol-5-yl group; characterized in that a pyrrolidone intermediate of the formula:

wherein Q and V / have the meaning given above, with the

Lithium, sodium or potassium salt of a phosphonate of the formula:

, CaIk-O) ₀ POCH ₀ COCH ₀ R

IV

wherein R has the meaning given above'and alk is an alkyl group having 1 to 3 carbon atoms is reacted.

Compounds obtained by the method according to the invention. have selective prostaglandin-like biological activity, are those of the following formulas:

OH

wherein W, Z and H are as defined above.

The following compounds are particularly preferred because of their selective biological activity:

1- (6'-carboxyhexyl) -5 _/ SS (3 "o ⁱ --hydroxy-4 ^ll -phenylbut-1 ^H-enyl) -2-pyrrolidone and the Methylester and 5ol epimer thereof,

-hydroxy-4 "-phenylbut-1-enyl) -2-pyrrolidone and the 5 ^ -sprimer thereof,

1 ~ (6'-carboxyhexyl) -5 / 3- (3"C<.- hydroxy-4- ^II- phenylbutanyl) -2-pyrrolidone and the 5oi epimer thereof,

1- ( ^6f- carboxyhexyl) -5 Z ⁵ - (3 "-oihydroxy-4" -phenoxybut-1 ^{! T} -enyl) -2-pyrrolidone and the 5 ^ .- epimer thereof,

1- (6 ^l -carboxyhex-2'-enyl) -5yS - (3 ^{tf <} ^ -hydroxy-4 "-phenoxybut-1" -enyl) -2-pyrrolidone and the 5 ^{C> C} peak thereof,

- | - (6 ^f -carboxyhexyl) -5 / S - (3 "cs-hydroxy-4" -phenoxybutanyl) -2-pyrrolidone and the 5 ei epimer thereof,

the compounds wherein 6 * - (tetraEol-5-yl) replaces the 6'-carboxy group of any of the particularly preferred compounds above,

213

and the compounds wherein a 3 "/ 3 hydroxy replaces the 3 ⁿ d hydroxy group of each of the above 6'-carboxy and 6 '- (tetrazol-5-yl) compounds.

The process according to the invention can be explained by the following six-step sequence, in which the two side chains, the o (or upper side chain and the cO or lower side chain are added to the pyrrolidone ring and in which a dissolved amino acid, D- or! -Glutamic acid, The choice of the D- or! -glutamic acid pathway provides the absolute confirmation of C5 of the 2-pyrrolidone ring, and necessarily states the need to resolve this position at the end of the synthesis In the following description, the D configuration becomes The compounds of the! configuration can be prepared by the same sequence of! -glutamic acid.

The synthesis sequence shown by Scheme A shows the methods by which the c-s chain is attached to the 2-pyrrolidone nucleus. In each case, the methods provide a Pyrroli'don intermediate 1_9, which deviates only at the C2 '~ C3' bond. The end products of the formula I can then be synthesized from the intermediate compound 1_9 according to the methods shown in Schemes B, C and D.

3 36

Scheme A - c * i - chain add

17

XCH ₀ CH (OY),

OY

CH ₂ OT

, , CHO

J Sfc ^ - OH

(G)

OH

N-

OH

A brief summary of the steps in Scheme A is as follows. The first step, designated (a), which shows the cyclization of D-glutamic acid to methyl D-pyroglutamate and the reduction of the pyroglutamate to 5-D-hydro 2-yl-2-pyrrolidone is known / V ^- . Bruckner, et al., Acta. Chim. Hung. Toraus, 21., 106 (1959) /. The second step (b) is the protection of the hydroxymethyl group by the protecting agent T, which may be any group suitable for the protection of the hydroxyl to alkylation, for example benzyl, dimethyl-1-butylsilyl, acetyl, 1-ethoxyethyl . tetrahydropyranyl or specifically steps (c) and (e) illustrate the alkylation of the sodium or Lithiumsälzes of pyrrolidone ± by alkylating agents of the formula:

X or XCH ₂ CH (OY) ₂ , where X is Cl, J or especially Br; Q is CO ₂ R ', N- (acyloxymethyl) tetrazol-5-yl having 2 to 5 carbon atoms in the acyloxy group, N- (Phthalidyl) tetrazol-5-yl, N- (tetrahydropyran-2-yl) tetrazol-5-yl or tetrazol-5-yl; Y is alkyl of 1 to 3 carbon atoms and V / and R ¹ are as defined above ., step (d) relates to the removal of the protective group T, wherein the method is for this depend on the identity of T _v step (f) is the removal of the protection of the Pyrrol'idonverbindung;1J3> in situ to ~ 1 (ethane- 2 ^l -al) -5-hydroxymethyl-2-pyrrolidone which may be in intimate equilibrium with the hemiacetal compound 2 ". Step (g) is a Wittig reaction of the equilibrium mixture, the bicyclo f4,3, olonan-5-one, 5. with a phosphorane of the formula PIwP = CH (CH ₂ ) -Q, wherein Q has the meaning given above and unprotected, to produce the corresponding 2-pyrrolidone compound JM9, wherein W is a double bond.

The reactions necessary for the production of the compounds according to the invention are arranged in the order such that no epimerization of the optically active center at C5 can occur. Since one of the two enantiomers of glutamic acid is assumed, therefore, the same configuration remains at the asymmetric centers in the \ products. Although it is assumed that racemic glutamic acid is produced, the racemic or raz products are produced.

The C5 position of the intermediate compounds and products of the invention will be drawn in the / 3 configuration, but the o> / configuration at the C5 position is also applicable provided that the starting glutamic acid has the correct configuration.

The first two steps of the reaction sequence are the condensation and esterification of D-glutamic acid to produce the corresponding D-methylpyroglutamate having the structure:

H ^CO 2 ^Me

/ E. Ekrdegger, u. a., HeIv. Chem. Acta., 38, 312 (1955); E. Sail, J. Am. Chem. Soc., 74, 851 (1952) 7.

The third and known step of the sequence, shown in Scheme A as step (a), is the reduction of the 5-carboxymethyl group.

₁₉ . 213 3 * 9

p of D-methyl pyroglutamate to produce 5-D-hydroxymethyl-2-pyrrolidone. This reaction is best carried out using a modification of the method described by 7. Bruckner, et al., / Äcta. Chem. Hung. Tomus, 2j_ _} 106 (1959) / explained method carried out. The D-methyl pyroglutamate is stirred with lithium borohydride in dry tetrahydrofuran or other ethereal solvent until the reduction is substantially complete. Isolation of the product as described gives 5-D-hydroxymethyl-2-pyrrolidone having the structure:

N-H

v ^ CH ₂ OH

For the alkylation of the amide nitrogen of 5-D-hydroxymethyl-2-pyrrolidone, it is recommended to protect the labile 5-hydroxymethyl water by means of the known tetrahydropyranyl group. This protection (Scheme A, step (b)) is best accomplished by contacting 5-D-hydroxymethyl-2-pyrrolidone with dihydropyran in the presence of an organic acid such as p-toluenesulfonic acid and in an inert solvent such as methylene chloride, chloroform, tetrahydrofuran or diethoxyethane , The suitable temperature range for this reaction is between the temperature of an ice bath and that of refluxing the solvent, and is preferably ambient. Upon formation of 5-D- (tetrahydropyran-2'-yloxymethyl) -2-pyrrolidone, J [is essentially complete, usually overnight, and it is first excessively removed by removing the organic acid by basic extraction and removal of the solvent and all Dihydropyrans isolated by Yakuumverdampfungsverfahren. The product is generally purified by column chromatography.

_ ₂₀ _ 213 369

Other protectants that are equally easy to use include all that will protect the hydroxyl from alkylation. Some examples are benzyl, acetyl, dimethyl-1-butylsilyl and 1-ethoxyethyl. These protectants are readily available and can be added by known methods to the 5-hydroxymethyl group. Your choice for synthesis purposes will depend on the C7 ¹ protecting group. If it is intended to use N-tetrahydropyran-2-yl as the protecting group for the acidic hydrogen of a C7'-tetrazol-5-yl (Q), then suitable C3 "-hydroxyl protecting groups (T) would be acetyl- or dimethyl-t-butylsilyl.

The 1- (alkylated) -2-pyrrolidone compounds (V7 and 1-8, Scheme A) are prepared by a combination of two reactions involving 5-D- (tetrahydropyran-2'-yloxymethyl) -2-pyrrolidone 1_ of each their T-group analogues. First, the sodium or lithium salt of pyrrolidone is prepared by combining a solution of compound A - in an inert organic solvent such as tetrahydrofuran, diethoxyethane or dioxane with a base such as n-butyllithium, phenyllithium or, especially, sodium hydride. The best temperature range for this salt formation is between ambient temperature and that of refluxing the solvent, but is preferably ambient. The entire base must be reacted before the start of the alkylation, which usually takes from 1 to 4 hours. Thereafter, the intended i- (alkylated) -2-pyrrolidone compounds ΛΊ_ or j_8 are formed by combining the above-prepared lithium or sodium salt of 2-pyrrolidone compound j_ with an alkylating agent of the following structure:

Q or

wherein X = Cl, J and especially Br, W and Q are as defined above, and X is alkyl of 1 to 3 carbon atoms.

This second part of the alkylation process is generally carried out by the addition of a mixture of alkylating agents in the inert organic solvent as defined above or, more particularly, by adding a mixture of the alkylating agent in a polar aprotic organic solvent such as dimethylformamide or dimethylacetamide to the mixture of the above Sodium or lithium salt of pyrrolidone 1_ performed in an inert organic solvent, followed by the contact between the mixture of alkylating agent and 2-? Yrrolidonnatrium- or -lithiumsalz at temperatures lying between Uragebungs- and Rückflußkochtemperatur of the solvent temperatures until the alkylation is essentially completed, usually overnight. ·

Of course, the alkylated 2-pyrrolidone resulting from the use of XCH ₂ CH (OY) _{2 can} also be prepared by using XCH ₂ CO ₂ Et as the alkylating agent, with selective conversion of the ester group of the resulting 1- (2'-ethyl acetate) - 5- (substituted) -2-pyrrolidone to aldehyde follows.

If there is the possibility that an acidic species is present in Q, then the alkylation process is most conveniently carried out by protecting or otherwise removing the acidic hydrogen. For example, in the case where E * is hydrogen, the best method is to use an ester derivative which can then be sequentially removed by alkaline hydrolysis at the end of the synthesis. If Q is tetrazol-5-yl, the best method in Sr

1 3 3

the acidic hydrogen, an acyloxymethyl as defined above, a phthalidyl group / W. ν. Daehne, J. Med. Chem., 13 ,, 607 (1970), I. Isaka, u. a., Chem. Pharm. Bull., 24, 182 (1976) / or a tetrahydropyran-2-yl group. The first two groups for tetrazol-5-yl protection are also removed by alkaline hydrolysis at the end of the synthesis (Scheme B), on the other hand, the THP group is removed by acid hydrolysis, and it is assumed for the following discussion that the acidic group Q-group hydrogen was protected unless otherwise stated.

The nature of the C2'-C3 'bond of the 2-Pyrrοlidonverbindung 17, which has been obtained by the alkylation step is determined by the nature τοη W in the alkylating agent: *

The choice of V / will also determine the unsaturated or saturated nature of the c * side chain of the final product of the synthesis, i. H. whether the final product will be an 8-aza-11-deoxy-PGE or an 8-aza-deoxy-PGEp.

Obviously, the choice of W only causes a difference in the character of the C2'-C3 ¹ bond of the ((side chain, and indeed the conversion of pyrrolidone compounds in which W is a double bond into those in which W is a simple bond is possible at the stage of pyrrolidone compound YJ_ the synthesis. for example, the 2-pyrrolidone compound 1_7 with the double bond in W in the 2-pyrrolidone with the simple binding at W by hydrogenation over a noble metal catalyst such as palladium on carbon at ambient temperature to 1. Equivalent hydrogen absorbed is converted.

I 3 «

Compound 17W = double bond Compound 1_7 W = simple

binding

In any event, the protecting group T is removed by methods known to those skilled in the art (step d, Scheme A) to forestall the formation of the OJ side chain. The resulting 2-pyrrolidone compounds of the following structure

Connection 19

where Y / and Q have the abovementioned meaning, then they are led through the Schemes B, C and D to produce the novel end products according to the invention.

The above 2-pyrrolidone compound 1_9 can also be obtained by contacting the hydrolyzed form of the 2-pyrrolidone having the structure:

Connection 18

wherein "ΐ and Ϊ are as defined above, with a phosphorane of the formula:

wherein the above defined Q is unprotected, e.g. COpH or tetrazol-5-yl prepared. The synthesis of Te trazo1-5-yl-phosphorans can be found in US Patent 3,953,466.

This sequence of reactions represented by steps (f) and (g) of Scheraas A can proceed in the following manner. When the preferred T-protecting group, tetrahydropyran-2-yl, is used in compound 8, then the acid hydrolysis becomes. Compound _ ^ 8 after usual for the Aeetalentfernung manner, for example by acetic acid in Y / ater at about 40 ⁰ C, both the tetrahydropyran-2-yl as well as the acetal to form 1- (2-iitlian ^l -al ) -5 _/ 5-hydroxymethyl-2-pyrrolidone, which may exist in intimate equilibrium with 4-aza-2-hydroxy-1-oxabicyclo4,3,0] nonan-5-one 5.

OH

Nonanone 5

The equilibrium mixture containing hemiacetal 5 can then be treated with about? Equivalent phosphorane as defined above in a polar aprotic solvent such as dimethyl sulfoxide or a mixture of an ethereal and polar aprotic solvent such as tetrahydrofuran and dimethyl sulfoxide at temperatures between 0 and 60 ° C, usually overnight, to give 2-pyrrolidone 1_9 wherein W is a double bond. It will be noted that the acidic hydrogen or the group Q is then used as an ester in the case of

Carboxylic acid or as an N-acyloxymethyl, N-phthalidyl or N-tetrahydropyran-2-yl group in the case of tetrazol-5-yl can be protected. If desired, this 2-pyrrolidone 1_9_ with W as a double bond can be converted to 2-pyrrolidone j_9 by the hydrogenation method described above, in which V / is a single bond.

Verschiedei

e end products according to the invention the 2 ~ pyrrolidone

22, carb. and tet., are prepared by oxidation of the 5/3-hydroxymethyl group of 2-pyrrolidone j_9 and the Horner-Wittig reaction of the 5/3-formyl-2-pyrrolidone compound 20 thus formed with the sodium or lithium salt of a phosphonate of the formula (MeO) P 1 CHpCCH ₀ R, wherein R is as defined above, followed by reduction of the thus formed 5- (4 "-substituted-but-1-ene-3" -onyl) moiety of 2-pyrrolidone 2J_ produced

· ·

Scheme B shows this illustrated method by which method the <o chain is added.

Scheme B Addition of the CO chain

JL

, W

OH

oxidation

20

(MeO) ₂ PCH ₂ CCH ₂ R

21

reduction

H OH 22-cart>.

22-tet. OH

, H

S-N

The aldehyde, 20 v / ird from the ^ / S-hydroxymethyl - ^ - pyrrolidone compound '1_9 by a modification of Pfitzner-Moffatt oxidation / X, E. Pfitzner and ME Moffatt, J. Am. Chem. Soc, 87_, -5661 (1965) 7 obtained hei of the contact between the 5 β -For my 1- compound 20_ and V / ater is avoided. For example, by stirring a slurry of 1- (7 ^f -Methylheptanato) -5ß-hydroxymethyl-2-pyrrolidone or other suitable 5 / ^{a-hydroxymethyl-2-pyrrolidone} in an inert carbon water base solvent such as toluene, xylene or, especially benzene, with dimethyl sulfoxide , a weak acid such as acetic acid or especially pyridinium trifluoroacetate and a water-soluble diimide such as diethylcarbodiimide or especially dimethylaminopropylethylcarbodiimide or, if desired, its hydrochloride salt, at temperatures between 0 ° C. and ambient over a period of 1 to 4 hours, the primary alcohol V9. oxidized ^to aldehyde 2 pounds. Other methods of achieving oxidation include the standard Pfitzner-Moffatt reaction and oxidation with chromium trioxide-pyridine complex / R. Ratcliffe, et al., J. Org. Chem., 35, 4000 (1970) /, although the better method is the reaction described above.

Is _2J_ 5 / 3- (4 "-substituted-but-1" s-3 "-onyl) -2-pyrrolidone compound by contacting the 5/2-formyl-2-pyrrolidone compound 2O _- with the sodium or lithium salt of a phosphonate of the formula:

(MeO) ₀ PGH ₀ CCH ₉ R

wherein R has the meaning given above, in a solution or slurry with an ethereal solvent such as tetrahydrofuran, or dioxane at Cimethoxyäthan between 0 and 50 ⁰ C lying temperatures, until the reaction is γ / esentlichen is complete, as evidenced by Reaktionsüberwa-

- - 28 -

method is established. The isolation of the product from this Horner-Wittig reaction, whose method is known to those skilled in the art, is carried out in the usual way with the aid of chromatography. Other methods include, for example, high pressure liquid chromatography and, in some cases, fractional recrystallization, the me-. method for the preparation of the phosphonates can be found in US Patent 3,932,389.

The hydrogenation and, if desired, the alkaline or acid hydrolysis of the 2-pyrrolidone compound 2J_ produce some of the end products of formula I with a 15-hydroxy group, and such hydrogenation step is the subject of application no. 200468, which describes the process ,

O Jf

The compounds of formula I wherein Q is CNHR "can be obtained from the tetrahydropyran-2"'- yloxy derivatives of compounds 22 - and 23 which have a COpH group on Q. This synthesis sequence is shown in Scheme C, wherein R ^{111 is} as defined above. These acid derivatives, the compounds 24. and 2-5, are prepared from carboxylic acids according to well-known methods, as described for imide and sulfonimide preparations γ / erderi. Preference is given to the method according to the procedure of Speziale and Hurd, in which the acyl or sulfonyl isocyanate with the above-mentioned derivatives of the compounds 2JZ and 2_3 in an inert Lösungsmit-. such as ether or tetrahydrofuran are brought together at temperatures generally between ambient and solvent reflux temperatures, usually over 100%. See the following references: / 21. J. Speziale, inter alia, J. Org Chem, ₁₁ 3O 4306 (1965), CD Hurd and AG Prapas, J. Org Chem, 24_, 388 (1959)....; Reactions of isocyanates with carboxylic acids in "Survey of Organic Synthesis". (Review of Organic Synthesis), CA Beuhler, DA Pearson, Wiley Interscience,

21 3 3 69

New York, 1970j N-Acylation of Amides and Imides, J. March, "Advanced Organic Chemistry: Reactions, Mechanism and Structure", McGraw-Hill, New York, 1968, 3. 340.7.

- 30 - * U

Scheme C - Imide and sulfocimide derivatives

22 * 23

R CNCO

1 V. w

CO ₂ H

7 X ^tl w, ^R

Z ^ '. _0TH p

'N

0 0 Il H ft U '

COCIiHCR

-CO,

Bf ¹ SO ₂ NCO

0

H H ι))

COCNHSO ₂ R

-CO,

CNHCR

nt Γ Ν

W

^ X ^

I » ¹

H OTHP

H OTHP

'N-

5nhcr

W

fi | h

'CKHSO ₂ R

H OH H OH

24 25

There are several other methods of preparing the compounds of formula I wherein Q is CONHR. "The first alternative route is the treatment of the 5- (4" -substituted-but-1 "-ene-3" -onyl) -2- Pyrrolidone compound 21_, wherein Q is COOH, with an acyl or sulfonyl isocyanate under the conditions described above for the procedure of Speziale and Hurd. The C - J 5 oxo group of the resulting aminated or sulfonated pyrrolidone intermediate is then hydrogenated to a hydroxyl group using the hydrogenation procedure described in Application No. 200468.

The second alternative route consists in condensing the nonanone compound 5 with a phosphorane of the formula Ph ₅ P =CH (CH ₂₎ CONHR "using the procedure described for the analogous preparation of pyrrolidone 1_9 from the nonanone 5. After optional hydrogenation of the resulting C5-C6 double bond, this route produces a pyrrolidone intermediate of the formula:

CONHR "

H CH ₂ OH

The above pyrrolidone aromatic amidoamide intermediate is analogous to the pyrrolidone compound VI_ and may be subjected to the subsequent steps shown in Scheme B for the preparation of the compounds of formula I wherein Q is CONHR ".

The Esterpi ^v oducts of the formula I wherein Q carboalkoxy, carbophenoxy or carbo-para-biphenoxy may be prepared from the corresponding free acids wherein Q is COOH .., using generally known methods of esterification, including the reaction with diazoalkanes' with 1 to 5 carbon atoms and the reaction of phenol or p-biphenol with the acid and dicyclohexylcarbodiimide.

Not only can the 8-Asa prostaglandins be obtained as shown in Scheme A and B, but they can also be obtained from the intermediate compound. 1J3 be synthesized by first attaching the lower side chain and subsequent formation of the upper side chain. The reactions used for this synthetic sequence are shown in Scheme D. They have already been described in detail in Scheme A and B. Reaction 1 is the cleavage of the dimethy1-t-butylsilyl protecting group designated T in the scheme and described supra. Reaction 2 is the oxidation of the primary alcohol group to an aldehyde group, which forms the clue for the addition of the lower side chain. This reaction has been described above. Reaction 3 is the Horner-Witting reaction described above. In this reaction the same kind of phosphonate is used as in the whole main synthesis. Reaction 4-1 is the reduction of the lower side chain enone group to an allyl group as described above. Reaction 4-2 is the protection of the hydroxyl function of the allyl group formed in Reaction 4-1. It is also described above. In reaction 5, the protection of the acetal group, which forms the clue for the upper side chain, is removed. It is a simple hydrolysis, which will be described below. Reaction 6 is the usual reversing reaction used to form the upper side chain of the prostaglandins and described above

has been. In reaction 7, the protection is again removed from the hydroxyl group and it is analogous to reaction 1. The symbols Y, T, R and Q have the meanings explained above.

f 3 3

Scheme D

Alternative reaction scheme for 8-aza-prostaglandin synthesis

N-CH ₉ -CH (OX),

CH ₂ OT

Y = Me, Et T = S UVIe ₂ 1 Bu

.11-Bu ₄ NF (reagent)

-CH ₀ -CH (OY),

CH ₂ OH

DAPCO DMSO

Oxidant

R ₂ CH ₂ C0CH ₂ P (o) (OMe) ₂ / NaH 7. F n-Bu ₄ NF (reagent)

1 . LiBet, H -78 ^; I · 2. Me ₂ t-BuSiCl

N-CH ₀ -CH (OI)

6th

(Phosphorane)

\ S ±± jj

In numerous in vivo and in vitro experiments, it has been demonstrated that the new prostaglandin analogs possess physiological activities with greater selectivity, potency and duration of action than the natural prostaglandins have, among other things, a test for the effect on an isolated smooth Muscle of a guinea pig uterus, inhibition of histamine-induced bronchial spasm in guinea pigs, effect on blood pressure in dogs, inhibition of exercise-induced ulceration in rats, diarrhea inducing activity in mice and inhibition of stimulated gastric acid secretion in rats and dogs ,

The physiological responses observed in these assays are important in determining the usefulness of the test substance for the treatment of various natural and pathological conditions. Such identified uses include: the vasodilator effect, the hypotensive effect, the bronchodilator effect, the contraceptive effect, and anti-ulcer activity.

The new 8-aza-H-deoxy-prostaglandins of the present invention have highly selective activity profiles compared to the corresponding naturally occurring prostaglandins, and in many cases have a longer duration of action. For example, the novel prostamimetric pyrrolidones of the invention possessing the substitutions of aryl (including Phenyl, substituted phenyl and of -thienyl) at R and carboxylic acid, carboxylic ester or tetrazol-5-yl at Q have useful vasodilatory activity. The major examples of the therapeutic importance of these pyyrolidone compounds are the modes of action of 1- (6'-carboxyhexyl) -5β- (3 "-hydroxy-4" -phenylbut "1" -enyl) -2-pyrrolidone and 1- (6 ') carboxyhexyl) -5o {- ^(3-tl -hydro3ry 4 ^fl -phenylbut - 1 "-enyl) -2-p30 ~ roli

21 3 3

Those who have hypotensive efficacy of similar potency to PGSp itself have been administered intravenous anesthetized dogs according to the method of U.S. Patent 3,956,284. At the same time, "other effects, such as bronchodilation and prevention of ulceration, compared to PGGE, are greatly reduced as measured by the methodology of US Pat. No. 3,956,284.

Another salient example of the therapeutic importance of the pyrrolidones of the present invention is the selective prevention of ulceration of compounds containing substitutions of aryloxy (including phenoxy and substituted phenoxy) with R and carboxylic acid, carboxylic ester or imide, tetrazol-5-yl or sulfonimide at Q respectively. For example, 1 - (6'-carboxyhexyl) -5β- (3 ^il- hydroxy-4 ^{: 1-} phenoxy-but-1- ^fl- enyl) -2-pyrrolidone exhibits excellent and selective antisecretory action upon oral administration to dogs.

The novel compounds of the present invention can be used in a variety of pharmaceutical preparations containing the compound or a pharmaceutically acceptable salt thereof. They can be administered in a variety of ways, depending on the nature of the disease and the condition of the patient.

The 8-aza-11-deoxy-1-6-aryl -> tetranor prostaglandin compounds of the invention, and their epimers, are valuable vasodilators. For the treatment of hypertension, these medicaments may be appropriately administered as an intravenous injection in amounts of about 0.5 to 10 mg / kg, or preferably in the form of capsules or tablets in dosages of 0.005 to 0.5 mg / lcg / day.

The 8-aza-11-deoxy-1-6-aryloxy-tetranor prostaglandin compounds and their spemies according to the invention are valuable anti-ulcer agents. For the treatment of gastric ulcers, these drugs may be administered in the form of capsules or tablets in amounts of 0.005 to 0.5 mg / kg / day.

Pharmacologically acceptable salts useful for the purposes described above are those having pharmacologically acceptable metal cations, ammonium, amine cations or quaternary ammonium cations.

Especially preferred are the metal cations derived from the alkali metals e.g. As lithium, sodium and potassium, and of the alkaline earth metals, z. Magnesium and calcium, although cationic forms of other metals., E.g. As aluminum, zinc and iron, are within the scope of the invention.

Pharmacologically acceptable amine cations are those derived from primary, secondary or tertiary amines. Examples of suitable amines are methylamine, dimethylamine, triethylamine, ethylamine, dibutylamine, triisopropylamine, N-methylhexylamine, deeylamine, dodecylamine, allylamine, crotylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, © C-phenylethylamine, 3-methylhexylethylamine, Ethylenediamine, diethylenetriamine and other aliphatic ^, cycloaliphatic and araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g. As piperidine, morpholine, pyrrolidine, piperazine and lower alkyl derivatives thereof, for. 1-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine and the like, as amines which solubilize water and contain hydrophilic groups, for example mono-, di- and triethanolamine, ethyldiethanolamine, N-butyl-ethanolamine , 2-amino-1-butanol, 2-amino-2-ethyl-1,3-

propanediol, 2-amino-2 * -methyl-1-propanol, tris (hydroxymethyl) aminomethane, N-phenylethanolamine, N- (p-tert-amylphenyl) diethanolamine, galactamine, N-methylglucarain, N-methylglucosamine, ephedrine, phenylephrine, Epinephrine, procaine and the like.

Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium and the like.

For the preparation of one of the numerous possible formulations, a wide variety of inert diluents, excipients or carriers can be used. Such substances include, for example, water, ethanol, gelatins, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohol, gums, polyalkylene glycols, petrolatum, cholesterol, and other known drug delivery vehicles Compositions containing auxiliary substances such as preservatives, wetting agents, stabilizers or other therapeutic agents such as antibiotics.

The following examples are illustrative only and are not intended to limit the scope of the appended claims in any way. The spectral data were determined using a Varian T-60 or A-60 NMR, a Perkin-Elmer grating infrared spectrometer and an LKB-900 mass spectrometer. Infrared Yields are reciprocal centimeters, and NMR data are given in (^ parts per million using TMS as a standard.

In general, below the temperatures described in the examples

% \ 3

len reactions described, 'if they are not specified, ambient or room temperature, which fluctuated between 15 and 30 ⁰ C to understand.

Unless otherwise indicated, the time required for the reactions described in the Examples was determined by TLC monitoring. The usual TLC system consisted of silica gel on glass (S. Merck silica gel plates, E. Merck, Darmstadt, West Germany) with benzene / ether or methanol / chloroform as eluents and vanillin / ethanol or iodine as developers. / "Introduction to Chromatography", J.M. Bobbitt, A.E. Schwarting, R.J. Gritter, Va.n Nostrand-Reinhold, N.Y., 1968 /. As a general rule, the reaction in question was considered to be essentially complete when the critical starting material TLC spot had disappeared or completely changed.

Off , Guid e: Tables :

The following examples are intended to explain the invention:

Example 1:

^ A-CTetra, hydroTO ^r ran-2 ^<-yloyvmeth ₁ vl) -2-p.vrrolid o _i n, _i .j_

In a flame-dried flask under a nitrogen atmosphere, 2.54 g (22.1 mmol) of 5-D-hydroxymethylene-2-pyrrolidone, prepared by the method of V. Bruckner, et al., Acta, Ciiim! Hung. Tomus, 2 ±, 106 (1959), and 50 ml of methylene chloride. To this solution was then added to acid at 0 to 5 ⁰ C 3.72 g (44.2 mmol) of redistilled dihydropyran and 0.2 g of p-toluenesulfonic (tosic). The solution was then allowed to warm to room temperature.

and she was stirred overnight. After diluting the reaction mixture with 20 ml of ethyl acetate, the solution was extracted with 2 × 5 ml of saturated sodium bicarbonate solution and 1 × 10 ml of saturated saline. The organic layer was dried with magnesium sulfate, filtered to remove the desiccant, and the solvent was removed in vacuo to give 4.1 g of gel oil, which was collected on a column of 50 g Merck silica gel, in By eluting with 1 L of chloroform, the less polar impurities were removed by eluting with 2 % methanol in chloroform and collecting 10 mL fractions, the product was separated and purified by combining the product fractions and removing Solvent under vacuum gave 3.95 g of the title compound 1_ as a yellow oil in 90 % yield NMR T-60 (DCCI) bs / 6.60 ppm (1H), m, J 4.60 ppm (1H), m, </ 4.05 - ο 3.25 ppm (5H), m, ^ 2.50 - (f 2.10 ppm, m, cT2.00 - cTi, 40 ppm (IOH). IR (CHCl ₃ solution) 3425, 2980, 2930, 2850, 1680, 1250-1200, 1025 cm ^-1 .

In addition, the dimethyl-t-butylsilyl protecting group may be substituted for the tetrahydropyran-2-yl group using the procedure of EJ Corey, et al., J. Am. Chem. Soc., 9 4 , 6190 (1974) for 5-D-hydroxymethylene-2-pyrrolidone. ,

Example 2:

I-C7 ^l ~ Cthth.vlheT) tanat.o _i ) -5 / 3 - (tetrah ₁ vdro , pyran-2 "-ylox.vmeth, vl ') - 2-T) .vrrolidone 2

Into a flame-dried flask, in which a nitrogen atmosphere prevailed, was added 0.725 g (18.7 mmol) of 62% sodium hydride dispersion in mineral oil and 10 ml

- 213.169 ..

added dry THF (tetrahydrofuran). To this mechanically stirred slurry was slowly added dropwise 3.74 g (18.7% BiMoI) of 5-D- (tetrahydropyran-2-yloxymethyl) -2-pyrrolidone J [in 10 ml of dry THF. After completion of the addition, the thick slurry was stirred for 30 minutes until no evolution of hydrogen ceased.

This was followed by the alkylation of the sodium salt.

To this slurry was then added dropwise at room temperature 5.34 g (22.5 mmol) of ethyl-6-bromoheptanoate in 15 ml of dry dimethylformamide (DMF). After completion of the addition] after about 15 minutes, the slurry was dissolved, and sodium bromide slowly began to precipitate out of the solution. The reaction mixture was stirred overnight, filtered, and the solvent removed from the filtrate under vacuum. To the residue was then added 100 ml of ethyl acetate, and this organic solution was extracted with 2 × 20 ml of water. After drying the organic layer with magnesium sulfate and filtering it to remove the desiccant, the solvent was removed from the filtrate under vacuum leaving a yellow oil which was chromatographed on a column of 120 g of Merck silica gel filled in chloroform , Elution with: (a) 250 ml of chloroform; (b) 500 ml of 5% ethyl acetate in chloroform; (c) 1110 ethyl acetate in chloroform and automatic collection of 10 ml fractions allowed separation and purification of the product. The product fractions were taken together and the solvent removed to give the title compound 2_ as a colorless oil, 3.39 g, yield 51 #.

NMR T-60 (DCCI _3): M / 4.60 ppm (1H) q, cf4,17 ppm J ₁ = 8 Hz :,

m, <f4.00 - 2.70 ppm (9H) ,. m, .cT2,6 - 1, 4 ppm, t. CF | , 3 ppm J ₁ = 8 Hz. (23H).

IR (HCCl ₃ solution) 2975, 2915, 2840, 1720, 1665, 1450, 1250 1200, 1125, 1025 cm ^-1 .,. ^: .

Ms-heated ticker (m / e- #) 356-1 $, 355-3 $, 310-17 $ 240-100 $, 194-83 $.

The procedure presented may be varied for the preparation of pyrrolidones having the formula shown below by substituting the corresponding alkylating agent for iithyl-7-bromo-heptanoate and optionally terminating the dimethyl-tert-butylsilyl analog of pyrrolidone ,

X = -CO ₂ C ₆ H ₅ -CO ₂ CH ₃

N- (CCetrahydropyran-2-yl) tetrazol-5-yl N- (acetyloxymethyl) -tetrazol-5-yl W = simple or cis double bond ΐ = THP or dime thyl-t-butylsilyl.

As mentioned, the 1- (substituted) -5 / 5 can (tetrahydropyran-2 -yloxyniethyl- or "Dime thyl-t-Butyl iloxyraetiij ^r l) -2-pyrrolidone by substitution of the appropriate alkylating agent for the ethyl-7- For example, when 1-6 '~ carboxymethylhex-2- ^l- ynyl) -5! ^ - (tetra-

hydropyran-2 "~ ylox3 / methyl) -2-pyrrolidone to be produced, are used as the alkylating agent methyl-7- ~ bromhept-5-enoate desired 1- (6'-1 ^IIF -Acetyloxymethyltetrazol-5". ^f ylhexyl) - 5 ^ (tetrahydropyran-2 "-yloxymethyl) -2-pyrrolidone are prepared, then can serve as the alkylating agent 6-bromo (i ^f -.acetyloxymethyltetrazol-5'-yl.) - n-hexane.

1- (2,2-diethoxyethyl) -5 P- (tetrahydropyran-2 "-yloxymethyl) -2-pyrrolidone 3. may also be prepared by the same procedure using 2-bromoacetaldehyde diethyl acetal as the alkylating agent.

DIAE. Preparation of 6-bromo-1-tetrazol-5'-yl-n-hexane can be accomplished by the following method.

   ι

A mixture of 2.98 g (23.5 mmol) of 7-hydroxyheptanenitrile, 1.60 g (30.0 mmol) of ammonium chloride, 0.032 g (0.76 mmol) of lithium chloride, 1.91 g (29.3 mmol) of sodium azide and "50 ml of dimethylformamide may be stirred under nitrogen for 18 hours or until the reaction is substantially complete, kept at 120 ^° C. The dimethylformamide may then be removed under vacuum and the resulting residue removed by one of the numerous methods such as chromatography or extraction This product, 6-hydroxy-1- (tetrazol-5-yl) hexane, can then be treated with phosphorus tribromide under appropriate conditions to give 6-bromo-1- (tetrazol-5-yl) hexane The acetyloxymethyl group can then be added by the method of V / V.V. Daehne, et al., Supra, while the N-tetrahydropyran-2-yl group can be added by the method of Example 1.

The treatment of .7- (Tetrahydropj ^'r ran-2-yloxy ^l) hept-5-ynnitril in the same V / else as above enables the preparation of 6- (tetrahydropyran-2'-yloxy) -1- (tetrazol ~ 5 ^u yl) hex-4-yn. This

213 349

Material can then be converted to 6-bromo-1- (tetrazol-5'-yl) hejr-4ene ^I by the method of German Offenlegungsschrift .2.121.361 (CA. 76: 24712d). Of course, the starting hept-5-ynnitrile can also be hydrogenated to the olefin prior to the conversion of the nitrile to the tetraapi using substantially the same procedure. The acidic hydrogen protecting groups of tetrazol-5-yl may also be added again by the above methods.

Example 3i C) - ^ e-hydroyyrneth ₁ yl-2-O.vrrolidon

To a solution of 200 ml of methanol and 3.99 g of THP-pyrrolidone 2_ was added 79 mg of p-toluenesulfonic acid (Tosic) and the solution was refluxed overnight. After treatment as described below, an NMR spectrum of the reaction mixture revealed the presence of a small amount of starting ethyl ester. Therefore, the reaction mixture was redissolved in 160 ml of methanol, 0.080 g of tosic acid was added, and the reaction mixture was again refluxed overnight. Removal of the solvent from the reaction mixture under vacuum gave a yellow oil which was dissolved in ethyl acetate and extracted with 1 x 10 ml of a 1: 2 mixture of saturated sodium bicarbonate and half-saturated Rochelle salt solution. The organic phase was dried over magnesium sulfate and filtered, and the solvent was evaporated to give the title compound 4, as a yellow clear oil, 2.528 g (yield 88 #).

NMR A-60 (DCCI _3), s. cf 3.86 ppm, m. (A ₅ OO - 3.33 ppm, m.f cf 3.20 - / 2.70 ppm (13H), m.c / 2.50 - / 2.00 ppm, m / i, 90 σ 1.20 ppm (LOH), partial spectrum.

IR (HCCl ₃ -LoSUrIg) 3550 - 3100, 2980, 2910, 2840, 1720, 1650, 1450, 1425 ,. 1410, 1250 -Ί190 cm " ¹ .

MS, LKB 9000, solid inlay (m / e - %) 70 eV 22-6 - 26 #, 194 19,8 #, 74 - 100 #, 13 eV 257 - 3,3 #, 226 - 100 #, 168 24 , 6 #.

On the other hand, the tetrahydropyran-2- ^methyl- yl group can be removed by hydrolysis in a 65:35 mixture of glacial acetic acid and water over a period of about 18 hours, essentially according to the procedure of Example 14.

In this case, the ethyl ester group of pyrrolidone 2 will be kept intact.

The above acetic acid / water hydrolysis process can also be used to remove the tetrahydropyranyl protecting group from the other pyrrolidone products of Example 2, which then produce the corresponding 1- (substituted) -5 / ^a- hydroxymethyl-2-pyrrolidones. However, if the tetrazole-5-yl protecting group is tetrahydropyran-2-yl, then it is advisable to use the dimethy1-t-butylsilyl group as T. These. Silyl group can be selectively removed with tetra-n-butylammonium fluoride by the method of Corey, supra.

Using the procedure with acetic acid for 1 ~ (2,2-diethoxyethyl) -5- (tetrahydropyran-2 "-yloxymethyl) -2-pyrrolidone 3_ of Example 2, removal of the tetrahydropyranyl group will be accompanied by cleavage of the acetal and cyclization so that the product is an equilibrium mixture of the open form and 4 "aza-'2-hydroxy-1-oxa-bicyclo ^ 3,4, 0] nonan-5 ~ on 5. ,

CHO

OH

The compound-containing equilibrium mixture can be converted to 1- (substituted) -5β-hydroxymethyl-2-pyrrolidones by the following procedure.

To a solution of 23.04 g (52.0 ml) of 5-triphenyiphosphoniopentanoic acid (bromide salt) in 46 ml of dry dimethylsulfoxide can dropwise 49.3 ml (98.6 ml) of a 2, ON solution of sodium silylsulf iny line thid be given in dimethylsulfoxide. To the resulting red solution then 3.27 g (20.8 mmol) of 4-aza-2-hydroxy-1-oxa-bicyclo / 3, 4, o-nonan-5-one 2 i ⁿ dry dimethylsulfoxide ( 63 ml). After further half an hour of stirring, or until it is substantially ready, the reaction mixture can be poured into 600 ml of ice water and then extracted with 2 χ 300 ml of ethyl acetate. The cold aqueous layer can with ethyl. be covered acetate and acidified to a pH of about 3 with 10 $> hydrochloric acid, and the aqueous layer with 2 χ 200 ml of ethyl acetate can be extracted. The combined organic extracts are washed with water and then with brine, and the organic layer can be dried over anhydrous sodium sulfate. Concentration of the filtered organic layer gives crude 1- (6'-carboxyhex-2'-enyl) -5i3-hydroxymethyl-2-pyrrolidone, which can be chromatographed. The acid can then be esterified with diazomethane.

This procedure can also be used for the preparation of 1 ~ (substituted) -5β-hydroxymethyl-2-pyrrolidones of the following formula:

^ V OH

in which X has the meaning explained in Example 2, by using the corresponding phosphonium salt for 5-Triphenylph.phosphonpentanz acid and then the acidic hydrogen with an N-Acyloxymetnyl group nach .. the by W. V. DaelinCj u. a., zit "with an N-tetrhydropyran-2-yl group according to the VerfahrensV eise of Example 1 or by esterification in the case of carboxylic acid is protected ·

Example 4:

1 - (J · -Met h.7lhe "Dtanato) -5.3-formyl-2-B.vrrolldon 6

In a getrockneten.und a nitrogen atmosphere containing over a flame flask 0.1286 g (7 -Methylheptanato ^t) (0.5 mmol) of 1- -5ß-hydroxymethyl-2-pyrrolidone 4 in 5 ml dry benzene. ' To this solution was added 0.1286 g (1.5 mmol) of dimethylaminopropylethylcarbodiimide hydrochloride (DAFC) and 0.142 g (2 mmol) of dimethylsulfoxide, followed by 5.08 g (0.55 mmol) of pyridinium trifluoroacetate after 5 minutes .. The reaction mixture was stirred under a nitrogen atmosphere Stirred for 1.75 hours at room temperature, then the benzene was decanted and the viscous second phase formed at the bottom of the flask was washed with 3 x 5 ml of benzene. The benzene solutions were taken together and the solvent was removed in vacuo to give 0.152 g of Tite Compound

a clear yellow oil. The crude product was used immediately and without further purification in the next reaction.

KIvIR T-60 (DCCI _3), d. ^ 9.72 ppm J ₁ = 3 Hz Oh), m. (f 4.37 </ 4.07 ppm (1H), s. / 3.70 ppm (3H) partial spectrum.

The above procedure can also be used to oxidize the other 1- (substituted) -5-hydroxymethyl-2-pyrrolidones of Example 3 to the corresponding 1- (substituted) -formyl-2-pyrrolidones.

Example 5:

1-r7 ^t -meth, ylheOtanato ') - ^ j3-C4 "-phenylbut-1'^{> t} -en-3" -onyl) -2- pyrrolidone 7_

In a dried flask over a flame having therein a nitrogen atmosphere, O, were 1188 g (2.97 mlvlol) of a 60 follow sodium hydride / mineral oil dispersion and 5 ml of THF were introduced. To this slurry was added a solution of 0.7815 g (3.24 ml viol) of dimethyl (3-phenylpropan-2-onyl) phosphonate in 5 ml of THF. Upon completion of hydrogen evolution, a white suspension formed, which was stirred for 15 minutes. To this suspension was added 0.6894 g (2.70 ml viol) of 1- (7'-methylheptanato) -53-formyl-2-pyrrolidone 6 in 10 ml of THF over 1 minute. Within 5 minutes, the reaction mixture became a clear yellow solution, which was stirred for a further 2 hours. The reaction mixture was quenched with glacial acetic acid to a pH of 5. The solvent was removed in vacuo and the residue was taken up in 100 ml of ethyl acetate. The organic solution was extracted with 2 × 10 ml of saturated aqueous sodium bicarbonate, 3 × 10 ml of water and 1 × 10 ml of saturated saline solution.

213 3 <p

hiert. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum to yield 1.141 g of the oil. This crude product was chromatographed on a column of 35 g of E. Merck silica gel filled in ethyl acetate. Slurry with iithyl acetate and automatic collection of 10 ml fractions allowed purification of the product. The product fractions were pooled and the solvent was removed in vacuo to give 0.614 g of the title compound 1_ as a colorless oil (Yield 61 <fc with respect to the starting alcohol).

NMR T-60 (DCCl ₃ ) s ./7.33 ppm (5H), dofd. / 6.73 ppm J ₁ =

7 Kz, J ₂ = 16 Hz, d. cf6,60 ppm J ₂ = 16 Hz (2H), m. cf 4,27

ppm center (1H), s. c / * 3.93 (2H), s. </ 3.73 ppm (3H) partial spectrum.

(CHCl ₃ solution) 2980, 2900, 2840, 1725, I685 (sh) _y 1675, 1625, • 0-1200 cm ^-1 .

MS, LKB9000 (w / w SS) 70 eV 372-20 <f>, 371-82 ^, 252-96 %, 226-24 *, 194-35 56, 12 eV 372-18 SS, 371-100 #, 252-24? 6, 226-39 %,

The other 1- (substituted) -5ß-formyl-2-pyrrolidone ^ ^r onnectivity of Example 4 can in the above method instead of j3 pyrrolidone to prepare the corresponding 1- (substituted) -5 / 3- (4 '-Phenylbut ~ 1 ⁿ -ene-3 "-onyl) -2-pyrrolidone compounds. In addition, phosphonates of the formula:

(MeO) ₂ PCH ₂ CCH ₂ Z 0 0

Z '= -C ₆ H ₄ CH ₃ (m) -O -thienyl

-C ₆ H ₄ OCH ₃ Ce)

-C ₆ H ₄ -C ₆ H ₅ Cm) -C ₆ H ₄ CF ₃ (J ₂ ) -, -C ₆ H ₄ Cl (ο) *

for dimethyl (3-phenylpropa3i-2-onyl) phosphonate for the preparation of the corresponding 1- (substituted) -5 / 3- (4 "-substituted but-1" -en-3- ⁱ '-on-7l) -2-pyrrolidone compounds v / ground. Subsequently, all pyrrolidones which include the 4 ^lf -phenyl ^{compounds are} referred to as 1- (substituted) -5,6- (4 "-substituted tt-1 ' ^l -ene-3" -one-3l- ^r ) -2-pyrrolidones.

ι BeisOiel 6 t

.1-f 7 '-Me thylheptanato) -5f3-C3 "-h.Ydrox.y-4" -phen.ylbut-1 "-enyl; -2-Pvrrolidon 8 -.'

Into a flame-dried, magnetic stir bar-equipped flask (in which an atmosphere was stirred) was added 0.5784 g (1.56 mlsol) of 1- (7'-methylheptanato) -5 / 3- (4 "). phenylbut-1 "s-3" where -onyl) -2-pyrrolidone 1_ ⁱⁿ 20 ml dry THF. The clear, colorless solution was cooled to -78 ⁰ C, and 1.56 ml (1.56 mmoles) was added dropwise Lithiumtriäthylborhydrid After 1 hour, a (DLC showed absence of starting Enoη, so that the reaction mixture was quenched with glacial acetic acid to pH 5, followed by removal of the solvent The residue was dissolved in 50 ml of ethyl acetate and this organic solution was then extracted with 1 x 10 ml of half-saturated aqueous sodium bicarbonate, 4 x 10 ml of water and 1 x 10 ml of saturated brine.

The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum to yield 700 mg of crude product. This product was chromatographed on a column of 9 g silica gel filled in ethyl acetate. Elution with ethyl acetate and automatic collection of 5-mol fractions separated the product from impurities. By combining the product fractions and removing the solvent under vacuum, 0.298 g of the titer compound _8 was obtained in the form of a colorless oil (Yield 51

T-60 (DCCl ₃ ) s. <f 7.37 ppm (5H), d. </ 5.72 ppm J ₁ = 7 Hz,

d. cT 5.62 ppm J ₁ = 7 Hz (2H), m. cf 4.67 - 4.33 ppm, "m./4.30.

cf3.83 ppm (2H), s. cf 3.73 ppm (3H), d. ^ 2.90 ppm J ₂ = 6 Hz (2H). Partialspektrum.

IE (HCCI solution) 3450-3200, 2975, 2900, 2830, 1725, 1665, 1250-1200 cm "" ¹ . ,

The other 1- (substituted) -5 / 3- (4 "-substituted but-1" -ene-3-oyl) -2-p7rolidone compounds of Example 5 can be used in the above procedure to prepare the corresponding 1- (subs substituted) -5 / ³ - (4 "-substituted th-3" -hydro3jybut-1 "-enyl) pyrrolidone compounds.

Example 7;

) '5,' ^ - C3 "-h, ydrox.y-4" -phenylbut-1 "-e

pyrrolidone 9

To a solution of 69 mg (0.185 ml) of 1- (7-methylheptanato) -5p ~ (3-hydroxy-4-phenylbut-1-enyl) -2-pyrrolidone 8 in 3 ml of methanol was added 0.185 ml (0.185 mAq.). Sodium hydroxide added ·

21 3 369

The reaction solution was then refluxed overnight and then neutralized to pH 4 by the addition of glacial acetic acid. The solvent was removed under vacuum and the oily residue γ / urde dissolved in 15 ml of ethyl acetate. The organic solution was extracted with 2 × 2 ml of water and 1 × 2 ml of saturated brine, dried with magnesium sulfate and filtered. The solvent was removed in vacuo to give the title compound 9.0 as a yellow oil, 59.4 mg, yield 89 ° h.

NMR T-60, DCCl ,, s. cf 7.33 ppm (5H), bs (/ 6.30 ppm center (1H), that is, / 5.73 ppm J ₁ = 7 Hz, ie cf 5.6 ppm JJ = 7 Hz (2H), m. cT4,6 -I cT3,2 ppm (4H), d. cf2,93 ppm J ₂ = 7Hz (2H) (Partialsppktrum).

IR HCOU solution, 3500 - 3100, 2980, 2920, 1700, 1600, 1250 1200 cm " ¹ .

By using the other 1- (substituted) -5β-hydroxybutenyl-2-pyrrolidones of Example 6 in place of pyrrolidone £ 5 in the above process, the cleavage of the methyl ester or acyloxymethyl scimbenz groups and the preparation of the following S-aza-H deshydroxyprostaglandin E ^ - and E ₂ compounds possible. The N-tetrahydropyra, n-2-yl protecting group, if used, can be removed by the method of Example 3 or 14.

X = -CO ₂ HZ ¹ = -C ₆ H ₄ CH ₃

tetrazol-5-yl-of-thienyl

-C ₆ H ₄ OCH ₃

C / H-CrHr

6 4 6 5 - ^C 6 ^H 4 ^CF 3

Example 8:

1- ^(7-t -Metkvlhe Dtanato ') -' / 3 - ( '4 "- Dhenoxybut-1' -en-3 ^t> -on.vl ') - 2 - pyrrolidone • 10

In a nitrogen atmosphere containing and over a flame dried flask, 22 mg (0.55 ml viol) of sodium hydride dispersion in mineral oil and 5 ml of THF were charged. To this slurry was added a solution of 0.1549 g (0.6 mmol) of dimethyl (3-pheno: 2-cyano-2-ynyl) phosphonate in 5 ml of THF. Upon cessation of the water-evaporation, a clear pale yellow solution remained, which was stirred for 15 minutes. To this solution was added 0.127 g (0.5 mmol) of 1- (7 ^l -methylheptanato) -5 / 3-formyl-2-pyrrolidone 6 in 5 ml of THF over 1 minute. Within 5 minutes, the reaction mixture became a clear yellow solution, which was stirred for a further 2 hours. The mixture was quenched with glacial acetic acid to pH 5. The solvent was removed in vacuo and the residue was taken up in 50 ml of ethyl acetate. The organic solution was extracted with 2: 5 ml of saturated aqueous sodium bicarbonate, 2 x 5 ml of water, and 1: 5 ml of saturated brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum to yield 0.231 g of yellow oil. This crude product was chromatographed on a column of 25 g B.Ivierck silica gel filled in cyclohexane. Elution with 50% chloroform in cyclohexane and automatic collection of 10 ml rinses allowed the product to be purified.

The product fractions were pooled and the solvent was removed under vacuum to give 53.6 mg of the title compound were recovered 1_0 (yield 28 ⁰ Io with respect to the starting alcohol).

IIvIR T-60 (DCCl ₃ ), m. cT 7.40 - 6.70 ppm (5H), m. </ 6,7 - 6,33 ppm (2H) s. cT4.67 ppm (2H), m. (^ 4,40 - 3,97 ppm '. (1H), see cT3,67 ppm. (3H).) Partial spectrum.

The other 1 - (substituted) -5ß-formyl-2-pyrrolidone compounds of Example 4 can be used in the above procedure instead of pyrrolidone _6 to prepare the corresponding 1- (substituted) -5ß- (4 ^M -Plienoxybut-1 " -en-3 "-onyl) -2-pyrrolidone compounds. In addition, phosphonates of the formula:

(MeO) ₂ PCH ₂ CCH ₂ -OY OO

Y = -C ₆ H ₄ CH ₃ (p.)

-C ₆ H ₄ CF ₃ Ca)

-. ^C 6 ^H 4 ^C 6 ^H 4 CE) -C ₆ H ₄ OCH ₃ (p)

-C ₆ H ₄ -Cl (0)

for dimethyl (3-phenoxypropane-2-onyl) phosphonate substituted for the preparation of these corresponding 2-pyrrolidone compounds.

213 U9

Example 9:. '

1-C7-methyl-thy-pentanoate o ) -50- (3 ^ft -h.vdr oxy-4 "-dhenox.but-1- enyl *)

-2-Toyrrolido nJJL. "

Into a dried equipped with a flame, with magnetic stirring, thermometer, and a nitrogen atmosphere flask was added 0.1046 g (0.27 mlvlol) 1- (7 ^I -Methylheptanato) -5 / 3- (4 "phenoxy" but-1 " -en-3 ⁿ -onyl) filled -2-pyrrolidone 10 in 5 ml dry THF. The clear, colorless solution was cooled to -78 ⁰ C and 0.27 ml (0.27 mmol) Lithiumtriäthylborhydrid was added dropwise over 15 minutes After 1 hour, TLC indicated absence of starting enone, so that the reaction mixture was quenched with glacial acetic acid to pH 5, followed by removal of the solvent under vacuum was dissolved in 25 ml of ethyl acetate, and this organic solution was then extracted with 1 χ 5 ml of half-saturated aqueous sodium bicarbonate, 1 χ 10 V vial and 1 x 10 ml of saturated brine The organic layer was dried over magnesium sulfate, filtered and d The solvent was removed under vacuum to give 101 mg of crude product. This product was chromatographed on a 25 g silica gel column filled in benzene. Elution with ethyl acetate and automatic collection from 5 ml fractions separated the product from impurities but did not separate the two epimers. The combination of the product fractions and the removal of the solvent under vacuum gave 85.6 mg of the title compound ΛΛ_ (Yield 82 #).

.NMR.T-60 (DCCl,) m. «/ 7,54 - 6,82 ppm (5H), m. / 5.94 - 5.73 ppm (2H), m. d 4.79 - 4.43ppm (1H), m. <^ A _} 35-3.94 ppm ppm (3H), s ^ 3,70 ppm (3H), partial spectrum.

IR (CKCl ₃ -LoSUiIg) 3600 - 3100, · 2980, 2920, 1730, 1670, 1600, 1200 - 1250. cm "" ¹ .

The other 1- (substituted) -5 / 3- (phenoxybutenoyl) -2-pyrrolidone compounds of Example 8 can be substituted for pyrrolidone 1_0_ in the method discussed above and give the corresponding 1 ~ (substituted) ~ 5 | 3 ( 4 "-phenoxy-3" -hydroxybut-1 "-enyl) -2-pyrrolidone compounds.

Example 10;

1 ~ ('6'-carboxyhexyl) ~ 5f3-C3 "-hydrox.y-4'-phenox.ybut-1" -enyl) -2 -T) -rolidone 12

To a solution of 50 mg (0.128 ml viol) of 1- (7'-methylheptanato) -5 ^ - (3 "-hydroxy-4" -phenoxybut-1 "-enyl) -2-pyrrolidone 1J_ in 3 ml of methanol was added 0.128 ml The reaction solution was refluxed overnight and then neutralized by the addition of glacial acetic acid to pH 4. The solvent was removed in vacuo and the oily residue was dissolved in 15 ml of ethyl acetate The solution was extracted with 2 × 2 ml of water / 1 × 2 ml saturated brine, dried over magnesium sulfate and filtered, the solvent was removed in vacuo to give the title compound 1_2_ as a yellow oil, 48.0 mg (Yield 99 '. #).

NMR T-60 (DCCl,) m. cT 7.40 - 6.82 ppm (5H), m. ei 6.73 to 6.17 ppm (2H), 5.87 ra tf -. 5.70 ppm (2H), m. ^ 4.7 - 4.4 ppm (1H), m. </ ~ 4.23 - 3.88 ppm (3H). Partialspektrum.

IR (HCClj solution) 3600-2900, 2920, 1700, 1670, 1600, 1200, 1250 cm.

By using the other 1 - (substituted) - (hydroxyphenoxybutenyl) -2-pyrrolidone compounds of Example 9 instead of pyrrolidone 1_1_ in the above process, the cleavage of the methyl ester or acyloxymethyl groups and the preparation of the following 8-aza-11- deshydroxy-prostaglandin-S, - and Ep compounds. The N-THP protective group can be cleaved off according to Example 14.

X = -CO ₂ H

.-Tetrazol-5-yl

V =

-C ₆ H ₄ CH ₃ -C ₆ H ₄ CF ₃ (m) - ^C 6 ^H 4 ^C 6 ^H 4 -C ₆ H ₄ OCH ₃ -C ₆ H ₄ -Cl (0)

Example 11r

1 - (I '-Met hylheOtanat0) - $ & - (3 trahydroOyran ^n-2 th "' -yloy.v- 4." - T3hen.ylbut-1-enyl) - * - 2 - p.vrrolidon

Into a flame-dried flask, under a nitrogen atmosphere, was added 128 mg (0.34-2 mmol) of 1- (7'-methyll-heptanato) -5f3- (3 "-hydroxy-4-phenylbut-1-enyl) -2 -pyrrolidone _9 and 5 ml of methylene chloride. This solution was

the "at O to 5 ⁰ C then 0.062 ml (0,6S4 mmol) redistilled Dihydropropan and 3 mg Tosic acid was added. The. solution was then for heating stirred to room temperature, allowed to stand and power. The reaction mixture was diluted with 10 ml iithylacetat and extraction with 2 χ 2 ml saturated sodium bicarbonate, 1 χ 5 ml of saturated saline treated. the organic layer was dried, filtered and the solvent removed under vacuum to give 0.135 g of yellow oil were obtained over magnesium sulfate. This was chromatographed on a column 15 g of E. Merck silica gel, filled in chloroform, chromatographed by elution with 1 L of chloroform, the less poloxic impurities were removed, the elution with 2% methanol in chloroform and the automatic collection of 10 mL fractions separated uAd cleaned the product. By combining product fractions and removing the solvent under vacuum, 0.1756 g of the title compound 1_3 were recovered as a yellow oil.

T-60 (DCCl ₃ ) s. (T 6.34 ppm (5H), m./5.77-5.37 ppm (2H), m.cT5.13-4.80 ppm (1H), sf cf 3.7 PPm (3H), Partialspektrum.

In addition, the 1- (substituted) -5 / 3- (4 "-substituted-3" -hydroxybut-1 "-enyl) -2-pyrrolidones of Examples 6, 7, 9 and 10 can be prepared in this process to prepare the corresponding THP Derivatives are used.

Example 12;

) ("- tetrah, yd ropyran-.2"'-yloxy-)

4 _{i i} -P ^lt henylbutanyl _-) -2-pyrrol_idon 1.4

To a solution of 156.5 mg (0.342 mmol) of 1- (7'-Methylheptanato) -5 / ⁵ - (3 ^Ii -tetrahydropyran-2 ^"f-yloxy-4" ~ phenyibut-1-enyl) -2-

pyrrolidone .1_3 in 10 ml of ethyl acetate was added 31 mg of 10 % palladium on charcoal and the whole mixture was placed in a Parr-V / mass reduction apparatus and shaken under pressure of 50 lbs of hydrogen for 4 hours. The slurry was then passed through Celite was filtered to remove the catalyst, and the solvent was removed from the filtrate to yield 158.2 mg of the title compound ΛΑ_ .

T-60 (DCGl ₃ ) s. cT7.33 ppm (5H), m. ό 5.13 - 4.67 ppm (1H), m. cf 4.57-4.33ppm (1H), s. J 3.73 ppm (3H) partial spectrum. , ,

In addition, the other THP derivatives of Example 11 wherein A is a single bond can be used in this process for the preparation of the corresponding hydrogenated derivatives

Example 13:

\ -C6 ^f - Caryboxyhexyl *) - 5 / ^ - C3 ^r> -te tr ah.vdr ο pyran-2 "'-yloxy-phenyl butanyl) -2 ~ pyrr oli don_ 1.5,

To a solution of 1582 mg (0.342 mmol) of 1- (7'-methylheptanato) -5β- (3 "-tetrahydropyrane" "yloxy-4" -phenylbutanyl) -2-pyrrolidone 14_ in 5 ml of methanol was added 0.342 ml ( The reaction solution was refluxed overnight and then neutralized by the addition of glacial acetic acid to pH 4. The solvent was removed in vacuo and the oily residue was dissolved in 15 ml of ethyl acetate The organic solution was extracted with 2 × 2 ml of water and 1 × 2 ml of saturated brine, dried over magnesium sulfate and filtered, the solvent was removed in vacuo to give the title compound 1_5 as a yellow oil, 134.2 mg (yield 89%). #).

NIvIR T-60 (DCCl ₃ ) s. J 7.37 ppm. (5H), m. J 4.4-3.2 ppm, if 2.92 (2H), partial spectrum.

In addition, the other hydrogenated derivatives of Example 12 can be used in this process for the preparation of the corresponding 6'-carboxylic acid and 6'-tetrazole-1-yl compounds.

Example 14:

1-C6'-carboxyhexyl) -5 / 3- (3 "-hydroxy.y-4-phenylbutyl, nyl *) - 2- pyrrolidone 16

Cβ-aza-11-desh _r ydroyy-1 6-phenyl-1 6-6; tetranor PGE _n 16 *)

A solution of 134.2 mg (0.3 mmol) Compound 1_5. Was stirred in 5 mL of a 65:35 mixture of acetic acid and water overnight under nitrogen at ambient temperature. The solvent was then removed by vacuum evaporation using an oil vacuum pump and the residue azeotroped with benzene. The crude product was then chromatographed on 15 g of ARCC7 silica gel eluted with 2% methanol in chloroform to give 82 mg of the title compound 1_6.

M T-60 (DCCl ₃ ) s. cf 7.17 ppm (5H), \ m. cT3.2 - 4.0 ppm (3H), d. <f 2.77 ppm J _β = 7 Hz (2H). Partialspektrum.

IR (HCCl ₃ solution) 3600 - 3100, 2930, 2860, 1700, 1660, 1250, 1200, 710 cm ^-1 .

In addition, this procedure may be used to remove the THP protecting group from the 6'-carboxylic acid and 6'-tetrazol-5-yl

Derivatives of Example 13 and the hydrogenated derivatives of Example 12 are applied.

Example 15;

- y -. ('6 ^t -l · IP ^ henylimidoh.eyylV5i ^! ^ -Γ3 "- ^ h.ydroy y-4 ^lt -υlen ylΐιut-1" - _! enyl) -2-pyrrolidone

To a solution of 64 mg (0.171 mL) of 1- (6 ^f -carboxyhexyl) -5β- (4 "-phenyl-3" -tetrahydropyrane "'- yloxybut-1" -enyl) -2-pyrrolidone prepared according to the procedure in Example 11, in 10 ml of dry tetrahydrofuran, 25.16 mg (0.171 mmol) of benzoyl isocyanate, prepared according to the method of AJ Speziale, J. Org. Chem., 27, 3742 (1962), in 5 ml of dry THF become. After refluxing overnight, the solvent can be removed under vacuum and the reaction material freed from protection by the procedure of Example 14 (THP group removed) to give the title compound.

Similarly, the following imide derivatives can be prepared by substituting the other appropriately protected carboxylic acids of Examples 7, 10 and 14

Im = NHCPh ι

NHCCH ₃

Z 'is explained in Example 7

V is explained in Example 10

W is a simple or cis double bond

Z is a simple or trans-double bond

Example 16:

1 - ( 6'- N -Me th, y.lsulfonimidohey ₁ vl ') - fi-r3 "-hydroxy -4" -phenylbut-1 "-enyl) -2-pyrrolidone

To a solution of 64 mg (0.171 mL) of 1- (6'-carboxyhexyl I) -5β- (4 "-pheny1-3" -1e trahydro-pyran-2 "'-yloxybut-1" -enyl) -2- pyrrolidone * prepared by the method of Example 11, in 10 ml of dry benzene, 20.7 mg (0.171 mmol) of methylsulfonyl isocyanate (AJ Speziale, see Example 16) in 5 ml of dry benzene at ambient temperature. After refluxing overnight, the solvent can then be removed under vacuum, and the resulting residue can be removed by the procedure of Example 14 to recover the title compound (THP group removed).

By substitution of phenylsulfonyl isocyanate for methanesulfonyl isocyanate in this process, the corresponding phenylsulfoximide derivatives can also be prepared.

In addition, the following sulfonimides can be generated by substituting the other appropriately protected carboxylic acids of Examples 7, 10, and 14.

Ϊ-Suf

Suf = NHSO ₂ CH ₃ MSO ₂ Ph

V is illustrated in Example-10 Z ¹ is illustrated in Example 7 W is a single or double bond Z is a single or trans double bond

Claims (3)

Invention imgsanspruch: 1 . Methods for the preparation of a Pyrrolidonverloindung the formula: and the C54 epimer thereof Q is a group of the formula -COOR ¹ , tetrazol-5-yl, N- (acyloxymethyl) tetrazol-5-yl having 2 to 5 carbon atoms in the acyloxy group, N- (phthaliayl) tetrazol-5-yl, K- (tetrahydropyran- 2-yl) .tetrazol-5-yl or a group of the formula -CONHR is j V / is a simple or cis double bond Z is a single or trans double bond; , 0H. , -E
M = 0, «v. or C is OH R is o-C-thienyl, phenyl, phenoxy, monosubstituted phenyl or monosubstituted phenoxy, wherein the substituent is chlorine, fluorine, phenyl, methoxy, trifluoromethyl or alkyl of 1 to 4 carbon atoms, R * is hydrogen, alkyl of 1 to 5 carbon atoms, phenyl or p Biphenyl is; and R "-COR" is ¹ or SO ₂ R "', wherein R ¹ " is phenyl or alkyl of Λ to 5 carbon atoms. and the alkali metal, alkaline earth metal and ammonium salts of those compounds which is a carboxylate or tetrasol-5-yl group, characterized in that a pyrrolidone of the formula: CH ₂ OT. II wherein T is a hydroxy Schutsgruppe, either (a) with a compound of the formula: III wherein X is chlorine, bromine or iodine and V / and Q have the meaning described above, or (b) with a compound of the formula XCHpCH (OY) ₂ , wherein X has the meaning explained above and Y is alkyl having 1 to 3 carbon atoms is reacted, and when the reaction is carried out with a compound of formula III, the protective group T is removed and the resulting alcohol is oxidized to the aldehyde, and then the second side chain by reacting the aldehyde 'with a phosphonate of the formula: CaCl-O) ₂ POCH ₂ COCH ₂ R. IV wherein alk is an alkyl group of 1 to 3 carbon atoms; and when the first reaction ₀ CH (OY) was carried out with a compound of formula XCH _9, in any order; (c) remove the group of swabs Y to liberate the aldehyde and add this with Hi ^ P = C (CH ₂ ), Q to add the -tb- * upper side chain is implemented; and (d) removing the protecting group T and oxidizing the resulting compound to convert the formed alcohol to the corresponding aldehyde, and reacting the resulting aldehyde with a compound of formula IV above, or the lithium, sodium or potassium salt thereof to add the lower side chain and, if desired, subject the resulting compound of formula I to subsequent reactions known per se for the preparation of other intended products of formula I. 2. A process according to item 1 for the preparation of a pyrrolidone compound of the formula 1 in which Q is -COOH, characterized in that it comprises the hydrolysis of a pyrrolidone compound of the formula I as defined in item 1, wherein Q is carboalkoxy, carbophenoxy or carbo-p biphenoxy is, provides. J5. Process according to item 1 for the preparation of a pyrrolidone compound of the formula I in which Q is carboalkoxy, carbophenoxy or carbo-p-biphenoxy, characterized in that it comprises the esterification of a pyrrolidone compound having the formula I explained in point 1, in which Q is -COOH , 4. Method according to item 1 for the preparation of a pyrrolidone compound of the formula: and C5 £ pimeren thereof, wherein Q ₅ V /, .Z and R in the point have meaning explained, characterized in that a pyrrolidone intermediate of the formula: wherein Q and W have the meaning explained in point 1, is condensed with the lithium, sodium or Xaliumsalz a phosphonate having the formula IV illustrated in point 1. 5 * process according to item 4, for the preparation of a compound of formula I ^f , wherein Q is -CONHR ", characterized in that a compound of formula I ¹ , wherein Q ^{1 is} COOH, with a reagent of formula R ¹¹¹ CONCO or R ^llf S0 ₂ NC0, where R ¹ "has the meaning described in point 1, is converted-"