IL32621A - Prostaglandins and analogs thereof - Google Patents

Description

PROST GL NDIN AND ANALOGS THEREOF This invention relates to compositions of matter, and to methods and intermediates for producing them. In particular, the several aspects of this invention relate to novel analogs of prostaglandin Ei (PGEi), to novel analogs of prostaglandin Fi (PGFia and PGFif¾), to novel analogs of prostaglandin Ai (PGAi), to novel methods for producing PGEi, PGFia* PGFip, PGAi, and the novel analogs thereof, and to novel chemical intermediates useful ί n those methods .

PGEi has the following structure: GFia has the following structure: PGF^ has the following structure: PGAi has the following structure: See Nature, 212, 28 (1966) for discussion of the stereochemistry of PGEi, PGFia, GF^, and PGA .

In formulas I, II, III, and IV, as well as in the formulas the plane of the cyclopentane ring. Heavy sol id' l ine attachments to the cyclopentane ring ndicaze substituents in beta configuration, i .e., above the plane of the cyclopentane ring.

PGEi, PGFia, and PGAi are derivatives of prostanoic acid which has the following structure and atom numbering: A systematic name for prostanoic acid is 7" [ (2β-οοίγ1 )cyclo-pent-l -yl ]heptanoic acid.

Compounds similar to formula V but with carboxyl-termi nated s ide chain attached to the cyclopentane ring in.beta configuration are designated 8-iso-prostanoic acids , and have the following formula: A systematic name for iso-prostanoic acid is 7_ [ (2P-oc.tyl )cyclo-pent-l^-yl ]heptanoic acid.

Prostaglandin E and its analogs produced according to the novel methods of this invention are represented by the formula: wherein Ri is hydrogen, alkyl of one to 8 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or ethyl substituted in the β-pos i t ion wi th substituted with zero to 3 fluoro; wherein R3 and R4 are hydrogen or alkyl of one to carbon atoms, inclusive; wherein CnHen is alkylene of one to 8 carbon atoms, inclusive, substituted with zero to 2 fluoro; and wherein indicates attachment of the -CnH2n_C00Ri moiety to the ring in alpha or beta configuration, and pharmacologically acceptable salts thereof when R_ is hydrogen.

Prostaglandin F and its analogs produced according to the novel methods of this invention are represented by the formula: wherein i, R2, R3, R4, and CnH2n are as defined above for formula VI I, and indicates attachment of the hydroxy and -CnH2n_C00Ri moieties to the ring in alpha or beta configuration, and pharmacologically acceptable salts thereof when Ri is hydrogen. Included in formula VI I I are compounds wherein the configuration of the hydroxy and -CnH2n_C00Ri moieties are, respectively, , , ,β, β, , and β,β.

Prostaglandin A, and its analogs produced according to the novel methods of this invention are represented by the formula: wherein Rx, R2, R3, R4, and CnH2n are as defined above for formula VI I , and indicates attachment of the -CnH2n-G00Ri moiety to the ring in alpha or beta configuration, and pharmacologically acceptable salts thereof when Ri is hydrogen. hydroxy is in or S conf i gu rat i on, and also both the racemic form (dl ) and the separate optical ly active enantiomers (d and 1 ).

Formula VI I represents PGEi when Ri, R3, and R4 are each hydrogen, R2 is pentyl, CnH2n is hexamethylene, the attachment of -CnH2n~C00 i to the cyclopentane ring is in alpha configuration, and the conf iguration of the side chain hydroxy is S.

Formula VI I I represents PGFi when Ri, R3, and R4 are each hydrogen, R2 is pentyl , CnH2n is hexamethylene, the attachments of hydroxy and -CnH2n-C00Rx to the ring are both in alpha configuration, and the configuration of the side chain hydroxy is S.

Formula VI I I represents PGFi when Ri, R3, ahd R4 are each hydrogen, R2 is pentyl , CnH2n is hexamethylene, the attachment of hydroxy to the ring is in beta conf iguration, the attachment of -CnH2n_C00R1 to the ring is in alpha configuration, and the configuration of the side chain hydroxy is S.

Formula IX represents PGAi when R1 } R3, and R4 are each hydrogen, R2 is pentyl , CnH2n is hexamethylene, the attachment of -CnH2p-C00Ri to the ring is in alpha configuration, and the configuration of the side chain hydroxy is S.

Al l compounds encompassed by formulas VI I , VI I I , and IX have the -CH=CR4CR2R30H side chain attached to the ring in beta con-figuration, with a trans OC l inkage, both as shown in those formulas.

With regard to formulas VI I , VI M , and IX, examples of alkyl of one to 4 carbon atoms, inclusive, are methyl , ethyl , propyl , butyl, and isomeric forms thereof. Examples of alkyl of one to 8 carbon atoms, inclusive, are those given above, and \ V. includes a 1 ky 1 -subs t i tuted cycloalkyl, are cydopropyl, 2-methyl cyclopropyl , ,2-d i methyl cycl opropyl .., 2,3~cliethylcyc1o-propyl , 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl , 3" propyl cyclobutyl , 2,3> -triethylcyclobutyl , cyclopentyl, 2,2-d imethyl cycl opentyl , J-pentylcyclopentyl , J-tert-butylcyclo-pentyl, cyclohexyl , - tert-butylcyclohexyl , J- isopropylcyclo-hexyl , 2,2-d imethyl cyclohexyl , cycloheptyl, cyclooctyl, cyclo-nonyl , and cyclodecyl . Examples of aralkyl of 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl, 1-phenyl ethyl , 2-phenyl propyl , -pheny Ibutyl , 3-phenylbutyl , 2- (l-naphthylethyl ) , and 1- (2-naphthylmethyl ) . Examples of phenyl substituted by one to 3 chloro or alkyl of one to carbon atoms, inclusive, are p-chlorophenyl , m-chlorophenyl , o-chlorophenyl , 2, -d ichloro-phenyl , 2, ,6-trichlorophenyl , p-tolyl, m-tolyl, o-tolyl, p-ethylphenyl, p-tert-butylphenyl , 2 , 'd imethyl phenyl , -chloro-2-methyl phenyl , and 2, -dichloro-3~methylphenyl .

Examples of alkylene of one to 8 carbon atoms, inclusive, are methylene, ethylene, trimethylene, tetramethylene, penta-methylene, hexamethyl ene, heptamethyl ene, octamethyl ene, and isomeric branched chain forms thereof.

Examples of alkyl of one to 8 carbon atoms, inclusive, substituted with one to 3 fluoro, are 2-f luoroethyl , 2-fluoro-butyl, 3~f luorobutyl , -f luorobutyl , 5-f luoropentyl , -fluoro- -methyl pentyl , 3"f luoroisoheptyl , 8-f luorooctyl , 3> -dif luoro-butyl, , 4-di f luoropentyl , 5, 5-d i f luoropentyl , and 5,5,5'tri-f 1 uoropentyl .

Examples of alkylene of one to 8 carbon atoms, inclusive, substituted with one or 2 fluoro, have the formulas -CH2CHF-, CH3 -CH2CF2", - CH2CH2 CHFCH2 ~ , ~ CH2CH2 CH CF " , -CH2CHCH2CHF- , -CH2CH2CHaCHFCHF-, -CHsCHsCHsCh CHsCHF- , -CH2CH2CH2CH2CH2CF2- , PGEi, PGF ia, PGF^, and PGAi, and their esters and pharmaco logical 1 y acceptab le salts., are extremely potent in causing various biological responses. For that reason, these compounds are useful for pharmacological purposes. See, for example, Bergstrom et al ., Pharmacol . Rev. 20, 1 (1968), and references cited therein. A few of those biological responses are systemic arterial blood pressure lowering in the case of PGEi, GF^, and PGAi as measured, for example, in anesthetized (pentobarbital sodium) pento 1 i n i urn- t reated rats with indwel l ing aortic and right heart cannulas ; pressor activity, s imi larly measured, for PGFia stimulation of smooth muscle as shown, for example, by tests on strips of guinea pig i leum, rabbit duodenum, or gerbi l colon; potentiation of other smooth muscle stimulants ; ant i 1 i pol yt ic activity as shown by antagonism of e i nephr i ne- ί nduced mobi l ization of free fatty acids or inhibition of the spontaneous release of glycerol from isolated rat fat pads ; inhibition of gastric secretion in the case of PGEi and PGAi as shown in dogs with secretion stimulated by food or histamine infusion; activity on the central nervous system; decrease of blood platelet adhesiveness as shown by platelet-to-glass adhesiveness, and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimul i , e.g. arterial injury, and various biochemical stimul i , e.g. , ADP, ATP, serotonin, thrombin, and col lagen.

Because of these biological responses, these known prostaglandins are useful to study, prevent, control , or al leviate a wide variety of diseases and undesi rable physiological condition in birds and mammals, including humans, useful domestic animals, pets, and zoological speciments, and in laboratory animals, for example, mice, rats, rabbits, and monkeys . this purpose, the compounds are used in a dose range of about 10 g. to about 10 mg . per ml . of a pharmacological l.y su i tab le l iquid vehicle or as an aerosol spray, both for topical appl ication.

GEi and PGAx are useful in mammals, including man and certain useful animals, e.g., dogs and pigs, to reduce and control excessive gastric secretion, thereby reducing or avoiding gastrointestinal ulcer formation, and accelerating the heal ing of such ulcers already present in the gastrointestinal tract. For this purpose, the compounds are injected or infused intravenously, subcutaneous 1 y, or intramuscularly in an infusion dose range about 0.1 g. to about 50 μ . per kg. of body weight per minute, or in a total daily dose by injection or infusion in the range about 0.1 to about 20 mg. per kg. of body weight per day, the exact dose depending on the age, weight, and condition of the patent or animal , and on the frequency and route of admi n i s trat ion .

PGEi, PGAi, PGFm, and PGF^ are useful whenever it is desired to inhibit platelet aggregation, to reduce the adhesive character of platelets, and to remove or prevent the formation of thrombi in mammals, including man, rabbits, and rats. For example, these compounds are useful in the treatment and prevention of myocardial infarcts, to treat and prevent post-operative thrombosis, to promote patency of vascular grafts fol lowing surgery, and to treat conditions such as atherosclerosis, arteriosclerosis, blood clotting defects due to l ipemia, and other cl inical conditions in which the underlying etiology is associated with l ipid imbalance or hyper 1 i p idem i a . For these purposes, these compounds are administered systemical 1 y, e.g., intravenously, subcu taneous 1 y , intramuscularly, and in the form administration is preferred. Doses in the range about 0.004 to about 20 mg. per kg. of body weight per day are used,, the exact dose depending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration.

PGEi, PGAi, PGFia, and PGFi are especially useful as additives to blood, blood products, blood substitutes, and other fluids which are used in artificial extracorporeal circulation and perfusion of isolated body portions, e.g., l imbs and organs, whether attached to the original body, detached and being preserved or prepared for transplant, or attached to a new body. During these circulations and perfusions, aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. This blocking is avoided by the presence of these compounds. For this purpose, the compound is added gradually or in single or multiple portions to the circulating blood, to the blood of the donor animal, to the perfused body portion, attached or detached, to the recipient, or to two or all of those at a total steady state dose of about .001 to 10 mg . per l iter of circulating fluid. It is especially useful to use these compounds in laboratory animals, e.g., cats, dogs, rabbits, monkeys, and rats, for these purposes in order to develop new methods and techniques for organ and l imb transplants.

PGEi is extremely potent in caus ing stimu lation of smooth muscle, and is also highly active in potentiating other known smooth muscle stimulators, for example, oxytocic agents, . e . g . , oxytocin, and the various ergot alkaloids including derivatives and analogs thereof. Therefore PGEi is useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators, for example, to control or prevent atonic uterine bleeding after abortion or delivery, to aid in after abortion or del ivery at a dose in the range about 0.01 to about 50 g. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range 0.01 to 2 mg. per kg. of body weight per day, the exact does depending^on the age, weight, and condition of the patient or animal .

PGEi, PGA, and PGFi.p are useful as hypotensive agents to reduce blood pressure in mammals, including man. For this purpose, the compounds are administered by intravenous infusion at the rate about 0.01 to about 50 g. per kg. of body weight per minute or in single or multiple doses of about 25 to 500 g. per kg. of body weight total per day.

GFxa and PGFip are useful in place of oxytocin to induce labor in pregnant animals, including man, cows, sheep, and pigs, at or near term, or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the compound is infused intravenously at a dose 0.01 to 50 g. per kg. of body weight per minute until or near the termination of the second stage of labor, i .e., expulsion of the fetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to 6o hours after the membranes have ruptured and natural labor has not yet started.

As mentioned above, PGEi is a potent antagonist of ep i neph i ne- i nduced mobil ization of free fatty acids. For this reason, this compound is useful in experimental medicine for both in vitro and in vivo studies in mammals, including man, rabbits, and rats, intended to lead to the understanding, pre-vent ion, symptom alleviation, and cure of diseases involving The compounds other than PGEi, PGFia, PGF^, and PGA, encompassed by formulas VI I , VI I I , and IX also cause one or more of the above biological responses. However, the natural prostaglandins, PGEi, PGF1CtJ and PGAi, and the PGEi reduct i on. product PGFi , uniformly cause multiple responses even at low doses.

For example, PGEi causes vasodepress ion and smooth muscle stimulation at the same time that it exerts its anti 1 ipot ytic activity. In striking contrast, the formula VI I , VI M , and IX compounds other than these natural prostaglandins are much more specific in causing pros tagl and i n- 1 i ke biological responses.

Each of the formula VI I , VI I I , and IX compounds other than GEi, GFia, PGFip, and PGEi is used in place of one of the latter for at least one of the pharmacological purposes indicated for the latter, and is su rpr is i ngl y and unexpectedly more useful for that purpose because it has a different and narrower spectrum of activity than the natural prostaglandin, and therefore is! more specific in its activity and causes smal ler and fewer undes ired side effects than the natural prostaglandin. Moreover, some of these unnatural prostaglandins have greater potency in causing one or more of the above-described biological responses than the corresponding natural compound within the scope of the same generic formula, VI I , VI I I , or IX.

To i l lustrate, in PGEX, the attachment of the -(CH2)e-G00H moiety* to the cyclopehtane ring of formula VI I is in alpha con-figuration.. The corresponding compound wherein said moiety is in beta conf igurat ion,,, i .e, , 8-iso-PGEi, has only a small fraction of the activity of PGEi in stimulating smooth muscle and in lowering blood pressure, whi le sti ll having substantial inhibi ory action toward platelet aggregation and the epine-phrine- induced mobi 1 ization of free fatty acids. i .e., 15(R)-PGEi, the compound has only a smal l fraction of the activity of PGEi in lowering blood pressure and in antagonism toward the epinephrine- induced mobil ization of free fatty acids, while sti ll having substantial smooth muscle stimulatory activity.

Substitution of PGEX at the ^"Position (see formula V) with fluoro gives a compound with about the same smooth muscle activity as PGEi but with less than one-third of the activity of PGEi in lowering blood pressure.

Increase of the alkyl chain of PGEi (R2 in formula VI I ) from pentyl to hexyl gives a compound with over four times the activity of PGEi in inhibiting the ADP-induced aggregation of platelets, about 2 $ more activity in stimulating smooth muscle, but less activity than PGEi in lowering blood pressure.

Although all of the compounds encompassed by formulas VI I, VI I I , and IX are useful for one or more of the purposes stated above for PGEi, PGFia, PGF^, and PGAi, certain of those compounds are especially useful because they have a substantial 1 y longer duration of activity than other compounds within the generic formulas, including PGEi, PGFi ^ P F^, and PGAi, and because they can be administered oral ly, sub 1 i ngua 11 y, ihtra-vaginal ly, or rectal 1 y, rather than by the usual intravenous, intramuscular, or subcutaneous injection or infusion as indicated above for the uses of these known prostaglandins and the other compounds encompassed by formulas VI I , VI I I , and IX. These qual ities are advantageous because they facil itate maintaining uniform levels of these compounds in the body with fewer, shorter, or smal ler doses, and make possible self-administration by the patient.

These special compounds have the following formulas: CH )p-CH Y wherein m is one to 6, p is zero to 1, n is one to 8, a is zero to 4, b is 5 to 7, and e is 6 or 7; wherein Ri3 is hydrogen, lk l f n o 4 arbon a oms inclusive or a harmacolo icall atoms; wherein Y is isobutyl, tert-butyl, 3, 3~d i f 1 uorobuty 1 , 4,4-d i f luorobutyl , or 4,4, 4-trif luorobutyl ; and wherein indicates attachment of the group, hydroxy, - (CH2 )n"C00Ri 3 , or - (CH2 )m-Z-C00Ri3j to the ring in alpha or beta position. Each formula includes compounds wherein the side chain hydroxy is in R or S configuration.

Examples of alkyl of one to carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, and isomeric forms thereof.

Pharmacologically acceptable cations within the scope of Ri3 in formulas X to XXI I are quaternary ammonium ions or the cationic form of a metal, ammonia, or an amine.

Especially preferred metal cations are those derived from the alkali metals, e.g., l ithium, sodium, and potassium, and from the alkal ine earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron, are within the scope of this invention.

Pharmacologically acceptable amine cations within the scope i3 in formulas X to XXI I are those derived from primary, secondary, or tertiary amines. Examples of suitable amines are methyl ami ne, d imethyl ami ne , t r imethyl am i ne, ethylamine, dibutyl-amine, tri i sopropy 1 am i ne , N-methyl hexy 1 am i ne, decylamine, do-decylamine, allylamine, crotylamine, cyclopentylamine, dicyclo-hexylamine, benzylamine, d ibenzy 1 ami ne, a-phenylethylami ne, β-phenylethylamine, ethyl ened i ami ne, d i ethyl enetr iam i ne, and l ike aliphatic, cycloal iphatic, and araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocycl ic amines, e.g., piperidine, morphol ine, pyrrol idine, piperazine, and lower-alkyl derivatives thereof, e.g., 1-methylpiperidine, 4-ethylmorphol ine, 1- isopropyl pyrrol idi he, 2-methyl pyrrol id i ne, 1,4-d imethyl p i peraz i ne, 2-methyl p i per i d i ne, and the like, as amine, N-butylethanolamine, 2-amino-l-butanol , 2-ami no-2-ethy'l -1,3-propaned iol , 2-ami no-2-methyl -1-propanol , tris (hydroxymethyl)? ami nomethane, N-phenylethanolamine, N- (p- tert-amyl phenyl )-d i ethanol ami ne, galactamine, N-methyl g 1 ucam i ne, N-methyl-glucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the 1 i ke .

Examples of suitable pharmacological l y acceptable quaternary ammonium cations within the scope of R13 in formulas X to XXI I are tetramethylammonium, tet raethyl ammon i urn, benzyl-trimethylammonium, phenyl t r i ethyl ammon i urn, and the l i ke.

In the case of Z, the divalent ethylene group, -CH2-CH2-, is substituted on either carbon atom, i .e., alpha or beta to the carboxylate function. For example, Z is -CH2-CHF-, -CHF-GH2-, -CH2-CF2-, -CF2-CH2-, -CHF-GHF- , -GH2-CH (CH3)- , -CH(CH3)-CH2-, -CH2-C(CH3)2-, -C (CH3)2-GH2- , -CH (CH3)-CH (CH3)- , and simi larly for ethyl , and for one fluoro and one methyl , one fluoro and one ethyl , and one methyl and one ethyl . Z is alternatively ethylene substituted on either carbon atom with propyl , isopropyl , butyl, isobutyl , sec-butyl , or tert-butyl .

Although al l of the compounds encompassed by formulas X to XXI I have the special advantages of long duration and oral , subl ingual intravaginal , and rectal routes of administration, there is a sti ll more l imited group of compounds encompassed by these formulas which have these qual ities in a particularly high degree. Those are the compounds which have a seven-carbon carboxyl terminated chain, i .e., m=4, and n=6, especial ly those with a total of 20 carbon atoms exclusive of branching, i .e. , p= , and a=l wherein Y is d i f luorobutyl or tr if luorobutyl , 2 when Y is isobutyl , and; 2 when Y is tert-butyl . Also regard-ing the possible variations in Z, those which give the greatest isobutyl, sec-butyl, or tert-butyl on the carbon atom alpha (adjacent) to the carboxylate function.

Also of particular value, importance, and uti l ity among the compounds encompassed by formula VI I I are compounds of the f o rmu 1 a : wherein i3 and are as defined above. These compounds are useful for the purposes assigned above to PGFia, but are surprisingly and unexpectedly more useful than PGFia for those purposes. It is known that PGFlct has substantial activity in raising blood pressure. The alpha-hydroxy isomer encompassed by formula XX I I I , 8- i so- PGFia, has only a small fraction of the pressor activity of PGFia. The beta-hydroxy isomer encompassed by formula XXI I I is also a mild pressor agent in striking contrast to PGFi which is a depressor agent. At the same time, these novel compounds, 8-iso-PGFia and 8-tso-PGFip and their salts and esters have substantial activity as nasal decongestants, as blood platelet aggregation inhibitors, and as oxytocics for labor inducement. Thus, these novel compounds of formula XXI I I are used for those purposes in place of PGFi with unexpected advantages since thei cardiovascular effects are similar to but substantial ly lower than those of PGFia.

PGEi, PGFta, GF^, and PGAi, and the other compounds encompassed by formulas VI I, VI I I , and IX, including the special compounds of formulas X to XXI I I are used for the above purposes in the free acid form, i .e., when i or R13 is hydrogen, in the ester form, or in pharmacologically acceptable salt form. When Howeve , it is preferred that the ester be a ky 1 of one to four carbon atoms, inclusive. Of those alkyl, methyl and ethyl are especially preferred; for optimum absorption of the compound by the body or experimental animal system.

Pharmacologically acceptab 1 e sal ts of these formula VI I to XXI I I compounds useful for the purposes described above are those with cations l isted above in the definition of 13.

As discussed above, the compounds of formulas VI I to XXI I I are administered in various ways for various purposes e.g. , intravenously, intramuscularly, subcutaneous 1 y, orally, intra-vaginally, rectal 1 y, sub 1 i gua 11 top i cal 1 y, and in the form of sterile implants for prolonged action.

For intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. For that purpose, it is preferred because of increased water solubi l ity that Ri in the formula VI I , VI I I, or IX compound and Ri3 in the formula X to XXI I I compound be hydrogen or a pharmacologically acceptable cation. For subcutaneous or intramuscular injection, sterile solutions or suspensions of the acid, salt, or ester form in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups, elixers, and simple solutions, with the usual pharmaceutical carriers are used for oral or subl ingual administration. For rectal or vaginal administration, suppositories prepared as known in the art are used. For tissue implants, a sterile tablet or silicone rubber capsule or other object containing or impregnated with the substance is used.

The compounds of formula VI I , including PGEi and the novel compounds of formulas X, XI I I , XVI , XIX, and XXI I , and the compounds of formula IX, including PGAi and the novel compounds The compounds of formula VI M , including PGFia, PGF^, and the novel compounds of formulas XI', . XIV, XVI I , XX, and XXI I I, ar prepared by carbonyl reduction of the corresponding hydroxy compounds encompassed by formula VI I , including PGEi and the novel compounds of formulas X, XI I I , XVI , XIX, and XXI I . In the case of the transformation of PGEi to a mixture of PGFia and PGFi , this reduction process is known. See, for example, Acta Chem. Scand. 16, 969 (1962 ) and J. Biol . Chem. 239, 4101 (1964). The other compounds encompassed by formula VI I , including the novel compounds of formulas X, XI I I , XVI , XIX, and XXI I are reduced with sodium borohydride by the same procedure to give th corresponding alpha and beta compounds of formula VI M , includin the novel compounds of formulas XI , XIV, XVI I , XX, and XXI I I .

The compounds of formula IX, including PGAi and the novel compounds of formulas XI I , XV, XVI I I , and XXI , are prepared by dehydration of the corresponding hydroxy compounds of formula VI I, including PGEi and the novel compounds of formulas X, XI I I , XVI , XIX, and XXI I . In the case of the transformation of PGEi to PGAi, this process is known. See, for example, Biochem.

Biophys. Res. Commun. 21, 13 (1965) and Pike et al ., Proc. Nobe Symposium I I, Stockholm (1966).; Interscience Publ ishers, New Yor pp. I62-I63 (1967). The other compounds encompassed by formula VI I , including the novel compounds of formulas X, XI I I , XVI, XIX and XXI I are dehydrated, with aqueous acetic acid, for example, to give the corresponding compounds of formula IX, including the novel compounds of formulas XI I , XV, XVI I I , and XXI .

According to one aspect of this invention, compounds of the Ei series, i .e.., compounds of formula VI I wherein Ri does not include hydrogen (hereinafter R7 rather than Ri), and compounds of the Ai series, i .e., compounds of formula VI I wherein i does CHART A I IX In Chart A, R2, R3, 4, CnH2n, and ^τ_ are as defined above. R7 has the same definition as Ri, above, except that hydrogen is not included. R6 is alkyl of one to 5 carbon atoms, inclusive. The reactants XXIV, XXV, XXVI , and XXVI I are all in exo con iguration with respect to the -CR4-CR2R3, -CR4-CR2R3, -C(0H)R4-C(0H)R2R3, and -C(0S02RS)R4-C(0S02R6)R2R3 moieties.

Chart A also shows the transformation of formula VI I final products to formula IX final products. As mentioned above, that transformation in the case of PGEi (VI I ) and PGAi (IX) is known, and is not part of this aspect of this invention.

The starting materials, i .e., olefin XXIV and epoxide XXV, are known to the art. See Belgian patent No. 702,^77; repMnted in Farmdoc Complete Specifications, Book 71^, No. 30,905* page 513, March 12, 1968.

In that Belgian patent, the reaction sequence leading to olefin XXIV is as follows : The hydroxy of 3-cyclopentenol is protected, for example, with a tet rahyd ropyranyl group. Then a diazoacetic acid ester is added to the double bond to give an exo-endo mixture of a b icyclo[3-1.0]hexane substituted at 3 with the protected hydroxy and at 6 with an esterified carboxyl . The exo-endo mixture is treated with a base to isomerize the endo isomer in the mixture to more of the exo isomer. Next, the carboxylate ester group at 6 is transformed to an aldehyde group or ketone group, -CH0 or -C=0, wherein R4 is as defined above. Then, said aldehyde group or said keto group is transformed by the Wittig reaction to a moiety of the formula which is in exo configuration relative to the bicyclo ring structure, and is the same as shown in formula XXIV, above. Next, the protective group is removed to regenerate the 3_hydroxy which is then oxidized, for example, by the Jones reagent, to give a wherein R2, R3, and R4 are as defined above, in exo configuration with respect to the -CR4=CR2R3. Final ly, compound XXVI I I is alkylated with an omega-ha 1 oes ter of the formula Br-CnH2ri-C00R7 or I -CnH2rrC00R7- , to give olefin XXIV, wherein CnH2n is as defined above, and the -CnH2n"C00R7 moiety is attached to the cyclopehtane ring in alpha or beta configuration. There are four isomers of olefin XXIV, exclusive of enantiomeric forms which double that number. Cis and trans forms with respect to the -CR4=CR2R3 moiety exist, and each of those can be alpha or beta with respect to the -CnH2n_C00R7 moiety. Said Belgian patent No. 702,477 describes the preparation of each isomer. The cis and trans isomers of the unalkylate ketone XXVII I are separated at that stage and the separate cis and trans isomers are each alkylated to an alpha and beta mixture of olefin XXIV, from which the alpha and beta isomers are separated. Alternatively, the cis-trans mixture of formula XXVIII is alkylated to a mixture of four isomers of olefin XXIV, alpha-cis, alpha-trans, beta-cis, and beta-trans, and the isomeric components of that mixture are separated from each other, or the mixture is used as such.

When it is desired to transform olefin XXIV to PGEi esters or PGAi esters according to Chart A by the novel methods of this invention, in olefin XXIV, R3 and R4 are hydrogen, R2 is pentyl, CnH2n >s hexamethyl ene, and the -CnH2n-C00R7 moiety is attached in alpha configuration. The 8-iso-PGEi esters or 8- iso-PGAx esters are prepared from the same olefins except that I - (CH2)6-COOR7 is required for the alkylation of YT to JCX-HV, and hexyl bromide is required to prepare the necessary Wittig reagent, hexyl t r i phenyl phosphon ium bromide, for example. Those intermediates are known in the art or are prepared by methods known in the art. The other Wittig reagents necessary to generate the generic moiety -CR4=CR2R3 wherein R2 , R3, and R4 are as defined generically above are prepared from compounds known in the art or which themselves are prepared by methods known in the art. Also, the other various omega-halo esters necessary to generate the generic moiety -CnH2n-C00R7 wherein CnH2n is as defined generical ly above are known in the art or can be prepared from methods known in the art.

To illustrate the avai labil ity of these intermediates to one of ordinary skil l in this art, consider the special compounds of formulas X to XXI I . The olefins of formula XXIV necessary as reactants to produce compounds of those formulas require as reagents the fol lowing ha 1 ides necessary to make the required Wittig reagents, CH3- (CH2 )p-CH2-X and Y- (CH2 )a"CH2-X , wherein X,/ Y, a, and p are as defined above. The CH3- (CH2 )p-CH2-X ha 1 ides are prepared by reacting the corresponding primary alcohols, all of which are known, with P&ft¾- or PCI3. The Y- (CH2 )a-CH2-X compounds wherein Y is (CH3)2CH-CH2- or (CH3)3 H- are prepared from the corresponding alcohols in the same manner. The lower molecular weight alcohols, e.g., (CH3)2CHCH2CH20H and (CH3)3CCH2CH2OH are known. The remainder of the alcohols are prepared by reacting the bromides corresponding to those known alcohols with sodium cyanide, hydrolyzing the resulting nitriles to the corresponding carboxyl ic acids, and then reducing those acids to the cor es-ponding primary alcohols with l ithium aluminum hydride, thus is 3, 3-d if luorobutyl are prepared from ketocarboxyl i c acids CH3-CO- (CH2)d-C00H wherein d is 2, 3, 4, 5, or 6. Al l of those ketoacids are known. The methyl esters are prepared and reacte< with sulfur tet raf 1 uor i de to produce the corresponding CH3-CF2- (CH2 )d"C00CH3 compounds , which are then reduced with l ithium aluminum hydride to CH3-CF2- (CH2 )d"CH20H and then trans formed to CH3-CF2- (CH2 )d~CH2X with PBr3 or PC13. The Y- (CH2 )a"CH2-X compounds wherein Y is 4,4-d i f luorobutyl are prepared from the known carboxyl ic acids H00C- (CH2 )f COOH wherein f is 3, 4, 5, 6, or 7. These d i carboxyl ic ac ids are esterif ied to CH3OOC- (CH2 )f-COOCH3 and then half saponified, for example with barium hyd roxide to give H00C- (CH2)f -COOCH3. The free carboxyl group is transformed first to the acid chloride wi£h t hionyl chlorid and then to an aldehyde by the Rosenmund reduction. Reaction of the aldehyde with sulfur tetraf luori de then gives CHF2- (CH2 ) -COOCH3 which by successive treatment with l ithium aluminum hydride and PBr3 or PC13 gives the necessary CHF2- (CH2)f-CHa-X. The Y- (CH2 )a"CH2-X compounds wherein Y is 4,4,4- tr if luorobutyl are prepared from aldehydes CH3OOC- (CH2 )f-CH0 prepared as above. Reduction of the aldehyde with sodium borohydride gives the alcohol CH3OOC- (CH2 )f-CH20H. Reaction with PBr3 or PC 13 then gives CH300C- (CH2 f -CH2-X .

Saponification of that ester gives the carboxyl ic acid which by reaction with sulfur tetraf luoride gives the necessary CF3- (CH2)f-CH2-X. For these reactions of SF4, see U.S. 3,211,723 and J. Org. Chem. 27, 3 6 (1962).

Also necessary to make olefins of formula XXI to prepare the special compounds of formulas X to XX I I are the omega bromides and iodides of the formulas Q- (CH2 )m-Z-C00Ri4 and Q- (CH2)n-C00R 14 wherein Q is Br or I , Ri4 is alkyl of one to 4 carbon atoms, inclus ive, and Z, m, and n are as def ined above. the carboxyl group to an acid chloride with thionyi chloride then to an alcohol with sodium borohydride, and then to the bromide with PBr3. The iodide is prepared by treating the bromide with sodium iodide in acetone. The compounds Q- (CH2 )m-Z-C00R14 are prepared starting with the appropriate succinic acid, H00C-Z-C00H, wherein Z is as defined above, all of which are known. These are transformed to the anhydrides and reacted with an alkanol Ri40H which gives opening to both isomers HOOC-Z-C00R14 and R1400C-Z-C00H. Then the free carboxyl is transformed to acid chloride with thionyi chloride, to aldehyde by the Rosenmund reduction, to alcohol with sodium borohydride, and to bromide with PBr3, giving Br-CH2-Z-C00Ri4 or Ri400C-Z-CH2-Br . This places the necessary substituents on Z in proper relationship to the -C00Ri4 moiety. Then the -CH2- is multipl ied as often as necessary by replacing -Br with -CN (sodium cyanide), hydrolyzing -CN to -COOHjand transforming -C00H to -CH2Br as described above. Finally -Br is replaced with -I if desired by reaction of the bromoester with sodium iodide in acetone.

By similar methods, all known to the art, all of the haloesters and Wittig reagents necessary to prepare al l olefins within the scope of formula XXIV are avai lable to those of ordinary ski ll in this art.

Chart A also shows the transformation of olefin XXIV to epoxide XXV. That is described in said Belgian patent No. 702,477, and is carried out by reacting olefin XXIV with hydrogen peroxide or a percarboxyl ic acid, for example, m-chloroperbenzoic acid or perlauric acid. This step is not a part of this aspect of the invention shown in Chart A.

The transformation of olefin XXIV to glycol XXVI is V pose are known in the art. See, for example, Gunstone, Advances in Organic Chemistry, Vol . 1, pp. 103-1^7 (i960), Interscience Publishers, New York. With the alpha cis form of olefin XXIV, two isomeric alpha erythro formula XXVI glycols are obtained with a cis hyd roxy 1 at i ng agent, e.g., osmium tetroxide, and wit the alpha trans form of olefin XXIV, two isomeric alpha threo formula XXVI glycols are obtained with the same cis hydroxylati agent. Similarly, the beta cis form of olefin XXI gives two isomeric beta erythro formula XXVI glycols with the same cis hyd roxy 1 at i ng agent, and the beta trans form of olefin XxlV gives two isomeric beta threo formula XXVI glycols. These alpha erythro, alpha threo, beta erythro, and beta threo isomer pairs of glycols are separated into the individual isomers, a more polar isomer and a less polar isomer, by silica gel chroma tography.

Transformation of the formula XXV epoxide to glycol XXVI (see Chart A) is carried out by reacting said epoxide with an acid with p less than 4. Examples of such acids are formic acid, chloroacetic acid, trichloroacetic acid, fluoroacetic acid, tri fluoroacetic acid, oxal ic acid, maleic acid, and the like. Especially preferred is formic acid. Usually it is sufficient merely to maintain the epoxide-acid reaction mixture at about 25° C. for 10 to 100 minutes. The glycol ester which results is then hydrolyzed to the glycol XXVI, advantageously with a weak base, e.g., sodium bicarbonate.

Referring again to Chart A, glycol XXVI is transformed to the corresponding b i s -a 1 kane-su 1 f on i c acid ester of formula XXVI I by reaction of XXVI with an a 1 ky 1 su 1 f onyl chloride or bromide, or with an a 1 kanesu 1 f on i c acid anhydride, the alkyl in each containin one to carbon atoms inclusive. A 1 k 1 - the byproduct acid. Especial ly suitable bases are tertiary amines, e.g., d imethylani 1 i lie or pyridine. It is usually sufficient merely to mix the two reactants and the base, and maintain the mixture in the range 0° to 25° C. for several hours. The formula XXVI I bis-sulfonic acid ester is then isolated by procedures known to the art.

Referring again to Chart A, bis-sulfonic acid ester XXVI I is transformed to final product VI I by reacting XXVI I with water. This reaction is carried out by mixing compound XXVI I with water at about 0° to about 6o° C. ■· In making PGEX or 8-iso-PGEi, usually 25° C. is a suitable reaction temperature, the reaction then proceeding to ^completion in about 5 to 10 hours. It is advantageous to have a homogenous reaction mixture. This is accompl ished by adding sufficient of a water-soluble organic diluent which does not enter into the reaction. Acetone is a suitable diluent. The desired product is isolated by evaporation of excess water and di luent if one is used. The residue contains a mixture of formula VI I isomers which differ in the configuration of the side chain hydroxy, being either R or S. These are separated from byproducts and from each other by sil ica gel chromatography. A usual byproduct is a mono-su 1 fon i c acid ester l ike the formula XXVI I bis-sulfonic acid ester except that the -0S02R6 moiety on the carbon adjacent the cyclopropane ring in that formula is replaced by -OH. This mono-su 1 fonic acid ester is esterified to the formula XXVI I bis-sulfonic acid ester in the same manner described above for the transformation of glycol XXVI to bis-ester XXVI I, and thus is recycled back to additional formula VI I final product.

For the transformation of bis-ester XXVI I to final product VI I , it is preferred to use the bis-mesyl ester, i .e., XXVI I does not change during the transformation of XXVM to VI I . Therefore, in the case wherein in formula XXVI I R≥ is pentyl, 3 and R4 are hydrogen, and CnH2n is hexamethy 1 ene , PGEi esters are obtained when the - (CH2)sC00R7 moiety is initially attached in alpha configuration, and 8-iso-PGEi esters are obtained when the -(CH2)6C00R7 is initially attached in beta configuration. However, both erythro isomers and both threo isomers of the alpha formula XXVI I bis esters give the same alpha formula VI I product in substantially the same yield, and the same is true in the beta case. Therefore, referring to Chart A, the formula XXIV starting material need not be separated into cis and trans isomers, and there is no need to separate the various erythro and threo isomers produced by hydroxylation of XXI to the glycol XXVI . In other words, all mixtures of erythro and threo isomers of formula XXVI I are equally useful, and as useful as any of the single isomers in producing final product VI I .

Referring again to Chart A, bis-sulfonic acid ester XXVI I is transformed to final product IX by heating XXVI I in the range o° to 100° C. with a combination of water, a base characterized by its water solution having a pH 8 to 12, and sufficient inert water-soluble organic diluent to form a basic and substantially homogenous reaction mixture. A reaction time of one to 10 hours is usually used. Preferred bases are the water-soluble salts of carbonic acid, especial ly alkali metal b i carbonates , e.g., sodium bicarbonate. A suitable diluent is acetone. The products are isolated and separated as described above for the transformation of bis-ester XXVI I to final product VI I . The same mono-su 1 fon ic acid ester observed as a by-product in that transformation is also observed during Also as for the production of VI I , during production of IX, alpha XXVI I gives alpha IX, beta XXVI I gives beta IX, all of the erythro and threo isomers of XXVI I are equally useful to produce IX, and for each case, alpha IX and beta IX, a mixture of R and S isomers is obtained. These R and S isomers are separated by si l ica gel chromatography.

Referring to Chart A, it should be noted that reactants XXIV, XXV, XXVI , and XXVI I are all in exo configuration. Quite unexpectedly, it was observed that substantially higher yields of final product VI I are obtained when the bis-sulfonic acid esters are in endo configuration rather than exo configuration with respect to the -C (0S02R6 )R4-C (0S02Ra )R2R3 moiety. These endo reactants are prepared by the same procedures described hereinabove and in the above-mentioned Belgian Patent No. 702,477 for the corresponding exo compounds, except for the use of the mixture of exo and endo b icyclo[3.1.0]hexane substituted at ]5 with the protected hydroxy, e.g., tetrahydropyranyloxy, and at 6 with an esterified carboxyl, mentioned above as being used as an early intermediate and being isomerized before further use substantially completely to the exo form. In place of that exo-endo mixture, the corresponding pure endo isomer is used as an intermediate. That endo configuration then is retained throughout the subsequent transformations described in said Belgian patent leading to olefin XXIV and epoxide XXV (Chart A), and to glycol XXVI and bis-sulfonic acid ester XXVI I as described hereinabove.

The necessary pure endo intermediate of the formula: is prepared by reacting endo-b icyclo[j5.1.0]hex-2-ene-6-car-boxylic acid methyl ester with diborane in a mixture of tetra-hydrofuran and diethyl ether, a reaction generally known in the artj to give endo-b i cyclo[3.1.0 ]hexan-3-ol -6-ca rboxyl ic acid methyl ester which is then reacted with dihydropyran in the presence of a catalytic amount of P0C13 to give the desired formula XXIX compound. This is then used as described above to produce eventually the endo isomer of all of the compounds and isomers encompassed by the formula of bis-ester XXVI I (Chart A). The procedure for transforming the endo isomers of bis-sulfonic acid ester XXVII to final product VI I, and the results of that transformation, i .e., isomerism of the formula XXVI reactant and of the formula VI I product, are the same as described above for the transformation of exo XXVI to VI I, except that the yield of product VI I is quite unexpectedly substantially greater from endo XXVI I than from exo XXVI I .

These formula VI I and formula IX final products prepared as described above are all R7 esters wherein R7 is as described above. For some of the uses described above, it is preferred that these formula VI I and formula IX compounds be in free acid form, or in salt form which requires the free acids as starting materials. These formula VI I and formula IX esters are difficult to hydrolyze or saponify without unwanted structural changes in the desired acids, There are three other procedures useful to make the free acid form of formula VI I and IX products.

One of those procedures is appl icable mainly in preparing the free acids from the corresponding alkyl esters wherein the alkyl group contains one to 8 carbon atoms, inclusive. That procedure comprises subjecting the alkyl ester corresponding to formula VI I or formula IX to the acylase enzyme system of a purpose are species of the orders Mucorales, Hypocreales, Monil iales, and Actinomycetales . Also especially preferred for this purpose are species of the families Mucoraceae, Cunning-hamellaceae, Nectreaceae, Monil iaceae, Dematiaceae, Tubercular-iaceae, Act i nomycetaceae , and St reptomycetaceae . Also especially preferred for this purpose are species of the genera Absidia, Circinel la, Gongronella, Rhizopus, Cunninghamel la, Calonectria, Aspergi l lus, Penicil l ium, Sporotrichum, Cladosporium, Fusarium, Nocardia, and Streptomyces .

Examples of microorganisms fall ing within the scope of those preferred orders, fami l ies, and genera are l isted in U.S. Patent No. 5,290,226.

This enzymatic ester hydrolysis is carried out by shaking the formula VI I or formula IX alkyl ester in aqueous suspension with the enzyme contained in a cultu e of one of the above-mentioned microorganism species until the ester is hydrolyzed. A reaction temperature in the range 20° to 30° C. is usual ly satisfactory. A reaction time of one to 20 hours is usually sufficient to obtain the desired hydrolysis. Exclusion of air from the reaction mixture, for example, with argon or nitrogen i s usual 1 y des i rab 1 e , The enzyme is obtained by harvest of cells from the culture, followed by washing and resuspension of the cells in water, and cell disintegration, for example, by stirring with glass beads or by sonic or ultrasonic vibrations. The entire aqueous disintegration mixture is used as a scource of the enzyme.

A ternati ely and preferably, however, the cellular debris is removed by centri fugation or fi ltration, and the aqueous supernatant or filtrate is used.

In some cases, it is advantageous to grow. the micro said alkyl containing one to 8 carbon atoms, inclusive, or to add such an ester to the culture and maintain the culture without additional growth for one to 24 hours before cel l harvest.

Thereby, the enzyme produced is sometimes made more effective in 5 transforming the formula VI I or IX ester to the free acid. An example of a useful alkyl ester for this purpose is methyl ol eate .

This enzymatic hydrolysis is generally useful for transforming prostaglandin alkyl esters to free acids, and thus is useful not only to prepare free acids corresponding to formula VI I and formula IX alkyl esters, but also to transform others I of the known prostaglandin alkyl esters and analogs thereof, for example, the alkyl esters of formula VI M and the esters of prostaglandins such as PGE2, PGE3, PGA2, PGA3, and the l ike.

See Bergstrom et al ., cited above, and references cited therein for other known prostaglandin alkyl esters which are hydrolyzed by this enzymatic process.

Although, as mentioned above, the esters encompassed by I formulas VI I and IX are not easi ly hydrolyzed or saponified to I 20 the corresponding formula VI I and IX free acids, certain of those esters are transformed to the free acids by another process.

Those esters are haloethyl esters wherein Ri is ethyl substituted in the beta-position with 3 chloro, 2 or 5 bromo, or 1, 2, or 3 iodo. Such esters, for example, wherein Ri is -CH2CC13, are transformed to free acids by treatment with zinc metal and an alkanoic acid of 2 to 6 carbon atoms, preferably acetic acid.

Zinc dust is preferred as the physical form of the zinc. Mixing the haloethyl ester with the zinc dust at about 25° C. for several hours usually causes substantially complete replacement 1 30 of the haloethyl moiety of the formula VI I or formula IX ester Referring now to Chart A, these formula VI I and IX halo-ethyl esters are prepared from the corresponding formula XXVI I bis-sulfonic acid esters wherein R7 is ethyl substituted in the beta-position with 3 chloro, 2 or 3 bromo, or 1, 2, or 3 iodo, preferably with 3 chloro. Those transformations are carried out as described above for the other XXVI I to VI I and XXVI I to IX transformat ions .

The formula XXVI I bis-sulfonic acid esters wherein R7 is ethyl substituted in the beta position with 3 chloro, 2 or 3 bromo, or 1, 2, or 3 iodo are prepared from the corresponding glycols of formula XXVI as described above for the other formula XXVI to XXVI I transformations.

The formula XXVI glycols wherein R7 is ethyl substituted in the beta position with 3 chloro, 2 or 3 bromo, or 1, 2, or 3 iodo are prepared by hyd roxylat ion of the corresponding formula XXIV olefin or formula XXV epoxide as described above for the other XXIV to XXVI and XXV to XXVI transformations. Alternatively, these haloethyl esters are prepared by es ter i f i cat ion of the formula XXVI glycol free acids (R7 is hydrogen) with the appropriate haloethanol, e.g., β,β,β-trichloroethanol when the haloethyl group is to be -CH2CC13. This es ter i f i cat ion is carried out by reacting the formula XXVI glycol free acid with the haloethanol in the presence of a carbod i imide, e.g., d icyclohexyl carbod i imide, and a base, e.g., pyridine. This mixture, advantageously with an inert diluent, e.g., dichloro- methane, usually produces the desired haloethyl ester within several hours at about 25° C. The glycol acids of formula XXVI necessary for this ester i ficat ion are prepared by hyd roxyl at ion of the fprmula XXIV olefin free acids as described above for the other XXIV to XXVI transformations. iodo are prepared by ester i f i cat ion with the appropriate halo-ethanol , e.g. , CCl3CH20H, as described above for the esterif ica tion of the formula XXVI glycol acid (R7=H) .

The necessary formula XX I V olefin free acids (RY is hydrogen) are prepared by saponification or hydrolysis of corresponding esters. That reaction, however, is difficult to carry out without partial isomerization of the alpha isomer to the beta isomer, or the beta to the alpha. Therefore, it is preferred to reduce the ring carbonyl of a formula XX I V olefin ester to hydroxy with sodium borohydride and then saponify that ester. The latter reaction takes place easi ly and without isomerization. Then the resulting hydroxy olefin with a free carboxyl group is oxidized back to the keto olefin of formula XX I V ( T is now hydrogen). For the latter oxidation, it is necessary to use a reagent which does not alter the moiety of formula XX I V compounds. The Jones reagent is suitabl for this oxidation (see J. Chem. Soc. (London) j59 (19^6) X.

Those three transformations, sodium borohydride reduction, saponification, and oxidation are al l carried out by general procedures known to those ski l led in this art.

Although this second route to the free acids of formulas VI I and I X has been i l lustrated with the exo compounds shown in Chart A, the route is equal ly appl icable by the same procedures and techniques to the above-discussed corresponding endo series of compounds.

A thi rd route to the free acids of formula VI I starts with a ketal of the formula: is hydrogen, alkyl of one to 8 carbon atoms, inclusive, cyclo-alkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one to 3 chloro or alkyl of one to carbon atoms, inclusive, wherein Ri2 are both alkyl of one to 6 carbon atoms, inclusive, or, l inked together, are 1,2-alkylene or l,j5-a 1 kyl ene of 2 to 6 carbon atoms, inclusive, and wherein indicates attachment or beta of the -CnH2n-C00Re moiety to the ring in alpha/configuration, and exo or endo configuration with respect to .the -CR BC 2R3 moiety. These ketals when Ri2 are both alkyl are prepared by reacting a keto-olefin of formula XXI (R7 becomes Ra as defined above) in either exo or endo configuration with respect to the -CR4=CR2R3 moiety with an orthoformic ester of the formula HC(0Ri2)3j where i n Ri2 is as defined above. When the Rig l inked together are 1,2-alkylene or l,3~al kylene, the same formula XXIV R? keto-olefin is reacted with a 1,2-glycol or a l>3"glycol of 2 to 6 carbon atoms, inclusive, in the presence of a strong acid, especially a sulfonic acid, e.g., p-toluene-sulfonic acid. Examples of 1,2-alkylene of 2 to β carbon atoms are -CH2CH2-, -CH2-CH (CH3)- , -CH (CH3)-CH (CH3)- , -C (CH3)2-CH2- , -C(CH3)2-C(CH3)2-, and -CHa-CH (CHaCH3)- . Examples of 1,3-alkylene of 3 to 6 carbon atoms, inclusive, are -CH2CH2CH2- , -CH2-CH(CH3)-CH2-, -CH(CH3)-CH2-CH2-, -CH(CH3)-CH(CH3)-CH2-, and -€Η2" C (CH3)s-CH2- . Examples of 1,2- gl ycol s and 1,3-glycols correspond to the above examples of 1,2-alkylene and 1,3-al kylene with an -OH at each free valence. These two processes are known generally to those skilled in the art.

Referring now to Chart A, the ketal of formula XXX is transformed via the ketals corresponding to epoxide XXV, glycol XXVI , bis-sulfonic acid ester XXVI I , to a ketal corresponding to wherein R2 , R3, R-t, R7 , R_2, CnH2n, and are as defined above. These transformations are carried out as described above for the transformations of XXIV to XXV, XXIV to XXVI , XXV to XXVI -to XXVI I , XXVI, /and XXVI I to VI I except that any free acid ketal glycol XXVI is esterified before transformation to ketal bis-sulfonic acid ester XXVI I , and except that the several ketals correspond-to formulas XXIV, XXV, XXVI , and XXVI I are in either exo or endo configuration rather than only in exo as shown in Chart A.

Then ketal XXXI is saponified by known procedures to the free acid form (R7 is hydrogen), and then hydrolyzed with an acid, for example, oxal ic acid, to form final product VI I (Chart A) wherein Ry is hydrogen.

These keta 1 - i nvol ved reactions are useful to produce formula VI I compounds wherein Ri is hydrogen when the -CnH2n"C00R8 moiety is attached either in alpha configuration and in beta configuration. When R3 and R4 are hydrogen, CnH2n is hexamethyl ene, and. the - (CH2 )6-C00R8 is attached in alpha configuration, PGEi (both R and S) is produced. When R3 and R4 are hydrogen, CnH2n is hexamethyl ene, and the - (CH2 )6-C00R8 is attached in beta configuration, 8-iso-PGEi (both R and S) is produced.

The procedures described in said Belgian Patent No. 702,477 for producing olefin XXIV (Chart A) usual ly result in the formation of a mixture of alpha and beta isomers with respect to the -CnH2n-C00R7 moiety. As described above, those two isomers lead preferred, there are two methods for favoring production of the preferred final formula VI I isomer.

One of those methods involves i somer i zat ion of the final product of formula VI I wherein R7 is as defined above or hydrogen. Either the alpha isomer of formula VI I or the beta isomer of formula VI I is maintained in an inert l iquid diluent in the range 0° to 8o° C. and in the presence of a base characterized by its water solution having a pH below about until a substantial amount of the isomer has been isomerized 10 to the other isomer, i .e., alpha to beta or beta to alpha.

I Preferred bases for this purpose are the alkal i metal salts of carboxyl ic acids, especially alkanoic acids of 2 to k- carbon atoms, e.g., sodium acetate. Examples of useful inert liquid diluents are alkanols of one to carbon atoms, e.g., ethanol .

This reaction at about 25° takes about one to about 20 days.

Apparently an equilibrium is establ ished. In the case of PGEi and 8-iso-PGEx, the equilibrium results in 9 parts of PGEi and I one part of 8-iso-PGEi. The mixtures of the two isomers, alpha and beta, are separated from the reaction mixture by known procedures, and then the two isomers are separated from each other by known procedures, for example, chromatography, re- crystallization, or a combination of those. The less preferred isomer is then subjected to the same i somer i zat ion to produce more of the preferred isomer. In this manner, by repeated isomerizations and separations, substantially all of the less preferred isomer of the formula VI I compound is transformed to more preferred isomer.

The second method for favoring production of a preferred final formula VI I isomer involves olefin XXIV (Chart A). Either the alpha isomer or the beta isomer of that formula XXIV olefin in the presence of a base and in range 0° to 100° C. unti l a substantial amount of the starting isomer has been isomerized t the other isomer. Preferred bases for this i somer i zat ion are alkal i metal amides, alkal i metal alkoxides, alkal i metal hydrides, and tr i arylmethyl alkal i metals. Especial ly preferre< are alkal i metal tert-al koxides of 4 to 8 carbon atoms, e.g., potassium tert-butoxide. This reaction at about 25° C. proceeds rapidly (one minute to several hours). Apparently an equi l ibrium mixture of both isomers is formed, starting with either isomer. In the case of olefin XXIV wherein R2 is pentyl , R3 and R4 are hydrogen, R7 is methyl, and CnH2n is hexamethyl ene, the equi l ibrium mixture contains about one-third alpha isomer and two-thi rds beta isomer. The isomer mixtures in the equi l ibrium mixture of formula XXIV olefins, including thus obtained are isolated by known procedures, and then the two isomers are separated from each other by known procedures, for example, chromatography. The less preferred formula XXIV isomer is then subjected to the same i somer i zat ion to produce more of the preferred isomer. In this manner, by repeated i somer i zat ions and separations, substantial ly al l of the less preferred isomer of the formula XXIV olefin is transformed to the more preferred isomer.

The f inal formula VI I , VI M , and IX compounds prepared by the novel processes of this invention, including the novel fina compounds of formulas X to XXI I I , in free acid form, are transformed to pharmacological ly acceptable salts by neutral ization with appropriate amounts of the corresponding inorganic or organic base, examples of which correspond to the cations and amines l isted above. These transformations are carried out by a variety of procedures known in the art to be general ly useful The qhoice of procedure depends in part upon the solubil ity characteristics of the particular salt to be prepared. In the case of the inorganic salts, it is usually suitable to dissolve the formula VI I, VI M, or IX acid in water containing the stoichiometric amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt of the prostanoic acid derivative. Evaporation of the water or addition of a water-miscible solvent of moderate polarity, for example, a lower alkanol or a lower alkanone, gives the sol id inorganic salt if that form is desired.

To produce an amine salt, the formula VI I, VI I I, or IX acid is dissolved in a suitable solvent of either moderate or low polarity. Examples of the former are ethanol , acetone, and ethyl acetate. Examples of the latter are diethyl ether and benzene. At least a stoichiometric amount of the amine corresponding to the desired cation is then added to that solution. If the resulting salt does not precipitate, it is usually obtained in solid form by addition of a miscible .diluent of low polarity or by evaporation. If the amine is relatively volatile, any excess can easily be removed by evaporation. It is preferred to use stoichiometric amounts of the less volatile ami nes .

Salts wherein the cation is quaternary ammonium are produced by mixing the formu la VI I , VI M, or IX acid with the stoichiometric amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.

Referring to Chart A, reactants XXIV, XXV, XXVI, and XXVI I , PGEi, PGFla> PGFip, PGAi, and the isomers thereof and the novel formula X to XXI I I compounds each have at least one center of asymmetry, and each compound encompassed by those formulas exists in two optically active forms, d and 1. Each of those compounds disclosed herein are to be construed as including the racemic dl form and the enantiomeric optically active d and 1 forms .

Optically active final products, d and 1, of formulas VI I, VII I, and IX, including PGE!, PGFia, PGF^, PGAi, and the novel compounds encompassed by formulas X to XXII I are obtained by resolution of those final compounds or by resolution of one of the reactants, formulas XXIV, XXV, XXVI, XXVI I, or VII, used to make them. When final compound VI I , VI I I, or IX is a free acid, the dl form thereof is resolved into the d and 1 forms by react-ing said free acid by known general procedures with an optically active base, e.g., brucine or strychnine, to give a mixture of two d i as tereo i somers which are separated by known general procedures, e.g., fractional crystall ization, to give the separate d i as tereo i someri c salts. The optically active acid of formula VI I, VI I I, or IX is then obtained by treatment of the salt with an acid by known general procedures. Alternatively, the free acid form of olefin XXIV or glycol XXVI is resolved into separate d and 1 forms and then esterified and transformed further to the corresponding optically active form of the final product VI I , VI M, or IX as described above.

Alternatively, olefin reactant XXIV or glycol reactant XXVI, in exo or endo form, is transformed to a ketal with an optical 1 y active 1,2-gl ycol , e.g. , D- ( — )-2,3"butanediol , by reaction of said glycol with the formula XXIV or XXVI compound in the presence of a strong acid, e.g., p-toluenesu Ifon ic acid. then hydrolyzed with an acid, e.g., oxalic acid, to the original keto compound, XXIV or XXVI , now in optical 1 y active form.

Alternatively, the ketal d i as tereo isomer mixture on each separated diastereoisomer, is transformed to the ketal corres-ponding to formula VI I as described above, the di as tereo isomers being separated from each other if the mixture of ketal di as tereo isomers is used, and then the optically active ketal of the formula VI I compound hydrolyzed with an acid, e.g., oxalic acid, to the optically active formula VI I compound.

These reactions involving optically active glycols and ketals for resolution purposes are generally known in the art. See Chem. Ind. 1664 (1961) and J. Am. Chem. Soc. 8 , 2938 (1962 .

The invention can be more fully understood by the followin examples: (all temperatures are in degrees centigrade) Example 1. β-Εχο- (l 1 , 2' -ery thro and threo-d i hydroxyheptany 1 )- 2a- (6" -carboxyhexyl )-bicyclo [3.1.0] - hexan-3-one (XXVI, R7=H).

To 100 mg. of 6-exo- (l1 -*ci s-heptenyl )-2a- (6" -ca rboxyhexy 1 )-bi cycl o- [3.1» 0] - hexan-3-one (XXIV) cooled to 0° under nitrogen, is added a solution made up of 8 ml. dry formic acid (distilled from boric anhydride) to which has been added 10 p] of 90$ hydrogen peroxide and 65 mg. dry sodium bicarbonate, all nitrogen purged before the addition. After 30 mi nutes, . the ice bath is removed and the mixture is sti rred 1,5 hours at room temperature. The formic acid is removed at 25° i n vacuo and benzene is then added and removed in vacuo to complete removal of formic acid.

To the residue i s added 10 ml. methanol and 2.5 ml . saturated sodium bicarbonate. This stands at 5° overni ght, and then is acidified to pH 4. The methanol Is removed in vacuo, and the solution is adjusted to pH 3 and extracted with ethyl acetate.

The extracts are washed, dried, evaporated, and chromatographed on 15 g. acid-washed sil ica gel. Elution is with 25, 35* 50, 75 and 100$ ethyl acetate-Skel 1 y B (isomeric hexanes) and 1 and 10$ methanol -ethyl acetate. The fi rst. material eluted, 7 mg. has TLC mobil ity l ike starting material. Then 10 mg. of a mixture of two materials, one with U.V. absorption are eluted.

This is followed by 35 mg. of partly crystall ine material showing infrared and NMR spectra consistent with structure XXVI, R7=H.

The mass spectrum of this material shows the molecular ion (35*0 and also 253 (cleavage between the glycol hydroxyls) as a strong ion peak. The next material eluted (with ethyl acetate) is 50 mg. of non-crysta 11 i ne mater ial , also having NMR and IR spectra very similar to the glycol above, and a mass spectra vi rtua 11 y Example 2. β-Εχο- (e rythro and threo-1' ,2' -di hydroxyhepty 1 )- 2a- (6"-carbomethoxyhexyl )-[3.1.0] -hexan-3-one (XXV I , 7=CH3 ) .

To 1.90 g. of 6-exo- (l1 -c i s-heptenyl ) -2a- (6" -car borne t oxy-hexyl )-[3.1.0]-hexan-5-one (XXIV, R7=CH3) at 0° is added a mixture of 50 ml. 98$ formic acid, 650 mg. sodium bicarbonate, and O.18 ml. 90$ hydrogen peroxide which has been cooled to 0° and purged with nitrogen. The solution is stirred at 0° for one-half hour and then allowed to warm to room temperature over two hours. Formic acid is removed in vacuum and benzene is added. This is also removed in vacuum and the residue is extracted with ethyl acetate. This is washed with water, bicarbonate, saturated salt, and dried with sodium sulfate.

Evaporation gives a residue consisting of formates of the glycol These are hydrolyzed with 50 ml . methanol and 10 ml. saturated sodium bicarbonate at 25° for two hours. Water (40 ml.), is added, the methanol removed in vacuum, the aqueous suspension is acidified to pH 5 and extracted with ethyl' acetate. This is washed with water, saturated salt, dried with sodium sulfate, and evaporated. The residue is chromatographed on.150 g, silica gel and eluted with 750 ml. each of 25, ¾.50, 75# ethyl acetate Skelly B, collecting 150 ml. fractions. Fractions 12-15, 78 mg consist of a mixture of two isomeric glycols of structure XXVI, on silica gel plates developed with A IX system, but on a boric acid- treated plate it shows two spots of nearly equal intensity at Rf.a0.62 and 0.52. The upper spot corresponds to the less polar threo glycol (see above). The NMR spectrum shows a 3 proton singlet at 3.67$ (0CH3) ; about protons, multiplet, between 2.7 and 3.6s, for carbinolic and hydroxylic protons; 5 protons as cyclopropyl proton is evident at 0.6β. „ Fract i ons 16-21, 685 mg. are also one spot on silica gel plates, but show two spots. f. 0.46 and 0.26 on boric acid treated plates and consist of the more polar erythro and threo glycols (below). The less polar of the two has the same mobility on boric acid treated plates as the more polar threo isomer. Its IR and NMR spectra are very similar to that of fractions 12-15 above. The mass spectrum shows 350 (M-l8); 332 (M-2H20); 292 (350-58); 267 (M-lOi); 235 (267-32).

Example 3. 6-Exo- (erythro-1 ' , 2' -d i hydroxyhepty 1 ) -2a- (6" -carbo- methoxyhexyl ) -b i eye 1 o- [3- 1 · 0] - hexan-3-one (XXVI , R7=CH3).

To a solution of 0.39 g. of 6-exo- (ci s-1 ' - heptenyl ) -2a- (6" -carbomethoxyheptyl ) -bi cycl o- [3.1.0. ] -hexan-3-one in 8 ml. pyridine is added 0.32 g. of osmium tetroxide. After stirring at 25° for fifteen hours, a solution of 1.0 g. of sodium bisulfite in 16 ml. water and 10 ml. pyridine is added and stirring is continued for five hours. The dark solution is diluted with water, extracted with chloroform and the extracts are washed several times with water, dried, and evaporated. The residue is chromatographed on 0 g. silica gel, eluting with 50 to 100$ ethyl acetate i n Skel 1 ysol e B. The less polar erythro glycol isomer obtained amounts to 0.150 g., the more polar, O.18O g.

The less polar erythro isomer is crystalline (mp. 70-71° from ethyl acetate Skelly-B); v= 3460, 17^0, 1715, 1250, 1215, 1190, 1175, IO95, 1065, 1055 cm"1, and mass spectral ions at 368 (M+), 350, 337, 319, 267, 250, and 235 mass units.

Anal. Calcd. for C2lH3605: C, 68.44; H, 9.85 Found: C, 68.46; H, 9.87.

The more polar isomer is also crystall ine; v=3430, 334-0, 1055, 1055 cm"1. The mass spectrum is the same as for the less polar isomer. The melting point is 1-42.5° after recrysta 11 i za-tion from ether-Skelly=B.

Anal. Found: C, 68.63; H, 9.79.

Example 4. 6-Exo-(threo-l ' , 2' -d i hydroxyhepty 1 )-2 - (6" -carbo- methoxyhexy 1 ) -bi cycl o- [3.1.0] -hexane-3-one (XXVI, In the same manner as in Example 3, above, the trans isomer, 500 mg., gives l80 mg. of a less polar glycol and 110 mg. of more polar glycol. These are not obtained crystalline, but corr respond in TLC behavior to two of the glycols obtained by perform! c acid, , hydroxylati on of XXIV, cis, R7=CH3 above (Rf.=0.62 and 0.46 on boric acid-treated plates).

Example 5. 6-Exo- (erythro-11 ,2' -di hydroxyheptyl )-2β- (6"-carbo- methoxyhexy 1 ) -bi cycl o- [3.1.0] - hexan-3-one (XXV I , R =CH3).

In the same manner as above 0.50 g. of 6-exo- (l ' -c i s-heptenyl )-2β- (6" -carboxyhexy 1 )bicyclo-[3.1.0] -hexan-3-one {XXIV), is treated with 0.42 g. of osmium tet ro i.de i n 10 ml . pyri di ne. Chromatography of the crude products gives 283 mg. of the less polar erythro isomer XX I, R7=CH3, mp. 42° .from ether. SkeHy- solve-B, Rf.=0.40 on sil ica gel, developed with ethyl acetate.

Anal. Calcd. for C21H3e05: C, 68.44; H, 9.85 Found: C, 68.21; H, 9.80.

The more polar erythro isomer consists of 148 mg. of crystal 1 i ne material , m;p. 58-59°* from ether, Rf.=0.19.

Anal. Found: C, 68.27; H, 9.97.

These two glycols have nearly identical infrared and NMR spectra: v=3400, 1735, 17 , 1240, 1.200, 1170, 1060, 735 cm"1 and 3.6 In the same manner as above, 0.50 g. of 6-exo- (l ' - trans-heptenyl )-2β- (6"-carboxyhexyl )bi cycl o-[2.1.0] -hexan-3-one (XXIV) is hydroxylated with osmium tetroxide to give 219 m . of the less polar threo isomer and 129 mg. of the more polar threo isomer of structure XXVI, The less polar material is crystal lized .from ether-Skel 1 ysol ve B, mp. 46-47°, , Rf. =0.40 (silica gel plate, developed with ethyl acetate).

Anal. Calcd. for C21H3e05: C, 68.44; H, .9.85.

Found: C, 68.31; H, 9-75.

The more polar threo isomer is recrystall i zed from ether, mp. 77-78°, Rf.=0.23.

Anal. Found: C, 68.58; H, 10.11.

Thin layer chromatography of the four glycols of structure XXV I , β-s i de cha i n, on silica gel plates sprayed w i th 10 bor i c aci d i n methanol and dr i ed 30 mi nutes at 70° , gi ves the following Rf. values: less polar erythro 0.75; less polar thre 0.70; more polar threo 0.60; and more polar erythro 0.46.

The infrared and NMR spectra of the threo isomers are very similar to those of the rythro isomers above.

Example 7. dl -Prostaglandi n Ex Methyl Ester and dl -15- I sopro- staglandin Ei Methyl Ester A. A solution of 0 mg. of the more polar erythro isomer of XXVI, -side chain, R7=CH3 in 9 ml. pyridine is cooled to 0°,and treated with 1.3 ml. methanesul f onyl chloride. After one hour at 0°, the ice-bath is removed, and the mixture is stirred one hour additional. It is then cooled again to 0°, dried, and evaporated. This crude dimesylate residue shows essentially one spot on TLC, strong infrared absorptions at 1740, 1350, 1175 and 910 cm"1 and prominent ion peaks. in the mass spectrum at 332 (M-2CH3S03H) , 301 (332-31) and 300 (332-32) mass units. It is rather unstable to the usual chromatographic purifications. It is dissolved i n 27 ml. acetone and diluted with 13.5 ml. water and the resulting solution stored at 25° for six hours. The mixture is concentrated in vacuum, extracted with methylene chloride, which is washed, dried and evaporated.

Chromatography on 0 g. sil ica gel and elution wi th i ncreasi ng proportions of ethyl acetate in Skel 1 ysol ve-B gives the following materials: A. 75 mg. of unknown, least polar products; B. 389 mg. of a mixture of two glycol monomesylates ; C. 27 mg. (5.3$) of the R isomer, dl -15- i soprostagl andi n Ex methyl ester; and D. 34 mg. (6.7#) of crystal line dl -prostaglandi n · Et methyl ester (the S i somer).

Fraction B, the two monomesylates are characterized as follows: prominent ions i n the mass spectrum at 350 (M-CH3SO3H) , 332 (350-18), 301 (323-31), 300 (332-32), 319 (350-31), 318 (350-32), Infrared absorptions at v=3500, 17 5, 1340, 1170, 920 cm"1, and in the NMR, one proton as a broad multiplet 5.0-4.βδ, 3 proton singlet at 3.78 (OCH3), one proton as a doublet of doublets, 3>4l8, J=7.5 and 3.5 cps, a3-proton singlet at 3.1s (S-CH3), and to 6-endo cyclopropyl hydrogen as a multiplet 0.85-0.5$.

Fraction C, . dl -15- i soprostaglandi n Ex methyl ester, has infrared and NMR spectra identical to those of the optically active 15 (R)-PGEj methyl ester. The mass spectrum shows the molecular ion, 368, and other prominent ions at 35Ό, 332, and 297 mass uni ts.

Fraction D is recrystal 1 ized from ether-Skel 1 ysol ve-B, mp. 55-57°. The NMR and i nf rared spectra and TLC behavior are identical to those of natural PGEi methyl ester. The mass spectrum shows peaks at 368, 350, 332, and 297 mass units, and ultraviolet absorption at 278 mju (e = 26000) developed after adding a little 50 aq. OH to a sample in ethanol .

Anal. Calcd. for CaiHaeOs: C, 68.44; H, 9.8 Found: C, 68.08; H, 9.92.

B. The less polar erythro isomer of structure XXVI, -side chain, R7-CH3, treated as above gives $ dl-PGEi methyl ester and an equal amount of its 15-epimer.

C. The more polar threo isomer of structure XXVI, a-side chain, simularly gives $ d 1 -PGEi, methyl ester and.5.5$ of i ts 15-epimer.

P. In the same way as above, the mixture of mono-mesyl ates obtained from the above sol vol ys is reactions is reconverted to the bismesylate and solvolyzed, giving 5$ yield of dl -PGEi, methy ester and an equal amount of its 15-epimer.

Example 8. dl -Prostagl and i n E.

To a dried sample, 329 mgt J of the glycol acid XXVI, a-side chain, R7=H,! cons i st i ng of the more polar erythro and threo i somers, . i s added 20 ml . methylene chloride, 3.3 ml . trichloro-ethanol, 1.8 ml. pyridine, and then 0.33 g. of di cyclohexyl -carbodi imi de. After stirring two hours at 5°* the entire reaction mixture is poured onto a column of 100 g. sil ica gel. Elution with 2 1, of 25-75$ ethyl acetate-Skel 1 y B, gradient, gives 00 mg. of the desired β, β-tri chl oroethyl ester of 6-exo- (l» ,2' -di hydroxyhepty 1 ) -2a- (6" -carboxyhexyl )-bi cyclo- [3.1.0] -hexan-3-one (XXVI, a-side chain) contami nated wi th a li le cr s alline dic loh x lure his eri l has group and is otherwise similar to the corresponding methyl ester, XXVI, -side chain, 7=CH3.

The 300 mg. of glycol tr i chl oroethyl ester obtained above is treated at 0° under nitrogen in 7.5 ml. pyridine with 0.8 ml. methanesul fony 1 chloride. After 5 minutes at 0°, it is allowed to warm to room temperature and stir two hours total. It is again cooled in ice, and 5 ml. water is added. After stirring 5 minutes at 0°, ethyl acetate is added, and it is washed twice with water, twice with IN hydrochloric acid, then w i th bi ca rbonat saturated salt, dried over sodium sulfate, and evaporated. The residue, 348 mg., by thin layer chromatography consists largely of a material less polar than the starting glycol. To this is added 8 ml. acetone and 2 ml. water, and the resulting solution is allowed to stand at 5° under nitrogen for 68 hours. Water is then added, acetone is removed in vacuo, and the products are extracted with ethyl acetate. This is washed wi th bi carbonat saturated salt, dried over sodium sulfate, and evaporated, crude weight 515 mg. Chromatography on 50 g. silica gel and gradient elution with 1 1. of 25-100$ ethyl acetate-Skel 1 y B, followed by ^ methanol -ethyl acetate gives four peaks.

No. 9-15, 88 mg. and No. 17-26, 117 mg. consists of mono-mesylates. infrared spectra of these are very similar, OH (3500 cm X); C=0 (1 5 cm"1); 1340, 1170, 920, 800, 720 cm*1.

No. 32-40, 15 mg. moves on TLC slightly faster than the methyl ester of 15-iso-PGEi, and undoubtedly consists of its corresponding trichloroethyl . ester.

No. - 7, 12 mg. moves slightly faster on TLC than the methyl ester of PGEX and shows in the NMR two olefinic protons centered at · two rotons of the trichloroeth l ester rou In the same manner as above, 200 mg. of the less polar erythro-threo pair of glycols of structure . XXV I , α-side chain, Rr^Hj ls converted to the tr i chl oroethy 1 esters, the bi smesylates, and solvolyzed, giving 8.5 mg. of the trichloroethyl ester of dl-PGEi, identical to that above.

Fractions 43-47, 12 mg, above, are dissolved in 1 ml. of 9 O acetic acid and stirred with about 100 mg. zinc dust at 25° for two hours, when TLC shows no ester remaining. Ethyl acetate is added, and the solution is decanted into a separatory funnel and washed several times with water, then saturated salt, dried with sodium sulfate, and evaporated. The residue is chromato-graphed on 5 g. si 1 i ca gel eluti ng wi th 50 ml . each of 50, 75, 100$ ethyl acetate-Skel 1 y B, and $ methanol -ethyl acetate.

Fractions 7-9) 6.5 mg., are largely crystal 1 i ne, move on TLC like PGEt, and after two recrystal 1 izations from ethyl acetate-Skelly B, melt at 115. -115°, wt. 3. mg. Mixed melting point with. natural PGEX (mp. 114-115°) is 109-114°. The optical rotatory dispersion curve shows no optical activity between 475 and 2 0 mjj (sens. 0.001°), and the mass spectrum is identical to that of natural PGEi. Biological activity is greater than 50$ of natural PGEX in two systems.

The recovered mono-mesylate fractions from the preceeding experiment, 205 mg., are remesylated and solvolyzed as, above, and the trichloroethyl ester fractions (ca. 6 mg.) are hydrolyzed with zinc and acetic acid. In this way a further 2 mg, of dl-PGEj, mp. 113-115° is obtained, making the total yield of pure d1° GEi, 5>4 mg., or 1.6$ overall from the glycol acid.

Example 9. dl »8° I soprostaglandi n E^ Methyl Ester. pyridjne is cooled to 0° and treated with 1.25 ml. methanesulfo chloride. The solution is stirred at 0° one hour, and then allowed to warm to room temperature over an addi tional hour period. Then the mixture is cooled, ice is added, and the product extracted with methylene chloride. The extracts are washed with cold 5 hydrochloric aci d, . d r i ed, and evaporated to leave 0.71 g. of a brown oil.

In the same way, the other three racemates of structure XXVI, β-side chain, R=CHa are al so converted to bi smesylates. The mobilities of these products on. silica gel plates developed with 05? ethyl acetate-cycl ohexane is as follows: more polar erythro and threo bi smesylates, . FCf. =0.47; . less polar erythro and threo bismesylates Rf,=0.57. All four give similar infrare and NMR spectra; v= 174 . 1360, ll80, 970, 915, 7 0 cm'1; one-proton mul t iplets at about 4.8 and 4.3 S (proton on carbon bearing a mesyloxy group), three-proton singlets at 3.65 and six proton singlet at 3.1 Anal. Calcd. for CS3H4o09S2: C, 52.65; H, 7.68; S, 12.22.

Found: C, 52.32; H, 7.74; S, 12.21.

The crude bismesylate from the more polar erythro glycol is solvolyzed at 25° in 40 ml. acetone and 20 ml. water for fiv hours. After the usual work-up, the crude products are chroma- tographed on 60 g. silica gel, el ut i ng w i th 10-100$ ethyl aceta in cyclohexane. The following materials were eluted, in order of their polarity; A. 9 mg. of a less polar mono-mesylate of l col XXVI, β-side chain, R7=CH3; B. 34l mc. of an incomplete β-side chain, dl -15- i so-8- i so PGEi methyl ester; C. 50 mg. (10¾J yi l-8-iso PGEX methyl ester; D. 10 mg. dl-PGEx methyl ester. These are characterized as fol lows: A. v= 5400, 1745, 1175 and 920 cm"1, > Et0H 220 mjj (5,000) max indicating some contamination by PGAi-type compounds.

B. This mono-mesylate, contaminated (by TLC evidence) ,-wi th dl -15- i so-8- i so PGEi methyl ester is partially crystalline, and is recrystal 1 i zed from acetone-Skel 1 ysol ve B to give the pure mono-mesylate, mp. 95-94°, V = 3510, 5 0, 3030, 3010, 1745, -15 0, 1205, 1175, 1170, 1030, 990, 920, and .810 cm"1. In the; NMR, a three proton singlet at 5.0 5 shows the presence of one S-CH3 group.

Anal. Calcd. for C22H3807S: C, 59.17; H, 8.58; S, 7.18.

Found! C, 59.59; H, 8.77; S, 7.00.

C. This material exhibits the same mobility (Rf . =0.40) on silica gel plates developed in ethyl acetate as does authentic 8-iso-PGEi methyl ester and gives ^ί?Η 78 mjj (25,400) on treatment with base. After recrystal 1 i zati on from ether-Skellysolve B, it melts at 52-55°, V = 5^00, 1740, 1240, 1200, 1175, 975 cm"1. The NMR spectrum is like authentic material showing a broad mul t i pi et, 5.0-5.8<5 for the C13, Ci4 olefinic protons. Prominent ions at 550, 552 and 277 are present in the mass spectrum.

Anal. Calcd. for G21H3e05i C, 68.44; H, 9.85.

Found: C, 67.80; H, 9-98.

The bi smes late prepared from the less. polar threo glycol XXVI, β-side chain, 7SCH3, . on .sol vol ys i s as above gives 5.4$ yield of d 1 -8- i so-PGEi methyl ester. From the more polar threo glycol XXVI, β-side chain, R7=CH3, the yield is 11$, and from the less polar erythro 8.0$. Solvolysis of the less polar above^gives 10$ dl-8-iso PGEX methyl ester. In each case -2$ dl-PGEi methyl ester is also formed. From the more polar threo bi smesyl ate solvolysis, one of the mono-mesylates is Obtained crystall ine, mp. 85-87° from acetone^Skel 1 ysol ve B.

Anal. Calcd. for C22H3a07S: C, 59.17; H, 8.58; S, 7.18.

Found: C, 58.95; H, 8.71; S, 7.01.

Example 10. 8- I so-Prostagland i n Ea To 1.2 g. of 6-exo- (l1 -ci s-heptenyl )-2β- (6" -carboxyhexyl )-bicyclo-[3.1.0] -hexan-3-one (XXIV), under nitrogen is added a cold (0°) solution of 225 mg. sodium bicarbonate and 0.1 ml. 90$ hydrogen peroxide in 25 ml. 98$ formic acid. After stirring at 0° for 0.5 hour/ the ice-bath is removed and stirring is continued a further 1.5 hours. The formic acid is removed in vacuo, 25 ml. benzene is added, and this is also removed in vacuo. The residue is extracted w i th ethyl acetate which is washed with water, saturated salt, dried with sodium sulfate, and evaporated. To the residue is added ml. methanol and ml . of saturated aqueous sodium bicarbonate. This is sti rred o at 25 two hours, concentrated in vacuo to remove methanol and acidified to pH 2-J. The products are extracted with ethyl acetate which is washed with water, dried, and evaporated, leaving I.38 g. of a mixture of epimeric glycol acids, XXVI, β-side chain, Y=H. These are esterified in l40 ml. methylene chloride with 23 ml . tr ί chl oroethanol , 12.6 ml. pyridine and . 1 g. di cyclohexyl ca rbod i imi de at 25° for two hours. Then ml. water is added, and after stirring five minutes, is washed with 1 N hydrochloric acid, sodium bicarbonate solution, dried, and evaporated. The residue is dissolved in benzene, filtered to remove some di cyclohexyl urea, and chromatog raphed on 150 g. structure XXVI, β-s i de 'chai n The less polar, 700 mg shows one spot on TLC (sil ica gel, 50 ethyl acetate-cycl ohexane the more polar 800 mg. shows two very close spots on the same I TLC system. The Rf. values of these tri chl oroethyl esters are similar but sl ightly greater than those of the corresponding methyl esters, above.

To 667 mg. of the less polar glycol XXVI, β-side chain above, is added l6.5 ml. pyridine and then at 0°, I.67 ml. methanesul fony 1 chloride. The mixture is stirred at 0° for ten minutes, and 1 3 + hours longer with the ice-bath 1 removed. It is then again cooled at 0°. 15 ml. water i s added, and the mixture is extracted with ethyl acetate,. This is washe several times with cold dilute hydrochloric acid, aqueous sodiu bicarbonate, dried, and evaporated. The crude bismesylate is stirred in 53 ml . acetone and 26 ml. water under nitrogen at ° overnight. It is concentrated in vacuo, extracted with ethyl acetate, which is washed, dried, and evaporated. The j residue is chromatographed on 75 g. silica gel and eluted with increasing amounts of ethyl acetate in Skellysolve B. After two main peaks of material, 276 mg. and 103 mg., of unrearrange glycol mono-mesylates, are eluted 3^ mg. of 8- i so-prostagl and ί n Εχ, t r i chl oroethyl ester, showing two olefinic protons between .0 and 6.0i (H13 at 5.28<$, J=15 and 9.5 cps, and Ha4 at 5.7$, J=15 and 7 cps); two protons of the tr i chloroethyl group as a singlet, .8 The 3^ mg. of 8- i soprostagl andi n Ej. tr ichloroethyl ester which is washed several times with water, dried, and evaporated. The residue is chroma tog raphed on 5 g. Silicar-CC4 (Mai 1 i nckrodt) acid-washed sil ica gel and eluted with 50-100$ ethyl acetate-Skellysolve B. The fractions corresponding in TLC mobil ity to 8- i so^prostagland i n Ej. on the A IX system, 15 mg., are combined and crystall ized from ethyl acetate-Skel 1 ysol ve B, mp. 101-102°. This material shows no optical rotation between 7 and 230 nnu, and the NMR and mass spectra are identical to those of the " natu ral " i somer , Anal. Calcd. for C20H3 O5: C, 67.76; H, 9. 7.

Found: C, 67.56; H, 9.60.

Example 11. dl -Prostaglandi n Aj and dl -Prostaglandi n Bx Methyl Esters .

A mixture (150 mg. ) of the less polar erythro and threo glycols XXVI, -side chain, R7=CH3^ is treated in 4 ml. pyridine with 0.4 ml. methanesul fony 1 chloride at 0° and then allowed to warm to room temperature over two hours. Ice is then added, the product is extracted with ethyl acetate which is washed with cold dilute hydrochloric acid, sodium bicarbonate, dried, and evaporated. The crude bismesylate is dissolved in 15 ml. acetone to which is added 2 ml. water and 4 ml. saturated sodium bicarbonate solution, and the resulting mixture is refluxed under nitrogen for four hours. After acidification, the mixture is extracted with ethyl acetate, and the extracts washed, dried, and evaporated. The crude residue is briefly treated with exces ethereal diazomethane and chromatographed on 20 g. sil ica gel . Eiution with increasing proportions of ethyl acetate in cyclohexane gives a total of 71 mg. (50$ yield) of a mixture of dl-PGAx and dl-PGBt methyl esters. Early fractions. of the main EtOH material. The remainder of the material of the main peak, 6 mg. (λ max 219 (7530); 278 (10,150) is a mixture consisting of 65$ dl-PGAi methyl ester and 3 $ dl -PGBj. methyl ester.

Following the procedure of Example 11 but starting with a mixture of the less polar erythro and threo glycols XXVI, β-side chain, R7=CH3, there are obtained dl -8-PGAi ; methyl ester and dl-8-PGB! methyl ester.

Example 12. 6-Exo- (l' , 2l -di hydroxy hep tenyl )-2β- (6" -ca rbomethoxy- . hexyl )-bi cyclo-.[3.1.0] -hexan-3-one (XXVI, a-side chain, A mixture of 4.73 g. of crude 6-exo- (l ' , 2' -oxi doheptany 1 ) -2β- (6" -carbome thoxyheptyl ) -b i eye 1 o- [3.1.0] -hexan-3-one (XXV, β-side chain) (prepared from 5.0 g. cis, trans olefin)^9.5 ml. of formic acid^and 13.5 ml. of methylene chloride is allowed to stand at room temperature for 15 minutes. The mixture is then evaporated at reduced pressure to a dark oil which is dissolved in 250 ml . of methanol, 102 ml . of saturated aqueous sodium bicarbonate added, the mixture purged of oxygen by a nitrogen stream and sti rred at room temperature for 4.5 hours. After concentrating to 1/4 volume, the mixture is extracted 4 times with methylene chloride, the combined extract washed with water, dried and evaporated.. Crude weight 4.70 g. The oily material is chromatographed over 500 g. of sil ica gel as follows: (SSB is Skel 1 ysol ve B) : 2.5 1. 25$ EtOAc in SSB, 1.78 g, d i sea rded 1.5 1 50$ EtOAc in SSf 3.5 1 50$ EtOAc in SSB) glycol 1 r . f. , 100$ EtOAc, 0. 1.0 1 75$ EtOAc in SSB 4.0 1 75< EtOAc i n SSB) f 0.75 g glycol 2 r. f . , 100$ EtOAc, Q2 Glycol 1 is a mixture o less polar erythro and less polar threo forms; glycol 2 is more polar threo form, and glycol 5 is more polar erythro form.

Following the procedure of Example 12 but starting with 6-exo- (l1 ,2' -oxi doheptanyl )-2a- (6" -carbom^thoxyheptyl ) -bi cycloid.1.0] -hexanO-one (XXV, a-side chainjj there are obtained the a-side chain glycols of formula XXVI corresponding to the β-side chain glycols obtained as described above.

Example 1>. 8-lso-PGEj from PGEj A solution of 1.00 g. of PGEX and 5 g. of potassium acetate in 100 ml. of 95$ ethanol is al lowed to stand at room temperature under nitrogen for 6 days] then, is concentrated by evaporation under reduced pressure to about one third volume. The concentrated mixture is di 1 uted wi th 75 ml . of cold water and .dilute hydrochloric acid is added unti l the mixture reaches pH 3· The acidified mixture is extracted twice with ethyl acetate, then is saturated with sodium chloride and extracted once more with ethyl acetate. The ethyl acetate extracts are combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated under reduced pressure, then dried under a stream of nitrogen to remove acetic acid from the residue. Thin layer chromatographic analysis shows that the residue comprises a mixture of PGEi, 8-iso PGEj. and PGAx . Crysta 11 i zat i on of this residue from a mixture of acetone and Skel 1 ysol ve B gives 0Λ3 g. of crystal l ine PGEX, pure by thin layer chromatographic analysis. The mother liquors from the crystal 1 ization are chromatographed over 50 g. of Sil icagel (CC- ) and developed with mixtures of ethyl acetate and cyclohexane, taking 50 ml. fractions, as f ol 1 ows : Fractions 21-25 0$ ethyl acetate - 40 cyclohexane Fractions 26-50 100$ ethyl acetate The fractions are evaporated and the residues are analyzed by thin layer chromatography (silicagel, developed with the Bush A- IX system).. Fractions 23-25 (55 mg. ) comprise 8-iso PGEX and on crystallization from acetone-Skel 1 ysol- e B. mixture 46 mg. of 8- i so PGE ! melting at 72-75° C. is obtained. Fractions 27-50 after crysta 11 i zat i on, give 4l mg. of PGEX. Fractions 5-9 (399 mg. ) are shown by thin layer chromatographic analysis to be PGAX .

Example 14. PGEt from 8-iso PGEi.

To a solution of 100 mg. of 8-iso PGEX in 50 ml. of 9 $ ethanol is added 2.2 g. of potass i urn acetate . After the potassi acetate is dissolved, the mixture is allowed to stand at room temperature under nitrogen for 92 hrs.; then is concentrated under reduced pressure leaving a residue. Water is added to the residue, then 1 N hydrochloric acid is added to the mixture to bring the pH to about 5 ~ > and the mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with water, then w i th saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated under reduced pressure to give a pale yellow residue comprising PGEj, as shown by thin layer chromatographic analysis. This residue is twice crystallized from a mixture of ethyl acetate and Skel 1 ysol ve B and gives from the second crystallization 57 m . of PGE! having a melting point of 112-114° C. The combined mother liquors from the two crystall izations are evaporated under reduced pressure and the residue is treated with potassium acetate in ethanol and worked up as described above to obtaine a further 12 mg. of crystalline PGEx. - - 1 - - - - " - - I A solution of 440 mg. of 6-exo- (cis-1' -heptenyl ) -2a- (6"-ca bomethoxyhexyl )-bi cycl o- [3.1.0] -hexan-3-one i n 48 ml . i sopropy 1 alcohol is cooled in an ice-bath. While stirring, a solution o 480 mg. sodium borohydride in.4.8 ml. water is added. The mixture is stirred 2 1/2 hours while the ice gradual 1 y mel ts an the temperature rises toward room temperature. Then 2 ml. acetone is added, followed by 2.4 ml. acetic acid i n 24 ml, water. The organic solvent is removed in vacuo and the residue extracted with ethyl acetate. This is washed with bicarbonate, saturated salt, dried over sodium sulfate, and evaporated. The crude mixture of 3-alcohols is dissolved in ΐβ ml. methanol and 8 ml . 1 I . sod i urn hyd roxi de is added. The mi xture i s s t i r red two hours under nitrogen at 25 then the clear solution is acidified by adding 5 ml. water and 12 ml , 1 N hydrochloric acid. Methanol is removed in vacuo and the product extracted with ethyl acetate. The extracts are washed with water, saturated salt, dried i th sodium sul fate, . and evaporated. The residue has a NMR spectrum cons i stent w i th the structure, 6-exo (l! -heptenyl )-2a- (6"-carboxyhexyl ) -bi cycl o- [3.1.0] -hexan-3-ol .

This crude product is dissolved in 100 ml. acetone, cooled to 0°, and treated with 1 ml. Jones reagent for ten minutes. ^ Then 4 ml. isopropyl alcohol is added, fol lowed by 40 ml . water and the acetone is removed in vacuo. The product is extracted with ethyl acetate, which is washed with 1 N hydrochloric acid, saturated salt, dried with sod i urn sul fate, , anc†"evaporated. The crude product is chromatographed on 50 g. of Mai 1 i nckrodt Silicar CC-4, and eluted with 5, 7 1/2, 10, 15, 25, 0# ethyl acetate-Skel 1 y B. Fractions 9-12 contain j503 mg. of 6-exo- (l ' -ci s- heptenyl ) -2a- (6" -carboxyhexy 1 ) -bi cycl o- [3· 1 · 0] -hexan- In the same manner as above, 0 mg. of 6-exo- (l 1 -ci s-heptenyl )-2β- (6" -car borne thoxyhexyl )-bicyclo-[3.1.0) -hexan<-3-one is reduced with sodium borohydride, sapon i f i ed, and reoxidized. Chromatography of the crude product as above gives 2jk mg. of pure 6-exo - (l' -c? s- heptenyl )-2β- (6" -car boxy hex yl )-bi cyclo- [3.1.0] -hexan-3-one (XXIV) in fractions 12-14, whose NM and IR spectra are consistent with the above formula.

Following the procedure of Example 15 but starting with 6-endo- (l1 -ci s- heptenyl )-2a- (6" -car borne thoxyhexyl )-bicyclo-[3.1.0] -hexan-3-one there is obtained 6-endo- (l ' -c i s-heptenyl ) -2a- (6" -ca rboxyhexyl )-bicyclo-[3.1.0] hexan-3-one, and starting with 6-endo- (ΐ' -ci s-heptenyl )-2β- (6" -car borne thoxyhexyl ) -bi cycloid.1.0] -hexan-3-one there is obtained 6-endo- (l1 -ci s-heptenyl )-2β- (6" -ca rboxyhexyl ) -bi cycl o- [3.1 · 0] - hexan-3-one .

Example l6. 8- i so-PGFia and 8- i so-PGF^.

A solution of 100 mg. of .8- i so-PGEx methyl ester in 5 ml. of isopropanol is cooled in an ice bath and sti rred then 50 mg. of sodium borohydride in 1 ml. of water is added ί n one portion. After addition of the borohydri de, sti rr i ng is continued for 2.5 hrs. while the ice bath melts, at which time thin layer chromatographic analysis (sil icagel, developed three times with ethyl acetate) of a portion of the reaction mixture shows that the starting material is essentially gone. Acetone is then added and the mixture is stirred for I min.j then i s neutral i ze with dilute aqueous acetic acid, and concentrated under reduced pressure unti l most of the isopropanol is removed. The residual mixture is extracted wi th ethyl acetate and the ethyl . acetate extract is dried over sodium sulfate and evaporated under reduce pressure to give a nearly colorless residue. The residue is Fract ί ons Sol vent Wt. el utedj mg. 1-5 40$ Ethyl acetate-- 60$ cyclohexane β-io 66$ ethyl acetate · 3 $ cyclohexane 11 100$ ethyl acetate 2 12 1 13 0 14 •! II 4 42 16 5$ methanol 95$ ethyl acetate 38 (crystallin 17 12 18 7 19 4 2 21 1 22 0 Fractions 15, l8, 19, and 20 are combined and rechroma tog ra phed as above. Corresponding fractions of the first and second chromatograms are combined, thus obtaining a total of 6l mg. of partly crystall ine material, (the more polar of the two product 13 mg. of a mixture, shown by TLC ana 1 ys i s to be mainly the mor polar product, and 15 mg. of a less polar product, 8-iso-PGFip. The more polar fraction, 8-iso-PGFia, is crystal 1 i zed from a mixture of ether and Skellysolve B (mixed hexanes) to give 8 mg of 8- i so-PGFia as waxy crystals having a melting point of 60-6l Example 17. Equil ibration of 6-exo- (c i s-1 ' -hepteny 1 )-2o (6" -ca bomethoxyhexyl ) r i cyclo-[3.1.0] -hexan-3-one and the 2-β- isomer thereof. 6-exo- (cis-l( -heptenyl )-2 - (6" -carbomethoxyhexyl )-bicydo- and the mixture is maintained under nitrogen at 25° C. for one hour. Then, sufficient hydrochloric acid (3 N) is added to neutral ize the potassium tert-butox i de. The mixture is diluted with 500 ml. of water and then extracted 3 times with 100-ml . portions of ethyl acetate. The ethyl acetate extracts are dried and evaporated to give a residue which is chromatographed over sil ica gel (el uti on wi th 5 ethyl acetate in Skel lysolve B) to give after evaporation of the eluates, 38Ο mg. of starting material (alpha) and 700 mg. of the corresponding beta isomer. Fol lowing the above procedure but using the beta isomer as starting material, the same results were obtained.

Example 18 6-Carbethoxyb icyclo[3.1.0 ]hexan-j5-ol and 6-carbethoxyb icyclo [3.1.0 ]hexan-2-ol .

A solution of 96. 6 g. of 6-carbethoxyb icyclo[3.1.0 Jhexene in 500 ml . of dry ether is stirred under n i trogen, about one half of 266 ml . of 1.0 M boron hydride in ether is added dropwise at room temperature. The reaction mixture is cooled to 0° C. and the remaining boron hydride solution is added. Addition of the boron hydride solution requires about 45 min. The reaction mixture is then stirred at room temperature for 5 min. and then the solvent is removed by evaporation under reduced pressur The residue is dissolved in 500 ml . of ether and cooled to 0° C. with an ice-methanol bath} then 150 ml . of 3 N aqueous sodium hydroxide is added over a period of 10-15 min.. while keeping the temperature below 5° C., followed by addition of 8o ml . of 30 hydrogen peroxide over a period of 15 min. while keeping the' temperature below 10° C. The mixture is then stirred 55 min. at room temperature and the layers are separated. The water layer is extracted twice with ether and j5 times, with ethyl acetate. The organic solutions are combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and evaporated under reduced pressure, leaving 89 g. of a residue comprising a mixture of 6-carbethoxyb i cyclo[3.1.0 ]hexa 3-ol and 6-carbethoxyb icyclo[3.1 · 0 ]hexan-2-ol · The mixture is mai nl y 5'ol .

Exam le 19 6-Carbethoxyb icyclo[3.1.0 ]hexan-3-ol tetrahydro- pyranyl ether and 6-carbethoxyb icyclo[3.1.0]hexan- 2-ol tetrahydropyranyl ether.

A mixture of 88.0 g. of a mixture of 6-carbethoxyb i cycloid.1.0 ]hexan-j5-ol and 6-carbethoxyb and 88 ml . of dihyd ropy ran is cooled to 0° C. and 40 drops of mixture is then diluted with methylene chloride and washed with cold saturated aqueous sodium bicarbonate. The layers are separated and the aqueous layer is extracted three times with methylene chloride. The organic layers are combined and washed with water (the water washes are back-ext racted ) , dried over sodium sulfate and evaporated under reduced pressure leaving a residue. This residue is distilled under reduced pressure, giveing 18 g. of a forerun boiling at 4o° C. between 1.3 and 0.4 mm. Hg., and then 75.3 of a mixture of 6-ca rbethoxyb i eye 1 o-[3.1 · 0 ]hexan-3-ol tet rahyd ropyranyl ether and 6-carbethoxy-b i cyclo[3.1.0 ]hexan-2-ol tet rahyd ropyranyl ether boil ing at 98- 131° C. over a pressure range of 0.3" 1.0 mm. Hg.

Example 20 PGEi from PGEX methyl ester.

A. Enzyme preparation A medium is prepared consisting of 2$ corn steep l iquor (a mixture of equal parts of cerelose and glucose) in tap water. This is brought to pH 4.5 by adding hydrochloric acid, and 1$ of methyl oleate is added. Four 500 ml. flasks each containing 100 ml . of the above medium are inoculated with Cladosporum resinae (Cl-11, ATCC 11,274) and are placed on a shaker at room temperature (about 28° C.) for 4 days. The culture is then placed in 4o ml . centrifuge tubes and centrifuged at about 2000 rmp. in a clinical centrifuge. The liquid is decanted from the centrifuge tubes and the collected cel ls are washed with cold water. The washed cells from 2 centrifuge tubes are suspended in 50 ml . of ice cold 0.05 pH 7.0 phosphate buffer and placed in small Waring blender cup chilled with ice. Glass beads are added and the suspended cells are churned in the blender for 15 minutes. The resulting suspension of broken cells is centrifuged in a cl inical centrifuge at about 2000 r.p.m. resinae acylase and can be used directly for the hydrolysis of PGEi alkyl esters or can be stored, preferably frozen, until needed.

B. Esterase hydrolysis of PGEi methyl ester Ten mill il iters of the supernatant liquid containing Cladosporium resinae acylase, prepared as described in part A of this example and 50 mg. of PGEi methyl ester are shaken at room temperature under nitrogen for about 19 hrs., then 70 ml . of acetone is added and the mixture is filtered giving a filtrate and an insoluble residue. Thin layer chromatographic analysis (silica gel plate, developed with CHCl3:H0Ac, CH30H 90:5:5) shows that both the filtrate and the insoluble residue obtained by filtration contain PGEi. The filtrate is evaporated under reduced pressure and gives 40-50 mg. of a sl ightly yellow oi l comprising PGEi. Both this oil and the insoluble residue are combined and chromatographed over 10 g. of acid washed silica gel (Sil ic ARCC-4, Ma 11 i nckrodt ) . Elution is with mixed hexanes (Skellysolve B) containing increasing amounts of ethyl acetate, collecting 50 ml . fractions as fol lows: F ract ion Sol vent 1 Skel 1 ysol ve B 2 40 ml . Skellysolve B - 10 ml . ethyl acetate 3 30 Λ 20 " 4 25 " 25 20 " 30 6 10 " 4o 7 5 " 5 " 8 ethyl acetate 9 ft 11 12 100 ml . of ethyl acetate Fractions 6 to 12 are combined and crystall ized from a mixture of acetone and hexanes (Skellysolve B). The crystals are separated by filtration, wased with ether, and dried to give The optical rotatory dispersion curve is identical with the optical rotatory dispersion curve of authentic PGEi.

C. Esterase hydrolysis of dl PGEj methyl ester Twelve mill il iters of the supernatant l iquid containing Cladosporium resinae acylase, prepared as described in part A of this example and kept in frozen storage for about 3 weeks and 129 mg. of dl-PGEi methyl ester are mixed and shaken at room temperature under nitrogen for about 20 hrs., then the mixture is diluted with 100 ml . of acetone, fi ltered, and the filtrate is evaporated under reduced pressure leaving a residue comprising dl-PGEi. The residue is chromatographed over Sil ic A CC-4 (Ma 11 i nckrodt ) .

The column is eluted with mixtures of Skellysolve B and ethyl acetate, and ethyl acetate and methanol, as follows : Fract ion Solvent ml . ethyl acetate 1 1 12 50 ml . ethyl acetate + 1% methanol 13 1$ 14 2$ 2 16 17 The fractions are evaporated and analyzed by thin layer chromatography. Fractions 7-9 contain d,l-PGEi methyl ester (total wt . 66 mg.), fractions 10 and 11 contain a mixture of Example 21 d 1 -8- i so- PGE i methyl ester from endo series.

A solution of 7 mg. of 6-endo- (l 1 ,21 -d i hydroxyheptyl )-2β- (6"-carbomethoxyhexyl |-b icyclo[3.1.0]-hexan-3-one in 2 ml . of dry pyridine is cooled in an ice bath and stirred under nitrogen, then 0.5 ml . of methanesu 1 fonyl chloride is added and the mixture is stirred for 2 1/2 hrs. in the melting ice bath. The mixture is then cooled in a fresh ice bath, and is diluted with 10 ml . of cold water, stirred for 10 min. It is then poured into a separatory funnel containing ice and extracted with j5 25_ml . portions of cold ethyl acetate. The ethyl acetate extracts are combined, washed with 15 ml . cold water, 15 ml . cold 10$ sulfuric acid, 15 ml . cold aqueous 10$ sodium carbonate, and 2-15 ml . portions of cold water, then dried over sodium sulfate and evaporated under reduced pressure leaving a residue com-prising the bis-mesylate of 6-endo- (l 1 ,2 ' -d i hydroxyheptyl }-2β- (6"-ca rbomethoxyhexy 1 )-bicyclo[3-l.0 ]-hexan-3~one . This res i due is dissolved in 2 ml . of acetone plus 1 ml . of water and allowed to stand about 18 hrs. at room temperature, then the mixture is evaporated under reduced pressure. To the residue is added ml . of water, and the mixture is extracted with 520-ml . portions of ethyl acetate. The ethyl acetate extracts are combined and washed with 10 ml . of saturated aqueous sodium bicarbonate, dried over sodium sulfate, and evaporated under reduced pressure leaving a residue which on thin layer chroma- tographic analysis (sil ica gel plate developed with ethyl acetate) is shown to comprise d , 1 -8- i so-PGEi methyl ester.

Example 22 PGEi and 15 epi-PGEi, from endo series A solution of 0.115 g. of 6-endo- (l ' ,2 ' -d i hydroxyheptyl )-2a- (6"-carbomethoxyhexyl )-b icyclo[3,l .0 ]-hexan-3~one in ml. of dry pyridine is cooled in an ice bath and stirred under nitro en while 0.6 ml . of methane sulfon l chloride is added. about 2 1/2 hrs., then the reaction mixture is cooled in a fresh ice bath and the reaction mixture is diluted with 10 ml-, of a mixture of ice and water, and stirred for a further 10 min. The mixture is then poured into a separatory funnel containing crushed ice and extracted with 3 25_ml . portions of cold ethyl acetate. The cold ethyl acetate extracts are combined and washed with cold water, cold 10$ sulfuric acid, cold aqueous sodium carbonate, and cold water, then dried over sodium sulfate and potassium carbonate, and evaporated under reduced pressure at below o° C. leaving a residue comprising the bis mesylate of 6-endo- (l ' ,2 '-d i hydroxyheptyl )-2a- (6"-ca rbomethoxy-hexyl )-b icyclo[3.1.0]-hexane-3~one. This residue is dissolved in ml . of acetone, then 2 ml . of water is added and the mixture is al lowed to stand about 18 hrs. at room temperature, then is diluted with 5 ml . of water and extracted with 3 30-ml . portions of ethyl acetate. The ethyl acetate extracts are combined and washed with 5 ml . of saturated aqueous sodium bicarbonate, dried over sodium sulfate, and evaporated under reduced pressure at below 4o° C. leaving 0.102 g. of residue comprising PGEi methyl ester. This: residue is chromatographed over 15 g. of silica gel , and eluted with 15 ml . portions of solvent as follows: Fraction Solvent 1-6 2 $ ethyl acetate - 7 $ Skellysol 7-11 50$ " " 50# 12-16 75$ " " 25# 17-21 100$ " " 22-24 95$ " " 5# methanol.

The eluted fractions were evaporated and analyzed by thin layer chromatography (ethyl acetate on sil ica gel ). Fractions I7-I9 (combined wt . 19 mg.) are PGEi methyl ester. Fractions 12 mg . ) are largely PGA'i methyl ester and fraction 9 (13 mg. ) 15-ep i - PGAi methyl ester.

Example 23 Endo-b icyc 1 o[3 · · 0 ]hexan-3" o 1 -6- ca rboxy I i c acid methyl ester.

A mixture of endo-b i cycl o[3.1.0 ]hex-2-ene- 6-carboxy 1 i c acid methyl ester (1Q3 g. ) and anhydrous diethyl ether (650 ml . ) is sti rred under nitrogen and cooled to - 5° C . A one molar solution (28 ml . ) of diborane in tet rahyd rof u ran is added c!ropwise during 30 minutes whi le keeping the temperature below 0° C The resulting mixture is then sti red and al lowed to warm to 25° C. during 3 hours. Evaporation under reduced pressure gives a residue which is dissolved in 650 ml . of anhydrous diethyl ether. The solution is cooled to 0° C, . and 3 normal aqueous sodium hydroxide solution (lJ2 ml . ) is added dropwise under nitrogen and with vigorous stirring during 15 minutes,, keeping the temperature at 0° to 5° C, Next. 30$ aqueous hydrogen peroxide (9 ml . ) is added d ropwise with sti rring during 30 minutes at 0° to 5° C. The resulting mixture is sti rred an hour whi le warming to 25° C. Then. 500 ml . of saturated aqueous sodium chloride, solution is added., and the diethyl ether layer is separated. The aqueous layer is washed with four 200-ml . portions of ethyl acetate, the washings being added to the diethyl ether layer, which is then washed with saturated aqueous sodium chloride solution, dried, and evaporated to give 115 g. of a res idue. This res idue is disti l led under reduced pressure to give 69 g. of a mixture of the methyl esters of endo-b i eye 1 o-[3· 1.0 ]hexan~3"ol -6-carboxyl ic acid and endo-b i cycl o[3- 1.0 ]-hexan-2-ol -6-carboxyl ic acid; b , p „ 86-95° C, at 0.5 mm, Example 2 Endo-b i cycl o[ 3.1.0 ]hexan-3-o 1 -6- ca rboxy 1 i c acid methyl ester tetrahydropyranyl ether. at 15"20° C, during addition of 3 ml , of anhydrous diethyl ether saturated with hydrogen chloride. The temperature of the mixtur is then kept in the range 20° to 30° C - for one hour with cool ing, and is then kept at 25° for 15 hou s. Evaporation give a residue which is disti l led under reduced pressure to give 66 g of a mixture of the methyl es ters - te rahyd ropy rany 1 ethers of endo-b i eye 1 o[ 3 · 1 < 0 ]hexan-'3-oi '6-ca rboxy 1 i c acid and endo-b i cyclo[3 ■ 1 - 0 ]hexan-2-ol '6-carbcxyl i c acid; b .p. 96- 10 ° C, a 0.1 mm .

Examp 1 e 25 Endo-6- hyd roxymethy lb i eye 1 o[3 > -1 · 0 ]hexan- -0? - tet rahyd ropyrany 1 ether A solution of the mixture (66 g. ) of products obtained according to Example 24 in 300 ml ., of anhydrous diethyl ether is added dropwise during minutes to a sti rred and cooled mixture of l ithium aluminum hydride (21 g. ) in 1300 ml . of anhydrous diethyl ether under nitrogen. The resulting mixture i sti rred 2 hours at 25° C„ , and is then cooled to 0° C. Ethyl acetate (71 ml , ) is added, and the mixture is sti rred 15 minutes Water (235 ml . ), is then added, and the diethyl ether layer is separated, The water layer is washed twice with diethyl ether and twice with ethyl acetate= A solution of Rochel le salts is added to the aqueous layer, which is then saturated with sodium chloride and extracted twice with ethyl acetate. All diethyl ether and ethyl acetate solutions are combined, washed with saturated aqueous sodium chloride solution , dried, and evaporat to gi e 6l g. of a mixture of the 3- tetrahydropyranyl ethers of endo-6- hyd roxymethy 1 b i eye lo[3- 1 · 0 ]hexan-3~o 1 and endo-6- hyd roxy methy 1 b i eye 1 o[3- 1 , 0 ]hexan-2-ol , Example 26 Endo-b i eye lo[3 - 1.0 ]hexan-3_ol -6-carboxa 1 dehyde " -10° C, Jones reagent (75 ml , of a solution of 21 g. of chromic anhydride., βθ ml . of water, and 17 ml . of concentrated sulfuric acid), precooled to 0° C,, is added dropwise with stirring during 10 minutes at -10° C. After 10 minutes of additional stirring at -10° C., isopropyl alcohol (35 ml . ) is added during minutes, and stirring is continued for 10 minutes The re-I action mixture is then poured into 8 1 - of an ice and water mixture. The resulting mixture is extracted 6 times with di- ch loromethane , The combined extracts are washed with aqueous sodium bicarbonate solution, dried, and evaporated to give 27 g. of a mixture of the tet rahyd ropy rany 1 ethers of endo-b i eye.1 o- [3.1.0 ]hexan-3"ol -6- ca rboxa 1 dehyde and endo-b i eye 1 o[3 · 1 ■ 0 ]hexan- 2-ol -6- ca rboxa 1 dehyde ! Example 27 Endo-6- (cis- and t rans - 1- hepten y 1 )-b i eye 1 o[3 - 1 0 ]- 15 hexan-3*ol tetrahydropyranyl ether.

A mixture of hexyl bromide (100 g. ), t r i phen y 1 phosph i ne (ΐβό g.), and toluene (300 ml .) is stirred and heated at reflux for 7 hours. The mixture is then cooled to 10° C., and the crystals which separate are col lected by fi ltration., washed with j 20 toluene, and dried to give 1 7 g. of hexy 1 tr i phenyl phosphon i urn bromide; m,p. 197-200° C.

A mixture of hexy 1 r i phen y 1 phosphon i urn bromide (102 g. ) and benzene (1200 ml . ) is stirred under nitrogen during addition of a solution of butyl l ithium in hexane (146 ml . of a 15$ solution -w/v). The resulting mixture is stirred 30 minutes.

Then a solution of the mixture (27 g. ) of products obtained according to Example 26 in 300 ml . of benzene is added dropwise with stirring during 30 minutes. The mixture is heated and sti rred at 70° C. for 2,5 hours, and then is cooled to 25° C. combined., washed with water, and dried to give 58 g „ of a mixture of the tet rahyd ropy rany 1 ethers of endo-6- (cis- and tra 1-hepteny 1 )-b i cyclo[3.1 , 0 ]hexan~3"Ol and endo-6- (cis- and trans 1-heptenyl )-b i cycl o[ » 1 -0 ]hexan-2-o 1 = Example 28 Endo-6- (c i s - and t rans - 1- hepteny 1 ) -b i cycl o[3.1 f 0 ]- hexan-3~ol .

Oxal ic acid (3 g.) is added to a solution of the mixture (58 g,) of products obtained according to Example 27 in 1500 ml of methanol . The mixture is heated under reflux with stirring for lt5 hours. Evaporation under reduced pressure gives an oil which is dissolved in d i ch 1 oromethane , That solution is washe with aqueous sodium bicarbonate solution, dried and evaporate under reduced pressure. The residue is dissolved in an isomer hexane mixture (Skel lysolve B), and ch romatog raphed on 600 g. of wet-packed sil ica gel , The column is eluted with 2 h of Skel lysolve B, and then successively with 1 1. of 2.5$^ 2 1 „ o 5t, 2 1. of 7, $, 5 1. of 10%, and 3 1 , of 15^ ethyl acetate i Skel lysolve B, Evaporation of the combined fractions correspo ing to the 10$ and 15$ ethyl acetate gives l6 g. of a mixture endo-6- (cis- and trans - 1- heptenyl ) -b i cycl o[ e 1, 0 ]hexan-3_o 1 an endo-6-(cis- and t rans - 1- hepteny 1 )-b i eye 1 o[3.1 c 0 ]hexan-2-o 1 J Example 29 Endo-6- (cis- and t rans - 1- hepteny 1 ) -b i cycl o[3 , 1.0 ]- hexan-3~one .

A solution of the mixture (15 g .. ) of products obtained according to Example 28 in 50 ml . of acetone is cooled to -10 and stirred while adding 30 ml . of Jones reagent (Example 26) dropwise during 10 minutes. The resulting mixture is stirred 10 minutes at -10° C. Then, isopropyl alcohol (15 ml .. ) is add and stirring is continued for 10 minutes. The mixture is pour l of a er he a er is ex ac e imes wi h aqueous sodium bicarbonate solution, dried, and evaporated to give an oi l . The oi l is chromatographed on 500 g, of si l ica gel wet-packed with isomeric hexanes (Skel 1 yso 1 e B ), eluting successively with 2 1 , of Skel lysolve B, 2 1. of 2 t $ ethyl acetate in Skel lysolve B, and 10 1 , of 5$ ethyl acetate in Skel lysolve B The fi rst 1.5 1. of the $ ethyl acetate in Skel lysolve B eluate is evaporated to give 5-9 g* of endo-6- (cis- and t rans - 1- heptenyl ) -b i cyclo[ , .1.0 ]hexan-j5-one ; Rf 0f62 on thin layer chromatography with si l ica gel plates developed with 20$ ethyl acetate in cyclohexane.

Fol lowing the procedures of Examples 27, 28 and 29* but using in Example 27 butyl bromide, pentyl bromide,,, heptyl bromide, and octyl bromide in place of hexyl bromide, there ar obtained the 1-pentenyl , 1-hexenyl , 1-octenyl , and 1-nonenyl compounds corresponding to the product of Example 29* Also fol lowing the procedures of Examples 27* 28, and 29* but using in Example 27 primary bromides of the formula X- (CH2 )cj-CH2B r , wherein d is one, 2,. > or 4, and X is isobuty tert-butyl , 3, 3-d i f 1 uorobut yl , 4,4-di f luorobutyl , and 4,4,4-tr i f luorobutyl , in place of hexyl bromide, there are obtained compounds corresponding to the product of Example 29 with X- (CH2 )d"CH=CH- in place of the 1-heptenyl moiety.

Also fol lowing the procedures of Examples 27* 28, and 29 but using in Example 27 the other primary and secondary bro- R3 mides of the formula R2-CH-Br wherein R2 and R3 are as defined above in place of hexyl bromide, there are obtained compounds R3 corresponding to the products of Example 29 with R2-C=CH- in place of the 1-heptenyl moiety.

Also fol lowing the procedures of Examples 27, 28, and 29 after Example 29 the exo compound corresponding to the endo product of Example 29 and to each of the endo products defined after Example 29 are obtained. The necessary exo b i eye lo[3 · 1 * 0 ] hexane reactants are prepared as described in Belgian Patent No, 702,477, Example 30 Endo-6- (cis- and t rans - 1-octeny 1 ) -b i eye 1 o[3 , 1 = 0 ]- hexan-3-ol tetrahyd ropy ran yl ether, A mixture of heptyl bromide (100 g. ). t r i pheny 1 phosph i ne (150 g. ), and toluene (300 ml .) is stirred and heated at reflux for 7 hours. The mixture is then cooled to 10° C ., , and the crystals which separate are col lected by fi ltration; washed with toluene, and dried to give heptyl tri phenyl phosphon ium bromide,, A mixture of heptyl tr i phenyl phosphon i urn bromide (105 g») and benzene (1200 ml, ) is stirred under nitrogen during addition of a solution of butyl l ithium in hexane (l46 ml . of a 15$ solution - w/v), The solution is stirred 30 minutes, Then a solution of the mixture (26 g.) of products obtained according to Example 26 in 100 ml . of benzene is added dropwise with stirring over 30 minutes. The mixture is heated and stirred at 60-70° C. for 2.5 hours, and then is cooled to about 25° C. The resulting precipitate is col lected by fi ltration and washed with a l ittle benzene, The filtrate and benzene wash are combined, washed three times with 250-m portions of water, and dried over sodium sulfate. The resulting benzene solution is evaporat to dryness to give 40 g. of a mixture of the tet rahyd ropy ran yl ethers of endo-6- (cis- and t rans - 1-octeny 1 ) -b i eye lo[3.1.0 ]-hexan-3~ol and endo-6- (cis- and t rans - 1-octen yl ) -b i eye 1 o[3 - 1 *0 ]-hexan-2-ol , Example 31 Endo-6- (cis- and t rans - 1-octeny 1 )-b i eye 1 o[3- 1.0 ]- hexan- ~ol . of methanol . The mixture is heated under reflux with stirring for 1 5 hours. Evaporation under reduced pressure gives an oi l which is dissolved in 400 ml, of dichloromethane, That solution is washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, and evaporated under reduced pressure. The residue (31 g.) is dissolved in 100 ml . of an isomeric hexane mixture (Skellysolve B) and ch romatog raphed over βθθ g, of wet-packed si l ica gel . The column is eluted with 2 1. of Skellysolve B, and then successively with 1 1. of 2„5%, 2 1 , of 5^ 2 1 , of 7.5$, 5 1. of 1058 and 3 1. of 15 ethyl acetate in Skel lysolve B. Evaporation of the combined fractions corresponding to the 10$ and 15 ethyl acetate gives 1 ^ g* of a mixture of endo-6-(cis-and t rans - 1-octenyl )-b i cycl o[3.1.0 ]hexan~3-ol and endo-6- (cis-and t rans - 1-octeny 1 )-b i cycl o[3 f 1.0 ]hexan-2-ol .

Example 3 Endo-6- (c i s - and t rans - 1-octeny 1 )-b i eye 1 o[3 , 1 , 0 ]- hexan-3~one, A solution of the mixture (15-5 g. ) of products obtained according to Example 31 in ^50 ml . of acetone is cooled to -10° C. and stirred while adding 30 ml , of Jones reagent (Example 26) dropwise during 10 minutes, keeping the temperature between -10° and 0° C. Sti rring is continued for 10 minutes fol lowing addition of the Jones reagent; then 15 ml , of isopropyl alcohol is added and stirring is continued for 10 minutes. The mixture is pou red into 2.5 1 , of water.

·".. The water is extracted with 5 500-ml . portions of dichloromethane. The combined extracts are washed with aqueous sodium bicarbonate, dried over sodium sulfate, and evaporated to give an oil . The oi l is dissolved in 100 ml , of isomeric hexanes (Skellysolve Bj and chromatographed on 500 g. of si l ica el wet- acked with Skell solve B. The column is 2 1 , of 2.5$, and 8 1. of 5ί ethyl acetate in Skellysolve B. The first two l iters of the $ ethyl acetate in Skellysolve B eluate is evaporated to give 4,8 g. of endo-6- (cis- and trans-1-octenyl )-bicyclo[j5.1.0 ]hexan-3-one , Example 33 Methyl 6-endo- (l-octeny 1 ) -3-oxob i eye 1 o[3.1.0 ]- hexane-2- heptanoate „ A solution of 4.8 g. of endo-6-(cis- and trans -1-octenyl )-b i cycl o[ > 1.0 ]hexan-3-one from Example 32, and 12..7 g. of methy 7" i odoheptanoate in 75 ml . of tet rahyd rof u ran is prepared, and nitrogen is bubbled through the solution for 5" 10 minutes. A solution of 3.91 ·· of potassium tert-butoxide in 150 ml , of tet rahyd rof u ran is similarly flushed with nitrogen. The two solutions are then simultaneously added dropwise, at 25° C, at one end of a 70-8o cm, horizontal tube over a period of 45 minutes. The reaction mixture drips from the tube into a flask containing 4θ ml , of 5$ hydrochloric acid.. The mixture is concentrated under reduced pressure in a bath at 40-50° C., to remo most of the tet rahyd rof u ran . The residue is diluted with 100 m of water, and then is extracted with 4 100-ml , portions of ethy acetate* The first three ethyl acetate portions are combined and washed with 5$ aqueous sodium thiosulfate and then with aqueous saturated sodium chloride. The aqueous washes are back extracted with the fourth ethyl acetate extract. The ethyl acetate extracts are then combined, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give an oil . This total crude oi l is dissolved in Skel lysolve B and chroma-tographed over 300 g. of alumina (Grade l l ). The column is eluted with 1.5 1 of 10$, 1.5 1. of 20$, and 1.4 1.. of 50 benzene in Skellysolve B, and final ly with 1,6 1. of benzene. The 10 and 20$ benzene in Skel l solve B elua e are eva ora ed starting ketone, The last 1000 ml , of the 50$ benzene eiuate and the benzene eiuate are evaporated to give 1-192 g, of oil .. This oil is dissolved in Skellyso e B and chroma tog raphed over 150 g. of si l ica gel . The column Is eluted with 750 ml . of Skei lysolve B and then successively with 750 ml = of 2- $ 5000 ml . of 5$ and 750 ml of 10$ ethyl acetate in Ske's iysolvs taking a first fraction of 750 ml, of Ske i 1 ysolve B, fo'' lowed b 150 ml s fractions Fractions 11 to 15 are evaporated and combined to give 0.62 gr of methyl 6-endo- (l~octenyl )~ 3' cxob i eye 1 o [J.I 0]hexane-2-heptanoate (less polar isomer)- Fractions l6 t 20 are combined to give 0,238 g. of methyl 6-endo- (l-octen l )■· 3~oxob i cycl o [3 1 - 0 ]hexane-2-heptanoate (more polar isomer), .|x91P-L¾_.2,t Methyl 6-endo- (l-octenyi )-3_oxob i cyc!o[3 · 1 - 0 ]- hexane-2- heptanoate .

A solution of 3*0 - of potassium .t-butoxide in 400 ml ■ of tatrahydrofuran is added dropwise with stirring, under nitr gen v at 25° C, over a 45-minute period to a solution of 3-75 of endo-6- (c i s - and t rans- 1-octeny 1 )-b cycl o[ , 1 · 0]hexan-3* ne and 14,7 g~ of methyl 7- i odoheptanoate in 200 ml . of tetrahycir furan. The reaction mixture is stirred about 15 minutes after addition of the butoxide solution is over: th¾n 40 ml , of 5$ hydrochloric acid is added This mixture is diluted with 150 of water and extracted with 4 100-ml , portions of ethyl acetat The first three ethyl acetate extracts are combined- washed wi 5$ aqueous sodium thiosulfate and then with saturated aqueous sodium chloride, The fourth ethyl acetate extract is used as backwash. The ethyl acetate extracts are combined^ dried over sodium sulfate., and evaporated under reduced pressure to give an o! This crude oil is dissolved in 50 mi . of Ske lyscive successively with 1.5 of 20$, and 1,5 of 50$ benzene in Skellysolve B, and final ly with 1.5 1. of benzene. The 50$ benzene in Skellysolve B and th® first 300 ml , of the bsnzene e!uate are evaporated to give 1. 13 g. of oi l . Th»s oi l is dissolved in Skel lysolve B and chromatographed over sil ica gel The column is eluted with 750 ml , of Skellysolve B., then with 750 ml . of 2,5$ and 3000 ml . of 5< ethyl acetate in Skellysolv B taking fractions of 750 ml,, 50 ml ,, and then successively 150 ml Fractions 9" 12 are evaporated and combined to give 0,866 g„ of methyl 6~endo- (l-octeny 1 )-j5-oxob i eye lo [3.1 , 0 ]-hexane-2-heptancate (less polar isomer). Fractions 12 to 2C are evaporated and combined to give 0„312 g. of methyl 6-endo- (l-octenyl )- "Oxob icyclo[3.1 » 0 ]hexane-2- heptanoate (more po 1 a r i somer^, Example 35 Methyl 6-endo- (l,2-d i hydroxyoctyl )~3~oxob I cyclo- [3- 1.0 Jhexane- 2 -heptanoate, A solution of 1 = 5 g- of methyl 6-endo- (l-octeny < )-3~oxo~ blcyclo[3! l»0]hexane-2-heptanoate (less polar isomer from Examples 33 and 34) and 1.3 9-· of osmium tetroxide in 30 ml . o pyridine is stirred at 25° C, for 1 hours; then a solution of 3-6 g~ of sodium bisulfite in a mixture of 60 ml ., of water and 39 ml . of pyridine is added, and stirring is continued for about 5.5 hours. This mixture is di luted with 100 ml , of wate and is extracted with 3 400-ml . portions of chloroform. The chloroform extracts are combined, washed with 100 ml . of water dried over sodium sulfate, and evaporated under reduced pressu to give I.56 g, of an oi l . The oi l is dissolved in 40 mi , of 40$ ethyl acetate in Skel lysolve B and chromatographed over 1 0 g, of si l ica gel . The column is eluted with 2,1 1 » of 0$ fractions 6 to 8, amounts to 0.644 g, The morf polar glycol 3 obtained in fractions 9 to 16, amounts to 0.712 g.

Example j56 Methyl 6-endo- (l,2-d i hydroxyoctyl )-5~>-oxob \ cyc^o- [3.1.0 ]hexane-2 -heptanoate.

A solution of 0.55 g. of methyl 6-endo- (l-octenyl V-J-oxo-b i eye 1 o[5< 1.0 ]hexane-2- heptanoate (more polar isomer from Examples 33 and 34) and 0.43 g, of osmium tetroxide in 10 ml , of pyridine is stirred at 25° C. for about 15 hours; then a solution of 1.2 g. of sodium bisulfite in a mixtu e of 20 m'l , of water and 13 ml , of pyridine is added., and stirring is continued for 5"6 hours. This mixture is di luted with 40 ml . of water and extracted with 3 l40-m] , portions of chloroform. The chloroform extracts are combined., washed with 40 ml , of water, dried over sodium sulfate, and evaporated under reduced pressure to give 0.5 g. of methyl 6-endo- (l,2-d i hydroxyoctyl )-3~oxyb icyclo-[3 f 1.0 ]hexane-2- hf!ptanoate .

Example 3 20-Methyl pros tag 1 and i n E Methyl Ester and 1.5-epl- 20-Methyl prostagl and i n Ea Methyl Ester A solution of 0,63 g. of methyl 6-endo- (l,2-d i hydroxyoctyl )-3-oxob icyclo[3« 1.0 ]hexan-2 -heptanoate (less polar glycol , fractions 6 to 8 of Example 35) in 20 ml . of pyridine is stirred under nitrogen while cool ing in an ice bath. Two ml . of methane-sulfonyl chloride is added, and th© solution is stirred for 2.5 hou s in the melting ice bath. The solution is di luted with 30 ml . of ice and water, stirred for 10 minutes, and transferred to a separatory funnel containing crushed ice. The mixture is extracted with 3 100-mt /. portions of cold ethyl acetate. The ethyl acetate extracts are combined and washed with 70 ml . of cold. 10$ sulfuric acid^ then with cold aqueous sodium bicar-benate, and twice with ice water, Tb eth l acetate solution Is and evaporated to give Ο.89 g. of dimesylate as an oi l . The oi l is dissolved i n j56 ml . of t@t rahyd rof u ran , di luted wi th 12 ml , of water, and al lowed to stand about 20 hours at room temperature. The mixture is di luted wi th 25 ml . of water and corcen-trat@d under reduced pressure to remove tet rahyd rofu ran .. The mixture is then di luted wi th 50 ml , of water and extracted wi th 5 100-ml , portions of ethyl acetate. The ethyl acetate extracts are combined and washed wi th saturated aqueous sodium b i ca rbonate , and twice with saturated aqueous sodium chloride, then dried over sodium su lfate and evaporated to dryness to give 0 ,6 > g= of oi l . This oi l is dissolved in a mixture of 25$ ethyl acetate In Skel l ysolve B and ch romatog raphed over 0 g. of s i l ica gel , The column is eluted wi th KOO ml . of 25 , 250 ml , of 50$, and 250 ml . of 7 $ ethyl acetate in Skel l ysolve B, then wi th 250 ml , of ethyl acetate, and f inal l y wi th 250 ml . of ethyl acetate containing $ methanol , taking f i rst 2 150-ml . fractions and then 50 ml ., fractions , Fractions 20 and 21 (ethyl acetate containing 5$ methanol ) are evaporated to give 69 mg, of 20-methyl pros tag 1 and i n Ei methyl ester. Fractions 14 to 16 (75$ ethyl acetate in Skel l ysolve B, then two ethyl acetate fractions) are evaporated to give 97 mg. of 15_ep i -20-methyl pros tag 1 and i n Ei methyl ester.

The more polar g l ycol (0.70 g. , fractions 9 to 16 in Example 35) is treated. with methanesu 1 f ony I chloride, then sol ol yzed and worked up as described above to give 0.69 g» of oi l . This oi l is ch romatog raphed as described above to give 139 mg . of 20-methylpnbstaglancUn Ej. methyl ester and 126 mg, of 15-ep i -20-methy 1 p ros tag 1 and i n Ei methyl ester.

The 20-methy 1 pros tag 1 and i n Ei methyl ester obtained from the chrcmato rams in the two ex eriments described above is i I Skel iysol e B to give an analytical sample of 20-methy ! ros ta-giandin Εχ methyl ester, m.p. 67-68° C ; mass spectrum spectral peaks at 382, 36 , }½3 333, 315, 314, 297.- 293, 279, 47 and 20 .

The 15-ep ί -20-methy 1 pros tagl and i n Ej methyl ester obtained from th<¾ chromatograms. in the two experiments described above i combined and crystal l ised from a mixture of ether and Skel iysolve B to give 15~ep i -20-methyl pros tag 1 and i n Ei methy1 ester,, Exampl 38 8- I so-20-methyl pros tag 1 and i n Ei Methyl Ester and 8- I sc-15-ep i -20-methy 1 pros tag t and i n Ei Methy:' Ester Fol lowing the procedure of Example 37, 0.-54 ? of methyl 6-endo- (l,2-d i hydroxyocty 1 }-3"Oxob i cyclo[3.1.0 ]hexane-2p-heptanoate (obtai ed according to Example 36) is treated wi h methanesu 1 fony 1 chloride in pyridine., and worked up to obtain 0, 6 g. of dimesylate. The dimesylate is dissolved in 20 ml . acetone, di luted with 12 ml t of water s and al lowed to stand about 20 hours at 25° C » The mixture is di luted with 25 ml . o water, and concentrated under reduced pressure to remove the acetone, then it is extracted with ethyl acetate, the extract being washed, dried and concentrated as described in Example 3 to give C.31 g, of oi l , The oi l is dissolved In 20 mk of 25$ ethyl ' acetate in Skel iysolve B and chromatographed over 50 of si l ica gel . The column is eluted with 300 ml . of 300 ml , of 0$, and 250 ml . of 7 $ ethyl acetate in Skel iysolv , then with 250 ml . of ethyl acetate, and 250 ml, of 5$ methanol ethyl acetate. An eluate fraction of 200 ml , is taken, then 100-ml , fractions.* fol lowed by 50-m . fractions .

Fractions 1 to l6 (ethyl acetate, then $ methanol ? rs ethyl acetate) are evaporated and combined to give 39 nig, of - - - evaporated and combined to gi e 51 mg- of 8- ! so- 15"β I -20-methy ! ros tag 1 and i n Ex methyl ester.

Example 39 Methyl 6- Endo- (7-methy 1 - 1-octeny 1 ) -3-oxob \ eye 1 o- [3-1 Ό ]hexane-2~heptanoate , Fol lowing the procedures of Examples 30^ 3- 5 32 and 3^ but using in Example 30 1- romo-6~methyl heptane in place of 1-b romoheptane there is obtained from the final chromatogram » methyl 6- endo- (7-methy 1 - 1-octeny 1 ) -3-oxob i cyclo[ · 1 >0 ]hexane-2-heptanoate as two isomers s a less polar and a more po iar, Example o Methyl 6-Endo- (7-methyl-l »2~di hydroxyoctyl )~3~ oxob i cyclo[3» - 0 ]hexane-2- heptanoate .

A solution of 1,0 g„ of methyl 6-endo- (7-methyl -1-octenyl )-3-oxob icyclo[3»1.0]hexane-2-heptanoate (less polar isomer* obtained according to Example 39) in 13*5 ml . of tetrahydro-furan is warmed to 50° C, and a warm solution of 530 mg, of potassium chlorate and 35 mg , of osmium tetroxide in 6,5 ml , of water is added with stirring. The mixture is stirred for hours at 50° C„ ; then it is concentrated under reduced pressure to remove the tetrahydrofuran . The mixture is di luted with water and extracted with 3 portions of d i chloromethane. The dichloromethane extracts are combined^ washed with water, dried over sodium sulfate,, and evaporated under reduced pressure to give 1.0 g, of oil . The oil is chromatographed over 120 g* of sil ica gel < The column is eluted with 500 ml . of 10% > 1000 ml . of 2 $, 1000 ml . of 35$, 1000 ml . of $ > 1000 ml , of 50$, and 1000 ml . of 60% ethyl acetate in Skel lysc ve B, The 3 $ ethyl acetate eluate is concentrated to give 255 mg= of the less polar form of methyl 6-endo- (7-methyl -ls2-d\ hydroxyoctyl )-3-oxob icyclo[3'1.0]hexane-2'-heptanoateI The 0$ ethyl acetate eluate is concentrated to give 248 mg. of the more polar form.

Example 4l 20,20-Dimethylprostaglandin Ei Methyl Ester and -ep i -20,20-d imethyl pros tag 1 and i n Ei Methyl Ester. A solution of 0.255 g. of methyl 6-endc- (7-methyl - 1,2-d i hyd roxycctyl ) -3-oxob j eye 1 o[3« 1.0 ]hoxane-2-heptanoate (less polar glycol , obtained according to Example 4θ) in 7 ml , of pyridine is stirred under nitrogen while cool ing in an ice bath and 0.7 ml . of methanesu I f ony 1 chloride is added, Stirring is continued for 2.5 hours. The solution 'is di luted with 30 ml , of ice and water, and stirred for 10 minutes : then it is transferred to a separatory funnel containing crushed ice and extracted with 3 100-ml . portions of ethy! acetate. The ethyl acetate extracts are combined, washed with cold 1C# sulfuric acid, cold 10 ?S sodium carbonate^ and ice water, then dried over sodium sulfate and evaporated to give 338 mg. of dimesytate as an oil . This oil is dissolved in 8 ml . of acetone,, diluted with 4 m . of water, and allowed to stand at 25° Co for about 20 hours , The reaction mixture is then di luted with 25 mi , of water and concentrated under reduced pressure to remove acetone; then 50 ml . of water is added and the mixture is extracted three times with ethyl acetate. The ethyl acetate extracts are combined, washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated to give 8 mg , of an oil .

Fol lowing the above procedure, but starting with the more polar glycol (248 mg,, obtained according to Example 4o), there is obtained 270 mg, of an oil identical by thin layer chromatographic analysis to the oil obtained above from the less polar glycol . These two oils are combined (528 mg . ) and chromatographed over 70 g. of si l ica gel . The column is eluted 1 1 f 1 1 of 4θ 1 of 0* and ethyl acetate, and 1 1. of 5$ MeOH in ethyl acetate, taking 75-ml . fractions. Eluate fractions 6j to 73 are evaporated an combined to give 64 mg. of 15-ep i -20, 20-d imethyl pros tag 1 and i n . Ei methyl ester; infrared absorption at 30, 1740, 1250, 1200 II65, 1075 and 970 cm.

Eluate fractions 88 to 104 are evaporated and combined to give 111 mg . of 20, 20-d imethyl pros tagl and i n Ei methyl ether. This is crystall ized from a mixture of ether and Skellysolve B to give an analytical sample of 20, 20-d i methyl p ros tag 1 and i n Ei m.p. 75-760 C ; mass spectrum spectral peaks at 378, 360, 347, 297, 279 and 218; infrared absorption mull at 3310, 1735, 1325 1310, 1290, 1275, 1260, 1225, II95, II50, 1105, IO65 and 975 c Example 42 8- lso-20,20-dimethylprostaglandin Εχ Methyl Ester and 8- I so- 15-ep i -20, 20-d imethyl pros tagl and i n Ei Methyl Ester.

Following the procedures of Examples 40 and 4l but using in Example 40 the more polar methyl 6-endo- (7-methyl - 1-octenyl 3~oxobicyclo[3.1.0]hexane-2-heptanoate in place of the less polar isomer, there are obtained 8- i so-20, 20-d imethyl prosta-glandin Ei methyl ester; mass spectrum spectral peaks at 396, 378, 360, 3 7, 297, 279 and 218. Rf 0.47 on thin layer chromatography on silica gel with the A- I X solvent system, and 8- i so-15-ep i -20, 20-d imethyl pros tagland i n Ei methyl ester; mass spectral peaks at 396, 378, 360, 347, 297, 279 and 218; R O.36 on a si lica plate with the A- I X solvent system.

Example 4 19-Methyl pros tagl and i n Ei Methyl Ester and I - Ep i -19-methyl pros tagl and i n Ei Methyl Ester.

Following the procedures of Examples 30, 31, 32 and 34 bu using in Example 30 5-methy 1 hexyl bromide in place of heptyl heptanoate as two isomers., a less polar and a more polar.

Fol lowing the procedures of Examples 40 and 41, but using in Example 4o the less polar isomer of methyl 6-endo- (6-methy 1 -1-heptenyl )-J-oxob i cyclo[3- 1.0 ]hexane-2-heptanoate in place of methyl 6-endo- (7_methyl - 1-octenyl )-J-oxob i cyclo[3.1 - 0 ]hexane-2-heptanoate there are obtained 19-methylprostaglandin Ei methyl ester, m.p. 52-53° 'C ; infrared absorption (mul l) at 3430, 3290 17 0, 1675 (weak), 1300, 1275, 1225, 1200, 1170, I065 and 990 cm. 1 ; and 15-ep i - 19-methy 1 p ros tag 1 and i n Ei methyl ester; infrared absorption at 3420, 1740, 1250, 1200, 1165, 1075 and 1035 cm. mass spectrum spectral peaks at 382, 36 , 351, 3 6, 297, 293, 279 and 247.

Example 44 19-Methylprostagland in Ai Methyl Ester and 19-Methy prostagland i n Ai .

A solution of 200 mg . of 19-methylprostaglandin Ei methyl ester in a mixture of 2 ml . of tetrahydrofuran and 2 ml . of 0.5 ϋ hydrochloric acid is stirred under nitrogen at 25° C. for 5 days. The reaction mixture is then di luted with saturated aqueous sodium chloride and extracted with ethyl acetate. The ethyl acetate extract is washed with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated to give 1 9 mg. of an oil . The oil is ch romatog raphed over 25 g. of sil ica gel and eluted with 350 ml . of 20$, 400 mi . of 30$, 500 ml . of 40#, 1000 ml . of 50$, and 500 ml . of 6o# ethyl acetate in Skellysolve B, then with 500 ml . of ethyl acetate, taking 25 ml . fractions. Eluate fractions 17-22 are concentrated and combined to give 45 mg, of 17-methyl prostagl and i n Ax methyl ester.

U . V. (ethanol solution) maximum at 217 ιτιμ, shoulder at spectrum maximum was 78 ιτιμ, shoulder at 235 τι (l9~methyl-prostaglandin Bi methyl ester). Eluate fractions 28-3 are concentrated and combined to give 25 mg. of 19-methyl pros ta-glandin Ax; infrared absorption at 3320, 1720, and 1 85 cm. Example 45 Methyl 6-Endo- (6,6-d imethyl -1-heptenyl )-3_oxo- bicyclo[3.1.0 ]hexane-2-heptanoate.

Following the procedures of Examples 30, 1* 32 and 3^, but using in Example 30 1-b romo-6,6-d imethyl heptane in place of 1-b romoheptane there is obtained from the final chromatogram methyl 6-endo- (6, 6-di methyl -1-heptenyl )-3-oxobicyc1o[3.1.0]-hexane-2- heptanoate as two isomers, a less polar and a more polar.

Example 46 Methyl 6- Endo- (6,6-d imethyl -1,2-d i hyd roxyheptyl )~3~ oxob i eye lo[3.1.0 ]hexan -2 -heptanoate.

A solution of 12.0 g. of methyl 6-endo- (6, 6-dimethyl -1-heptenyl )-3_oxobicyclo[3.1.0]hexane-2-heptanoate (less polar isomer, obtained according to Example ) in 150 ml . of tetra-hydrofuran is warmed to 50° C. and stirred under nitrogen; then 1 g. of sol id osmium tetroxide is added to the solution followe immediately by a warm solution of 6.5 g. of potassium chlorate in 76 ml . of water, added in one portion. The reaction mixture is stirred for 5 hours at 50° C. under nitrogen; then it is concentrated under reduced pressure to remove the tetrahydro-furan. The mixture is di luted with water and extracted three times with d ichloromethane. The d i ch 1 oromethane extracts are combined, washed with water, dried over sodium sulfate, and evaporated under reduced pressure to give 14.0 g. of an oil . The oil is chromatographed over 2 kg. of sil ica gel . The column is eluted with 8 1. of 1536, 12 1. of 25$, l6 1. of 35$, and combined to give 9·0 g. of methyl 6-endo- (6,6-d imethyl -1,2 -d i hyd roxyheptyl )-3~oxob i cyclo[3.1 · 0 Jhexane- 2-heptanoate . Example 7 19,19_Dimethylprostaglandin Ei Methyl Ester and -Epi -19,19-dimethylprostaglandin Ei Methyl Ester. A solution of 9.0 g. of methyl 6-endo- (6,6-d imethyl -1,2-d i hyd roxyheptyl )-J-oxob i cyclo[5« 1 · 0 ]hexane 2-heptanoate (obtai according to Example 46) in 110 ml . of pyridine is stirred und nitrogen and cooled in an ice bath while 10.7 ml . of methane-sulfonyl chloride is added dropwise oyer a period of .15 minute The mixture is stirred for 2.5 hours at 0° C, then is cooled to -10° to -15° C. with a dry ice-acetone bath and 10 ml . of ice and water is added slowly, with good stirring, while keepi the temperature below 0° C. The mixture is poured into 500 ml of ice and water. Then 200 ml . of cold 1:3 d i chloromethane-ether mixture and 440 ml . of cold 3 hydrochloric acid are added, and the mixture is separated rapidly. The mixture is extracted three more times with 200-ml . portions of cold 1:3 d i chloromethane-ether mixture. The dichloromethane-ether extracts are combined, washed with cold 2 sulfuric acid, cold 10$ aqueous sodium carbonate, and cold saturated aqueous sodiu chloride, then dried over sodium sulfate and potassium carbona and evaporated to give 14.0 g. of oil . This oil is dissolved in 450 ml . of 2:1 acetone-water and allowed to stand at about 25° C. for about 20 hours. The reaction mixture is diluted wi 200 ml . of water and concentrated under reduced pressure to remove acetone. Then, 100 ml . of water is added and the mixtu is extracted 4 times with ethyl acetate. The ethyl acetate extracts are washed with aqueous sodium bicarbonate and aqueou sodium chloride, dried over sodium sulfate, and evaporated to 8 1. of 4o#, 20 1. of 6o#, and 20 1. of 8o# ethyl acetate in Skellysolve B, then 20 1. of ethyl acetate and 4 V. of $ methanol in ethyl acetate, taking βθθ-ml . fractions. Eluate fractions 66 to 72 are evaporated and combined to give 1.253 g. of 15-epi -19,19'd imethyl prostaglandi n Ei methyl ester; infrared absorption at 3420, 17 0, 1 45. 1200, 1165, 1075, 1020 and 970 cm . 1.

Eluate fractions 96-Hl are evaporated and combined to giv I.228 g. of 19, 19" Example 48 19,19-Dimethylprostaglandin Fia and 19, 19~D imethyl - prostaglandin F16.

A solution of 500 mg . of 19, 19~d imethyl pros tag 1 and i n Ei methyl ester in 25 ml . of isopropanol is stirred at 0° C. under nitrogen, and a cold solution of 250 mg. of sodium borohydride in ml · of water is added. The mixture is stirred at 0° C. for 2.5 hours, then 1 ml . of acetone is added and the mixture is stirred for 10 minutes at 0° C. The mixture is made sl ightl acidic (pH 5"6) with acetic acid, and is then concentrated under reduced pressure to remove the acetone and isopropanol . This mixture is poured into saturated aqueous sodium chloride and extracted 3 times with ethyl acetate. The ethyl acetate extracts are combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated to give white sol id. This mixture (503 mg „ ) is d i ssol ved in 15 ml . of methanol, cooled to about 5° C. and stirred under nitrogen whil 2 ml . of 0$ aqueous potassium hydroxide is added. The mixture is then stirred, under nitrogen, for 4 hours at 25 C. The mixture is di luted with 100 ml . of water and extracted once wit ethyl acetate. The aqueous phase is acidified with dilute hydrochloric acid and extracted 4 times with ethyl acetate. Th ethyl acetate extracts are combined, washed 3 times with water and once with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated to give 506 mg. of white crystal l ine material . This crystall ine material is chromato-graphed over 150 g. of sil ica gel . The column is eluted with 500 ml . of 50$ and 500 ml . of 75$ ethyl acetate in cyclohexane, then with 4000 ml . of ethyl acetate followed by 500 ml . of 10$ and 500 ml . of 5$ methanol in ethyl acetate. The ethyl acetate-cyclohexane eluates are discarded, then 50 ml . eluate fractions are taken beginning with the ethyl acetate eluate. Fractions 16 to 35 are evaporated and combined to give 135 mg. of 19, 19-d imethy 1 p ros tag 1 and i n Fia which is recrys ta 11 i zed from a mixture of ethyl acetate and Skellysolve B to give 19,19-dimethylprostaglandin Fia, m.p. 107-109° C., infrared absorption at 3320, 2700, 1710, 1325, 1305, 1290, 1275, 1240, 1210, 1200, 1095, 1050, 1020, 98 , 975 and 945 cm." 1; mass spectrum spectral peaks at 384, 366, 348 and 294.

Fractions 46 to 84 are evaporated and combined to give 211 mg. of 19, 19"d imethyl PGFi , which is recr ys ta 11 i zed from a mixture of ethyl acetate and Skellysolve B to give 19,19-d imethyl pros tag 1 and i n Fifi, m.p. 145-146° C ; infrared absorptio at 3360, 27ΟΟ, I7IO, I305, 1290, 1220, IO80, IOI5, 995, 970 and cm Example 49 Methyl 6- Endo- (l-hepteny 1 )-j5_oxob i cycl o[3.1.0 ]- hexane-2- (2 ,2 -d i methyl heptanoate) .

A solution of 6.33 9· of endo-6- (l-heptenyl )-b i cycl o[3.1 · 0 ]-3-one (obtained according to Example 29) and 14.6 g. of methyl 7- iodo-2,2-d imethyl heptanoate in 200 ml . of tet rahyd rof u ran is stirred at 25° C. under nitrogen, and a solution of 3.8 g. of potassium jt-butoxide in 8θΟ ml . of tet rahyd rof u ran is added slowly over a 45 minute period. Then, 70 ml . of 5$ hydrochloric acid is added, fol lowed by 5 m' · of pyridine. The mixture is concentrated under reduced pressure to remove most of the tet rahyd rof u ran and diluted with 200 ml . of ice water. The mixture is extracted with 2 200-ml . portions of :1 ether-d i chloromethane. The ether-d i chloromethane solution is washed sudcess ί vel y with dilute hydrochloric acid, water, dilute aqueous sodium thiosulfate, and saturated aqueous sodium chloride. The washed solution is dried over sodium sulfate and evaporated under reduced pressure to give 16.9 . of oil . The oil is chromatographed over 1.5 kg. of sil ica gel packed wet with 2$ methanol in d i ch 1 oromethane . The column is eluted with 6 1. of d ichloromethane, 6 1. of 1$, and 6 1. of 2$ methanol in dichloro-methane, taking 300 ml . fractions. Fractions 25 to 36 are evaporated and combined to give 4.25 g. of methyl 6-endo- (l-heptenyl )-3~oxob i cyclo[3.1 · 0 ] hexane-2- (2, 2-d imethyl heptanoate) (less polar isomer).

Example 50 Methyl 6-Endo- (l,2-di hyd roxyhepty 1 )-3"Oxob icyclo- [3.1.0 ]hexane-2- (2,2-d imethyl heptanoate) .

A solution of 10.38 g. of methyl 6-endo- (l- heptenyl )-3" oxob icyclo[3.1.0]hexane-2- (2, 2-dimethyl heptanoate) (less polar isomer, obtained according to Example 49) in 250 ml . of tetra-hyd rof u ran is warmed to 50° C. and stirred. Osmium tetroxide chlorate in 100 ml . of water is added and the mixture is stirred at 50° C. for 2 hours and 0 minutes. The mixture is concentrated by distillation under reduced pressure to remove most of the tet rahyd rof u ran . The aqueous residue is extracted with d ichloromethane. The dichloromethane extract is washed with water and aqueous saturated sodium chloride, dried over sodium sulfate, and evaporated under reduced pressure to give 14.1 g. of an oil . The oil is chromatographed over 1 00 g. of sil ica gel wet packed in 1:1 ethyl acetate-cyclohexane. The column is eluted with 1:1 ethyl acetate-cyclohexane, taking 200 ml . fractions. Fractions 20 to 5 are evaporated and combined to give 7.3 g. of methyl 6-endo- (l ,2-d i hyd roxyhept yl )-3-oxob i cyclo[3.1.0 ]hexane-2- (2,2-d i methyl heptanoate) . F ract ions 10 to 19 are evaporated and combined, and dissolved in 200 ml . of tert-butanol . A solution of 2.5 g. of sodium hydrosulfite in 6o ml . of water and 30 g. of Magnesol (magnesium sil icate) are added, and the mixture is stirred JO minutes at 25° C.

The mixture is filtered, and the filtrate is concentrated under reduced pressure to remove the tert-butanol . The residue of oil and water is extracted with dichloromethane, and the extract is washed with aqueous sodium chloride, dried over sodium sulfate, and evaporated under reduced pressure to give 2.56 g. of oil . The oil is chromatographed over 200 g. of si l ica gel . The column is eluted with 1:1 cycl ohexane-ethyl acetate, taking 30-ml . fractions. Fractions 16 to 3 are evaporated and combined to give a further 0.770 g. of methyl 6-endo- (l,2-d ί hy-; droxyheptyl )- 3-oxob i cycl o [3.1.0]hexane-2- (2 ,2-d i methyl heptanoate) (total yield 8.07 g. ) .

Example 51 2,2-Dimethylprostaglandin Ex Methyl Ester and I5- (obtained according to Example 50 ) in 100 ml . of pyridine is stirred under nitrogen and cooled in an ice bath while 10.0 ml. of methanesu 1 fonyl chloride is added dropwise over about 15 minutes. The mixture is stirred 2.5 hours at 0° C; then 5 ml. of water is added dropwise while keeping the temperature below 5° C. The mixture is diluted with 100 g. of ice and extracted with 1:5 dichloromethane-ether. The d i chloromethane-ether extract is washed with ice-cold dilute hydrochoric acid (100 ml. cone, hydrochloric acid mixed with 4-00 ml. of ice and water)* aqueous sodium bicarbonate, and saturated aqueous sodium chlorid dried over sodium sulfate and evaporated under reduced pressure to give 10.2 g. of oil. The oil is dissolved in 500 ml. of acetone and diluted, with stirring, with 150 ml. of water. The mixture is allowed to stand at 25° C. for about 20 hours; then it is diluted with 500 ml. of water and concentrated under reduced pressure until most of the acetone is removed, and extracted with 1:5 dichloromethane-ether mixture. The dichloromethane-ether solution is washed successively with dilute aqueous sodium bicarbonate and saturated aqueous sodium chloride dried over sodium sulfate, and evaporated under reduced pressure to give 10.0 g. of oil. The oil is chromatographed over 1500 g. of silica gel wet-packed in 1:1 ethyl acetate-cyclohexane . The column is eluted with 8.5 1. of 2:1 ethyl acetate-cyclohexane, 2 1. of 1058 and 2.5 1. of 20$ methanol in ethyl acetate, taking 100-ml . portions. Fractions 84 to Ιθβ are evaporated and combined to give 1.18 g. of 15~ep i -2 ,2-d imethyl pros tag 1 and i n Εχ methyl ester; mass spectrum spectral peaks at 596, 78 and 5^0; infrared absorption at 5½20, 1730, 1520, 1250, 1195, 1150, 1075, 1025, and 970 cm."1.

Fractions Ιΐβ to 150 are evaporated and combined to give spectrum spectral peaks at 396.» 378 and 36Ο; infrared absorption at 3390, 1730, 1320, 1250, 1195, 1150, 1075, 1020 and 970 cm." 1.

Example 52 2 ,2-D imethyl prostagl and i n Fla Methyl Ester and 2,2- Dimethylprostaglandin F ιβ Methyl Ester.

A solution of 100 mg. of 2, 2-d imethyl p ros tag 1 and i n Ei methyl ester in 5 ml . of isopropanol is cooled to 0° C. in an ice bath, and a solution of 50 mg. of sodium borohydride in 1 ml . of water is added. The mixture is stirred in the melting ice bath for 2.5 hours; then the reaction mixture is treated with 1 ml . of acetone stirred for 10 minutes. Dilute acetic acid is added until the mixture is neutral, and the mixture is concentrated under reduced pressure until most of the isopropanol and acetone have been removed. The residue is diluted with ml . of water and extracted with 15 ml . of ethyl acetate. The ethyl acetate extract is dried over sodium sulfate and evaporated under reduced pressure to give 100 mg. of residue.

This procedure is repeated with βθθ mg . of 2 , 2-d imethyl -prostaglandin Ej methyl ester as starting material, and βθθ mg. of crude product is obtained. The two products are found 'by TLC analysis (sil ica gel developed with ethyl acetate and spots developed with vanil l in-phosphoric acid reagent) to be the same, and they are combined (700 mg.) and chromatographed over 70 g. of si l ica gel, wet packed in 2:1 ethyl acetate-cycl ohexane . The column is eluted with 500 ml . of ethyl acetate, 500 ml . of 1%, 500 ml . of 3$ and 500 ml . of 10$ methanol in ethyl acetate, taking 25 ml . fractions. Fractions 32-3^ are evaporated and combined to give 170 mg . of 2 , 2-d imethyl p ros tag 1 and i n Fia methyl ester; m.p. 54-6o° C. ) mass spectrum spectral peaks at 398, 380, 362, 327 and 308. m.p. 69-74° C ; mass spectrum spectral peaks at 598, 380, 362, 327 and 308.

Example 53 2,2-D imethyl pros tag 1 and i n F^.

A solution of 200 mg. of 2 ,2-d imethyl p ros tagl and i n F^ methyl ester in 5 ml . of methanol is mixed with 2.8 ml . of 45$ aqueous potassium hydroxide, and the mixture is allowed to stand at 25° C. under nitrogen for about 20 hours. TLC analysis of the reaction mixture showed reaction to be complete. The mixture is diluted with 0 ml . of water and extracted with 15 ml . of ethyl acetate. The aqueous solution is made acid with cold dilute hydrochloric acid and extracted with 2 25~ml . portions of ethyl acetate. The ethyl acetate extracts are combined and washed 3 times with water, dried over sodium sulfate, and evaporated to give 182 mg. of crystall ine residue. This is recrystal 1 ized from an ether-pentane mixture to give 142 mg. of 2,2-dimethylprostaglandin Fifi, m.p. 102-106° C ; mass spectrum spectral peaks at 384, 366, 348 and 294.

Examp 1 e 54 2,2-Dimethylprostaglandin Fi0 Fol lowing the procedure of Example 53 but using 2,2-di-methyl pros tagl and i n Fi methyl ester in place of 2 ,2-d imethyl -prostaglandin F ιβ methyl ester there is obtained 2, 2-d imethyl -prostaglandin Fia, m.p. 108-112° C, mass spectrum spectral peaks at 38 , 366, 3 8 and 294.

Example 55 Methyl 6-Endo- (l-heptenyl ) -3~oxob i cyclo[3.1 · 0 ]- hexane-2- (3, 3"d imethyl hep tanoate) .

A) Methyl 7- lodo-3,3_d imethyl heptanoate A cold mixture of 110 ml . of 96 sulfuric acid and 13 ml . of water is stirred while 24 g. of boron trifluoride gas is passed in. A mixture of 83 g. of 6-chloro-2-methyl hexan-2-ol and 107 g. of 1,1-d i chloroethene is added to the sulfuric acid keeping the temperature at 0-5 C. The mixture is then stirred at 10-15° C. for two hours, and is poured over crushed ice.

The mixture is extracted with l.-l ether-Skel 1 ysolve B. The ether-Skel 1 ysol ve B solution is extracted with cold dilute aqueous sodium hydroxide. This alkal ine solution is made acid with dilute hydrochloric acid and is extracted with 1:1 ether-Skellysolve B. The ether-Skel 1 ysol ve B solution is washed with water, then with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated under reduced pressure to give 5 g. of 7-chloro-5,3-d imethyl heptanoic acid. This acid is dissolved in 125 ml . of ether and excess diazomethane in ether is added at room temperature. After 3* minutes the excess diazomethane is destroyed by addition of acetic acid.

The mixture is washed with di lute hydrochloric acid, dilute aqueous potassium hydroxide, water, and saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated under reduced pressure to give 48.6 g. of methyl 7"chloro-3,3"dimethyl-heptanoate. A solution of this ester (48.6 g.) in 750 ml . of dry acetone and 75 g. of sodium iodide is stirred for 40 hours while heating under reflux. The mixture is cooled and filtered, and the filtrate is concentrated to remove most of the acetone. The concentrated filtrate is diluted with water and extracted with 1:1 ether-Skel 1 yso 1 ve B. The ether-Skel 1 y-solve B extract is washed with water, dilute aqueous sodium thiosulfate, water, saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated by evaporation under reduced pressure to give a residue. This residue is distilled to give 6l.5 g. of methyl 7" \odo-5' )5~ -d imethyl heptanoate having a boil ing point (center cut) of 79° C. at 0.0 mm.

B) Methyl 6-Endo- (l-heptenyl )-j5-oxob icyclo[3.1.0]hexane-2- Following the procedure of Example 9 but using methyl 7~ iodo-3*3-dimethyl heptanoate in place of methyl 7-iodo-2,2-d imeth 1 heptanoate there is obtained methyl 6-endo- (l-heptenyl )-3-oxob i cyclo[3.1.0 ]hexane-2- (3 ,3-d imethy 1 heptanoate) , separated on chromatography into less polar and more polar i somers .

Example 5 3, 3-D imethyl pros tag 1 and i n Ei Methyl Ester and -Ep i -3>3-d imethyl pros tagl and i n Ei Methyl Ester.

Following the procedures of Examples 50 and 5 but using methyl 6-endo- (l- heptenyl )~3-oxob i cyclo[3.1.0 ]hexane-2- (3*3" d imethy 1 heptanoate) (less polar isomer) in place of methyl 6-endo- (l- heptenyl )-3~oxob i cyclo[3.1.0 ]hexane-2- (2,2-d imethyl -heptanoate) in Example 0 there are obtained 3* 3"d i methyl -prostaglandin Ei methyl ester, m.p. 37"38° C. ; mass spectrum spectral peaks at 396, 378, 360, 32 * 307 and 293; infrared absorption at 3400, 1740, 1325. 1230, 1150, 1130, 1075* 1015 and 9 5 cm. 1 ; and 15~epi -3*3~d imethyl pros tagl and in Ei methyl ester; mass spectrum spectral peaks at 396, 378, 360, ^7, 346, 325* 307 and 293; infrared absorption at 3420, 1735, 1330, 1230, II50-II35, 1075* IOI and 970 cm."1.

Examp 1 e 57 Methyl 7- [endo-6- (l- heptenyl )~3-oxob i eye 1 o[3.1.0 ]- hex-2-yl ]heptanoate.

A solution of potassium tert-butoxi de (1.45 g.) in 50 ml. of tetrahydrofu ran is added dropwise during 20 minutes with stirring to a . solution of endo-6- (cis- and t rans - 1- heptenyl )-b i cycl o[3.1.0 ]hexan-3~one (l.OO g.) and methyl 7- iodoheptanoate (4.1 g.) in 25 ml. of tet rahyd rof u ran at 0° C. while bubbling nitrogen through the reaction mixture. Then, $ hydrochloric acid (25 ml.)! is added, tet rahyd rof u ran is evaporated, two volumes of water is added, and the mixture is extracted three aqueous sodium thiosulfate solution, dried, and evaporated.

The residue is chromatographed on 100 g. of sil ica gel, eluting with 500 ml . Skellysolve B, 500 ml . 2.5$ ethyl acetate in Skellysolve B, 1500 ml . 5# ethyl acetate in Skellysolve B, and 700 ml . 10$ ethyl acetate in Skellysolve B, col lecting 100 ml . fractions. Fractions 15"19 are combined and evaporated to give 566 mg. methyl 7- [endo-6- (l-heptenyl )-3-oxob i cyclo[3, 1 , 0 ]hex-2a-yl ]heptanoate. Fractions 20-24 are combined and evaporated to give 1 1 mg . the corresponding 2β- y 1 isomer.

Example 58 Methyl 7- [endo-6- (l,2-d i hydroxyheptyl )-3-oxo b icyclo [3.I.0 ]hex-2 -yl ]heptanoate.

A solution of potassium chlorate (4.0 g.) and osmium tetroxide (0.26 g.) in 48 ml . of water is added to a solution of methyl 7" [endo-6- (l-heptenyl )-3-oxob i cyclo[3.1 ,0 ]hex-2a-yl ]-heptanoate (4.0 g.) in 100 ml . of tetrahydrofu ran . The mixture is heated with stirring 5 hours at 50° C. Then, tetrahyd rofu ran is evaporated and 50 ml. of water is added to the residue. The mixture is extracted with three 150-ml . portions of dichloro-methane. The combined extracts are washed with water, dried, and evaporated. The residue is chromatographed on 400 g. of sil ica gel, eluting with 4.4 1. 40# ethyl acetate in Skellysolve B, 4 1, 5056 ethyl acetate in Skellysolve B, and 1.2 1. ethyl acetate, collecting 400-ml . fractions. Fractions 6-9 and fractions 12-14 are separately combined and evaporated to give I. 7 g. and I.l8 g., respectively, of two isomeric forms, less polar and more polar, respectively, of methyl 7" [endo-6- (1,2-d i hydroxyheptyl )-3~oxob i cyclo[3.1.0 ]hex-2 - yl ] heptanoate.

Examp 1 e 59 Methyl 7- [endo-6- (l,2-d imes yloxyheptyl )~3"Oxo- b i cyclo[3.1.0^hex-2 -yl Jheptanoate.

Methanesu 1 fonyl chloride (l ml .) is added with stirring to ■ b i cycl ο[3· 1.0 ]hex-2 - yl ]heptanoate (520 mg„) in 4 ml . of pyridine at 0° C. under an atmosphere of nitrogen. The mixture is sti rred at 0° C. for 2 hours. Then, 5 ml . of ice-cold water is added, and the mixture is sti rred 5 minutes. A mixture of ice and water (15 ml . } is added, and the total mixture is extracted three times with 100-ml . portions of ethyl acetate.

The combined extracts are washed ice-cold and successively with saturated aqueous sodium chloride solution, 10$ sulfuric acid, the salt solution, 10$ aqueous sodium carbonate solution, and the salt solution, dried, and evaporated to give methyl 7" [endo-6- (l,2-dimesyloxyheptyl )~3-oxob icyclo[3.1.0]hex-2a-yl Jheptano-ate .

Example 6θ PGEi Methyl Ester.

A solution of 1/6 of the dimesylate of Example 59 in a mixture of ml . of acetone and 2 ml . of water is maintained 16 hours at 25° C. An equal volume of saturated aqueous sodium chloride solution is then added, and the acetone is removed by evaporation. The residual solution is extracted with 80 ml . of ethyl acetate. The extract is washed success ivel y with 10$ aqueous sodium carbonate solution and saturated aqueous sodium chloride solution, dried, and evaporated. The residue is ch romatographed on 10 g. of si l ica gel , eluting with 100 ml . $, 100 ml . 50$, 100 ml . of 7 $, and 100 ml . of 100$ ethyl acetate in Skel lysolve B, and then with 100 ml . of 5$ methanol in ethyl acetate, col lecting 20-ml . fractions. Fractions 13-1β are combined and evaporated to give 15.3 mg. 15~epi~PGEi methyl ester. Fractions 17-20 are combined and evaporated to give 14.9 g. PGEi methyl ester.

Claims (1)

1. 2501 WHAT IS CLAIMED IS: -1 compound of the formu wherein R13 is hydrogen, alkyl of one to carbon atoms, inclusive, or a pharmacologically acceptable cation; and wherein <^ indicates attachment of the hydroxy to the ring in alpha or beta configuration. -2- A compound according to claim 1 wherein the ring hydroxy adjacent the - (CH2 )e-C00Ri 3 moiety is attached in alpha conf i gu ration. -5- A compound according to claim 1 wherein the ring hydroxy adjacent the - (CH2 )6-C00Ri 3 moiety is attached in beta configuration. -4- A compound according to claim 2 wherein R13 is methyl or ethyl . -5- A compound according to claim 3 wherein R13 is methyl or ethyl . -6- A process for producing a product of the formula: 2501 wherein Ri is hydrogen, aikyl of one to 8 carbon atoms , inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substi tuted with one to 3 chloro or alkyl of one to carbon atoms, inclusive, or ethyl substituted in the β-pos i ti on wi th 3 chloro, 2 or 3 bromo, or 1,2, or 3 iodo; wherein R2 is hydrogen or alkyl of one to 8 carbon atoms, inclusive, substi tuted with zero to 3 fluoro; wherein R3 and RA are hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein CnHsn is alkylene of one to 8 carbon atoms, inclusive, substi tuted wi th zero to 2 fluoro; and wherein indicates attachment of the hydroxy to the ring in alpha or beta configuration, which comprises reacting sodium borohydride with a compound of the f o rmu 1 a : wherein Ri , R2, R3, R4, and CnHan are as defined above. -7- A process according to claim 6 wherein the a lpha-hyd roxy isomer of said product is isolated. A process according to claim 6 wherein the beta-hyd roxy isomer of said product is isolated. -9- A process according to claim 7 wherein R2 is pentyl, R3 and 4 are hydrogen, and CnH2n is hexamethylene. A process according to claim 8 wherein R2 is pentyl, R3 and R4 are hydrogen, and Cnf½n is hexamethylene. 2501 A process according to claim 9 wherein Ri is methyl or ethyl. -12- A process according to claim 10 wherein Ri is methyl or ethyl. ttorneys for Applicant