IE45506B1 - 1,5-disubstituted-2-pyrrolidones - Google Patents

Description

This invention relates to a novel series of intermediates employed in the preparation of l,5-disubstituted-2-pyrro!idones having prostaglandin-like chemical structure and biological character.

This application is divided out of Patent Specification No. 45506 novel prostaglandin-like compounds which have selective and potent biological activity and which have the structure: and the C5 epimer thereof wherein: Q is O 0 II K —COR^, tetrazol-5-yl or —CNHR A is a single or cis double bond; B is a single or trans double bond; U is 'OH or HO H; 4S3Ud - 3 R2 is α-thienyl, phenyl, phenoxy, monosubstituted phenyl or monosubstituted phenoxy, said substituents being chloro, fluoro, phenyl, methoxy, trifluoromethyl or alkyl having from one to three carbon atoms; R^ is hydrogen, alkyl having from one to five carbon atoms, phenyl or p-biphenyl; R, is 4 II -CR5 or ·—SO„R_, said R_ being phenyl or alkyl having from one to 2 5 □ five carbon atoms; and the alkali metal, alkaline, earth 10 metal and ammonium salts of those compounds having a carboxylate or tetrazol-5-yl group.

In addition the parent application comprises intermediates which will allow the preparation of the final products above and which have the structures and the C5 epimer thereof wherein W is O II —CORj, tetrazol-5-yl, N-(acyloxymethyl)tetrazol-5-yl having from two to five carbon atoms in the acyloxy group, N-(phthalidyl)tetrazol-5-yl or N-(tetrahydropyran-2-yl)t.etrazol-5-yl, and A, B, R2 and are each defined as above. - 4 The present invention provides compounds of the structure:- and the C5 epimer thereof 5 wherein A is a single or cis double bond; W is —COR,, II 3 0 tetrazol-5-yl, N-(acyloxymethyl)tetrazol-5-yl having from two 10 to five carbon atoms in the acyloxy group, N-(phthalidyl)tetrazol-5-yl or N-(tetrahydropyran-2~yl)tetrazol-5-yl; is hydrogen alkyl having from one to five earbon atoms, phenyl or jo-biphenyl.

The compounds of the present invention are prepared in 15 an optically active form starting with a resolved amino acid, D- or L-glUtamic acid. It is noted that the choice of the route starting from D- or L-glutamic acid establishes 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 discussion to follow, the D-configuration is shown. The L-configuration - 5 compounds are prepared by the same sequence from L-glutamic acid.

The synthetic sequence shown by Scheme A illustrates the methods by which the a chain is attached to the 2-pyrrolidone nucleus. It will be noted that the methods prepare in each instance a pyrrolidone intermediate 19 differing only at the C2‘—c3' bond. The products of the present invention are then synthesized from intermediate 19 according to the method presented in Scheme B. - 6 45006 OH NH„ H' COjH V _ Scheme A- a CHAINATTACHMENT (c) (a) (b) N—H V 0 CHjOH N—H k CHjOT (e) xch2ch(oy)2 OY OY (,) | CH^OT CHjOT Ph3P=CH(CH2)W AS 5 0 6 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 reduction of the pyroglutamate to 5-D-hydroxy-2-pyrrolidone is known [V. Bruckner et al., Acta. Chim. Hung, Tomus, 21, 106 (1959)]. The second step (b) is the protection of the hydroxymethyl group with protecting agent T which can be any group suitable for the protection of the hydrcst/1 against alkylation,· for instance, benzyl, dimethyl-t-butyl silyl, acetyl, 1-ethoxyethyi, or especially tetrahydropyranyl. Steps (c) and (e) illustrate the alkylation of the sodium or lithium salt of pyrrolidone 2 Ly alkylating agents of the formula or XCHjCHiOY)^, respectively, wherein X is Cl, I, or especially Br; W is CC^Ry N-(actyloxymethyl)tetrazol-5-yl having from two to five 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 having from one to three carbon atoms, and A and R^ are defined as above. Step (d) is the removal of protecting group T, the method of which will depend upon the identity of T, Step (f) is the deprotection of the pyrrolidone compound 18 to produce in situ l-(ethan-2'-al)-5hydroxymethyl-2-pyrrolidone which can exist in intimate equilibrium with the hemi-acetal compound 5. Step (g) is a Wittig reaction of the equilibrium mixture containing bicyclo[4,3,0]nonan-5-one 5 with a phosphorane of the structure Ph3P=CE(cH2)3W wherein W, defined above, is unprotected to produce the corresponding 2-pyrrolidone compound 19 wherein A is a double bond. 4550Q - 8 The reactions necessary to produce the products of the invention are arranged in order so that no epimerization 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 preserved in the products. Also by starting with racemic glutamic acid, the racemic or rac products are produced.

The C5 position of the intermediates and products of the present invention will be drawn in the β configuration but the a configuration at the C5 position is applicable also, provided that the starting glutamic acid has the proper configuration.

The first two steps of the reaction sequence are the condensation and esterification of D-glutamic acid to produce the corresponding D-methyl pyroglutamate of the structure: E Segel, J. Am. Chem. Soc., 74, 851 (1952)].

The third, and known, step of the sequence shown in Scheme A as step (a) is the reduction of the 5-carboxymethyl group of D-methylpyroglutamate to produce 5-D-hydroxymethyl-2pyrrolidone. This reduction is most conveniently conducted by employing a variation of the method reported by V. Bruckner, et al. TActa. Chem. Hung. Tomus, 21, 106 (1959)].

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-E~hydroxymethyl-2pyrrolidone of the structure: N—H CH20H In order to alkylate the amide nitrogen of 5-D--hyclroxymethyl-2-pyrrolidone, it is appropriate to protect the labile 5-hydroxymethyl hydrogen with the known tetrahydropyranyl group. This protection (Scheme A, step (b)) is most conveniently accomplished by contacting 5-D-hydroxymethyl-2pyrrolidone with dihydropyran in the presence of an organic acid such as p-toluene sulfonic acid and in an inert solvent such as methylene chloride, chloroform, tetrahydrofuran or diethoxy ethane. The appropriate temperature range for this reaction is from that of an ice bath to that of refluxing solvent and preferably ambient. After the formation of 5D-(tetrahydropyran-2'-yloxymethyl)-2-pyrrolidone is substantially complete, usually overnight, it is isolated by first removing the organic acid by basic extraction and removing the solvent and any excess dihydropyran by vacuum evaporation techniques. The product is most commonly purified by column chromatography.

Other protecting agents that can be employed with equal facility include any which will protect the hydroxyl from alkylation. Some examples are benzyl, acetyl, dimethyl-tbutyl silyl and 1-ethoxyethyl. These protecting agents are - 10 45506 readily available and can be attached:to the 5-hydroxymethyl group by known methods. Their selection for synthetic purposes will depend upon the protecting group at C71. For instance, if it is desired to employ K-tetrahydropyran-2-yl as a protecting group for the acidic hydrogen of a C7' tetrazol-5-yl (W), appropriate C3 hydroxyl protecting groups (T) would be acetyl or dimethyl-t-butyl silyl.

The 1-(alkylated)-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 1. or any of its T group analogs. First the sodium or lithium salt of pyrrolidone 1. is prepared by contacting a solution of compound 1, in an inert organic solvent such as tetrahydrofuran, diethoxyethane or dioxane with a base such as nbutyl lithium, phenyl lithium or especially sodium hydride.

The appropriate temperature range for this salt formation is ambient to that of refluxing solvent and preferably alribient.

All bases must be reacted before starting the alkylation which usually requires times of 1 to 4 hours. Then, the desired 1(alkylated)-2-pyrrolidone compounds 17 and 18 are respectively formed by contacting the above prepared lithium or sodium salt of 2-pyrrolidone compound jL with an alkylating agent of the structure: wherein X is Cl, 1 and especially Br, W and A are each defined as above and Y is alkyl having from one to three carbon atoms. This second part of the alkylation 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 j. in an inert organic solvent and then by allowing contact between the mixture of alkylating agent and 2-pyrrolidone sodium or lithium salt at temperatures of ambient to solvent reflux until the alkylation is substantially complete, usually overnight.

Of course, the alkylated 2-pyrrolidone resulting from use of XCH_CH—(0Y)_ can also be prepared by employing XCKLCO.Et as 2 2 2 the alkylating agent followed by selective conversion of the ester group of the resultant l-(2'-ethyl acetate)-5-(substituted)2-pyrrolidone to aldehyde.

When there is the possibility of having an acidic hydrogen present in W, the alkylation procedure is most conveniently executed by protecting or otherwise removing that acidic hydrogen. For example, in the case where Rg is hydrogen, the best method is employment of an ester derivative which can then be removed by alkaline hydrolysis at the end of the synthetic sequence. In the case where W is tetrazol-5-yl, the best method is replacement of the acidic hydrogen by an acyloxymethyl as defined above, a phthalidyl group [W. v.

Daehne, J. Med. Chem., 13, 607 (1970); I. Isaka, et al., Ghem., Pharm. Bull,, 24, 102 (1976)] or a tetrahydropyran-2-yl group.

The first two groups for tetrazol-5-yl protection will also be removed by alkaline hydrolysis at the end of the synthesis (Scheme 3) but the TKP group will be removed by acidic hydrolysis. It will be assumed in the ensuing discussion that the acidic hydrogen of the W group has been protected unless otherwise stated. - 12 The character of the C2'—C31 bond of the 2-pyrrolidone compound 17 obtained from the alkylation step is determined by the nature of A in the alkylating agent.

The selective of A will also determine the unsaturated or saturated character of the α-side chain of the final product of the synthesis; that is, whether the final product will be an 8-aza-ll-desoxy PGE^ or an 8-aza-desoxy PGE2· Obviously, the selection of A only causes a difference in the character of the C2'—C31 bond of the α-side chain and in fact, conversion from pyrrolidone compounds where A is a double bond to those where A 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 A may be converted to the 2-pyrrolidone compound 17 with the single bond at A by hydrogenation over a noble metal catalyst such as palladium on carbon at ambient temperature until 1 equivalent of hydrogen is absorbed.

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 ω-side chain The resulting 2-pyrrolidone compounds of the structure: Compound 19 wherein W and A ar;; each defined as above, are then carried through Scheme B, to produce the novel final products of the present invention.

The above 2-pyrrolidone compound 19 can also be prepared by contacting the hydrolyzed form of the 2-pyrrolidone of the structure: Compound 18 wherein Y and T are defined as above with a phosphorane of the 10 structure: Ph3P=CH(CH2)3W wherein W, defined as above, is unprotected, e.g. CO2H or tetrazol-5-yl. The synthesis of the tetrazol-5-yl phosphorane will be found in U.S. 3,953,466.

This subset of reactions, illustrated by steps (f) and (g) of Scheme A, can be executed in the following manner. If - 14 the preferred T protecting group, tetrahydropyran-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 to form l-(ethan-2'-al)-53-hydroxymethyl-2pyrrolidone which can exist in intimate equilibrium with 4aza-2-hydroxy-l-oxa-bicyclo[4,3,0]nonan-5-one 5., nonanone 5_ The equilibrium mixture containing hemiacetal 5_ can then be 10 contacted with about 2 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 0°C. to 60°C, usually overnight, to produce 2-pyrrolidone 19 wherein A is a double bond.

It will be noted that the acidic hydrogen or group W can then be protected as an ester in the case of the carboxylic acid or as an N-acyloxymethyl, N-phthalidyl or N-tetrahydropyran-2- 15 yl group in the case of tetrazol-5-yl. This 2-pyrrolidone 19 with A as a double bond can, if desired, be converted to 2pyrrolidone 19 wherein A is a single bond by the hydrogenation method described above.

The final products of the present invention, the 2-pyrrolidone compounds 20, are prepared by oxidation of the 53-hydroxymethyl group of 2-pyrrolidone 19 to form the 5p-formyl-2pyrrolidone compound 20.

Scheme B illustrates tnis outlined process.

Scheme B w-CHAIN ATTACHMENT The aldehyde 20 is obtained from the 5j3-hydroxymethyl-2pyrrolidone compound 19 by a modification of the Pfitzner Moffatt oxidation [K. E. Pfitzner and Μ. E. Moffatt, J. Am. Chem. Soc., 87, 5661 (1965)] which avoids contact of the 5βformyl compound 20 with water. For example, stirring a slurry 4550® - 16 of 1-(7 '-methylheptanato)-5p-hydro3cymethyl-2-pyrrolidone or other appropriate 5p-hydr6xymethyl-2-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 trifluoroacetate and a water soluble di imide such as diethyl carbodiimide or especially dimethylaminopropylethylcarbodiimide or, if desired, its hydrochloride salt, at temperatures of 0°C. to ambient for 1 to 4 hours, will oxidize the primary alcohol 19 to aldehyde 20.

IO Alternate methods to achieve oxidation include the usual Pfitzner-Moffatt reaction and oxidation with chromium trioxidepyridine complex [R. Ratcliffe, et. al., J. Org. Chem., 35 4000 (1970)] although the method of choice is the reaction described above.

The following examples are merely illustrative, and in no way limit .the scope of the appended claims. The spectral data were obtained on a Varian (Registered Trade Mark) T—60 or 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 6 parts per million using TMS as a standard.

In general, the temperatures of the reactions described in the examples when unspecified, will be taken to mean ambient or room temperature which varied from 15° to 30°C.

The time requirement of the reactions described in the examples, unless otherwise stated, was determined by monitoring with thin layer chromatography (TLC). The usual TLC system was silica gel on glass (E. Merck Silica Gel plates, E, Merck Dormstadt, W. Germany) with benzene/ether or methanol/chloro30 form as eluants and vanillin/ethanol or iodine as developers. [Introduction to Chromatography J. M. Bobbitt, A. E. 5 0 6 - 17 Schwarting, R. J. 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 had disappeared or had quit changing.

The compounds of the invention will now be described with reference to Example 4. The intermediates used in the preparation of the compounds of this invention are described in Examples 1 to 3.

EXAMPLE 1. 5β-(Tetrahydropyran-2'-yloxymethyl)-2-pyrrolidone i· Into a flame dried flask under a nitrogen atmosphere was put 2.54 g. (22.1 mmoles) 5-D-hydroxymethylene-2-pyrrolidone, prepared according to the method of V. Bruckner et. al., Acta Chim. Hung. Tomus, 21., 106 (1959), and 50 ml. methylene chloride. To this solution at 0°C to 5°C was then added 3.72 g. (44.2 mmoles) redistilled dihydropyran and 0.2 g. p-toluenesulfonic (tosic)acid. The solution was then allowed to warm to room temperature and to stir overnight. After dilution of the reaction with 20 ml. ethyl acetate, the solution was extracted with 2x5 ml. saturated sodium bicarbonate solution and 1 x 10 ml. saturated brine. The organic layer was dried with magnesium sulfate, filtered to remove the drying agent, and the solvent was removed in vacuo to give 4.1 g. yellow oil.

This oil was chromatographed on a 50 g. column of Merck silica gel packed in chloroform. Elution with IL. chloroform removed less polar impurities. Elution with 2% methanol in chloroform and collection of 10 ml. fractions separated and purified the product. Combination of the product fractions and removal of solvent in vacuo gave 3.95 g. of the title compound as a yellow oil, 90% yield. NMR T—60 (DCCL3)b.s. «6.60 ppm (IH), m. «4.60 ppm (IH), m. «4.05—«3.25 ppm (5H), m. ($2.50—«2.10 ppm, m. «2.00—«1.40 ppm (10H). IR(CHC13 solution) 3425, 2980, 2930, 2850, 1680, 1250—1200, 1025 cm1. 4550β - 18 Additionally, the dimethyl-t-butyl silyl protecting 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-25 pyrrolidone.

EXAMPLE 2. 1-(7’-Ethylheptanato)-5β-(tetrahydropyran-2-yloxymethyl)-2pyrrolidone 2..

Into a flame dried flask containing a nitrogen atmosphere 10 was put 0.725 g. (18.7 mmoles) of 62% sodium hydride dispersion in mineral oil and 10 ml. dry THF. To this mechanically stirred slurry was then slowly added dropwise 3.74 g. (18.7 mmoles) of 5-(£>-(tetrahydropyran-2-yloxymethyl)-2-pyrrolidone X in 10 ml. dry THF. After the addition was complete, the thick slurry was stirred for 30 minutes until all hydrogen evolution had ceased.

The alkylation of the sodium salt was then performed.

To this slurry at room temperature was then added dropwise 5.34 g. (22.5 mmoles) of ethyl-7-bromoheptanoate in 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 in 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; 45306 - 19 (c) lL. 10% ethyl acetate in chloroform; and automatic collection of 10 ml. fractions allowed the separation and purification of the product. The product fractions were combined and stripped of solvent to yield the title compound 2 as a color5 less oil 3.39 g. 51% yield.

NMR T—60 (DCClg):M 64.60 ppm (1H), q. 64.17 ppm = 8 hz., m. 64.00—2.70 ppm (9H), m, 62.6—1.4 ppm, t. fil.3 ppm Jg = 8 hz. (23H).

IR (HCC1.J solution) 2975, 2915, 2840, 1720, 1665, 1450, 3 -1 10 1250—1200, 1125, 1025 cm .

MS-heated inlet (m/e-%) 356—1%. 355—3%, 310—17%, 240—100%, 194—83%.

The foregoing procedure can be adapted to the preparation 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 = —CO.CH 2 o O —CO2CH3 N-(tetrahydropyran-2-yl)tetrazol-5-yl N- (acetyloxymethyl)tetrazol-5-yl A - single or cis double bond T*= THP or dimethyl-t-butyl silyl - 20 As stated the l-(substituted)-5β-(tetrahydropyran-2-yloxymethyl or dimethyl-t-butyl siloxy methyl)-2-pyrrolidones can be prepared by substitution of the appropriate alkylating agent for the ethyl-7-bromoheptarioate. For instance, if 15 (6'-carboxymethylhex-21-enyl)-5β-(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 1-ylhexyl)-5β-(tetrahydropyran-2-yloxymethyl) -2-pyrrolidone is to be prepared, the alkylating agent 1C will be 6-bromo-l-(1'-acetyloxymethyltetrazol-5'-yl)-n-hexane. 1-(2,2-Diethoxyethyl)-5β-(tetrahydropyran-2 ''-yloxymethyl)pyrrolidone can also be prepared by the same procedure by employing 2-bromoacetaldehyde diethyl acetal as the alkylating agent.

The preparation of 6-bromo-l-tetrazol-5'yl-n-hexane can be accomplished by the following method.

A mixture of 2.98 g. (23.5 mmoles) 7-hydroxyheptanenitrile, 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. dimethylformamide can be heated to 120° under nitrogen with stirring for 18 hours or until the reaction is essentially complete. The dimethylformamide 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-l-(tetrazol-5-yl)hexane, can then be treated with phosphorus tribromide under appropriate conditions to produce 6-bromo-l-(tetrazol-5-yl)hexane. The E'-acetyloxymethyl group can be attached by employing the method of W. V. Daehne 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-yne- 21 4 55 OS nitrile in the same manner as above will allow preparation of 6-(tetrahydropyran-2'-yloxy)-1-(tetrazol-5'-yl)hex-4-yne.

This material can then be converted into 6-bromo-l-(tetrazol5'-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 the 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.

EXAMPLE 3. 1-(71-Methylheptanato)-5β-hydroxymethyl-2-pyrrolidone 4.

To a solution of 200 ml. methanol and 3.9S g. 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 redissolved in 160 ml. methanol, .080 g. tosic acid added, and the reaction again refluxed overnight. Removal of the solvent in vacuo from the reaction 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 sodium Rochelle'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 (DCClg) s. 63.86 ppm, m. ¢4.00—3.33 ppm, m. 53.20— 52.70 ppm (13H), m. ¢2.50—$2.00 ppm, m. ¢1.90—51.20 ppm (10H), partial spectrum.

IR (HCClg solution) 3550—3100, 2980, 2910, 2840, 1720, 1650, 1450, 1425, 1410, 1250—1190 crn1. 45503 - 22 MS, LKB 9000, solid inlet (m/e%) 70eV 226—26%, 194— 19.8%, 74—100% 13eV 257—3.3%, 226—100% 168—24.6%.

Alternatively the tetrahydropyran-21 -yl group can be removed by hydrolysis in a 65:35 mixture of glacial acetic acid: water for ca. 18 hours at about room temperature and the product isolated by removal of solvent and chromatography.

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

The foregoing acetic acid, vater hydrolysis procedure can also be used to remove the tetrahydropyranyl protecting group from the other pyrrolidone products of Example 2 which then will produce the corresponding 1-(substituted)-5f3-hydroxymethyl-2pyrrolidones. 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, opt, cit.

On application of the acetic acid procedure to 1-(2,2diethoxyethyl)-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 equilibrium mixture of the open form and 4-aza-2hydroxy-l-oxa-bieyelo [3,4,0] nonan-5 -one 5..

The equilibrium mixture containing compound 5 can be converted 5 0 6 - 23 to 1-(substituted)-5fj-hydroxymethyl-2-pyrrolidones by the following procedure.

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 methylsulfinylmethide 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-l-oxabicyclo[3,4,0j nonE.n-5-one 5. in dry dimethyl sulfoxide (63 ml).

After being stirred for an additional half hour or until substantially complete, the reaction can be poured into 600 ml. of ice-water and then can be extracted with 2 x 300 ml. of ethyl acetate. The cold 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. Concentrating the filtered organic layer will afford crude 1-(61-carboxyhex-2'20 snyl)-5p-hydroxymethyl-2-pyrrolidone which can be chromatographed. The acid can then be esterified with diazomethane.

This procedure can also be used to prepare 1-(substituted)5p-hydroxymethyl-2-pyrrolidones of the structure.

X 4SS06 - 24 wherein X is the same as that of Example 2, by substituting the appropriate phosphonium salt for 5-triphenylphosphonopentanoic acid and then protecting the acidic hydrogen with an N-acyloxymethyl group according to the procedure described by W. V. Daehne et. al., op. ci'c., with an N-tetrahydrofuran-2yl group according to the procedure of Example 1 or by esterifying in the case of the carboxy acid.

EXAMPLE 4 1- (7' -Methylheptanato) -5p-formyl-2-pyrrolidone 6..

To a flame dried flask containing a nitrogen atmosphere was added 0.1286 g. (0.5 mmoles) l-(7'-methylheptanato)-53hydroxymethyl-2-pyrrolidone in 5 ml. dry benzene. To this solution 0.1286 g. (1.5 mmoles) dimethylaminopropylethylcarbodiimide hydrochloride (DAPC) and 0.142 ml. (2 mmoles) dimethyl sulfoxide were added followed after five minutes by 0.108 g. (0.55 mmoles) of pyridinium trifluoroacetate. The reaction was stirred under a nitrogen atmosphere at room temperature for 1.75 hours, then the benzene vzas 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 0.152 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 (DCClg), d. 6 9.72 ppm J^hz (IH), m. 6 4.37— 4.07ppm (IH), s. 63.70ppm (3H). partial spectrum.

The foregoing procedure can also be used to oxidize the other 1-(substituted)-5f3-hydroxymethyl-2-pyrrolidones of Example 3 to the corresponding 1-(substituted)-5p-formyl-2pyrrolidones.

Claims (3)

1. CLAIMS:1. A compound of the structure and the C5 epimer thereof wherein: 5 A is a single or cis double bond; W is -C^ORy tetrazol-5-yl, N-(acyloxymethyl)tetrazol-5-yl, having from two to five carbon atoms in the acyloxy group, N-(phthalidyl)10 tetrazol-5-yl or K-(tetrahydropyran-2-yl)tetrazol-5-yl; and Rg is hydrogen, alkyl having from one to five carbon atoms, phenyl or £-biphenyl.

2. A compound of claim 1 wherein W is II —CORg, 15

3. A compound of claim 1 wherein W is tetrazol-5-yl, N-(acyloxymethyl)-tetrazol-5-yl or N-(tetrahydropyran-2-yl)tetrazol-5-yl.