CA1084939A - Preparation of novel pyrrolidone derivatives - Google Patents

Abstract

ABSTRACT
Preparation of novel 1,5-disubstituted-2-py-rrolidone compounds useful as intermediates for the preparation of 2-pyrrolidone derivatives having selective prostaglandin-like activity, which comprises condensing a pyrrolidone intermediate of the formula:

Description

-- , This is a divisional of Patent Application No.
283,598 filed, July 27, 1977.
This invention relates to a novel series of 1,5-disubstituted-2-pyrrolidones which are prostaglandin-like in chemical structure and are useful intermediates for the preparation of the novel biologically-active 2-pyrrolidones disclosed in Application No. 283,598.
The C20 unsaturated fatty acids, known as prostaglandins, form a large family of naturally-occurring compounds. These molecules may have as many as five asymmetric centers and are present in and evoke response from a diversity of biological tissues. An example of a particular species of the prostaglandin E genera is PGE2 pictured below.
il .
~ 102H
H~
prostaglandin E2 According to tha notation usually employed to describe the stereochemistry of prostaglandins, a heavy solid line represents the ~ configuration which is defined as a bond coming up out of the plane of the paper and toward the reader. In a like manner, a dotted or hashed line represents the configuration which is defined as a bor.d going behind the plane of the paper and away from the reader. Thus, the configuration of the prostaglandin E2, pictured above is a at carbon atom 8 and B at carbon atom 12. [S. ~ergstrom, et al., Acta~ Chem. Scand., 16, 501 .' q~

(1962)].
By the same terminology, a wavy line represents a mixture of the two forms a and ~ Thus, a 2-pyrrolidone of the formula:
o H OH
represents a mixture of the epimers ~,,~ ~C02H

and H~ OH
o ~N~c~2H
¦ 8I B
-H- OH
By reference to the pyrxolidone of Formula B
and prostaglandin E2 shown above, a stereochemical compari~on can be made between the two sets of compounds.
The stereochemistry at positions 12 and 15 is the same in both types but that at position 8 is different. That is, lS the configuration of the C8-C7 bond of the prostaglandin E is a, but that of the N8-C7 bond is in the plane of the paper according to the representation of the formula above. Another way to represent the above two examples which will develop a better appreciation of this difference in configuration is the edge-on formula below:
O O

H- ~ H
B H B
prostaglandin E pyrrolidone 49;~9 where A and B stand for the two side chains of the examp;es.
Here the formula depicts the eclipsing of the A-C8 bond with the C12-H bond and the eclipsing of the C12-B bond with the C8-H bond in the case of the prostaglandin E and the bisecting position of the A-N8 bond with respect to the dihedral angle formed by B-C12-H in the case of the pyrrolidone. This difference in conformation is a result of the planarity generated by the amide moiety of the pyrrolidone. ["Basic Principles of Organic Chemistry", J. D. Roberts and M. C. Caserio, W. A. Benjamin, New York, 1965, p. 674].
A systematic name for a 1,5-disubstituted-2-pyrrolidone of the formula:
~"~, ~,~ CO 2H

OH
is 1-(6'-carboxyhexyl)-5~-(3"~-hydroxyoct-1"-enyl)-2-pyrrolidone and it also can be named as a derivative of 11-desoxyprostaglandin E1; that is, 8-aza-11-desoxy PGEl.
The corresponding 8-aza-11-desoxy PGE2 compound has the formula:

f \IN/ -- ~/~<02H
~~
where the single bond between C2' and C3' has been replaced by a double bond. The corresponding 8-aza-11-desoxy PGEo compound has the formula:

~ ~f 2H

where the double bond between Cl" and C2" has been replaced by a single bond.

~084939 The above pyrrolidones have several centers of asymmetry, and can exist in the racemic (optically inactive) form and in either of the t~o enantiomeric ~optically active) forms, i.e. the dextrorotatory (~) and levorotatory (L) forms. As drawn above, each pyrrolidone structure represents the particular optically active form or enantiomer which is derivable in part from D-glutamic acid. The mirror image or optical antipode of each of the above structures represents the other enantiomer of that pyrrolidone and is derivable in part from ~-glutamic acid.
For instance, the optical antipode of 1-(6'-carboxyhexyl)-5~-(3"~-hydroxyoct-l"enyl)-2-pyrrolidone is drawn as: O
Il - ~N ~ ~ CO2H
L ""~ ~
HO
and is called 1-(6'-carboxyhexyl)-5~-~3"~-hydroxyoct-1"-enyl)-

2-pyrrolidone The racemic form of the above pyrrolidone contains equal numbers of a particular enantiomer and its minor image. When reference to the racemate of a compound con-tained herein is intended, the symbol "rac" will precedethe compound's name. This term will then mean and is pro-perly represented by an equimolar mixture of the D and the L or enantiomeric forms.
A pair of optical isomers which are optical antipodes or enantiomers are related through inversion of the absolute configuration at all of their centers of asymmetry. Contrastingly, when the relationship is an inversion of absolute configuration at one or more but not all of the centers of asymmetry, the pair of isomers are epimers or diastereomers~ For instance, 1-(6'-carboxyhexyl)-5~-(3"~-hydroxyoct-1"-enyl)-2-pyrrolidone and 1-(6'-carboxyhexyl)-5~-(3"~-hydroxyoct-1"-enyl)-2~pyrrolidone are diasteromers related by an inversion of configuration about ~84939 the C5 atom and are shown respectively as:

~N ~ ~2H
-H 'OH

N ~ ~ CO2H
L "",~
"OH
It is a fact that chemical experimentation on either member of an enantiome~ic pair upon a mixture of the two will produce the same and identical results.
Substitution of a nitrogen atom for the carbon atom at C8 causes a dramatic change in the three dimensional conformation of the resultant prostaglandin. Because structure is related to biological activity and often a subtle change in structure such as a conformational change will have a profound effect upon the biological activity, such molecular modification of prostaglandins by substitution of heteroatoms has been investigated recently.
The novel biologically-active 2-p~rrolidones disclosed in Applcation No. 283,598 have resulted from such an investigation.
Thus Application No. 283,598 describQs and claims a process for the preparation of a novel 1,5-disubstituted-2 - pyrrolidone compound of the formula:
o ...I
R' H

or the C5 epimer thereof, wherein Q is -COOH o~ -COOR, R
is alkyl of from one to five carbon atoms; W is a single or cis double bond; Z is a single or trans double bond;
M is H 'OH or HO 'H and R' is phenyl or phenoxy, which 10~3~939 comprises reducing a 3"-oxo-pyrrolldone intermediate of the formula:

\Q
.~.II
H ld wherein Q, W, Z and R' are as defined above, to convert the oxo substituent at the 3"-position to a-hydroxy or ~-hydroxy.
The intermediate compounds of Formula II above are novel compounds.
In accordance with the present invention there is provided a process for the preparation of a pyrrolidone compound of the Formula II as defined above, which comprises condensing a pyrrolidone intermediate of the formula:

...III
_ CH0 wherein Q and W are as defined above, with the lithium, sodium or potassium salt of a phosphonate of the formula:
(alk 0)2pocH2cocH2R ............ IV
wherein R is as defined above and alk is an alkyl group of from 1 to 3 carbon atoms.
The intermediate pyrrolidone compounds of Formula II may be prepared in an optically active form by a six step sequence which attaches the two side chains, the a or top side chain and the ~ or bottom side chain, to the pyrrolidone ring and starts with a resolved amino acid, D- or L-glutamic acid. The choice of the starting D- or L-qlutamic acid es~ablishes the absolute confirmation of C5 of the 2-pyrrolidone ring and pre-empts the necessity of resolving this position at the end of the synthesis.
In the examples and description to follow, the D-configura-tion is shown. The L-configuration compounds are prepared ~08493S

by the same sequence from L-glutamic acid.
The synthetic sequence shown by Scheme A illus-trates the steps by which the ~ chain is attached to the 2-pyrrolidone nucleus. It will be noted that the steps prepare in each instance a pyrrolidone intermediate 19 differing only at the C2'-C31 bond. The compounds of Formula II are then synthesized from intermediate 19 according to the steps illustrated in Scheme B.

~ ~8493~

SCHEME A - ~ CHAIN ATTACHMENT
1~
OH

~`
(a) i, o H

(b) ~

/ ~ ~ N-H
(C)/ ~ \
CH2T\
X ~ ~ Q ~ 2CH(OY)2 o 7 ~ ~N ~< 18 ~ OY
\ 2 ~
\ (f3 ~ ~CH20T
O O
(d~

(g) /

~ W Ph3p=cH(cH2)3Q
19 ~ N
~ OH

~4939 g A brief summary of the steps in Scheme A is as follows~ The first step, marked (a~, illustrating the cyclization of D-glutamic acid to methyl D-pyroglutamate and the reductlon of the pyroglutamate to 5-D-hydroxy-2-pyrrolidone is known [V. Bruckner et alr, ActaO Chim. Hung.Tomus, 21, 106 ~1959~]. The second step (b) is the pro-tection of the hydroxymethyl group with protecting agent T
which can be any group suitable for the protection of the hydroxyl against alkylation; for instance, benzyl, dimethyl-t-butyl silyl, acetyl, l-ethoxyethyl, or especially tetra-hydropyranyl. Steps tc) and (e~ illustrate the alkylation of the sodium or lithium salt of pyrrolidone 1 by alkyl-ating agents of the formula X ~ Q
or XCH2CH(OY)2, respectively, wherein X is Cl, I, or especially Br; Y is alkyl having from one to three carbon atoms, and Q and W are as defined above. Step (d) is the removal of protecting group T, the method of which will depend upon the îdentity of T. Step (f) is the deprotection of the pyrrolidone compound 18 to produce ln situ l-(ethan-2'-al)-5-hydroxymethyl-2-pyrrolidone which can exist in intimate equilibrium with the hemiacetal compound 5. Step (g) is a Wittig reaction of the equilibrium mixture con-taining bicyclo[4,3,0]nonan-5-one 5 with a phosphorane of the structure Ph3P=CH~CH2)3Q wherein Q, defined above, is unprotected to produce the corresponding 2-pyrrolidone compound 19 wherein W is a double bondO
The reactions necessary to produce the compounds of the invention are arranged in order so that no epimeri-zation of the optically active center at C5 will occur.Therefore, by starting with either of the two enantiomers of glutamic acid, the same configuration at the asymmetric centers is preser~ed in the products. Also by starting with racemic glutamic acid, the racemic or rac products are produced.
The C5 position of the compounds of the present in~ention will be drawn in the ~ configuration but the ~

108~93S

configuration at the C5 position lS applicable also, pro-vided that the startins glutamic acid has the proper con-figuration.
The first two steps of the reaction se~uence are the condensation and esterification of D-glutamic acid to produce the correspondlng D-methyl pyroglutamate of the ~ormula: ~
N-H
4 sl H ~C02Me [E~ Hardegger, et alO, Helv. Chem. Acta., 38, 312 (1955);
Eo Segel, J Am. ChemO SocO, 74, 851 (1952)3.
The third, and known, step of the sequence shown in Scheme A as step (a) is the reduction of the 5-carboxy-methyl group of D-methylpyroglutamate to produce 5-D-hydroxymethyl-2-pyrrolidonec This reaction is most convenlently conducted by employing a variation of the method reported by V~ ~ruckn~r, et al~
[Acta. Chem~ Hung. Tomus~ 21, 106 (1959~]o 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 in the reported manner gives 5~D-hydroxymethyl-2-pyrrolidone of the formula:
O

~' N-H
._~
H~ CH2OH
In order to alkylate the amide nitrogen of 5-D-hydroxymethyl-2-pyrrolidGne, it is appropriate to protect the labile 5-hydroxymethyl hydrogen with the known tetra-hydropyranyl group This protection (Scheme A, step ~b)) is most conveniently accomplished by reacting 5-D-hydroxy-methyl-2-pyrrolidone with dihydropyran in the presence of an organic acid such as p-toluenesulfonic acid and in an -inert solvent such dS methy ene ch ! oride, chloroform, tetra-hydrofuran or diethoxy efhane- The appropriate temperature range ~or thls reaction ~s from that of an ice bath to that of refluxlng sol~ent and preferably amblentc After the formatlon of 5-D-~tetYahydropyran-2'-yLoxymethyl)-2-pyrroli-done 1 is substantlally complete, usually overnight, it is isolated by fi~st removing the organic ac~d by basic extraction and remov-.ng the solvent and any excess dihydro-pyran by vacuum evaporation techniques~ The product is most commonly pur if ied by colum~ chromatography D
Other protecting agents that can be employed with equal facility lnclude any which will protect the hydroxyl from alkylation. Some examples are benzyl, acetyl, dimethyl-t-butyl silyl and l-ethoxyethylO These protecting agents -are readily available and can be attached to the 5-hydroxy-methyl group by known methodsc Their selection for syn-thetic purposes will depend upon the protecting group at C7lo For insta~ce, if it is desired to employ N-tetra-hydropyran-2-yl as a protecting group for the acidic hydro-gen of a C7' tetra~oi-S-yl ~W~ appropriate C3" hydroxyl protecting groups (T) would be acetyl or dimethyl-t-butyl silyl.
The l-(alkylatedJ-2-pyrrolidone compounds [17 and 18 Scheme A~ are prepared by a combination of two reactions which are performed upon 5-D-(tetrahydropyran-2'-yloxymethyl~-2-pyrrolidone ~ of any of its T group analogs~
First, the sodium o~ lithium salt of pyrrolidone 1 is pre-pared by reacting a solution of compou~d 1 in an inert organic solvent such as tetrahydrofuran, diethoxyethane or dioxane with a base such as n-butyl lithium, phenyl lithium or especially sodium hydride~ The appropriate temperature range for this salt formation lS ambient to that of refluxing solvent and preferably amblent All the base must be reacted before staEtlng the alkylation which usually requires times of 1 to 4 hours~ Then, the desired l-(alkyl-ated)-2-pyrrolidone compounds 17 and 18 are respectively formed by reacting the above prepared llthium or sodium 93g salt of 2-py~r2Lidone compound 1 wlth an alkylating agent of the formula:
x ~ Q or XCH2CH(OY)2 wherein X, Y~ W and Q are as defined above~ This second part of the alkylat.ion procedure is usually conducted by addition of a mixture of the alkylating agent in the inert organic solvent previously defined or especially by addition of a mixture of the alkylating agent in a polar aprotic organic solvent such as dimethylformamide or dimethylacetamide to the above formed mixture of the sodium or lithium salt of pyrrolidone 1 in an inert organic solvent and then by allowing contact between the mixture of alkyl-ating agent and 2-pyrrolidone sodium or lithium salt at temperatures of ambient to solvent reflux until the alkylation is substantlally complete, usually ovarnight.
Of course~ the alkylated 2-pyrrolidone resulting from use of XCH2CH~OY32 can also be prepared by employing XCH2CO2Et as the alkylating agent followed by selective convexsion of the ester group of the resultant l-(2'-ethyl-acetate)-5-(substituted)-2-pyrrolidone to aldehydeO
When there is the possibility of having an acidic hydrogen present Q, the alky1ation procedure is most convenie,ntly executed by protecting or otherwise removing that acidic hydrogen= For example, in the case where R' is hydrogen, ~he best method is employment of an ester derivative which can then be removed by alkaline hydrolysis at the end of the synthetic sequenceO It will ~e assumed hereinafter that the acidic hydrogen of the Q group has been protected unless otherwise stated~
The character of the C2'-C3' bond of the 2-pyrrolido,ne compound _ obtained from the alkylation step is determi,ned by the ,nature of W in the alkylating agent X ~ Q
The selection of W will also determine the unsaturated or saturated character of the a-side chain of the final product of the syntheslsO
Obviously, the selection of W only causes a :~8'~939 difference in the character of the C2'-C3' bond of the -side chain and in fact, conversion from pyrrolidone compounds where W is a double bond to those where W is a single bond is possible at the pyrrolidone compound 17 stage of the synthesis. For instance, the 2-pyrrolidone compound 17 with the double bond at W may be converted to the 2-pyrroli-done compound 17 with the single bond at W by the hydro-genation over a noble metal catalyst such as palladium on carbon at ambient temperature until 1 equivalent of hydrogen is absorbed.

Q ~ ~ ~ ~ ~ ~ Q

Compound 17 A = double bond Compound 17 A = single bond In either case, the protecting group T is removed (step d, Scheme A) by methods known to those familiar with the art in anticipation of the formation of the ~-side chainO The resulting 2-pyrrolidone compound of the formula:

~ N~ ~\Q
I ~ OH
Compound 19 wherein W and Q are as defined above, is then carried through the steps of Scheme B, to produce the novel inter-mediate compound of Formula II~
The above 2-pyrrolidone compound 19 also may be prepared by contacting the hYdrolYzed form of the 2-pyrrolidone of the formula:

N ~
OY
L _~r Compound'l8wherein Y and T are as defined above with a phosphorane of the formula:

~08-~93~

Ph3P=CH(CH2~3Q
wherein Q defined as above, is unprotected, eOg. CO2H or tetrazol-5-ylO
Thls slSbset of reactions, illustrated by steps (f) and (g) of Scheme A, can be executed in the following mannerO If the preferred T protecting group, tetrahydro-pyran-2-yl, is used in compound 18, then acid hydrolysis of compound 18 according to the usual method for acetal removal such as acetic acid in water at ca. 40~C. will cleave both the tetrahydropyran-2-yl and the acetal form l-(ethan-2'-al)-5~-hydroxymethyl-2-pyrrolidone which can exist in intimate equilibrium with 4-aza-2-hydroxy-1-oxa-bicyclo[4,3,0]nonan-5-one 5~ O

~ CHO _ ~ ~ OH

nonanone 5 The-equilibrium mixture containing hemiacetal 5 can then be cont~cted with two equivalents of phosphorane as defined above in a polar aprotic solvent such as dimethylsulfoxide or a mixture of an ethereal and polar aprotic solvent such as tetrahydrofuran and dimethylsulfoxide at temperatures of 0C~ to 60, usually overnight, to produce 2-pyrrolidone 19 wherein W is a double bond~ The acidic hydrogen or group Q then may be protected as an ester in the case of the carboxylic acidO This 2-pyrrolidone with W as a double bond, if desired, may be converted to 2-pyrrolidone 19 wherein W is a single bond by the hydrogenation method described aboveO
The intermediate compounds of Formula II, may be prepared by oxidation of the 5~-hydroxymethyl group of 2-pyrrolidone 19 and Horner-Wittig reaction of the thus formed 5~-formyl-2-pyrrolidone compound 20 with the sodium or lithium salt of a phosphonate of the formula ~MeO)2PCH2~CH2R wherein R is as defined above to form the desired 5-(4"-substituted-but-1"-en-3"-onyl~ substituted 2-pyrrolidone 21.
Scheme B illustrates this process, the method of which attaches the ~-chainO
SCHEME B
t~)-CHAIN ATTACHMENT

~N ~/ --Q
~OH
¦ oxidation Q
~0 ~MeOJ2PCH2~C~12R
Q

~ R

The aldehyde 20 is obtained from the 5~-hydroxy-methyl-2-pyrrolidone compound 19 by a modification of the 10 Pfitzner Moffau oxidation [K. E. Pfitzner and M~ E. Moffatt, J~ Am. Chem. Soc., ~7, 5661 (1965)] which avoids contact of the 5B-formyl compound 20 with water~ For example, stirring a slurry of 1-(7'-methylheptanato~-5~-hydroxymethyl-2-pyrrolidone or other appropriate 5~-hydroxymethyl-2-15 pyrrolidone in an inert, hydrocarbon solvent such as toluene,xylene or especially benzene with dimethyl sulfoxide, a weak acid such as acetic acid or especially pyridinium trifluoro-acetate and a water soluble diimide such as diethyl carbo-diimide or especially dimethylaminopropylethylcarbodiimide or, if desired, its hydrochloride salt, at temperatures of 0C. to ambient for 1 to 4 hours, will oxidize the primary alcohol 19 to aldehyde 200 Alternative methods to achieve oxidation include the usual Pfitzner-Moffatt reaction and oxidation with chromium trioxide-pyridine complex [R. Ratcliffe, et al., J~ Org~ ChemO, 35 4000 (1970)]
although the method of choice is the reaction described above.
The 5B-(4"-substituted but-1"-en-3"-onyl)-2-pyrrolidone compound 21 is prepared by reacting the 5~-formyl-2-pyrrolidone compound 20 with the sodium or lithium salt of a phsophonate of the formula:

(MeO)2~CH2~CH2R
wherein R is as defined above in a solution or slurry with an ethereal solvent such as tetrahydrofuran, dimethoxyethane or dioxane at temperatures from 0 to 50CO until the reaction is essentially complete, as determined by reaction monitoring methods. The isolation of the product from this Horner-Wittig reaction, the method of which is known to those familiar with the art~ is accomplished in the usual fashion by chromatography. Other methods include high pressure liquid chromatography and in some cases fractional recrystallization The preparation of the phos-phonates is disclosed in United States Patent NoO 3,932,3890 The following Examples illustrate the invention.
The spectral data were obtained on a Varian T-60 or an A-60 NMR, a Perkin-Elmer Grating Infrared Spectrometer and an LKB-9000 mass spectrometer. The infrared data are given in reciprocal centimeters and the NMR data are given in parts per million using TMS as a standardc In general, the temperatures of the reactions described in the Examples9 when unspecif~ed, w$11 be taken to mean ambient or room temperature which ~aried from 15 to 30~Co The time re~uirement of the reactions described in the Examples, unless otherwise stated, was determined by monitoring with thin layer chromatography (TLC). The

3 ~

usual TLC system was sllica gel on glass ~E. Merck Silica Gel plates, E~ Merck Dormstadt, WO Germany3 with benzene/-ether or methanol/chloroform as eluants and vanillin/ethanol or iodine as developers ~"lntloduction to Chromatography"
J. M. Bobbitt, A. E~ Schwarting, Rc JO Gritter, Van Nostrand-Reinhold, N.Y. 1968]~ As a general rule, the reaction in question was deemed essentially complete when the TLC
spot representing the critical starting material ha~
disappeared or had quit changingO

5B-~Tetrahydropyran-2~-yloxymeth~l~-2-pvrrolidone 1 Into a flame dried flask under a nitrogen atmos-phere was put 2~54 gO (22.1 mmoles) 5-D-hydroxymethylene-2-pyrrolidone, prepared according to the method of V.
Bruckner ete al., Acta. Chlm~ Hung~ Tomus, 21, 106 (1959), and 50 ml~ methylene chloride. To this solu~on at 0C. to 5C~ was then added 3072 g~ (44t2 mmoles) redistilled di-hydropyran and 002 gO _-toluenesulfonic (tosic)acidO The solution was then allowed to warm to room temperature and to stir overnîghtO After dilutlon of the reaction with 20 ml.
ethyl acetate, the solution was extracted with 2 x 5 mlO
saturated sodium bicarbonate solution and 1 x 10 ml.
saturated brineO The organic layer was dried with magnesium sulfate, filtered to remove the drying agent~ and the solvent was removed ln vacuo to give 4 1 gO yellow oilO
This oil was chromatographed on a 50 g. column of Merck silica gel packed in chloroform~ Elution with lL~ chloro-form removed less polar impurities~ Elution with 2%
methanol in chloroform and collection of 10 ml~ fractions separated and purified the product~ Combination of product fractions and removal of solvent in vacuo gave 3~95 g. of the title compound 1 as a yellow oil, 9o% yield. NMR T-60 (DCC13)b~so ~6~60 ppm ~lHj, m. ~4~60 ppm (lHi, m. ~4~05-~.25 ppm (5H), m~ ~2.50-~20LO ppm, mO ~2~00 - ~1~40 ppm (lOH)o IR(CHC13 solution) 3425, 2980, 2930, 2850, 1680, 1250-1200, 1025 cm~l Additionally, the dimethyl-t-butyl silyl protect-ing group can be employed in place of the tetrahydropyran-2-yl group by applying the procedure of E~ J. Corey, et.

al., J. Am. Chem. Soc., 94, 6190 (1974) to 5-D-hydroxy-methylene-2-pyrrolidone.

1-(7'-(Ethylheptanato)-5~-(tetrahydropyran-2"-yloxymethyl)-2-pvrrolidone 2 Into a flame dried flask containing a nitrogen atmosphere was put 0.725 g. (18.7 mmoles) of 62% sodium hydride dispersion in mineral oil and 10 ml. dry T~F. To this mechanically stirred slurry was then slowly added dropwise 3.74 g. (18.7 mmoles) of 5-D-(tetrahydropyran-2-yloxymethyl)-2-pyrrolidone 1 in 10 ml. dry THF. After the addition was complete, the thic~ slurry was stirred for 30 minutes until all hydrogen evolution had ceased.
m e alkylation of the sodium salt was then performed.
To this slurry at room temperature was then added dropwiee 5.34 g. (22.5 mmoles) of ethyl-7-bromo-heptanoate is 15 ml. drY DMF. At the completion of the addition, ca 15 minutes, the slurry had dissolved and sodium bromide slowly started to precipitate from the solution. The reaction was stirred overnight, then filtered, and the solvent was removed in vacuo from the filtrate. To the residue was then added 100 ml. ethyl acetate and this organic solution was extracted with 2 x 20 ml. water. After drying the organic layer with magnesium sulfate and filtering it to remove the drying agent, the solvent was removed ln vacuo from the filtrate to give a yellow oil which was chromatographed on a 120 g.
column of Merck silica gel packed in chloroform. Elution with: (a) 250 ml. of chloroform; ~b) 500 ml. 5% ethyl acetate in chloroform; (c) lL. 10% ethyl acetate in chloro-form; and automatic collection of 10 ml. fractions allowed the separation and purification of the product. The pro-duct fractions were combined and stripped of solvent to yield the title compound 2 as a colorless oil 3.39 g. 51% yield.
NMR T-60 (DCC13~:M ~4.60 ppm (lH), q. ~4.17 ppm Jl = 8 hz., m, ~4.00 - 2.70 ppm (9~), m, ~2.6 - 1.4 ppm, 35~

t. ~1.3 ppm Jl = 8 hz. (23H).
IR (HCC13 solution) 2975, 2915, 2840, 1720, 1665, 1450, 1250-1200, 1125, 1025 cm 1 ~ .S-heated inlet (m/o-%) 356-1~, 355-3%, 310-17%, 240-100%, 194-83%.
The foregoing procedure can be adapted to the pxeparation of pyrrolidones of the structure below by substitution of the appropriate alkylating agent for ethyl-7-bromoheptanoate and optionally by employment of the dimethyl-t-butyl silyl analog of pyrrolidone 1~

~\~\X
~I~/OT

~-(tetrahydropyran-2-yl)tetrazol-5-yl N-(acetyloxymethyl)tetrazol-5-yl W = single or cls double bond T = THP or dimethyl-t-butyl silyl.
As stated the l-(substituted)-5~-ttetrahydropyran-2"-yloxy-methyi or dimethyl-t-butyl siloxy methyl)-2-pyrrolidones can be prepared by substitution of the appropriate alkyl-ating agent for the ethyl-7-bromoheptanoate. For instance, if l-~6'carboxymethyl-2'-enyl)-5~-(tetrahydropyran-2"-yloxymethyl)-2-pyrrolidone is to be prepared, the alkylating agent will be methyl-7-bromohept-5-enoate. If 1-~6'-1'''-acetyloxymethyltetrazol-5'''-ylhexyl)-5R-(tetrahydropyran-2"-yloxymethyl)-2-pyrrolidone is to be prepared, the alkyl-ating agen will be 6-bromo-1-(1'-acetyloxymethyltetrazol-5'-yl)-n-hexane.
1-(2,2-Diethoxyethyl)-53-(tetahydropyran-2"-yloxymethyl)-2-pyrrolidone 3 can also be prepared by the same procedure by employing 2-bromoacetaldehyde diethyl acetal as the alkylating agent.
The pxeparation of 6-bromo-1-tetrazol-5'-yl-n-hexane can be accomplished by the following method.

A mixture of 20S8 g (23.5 mmoles) 7-hydroxy-heptanenitrile, 1.60 g. (30 0 mmoles) ammonium chloride, 0.032 g. (0.76 mmole) lithium chloride, 1.91 g. (29. 3 mmoles) sodium azide and 50 ml. dimethyl formamide can be heated to 120 under nitrogen with stirring for 18 hours or until the reaction is essentially complete. The dimethyl formamide can then be removed in vacuo and the resulting residue can be purified by one of several 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 produce 6-bromo-l-(tetrazol-5-yl)hexane. The N'-acetyloxymethyl group can be attached by employing the method of W. V. Daahne et. al.
opt. cit. while the N-tetrahydropyran-2-yl group can be attached according to the method of Example 1.
Treatment of 7-(tetrahydropyran-2'-yloxy)hept-5-ynenitrile in the same manner as above will allow prepara-tion of 6-(tetrahydropyran-2'-yloxy)-1-(tetrazol-5'-yl)hex-

4-yne. This material can then be converted into 6-bromo-1-(tetrazol-5'-yl)hex-4-ene according to the procedure of Ger, Offen. 2,121,361 (C.A. 76:24712d). Of course, the starting hept-5-ynenitrile can also be hydrogenated to the olefin before converting th~ nitrile to the tetrazole, essentially by following the same procedure. Again the protecting groups for the acidic hydrogen of the tetrazol-5-yl can be attached by the above methods.

1-(7'-Methylheptanato)-~B-hydroxymethyl-2-pyrrolidone 4 .
To a solution of 200 ml. methanol and 3.99 g.
3C THP-pyrrolidone 2 was added 79 mg p-toluene sulfonic (tosic) acid and the solution was refluxed overnight. After work up 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 redis-solved in 160 ml methanol, .0~0 g. tosic acid added, andthe reaction again refluxed overnight. Removal of the solvent 9~

ln vacuo from the reactlon 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 ~ochelle's salt solution. The organic phase was dried over magnesium sulfate, filtered and the solvent evaporated to give the title compound 4 as a clear yellow oil 2.528 g. (88~)~
NMR A-60 (DCC13) s. ~3.86 ppm, m. ~4.00 - 3.33 ppm, m. ~3.20-~2.70 ppm (13~), m. ~2.50 - ~2.00 ppm, m.
~1.90 - ~1.20 ppm (lOH), partial spectrum.
IR (HCC13 solution) 3550-3100, 2980, 2910, 2840, 1?20, 1650, 1450, 1425, 1410, 1250-119~ cm 1.
MS, LKB 9000, solid inlet (m/e%)70eV 226-26%, 194-1908%, 74-100% 13eV 257-3.3%, 226-100%, 168-24.6%.
Alternatively the tetrahydropyran-2'''-yl group can be removed by hydrolysis in a 65:35 mixture of glacial acetic acid:water for ca. 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 foregoing acetic acid, water hydrolysi~ pro-cedure can also be used to remove the tetrahydropyranyl protecting group from the other pyrrolidone products of Example 2 which then will produce the corresponding l-(sub-stituted)-5~-hydroxymethyl-2-pyrrolidones. However, if the tetrazol-5-yl protecting group is tetrahydropyran-2-yl, then it will be appropriate to employ the dimethyl-t-butyl silyl group as T. This silyl group can be selectively removed with tetra-n-butyl ammonium fluoride according to the method of Corey, ~. cit.
On applicat~on of the acetic acid procedure to 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, to yield as product an equillbrium mixture of the open form and 4-aza-2-hydroxy-1-oxa-bicyclo[3,4,0]nonan-

5-one 5.

~0~939 o o N ~ C~o \ ~ N
~ OH ~ O

The equilibrium mixture containing compound 5 can be con-verted to l-(substituted)-5B-hydroxymethyl-2-pyrrolidones by the following procedure.
The other l-(substituted)-5~-formyl-2-pyrrolidone compounds of Example 4 can be employed in the foregoing procedure in place of pyrrolidone 6 to make the corresponding l-(substituted)-5~-(4"-phenylbut-1"-en-3"-onyl)-2-pyrroli-done compounds. In addition, phosphonates of the structure:
(MeO)2lPCH2CCH2Z
O O
Z = -C6H4CH3 (_) -~-thienyl -C6H40C~3 (p) -C6H4-C6H5 (m) -C6H4CF3 (~) -C6H4Cl (o) can be substituted for dimethyl-(3-phenylpropan-2-onyl)-phosphonate to make the corresponding l-(substituted)-S~-(4"-substituted but-1"-en-3"-onyl)-2-pyrrolidone compounds.
Hereafter, all pyrrolidones including the 4"-phenyl com-pounds shall be known as l-(su~stitu~ed)-5~-(4"-substituted but-l"-en-3"-onyl)-2-pyrrolidones.
To a solution of 23.04 g. (52.0 mmoles) of 5-triphenylphosphoniopentanoic acid ~bromide salt) in 46 ml.
dry dimethyl sulfoxide can be added dropwise 49.3 ml.
(98.6 mmoles) of a 2. ON solution of sodium methylsulfinyl-methide in dimethyl sulfoxide~ To the resultant red solution can then be added over the course of 1.0 hour 3.27 g. (20.8 mmoles) of 4-aza-2-hydroxy-1-oxa-bicyclo[3,4,0]-nonan-5-one 5 in dry dimethylsulfoxide (63 ml.). After being stirred for an additional half hour or until sub-stantially complete, the reaction can be poured into 600 ml.

49~

of ice-water and then can be extracted with 2 x 300 ml. of ethyl acetate. The co~d aqueous layer can be covered with ethyl acetate and acidified to pH~3 with 10~ hydrochloric acid after which the aqueous layer can be extracted with 2 x 200 ml. of ethyl acetate. The combined organic extracts are washed with water, followed by brine, and the organic layer can be dried over anhydrous sodium sulfate. Con-centrating the filtered organic layer will afford crude 1-(6'-carboxyhex-2'-enyl~-5~-hydroxymethyl-2-pyrrolidone which can be chromatographedO The acid can be esterified with diazomethane.
This procedure can also be used to prepare 1-(substituted)-S~-hydroxymethyl-2-pyrrolidones of the structure.

~ ~ _ ~ ~X
~ H
wherein X is the same as that of Example 2, by substituting the appropriate phosphonium salt for 5-triphenylphosphono-pentanoic acid and then protecting the acidic hydrogen with an N-acyloxymethyl group according to the procedure des-cribed by W V~ Deahne et. al., op. cit., with an N-tetra-hydropyran-2-yl group according to the procedure of Example 1 or by esterifying in the case of the carboxy acid.
EXAMPhE 4 1-(7~-Methylheptanato)-5B-formyl-2-pyrrolidone 6 To a flame dried flask containing a nitrogen atmosphere was added 0.1286 g. (0.5 mmoles)-1-(7'-methyl-heptanato)-5~-hydroxymethyl-2-pyrrolidone 4 in 5 ml. dry benzene. To this solution 0.1286 g. (1.5 mmoles) dimethyl-aminopropylethylcarbodiimide hydrochloride ~DAPC) and 0.142 ml. (2 mmoles~ dimethylsulfoxide were added followed after five minutes by 0.108 gO (0.55 mmoles) of pyridinium trifluoroacetate~ The reaction was stirred under a nitro-gen atmosphere at room temperature for 1.75 hours, then the benzene was decanted and the viscous second phase which had formed at the bottom of the flask was washed with 3 x 5 ml. benzene. The benzene solutions were combined and the solvent was removed in vacuo to give -.153 g. of the title compound 6 as a clear yellow oil. The crude product was used immediately and without further purification in the next reaction.
NMR T-60 (DCC13), d. ~9.72 ppm ~1=3hz(lH~, m. ~4.37 - ~4.07 ppm (lH), s. ~3.70 ppm (3H) partial spectrum.
The foregoing procedure can also be used to oxidize the other 1-(substituted)-5~-hydroxymethyl-2-pyrrolidones of Example 3 to the corresponding l-~substi-tuted)-5~-formyl-2-pyrrolidones.

1-(7'-Methylheptanato)-5~-(4"-phenylbut-1"-en-3"-onyl)-2-pyrrolidones 7 Into a flame dried flask containing a nitrogen atmosphere was put 0.1188 g. (2.97 mmoles) of a 60% sodium hydride mineral oil dispersion and 5 m. THF. To this slurry was added a solution of 0.7815 g. (3.24 mmoles) of dimethyl(3-phenylpropan-2-onyl)phosphonate in 5 ml. THF.
After the evolution of hydrogen ceased, a white suspension occurred which was stirred for fifteen minutes. To this suspension was added 0~6894 g~ (2O70 mmoles) of 1-(7'-methylheptanato)-5~-formyl-2-pyrrolidone 6 in 10 ml. THF
over a period of 1 minute. Within five minutes, the reaction became a clear yellow solution and was stirred for an additional two hours~ The reaction was quenched with glacial acetic acid to pH 5. The solvent was removed ir vacuo and the residue was taken up in 100 ml. ethyl acetat_.
The organic solution was extracted with ~ x 10 ml. saturated aqueous sodium bicarbonate, 3 x 10 ml. water and 1 x 10 ml, saturated brine. The organic layer was dxied over m~gnesium sulfate, filtered and the solvent removed ln vacuo to give 1.141 g. yellow oil. This crude product was chromatographed on a 3S g. column of E. Merck silica gel packed in ethyl acetate.
Elution with ethyl acetate and automatic collection of 10 ml. fractions allowed the purification of the product.

9;~

The product fractions were combined and the solvent removed in vacuo to give 0~614 g~ of the title compound 7 as a colorless oil ~61~ yield from the starting alcohol).
NMR T-60(DCC13)s.67=33ppm(5H), dofd.~6.73ppm JlC7hz J2=16hz, dc~6O60ppm J2=16h~ (2H), mO~4.27ppm center (lH), s.~3.93 (2H~; s~ 63073ppm (3H) partial spectrum.
IR~CHC13 solution)2980, 2900, 2840, 1725, 1685(sh), 1675, 1625, 1250-1200 cm~1 MS,LKB9000(m/e %)70eV 372-20~, 371-82%, 252-96%, 226-24%, 194-35~, 12eV 372-l8~, 371-100%, 252-24%, 226-39%.

1-(7'-Methylheptanato)-5~-(4"-phenoxybut-1"-en-3"-onyl)-2-pyrrolidone 10 Into a flame dried flask containing a nitrogen atmosphere was put 22 mg. (0O55 mmoles) of sodium hydride disper6ion in mineral oil and 5 ml. THF. To this slurry was added a 601ution of 0~1549 g~ (0.6 mmoles) dimethyl-(3-phenoxypropan-2-onyl)pho~phonate in 5 mlO THF. After the evolution of hydrogen cea~ed, there was a cl~ar, pale yellow solution which was stirred for fifteen miutes. To this solution was added 0~1277 g. (0.5 mmoles) 1-(7'-methyl-heptanato)-5~-formyl-2-pyrrolidone 6 in 5 ml. THF over a period of 1 minute. Within five minutes, the reaction had become a clear yellow solution and was stirred for an addi-tional two hours~ The reaction was quenched with glacialacetic acid to pH 5. The oeolvent was removed in vacuo and the residue was taken up in 50 ml. ethyl acetate. The organic solution was extracted with 2 x 5 ml. saturated aqueous sodium bicarbonate, 2 x 5 ml. water and 1 x 5 ml.
saturated brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed in vacuo to give 0.231 g. yellow oil This crude product was chromatographed on a 25 g. column of E. Merck silica gel packed in cyclo-hexane. Elutlon with 50~ chloroform in cyclohexane ard auto-matic collection of 10 ml~ fraction~ allowed the purificationof the product. The product fractions were com~ined and the solvent removed ln vacuo to give 53.6 mg of the title com-iO~'~9;~9 pound 10 (28% from ~he startlng alcohol3.
NMR T-60 iDCCi3~, m~ ~ 7,40-6.70 ppm (5H)~ mO~607-

6.33 ppm t2~3 s.~4,67 ppm ~2H3, m ~4~40-3097 ppm (lH), s.
~3.67 ppm ~3H), partial spectrumO
The o~h~r l-(substltuted)-5~-formyl-2-pyrrolidone compounds of Example 4 can be used in the foregoing proced-ure in place of pyrrolldone 6 to make the corresponding 1-(substituted)-5~-~4"-pheno.Yybut-l"-en~"-onyl)-2-pyrrolidone compounds. In addition, phosphonates of the structure:
(MeO32~CH2&cH2 V C6 ~CH3 (~) -C6H4CF3 (m) -C6H4-C6H5 (E~) -C6H40CH3 (p) -C6H4-Cl (o ) can be substituted for dimethyl(3-phenoxypropan-2-onyl)-phosphonate to make tho~e correspondlng 2-pyrrolidone compoundsO

Claims (3)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a pyrrolidone compound of the formula:
...II
and the C5 epimer thereof wherein Q is a group of the formula -COOR'; wherein R' is hydrogen or alkyl having from one to five carbon atoms; W is a single or cis double bond; Z is a single or trans double bond; R is phenyl or phenoxy, and the alkali metal, alkaline earth metal and ammonium salts of those compounds wherein Q is a carboxylate group; which comprises condensing a pyrrolidone intermediate of the formula:
...III
wherein Q and W are as defined above, with the lithium, sodium or potassium salt of a phosphonate of the formula:
(alk O)2POCH2COCH2R ...IV
wherein R is as defined above and alk is an alkyl group of from 1 to 3 carbon atoms.

2. A process according to claim 1, for the pre-paration of a pyrrolidone compound of Formula II, wherein Q is -COOH which comprises hydrolyzing a pyrrolidone com-pound of Formula II, wherein Q is -carboalkoxy.

3. A process according to claim 1, for the prepara-tion of a pyrrolidone compound of Formula II, wherein Q is carboalkoxy, which comprises esterifying a pyrrolidone compound of Formula II wherein Q is -COOH.