CA1076587A

CA1076587A - Prostaglandin derivatives and process for preparing the same

Info

Publication number: CA1076587A
Application number: CA248,275A
Authority: CA
Inventors: Jacques Simiand; Charles Pigerol; Pierre L. Eymard; Alain Jean
Original assignee: Labaz SA
Current assignee: Labaz SA
Priority date: 1975-03-21
Filing date: 1976-03-19
Publication date: 1980-04-29
Also published as: FR2304340B1; MX3301E; BE839761A; CH611881A5; ES446239A1; DK140937C; SE7603400L; GB1529852A; AT348163B; IE42966L; PT64919B; DE2612114A1; FR2304340A1; SE418290B; NO144147B; FI61692C; DK140937B; ATA195676A; AU501105B2; FI61692B

Abstract

ABSTRACT OF THE DISCLOSURE
Prostaglandin derivatives having the general formula:

Description

76S~37 This invention relates to the prostaglandi:ns and i~
co:ncerned with novel compounds related in s-tructure to prostaglandin E1 which has the structural formula:

10 ~ 2 ~ Cll ~' CH2 ~ C~I / CH2 ~ 2 / lC-OH
1 OH C ~14 ~ CH 16H2- CH2~ g 2--C~I2 3 and to a process for preparing the said novel compounds.
Pro~taglandin E1 is normally abbreviated to ~PG~1n, In accordance with common usage the formula of P~E1 can also be :-written as:
O
¦¦ \ ~ ~ COOH
~~ ~
~H OH

'~he compounds with which the present inventiorl is concerned are those corresponding to the general formula: !

Iq /CH2--CH2--'CH2~ CH2-' 2 CH2 (I) ~ HC~ CH C -' 2~ CH2'' 2 CH2 wherein R represents hydrogen~ methyl or ethyl"
The compounds of formula (I) posse~s isomeric centres and thus ca-n be produced as optical isomers, position isomer~ or mixture~ of these isomer~O The mixtures of these i~omer~ can be resolved9 if de~ired~ at appropriate ~tage~ by method~ known to those skilled in the art to obtain the respective i:ndividual - ison~ers.
It is to be under~tood tha-t these isomer~ as well ~8 mixtures thereof are included within the ~cope of the pre~ent inventionO
,,.

765~37 The compound of formula (I) wherein R represent~
hydrogen can be prepared by saponification in an alcoholic medium, ~uch a~ methanol9 of a D~ carboalkyloxy_1_hexyl_5_ (3'-hydroxy~ octen-(E~-yl)-2-pyrrolid~non~ oPthe gene~al formula:

N ~ C-OR1 (II) ~\~/ :
OH
wherein R1 repre~ent~ a linear or branched alkyl group containing from 1 to 7 carbon atom~, the saponi~ication being effected by mean~ of an alkali, for example ~odium hydroxide~ and hydrolysis of the resulting alkali metal ~alt of the compound of fo~mula (II) by mean~ of a strong acid, ~or example hydrochloric acid, to form the required compound of for~ula (I).
The other compound~ of formula (I)~ namely those wherein R repre~ent~ methyl or ethyl can be prepared by reducing D~ carbomethoxy_ or carboethoxy~ hexyl-5-(3'-oxo-1'-octen-(E)_yl)_2 pyrrolidinone of the formu:La:

/\~/\ ~/\/ 2R2 ~
wherein R2 repre~ents methyl or ethyl, with a ~uitable reducing agent, for example ~odium borohydride in an inert medium, for example dimethoxyethane.
The reduction in que~qtion can be carried out at a temperature between 0 and ~5C.~ preferably at 0C.
Ihe compound~ of formula (III) can be prepared by a route in which the initisl ~tarting product is a known and easily acces~ible compound, namely~ D -pyroglutamic acid of thè formula: :

~ NH
(IV)

-2- .

.. , . ~ .
, , .

65~

Es-terification o~ the compound of formula (IV) wi-th ethanol in the presence of an ~cid9 for example, P-toluene~ulphonic acid, provide 9 e-thyl D~_pyroglu-tamate of the formula:
. .

Il H (Y) `

which, after reduction by means of ~odium borohydride in a ~olvent, ~or example methanol, provides D~-5-hydroxymethyl-2-pyrrolidinone of the formula:

o ~H (VI) ~ he compound~ of formulae (V) and (VI) are known products, which have been published in J, ~m, Chem. Soc. ~, 3121-3125 (1948).
The alcohol ~unction of the compound o~ formula (VI) i9 ~hen blocked with 293-dihydropyran in an inert medium~ for example methylene chloride, and in the presence of an acid, for example -toluene~ulphonic acidg a~ a re~ult of tthich there i~ obtained D~_2~_tetrahydropyr~nyl-5-oxymethyl-2_pyrrol~.dinone of the formula: .

O
~ H ~ (VII) i CH20 ~ J

~ 3 ~7658~

~vhich i9 then trea-ted with methyl or ethyl 7-bromoheptanoate of the formula:
1l R2-O~C-(CH2)6~Br (VIII) in which R2 has the ~ame meanings a~ in formula (III) 9 in a sol~ent, preferably toluene, and in the presence of sodium amide~ to obtain a compound of the general formula:

~ N ~ C02R2 (IX) < ~
aEI20 ~ J
o in wh.ich R2 ha~ the same meaning~ a~ in :Eormula (III) ~ he D~ carbomethoxy- or carboethoxy-1-hexy1-2~
tetrahydropyranyl-5-oxymethyl-2-pyrrolidinone of fo.rmula (IX) i9 then hydrolysed in an acid medium, for example, hydrochloric acid, and in the presence of a ~olvent, for example methanol~ ~o as to regenerate the alcohol function and thus obtain the corresponding D~-~ -carbomethoxy- or carboethoxy-1-hexyl~5-hydroxymethyl-2-pyrrolidinone of the formula:

~ ~J ~ C02~2 (X) < .
C~2H
in which R2 has the same meanings a~ in formula (III) 7 the primary alcohol function then being oxidi~ed to an aldehyde function in an inert medium7 for example benzene 9 under the combined action of dimethylsulphoxide, dicyclohexylcarbodiimide and dichloroacetic acid to obtain D~ carbomethoxy- or carboethoxy-1-hexyl-5 carboxaldehyde-2-pyrrolidinone of the formula:

`` ~ 76587 C02R2 (XI) C _ H
o ; in which R2 has the same meaning~ a~ in formula III. The aldehyde function in the compound of formula (XI) i9 then subjec-ted to a Wittig reaction with 1-triphenylphosphoranylidene-2-heptanone of -the formula:
O
(C6H5)3P = ~H-B-C5H11 (XII) 90 as to form the corresponding D~-w- carbomethoxy- or carboethoxy-: 1-hex~1-5-(3'-o~o~ octen-(E)-yl)-2-pyrrolidinone o~ formula III, ~ he methyl or ethyl 7-bromoheptanoate o:E ~ormula VIII
can be obtained ~rom suberic acid, that i~ to say, octanedioic acid, by fir~t of all preparing the methyl or ethyl monoester of suberic acid in accordance with a procedure which iq described in Helv, Chim~ Acta, 12, page 466, and then subjecting this compound to the action o~ silver nitrate, thus yielding methyl or ethyl silver suberate, and finally causing the silver salt thus formed to react with bromine in an inert medium, ~or example carbon tetrachloride, using the procedure mentioned in Org. Synth, Coll. 9 Vol~ 3, page 578 The compound of formula (VIII) in which R2 repre~ent~
methyl is a kno~n product, having been published with its method ~ o~ preparation in Chemi~che ~erichte~ 75~ pages 291-297 (1942).
: The compound o~ formul~ (VIII) in which R2 represents ethyl is al~o a known product having been described with its method of preparation in J Chem SocO 1950 P. 1740 This latter product may al90 be prepared by the method referred to abo~e and publi~hed ` ~7~7 in Chemische Berichte, 75B, pages 291-297 (1942).
As regards the phosphoru~-containing compound of formula XII, this can be obtained by first preparing di-n-pentylcadmium by mean~ of n-pentylmagne~ium bromide and cadmium chloride by the method described in Chem, ~ett. 2, 197-200 (1973)~
and then cau~ing the cadmium derivative thus formed to react with monochloroacetyl chloride. The 1-chloro-2-heptanone thus obtained is then treated with triphenylphosphine to form triphenyl-2-oxo-hept~rlphosphonium chloride of the formula:
o 6H5)3P -CH2~ll_C5H11Cl ~3 (XIII) ~nd this latter compound is then subjected to treatment with potassium carbonate in an aqueous medium to obtain the required compound of formula (XII). The compound of îormula (XIII) i9 a kno~rn product, having been referred to in ~etrahedron letters, 773-774 (1972), Ag an alternative procedure, the compound of formula (XII) csn be prepared in accordance with the method described in JJ Org. ahem, Vol. 37, No 119 1972.
Among the starting-compounds of formula (II) those in which X1 repre~ents methyl or ethyl are also compounds included within the scope of formula (I) 9 for which a proce~s OI pre-paration is de~cribed hereabove. The other esters of fo~mul~ (II) can all be prepared in accordance with the aforesaid method given for the preparation of the methyl and ethyl e~ters of both formulae (I) and (II)A
The compounds of the invention have been found to possess valuable pharmacological propertie~,, Most of the~e properties are characteristic of the natural prostaglandins in general and of the prostaglandin E19 also knoum as PG~ in ~ 7~5~7 particular Tests carried ou-t with the compounds of the in-vention have shown that, depending on the dose aaministered9 they exert in particular a contracting action on the smooth intestinal and uterine muscles, a vasodilatory effect as well as an inhibiting action on gastric secre-tion~ Fur-thermore~ as will be described subsequently in greater detail, it has been found that the compounds of formula (I) have; in addition to -their other properties, a bronchodilatory activity capable of being used particularly in the treatment of asthma and pathological states affecting the respiratory system.
~ or ~everal years, the pro~taglandins have aroused particular interest at pharmacological and therapeutic levels.
They are, in fact~ natural compounds which are very widely distributed in the tissues of mammals and of ~hich several have been i~olated from human seminal liquids.
The prostaglandins have a very wide range of activity, which seems to result from -their influence on the synthesis of 3~,5'-cyclic adenosine monophosphate (cyclic AMP).
According -to their chemical configuration~ they have various pharmacological actions such as hypertensive, hypotensive or anti-ulcerogenic activity~or depending on the part of the body concerned, a stimulating or relaxing effect upon smooth muscle, all of which actions become apparent at very closely related doses.
This lack of specificity on the part of ~natural prostaglandins is moreover responsible for most of the ~econdary effects which they can produce Of the natural prostaglandins~ the prostaglandin referred to above and known as PGE1 seems to be amongst -the most active, as has been sho~n in Chimie Therapeutique 1, 34 ~1969)o PGE1 is for example capable of stimulating -the intestinal and uterine smooth muscle, of causing ~asodilation and bronchodilation, ~ .

76~7 of reducing gastric secretion and inhibiting platelet aggregation at infinitesimal doses of the order of a nanogram.
However PGE1 ha~ cer-tain disadvantages which are inherent in the natural prostaglandin~$ because of its lack of specificity For example 9 PGE1 9 by its spasmogenic action on the alimentary canal will produce certain side-effec-ts such as nausea, vomiting snd diarrhoeau It is therefore de~irable to have available a ~ynthetic prostaglandin ~rhich shows a greater specificity as regards therapeutic action, thereby eliminating certain di~advantages of PGE1, especislly those referred to above.
The compounds of the invention achieve this objective.
In actual fact9 pharmacological tests carried out with these compounds and for compari~on purpo~es with PGE1 have shown that the compounds of formula (I), in the same way as PG~1; contract the smooth in-testinal and uterine mu~cles, dilate the blood vessels as well a~ the bronchi and i~hibit gastric secretion.
However the compound~ of the invention function in a much more ~peci~ic manner than PGæ1 at the bronchial level and to a leaser degree at the vascular level.
~ or example, it has been found that -the compound of formula (I) in which R corresponds to a hydrogen atomy i~e.
D~ 8-aza~ deoxy-P~E1, has a b~onchodi~atory activity which is sub~tantially equal to that of P~æ1~ while being 10 to 100 times le~s active than PGE1 as a va~odilator, 200 times le~s powerful than PGE1 as a spasmogenic agent at the in-testinal and uterine levels and 30 times less active than PGEl in reducing the volume of ga~tric secretions.
The compounds of the invention are thus capable of being used therapeutically in the treatment of pathological states which affect the respirstory system, and e~pecially a~thma, with ~ubs-tantially none of -the secondary effects previou~ly referred ,. ' " ' . :

~76~i~37 to in respect of PGE1, Independently of their pharmacological utility, the 2-pyrrolidinone derivatives of the invention have in addition certain advan-tages over PGE1, particularly as regard9 their preparation PGE1, being a natural product, can be obtained for example by extraction from natural materials, especially from vesicular gl~nds of sheep9 lungs of pigs or even from human seminal pla~ma. It is evident that such sources of supply will only permit this product to be ob-tained in limited quantities and with the use of expensive equipment "and this will have the effect of increa~ing the co~t of the product to a ~ubstantial extent.
~urthermore, production of PGE1 by a synthetic route cam10t be achieved without great difficulties due to the several centres of asymmetry present in the molecule. These difficulties will have the effect of increasing the number of stages in the preparation of the compound with a consequent increase in the manufacturing cost.
The synthesis of the compounds of formula (I) in accordance with the invention sub~tantially avoids these difficulties.
Their simpler chemical structure which in fac-t, eliminates the asymmetry at the 8 and 11 carbon atom position~
of PGE1 7 has the result of facilitating -the chemical synthesis.
~urthermore, the s-tarting products required for the preparRtion of the compounds of the invention csn be easily obtained, and hence it will be possible to prepare the compounds of the invention in much larger quantities than is possible when s-tarting from natural tissues as in the case of PGE1~
These importan-t advantages inherent in the preparation of the compound~ according to the invention will contribu-te to their being shown preference over PGE1~

. : . ....... :

.

The results of a number of pharmacological tests carried out with a compolmd of the invention i.e. D~-8-aza~
deoxy-PGE1 are set out below. '~hese tests show the markedly specific nature of its action on the bronchial tube~ and its much les~ ~pecific action at the vascular level. In each of these trials, the compound tested, as well as PGE1, used for comparison purpose~ were employed in the form of ethanolic solutions diluted ~vith distilled water.
I ~ D
There was used for this purpose the MAGNUS technique ~Arch Ge~. Physiol9, 102, 123 (1904)].
It wa~ found that, on the ileum of a guinea pig, the compound of the invention produce~ an ample and reproducible spasm in a do~e of 0.2 X 10 3 g/ml of bath, wherea~ when using PG~1, a dose of 0.1 X 10 5 g/ml is suffic~ent for obtaining a spasm of the same intensity Used on the uterus of a rat, w'nich had been blocked prior to the oestral cycle by means of stilboestrol, it was found that PG~1 contracts this organ in an intense and regular manner in a dose of 0.3 X ~0 5 g/ml, whereas it is necessary to introduce into the bath a dose 200 times larger, iOe. 0.6 X 10 3 g/ml, of the compound of the invention~ in order to obtain an equivalent spa~m.
Nloreover, an inactive do~e of the compound of the invention, of the order of 10 4 g/ml, placed in contact ~ith the ileum or the uterus 30 seconds before a dose of PGE1 of the order of 10 5 g/ml doe~ not modify the action of thi~ lat-ter compolmd on the organ being studied.

II - Cardiovascular action .:
'~he effect of different doses of the compound of the invention or of PGE1 on systolic arterial pres~ure, diastolic arterial pressure, electrocardiogram, cardiac frequency and :' , 10 - . . , ' 765~7 femoral ra-te of flow was inve~tigated in -the conventional manner in dog~.
Admini~tered intravenouslyg in a dose of 0 5 to 1 ~g/kg9 PGE1 immediately cause~ a ~ystemic arterial hypotension having an effect on both the ~ystolic and the dia~tolic pre~sure.
The mean pre~sure i9 reduced, dependin~ on the animal, from 5~0 to 21~o 0~ it~ initial value, while the rate of arterial flow i9 increa~ed to a ~ubstantial degree, of the order of 3~% to 100%
of its initial valueO On the other hand, a moderate ~inu~al tachycardia becomes apparent. The~e results show that GE1 is a very powerful vasodilating agent~
A~ regard~ the compound of the inven-tion, it wa~
ob~erved that~ admini~tered intravenou~ly and in do~es between 5 and 50 ~g/kg, this compound produces the-same effects a~ PGE
on the cardiovascular sy~tem.
These re~ult~ show that the vasoailatory action of the compound of the invention appears at do~e~ which are 10 to 50 time 9 greater than tho~e required for PGE1.
In order to obtain an analogous effect with papaverine, it is necessary to have a do~e of 50 to 100 times larger than that required for the compound of the invention.
When sdministered into the femoral artery, -the compound of the invention increa~es the arterial flow -to a degree which i~
much ~maller than that obtained with PGE1.
~ or example 9 in a dose of 1~g/kg, the compound of the invention cau~es a variation of +100% of the initial femoral f~ow, whereas PGE1~ in a dose of 0.01 ~g/kg, already cau~e~ a variation of ~173%. The~e re~ult~ show that when administered intraarterially, the compound of the invention i9 more than 100 time~ le~s active than PGE1o Bronchodilator,~ activi ~ ~
There wa~ used for thi~ purpo~e the technique developed --11-- . ~

s~

by KONZE~T & ROSS~ER (Arch Exp Path PharmakolO, 1940, 195, 71-74), the spasm-promoting age-nt being acetylcholine~
The result~ show that the compound of the invention has a con~iderably bronchodilatory activity of the order of 48%, 2 minutes after it has been admini~tered intrsvenou~ly in 8 do~e of 2.5 ~g/kg. ~ikewise with 5 ~g/kg9 the reduction of the bronchogpasm i9 77~, 2 minutes after intravenous administration of the compound of the invention, with a duration of ahout 10 minutes PGE1 i9 a very powerful bronchodilating agent7 since at a do3e of 2 ~g/kg, administered intravenously, it inhibit~
74% of the bronchospa~m, 2 minute~ after being administeredO
If the two parameters, inte:nsity and duration of action, are considered, the compound of the in~ention is just as active as PGEl, since in a dose of 5 ~g/kg~ admini~tered intravenously, they each inhibit by 45% on average the bronchospasm obtained with acetylcholine, over a period of 10 minutes.
IV - ~ction on the ~stric ~ecretion of a rat.
There wa~ inve~tiga~ed in a conventional manner the effect of the compound of the invention on the gastric ~ecretion and acidity of female rats subjected beforehand to a hydrous diet for 24 hours~ and then to complete fa~ting for the following 24 hours.
The re~ults show that, in a dose of 10 mg/kg, the compound of the invention reduce 9 to a considerable degree~ that i~ to 3ay9 by about 58%, the volume of gastric ~scretions.
~urthermore, the total acidity i~ reduced by 72%, while the pH
i~ rai~ed from 1.9 for the control animal3 to 4.0 for the treated animals Under conditions similar to those used above~ P~E1 reduces by 50% the volume of ga~tric secretion~ in a dose of 0~3 ; mg/kg (Gastroenterology~ 1968, volume 55, No. 4~ page~ 481-487), which shows that the compound of the invention is about 30 time~

~7658~

less active than PGEl in this test.
Pharmaceutical and veterinary compositions containing as essential active ingredient at least one compound of the invention can be made up in any form which is suitable for their administration in human and veterinary therapy. For ease of administration the composition will normally be made up in a dosage unit form appropriate to the desired mode of administra-tion, for example, a compressed tablet for perlingual adminlstra-tion, a pill, a powder, a capsule, a syrup for oral adminis-tration, a suspension for oral or aerosol administration, a suppository for rectal administration, a cream or an ointment for topical or local administration or a sterile solution or suspension for parenteral administration~
These therapeutic compositions will be prepared in accordance with known techniques by associating at least one compound of formula (I) in the form of a mixture of isomers or of an active isomer with an appropriate non-toxic diluent or excipient and then if required making up the resulting admiXture in the desired dosage unit form. Examples of suitable diluents -` 20 and excipients are distilled water, ethanol, talc, magnesium stearate, starch and cocoa butter.
The range of active substance used may, for example, be 0.5~ug. to 3000 ~g. daily in 1 to 60 aerosol inhalations for ~ -asthma or other affections of the respiratory system and O.l,ug. to l~lg. intravenously per minute and per kilo of body-weight to obtain a vasodilatory effect or an action on smooth -~
muscle.
The following Examples illustrate the preparation of ; the compounds of the invention.
; 30 In these Examples, the analytical results obtained from infrared (I.R.) spectra and nuclear magnetic resonance spectra (N.M.R.) comprise the following abbreviations, which indicate:

::

.
.. . . ............. . .
. ,~ ' ' ' ',. '' . ' 1~7G~
I.R. Spectrum f = weak ab~orption m = average absorption ~ = ~trong absorption N~M.R. ~ rum ~ or chemical displacemen-t indicated the difference between the field force~ at which ~ignals are obtained for the nuclei of the ~ame type, such as the proton, but ~ituated in a different molecular environment pp~ = part per million T _ triplet M = multiplet Q = quadruplet S = singlet CDC13 = deuterum-containing chloroform, used a~ reference and as solvent~
.EXAMPIE 1 ~ ~ 1-m ~ E
A _ (a) ~
Into a four~litre three-necked spherical flask equippea with a mechanical ~tirrer and a dropping funnel were poured 1.4 litres of water and then there were introduced 27 g. (0 48 mol) of potassium in tablet formO After the pota~sium had dis~olved, 91 g. (0.48 mol) of methyl monosuberate were added and then a solu-tion of 8105 g. (0~48 mol) of silver nitra-te in 900 ml, of water wa~ poured in dropwi~e while ~tirring vigorou~lyO Suction-filtering wa~ effected and the re~ulting precipitate was wa~hedwith a little methanol and then dried under vacuum to a constant 3iL~765~7 weight (36 hour~ at 100C) There were obtained in this way 111 g. of sil~er and methyl suberate~ thi~ repre~enting a yield of 78%
(b) ~ ~
Into a 500 ml~ three necked spherical flask e~quipped with a dropping funnel9 a mechanical ~-tirrer and a water condenser equipped with a calcium ~hloride trap were poured 170 ml. of dry carbon tetrachloride. The 111 g. (about 0.38 mol) of ~ilver and me-thyl subera-te, prepared as previou~ly described, 7 rrere then added, cooling wa~ effected with iced water and 20 ml~ (Or~65 mol) of dry bromine were ~lowly introduced. The reaction wa~ ~ery exothermic After the additiong the reaction mixture was refluxed for 90 minutes with the aid of an oil bath, allowed to cool, ; filtered and then the resulting precipitate was wa~hed with 100 ml.
of hot carbon tetr~chloride~ ~he organic phase obtained was then wa~hed with a 10% aqueou~ solution of pota~sium carbonate, followed by drying and elimination o~ the solvents.
The residual oil thu~ obtained wa9 di~tilled under vacuum and the fraction pas~ing over in the temperature range 100 to 107C./4mm.Hg. wa~ collected, There were thu~ obtained 27g of crude product, which was purified by chromatography on a silica gel column (420g of silica)~ using ~ucce~sively the following eluants ~ twice wnth 500 ml.of hexane~ four time~ with 500 ml. of a 1/4 mixture of benzene and hexane, and then once with 500 ml. of etherO
Using thi~ procedure9 there were obtained 18.~ gO of methyl 7-bromoheptanoate in the form of a colourle~ limpid liquid9 this representing a yield of 17~. P"P. 115C./8mm.~g.
I.R. Spectrum : _C0 (e~ter) at 1740 cm 1(~) ~C0 (ester) at 1200 cm~1(m) _C-Br at 640 cm l(f) ; /s~

. .

~65~37 B - Pre ~ 09 (a) 1-~hlo~
Into a 1-litre three-necked spherical flask equipped ~ith a water condenser, 8 dropping funnel and a mechanical stirrer device were poured 330 ml. of dry ether and then there were added 16.3 g, (0.66 g-atom) of magnesium turnings. ~he resulting mixture was hea-ted u~der reflux and then~ while maintaining the ether under reflux9 101 g~ (0.66 mol) of n pentyl bromide were poured in dropwise. '~'~en all the magnesium had disappeared~ the ~olution was diluted with an equal volume of ether and then 96 g~ of dry cadmium chloride were added while - stirring. The resulting mixture was heated for one hour with the aid of an oil ba-th, the temperature of which wa~ kept in the region of 40C (reflux of the ether). ~he ether was eliminated by distillation, while progressively replacing it with 350 ml, of anhydrous ben~ene, and the distillation was stopped when a temperature of 70C was reached. The reaction mixture was cooled on an iced water bath and then a solution of 78 g. (0,66 mol) of monochloracetyl chloride in 150 ml~ of dry benzene was added dropwise, During the additiong the temperature of the reaction medium was ad~usted 90 a~ not to exceed 40C. Reaction was allowed to take place for 1 hour and then the reaction mixture wa~ heated for 2 1/2 hours by mean~ of an oil bath at 40C.
; After cooling, the reaction mixture wa9 poured into250 g~ of ice and 750 ml. o~ N sulphuric acid were added thereto, The aqueous phase was taken up in benæene and the organic phase was successively treated with an aqueous ~olution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloricle. The resulting organic fraction was dried, the ~olvents were eliminated and distillation was carried out with a Ne~ter_ ~aust columng after having effected a first rectification with a .
, .

~ 8~

Vigreux column~ ~he fraction pas~ing over at 86,5 to 87C,/20 mm,Hg was collectedO
In this ma~ner there were obtained 27 g. of 1-chloro 2-heptanone in the form of a colourles~ limpid liquid, this representing a y-leld of 28%.
N,M,R, Spectrum (CDC13) : ~= 0,9 ppm (T) 3P (C~I3) = 1~4 ppm (~) 6P (~2) = 2,6 ppm (T) 2P (COC~I2) ~ 4.2 ppm (S) 2P (~I~2Cl) (b) ~
Into a 250 ml. three-necked spherical flask equipped with a water condenser wcre poured 12,25 gg of 1 chloro-2 hepta-none, prepared a~ previously described, and then a ~olution of 26,7 g, of triphenylphosphine in 100 ml, of chloroform was added, The re0ulting reaction mixture was heated for 3 hours on an oil bath at 70C, (reflux of -the chloroform). After cooling~ the ~olvent wa~ eliminated9 the residual oil thus obtained was taken up in 80 ml, of acetone~ and then the solution ~o formed was placed in a refrigerator for 12 hours, rrhe crystals obtained were 9uction-filtered, washed with a little iced acetone and then dried under vacuum.
In this manner~ there were obtained 24 g, of 2-oxo-heptyltriphenylpho~phonium chloride in the form of a crystalline and hygroscopic white powder9 thi~ representing a yield of about 72%.
Thin-film chromatography of the product a~ thus obtained shows a main stain having a Rf of 0,8 snd three secondary stains having respectively Rf values of 0,85, 0~90 and 1.00~ using as solvent a 40/40/19/1 mixture of hexane/chloroform/ethanol/ammonia.
(c) l-~riPhen~l~h ~
A solution of 30 g, of 2-oxo~heptyl-triphenylphosphonium chloride, prepared a~ previously described, in 300 ml, of chloro-..
: ', , , ~L~7~5~

form, W8S introduced into a spherical flask~ This solution was treated firstly with an aqueou~ solution of potassium carbonate 9 and then with a saturated ~olution o~ sodium chloride. 'rhe reaction mixture was dried~ the solven-t eliminated and the residual oil thus obtained taken up in about 30 volumes o~ hexanec In this mannert there were obtained 17 g of 1-triphenylphosphoranylidene-2-heptanone, in the form of white crys-talsg this representing a yield of about 62~o~ A thin-film chromatography of the produot thus obtained revealed a main stain ha~ing a Rf o~ 0.2 and a secondary stain having an Rf o~ 0~5~
using as solvent a 90/25/4 mixture of benzene/dioxane/acetic acidO
C Preparation o~ the D~ carb p~rrolidinone (a) Ft v~ D~_~yro~lutamate Into a 2-litre three-necked spherical flask e~uipped - with a mechanical stirrer and a water condenser above which was a calcium chloride trap were poured 900 ml. of absolute ethanol, and then 100 g o~ DI-pyroglutamic acid and 10 g. of ~-toluene-sulphonic acid were added ~he reaction medium ~s heated for 16 hours by means of an oil bath at 100C. After cooling, about 800 ml. o~ alcohol were eliminated and the re~idue w~ taken up in 200 ml. of ~ethylene chloride. ~he organic phase was washed with a 20% aqueous solution oP pota~sium carbonate and then with a satur~ted aqueous solution o~ sodium chloride. Drying took place~ the solvents were eliminated and distillation took place, - with the ~raction passing over at 138C./0.3 mm~Hg -being collectedO
In this manner, there were ob-tained 9002 g. of ethyl D~-pyroglutamate in the form of agglomerated white crystals, this representing a yield o~ sbout 74~.
I R. Spectrum (K~r) : - NH at 3200 cm 1 (m) - C0 (ester) at 1735 CIU 1 (I`) - CO_~I at 1700 cm 1 ~1~376~8~

N,M.R, Spectrum (~D~13) : S= 1,2 ppm (~r) 3P (CH3) = 2,3 ppm (M) 4P (~H2~H2) = 4,2 ppm (Q) 3P (~H2_C'H3 ~ :
tertiary CH) = 7,2 ppm (S) lP (NH) (b) D ~ 1r~e~ l 7-~Y~ g:L$Y~
Into a 1-litre three-necked spherical fla~k e~uipped with a mechanical ~tirrer were introduced 440 ml. of me-thanol and 330 Ml, of water~ q'he ~olution wa~ cooled to 0C, by means of à cryo~tat and 15,7 gO of ethyl D~_pyroglutamate~ prepared as ~
~reviou~ly de~cribed, were added thereto, 2208 g, of sodium --borohydride were then added in 3m~11 portions and the temperature :
wa~ kept at 0C. for 90 minute~, The reaction mixture wa~ then allowed to return to normal temperature and left for 24 hour3, ~here wa~ then c~rried out a continuou~ ex-traction wi-th me~hylene ~:
chloride for 4~ hour~O ~he solvent~ were elimina-ted and the residual oil which wa~ obtained was taken up in 2 volumes o~
acetone, .:~:
In thi~ manner, there were obtained 9 g, of DI_5_hydroxy_ methyl-2-pyrrolidinone in the form of a light yellow cry~talline powder, thi~ repre~enting a yield of 81C~o, M~Po 65,5C, I,R, Spectrum (K~r) : NH, OH at 3260 cm 1 (m) 3210 cm~1 (m) CO at 1670 cm 1 (c) D'~ L~Lh~
Into a 1-litre three-necked ~pherical fla~k equipped ~ with a calcium chloride trap and a mechanical stirrer were poured ;' 450 ml, of me-thylene chlorid.e dried on a 4R screen and there were then added 23 g, of D~-5-hydroxymethyl-2-pyrrolidinone~ prepared a~ previou~ly de~cribed7 and 26 g, of freshly di~tilled 2,3-di-hydropyran. A solution of 600 mg, of ~-toluene~ulphonic acid in .
;~
v_ .

765~

120 ml of anhydrous tetrahydrofuran was then poured in dropwise.
Reaction was allowed to take place for 90 minutes a-t normal temperature, after which neutralisation to pH 6 to 7 was carried out ~th 10 ml. of pyridine and then the reaction medium was diluted to 1~1itre with methylene chlorideO ~he organic phase was washed with water and then with a saturated aqueous solution of sodium chloride. The organic fraction was dried, the solvents were elimina-ted and the residual oil obtained was taken up with an equal volume of i~opropylether. In thi~ manner, there were obtained 30 g of D~_2l_tetrahydropyranyl_5_oxymethyl_2-pyrro_ lidinone in the form of a white powderS thi~ representing a yield of about 75%.
Mo ~, 1st melting at about 50C
2nd melting at 82 - 95~.
Observation of the melting or fu~ion under a microscope made it pos~ible to distinguish two allotropic varieties, one melting at around 45-46C. and the other at around 88-90Co A
partial separation of these two varieties was obtained by re-crystalli~ing the initial mixture in 4 volumes of isopropylether.
In thi~ case, the first crop con~i~ts of crystal~ melting at around 88 - 90C, (d) ox~m~e9b~ y~9~ 9~
Into a 1-litre three-necked ~pherical fla~k equipped with a nitrogen inlet, a mechanical stirrer and ~ water condeneer equipped with a calcium chloride trap were introduced 100 ml, of dry toluene, 3.9 gO (0.1 mol) of sodium amide and then, dropwise, a solution of 20 gO of ~-2'-tetrahydropyranyl~5-oxymethyl-2-pyrrolidinone, prepared as previou~ly described, in 300 mlJ of toluene. The reaction medium was hea-ted under reflux for 1 hour and then9 after cooling, there was poured in dropwise a ~olution of 23 g~ (0~1 mol) of methyl 7-bromoheptanoate, prepared a~

~765~37 described in ~ (b) above, in 500 ml. of dry toluene. Heating under reflux took place for 24 hours with the aid oE an oil bath at 120C. After cooling, the reaction mixture was poured into 100 ml. of iced water, decantation took place and the resulting organic phase was washed with water and then with an aqueous solution of sodium chloride. Drying took place and the solvents were eliminatedO
In this manner, there were obtained 32 g. of DL- ~-carbomethoxy-l-hexyl-2'-tetrahydropyranyl-5-oxymethyl-2-pyrrolidinone in the form of a yellow oil which was sufficient-ly pure to be subsequently used as such~
Yield : 94 ~
I~Ro Spectrum (film) : a~sence of OH band CO (ester) at 1740 cm 1 ~F) - CO (amide) at 1690 cm 1 (F) (e) DL-L~Carbomethoxy-l-hexyl-5-hydroxymeth~1-2-Pyrro-lidinone Into a 250 ml. three-necked spherical flask equipped with a mechanical stirrer were poured 130 ml. of methanol and then 32 g~ of DL-~-carbomethoxy-l-hexyl-2'-tetrahydropyranyl-5-oxymethyl-2-pyrrolidinone, prepared as previously described. The resulting solution was cooled with an iced water bath and then 50 ml. of a solution of N hydrochloric acid were added. The reaction was allowed to take place for 2 1/2 hours at ambient i temperature, the methanol was eliminated and 100 ml. of ~ methylene chloride were added. The resulting mixture was ;~ decanted and the organic phase washed, first with a 10~ aqueous ; solution of potassium carbonate and then with a saturated aqueous solution of sodium chloride. Drying took place and the solvents were eliminated, so yielding an oil which was allowed to crystal-lize in a refrigerator.
In this manner, there were collected 11.6 g. of DI-~-' , ' ' ' ' 765~37 carbomethoxy-l-hyxyl-5-hydroxymethyl-2-pyrrolidinone in the form of an almost white powder, this representing a yield of 48%.
The purity of the product as thus obtained is generally satisfactory. However, if so desired, this product can be purified by chromatography on a silica gel column, using in succession the following eluants: methylene chloride, a 2/1 mixture of methylene chloride/acetone, a 1/1 mixture of methylene chloride/acetone and 1/2 mixture of methylene chloride/acetone.
Thin-film chromatography of the product thus obtained revealed three stains, of which the respective Rf values were 0.4, 0.45 and 0.50, using a 79/14/7 mixture of benzene~methanol/
acetic acid.
I.R. Spectrum (CCQ4, 5~) : OH at 3350 cm 1 CO (ester) at 1740 cm 1 (F) CO-N at 1670 cm 1 (F) (f~ DI-~-carbomethoxy-l_hexyL-S-carboxaldeh~de~2-~rrolidinone Into a 250 ml. three-necked spherical flask equipped with a mechanical stirrer, a calcium chloride trap and a nitrogen inlet were introduced 60 ml. of anhydrous dimethylsulphoxide and 120 ml. of dry benzene. There were then added 5.15 g (0.02 mol) of DL-w-carbomethoxy-l-hexyl-5-hydroxymethyl-2-pyrrolidinone, prepared as previously described, and 12.4 g.
(0.06 mol) of dicyclohexylcarbodiimide. The resulting mixture was cooled to 0C. with a bath of ice and salt and then lo 06 ml.
(0.02 mol) of dichloroacetic acid were added. A white precipitate of dicyclohexylurea was quickly formed. The reaction medium was allowed to return to ambient temperature at which it remained while stirring for 6 1/2 hoursO At this stage, the aldehyde so formed can be isolated by either of the following two differen-t methods:

(1) 4.4 g. of oxalic acid are added and reaction is i5~7 ' allowed to take place for about 30 minutes OC., after which the substance so formed is filtered and the precipitate washed with benzene and then diluted to 300 ml.
with chloroform. The resulting solution is neutralised with, for example, pyridine and the reaction medium is treated with water and then with a saturated aqueous solution of sodium chloride. Drying takes place, the solvents are eliminated under vacuum, so as finally to obtain 3 g. of DL-~-Carbomethoxy-l-hexyl-5-carboxaldehyde-2-pyrrolidinone, in the form of an oil -which can be used as such or purified by chromatography on a silica gel column;
t21 5 g. of ice are added and reaction is allowed to take place for 15 minutes, after which the substance obtained is iltered, the resulting precipitate is washed with a little benzene and the solvents are re-moved under vacuum. The residual oil which is obtained is taken up in a few millilitres of ether and the resulting solution is placed in a refrlgerator. The solution is then filteredJwashed with ether, the ether is eliminated and the residue so obtained is taken up in 150 ml.
of chloroform. The organic phase so formed is washed with water and then with a saturated aqueous solution of sodium chloride, followed by drying. The solvents are removed and there are thus obtained ; - 23 -' .

,-, , . ~
.

~L0~6~87 12 g. of an oil containing about 3 g. of dimethylsulphoxide, 4 g. of dicyclohexyl carbodiimide and 5 g. of the required aldehyde. This oil can be used as such or purified by chromatography on a silica gel column, using the following eluants methylene chloride, a 3/1 mixture of methylene chloride/acetone, and a 1/1 mixture of methylene chloride/acetone.
I.R. Spectrum (CHC13~:CO (ketone) at 1670 cm 1 (F) CO (esterj at 1730 cm 1 (F) N.M~R. Spectrum (CDCL3): aldehyde peak at 9.7 ppm ester peak at 3.7 ppm (g) DL-~-Carbomethoxy-l-hexyl-5-(3'-oxo~ octen-(E)-y~-2 ~pyrrolidinone Into a 500 ml. three-necked spherical flask equipped with a water condenser, a dropping funnel and a nitrogen inlet were poured 120 ml. of anhydrous dioxane, and there were then added 5 g. (about 0.02 mol) of DL-~-Carbomethoxy-l-hexyl-5-carboxaldehyde-2-pyrrolidinone, prepared as previously described~
~here was then introduced dropwise a solution of 11 g. (about 0.03 mol) of 1-triphenylphosphoranylidene-2-heptanone, prepared as described in B (c) above, dissolved in 240 ml~ of dry benzene. The reaction mixture was h~ated under reflux for 8 1~2 hours by means of an oil bath at 90C. and then, after cooling, the solvents were removed under vacuum. The residual oil obtain-ed was taken up in a fex millilitres of ether and the resulting solution was placed in a refrigerator for several days. The precipitate of triphenylphosphine oxide was then filtered, suction-filtered and washed with ether. The resulting solution was collected and the ether eliminated. There were thus obtain-ed 18.5 g. of an oil which was purified by chromatography on a ~7~5!3~

silica gel eolumn (700 g. of silica), using successively fractions of 800 ml. of the foll~wing eluants : one fraction of methylene chloride, three fraetions of methylene chloride/5~ ethyl acetate, five fractions of methylene chloride/lO~ ethyl acetate and eighteen Fractions of methylene ehloride/20% ethyl aeetate. In this manner, there were obtained 5.5 g. of DL-~-'carbomethoxy-l-hexyl-5-(3'-oxo-1'-octen-(E)-yl)-2~pyrrolidinone, in the form of a brown oil, this representing a yield of about 79~.
I.R. Speetrum (CHC13 10%) : CO (ester) at 1730 em (F) ; lO CO (ketone) at 1675 cm (F) N~M.R. Speetrum (CDC13): ~= 3.6 ppm (S) 3P (COOCH3) = 6 ppm to 7.3 ppm (M) 2P (HC-CH) th) DL-~-carbomethoxy-l-hexyl-5-(3~-hydroxy-l~-octen ~E)-yl)-2-p~rrolidinone , Into a l-litre three-neeked spherical flask equipped with a meehanical stirrer and a ealeium ehloride trap were introduced 400 ml. of dry dimethoxyethane and there were then added 5 g. (0.014 mol) of DL- w-carbomethoxy-l-hexyl-s-(3~-oxo-l'-oeten-(E)-yl)-2-pyrrolidinone, prepared as previously deseribed.
The solution was cooled to 0C. by means of a eryostat and l.0~ g.
(0.028 mol) of sodium borohydride were added in small portions.
Reaetion was allowed to take place for 45 minutes at 0C~ and 50 ml. of water were then earefully added, followed by 100 ml. of a 2% aqueous solution of tartarie aeid (final pH of th~ solution was about 4). The resulting reaction medium was extraeted several times with methylene ehloride, the organie phases were eombined and washed with water and then with a saturated aqueous ; solution of sodium ehloride. The organic fraction was dried and the solvents removed. There were thus obtained 5 g. of an oil, which was purified by ehromatography on a silica gel eolumn (320 g. of silica), using in suecession fractions of 320 mg. of the following eluants : eight fraetions of methylene ehloride/20 , 658~

ethyl acetate and ten fractions of methylene chloride/50% ethyl acetate.
In this manner, there were obtained 2.7 g. of DL-~carbomethoxy-l-hexyl-5-(3'-hydroxy~ octen-(E)- yl)-2-pyrro-lidinone, in the form of a colourless oil, this representing a yield of about 54%.
This compound only presents a single peak (nephroid) by silica gel thin-film chromatography, using as eluant a 1/1 mixture of chloroform/ethyl acetate.
Rf about 0.35.
I.R. Spectrum (CHC13) : broad OH at 3430 cm 1 (m) and at 3600 cm~l (f) COO- at 1730 cm 1 (F) -CO-~ at 167 cm 1 (F) N.M.R. Spectrum (CDCL3) ~= O.9 ppm (T) 3P (CH3-CH2-CH2) = 2.3 ppm (S) lP (OH exchangeable with trifluoacetic acid) = 3.6 ppm (S) 3P (COOCH3) 20 Preparation of DL-~-Carbox~ hexyl-5-(3'-hydroxy~l'-octen-(E)-ylL-2-~yrrolidinone or DL-~-a~a-ll-deoxY-PGEl Into a 250 ml. three-necked spherical flask equipped with a mechanical stirrer were poured 100 ml. of methanol and then 2.6 g of DL-~-carbomethoxy-l-hexyl-5-~3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinone prepared as previously described. The resulting solution was cooled to 0CO with the aid of an iced water bath and then there were slowly introduced 40 ml. of a 0.5 N sodium hydroxide solution. Reaction was allowed to take place for 2 1/2 hours at ambient temperature, following which 20 ml. of water were added and the resulting aqueous solution was washed with a 25% aqueous solution of hydrochloric acid to a pH

~7~ii5137 o~ 29 whereafter e~traction took place sever~l time~ ~vith ethyl ace~a~e. The organic phases obtained were combined and then wa~hed with 8 ~aturated aqueou~ ~olution of ~odium chloride, following which they w~re drie~ and the so'lvents eliminated.
In thi~ ma~er9 there were obtained 201 g- of the required D~ carboxy 1-hexyl-5-(3'-hydro~cy~ octen-(E ) yl)-2 pyrrolidinone or D~ 8-aza~ deoxy-POE:19 in the form of a partially cry~tallized hyeroscopic gel~ thi~ repre~enting a y~ld of sbout 85%, Chr~matography ~ith ~ silical gel thi~ film and using, eluant, a 90/25/4 mixture of ben~ene/dioxane/acetic acid ~howed a main ~tain of Rf - 0033 and two ~econd~ry stain~ of re~peotively Rf value~ of 0.39 ~nd 1.
IoR~ Spe~trum (CHC133 : CO (acid) at 1710 cm 1 (F) CO_N at 1665 cm 1 N.M.R. Spectrum (DMSOd6) : compatible ~pectrum E

A .
(a) A ~u~pension of 408 g9 (002 mol) of ~odium hydride in 150 ml.
OI anhydrou~ benzene ~as cooled in an ice bath. While stirring, 32003 g. (0.2 mol) of ethyl malonste in 150 ml. of aimethyl~orma-mide w~s added drop-b~r-drop,.
Af~er this operation, etirrirlg wa~ maint~ined at room-temperature for 12 hours snd 004 gO o~ pota~ium iod~de and 32.9 g~ o~ 5-a¢eto~y-pentyl :3chloride (prepared in accordance ~ith the method describsd in J. A~ Chem, Soc. t 1947, ~, 2581 ) were addedO The mixture ~va8 heated at 125C. for 24 hour~ aIld then concentrated und~r vacuum. ~he re~idue ~o formed was taken up in 100 ml" of 5%-~ulphuric acid. ~o thi~ solutio~ wa~ added 7 ~ S ~ 7 ~ gl of ammonium chloride and 500 mlO of ether. After ~iltration, the precipitate was wa~hed with ether and the filtrate was wa~hed ~ith w~ter saturated with ~odium chlorideO ~he ~queous pha~e ~a~ again e2tracted with 100 ml~ o~ methylene chloride.
~he organio fractions were dried over ~odium ~ulphate and con-centrated to provide 35 g. of ethyl (5-acetoxypentyl)-malonate ~n the form of a-n oil.
Yield : about 60%
(b) Eth~ nn ~tanoste A mi~ture of 57,6 g. (0.2 mol) of ethyl (5-acetoxy-pentyl)-malo~ate, prepared a~ pre~iousl~ described~ and 100 ml.' of a 48~-~queou~ ~olut~on o~ hydrobromlc acld ~a~ refluxed for 20 hour3 ~nd then concentrstea by distillation to an inner temperature of 120~. ~he cooled re~idue wa~ taken up in ether. ~he eth~real solution wa~ ~ashed with water ~aturated with sodium chloride and dried~l ~he ether wa~ elimin~ted to provi~e 38 g, of a dark ~viscou~ l~quid ~yield about 935~) con~tituted by crude 7-bromo-heptanoic ac~d. ~o this crude product ~ere then added 31 ml. o~
absolute ebhanol9 72 ml O of snhydrou~ b~n~ene and 3 ~rop3 of con~entrated sulphuric ac~d. ~he r2action medium wa~ reflu~ed ~ith a ~sn-Stark ~ystem ~or 24 h~ur~ and then 100 ~1D of benzene were ~dded~ ~h~ mi~ture wa9 ws~hea ~ith a 10%-~olut~on o~ sodium bicarbonate ~nd th~n with water to neutralit~, ~he eolution wa~
dr~ed, concentrated and the ~ily re~due was di~tll~ed9 - In this manner, there w~re obtained 35 g. of ethyl 7 bromoheptanoate ~hich i~ homogeneou~ in thin layer chromatograph~
~.P, : 98C. (under 1 mm/Hgo ) Y~eld : ~bout 82~
; N.M.R. Spectrum (CDC13) : ~ ~ 1.25 ppm (~) (CH3) . 30 = 4~15 ppm (Q) (C~20CH) = 2.3 ppm (T) (CH2_C0_0) = 3.4 ppm ('~) (CH2 ~r) -28~

~7~5~7 (a) I~ t~
~ o 48 g. ~2 moîa) of ~odium hydride lwere added 250 ml. o~
dry ether an~ 236 ~ (2 mol~) oî ~thyl carbonste. Under refl~x9 ~r~ ~dded 114 g. (1 mol) of 2-heptanone in 250 ml. oî etherg drop by-drop over a period o~ 7 hour~. Heatin~ WaQ maintained ~or 12 hour~t and the reaction medium ~ cooled in an ice bath.
A~ter that~ 125 ml, OI glacial ~cetic acid were added drop~by drop9 while light refluxing W~9 maintained9 aîter which water W88 10 introduced ~o ~ to completely dlssolve the precipitate" ~he organic phs~e wa~ decanted out9 ~a~hed tvith a solution o~ ~odium bicarbo~te amd then ~ith water to neutrality. ~he ethereal ~olution v~as dried~ concentrated and di~tilled.
In this manner, there were ob~ned 145.5 ~. o~ ethyl 3-o~o-c~prylate9 boiling at 122 - 124C under 20 mm/~Ig.
~i01d: about 7B9to~
n22 = 1.4320 N~MoR~ Spectrum: ~; = 304 ppm (_CO_CH2 C0-) ~b) ~:~
To 93 g~, (0.5 mol) of ethyl 3~o:~o-caprylate9 prepared as previou~lsr de~cribed9 cooled in an i~e bsth9 Yver~ sdded9 drop by-drop~ 200 mlO of sodium hydroxyde. ~he mixture was ~tirr~d at room-temper~turc until the ~e~atin~ oil di~appeared (about 7 hour3). The ~olution ~a~ extracted ~vith ether and t~e aqueou~
pha~e wa0 acidi~ied with 10%~hydrochlor~c aoid ~ h provided a - wl~ite precipitate O Thia precipi tate ~ ~uction-~iltered~ waehed twice with ~old water and recry~tallized from petroleum ether~ to gi~e 70 g~ (Y~eld :86~) of 3-oxo-caprylic acid (MoP~ 73~74C~) in the :fo~ of white ~lake~ o a solution of 90 g,. (0',~57 mol) o~
30 thi~ acid in 360 ml~ of methylene chlorlde ~ere ~dded9 drop-by-drop and ~t 25Ct 8207 go of thionyï chloride di~olved in 45 mlO
o~ methylene ¢hloride. The Dlixture waæ ~tirred ~or 7 hours th~

' .,~.
.

~C176~3 ol allowed to stand at room-temperature for 65 hours. The solvent was eliminated and the residue was distilled.
In this manner, there were obtained 81 g. of l-chloro-2-heptanone in the form of a pale yellow oil which is homogeneous in thin layer chromatography.

BDP~: 86 - 87C (under 20 mm/H~g).
- n25 = 1. 4400 N.M.R. Spe~trum : (CDC13) : ~= 4.1 ppm (ClCH2-CO-) = 2.5 ppm (-CO-CH2-) ' (c) 2-Oxo-hePtyl-triphenylphQ ~h~nium~ hl ~ i~e This compound was prepared by following the same procedure as that described in Example 1 B, (b).
(d) l-Triphenylphosphoranylidene-2-heptanone This compound was prepared by following the same procedure as that~described in Example 1 B, (c).
C - Preparation of DL-~carboethoxy-l-hexyl-5-(3'-hydroxy-1'-octen-~E)-yl)-2-pyrrolidinone (a) DL-~-Carboethoxy-l-hexyl-2'-tetrahydropyranyl-5-oxymethyl-2-pyrrolidinone A mixture of 19.9 g. (0.1 mol) of DL-2'-tetrahydro~

pyranyl-S-oxymethyl-2-pyrrolidinone, prepared as described in Example 1 C, (c), 3.9 g. (0.1 mol) of sodium amide and 400 ml. of dry toluene was heated for one hour. After cooling, there was added, drop-by-drop, a solution of 23.7 g. (0.1 mol) of ethyl 7-bromoheptanoate, prepared as previously described, in 50 ml. of dry toluene. The reaction medium was refluxed for 24 hours and then poured into 500 ml. o~ iced water. The organic phase was washed with water saturated with sodium bicarbonate and then with pure water to neutrality. After drying, the solvents were elimintated.
In this manner, there were obtained 32 g. of DL-~-carbo-ethoxy-l-hexyl-2'-tetrahydropyranyl-5-o~methyl-2-pyrrolidinone in the ' ' . . :.

6 5~

form o~ ~n oil which ~as almost pur~.
Yield : 90%
~ hrther purificat~on WaE e~seted by ¢hromatogr~phy on a ~ilica gel colum~t An inltia~ elution wa8 c~rriad o~t ~ith hexane to eliminate the ethyl 7-bromoheptanoate which had not reaote~ and a ~econd ~lutio~ ~ith ben3ene ~ eluent~ which provided the d~ired produ~t with a ~ery high degree o~ purity~
Rf = 0~5 (thin layer ohromatography ~ith acet~ne~n~thylene chloride 20/8~ ol~ent) 10 I.R.' Specitrum (film) : C0 (e~ter) at ?735 cm ~
~0 (amide) at 1690 cm 1 a o_c at 10~0 cm~1 .
N.M,iR~t Spectrum (CDCl3) ~ 25 ppm (CH3-cH~-ot - 401 ppm (-CH2-0) - 496 ppm (O_CH_0) (b) ~ ~ =h~ h:Y:a:::::::
l$di~on,e A solution oP 17.75 g. (0,05 ~ol) of D~ carboethoxy-1-hexyl-2't~trahyd~opyranyI-5~oxym~thyl 2-pyrrolidinone,r pre-p~re~ as previou~ly ~eacribed, 100 ml~` o~ eth~nol ~nd 50 ~l~ o~
hydroehlorlc a~id 1~ w~ stlrred at room-tempera~ur~ ~or 3 hour~
The ethanol Wa9 ellm~nated u~der ~8auu~, ~h2 r~idue wa3 wa~h~d with water9 ~atur~ted w~h ~odium bioarbo~ate and tben with 200 ml. o~ pure ~aterO~ A~ter drying, the ~ol~ent~ wero eli~n~ted, which provlded 10 g. o~ sn oil~ '~hl3 o$1 ~ae puri~ied by chromatograph~ on a ~llical g~l oolumn and the ~puriti~ were : eliminated with chloroform ~ elution sge~t. ~lution wa~ then carried out with ~ 20/80 aceto~e/methylene chlor~de m~%ture a~
~o~vent.' In thi~ manner~ there ~ere obta~ned 9~2 g. of D~
a~rboethoxy-1~hex~l~5 hydro~ymRthyl_2-pyrrolidlno~e in the ~or~ o~
an oil whioh i9 homogeneou~ in thin layar chrom~tography.

"
. ' . . ~
i , .

Yield : ~7%
Rf ~ 0.8 (thin layer chromatography with benzene/methanol/acetic acid 79/14/7 as solvent) I.R. 5pectrum (film) : OH at 3380 cm 1 CO (ester) at 1730 cm~
CO (amide) at 1650 cm N.M.~. Spectrum (CDC13) : ~= 1.25 (CH3-CH2) = 4.1 (CH20) = 4.3 ~OH) (c) DL-~-Carboethoxy-l-hexyl-5-carboxaldeh~ -2-~ olidinone A mixture of 5.42 g. (0~02 mol) of DL-~-carboethoxy-l-hexyl-5-hydroxymethyl-2-pyrrolidinone, prepared as previously described, 12.4 9. of dicyclohexylcarbodiimide, 120 ml. of anhydrous benzene and 60 ml. of anhydrous dimethylsulphoxide was cooled to 0C. To this mixture was added, drop-by-drop, 1.06 mol of dichloracetic acid. After this operation, the reaction medium was stirred at room-temperature for 7 hours and 4.4 g. of oxalic acid were added by small fractions at 0C. The ~20 mixture was allowed to react for 30 minutes at the same tempéra-ture and then filtered. The precipitate was washed with toluene and the filtrate was taken up with 300 ml. of chloroform. The chloroform solution was washed with water saturated with sodium bicarbonate and then with distilled water to neutrality. After drying, the solvents were eliminated under vacuum. The oil so obtained was taken up in 50 ml. of etherO After filtration, the filtrate was chromatographed on a silica gel column.
An initial elution was carried out with methylene chloride to eliminate impurities (dicyclohexylcarbodiimide, dimethylsulphoxide etc...) and then with a 20/80 acetone/
methylene chloride mixture.

In this manner, there were obtained 5 g. of DL-~-. .
.

~6~

carboethoxy-l-hexyl-5-carboxaldehyde-2-pyrrolidinone in the form of a brown oil ti-trating 94.1 ~0 of purity.
Yield: 92 %
I.R. Spectrum (CHC13) : CO (ester) at 1730 cm CO (amide) at 1670 cm N.M.R. Spectrum (CDC13) : = 1.1 ppm (CH3) = 4.9 ppm (OH enol) = 9.65 ppm (CHO) (d) DL-~ Carboethox_ l-hex~1-5-(3~-oxv-l'octen-(E)-~ -2-pyrrol dinone A mixture of 5.38 g (0.02 mol) of DL-~-carboethoxy-1- hexyl -5-carboxaldehyde-2-pyrrolidinone, prepared as described above, 7.08 g. (0.02 mol) of 1-triphenylphosphoranylidene-2-heptanone prepared as previously described, 120 ml. of anhydrous dioxane and 240 ml. of anhydrous benzene was refluxed for 12 hours.
j The solvents were eliminated under vacuum and the residual oil was taken up in 20 ml. of ether. After filtration, ; 20 the filtrate provided 7 g. of an oil which partially crystallized after being allowed to stand at room-temperature. Two chromat~-, graphies on silica gel column provided an oil which still contained aromatic impurities. These impurities were eliminated , by chromatography on silica gel plates using a 20/80 ace-tone/
'~ methylene chloride mixture as elution agent (Rf = 0.8).
In this manner, there were obtained 6.5 g. of DL ~
-' carboethoxy-l-hexyl-5-(3'-oxo-1'-octen-(E)-yl)-2-pyrrolidinone (99% of purity).

Yield: 89%
30 I.R. Spectrum (CHC13) : CO (ester) at 1725 cm CO (amide and -CH=CH-CO) at 1675 cm C = C at 1630 cm 1 , ~:

, . ~ :':
.

7t~587 N.M.R. Spectrum (C~C13) : ~= 0.9 ppm (CH3) = 1.25 ppm (CH3 ester) - 1.4 ppm (C11N2) = 4.2 ppm (CH2-0) = 6.2 and 6.7 ppm (-CH=CH-CO) (e) DL-~-Carboethoxy-l-hexyl-5-~3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinone or DL-8-aza~ deox~-PGE
ethyl ester A solution of 3.65 g. (0.01 mol) of DL-~-carboethoxy-1-hexyl-5-~3' oxo-1'-octen-(E)-yl)-2-pyrrolidinone, prepared as described above, in 150 ml. of anhydrous dimethoxyethane was cooled to 0C. To this solution, 0.700 g. of sodium boro-hydride was added by small fractions and the resulting mixture was allowed to react at 3C for 2 hours. After this operation, 10 ml. of iced water were added ~ollowed by 20 ml. of 2~-solution of tartarlc acid. The mixture was extracted with methylene chloride and the organic phase was washed several times with pure water in order to eliminate the traces of dimethoxyethane and then with water saturated with sodium chloride. After drying, the solvents were eliminated under vacuum leaving an oily residue which contained the desired product at 98.8% of purity.
In this manner, there~was obtained DL-~-carboethoxy-l-hexyl-5-(3'-hydroxy~ octen-(E)-yl)-2-pyrrolidinone.
Rf = 0.33 ~thin layer chromatography with acetone/methylene chloride 20/80 as solvent) - I.R. Spectrum (CHC13) : OH at 3420 cm CO (ester) at 1730 cm ]
CO (amide) at 1670 cm 1 N.M.R. Spectrum (CDC13) : ~= 4.15 ppm (O-CH2) H
= 5.65 ppm ( /C = C

: .. , ~ ,: . . . . . .

76 5~ ~
- O09 ppm (CH3) - 2,3 ppm (OH) .

E~
For th~ particular purpo~e of tre~ting affection~ of th~ re~plratory tract9 a~ aerosol ~a~ prep~red in a~c~rdance ~ith $nown technique~ comprising a~ a~ti~e ingredie~t 2 m~ of DI_~
: carboxy-l-h~xyl~5-~3~-hydroxy~ oeten-(E)-yl)-2-pyrrolidinone together ~lth an ~nert propellant and 10 g. o~ ethanolO

:
.~ .
.

' : . :
.

Claims

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 prostaglandin derivatives having the general formula:

(I) wherein R represents hydrogen, methyl or ethyl, which comprises:
a) saponifying an ester of the general formula:

(II) wherein R1 represents a linear or branched alkyl group contain-ing from 1 to 7 carbon atoms, in an alcoholic medium by means of an alkali and hydrolising the resulting alkali metal salt of the compound of formula (II) by means of a strong acid, to form a prostaglandin derivative of formula (I) in which R is hydrogen, or b) treating a ketone of the general formula:

(III) wherein R2 represents methyl or ethyl, with a reducing agent in an inert medium to provide a prostaglandin derivative of formula (I) in which R is methyl or ethyl.

2. Process according to claim 1, wherein an ester of the general formula (II) in which R1 has the aforesaid meanings is saponified in an alcoholic medium by means of an alkali and the resulting alkali metal salt of the compound of formula (II) is hydrolised by means of a strong acid.

3. Process according to claim 2, wherein DL-5-hydroxymethyl-2-pyrrolidinone of the formula:

(VI) is treated with 2,3-dihydropyran in an inert medium and in the presence of an acid to obtain DL-2'-tetrahydropyranyl-5-oxymethyl-2-pyrrolidinone of the formula:

(VII) which is reacted with an alkyl 7-bromoheptanoate of the formula:

(VIII') in which R1 represents a linear or branched alkyl group contain-ing from 1 to 7 carbon atoms, in a solvent and in the presence of sodium amide to form a compound of the formula:

(IX') which compound of the formula (IX') is then hydrolysed in an acid medium and in the presence of a solvent to yield the corresponding DL-.omega.-carboalkoxy-1-hexyl-5-hydroxymethyl-2-pyrrolidinone of the formula:

(X') in which R1 has the aforesaid meaning, the primary alcohol function of which is oxidised to an aldehyde function in an inert medium under the combined action of dimethylsulphoxide, dicyclohexylcarbodiimide and dichloroacetic acid, thereby obtain-ing DL-.omega.-carboalkoxy-1-hexyl-5-carboxaldehyde-2-pyrrolidinone of the formula:

(XI') which is then subjected to a Wittig reaction with 1-triphenyl-phosphoranylidene-2-heptanone of the formula:

(XII) so as to form the corresponding DL-.omega.-carboalkoxy-1-hexy1-5-(3'-oxo-1'-octen-(E)-yl)-2-pyrrolidinone of the formula:

(III') in which R1 has the aforesaid meaning, which ketone of the formula (III') is treated with a reducing agent in an inert medium to provide a prostaglandin derivative of the aforesaid formula (II), the said derivative of the formula (II) is saponified in an alcoholic medium by means of an alkali and the resulting alkali metal salt of the compound of formula (II) is hydrolised by means of a strong acid.

4. Process according to claim 3, wherein the compound of formula (VI) is obtained starting from DL-pyroglutamic acid of the formula:

(IV) which is esterified with ethanol in the presence of an acid to provide ethyl DL-pyroglutamate of the formula:

(V) and the ester of formula (V) is reduced with sodium borohydride in a solvent.

5. Process according to claims 2 or 3, wherein the alcoholic medium is methanol.

6. Process according to claims 2 or 3, wherein the alkali is sodium hydroxide.

7. Process according to claims 2 or 3, wherein the strong acid is hydrochloric acid.

8. Process according to claims 2 or 3, wherein R1 represents methyl or ethyl.

9. Process according to claim 3, wherein the reducing agent is sodium borohydride.

10. Process according to claim 9, wherein the reduction is effected at a temperature between 0° and +5°C.

11. Process according to claim 1, wherein a ketone of the general formula (III) in which R2 has the aforesaid meaning treated with a reducing agent in an inert medium.

12. Process according to claim 11, wherein DL-5-hydroxymethyl-2-pyrrolidinone of the formula:

(VI) is treated with 2,3-dihydropyran in an inert medium and in the presence of an acid to obtain DL-2'-tetrahydropyranyl-5-oxymethyl-2-pyrrolidinone of the formula:

(VII) which is reacted with an alkyl 7-bromoheptanoate of the formula:
(VIII) in which R2 represents a methyl or ethyl radical, in a solvent and in the presence of sodium amide to form a compound of the formula:

(IX) which compound of the formula (IX) is then hydrolysed in an acid medium and in the presence of a solvent to yield the corresponding DL-.omega.-carbomethoxy- or carboethoxy-1-hexyl-5-hydroxymethyl-2-pyrrolidinone of the formula:

(X) in which R2 has the aforesaid meaning, the primary alcohol function of which is oxidised to an aldehyde function in an inert medium under the combined action of dimethylsulphoxide, dicyclohexylcarbodiimide and dichloroacetic acid, thereby obtaining DL-.omega.-carbomethoxy- or carboethoxy-1-hexyl-5-carboxaldehyde-2-pyrrolidinone of the formula:

(XI) which is then subjected to a Wittig reaction with 1-triphenyl-phosphoranylidene-2-heptanone of the formula:
(XII) so as to form the corresponding DL-.omega.-carbomethoxy- or carboethoxy-1-hexyl-5-(3'-oxo-1'-octen-(E)-yl)-2-pyrrolidinone of the aforesaid formula (III), and the compound of the formula (III) thus obtained is treated with a reducing agent in an inert medium.

13. Process according to claim 12, wherein the compound of formula (VI) is obtained starting from DL-pyroglutamic acid of the formula;

(IV) which is esterified with ethanol in the presence of an acid to provide ethyl DL-pyroglutamate of the formula:

(V) and the ester of formula (V) is reduced with sodium borohydride in a solvent.

14. Process according to claim 11, wherein R2 is methyl.

15. Process according to claim 12, wherein R2 is methyl.

16. Process according to claim 15, wherein the compound of formula (VI) is obtained starting from DL-pyroglutamic acid of the formula:
(IV) which is esterified with ethanol in the presence of an acid to provide ethyl DL-pyroglutamate of the formula:
(V) and the ester of formula (V) is reduced with sodium borohydride in a solvent

17. Process according to claim 11, wherein R2 is ethyl.

18. Process according to claim 12, wherein R2 is ethyl.

19. Process according to claim 18, wherein the compound of formula (VI) is obtained starting from DL-pyroglutamic acid of the formula:

(IV) which is esterified with ethanol in the presence of an acid to provide ethyl DL-pyroglutamate of the formula:

(V) and the ester of formula (V) is reduced with sodium borohydride in a solvent.

20. Process according to claims 11 or 12, wherein the reducing agent is sodium borohydride.

21. Process according to claims 11 or 12, wherein the inert medium is dimethoxyethane.

22. Process according to claims 11 or 12, wherein the reduction is effected at a temperature between 0° and +5°C.

23. Process according to claims 11 or 12, wherein the reduction is effected at 0°C.

24. Prostaglandin derivatives having the general formula:

(I) wherein R represents hydrogen, methyl or ethyl, whenever obtained by a process according to claim 1 or its obvious chemical equivalents.

25. DL-.omega.-carboxy-1-hexyl-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinone, whenever obtained by a process according to claims 2, 3 or 4, or their obvious chemical equivalents.

26. Prostaglandin derivatives according to claim 24, wherein R is methyl or ethyl, whenever obtained by a process according to claim 11 or its obvious chemical equivalents.

27. Prostaglandin derivatives according to claim 24, wherein R is methyl or ethyl, whenever obtained by a process according to claim 12 or its obvious chemical equivalents.

28. Prostaglandin derivatives according to claim 24, wherein R is methyl or ethyl, whenever obtained by a process according to claim 13 or its obvious chemical equivalents.

29. DL-.omega.-carbomethoxy-1-hexyl-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinone, whenever obtained by a process according to claims 14, 15 or 16, or their obvious chemical equivalents.

30. DL-.omega.-carboethoxy-1-hexyl-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinone, whenever obtained by a process according to claims 17, 18 or 19, or their obvious chemical equivalents.