DE2221443A1 - New prostaglandin analogs and processes for their preparation - Google Patents

Description

HCHflAWWÄlTI DR, JUR. DIPUCHEM. WAITER 8EIi April 28, 1372 AtFRSOHO = PPENHR

DR. JUR. ΟΙ? 1.-ΟΪ5Μ. II-J. WOLFF

DR. JUR. HANä -JiiiL 3SlL

«II MAMKFUXT AM MAlN-UOCUSf

Our no. 17 813

The Upjohn Company Kalamazoo, Michigan, V.St.A.

New prostaglandin analogs and processes for their preparation.

The present invention relates to novel analogs of some known prostaglandins, including prostaglandin E (PGE _1), prostaglandin E ₂ (PQE _2), prostaglandin E, (pQE), prostaglandin P ₁ (PQP _la and PQP _LSS), prostaglandin P ₂ (PGP ₂ -, and PQP _2ß ), Prostaglandin P, (PGP ^ and PGF, _ß ), Prostaglandin A ₁ (PQA ₁ ), Prostaglandin A ₂ (PQA ₂ ), Prostaglandin A ₅ (PGA ₃ ), Prostaglandin B ₁ ( PGB ₁ ), prostaglandin B ₂ (PGB ₂ ) and prostaglandin B ₅ (PQB,) and the dihydro derivatives of PQE ₁ , PQF ₁ , PQF _lß , PQA ₁ and PGB ₁ , as well as new processes for the preparation of these new prostaglandin analogs , as well as new intermediates occurring in these processes.

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The well-known Protttiglar> djne mentioned above are derivatives the? rc st anic acid, which has the following Forir.el:

Your eysteraatiecher>? Name is l heptanoic acid.

BelBpIeTe for well-known Prontaglandins are:

COOH

PGFi ₀ I.

COOH

OH

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0OH

COOH

The well-known prostaglandins PGE «,
PGBrt agree with the corresponding PG ₁ compounds with the difference that the carbon atoms 5 and 6 are linked by a cis double bond »For example, PGrE _{0 has the} following formula:

COOH

The known prostaglandins PGE- and PGF- are the same with the corresponding PGP ^ compounds with the deviation

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* ·: · ■■

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It is ensured that the carbon atoms 17 and 10 are linked by a double bond. £ Jo owns be ie pi ( ¹ I εν / a PGE- following Porncl

OH

Me 13,14-J) iliydro ~ derivatives of PGK

iP ₁ .

_ß ,

and

PGB. are identical to the corresponding PG ₁ compounds with the fact that the carbon atoms 15 and 14 are linked by a linear bond. So C owns TDihydro-TGE. the following formula:

The above Proeta ^ landin formulas show several asymmetries - centers on. Each part has a molecule of the one in question optically active form. . ftee from certain mammalian tissues, J5.B. VeBicular glands of sheep, pig lungs or similar Sarcenplp.ßma available prostate ^ lFxndins again (bzv /.

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of the reduction or dehydration product so obtained prostaglandins), see a.B. Ber ^ strorn et al., Pharmacol. : tev. '2o, 1 (1968) and references there. J) ao mirror image of each formula ^ ibt d? S foIeMiI of the other enantiomeric form of the prostaglandin in question. The raceraic form consists of the same characteristics of both Types of molecules, one of which is represented by one of the formulas above and the other by the corresponding mirror image be, lieide i'orneln thus become a definition of a racemic prostaglandin is required. To stereochemistry the prostaglandins are referred to Nature 212, 38 (1966). For the sake of simplicity, the terms

"and sometimes the optically active form of prostaglandin with the same configuration as PGE ₁ from Sä'v« retierreweben. If the racemic form of a prostaglandin is present, the word "racemic" is placed in front of the prostaplanctin name, ie the name then reads "racemic PGB ₁ " or "racemic PGF ₁ ^" or del.

In the above formulas as well as in the formulas below dashed lines denote substitution on the C3'clopentane ring in the c / configuration, i.e. below the plane of the cyclopentane ring. Bold lines on the cyclopentane ring denote substituents in the ß-confi ^ uration ^ i.e. above the level of the cyclopentane ring.

The exact prostanoic acid analogs of the invention are made by the following formula or the combination of this formula and its mirror image circumscribed:

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CH ₂ -V-COOR ₁

in which

one of the four following carbocycles

,or

E has the radical -CHpCH «- or trans-CH = CH-, R. a hydrogen atom, an alkyl radical with 1 Ms 8 carbon atoms or a pn ecologically acceptable cation, Rp an alkyl radical with 1 to carbon atoms and V some the radical - (CK _? ),- or

₂ )., - represent under the Liaß ^ abe that jj is a -CHpCHp group only if V is a - (0H _o ) c-Hest, in which M is also a 1-lentyl or cis-i-Pent -2-enylrect means ... · ... '

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ν - 2221441

with the indication that W can be a cis-i-pent-2-enyl radical if 3i is trans-CH = CH- and V -CH = CH- (CH ₂ ) -. In the above formula, **> j also denotes the bond of the hydroxyl group to the cyclopentane ring in the 0 ^ - or ß-formation.

Ponnel I results in PGK-like connections if

is, PGP. -like compounds when

HO _xv

is, PCrPo-like connections ¹ } v / enn

HO

is, PGA-style compounds, though

is and PCrB-like compounds if

iet.

Ponnel I represents PG-like compounds when E trans-site = CH-, V - (CH ₂ -) ₅ - and M is the 1-pentyl radical; PGg im ^ cn, vennr S trrns-CH = CiI-, V eiS-GH = CH - (^) ₅ - and

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W eats the 1'entyl radical; KU-like compounds, v / enn 3. trane-örieC'i "-, V CiS-CII = CH- (OH ₂ )., - and W der i-Pent-2-enylreöt \\ nd 13.1 A- üihydro-Κτ, .- Compounds when K -CH ^ CHg-, V - (OHg) C- and V / is the 1-pentyl radical. In formula I, the configuration of the alkoxy group on carbon atom 15 (X-ständip, v / ie «in the value of the hydroxyl group in the well-known Frostai Lambs.

The following formulas II to XVII give the new inventions Pi-osta ^ landin analogues in the form of 15-alkyl ethers v / ieder:

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ο "

IV

VIM

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0R _;

COOKi

COOR ₁

COORi

COOR _x

Xl Xl

OR ₂

OR ₂

COORi

COORi

COORi Xl XIV

XV

OR ₂

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COOR ₁ XVI

XVII

The new prostanoic acid analogs according to the present invention "have an alkoxy group at C-15, that is, the position which is occupied by the side chain hydroxyl group in the naturally occurring prostanoic acid. The new prostanoic acid analogs become more square-shaped referred to as 15-alkyl ethers of the irostaglandins, for example "PGE ^ -15-ynethyl ether ¹¹ and the like".

As examples of alkyl radicals having 1 to 5 carbon atoms in the Porireln I to XVII are mentioned: the Kethyl-, üthyl-, Propyl, butyl and I-entyl radicals and their isomeric forms. Examples of alkyl radicals with 1 to 8 carbon atoms are those just mentioned, as well as the hexyl, heptyl and octyl radical and their isomeric forms. /

Like the natural prostaglandins mentioned above, the new 15-alkyl ethers also have several centers of asymmetry. As in the case of the formulas for the known prostaglandins, the formulas I biv <3 XVII should also include the optically active prostanoic acid analogues with the same absolute configuration as PGE from sausage animal species. The new prostanoic acid derivatives according to the present invention also the

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corresponding racemic compounds. To paraphrase z.ß. of the racemic PGE. compounds, Formula II is required along with their mirror image. Will be used in the subsequent Description of the word "racemic" the name of a new prostanoic acid derivativeB prefixed, it is intended to denote a racemic compound which is produced by a combination of the corresponding formula I to XVII and their mirror image is shown. If the word "racemic" is missing, the optically active connection meant by the respective

/ the formula I to XVII is shown and has the same absolute configuration as PGE ₁ from animal tissue.

, PGE ₂ , PGE. ,, Dihydro-PGE.j and the corresponding -, PGA and PGB compounds, dliren esters and pharmacologically acceptable salts are extremely effective in generating various biological reactions and are therefore suitable for pharmacological purposes, see e.g. Bergstrom et al., Pharmacol. Rev. 2o, 1 (1968) and references there. Such biological effects are, for example, the systematic lowering of arterial blood pressure by PGE and PGFβ compounds, measured for example in rats anesthetized with pentobarbital sodium and treated with pentolinium, with an introducing cannula in the aorta and right ventricle; Blood pressure activity, measured analogously, of PGF ₀ ^ compounds; the stimulation of the smooth muscles, demonstrated for example on strips of guinea pig ileum, rabbit duodenum or colon of voles; the enhancement of other smooth muscle stimulants; the antilipolytic effect, demonstrated by the antagonism of the mobilization of free fatty acids induced by epinephrine or the inhibition of the spontaneous release of glycerol from isolated rat fat puffs; the inhibition of gastric secretion by PGE and PGA compounds

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Dogs »whose secretion is through food or histamine infusion had been stimulated; the effect on the central nervous system; Decrease in platelet adhesion, proven on the adhesion of blood platelets to glass, and the inhibition of physical effects, e.g. damage to the Arteries, or biochemical action, e.g. ADF, ATP, serotonin, thrombin or collagen induced platelet aggregation and thrombosis. PQE and PGB compounds also promote skin growth and keratinization, 'as shown by application to segments of embryonic Ktiken and rat skin "

Because of their biological effects, the known prostaglandins are useful for studying P "prevention, control or alleviation of numerous diseases and undesirable physiological conditions in birds and mammals including humans, farm animals, Domestic animals and zoological species, as well as laboratory animals such as mice, rats, rabbits and monkeys.

For example, the compounds, especially the PGB compounds, in mammals including humans used to swell the nose. To this end the compounds are in doses from about 1o / Ug to about 10 mg per milliliter of a pharmacologically suitable liquid carrier or used as an aerosol spray for topical application.

The PGE and PGA compounds are found in mammals including humans as well as certain farm animals such as dogs and Pigs are useful for reducing and controlling excessive gastric secretion, which leads to the formation of gastric ulcers be reduced or avoided and the healing of those

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pre-existing ulcers can be accelerated. ' For this purpose, the compounds are injected or infused intravenously, subcutaneously or intramuscularly, at an infusion dose of about 0.1 / ug to about 500 / ug, per kg of body weight per hour, or with a total dose per day by injection or infusion of about o , 1 to about 20 mg per kg of body weight _f , the exact amount depending on the age, weight and condition of the patient, the frequency and type of administration.

The PGE, PGP ^ and PGF _β compounds are useful for inhibiting platelet aggregation, reducing the tendency of platelets to adhere, and for eliminating or preventing thrombosis in mammals including humans, rabbits and rats. For example, the compounds can be used for the treatment and prevention of myocardial infarctions, for the treatment and prevention of post-operative thromboses, for accelerating the opening of vascular plugs after surgical interventions and for the treatment of disease states such as atheroscrosis, arteriosclerosis, blood coagulation due to lipemia, and against other clinical ones Conditions in which the underlying etiology is related to lipoid imbalance or hyperlipidemia. For the purposes mentioned, the compounds are administered systemically, for example intravenously, subcutaneously, intramuscularly or in the form of sterile implants for permanent action. Intravenous administration is preferred for rapid absorption, especially in emergency situations. Doses of about 0.05 to about 20 mg per kg of body weight per day are used, the exact amount again depending on the age, weight and condition of the patient and the frequency and type of administration.

Si · PGE-, PGP. - and PGP _ß -compounds are in particular as

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Additives to blood, blood products, blood substitutes and other liquids useful for artificial, out-of-body Circulation and perfusion of isolated parts of the body, e.g. limbs and organs, which are still at the Donor bodies are located, separated from them and preserved or prepared for transplantation or are already on Body of the recipient. During these circulations, aggregated platelets tend to block the blood vessels and parts of the circulation device. This blocking is avoided in the presence of the above compounds. For For the stated purpose, the compounds are added gradually or in one or more portions to the circulating blood, the Blood from the donor, the perfused body part, the recipient

/ Stages
or added to both or all of them in a steady total dose of about 0.01 to 10 mg per liter of circulating fluid. The compounds are particularly useful when administered to laboratory animals such as cats, dogs, rabbits, monkeys and rats for the development of new methods and techniques for organ and limb transplantation.

The PGE compounds are extremely effective smooth muscle stimulators, as well as being highly active in strengthening other known smooth muscle stimulators such as oxytocin agents such as oxytocin and the various ergot alkaloids including their derivatives · and analogs. PGEp, for example, is therefore useful instead of or together with less than usual amounts of these known stimulators, for example for relief look up the symptoms of paralytic hay or to control or prevent atonic uterine bleeding Miscarriage or childbirth, or to facilitate placenta rejection, as well as during the puerperium. For the latter is the PGE compound by intravenous infusion right after the miscarriage or delivery in one

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Dose from about o, o1 to about 5o / Ug per kg of body weight per Administered minute until the desired effect is achieved. Subsequent doses are given intravenously, subcutaneously, or intramuscularly injected or infused during the puerperium in an amount of o, o1 to 2 mg per kg of body weight per day, the exact dose being based on age, weight and condition depends on the patient.

The PGE and PGF _β compounds are also useful as hypotensive agents for lowering blood pressure in mammals, including humans. For this purpose, the administration takes place by intravenous infusion in an amount of about 0.01 to about 50 / Ug per kg of body weight per hour, or in one or more .Dosen of about 25 to 500 / Ug per kg of body weight per day.

The PGE, PGP ₀ ^ - and PGF _β -compounds can also be used instead of oxytocin for inducing labor in pregnant females such as cows, sheep and pigs as well as in humans, at or near the time of birth, or in the case of intrauterine death of the fetus about 20 weeks before the time of birth. For this purpose, the compounds are infused intravenously at a dose of o, o1 to 50 / Ug per kg body weight per minute, until or almost until the end of the second stage of labor, ie the expulsion of the fetus. The compounds are particularly useful when have not started natural labor one or more weeks after the time of birth, or 12 to 60 hours after the membrane has ruptured without the natural labor having started

The PGE, PGF, and PGF _β compounds are also useful for controlling the conception cycle in ovulating female mammals as well as in humans. To this end, will

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for example FGF «, systemically in a dose of o, o1 administered to about 20 mg per kg of body weight, expediently during the period of about the time of ovulation begins and ends around the time of the menses or shortly before. It is also the expulsion of an embryo or Fetus by similar administration of the compound during the first trimester of gestation or pregnancy. caused·

Since the PGE compounds are effective antagonists of the mobilization of free fatty acids induced by epinephrine, these compounds are useful in experimental medicine for studies in vitro and in vivo on mammals such as rabbits and rats and in humans, for understanding, prevention, relief and healing of diseases associated with abnormal lipoid mobilization and high free fatty acid content such as diabetes mellitus, vascular disease and hyperthyroidism.

The PGA compounds, their derivatives and salts increase the blood flow in the kidney of mammals, whereby the volume and electrolyte content of the urine are increased. The PGA compounds can therefore be used against kidney dysfunction, in particular in the case of severely impaired kidney blood flow, for example in the case of hepatorenal syndrome and the onset of rejection of a transplanted kidney. In cases of excessive or undesirable ADH (antidiuretic hormone, vasopreesin) secretion, the diuretic effect of these compounds can be even greater. In anephritic conditions, the vasopresein effect of the compounds is particularly beneficial. The PGA compounds are suitable, for example, for the relief and elimination of edema, which result, for example, from massive surface burns, and for the treatment of shock. To those"

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For this purpose, the compounds are preferably first injected intravenously in doses of 10 "to 10000 / ug per kg of body weight, or intravenously infused in an amount of 0.1 to 20 / Ug per kg of body weight per minute until the desired effect is achieved. Subsequent doses can be administered intravenously, intra- ' Injected or infused muscular or subcutaneous, when using doses of 0.05 to 2 mg per kg of body weight per day.

Promote and accelerate the PGE and PGB links dae growth of epidermal cells and keratin in animals including humans, see B. valuable pets, zoological Species and laboratory animals. Because of this will be the compounds used to promote and accelerate the healing of damaged skin, for example at Burns, wounds, abrasions and after surgical procedures. The connections are still useful for Promotion and acceleration of the growth of skin pieces (autografts), especially small deep (Davis) inserts, the skin-free areas should cover by subsequent growth outwards, and to delay the rejection of their own Skin (homografts).

For the above purposes, the compounds are preferably applied topically or near the site where cell growth or keratin formation are desired, preferably as an aerosol liquid or finely divided powder spray, as an isotonic solution in the case of moist compresses or as a lotion, cream or ointment together with standard pharmaceutically acceptable diluents administered. In some cases, for example in the case of severe fluid loss as a result of extensive burns or for other reasons, a systemic one is recommended Administration, for example by intravenous in-

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, ionization or infusion, alone or in combination with the usual infusion of blood, plasma or blood substitute. Further Routes of administration are subcutaneous or intramuscular administration close to the site to be treated, oral, sublingual, buccal, rectal or vaginal administration. The exact dose depends on the route of administration, age, Weight and condition of the patient. For example, it is used in a wet envelope for topical application in the case of burns of the second and / or third degree with

2
range from 5 to 25 cm suitably an isotonic aqueous solution with 1 to 500 / ug / ml of the PGB compound, or a multiple of this concentration of PGE compound. Especially when used topically, these prostaglandins are best treated with antibiotics such as gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin and oxy tetracycline, with other antibacterial agents such as mafenide hydrochloride, sulfadiazine, furazolium chloride or nitrofurazone or with corticoid gterison, e.g. Methylprednisolone or fluprednisolone used; the latter components are used in the concentration customary when they are used alone.

The new PGE-like compounds of _{the formulas II to V, the new PGF 0} / - and PGF _ß -like compounds of the formulas VI to IX, the new PGA-like compounds of the formulas X to XIII and the new PGB-like compounds of the formulas XIV through XVII cause the same biological responses described above for the PGE, PGF ₀ ^, PGF _β , PGA and PGB compounds. The new compounds can therefore be used for the purposes indicated above and are used in the manner described there.

The well-known PGE, PGF ^ -, PGF _ß ~, PGA and PGB compounds

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are all effective in several directions, even at low doses. For example, PGE. and PGE _{2 are} extremely effective as vasodic precursors and smooth muscle stimulation, and these compounds are effective anti-lipolytic gowns. In numerous applications, the known prostaglandins also show a very short duration of the biological effect. In contrast, the new compounds of formulas II to XVII are considerably more specific in causing prostaglandin-like biological reactions and their duration of action is prolonged. The new prostaglandin analogs are therefore surprisingly more useful than the above-mentioned known prostaglandins for at least one of the above-mentioned pharmacological purposes. When using the new prostaglandin analogs for this purpose, fewer undesirable side effects occur than when using the known prostaglandin. Because of the prolonged effect, smaller and smaller doses of the new prostaglandin analogs are also sufficient to achieve the desired result.

Another advantage of the new compounds over the known prostaglandins is that they are effective orally, can be administered sublingually, intravaginally, buccally or rectally, in addition to the usual intravenous, intramuscular, or subcutaneous injection or infusion as appropriate for the known prostaglandins. Because of This property makes it easier for the new compounds to maintain uniform levels of active substances in the Body with fewer or smaller doses or shorter administration, and they allow self-administration by the patient.

The 15-alkyl ether-PGE, PGF ^ -, PGF _β -, PGA and PGB compounds of the formulas II to XVII are used for the above-described corner in the form of the free acid, in ester form or in the form

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pharmacologically acceptable salts administered. When using L asterisks one uses those in which R ₁ corresponds to the above definition. Alkyl esters with 1 to 4 carbon atoms, in particular the methyl and ethyl esters, are preferred because of their optimal absorption by the human or animal body. Pharmacologically acceptable salts of the compounds of the formulas II to XVII are those with pharmacologically acceptable metal cations, with the ammonium ion, amine cations or quaternary ammonium cations. . ·

Particularly preferred metal cations are those of the alkali metals, e.g. lithium, sodium or potassium, and alkaline earth metals, e.g. magnesium or calcium, although also Cations of other metals, e.g. aluminum, zinc and iron, are possible. Pharmacologically acceptable amine cations are derived from primary, secondary or tertiary amines. Dimethylamine, triethylamine, ethylamine, dibutylamine, triisopropylamine, N-Kethylhexylamine, Decylamine, Dodecylamine, Allylamine, crotylamine, cyclopentylarain, dicyclohexylamine, Benzylamine, dibenzylamine, oZ-phenylethylamine, ß-phenylethylamine, Ethylenediamine, diethylenetriamine and similar aliphatic, cycloaliphatic and araliphatic amines with up to 18 carbon atoms, as well as heterocyclic amines, e.g. Piperidine, morpholine, pyrrolidine, piperazine and lower alkyl substituted derivatives thereof, e.g. 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrroiidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine and the like, also "^ mines with water-solubilizing or hydrophilic groups, e.g. mono-, di- and triethanolamine, ethyl diethanolamine, n-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, Tri- (hydroxyethyl) aminomethane, N-phenylethanolamine,

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N- (p-tert-amylphenyl) -diäthanolaniin _t Galactamih, NI et hy I-glucamine, N-itethylglucosamine, sphedrine, phenylephrine, epinephrine, procaine and the like.

Examples of suitable pharmacologically acceptable quaternaries Amraonium cations are the tetramethylaimnoniuin, tetraethyl ammonium, benzyltrimethylairanonium, phenyltriethylammonium ion and the like.

As already mentioned, the compounds of the formulas II up to XVII administered in different ways for different purposes, e.g. intravenous, intramuscular, subcutaneous, oral, intravaginal, rectal, buccal, sublingual, topical or in Form of sterile implants for 3) ineffectiveness.

For intravenous injection or infusion, sterile aqueous isotonic solutions are preferred. Because of the increased solubility in water, compounds II to XVII in which R _{1 is} a hydrogen atom or a pharmacologically acceptable cation are used for their preparation. For subcutaneous or intramuscular injection, sterile solutions or suspensions of the acid, salt or listers in aqueous or non-aqueous medium can be prepared, tablets, capsules and liquid preparations such as syrups, elixirs and simple solutions with the usual pharmaceutical carriers can be used orally or sublingually Administration used. Suppositories are made for rectal or vaginal administration. To produce implants, a sterile tablet or silicone rubber capsule or the like, which contains the active substance or is impregnated with it, is used.

The proetaglandin-15-alkylethers of the formulas I to XVII are obtained by the methods described below:

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/ ^ CH ₂ OCH ₃

OH

XVI

Scheme A

CK

CH ₂ OCH ₃

R ₃ O

XIX

CH ₂ OCH ₃ XX

R3Ö

CH ₂ OH

XXI R ₃ O '

.0

XX

R ₃ O

XXII I

.0

ο ·

i /

α. ,

XXV

»ΪΠ

2098Α7 / 1

XXVI

BATH ORIGINAL

XXVI

(»Λ

Scheme B

THPO XXVII

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THPO

OR

XXVM XXIX

COOH

THPO

XXX XXXI

COOH

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According to schemes A and B, the 15-alkyl ether-PGE ₂ compounds of the formula XXXI are formed from the intermediates of the formula XXYI.In these formulas, as in the rest of the description, Rp denotes an alkyl radical with 1 to 5 carbon atoms, where <am mostly the alkyl radicals methyl and ethyl / are preferred. The intermediates of the formula XXVI are via the intermediates according to the reaction sequence shown in Scheme A. XIX to XXY obtained, in which R ~ is a benzoyl or acetyl radical. In general, the benzoyl radical is preferred for reasons of easier cleaning, for economic reasons and because of higher yields.

In schemes A and B and in the schemes below, the formulas shown give optically active compounds again. The same reaction sequence is also applicable to the racemisehen compounds, which from the optically active compounds according to the present formulas and their mirror images; this gives the racemic Intermediate products and from them the racemic PG products.

Recently, the * 'ormel

JI-C5H1 ι

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"reported CEJ. Corey et al., J. Am. Chein. Soc." 91, 5675 (1969) / and later an optically active form \ röh 5; .J. Corey et al., J. Am. Chem. TJoc. 92, 397 (197o). The conversion of this intermediate to PGE ₁ and PGF 2 (V ⁱⁿ racemic or optically active form is also described in the above publications. The conversion to PGE 1 and PGF 2 was described by Corey et al., In J. Am. Chem. Soc. 93, 149o (1971).

The iodolactone of the formula XVIII according to scheme A is known (cf. Corey et al., Loc. Cit.). It is available in racemic or optically active (+ or -) form. The racemic form is used to make racemic products, and the left-handed (-) form is used to make prostaglandins of natural configuration.

The compound of the formula XIX has a residue of the formula R ~ 0 in the 4-position, in which R ^ has the above meaning. To prepare the compounds XIX by replacing the hydrogen atom of the hydroxyl group in the 4-position by an acyl radical R, processes known per se are used. If R, is a benzoyl radical, the compound XVIII is reacted with benzoic acid in the presence of a dehydrating agent, for example sulfuric acid, zinc chloride or phosphoryl chloride, or with benzoic anhydride.

Preferably, however, for example, an acyl halide, such as benzoyl chloride or acetyl chloride, is reacted agent with the compound XVIII in the presence of an absorbing hydrogen chloride, a tertiary amine such as pyridine, triethyl amine or the like. The reaction can he follow under different ReaktionBbedingungen by generally known methods. Generally mild conditions are used, KB 20 to 60 ° C, and the reaction participants are in

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liquid medium reacted with each other, e.g. in excess Pyridine or an inert solvent such as benzene, toluene or chloroform. The acylating agent will either used in stoichiometric amount or in excess.

Then the compound of the formula XX is prepared by de-iodination of the compound XIX using a reagent which does not react with the lactone ring or the OR radical, for example with zinc dust, sodium hydride, hydrazine / palladium, hydrogen and Raney nickel or platinum and the like. Particular is preferably tributyltin hydride in benzene at about 25 ⁰ C ₇ with 2,2'-azo £ IIS (2-methylpropionitrile) as initiator.

The compound XXI is obtained by demethylation of the compound XX with a reagent which does not attack the OR- residue, for example with boron tribromide or trichloride. The reaction is preferably carried out in an inert solvent at about 0 to 5 ° C.

The compound of formula XXII is then oxidized

from the hydroxymethyl group to the aldehyde group, avoiding destruction of the lactone ring. Suitable reagents for this purpose are dichromate / sulfuric acid, Jones reagent, and Bleitetrafcetat Collinb reagent (Iyridin-CRO_) is like. Particularly preferably at about 0-1O ⁰ C.

The compound of the formula XXIII is prepared by Vittig alkylation of the compound XXII using the sodium derivatives obtained from Mmethyl 2-oxo-heptylphosphonate. The trans-enone-lactone is formed atereospecific (cf. D.H. Wadsworth et al., J. Org., Chem. Vol. 30, p. 680 (1965)).

The compound of ^ ormel XXIV is obtained by reducing the

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Compound XXIII, v / obei a mixture of oi- and ß-isoiceren is formed. A known reducing agent for ketonic carboxyl groups, which does not reduce ester or acid groups or carbon-carbon double bonds, if the latter is undesirable, is used for this reduction. Examples of suitable reagents are the metal borohydrides, especially sodium, potassium and zinc borohydride, lithium (tri-tert-butoxy) aluminum hydride, metal trialkoxyborohydrides, for example sodium trimethoxyborohydride, lithium borohydride, diisobutylaluminum hydride, and the boranes, for example disiamylborane, if the reduction of a carbon-carbon double bond is not a problem.

For the production of PG analogs of natural configuration becomes the desired oU form of the compound XXIV of the ß-isomer separated by silica gel chromatography.

The compound of the ^ ormel XXV is obtained by alkylating the side chain hydroxyl group of the compound XXIV, ie by replacing the hydroxyl group with the ORp radical. Diazoalkanes can be used for this purpose, preferably in the presence of a Lem's acid, for example boron trifluoride etherate, aluminum chloride or pluoboric acid. If Rp is the methyl group, then diazomethane is used (cf. Fieser et al., "Reagents for Organic Synthesis", John Wiley and Sons, Inc., NY (1967), p. 191). Other ether groups OR ₂ are obtained by using the corresponding diazoalkane. For example, diacethane and diasobutane give the radicals -CCpHc and -OC.Hq. The reaction is carried out by mixing a solution of the diazoalkane in a suitable inert solvent, preferably ethyl ether, with the compound XXIV. Generally the reaction takes place at about 25 ° C. The diazoalkanes are known or can be prepared by known methods, see, for example, Organic Reactions,

209847/1 196

"22214 * 3

John tfiley and u _o ns, Inc., HY Vol. 8, pp 389-394- (1954).

Another method of alkylating the side chain hydroxyl group consists in the reaction with an alcohol in the presence of boron trifluoride etherate. You get for example with methanol and boron trifluoride etherate the methyl ether. The reaction takes place at about 25 ° C and is expedient followed by thin layer chromatography.

Another alkylation method is implementation Bit an alkyl halide, e.g. methyl iodide, in the presence of an alkali metal oxide or hydroxide, e.g. barium oxide, Silver oxide or barium hydroxide. An inert solvent may be useful, for example benzene or dimethylformamide.

The reactants are preferably stirred and kept at temperatures between 25 and 75.degree.

Another method is to first convert the hydroxyl group into a kesyloxy group (i.e. kethanesulfonate group) or tosyloxy group (i.e. toluenesulfonate group) and then this radical by reaction with a Metal alkoxide, e.g. potassium tert-butoxide, into the remainder ORp converts. The mesylate or tosylate is made by reaction of the compound XXIV with methanesulfonyl chloride or toluene. Obtained sulfonyl chloride in pyridine. It is then combined with the appropriate potassium or sodium alkoxide in pyridine mixed, with the reaction proceeding smoothly at about 25 ° C. Use is preferred to avoid life reactions equivalent denomination of the alkoxide, based on the mesylate. In this way one obtains intermediate products of the Forciel XXV, in which Rp is a normal, secondary or tertiary alkyl radical with 1 to 5 carbon atoms iet. the The latter method is particularly suitable for tertiary alkyl substitution, i.e. for the manufacture of products

209847/1196

τ 3ο -

2221U3

where R «eats a tert-butyl or tert-pentyl radical.

The compound of the - "crmel XXVI is then prepared by the deacylation of the compound XXV with an alkali metal carbonate, for example potassium carbonate in methanol at 25 ⁰ C etva, ·.

The process of making a compound of the formula

OR ₂

in which R «has the above meaning, consists in the fact that one of a combination of the formula

201817/11 * 6

222U43

in the IU has the above meaning ", starts out, the hydroxyl group is replaced by the radical OR _? and then the last OR is replaced by a hydroxyl group.

The conversion of compounds of formula XXVI in _2-like compounds of the formula XXXI can be seen from Scheme B, üie formula XXXI falls within the scope of the ^x Ormel III.

In stage a, the teti-ahydropyranyl ether XXVII is replaced by replacement the hydroxyl group in the ring through the tetrahydropyranyloxy radical manufactured. For this purpose, the compound XXVI is treated with dihydropyran in an inert solvent, see B « Methylene chloride, in the presence of an acidic condensate solvent implemented as p-toluenesulfonic acid. The dihydropyran is used in excess, preferably in 4 to 10 times the theoretical requirement. The implementation is usually finished after 15 Mb 30 minutes at 20 to 30 ° C.

In stage b, the lactol XXVIII is obtained by reducing the oxo group of the lactone XXVII, without reducing the 13,14-ethylene bond, manufactured. The use of diisobutylaluminum hydride, the reduction, is preferred for this purpose is expediently carried out at -6o to -7o ° C.

In stage c, the compound XXIX is prepared by Wittig alkylation using a Vittig reagent obtained from 4-carboxybutyl-triphenylphosphonium bromide and sodium dimethylsulfinylcarbanide. The Wittig reagent is formed in a known manner from an intermediate product of the ^x _{'ormel Hal- (CH 2} ). -COOH, in which Hal is chlorine or bromine, see, for example, Fieser et al., Loc. cit., pp. 1238-1242. Implementation with the

209847/1196

., a. 2221U3

Lactol XXVIII proceeds readily at about 25 ⁰ C. The compound XXIX is used as an intermediate for production of both PGE ₀ - ₀ as PGF, products according to Schemes B and C.

To prepare the IGEp compounds XXXI (Hl), the tetrahydropyranyl ether XXIX is oxidized on the 9-position hydroxyl group, preferably with Jojfines reagent, the 9-oxo compound being obtained in step d. Finally, in stage, the letrahydropyranyl group is replaced by hydrogen in a hydrolysis, for example with methanol / hydrochloric acid or with acetic acid / water / water / tetrahydrofuran at 40 -45 ° C., the formation of PGA ₂ compounds as by-products should be avoided.

It thus becomes a method of making a PGEp-like Compound of formula

COOH XXXl

provided in the IL having the above meaning, the is characterized in that one of a starting material the formula

209847/1196

XXVl

HO!

OR ₂

and subjects it to the following procedural steps in succession:

a) Replacement of the free ring hydroxyl group by the tetrahydropyranyloxy radical,

b) reduction of the Laclon-Gxo group to the hydroxyl group,

c) Wittig alkylation with a compound of the formula Hal- (CH ₂ ) .- COOH, in which Hai denote bromine or chlorine,

d) Oxidation of the 9-hydroxyl group to the oxo group and

e) Conversion of the tetrahydropyranyloxy group to the hydroxyl group .

In an analogous manner, racemic products of iorrnel XXXI and their mirror image produced by converting from a racemic starting equilibrium according to the formula XXVI and her reflection runs out.

Scheme C shows the conversion of the compounds XXVI into -like compounds of the iOreel XXXII ₁ in the Rahaen

209847/1196

of formula VII falls if r \ s <* denotes configuration,

Scheraa C

HO

XXVI-

stages
ac according to scheme B

THPO

COOH

XXIX

COOH

XXXiI

209847/1 196

The starting material of the formula XXVI is used in the 'compound XXIX converted by reactions a-c shown in Scheme B. The tetrtihydropyranyloxy group of compound XXIX becomes then with hydrolysis, for example with methanol / HCl "or with acetic acid / water / tetrahydrofuran at 4o-55 ° C replaces the hydroxyl group to obtain the products XXXII

There is thus a process for the preparation of PGFp ₀ ^ -like compounds of the formula

COOH XXXIl

in the Rg has the above meaning, provided »that is characterized in that one of a starting material of the formula

209847/1196

r 36-

XXVl

and this successive reaction stages subject:

a) Replacement of the hydroxyl group in the ring by a tetrahydropyranyloxy group _f

b) reduction of the lactone oxo group to the hydroxyl group,

c) Wittig-alkylation with a compound of ^{A <Ormel} Hal- (CH ₂ K-COOH, in which Hal is bromine or chlorine, and

d) Conversion of the iDetrahydropyi'anyloxygruppe into a hydroxyl group .

In the same way, racemioche products of the formula XXXII and its mirror image obtained from a racemic output material of the formula XXVI and its mirror image.

Scheme D shows a general method for the preparation of alkyl ester-IS-alkyl ether compounds XXXIV and corresponding

209847/1198

free acids XXXV, which can be used directly by themselves * or can be used for the production of esters and salts *

2098A7 / 1196

Scbor.ia D

E-CH-W

OH

(f)

XXXNI

CH ₂ -V-COOR ₅

(G)

CH ₂ -V-COOH

XXXIV

209847 / 1.196

BATH ORIGINAL

2221463

The compounds of the formula XXXIII in scheme D * are free acids or - «- alkyl esters of the PG ₁ compounds of PGE, PGP, PGF _β , PGA and PGB as well as the corresponding PG ₂ -, PG ^ - and 13,14-Dihydr0- PG ₁ connections. In formula XXXIII, D, E, V and W have the above meaning, R. is hydrogen or an alkyl radical having 1 to 8 carbon atoms.

The optically active starting materials of the formula XXXIII are known or can be prepared by known methods, see e.g. Bergstrom et al., Pharmacol. Rev. 2o, 1 (1968); U.S. PS 3,069,322; GB-PS 1 or 40544; Corey et al., J. Am. Chem. Soc. 92, 397 (197o), 92, 2586 (197o) and 93, 149o (1971). The Racemic Starting Materials XXXIII are also known or can be done according to known methods See, e.g., Just et al., J.Ara.Chem.Soc. 91: 5364 (1969), Corey et al., J. Am. Chem. Soc. 9o, 3245 (1968) and 91, 5675 (1969), Schneider et al., Chem. Commun. (Great Britain), 3o4 (1969) and Axen et al., Chero, Ooimnun, (UK), 6o2 (197o).

In stage f of scheme D, the various PGE and PGF compounds of the formula XXXIII and their mirror image subjected to a monoalkylation, the hydroxyl group on carbon 15 in tf - ^ - alkyl ether group. .in frame

of the present invention, ie with radicals OR ₀ , wherein R _{0 is} the. /will. ^^

has the above meaning. Suitable for this purpose the methods discussed above in connection with the alkylation of the compounds of formula XXIV became. One can thus either (1) diazoalkanes, e.g. diazomethane, or (2) alkylhalocenides, e.g. methyl iodide, ethyl chloride and the like, together with silver oxide, or (3) metal-alkoxyde insert. The conditions are generally identical to those for the production of the radical -ORp in the Compounds XXV according to scheme A, apart from the fact that one

209847 / 119S

2221U3

the reaction is controlled to keep the formation of impurities and by-products iniiiiEal au. The reaction time under various reaction conditions, such as temperature, concentration, cooling, presence of catalysts and the like, can be optimized by simply following the course of the reaction by thin-layer chromatography and comparing the formation of the C-15 ether with the formation of undesired by-products and impurities observed. The honohydroxy PGA and PGK compounds do not form vine products as easily.

The desired 15-alkyl ethers are obtained from the reaction mixture, Separated impurities and unreacted starting material in a known manner, for example by silica gel chromatography including thin-layer chromatography or column chromatography, or by countercurrent distributions, see Ramwell and Daniels, "Chromatography of the Prostaglandins", in "Lipid Chromatographie Analysis", Vol. 2, G.V. fcarinetti, ed., Marcel Dekker, Inc., II.Y., 1969.

In general, free carboxyl groups of the starting materials XXXIlI in which R 1 is a hydrogen atom are also esterified in this way, so that the corresponding alkyl esters are obtained rather than the free acids. In formula XXXIV, R _{5 is} an alkyl radical having 1 to 8 carbon atoms. In stage gv / the alkyl ethers with free acid group XXXV are produced from the esters XXXIV, several methods being possible. 1-'GF and PGB compounds can be saponified, 2.B. with sodium or potassium hydroxide, in V.'oif-e, which is known per se. PGE and PGA compounds, which are sensitive to the alkaline conditions commonly used in saponification, require other known methods of converting lanterns to acids. Special biversusst is here ui c enzymatic ^ hydrolysis, the

;: O H IU 7/1 1 3 6 BATH ORIGINAL

- .41

2221U3

is explained in more detail below.

Eo thus becomes a method of making a connection the i'ormel

CH ₂ -V-COOR ₅

E-CK-W OR ₂

provided, in which I), E, H ₂ , V and W have the above meaning, which is characterized in that in a starting material of the formula

CH ₂ -V-COOR ₄

OH

Γ ⁴² '222U43

in the D, L ·, R. _t Y and W have the above meaning, replaces the sidechain by a radical -OIU wherein Rp has the above meaning, and separating the ether from the jtieaktionsgemisch.

In an analogous manner, racemic products corresponding to the formula XXXIV and its mirror image are obtained from a racemic starting material of the i'onnel XXXIII and its mirror image. received outgoing.

Further useful production methods can be seen from Scheme E below.

209847/1196

HO

HO

Carbonyl

f ÖUÜJi'i, ί Oil

2221U3

E-CH-W

OR =

XXXVI

., CHa-V-COOR ₄

O _n

E-CH-W

OR?

ßase

XXXVI I

0.

CH ₂ -V-COOR ₄

0 9 ö A 7/1 1 9 6

BAD ORJGfNAt

" ^4A ~ 2221U3

The various IG-P (X - and PGJV-like compounds of the formulas VI -IX (XXXVII according to scheme E) are prepared by carbonyl reduction of the corresponding PGE compounds (XXXVI according to scheme E). For example, the carbonyl reduction of PGE ₀ - I5-ynethylether is a mixture of PGPp ^ -15-methylether and PGF _2ß -15-ynethylether.

The reduction of the ring-shaped carbonyl group takes place in a manner known per se for reducing king carbonyls in propanic acid derivatives, see, for example, Bergstrom et al., Arkiv Kemi 19, 563 (1963), Acta.Chem.Scand. 16, 969 (1962) and GB-PS 1 o97 533. Any reducing agent which reacts neither with carbon-carbon double bonds nor with ester groups can be used. Preferred reagents are lithium (tri-tert-butoxy) aluminum hydride, the metal borohydrides, in particular the sodium, potassium and zinc borohydrides, and the metal trialkoxy borohydrides, for example sodium trimethoxyborohydride. The mixtures of ck - and B- hydroxyl reaction products are broken down into the individual CJL and ß-lDOLieren ίηφη in a known manner for the separation of analogous pairs of isomers of proctanoic acid derivatives, see, for example, Bergstrom et al ., Loc. cit., Granstrom et al., J.Biol. Chem. 24o, 457 (1965) and Green et al., J. Lipid Research 5, 117 (1964). Particularly preferred separation processes are partition chromatography, both with normal and reversed phase, preparative thin-layer chromatography and countercurrent distributions.

The various PGA compounds of the formulas X to XIII (XXXVIII according to Scheme E) are obtained by acid dehydration the corresponding PGü-connections. Example

Acid dehydrogenation of PGE _o -15-ethyl ether results

the PGA ₂ -15-ethyl ether.

209847/119 6
BATH ORIGINAL

These acid dehydrations are done by methods that of acid dehydrogenations of known prostanoic acid derivatives ■ are known, see e.g. Pike et al., Proc. Nobel Symposium II, Stockholm (1966), Interscience Publishers ,. New York, pp. 162-165 (1967); GB-PS 1097 533. Alkanecarboxylic acids with 2 to 6 carbon atoms, especially acetic acid,. are preferred for this purpose. Also dilute aqueous solutions of linear acids, e.g. hydrochloric acid, in particular in the presence of a solubilizing diluent such as tetrahydrofuran, acidic dehydrations can be used for these can also be used, although it can partially hydrolyze an ester starting material.

The various PGB-like compounds of the formulas XIV to XVII (XXXIX according to scheme E) are obtained by basic dehydration of the corresponding PGE compounds or by bringing the corresponding PGA compound into contact with a base. For example, both -PGE ₁ -15-ethyl ether and FGA ..- 15-ethyl ether give the PGB.j-15-ethyl ether when treated with a P-ase.

These basic dehydrations and double bond shifts are carried out according to methods which are already known from similar reactions of known prostanoic acid derivatives see e.g. Bergstrom et al., J.Biol.Chem. 238, 3555 (1963). Suitable bases are all their aqueous Solution has a pH of more than 1o. Preferred bases are the alkali metal hydroxides, as a reaction medium a mixture of water and sufficient quantities of one with to form a homogeneous reaction mixture is suitable Water-miscible alkanol. The PGE or PGA compound is kept in this reaction medium until none is found further PGB connection forms what from the characteristic UV absorption close to 27 ° for the PGB compound can be seen

209847/1196

-46- 2221U3

In scheme E, the various symbols K, R ₂ , R ,, V, W and ^ have the meaning given above. The KECKIONAGES shown in Scheme E are also applicable to racemic compounds that are derived from. consist of the optiech active compounds of the formula shown and their mirror image, giving the corresponding racemic PGF, PGA and PGB products.

Scheme Έ shows preferred methods for converting PGE compounds into PGF compounds, in particular PGiV / compounds.

209847/1196

222U43

Scheme

R ₇ O

HO

^ CH ₂ -V-COOR ₄

"E-CH-W I

OR ₂

, CH ₂ -V-COOR ₆

^ E-CH-W

CH ₂ -V-COOR ₆

E-CH-W

I. ι

OR ₂

4 (0)

CHp-V-COOR ₄

E-CH-W

OR ₂ HO, ..CH ₂ -V-COOH

HO

209847/1196 XXXVI

XLI XXXV! I XL. I I

In scheme F, the orraels XXXVI to XLII represent optically active compounds; E, R £, V, W and ^ have the meaning given above, Rg is either an alkyl radical having 1 to 8 carbon atoms or a radical of the formula (A), - Si-, in which A is an alkyl radical having 1 to 4 carbon atoms Phenyl radical, a phenyl radical substituted by 1 or 2 fluorine atoms, chlorine atoms or alkyl radicals having 1 to 4 carbon atoms, or an aralkyl radical having 7 to carbon atoms, and R "is either a Waseeretoffatom or a radical (A) ^ - Si according to the above definition. The specified reaction sequence can also be applied to racemic compounds which consist of a mixture of the optically active compounds as shown and their mirror image.

The various PGF-15-alkyl ethers of formula XLII are prepared by subjecting the PGLC-15-alkyl ether (acids or alkyl esters) of the ^x Ormel XXXVI a carbonyl reduction. Although the compounds of the formula XXXVI and their racemates can be reduced directly to the corresponding compounds XXXVII, the 11-hydroxyl group before the reduction _{can be recommended for the preferred formation of the PGF 0} ^ compounds over the PGF _{β compounds} to convert by silylation into a radical of the formula (A) ^ - Si-O-. The various substituents A in the radical -Si- (A), can be the same or different, for example, -Si- (A) - a trimethylsilyl- , Dimethylphenylsilyl or methylphenylbenzylsilyl radical.

The compounds of the formula XL and XLI according to scheme F can (1) be esters, ie when R. in formula XXXVI is an alkyl radical , R is also an alkyl radical; furthermore (2) acids, ie compounds which were prepared from starting materials XXXVI without silylation, in which Rg is a hydrogen atom

201147/11

2221U3

or (3) silylated products in which Rg represents a radical (A), - Si-. If, as is preferred, the compounds of the formula XXXVI are subjected to a silylation before the reduction, H _{7 is} a radical (A), - Si-, otherwise a hydrogen atom.

The silylation is carried out in a known Vv'eise, see e.g. Pierce, "Silylation of Organic Compounds", Pierce Chemical Co., Rockford, St. (1968). Sufficient amounts of Silylation agent for converting the 11-hydroxyl group into a radical (A), - Si-O are required. The silylating agents are also known, see e.g. Post, "Silicones and Other Organic Silicon Compounds", Reinhold Publishing Corp., New York, N.Y. (1949).

If compounds of formula XXXVI are used in acid form, the carboxyl group is also converted into a -COO-Si- (A) - radical with excess silylating agent and a prolonged reaction time. It is immaterial whether the carboxyl group of the compounds XXXVI is _{esterified to form a -GuO-Si- (A) 5} group or not. .

According to stage i of scheme P, the mono- or di3ilylated PGE intermediates are the Formula XL reduced to the corresponding silylated PGP compounds XLI. These reductions of ring carbonyl groups are carried out according to known methods, see the statements made in connection with scheme E.

After reduction, the silylated PGP intermediates become XLI hydrolyzed in stage j to the compounds XXXVII in which the silyl groups Rg and R «are replaced by hydrogen are * This hydrolysis is carried out using known methods to convert silyl ethers and silyl esters into alcohols

20S847 / 1196

and carboxylic acids, see, for example, Pierce, loc. cit., esp. S, 447. * Ίη suitable reaction medium is a mixture of water and sufficient quantities of an organic diluent to form a homogeneous reaction mixture. The time required for hydrolysis is determined in part by the hydrolysis temperature. With a mixture of water and methanol at 25 C, several hours are usually sufficient for hydrolysis. At ⁰ ° C., several days are generally required.

The mixture of PGF-Ql and ß-hydroxy reduction products is converted into the individual Ot and ß isomers in a well-known manner disassembled.

Finally, in step k of scheme F, the PGP esters of the formula XXXVII are hydrolyzed by known methods or saponified to form acids XLII.

The PGF acids open a way to produce the PGE acids,

The free acids of PGE-15-alkyl ethers are obtained by oxidizing the corresponding PGF-15-alkyl ether acids. Suitable oxidizing agents are known; Jones reagent, ie acidified chromic acid, is particularly useful (see J. Chem. Soc. 39 (1946)). A suitable diluent for this reaction is acetone. One works with a slight excess of the oxidizing agent over the amount required to oxidize one of the secondary hydroxyl groups of the IGF compound. The reaction temperature is at least 80 as low as about O ⁰ C, preferred reaction temperatures are between -1 o and -5o ° C. The oxidation proceeds

209847/1196

rapidly and is usually over in about 5 to 20 minutes. Excess oxidizing agent is destroyed, for example by adding a lower alkanol, expediently isopropyl alcohol, then the PGE-15-alkyl ether in conventional V / ice insulated.

An example of other suitable oxidizing agents are silver carbonate on "Celite" (Chera. Commun. 11o2 (1969)), Mixture of chromium trioxide and pyridine (Tetrahedron letters 3363 (1968), J. Am. Chem. Soc. 75, 422 (1953) and Tetrahedron, 18, 1351 (1962)), mixtures of sulfur trioxide in pyridine and dimethyl sulfoxide (J. Am. Chera Soc. 89, 55o5 (1967)) and Mixtures of bicyclohexylcarbodiimide and dimethyl sulfoxide (J. Am. Chem. Soc. 87, 5661 (1965)) called ..

■ Like various 13,14-Mhydro-PGE.j-, -PGF ₁ . -, -PGP _{1 ß} -, -PGA ₁ - and -PGB ^^ - alkyl ethers of the formulas V, IX, XIII and XVII are obtained by reducing the carbon-carbon double bond of the corresponding PGE ₁ -, PGF ^ -, PGF _{1 ß} -, PGA ₁ - and PGB ₁ compounds with trans-T3,14 double bond in the hydroxyl-containing side chain. In the side chain of the starting material terminated by the carboxyl group there may also be an cis or trans double bond, such as in the case of PGE ^ compounds, which is reduced at the same time. Likewise, a 17,18 double bond is created by PG-z compounds. to -CHpCH «- reduced.

The above reductions are carried out by removing the unsaturated PGE, PGF ,. -, PGF _ß -, PGA or PGB-15-alkyl ethers according to the method described by van Tamelen et al., J. Am. Chem. Soc. 83, 3725 (1961), (see also Fieseir et al., "Topics in Organic Chemistry", Reinhold Publishing Corp., New York, pp. 432-434 (1963) and the following reference) with diimide. The unsaturated acid or ester

2OS8A7 / 1196

-52- 2221U3

is mixed with a salt of azodioformic acid, preferably an alkali metal salt such as the disodium or calcium salt, in the presence of an inert diluent, preferably a lower alkanol such as methanol or ethanol, and preferably in the absence of substantial amounts of water. For each equivalent of multiple bonds in the unsaturated compound, at least 1 colequivalent of the salt of azodi formic acid is required. The resulting suspension is then stirred, preferably with exclusion of oxygen, then the mixture is acidified, expediently with a carboxylic acid such as acetic acid. If a starting material is used in which R _{1 is} hydrogen, the carboxylic acid itself also serves to acidify an equivalent amount

suitable

of the azodiformic acid salt. Usually, reaction temperatures of from about 1o to about 4ο ⁰ C. Within this temperature range is completed the reaction is generally less than 24 hours. The desired dihydro product is then isolated in a conventional manner, for example by evaporating off the diluent and then separating off inorganic materials by solvent extraction.

In the case of unsaturated PGE, PGF ^ and PGF _ß starting materials, the reductions to the corresponding 13,14-dihydro-PGE _{1 r>} dihydro-PGF. , - and Dihydro-PGF ..., - compounds can also be carried out by catalytic hydrogenation. Palladium catalysts, in particular on charcoal, are preferred for this purpose. Furthermore, the hydrogenation is preferably carried out in the presence of an inert liquid diluent such as, for example, methanol, ethanol, dioxane, ethyl acetate and the like. The hydrogenation pressure can be between about normal pressure and about 3.5 atmospheres, hydrogenation temperatures between about 10 and about 100 ° C. are preferred. The resulting 13,14-dihydro product is conventionally prepared from the reaction

209847/1196

mixture isolated, for example with filtration or Centrifugation of the catalyst, followed by evaporation of the solvent.

The following scheme G shows biimide heductions and catalytic hydrogenations for the preparation of the new 13,14-dihydro compounds V, IX, XIII and XVII from the corresponding PGE-, PGP ₀ J-, TGFß-, ^ GA- and PGB- Connections of the PGg and PG, series. In this scheme owning), and W has the meaning given above,

209847/1196

Scheme G

CH ₂ -V-COOR ₄

CH = CH-CH-W I. OR ₂ XLIII

(CH ₂ ) e-C00R ₄

CH ₂ CH ₂ -CH- (CHa) ₄ -CH ₃ OR ₂ XLIV

209847/1196

-55- 222U43

Me free acids of the compounds II to V can be obtained from the Alkyl esters are produced by enzymatic hydrolysis. In this process, the alkyl esters are the acylase system a microorganism of the species Subphylum 2 from Phylum III, whereupon the acid is isolated. Microorganisms of the genera Mucorales, Hypocreales, Koniliales and Actinomycetales are particularly preferred. In addition, family microorganisms are preferred Mucoraceae, Cunninghasellaceae, Nectreaceae, Moniliaceae, Dematiaceae, Tuberculariaceae, Actinomycetaceae and Streptomycetaceae, and particularly preferred are microorganisms of the species Absidia, Circinella, Gongronella, Rhizopus, Cunnighamella, Calonectria, Aspergi3.1us, Penicillium, Sporotri churn, Cladosporium, Paarium, Nocardia and Streptomyces. Examples for microorganisms of the aforementioned genera, families and species are given in U.S. Patent 3 29o 226 listed.

The enzymatic ester hydrolysis takes place by using the PGE-15-alkylether-alkylester shakes in aqueous suspension with the enzyme, which in a culture one of the above Microorganisms is suspended until ester hydrolysis has occurred. Usually reaction temperatures are between 2o and 3o ° G satisfactory. A reaction time of 1 to 20 hours is generally sufficient for the desired hydrolysis the end. In most cases, it is advisable to exclude oxygen, for example by means of argon or nitrogen.

The enzyme is obtained by removing the cells from the culture separates, washes and resuspended in water, then the cells are comminuted, for example under lead with glass balls or by sonic or ultrasonic treatment. The entire aqueous mixture is then used as a source of enzyme. According to a preferred alternative, however, the cell residues are first centrifuged or filtered off,

209847/1136

-56- 2221U3

and you only work with the supernatant aqueous Liquid or the piltrat.

Occasionally it is advantageous to use the microorganisms in the presence of an alkyl ester of an aliphatic acid 1o to 2o carbon atoms in the acid chain and 1 to 8 carbon atoms in the alkyl group, or one add such ester to the culture and leave it for 1 to 24 hours without further growth before the cells secrete will. Occasionally an enzyme is obtained in this way which is more effective in converting the ester IV to free acid. A suitable alkyl ester for the stated purpose is ilethyl oleate.

The enzymatic hydrolysis is also dated on alkyl esters PGP, PGA and PGB types applicable.

Was an iG-15-alkyl ether acid produced, but If an alkyl ester is sought, the acid is advantageously esterified with the corresponding diazo carbon. When using diazomethane, for example, the methyl ester is obtained. Analogously with iazoethane, diazobutane and 1-diazo-2-ethylhexane, the ethyl, butyl and 2-ethylhexyl esters obtain.

The esterification with diazo carbon materials takes place by a solution of the diazo hydrocarbon in a suitable inert solvent, preferably in ethyl ether, mixed with the acid, expediently in the same or a different inert diluent. After the esterification has ended the solvent is evaporated and the ester is purified in a conventional manner, preferably by chromatography. The acid should not be longer than necessary for the desired esterification with the diaso-hydrocarbon

209847/1196

stay in contact, preferably about 1 to about 10 Take care to avoid unwanted molecular changes. Diazo hydrocarbons are known or can be used according to known methods, see e.g. Organic Reactions, John V / iley & Sons, Inc., New York, N.Y., Vol. 8, Pp. 369-394 (1954).

The PG -15-alkyl ethers of the formulas II to XVII in the form of the Free acid can be neutralized with suitable amounts of the appropriate inorganic or organic bases be converted into pharmacologically acceptable salts. These Conversions take place according to known methods for the production of inorganic, i.e. metal or ammonium salts, of amine acid addition salts and quaternary ammonium salts. The choice of method depends in part on the solubility properties of the salt to be produced. In the production of inorganic salts, the PG-15-alkyl ether acid is usually used dissolved in water, which corresponds to the stoichiometric amount of a hydroxide, carbonate or bicarbonate contains the desired salt. For example, when using sodium hydroxide, sodium carbonate is obtained or sodium bicarbonate a solution of the sodium salt. When evaporating the water or adding a water with water Miscible solvents of moderate polarity, for example a lower alkanol or a lower alkanone, the solid inorganic salt is obtained if this ^ 'orm is desired.

To produce an amine salt, the PG acid is used in one suitable solvents of moderate or low polarity solved, given as examples for the former ethanol, acetone and ethyl acetate and for the latter ethyl ether and benzene be. At least a stoichiometric amount of the amine is then added to this solution. If the result falls

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Not enough salt, it is usually made by adding it a miscible diluent of low polarity or obtained by concentration in solid form. Is the amine relatively volatile, an excess can easily be removed by evaporation. With less volatile amines "the use of stoichiometric amounts is preferred.

Quaternary ammonium salts are obtained by making the PG acid mixed with the stoichiometric amount of the corresponding quaternary ammonium hydroxide in aqueous solution and then evaporated.

In the following examples, the infrared absorption spectra were with an I-Erkin-Bucket-Spectrophülometer model 421 added. Palis unless otherwise specified, were undiluted Samples used. NMR spectra were recorded on a Varian A-60 spectrophotometer using solutions of deuterochloroform recorded with tetramethylsilane as internal standard (downfield). The mass spectra were based on an Atlas CK-4 mass spectrometer with a TO-4 source established (ionization voltage 7o ev). The ultraviolet spectra were obtained with a Cary spectrophotometer model.

As a solvent system in thin-layer chromatography was used among other things:

A IX: Ethylacetate-i-ssigsäure - ^^^ - Trimethylpentan-Wasaer (9o: 2o: 5o: 1oo).

see M. Hamberg and B. Samuelsson, J.Biol.Chem. 241, 257 (1966).

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" ^5S " 2221U3

Preparation 1

3 (X-Benz.oyloxy-5 Ot-hydroxy-4-iodo-^ ß-methoxymethylcyclopentaneacetic acid-7 ^ -lactone.

(Formula XIX: JR ₅ = benzoyl) (see scheme A).

To a mixture of 75 g of levorotatory iodolactone XVIII (EJ Gorey et al., J.Am.Chem.Soc. Vol. 92, p. 397 (197ο)) in 135 ml of dry pyridines, 3o.4 nl of benzoyl chloride were added in a nitrogen atmosphere with cooling added to maintain a temperature of about 2o-4o C, then stirring was continued for 30 minutes. Then about 250 ml of toluene. added and the mixture is concentrated under reduced pressure. The residue is dissolved in 1 liter of ethyl acetate and washed with 1 of the above sulfuric acid, saturated sodium chloride solution, saturated sodium bicarbonate solution and saturated sodium chloride solution. The ethyl acetate solution is dried over sodium sulfate and concentrated under reduced pressure, 95 g of a Gis being obtained. On crystallization, this gives the title compound with a melting point of 84-86 ° C, JsU-Q + 7 ° (CIICl ₅ ); IR absorption at 1768, 1722, I600, 157ο, 149ο, 1275, II80, 1125, 1o9o, I060, 1o3o and 71 ο cm "¹; NHR-Peks at 2.1-3.45, 3.3, - 3 , 58, 4.38, 5.12, 5.51, 7.18-7.58 and 7.83-8 _t o5 pounds.

According to the procedure of Example 1, the optically active i'orm of iodolactone XVIII is also replaced with acetyl chloride reacted by benzoyl chloride to give the corresponding intermediate in which R ~ is an acetyl group.

The procedure of preparation 1 is repeated, but below Replacement of the optically active form of iodolactone XVIII by

/ one obtains the corresponding racemate when using Benzoyl chloride and acetyl chloride the corresponding racemic

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Connections XIX.

Preparation 2

3 ο / -Benzoyloxy-5 oil -hydroxy ^ ß-methoxy-methylcyclopentane acetic acid-7 ^ -lactone

(Formula XX: R ₅ = benzoyl) (see Scheme A).

Add to a solution of 60 g of the optically active benzoxy compound XIX (see preparation 1) in 24o ml of dry benzene about 60 mg of 2,2'-azobis (2-methylpropionitrile) were added. The mixture is cooled to 15 ° C., then a solution of 75 g of tributyltin hydride in 600 ml of ether is added with stirring added at such a rate as to maintain a continuous reaction at about 25 ° C. After finished Reaction (as can also be seen in the thin-layer chromatogram), the mixture is concentrated under reduced pressure to a Gl, this v / ird with 600 ml ^ kellysolve B (isomeric Hescane) and 600 ml of water mixed and stirred for 3 ο minutes. The aqueous phase containing the product is separated and then with 45o ml of ethyl acetate and to saturate the aqueous Phase combined with sufficient solid sodium chloride. The ethyl acetate layer, which now contains the product, is separated off, dried over magnesium sulfate and concentrated under reduced pressure, 39 g of the title compound in In the form of an oil. An analytically pure sample provides the following

Values: O-Q -99 ° (CHGl ₃ ); IU absorption at 1775, 1715, I600 1585, 149o, 1315, 1275, 118ο, 111o, 107o, 1055, 1025 and 715 cm ""¹; NfcR feaks at 2.15-3.0, 3.25, 3.34, 4.84-5.17, 5.17-5.4, 7.1-7.5 and 7.8-8, 05 Si peaks in the mass spectrum at 29o, 168, 1o5 and 77.

Following the procedure of Example 2, all are optical

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active compounds of the formula XIX or the raeeraischen compounds, which are mentioned in connection with preparation 1, into the en-feprechenden optically active or racemic compounds converted to formula XX.

Preparation 3

5o (-Benzdyloxy-Scx-hydroxy ^ ß-hydroxymethylcyclopentaneacetic acid- ^ -lactone.

(Formula XXI: R, = benzoyl) (see Scheme A).

To a cold (0-5 ⁰ C) solution of 2o g of the lactone XX (see Preparation 2) in 32o mL of methylene chloride under nitrogen in a solution of 24.8 ml of boron tribromide in 32o mL of methylene chloride with vigorous stirring in the course of 5o min 0 to 5 ° C was added dropwise. The mixture is then stirred and cooled for a further 1 hour. After the reaction has ended, as can be seen from the thin-layer chromatography, a solution of 70 g of sodium carbonate monohydrate in 200 ml of water is carefully added. The mixture is stirred at 0 to 5 ° C. for 10-15 minutes, then saturated with sodium chloride, then the ethyl acetate layer is separated off. Further ethyl acetate extracts from the aqueous layer are combined with the main ethyl acetate solution, these solutions are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure, 18.1 g of the title compound being obtained in the form of an oil. An analytical sample melted at 116-118 ⁰ C, Z ° L7 _D -8o ° (CHCl,); IR absorption at 346o, 1735, 17o8, 160o, 158o, 149o, 1325, 1315, 128o, 12o5, 1115, 1090, 107o, 1035, 1025, 73o and 72o; NMR peaks at 2.1-3, o, 3.58, 4.83-5.12, 5.2-5.45, 7.15-7.55 and 7.8-8, o &.

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According to the instructions for preparation 3, all of the optically active compounds XX or those following preparation mentioned racemates in dis corresponding optically active or racemic Hydroxynethy !verbindungen converted XXI.

Preparation 4

-Benzayloxy-2ß-carboxaldehya-5 cZ-hydröxy-cyclopentanessigsäure-γ-lactone.
(Formula XXII: R ₅ = benzoyl) (see scheme A).

To a mixture of 150 ml of dry ethylene chloride and 28 g of Collin's reagent (JC Collins et al., Tetrahedron Lett. 3363 (1968)) at about 10 ° C., a cold (10 ° C.) solution of 5, og de3 optically active hydroxymethyl lactone XXI (see preparation 5) in 150 ml of methylene chloride added. After stirring for an additional 5 minutes, about 100 ml of dry benzenes are added, the mixture is filtered and the solution is concentrated under reduced pressure. The volume is adjusted to about 150 ml with benzene. This solution of the title compound XXII is used further directly. In an analogous approach, when the benzene solution is concentrated under reduced pressure, an oil is obtained which, when triturated with ether, ^{gives crystals of the optically active compound XXII with a melting point of 115 °} C. (decomposition); NMR peaks at 1.0-3.7, 4.9-5.2, 5.54-5.77, 7.2-7.6, 7.7-8, ο and 9.8 S.

According to the prescription of preparation 4, all optically active hydroxymethyl compounds of ^ ormel XXI or the after preparation 3 mentioned racemates into the corresponding converted optically active aldehydes of the formula XXII or their racemates, Pw in these compounds

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2221U3

Berizoyl- odor acetyl residue is »

Preparation 5

3oJ -Bensoyloxy-5W-hydroxy-2ß- (3-oxo-trans-1-octenyl) -1Oi cyclopentanesacetic acid- / "- laoton. ■

(Formula XXIII: R ₅ = benfcoyl) (see scheme A).

A solution of dimethyl 2-oxo-heptyl-phosphonate (Corey et al., J. Am. Chem. Soc, 9o, 3247 (196S)) in 36 ml of tetrahydrofuran is added to a cold (5 ° C.) suspension of Sodium hydride (55%, 162 g) in 180 ml of tetrahydrofuran was added. The mixture is then stirred at about 25 ° C. for 21/2 hours and then cooled to −10 ° C., after which a bensolic solution of the optically active aldehyde XXII (see preparation 4, 108 ml) is added. After 1 1/2 hours, 1.8 ml of acetic acid are added and the tetrahydrofuran is distilled off in vacuo. The residue is dissolved in ethyl acetate and the solution is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel using 25-3θ / £ ethyl acetate in Skellysolve B (isomeric hexanes) for elution gives the title compound of the formula XXIII.

If the process of preparation 5 is repeated, but with Krsat3 des aldehyde XXII by all other optically active aldehydes of formula XXII or their racemates, which are mentioned in connection with preparation 4, the corresponding compounds of formula XXIII are obtained, in which the remainder R _{7 is} identical to the one that reads R, in Aldehyde XXII.

The racemic aldehydes XXII give racemic products XXIII,

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222UA3

Preparation 6

3 O (-Benzoyloxy-5 o (-hydroxy-2ß- (3cx -hydroxy-trans-1-octenyl) -1c ^ -cyclopentaneacetic acid-Γ-lactone. (Formula XXIV: R ₅ = benzoyl, ^ = o ( ) ( Scheme A).

A solution containing 2.75 g of the ketone XXIII (see preparation 5) in 14 ml of 1,2-jjimethoxyethane is added to a mixture which consists of 4.94 g of anhydrous zinc chloride, while stirring and cooling to -1o ° C. 1.12 g of sodium borohydride and 48 ml of dry 1,2-methoxyethane had been prepared. It is stirred for 2 hours at ⁰ ° C., then 7.8 ml of water are carefully added, followed by 2 ml of ethyl acetate The mixture is filtered, the ethyl acetate solution is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to give a mixture of the W and β isomers of the product XXIV. This mixture is chromatographed on silica gel , v / obei is eluted with ethyl acetate, the Qf - (less polar) and β-isomers of the title compound XXIV being separated from one another.

According to the specification of preparation 6, the optically active ketones XXIII or their racemates, which follow on from Preparation 5 are mentioned, in which compounds R, a Benzoyl or acetyl radical, converted into the corresponding optically active hyuroxyl compounds XXIV or their racemates.

example 1

-Benzoyloxy-5CX -hydroxy-2β- (3 ei -methoxy-trans-1-octenyl) -1 -cyclopentane acetic acid-7 "-lactone.

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(Formula XXV: R ₀ = methyl and R, "= benzoyl) (see scheme A).

A mixture of 2, ο g of the Ο'-hydroxy compound XXIY (see preparation 6), 4, ο g of silver oxide and 50 ml of methyl iodide is refluxed with stirring for 68 hours. The mixture is then cooled and filtered, the filtrate v / It is concentrated to 2, ο g of an oil. By silica gel chromatography, eluting with 35 ^ ethyl acetate / Skellysolve B and combining the fractions containing the product free of starting material and impurities according to the thin-layer chroniatogram, the title compound of the formula XXV is obtained in the form of 1.16 g of a yellow oil, IR absorption at 1775 , 172o, 16oo, 1585, H9o, 1315, 1275, 1175, 1115, 11oo, 1o7o, 1o5o, 1o25, 97o and 715 cm "¹; HMR-Peake at 0.8 (wide), 1.4 (wide), 1.9 (wide), 2.3 (wide), 2.7 (wide), 3.15 (singlet), 5.1 (wide), 5.4-5.6 (triplet), 7.5 ( wide) and 7.8-8, ο (multiple «) <$.

If the process of Example 1 is repeated, but replacing the methyl iodide with other alkyl halides, the corresponding alkyl ethers XXV are obtained. With methyl bromide, ethyl chloride, isopropyl iodide, butyl bromide or pentyl iodide, compounds of the formula XXV are thus obtained in which R ₂ ^e * ^{n is} methyl, ethyl, isopropyl, n-butyl or n-pentyl radical.

Repeat the procedure of Example 1 using of methyl iodide or any other of the above alkyl halides as well as one of the optically active or racemic hydroxy compounds of the sleeves XXIV, which follow on from Preparation 6 are mentioned and in which R 1 is a benzoyl or acetyl rent, the optically active alkyl ethers are obtained der - "ormel XXV or the corresponding racemates.

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Example IA

-Benzoyloxy-2ß- (3c <-tert.-butoxy-trans-1-octenyl) -1 o (-cyclopentanescetic acid-X-lactone.
(Formula XXV: R ₂ = tert-butyl and IU = benzoyl) (see scheme A)

To a mixture of 2, ο g 3o {benzoyloxy-5-hydroxy-2ß- # "(3 Q / hydroxy-trans-1-octenyl) -1 d -cyclopentanessigsäure- y ~ la.ci.on XXIV (see Preparation 6) in 25 ml pyridine v / ground in a nitrogen atmosphere at 0 G while stirring slowly 4 ml methanesulfonyl chloride over the course of 15 minutes. The mixture is ^{then stirred for 2 1/2 hours at 0} ° C., then cooled to -15 ° C. mixed with 10 ml of ice and water. After about 5 minutes, the mixture is poured into 250 ml of ice and water. " Then 100 ml of a cold mixture of methylene chloride / ether (1: 3) are added, then 150 ml of cold 3N hydrochloric acid are added. The organic layer is separated, washed with 2% sulfuric acid, then with water, aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to give the 3ot-ftesyloxy intermediate.

To a mixture of 2.2 g of this intermediate and 2o ml Pyridine is a mixture of 0.55 g of potassium tert-butoxide and 10 ml of benzene are added and the resulting mixture is stirred for several hours at about 25 ° under nitrogen. Then the mixture is carefully poured into 10 ml of water and neutralized with cold 3xi hydrochloric acid. Afterward is extracted with benzene, the bensol extracts are combined with water and saturated sodium chloride solution washed, dried over anhydrous sodium sulfate and concentrated. The residue is filtered through silica gel chromatography worked up, with 35 '^ ethyl acetate / Skellysolve B

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eluted and those fractions pooled which, according to thin-layer chromatograms, found the product to be free from starting material and contain impurities. The title compound of the formula XXV is then obtained in this way.

If the procedure of Example 1A is repeated, but replacing the potassium tert-butoxide with sodium ethylate, Potassium isopropylate or sodium tert-pentyloxide, as well as furthermore using the benzoyl or acetyl form of the compound XXIV, the corresponding compound is obtained

a
XXV, in which R ₂ / ethyl, isopropyl or tert-pentyl radical

and R ~ represent a benzoyl or acetyl radical. Example 2

3 <jt »5 ^ -dihydroxy-2ß- (3 ot-inethoxy-trans-1-octenyl) -1 $ -cyclo« · pentane acetic acid-T-lactone.

(Formula "XXVi: R ₂ = methyl) (see scheme A).

A mixture of 1.91 g of the benzoyloxy compound XXV and 0.684 g of anhydrous potassium carbonate in 25 ml of dry methanol is stirred for 1 hour with exclusion of moisture. Then 25 ml of chloroform are added and the mixture is filtered, the filtrate is concentrated to an oil and taken up in 50 m3 of chloroform. The solution is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in a glass. This is chromatographed on silica gel, eluting with 40% ethyl acetate / Skellysolve B. Those fractions which, according to thin-layer chromatography, contain the desired product free of starting material and impurities are combined and give the ^x itel compound XXVI in the form of 1, og a pale yellow oil, peaks of the macose spectrum at 25o, 211, 193 and 179; IR absorption at 242o, 1765, 1175, 1090, 1035, 975 and 905 cm " ¹

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- THU -

2221U3

NKR peaks at 0.8-1.1 (cultiplet), 1.4 (broad), 1.9-2.4 (multiplet), 3.3 (singlet), 4.1 '(cultiplet), 5, 1 (multiplet) and 5.5 (cultiplet) £. The compound crystallizes from i'ither / ükellysolve B in needles with a melting point of 57.5-60 ° G.

According to the procedure of Example 2, all the alkyl ethers of the formula XXV, which are mentioned in connection with Examples 1 and 1A, are converted into the corresponding optically active alkyl ethers XXVI or the corresponding racemates. Thus, the compounds of the formula XXV, in which R _{2 is} ethyl, isopropyl, butyl, tert-butyl, n-pentyl or tert-pentyl iet, give the corresponding products XXVI, in which Rp is an ethyl, isopropyl, represents n-BulyJ.-, tert-BuLyI, n-pentyl or tert-pentyl radical.

Example 3

PGE ₂ -15-iaethylether (Formula III: R ₁ = hydrogen, R ₂ =

Kethyl) (Scheme B).

(a) The tetrahydropyranyl ether is prepared as follows: A mixture of 2.35 g of the 3 o /, 5 ^ -dihydroxy-2o (- (30 < -methoxytrans-1-octenyl) -1-il -cyclopentanesacetic acid - "/ - lactons XXVI, 3.5 g of hydropyran and about 0.1 g of p-toluenesulfonic acid in 150 ml of methylene chloride is stirred for 30 minutes. then the mixture is 2 χ with 1 above Natriurccarbonatlooung and then washed with saturated sodium chloride solution and dried over magnesium sulfate. When constricting at reduced 3.26 g of tetrahydropyranyl ether XXVII are obtained under pressure, which is free of starting material according to thin-layer chromatography eats.

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(b) The Lactol XXVIII is prepared as follows:

To a solution of the tetrahydropyranyl ether in 150 ml of dry toluene, a solution of 105 ml of diisobutylaluminum hydride (10 $ in toluene) is added in about 35 minutes at about -Go ⁰ C with stirring and exclusion of air is stirred after 30 minutes with cooling, then the cooling bath is removed and a mixture of 48 ml of tetrahydrofuran and 29 ml of water is added dropwise over the course of 20 minutes When concentrated under reduced pressure, the lactol of i'ormel XXVIII is obtained in the form of 3.11 g of a yellow CI. This product is free from lactoij according to thin-layer chromatogram.

(c) The compound of formula XXIX is treated with a Wittig reagent obtained, which is manufactured as follows:

7.36 g of 4-carboxybutyl-triphenylphosphonium _{broroid (prepared in a known V. e} ice from a compound of the formula Hal- (CH ₂ ) .- CCOH, in which Kai means bromine or chlorine) are added to a solution of sodium dimethylsulfinylcarbanide, which had been prepared from sodium hydride (57 / =, 1.4 g) and 30 ml of dimethyl sulfoxide. The mixture is then stirred at about 36 ° C. for 20 minutes. 3.11 g of the lactol of the formula XXVIII according to step (b) in 25 ml of dimethyl sulfoxide are added dropwise to this reagent. The mixture is stirred at about 25 ° C. for 3 1/2 hours and then diluted with about 3o tablespoons of benzene. Then a solution of 5.96 g of potassium bisulfate in 57 ml of water is added dropwise with cooling and stirring, the mixture is diluted with 200 ml of water and 100 ml of benzene and the phases are separated. The oatnish layer is washed with water and dried over magnesium sulfate. Kinengen under reduced pressure gives an oil which

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. 2221U3

stirred with ether to secrete some solid by-products. When the / ether is evaporated, an oil is obtained, which by silica gel ear omaLography under liquidation with 4o £ ethyl acetate / Skellysolve B is separated. Those Fractions that are free according to the thin layer chromatogram of starting material and impurities are combined to give 2, o? g of compound XXIX in Shape of a yellow GI.

(d) The compound of the formula XXlX becomes as follows 9-oxo compound XXX oxidizes:

To a solution of 0.887 g of 11-Tetrahydropyranyläther-15-Raethylätherverbinduiig According to step (c) in 2o ml of acetone at -2o ° C, 1.0 ml of Jones reagent (2.1 g of chromic anhydride, 6 ml of water and 1.7 ml of concentrated sulfuric acid are added dropwise. After stirring for 1/4 hour, 1 ml 2-propanol is added, then the mixture is stirred again. The mixture is poured into 100 ml of water and washed with methylene chloride extracted. The organic extracts are made with sodium chloride solution washed, dried over magnesium sulfate and concentrated under reduced i ^ rucic, the product of the Formula XXX receives.

(e) The 1 l-Tetrahydi'opyranyläther XXX is hydrolyzed as follows to the PGEp-15-methylether of the formula XXXI / The product of step (d) is dissolved in a mixture of 20 ml acetic acid, 10 ml water and j5 ml tetrahydrofuran and Left to stand for 3 hours at about 40 ° C. Then 50 ml of water are added, the mixture is frozen and freeze-dried with reduced JJrucX '. When the remaining CI3 is broken down by silica gel chromatography while luting with 40; 5 ethyl acetate / Skellysolve B, the product fractions free of starting material and impurities according to the thin-layer chromatogram are obtained

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222U43

the title connection of the i'ormol III in I'orm of ο, 4 g of a light brown, oil, leaks of the mass spectrum at 348, 334, 33o, 316, 2S8 and 277; IR absorption at 342o, 33oo-31oo, 265o, 1735, 171o, 1285, 124o, 1155, 1085, 1075 and 97o cm ** ¹ ; NMR peaks at ο, 8-1.1 (multiplet), 1.4 (broad), 2.3 (broad), 3.3 (singlet), 3.4-3.6 (Hulitplett), 4.0 -4.2 (Kulitplett). 5.5 (wide) lbs.

Following the procedure of Example 3, all the optically active alkyl ethers of the formula XXVI or the racemates mentioned in connection with Example 2 are converted into the corresponding intermediates of the formula XXIX and then into the PGEp-15 ~ alkyl ethers XXXI. For example, from the optically active compound of the formula XXVI, in which Rp is an isopropyl radical, the PGE ₂ -15 isopropyl ether is obtained. The racemate of the compound /.XVI, in which Rp is a butyl radical, gives the racemic IG> 3 ₉ -15-butyl ether. In an analogous manner, other intermediate products of the formula XXIX and end products of the formula III are obtained, in which R _{1 is} a hydrogen atom and R 1 is an alkyl radical having 1 to 5 carbon atoms, for example. , · PGE ₂ -15-ethyl ether and PGi) ₂ -15-pentyl ether.

Example 4

PGP _2o (-15-methylether (Formula VII: R ^ = hydrogen; R ₂ =

Methyl, ~ = oil) ( _see scheme C).

~ ΰΆΒ Tetrabydropyranyl ether intermediate XXIX v / ird hydrolyzed as follows: Kin Gcraisch axis 2, o7 g of the tetrahydropyranyl ether (see Example 3, stage c) _t 4o'Tal acetic acid, 2o ml of water and 6 ml of tetrahydrofuran is 4 1/2 hours at held about 38 ^° C. I add another 100 ml of water to it

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BATH ORIGINAL

222H43

added, the mixture is frozen and freeze-dried under refined pressure. The remaining oil-liquid mixture is broken down by silica gel chromatography under oiling rait Ao ^ ethyl acetate / Skellysolve B, those fractions being combined which, according to the thin-layer chromatogram, are free of starting materials and impurities. This gives 1.2 g of the title compound VII. Dieoe crystallizes from ether / Skellycolve B, melting point 52-55 C. Peaks in the Cas3 spectrum at 353, 35o, 336, 31B, 300, 264 and 261; IR absorption at 342o, 295o, 272o, 266o, 1715, 168ο, 133o, 127o, 12o5, 113o, 1o75, 98o and 925 cm "¹; NMR peaks at o, 8-1.1 (multiplet), 1, 5 (wide), 2.2 (wide), 3.3 (sinus toilet), 4, o-4.3 (multiplet) and 5.5 (wide) g.

If the process of Example 4 is repeated, but replacing the intermediate of the formula XXIX with compounds XXIX, which are mentioned in connection with Example 3, the corresponding optically active PCF ₂₀ ^ -alkyl ethers VII (XXXII), for example the PGFp ^, are obtained -15-isopropyl ether; racemic PGFp, -15-butyl ether; PGFp ^ -15-methyl ether and the like, in which Rp is a radical as defined above.

Example 5

PGÜ.-methylester-15-methyl ether (formula II: R ₁ and R ₂ - methyl),

(ß. Scheme D, where D « T)

, E = -CH = ClI-, HO '

and K ₅ * methyl, R. hydrogen, V = pentyl).

Hydrogen, V * _ (CH _? ) _R - and

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A mixture of ο, 25 g PGE ₁ , 1.2 g bilberoxyd and 50 * ml methyl iodide is refluxed with stirring for 2 days. The mixture is then cooled and filtered, the filtrate is concentrated. The residue is chromatographed on silica gel, eluting with 10 ^ acetone / methylene chloride. Those fractions which, according to the thin-layer chromatogram, contain the 15-methyl ether free of starting materials and impurities are combined and concentrated and give the compound of the formula II or XXXIV, which has the following peaks in the cash spectrum: 564, 332, 3o1, 3oo and 293.

The procedure of Example 5 is repeated, but replacing the PGE. by PGE ₅ or 13,14-dihydro-PGK ₁ , the corresponding methyl ester-15-methyl ether of PGE ₅ and 13,14-dihydro-PGE.,.

Likewise, according to the procedure of Example 5, but when the IGE _{1 is} replaced by racemic PGEp, racemic PGE-2 or racemic. 13,14-dihydro-PGE ₁ the corresponding methyl ester IS-methyl ether compounds of these racemic PGE compounds.

Furthermore, according to the procedure of "Example 5", when the methyl iodide is replaced by other alkyl iodides and when PGE., PGE ₂ * £ ^GE 3 ^or 13,14-dihydro-PGE., The corresponding alkyl ester-15-alkyl ethers of the formula are obtained XXXIV.

In addition, according to the procedure of Example 5, "when PGE _{1 is} replaced by PGF ₁ ^, PGF _1ß , PGF _2ci , ΓοΡ _2β , PGF ₅₀₁ , PGF _5ß , 13,14 -.-. IhVcIrO-PGP ₁ ^ or 13, 14-Dihydro-PGF _1ß or their hacemates, the corresponding Kethylester-15-ir.ethyläther-PGF compounds XXXIV and their racemates.

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BATH ORIGINAL

"■" ". 2221 /,

Example 5A

PGE ₂ -inethylester-15-n-ethyl ether

(Formula III: R. and R ₂ = I-ethyl). (see scheme I) ,. v / orin

, Ε β.-GH = GH-, R ₂ . and R ₅ »methyl, R- = hydrogen, V - -CH-CH- (CiI ₂ ), - and W = 1-jfentyl).

A solution of 1.6 g of PGE ₂ in 15o ml Kethylenchlorid is "treated at about 25 ⁰ C with an ethereal diazomethane solution, the o containing 5 ml of boron trifluoride etherate (see Fieser et al.," Reagents for Organic Synthesis ", S 192, John V / i3, ey a Sons, Inc., New York, NY (1967)) until the clear yellow diazomethane color persists for 10 minutes.

Excess diazomethane is then removed with a few drops Acetic acid is destroyed and the solvent is removed with reduced -i-tuck. The residue is purified by silica gel chromatography broken down into its components. Those fractions which, according to a layer chromatogram, contain the title compound free of starting material and impurities are combined to give the product of Formula III (XXXIV).

If the procedure of Example 5A is repeated, but replacing the IGE ₂ with IGE ₁ , IGE ₅ or 13,14-dihydro-PGE.j, the corresponding methyl ether-15-methyl ether of these compounds is obtained,

If the procedure of Example 5A is also repeated, replacing the diazomethane with other jiazoalkanes, so one obtains the corresponding alkyl ester-15-alkyl ether-PGE-

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2221U3

connections XXXIY. T-Iit diazoethane, diaaopropane or diasobutane and KrE. thus fo3.gea.de products of ^ ormel III (XXXIV) are obtained: PGä.j-ethyl ester-IS-äth.y lather; propyl ester-15-propyl ether; and GE I ¹ _{-.-butyl-15-butyl} ether Starting from PGlL-mothylester the compounds PGE ₁ -methyleßter-15 äthylef3ter, PGE.-raethyIester-15-propyl äter and PGE.-methylester-15-butyl ether.

Example 5B

methyl ester-15-methyl ether. (Formula VII: R .. and R _? = Methyl, r * «oil} (see scheme D, where \

KO \

, E - -CH = CiI-, R ₂ , R ₄ and R ₅ · ■ = methyl, V rr -CH = CH- (CH ₂ ), - and W = 1-pentyl).

HO /

A solution of 1, _{above-mentioned PGF 001} methyl ester in 2o ml of methanol is treated with ο.25 ml of boron trifluoride etherate at about 25 ° C. and left to stand for 1 hour. About 10 ml of water are then added and the mixture is concentrated in vacuo in order to remove most of the methanol. The residue is extracted with ethyl acetate and the combined ethyl acetate extracts are washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is taken up in a little methylene chloride and chromatographed on silica gel, the '-Citel compound of the formula XII (XXXIV) being obtained.

If the procedure of Example 5B is repeated, but under Replacement of the PGF ^ methyl ester by the iithyl, propyl,

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Isobutyl or heptyl esters of I ¹ Gi ¹ O ₀ , »ε ° are obtained correspondingly to the ethyl, propyl, isobutyl and iieptyl esters of -15-methyl ether.

Likewise, if the PGF is replaced by the procedure of Example 5, ₂₀ ; methyl ester through racemic PGF ^ q, -methyl ester the racemic PGF ₉ -methyl ester-15-methyl ether, analogously the ethyl, propyl, isobutyl and heptyl esters of the racemic PGF ~ give the corresponding racemic -15-methyl ether esters.

In addition, following the procedure of Example 5B, but replacing the methanol with other alcohols such as ethanol, propanol, butanol or pentanol, the corresponding PGF ₂ ^ -alkyl ester-15-alkyl ether compounds in which R _{2 is} ethyl, propyl or butyl - or pentyl radical.

Example 6

PGAp methyl ester methyl ether.

(Formula XI: R ₁ and R ₂ = methyl) (see scheme D, where * Ö =

, E * -CH = CH-, R ₂ and R _r - methyl, R- = hydrogen, \\ l V m -CHsCri- (CHg) ₅ -, W = 1-pentyl).

A mixture of 0.237 g of PGAp, 0.41 g of silver oxide and 40 ml of methyl iodide is refluxed for 17 hours with stirring, then cooled and filtered. The filtrate is concentrated to a yellow oil which, on silica gel chromatography with dilution with 0.5 to 1.0% methanol / ethylene chloride, gives 0.04 g of the title compound XI in a yellow C3o; leaks ira barrel range at 351, jJ3o, 291 and ? ^l jo;

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2221U3

(Ethanol) 217 (£ - 9 3οο) and 274 (£ - 155α) m / u.

According to the procedure of Example 6, IGA .. _t PGA, and dihydro-I'GA is also converted into the corresponding compounds XI, for example in PGA.-rcethylester-diethyl ether and the like.

Example 6A

₁ -I5- (tert-butyl) ether methyl ester. (Formula X: R ₁ = methyl, R ₂ »tert-butyl).

To a solution of 5, _{above-mentioned PGA 1} -niethyl ester in 50 ml of pyridine at ⁰ ° C., 7 ml of methanesulfonyl chloride are slowly added over the course of 15 minutes in a nitrogen atmosphere with stirring. The mixture is then ^{stirred for 2 1/2 hours at 0} ° C., cooled to -15 ° C. and mixed with 10 ml of brass and water. After another 5 minutes the mixture into 5oo ml i.is and water is poured, then 2oo ml of a cold 1: 3 mixture of methylene chloride and eye & us give ether, thereafter Zusats of 3oo ml of cold 3N hydrochloric acid ~. The organic layer is separated, ^f 2, washed $ sulfuric acid, water, aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and dried under reduced pressure, v / obei one da3 15 lJesylat obtained.

To a mixture of 4.13 g of the 15-mesylate and 3o ml Pyridine is a mixture of 1.12 g of potassium tert-butoxide and 2o ml of benzene added and the resulting mixture is stirred for several hours at about 25 ° C under nitrogen. This mixture is then carefully poured into 2oo ml of water and neutralized with cold 3N hydrochloric acid. Then it is extracted with benzene, the benzene extracts are combined,

2221U3

• washed with v / aeser and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on silica gel, whereby one with 50-100; ' / ithylacetat / Skellysolve B eluted and those Fractions combined, which according to thin-layer chromatograrcra contain the desired 15c ^ -tert-butyl ether. These result when lying at reduced pressure compound of formula X.

Example 7

PGBg ethyl ester methyl ether.

(Formula XV: R. and Rp = methyl) (see Scheme D, in which

, E = -CH = CH-, R ₂ and R ₅ = methyl, R. = water-

substance, V = -CH = CH- (CHg) ₅ -, W = pentyl

A solution of 1.65 g of PGBp is stirred with 5 g of silver oxide, 20 ml of methyl iodide and 200 ml of benzene and refluxed for 18 hours under a water separator. The mixture is then filtered and the filtrate is concentrated to a yellow oil. This is chromatographed on silica gel

en
Eluting with 2 $ acetone / methyl chloride, 0.3 g of the title compound XV is obtained in the form of a yellowish-brown oil, UV absorption λ. max. (ethanol) 277 (G = 25 45o) m / rev. Peaks in the mass spectrum at 331, 33o and 291.

According to the procedure of Example 7, PGB ₁ , IG3, and Dihydrc PGB _{1 are converted} into the corresponding compounds of the formula XV, for example into the PGB.-methyl-ester-methyl ether and the like.

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Example 8

FGF -m

(Formula VI: R ₁ and

and PG]? _1ß -met.hylester-15-methyl ether (formula VI: W = Q) (see Scheme E, wherein E is -CH-CH-, R ₂ and R * is methyl, V = - (CHg) ₅ -, \. i = 1-pentyl, ~ = Oi or B).

A solution of 0.6 g of sodium borohydride in 10 ml of methanol at ⁰ ° C. is added to a solution of 1.5 g of PGE ^ -methyiester-15-methyl ether (see Example 5) in 60 ml of methanol and the mixture is cooled at 0 ° C ⁰ C for 30 minutes. Then 10 ml of acetone are added and the solution is made slightly more saturated with dilute acetic acid in methanol. The mixture is concentrated under reduced pressure and the residue is taken up in methylene chloride. The resulting solution is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel which has been packed in 8 ^ liethanol / methylene chloride and rinsed with 300 ml of ethylene chloride, eluting with 2-1o ^ methanol / methylene chloride. Those fractions which, according to thin-layer chromatography, ^{contain the PGI 1} .. ^ methyl ester-15-methyl ether free of starting material and impurities are combined and yielded. the PGF ₁ ^ title compound of the formula VI, likewise those fractions are combined which, according to thin-layer theory, contain the PGP ^ o-inethyl ether-15-n-ethyl ether; they are also concentrated and give the IGF _{1 ß} title compound VI.

According to the procedure of Example B! -Official PGE.-alkyl ester-1b-alkyl ethers, those in Examples 3, 5 and 5A and

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2221U3

subsequently mentioned are converted into the corresponding optically active and racemic PGF ₀ ^ - and PGPß products.

Example 8A

-methyl ester-15-ethyl ether,
(Formula VII: R ₁ and R ₂ = I-jecnyl, ~ = CX) and PGFpβ-methyl ester-15-methyl ether. (Formula VII: ^ = ß) (see scheme F, where Ü »-CH = CH-, R ₂ , R. and R ₆ - methyl, j? R ₇ = (GH ₅ J ₃ Si-, V = - CH = CH- (CH ₂ ) y, W = 1-pentyl, ^ - & or ß).

A solution of 1.0 g of PGEp methyl ester-15-methyl ether (s. Example 1) in 2o ml of dry tetrahydrofuran is mixed with 5 ml of hexamethyldisilazane and 0.6 ml of triethylchlorosilane with exclusion of moisture for 20 hours "at about 25 ° C stirred, then the mixture is "concentrated under reduced pressure, the residue is taken up in 50 ml of dry benzene and narrowed down again. The residue is dissolved in 150 ml of cold Kethanolrj and while stirring with a cold (-Ιο C) solution of 2.8 g of sodium borohydride in 150 ml of methanol treated, v / obei the temperature is kept below about 1o C. After stirring for a further 10 minutes, add 5 ml of acetone and one sufficient to neutralize the mixture Amount of acetic acid added. Uas Geraisch becomes with diminished Pressure is reduced to about 75 ml, then about 75 ml Water added to hydrolyze the trimethylcilyl groups, then the mixture is stirred at about 25 ° C. for 3 hours. After removing the trimethylsilyl groups, what from the Thin layer chromatogram can be seen the mixture concentrated at reduced pressure, uiu the main amount of the Remove methanol. The one left behind? Solution is with Ethyl acetate was extracted and extracted with r, e; \ itti /: tor

4 7/1196
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Washed sodium chloride solution, dried over wassex-free magnesium sulfate and concentrated with reduced pressure. The stana is taken up in a small amount of methylene chloride and chromatographed on silica gel, eluting with 50-100 i'ithylaoetat / Skellysolve B. Those fractions which, according to thin layer chromatography, contain the Sd hydroxy title compound free of starting material and by-products are combined and give the product VII, leaks in the mass spectrum at 382, 364,

35o, 346 and 332; Ικ absorption at 341o _f 1735, 166o _# 1435, 1365, 1315, 124o, 1215, 1195, 117o, 1o9o and "97o cm"¹; HMR peaks at 5.42 (multiplet), 3.9 (cultiplet), 3.64, 3.49, 3.21 and 0.9 (triplet) £.

Ebeno those Fi * are actions according IHinnschichten- <~ chromatograi.jn the PGF2ß- ^FFIE 'fchylester-15 inöthyIäther contain, combined and concentrated to yield the _ß pGFP -2itelverbinaung VII obtained.

"you iederholt the _VEXF? ^<; .hröri vow Example 8A ₃ .However under lirsata the PGK ^ methyl ester '-' IS-nieit.ii.yläthers by the PGIü 15-n" ethyläthor (Example 3), we obtain, one IGF ₂₀ / -15-methyl ether. Likewise, all esters of PGK ₉ -I5-

{In the

methyl esters, which are mentioned in connection with Example 3, the corresponding esters of PGFp ^ -15-methyl ether.

Example 9

PGA ₁ methyl ether.

(Formula XrR .. = V / oxygen, R ₂ = methyl) (see scheme E, where E = -CH = CH-, H ₂ = ket-.yl, H ₄ = hydrogen, V = -

W = 1-pentyl).

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Yin Geiaisch. from o> 4 g of PGE., - 1 ij-methyl ether, 9 ml of oil and 1 ml of water is heated in ιϋ τ, ick π ίο ff 18 hours to 60 ° C. The gelatin is then concentrated under reduced pressure and the residue is chrowatographed on silica gel, eluting with ί'5 "Ίοο; ί Ä fchylaee'jat / Skellysolve B. Those fractions which free the desired product according to thin-layer chromatography contain starting material and impurities, are combined and concentrated, and "result in the PG-A.-Titeiverbindung X,

According to the formulation of Example 9, there are also embarrassing PGE compounds similar to Examples 3, 5 and 5A are mentioned, converted into the corresponding KuV alkyl ethers.

Example 1o

1'GB.j-diethyl ether.

(formula XJVt K, - '«ai-Kersrofi, K ₀ - methyl) (see scheme u, where £ = -CIi = GH-, R _? - Ktithyl, Ii, = - hydrogen, V = - (CH ₂ ) _r -, W = 1-pentyl).

In a mixture of 0.2 g of PGI-15-diethyl ether, 10 g of potassium hydroxide and 100 ml of 30% aqueous ethanol, it is kept under nitrogen for 10 hours at about 25 ° C. Then, the mixture is cooled to 1o ° C and neutralized by addition of 3N hydrochloric acid at 1o G. The resulting solution is extracted several times with ethyl acetate, the extracts are washed with water and saturated Hatriuri chloride solution, dried and concentrated to give the PGB. Title compound XIV.

According to the formulation of Example 10, all

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" ⁸³ " 2221U3

PGE compounds made following Examples 3, 5 and 5A are described, converted into the corresponding PGB-alkyl ethers. ·

Example 11

13 _f 14-dihydro-PGE ₁ -15-methyl ether "

(Formula V: R. = hydrogen, R ₂ = methyl) (see scheme G, in which

D - o .;

/ j, R ₂ - methyl, R. =. Hydrogen, V -

\ * \ - (CHp) ₁ -, W = 1-pentyl). HO ^{ά 5}

A solution of 100 mg I ¹ GJi ..- 15-inethylether in 1 ο ml ethyl acetate is shaken with hydrogen from about 1 atmosphere - ^ jerk at 25 ° C in the presence of 5% palladium / carbon (15 mg). Dabsi 1 equivalent of hydrogen is absorbed within about 90 minutes. The hydrogenation is then stopped and the catalyst is filtered off, the filtrate is evaporated and the residue is chromatographed on 25 g of silica gel, eluting with 50-100% ethyl acetate in ^u kellysolve B. Those fractions which, according to thin-layer analysis, contain the desired product free from raw materials and pehydration products are combined and give the 13,14-dihydro-PGE3-titanium compound Y.

After the ^v orschrift of Example 11 of the PGE.-15-methyl ether-ethyl H-Dihydro-PG't .- ^ is further for 13 - methylätheräthylecter reduced.

In addition, following the procedure of Example 11, PGii "-15 ~ methyl ether and PGE, -15-n-ethyl ether to give the 13,14-dihydro-iGi: ..-

2098 / »7 / 11ti6

BATH ORIGINAL

222H43

15-methyl ether reduced, one being responsible for the first rearction 2 and 3 equivalents of hydrogen are required for the second reaction.

In addition, according to the formula of Example 11, the ethyl esters and free acids of the PGE-15-alkyl ethers of the formulas II-IV are converted into the corresponding 13,14-Bihyaro-PGE-15-alkyl ethers by catalytic hydrogenation, the unsaturation corresponding to the starting material being converted Number of equivalents of hydrogen used, ie 1 equivalent for PGK ₁ compounds, 2 equivalents for PGF ₂ compounds and 3 equivalents for PGE, compounds.

Furthermore, according to the method of Example 11 15-me thy lather and its ethyl ester to 13,14-Hihydro-PGF .. ^ 15-methyl ether and its ethyl ester reduced.

In addition, the ethyl esters and the free acids of the IGi ¹ -15-alkyl ethers of the formulas VI-VIII are converted into the corresponding UfH-dihydro-PGI ¹ - or PGF _1ß -15-alkyl ethers by catalytic hydrogenation, using the number of hydrogen equivalents corresponding to the degree of unsaturation of the starting material is used.

Example 12

13, H-dihydro-PGA ₁ -methyl ether.

(Formula XIII: R ₁ = hydrogen, R ₂ = methyl) (see scheme G, where V = O

) R ₂ = methyl, R. »hydrogen, V - (CH ₂ J ₅ -, W = 1-pentyl).

209847/1198

222U43

A suspension of 5o mg Dinatriumazoaiformiat in 5 ml absolute ethanol is added with iiüfcren to a solution of 5o mg PGA ₁ -methylather in 1o ml absolute ethanol under nitrogen at 25 ⁰ C, lias mixture is acidified with ^ isesBig and then 8 hours at 25 ° C stirred under nitrogen. It is then concentrated under reduced pressure and the residue is mixed with a mixture of diethyl ether and water (1: i). The diethyl ether phase is separated off, dried and evaporated, thereby obtaining the 13,14-dihydro-PGA.-title compound XIII.

After the ^v orschrift of Example 12 is also the nethylester methyl ether e.um Liim-dihydro-PGA.-methyl ester. methyl ether reduced.

Further, following the procedure of Example 12, PGAp methyl ether is grounded and PGA, methyl ether. to the 13,14-dihydro-PGA .. methyl ether reduced, where iuan the degree of unsaturation dec ■ "■ amount of disodium azodiformate corresponding to the starting material begins.

In addition, according to the method of Example 12, the methyl esters and free acids of the 15-alkyl ethers of the PGE compounds II to IV, the PGF compounds VI-VIII, the PGA compounds X-XII and the PG3 compounds XIV-XVI by diimide -Heduction converted into the corresponding ^ tH-dihydro-PGE.-, -PGP ₁ -, -PGA ₁ - and -PGB.j-15-alkyl ethers, using the amount of disodium azodiformate corresponding to the degree of unsaturation of the starting material.

BATH ORIGINAL

201847/1198

Example 13

, -15-iiiQthylether.
(Formula VII: R ₁ ■ -. Y / hydrogen, R ₂ = methyl, scheme B, stage g, in which 3) = HO

, E = -CK = CH-,

HO
R ₂ and R ₅ - methyl, V = -CH = CH- (CH ₂ ) _-, W = 1-P3ntyl).

A solution of ο, 15 g FG? ₂ -methyl-ester-15-diethyl ether (see Example 5B) in a mixture of 4.5 ml of methanol and 1.5 ml of water is cooled to 5 ° C. and 0.6 ml of a 45% aqueous potassium hydroxide solution is added. The mixture is left to stand for 3 1/2 hours at about 25 0, then diluted with 75 ml of water and extracted with ethyl acetate in order to remove neutral material. The aqueous phase is acidified with dilute hydrochloric acid and extracted several times with ethyl acetate. The combined ethyl acetate extracts are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated, whereby the connection of the - * οπηβ1 VII is obtained, peaks in the mass spectrum at 353, 35o, 336, 318, 3oo, 264 and 261; IR absorption at 342o, 295o, 272o, 266o, 1715, 1680, 133o, 127o, 12u5, 113o, 1075, 9So and 925 cm " ¹ .

According to the formulation of Example 13, all esters of PGi ¹ ,, ^ -15-methyl ether, which are described in connection with Example 5B, and the esters of the rafemischen PGP ₂ . -15-methyl ether saponified to form the P ^G $ 2zk ~ 15-methyl ether or the racemic PGF ₂ ^ -15-methyl ether (free acid). The optically active and racenis see analogously

209947/1196

BATH ORIGINAL

Ester of the PGi? P _ß -1ij-iue thy lathers saponified with the formation of the free acids.

Example 14

-I5-methyl ether (formula III: R ₁ = hydrogen, R ₂ = methyl),

A solution of 0.1 g of PGF ₀ . -15-methyl ether in 40 ml of acetone is cooled to -1o G and mixed with 11o% of the theoretical amount of Jones reagent (b composition 21 g of chromic anhydride, 60 ml of water, 17 ml of concentrated sulfuric acid), which had been precooled to ^{0 ° C} , added while stirring vigorously. After about 10 minutes, 1 ml of isopropyl alcohol is added to the cold reaction mixture. After 5 minutes the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is mixed with 5 ml of saturated sodium chloride solution and the mixture is extracted with maize with ethyl acetate. The combined ethyl acetate extracts are then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel, eluting with 50-10050 ethyl acetate / Skellysolve B. Those fractions which, according to thin-layer chromatography, contain the desired product are combined and give the ^x 'itel compound of ^x ' formula III, peaks in the Eats spectrum at 348, 334, 33o, 316, 298 and 277; IR absorption at 342o, 32oo (broad), 265o, 1735, 171o, 1285, 1240, 1155, 1085, 1075 and 97o cm " ¹ .

Repeating the procedure of Example 14, but replacing the PGF _{2o <-15-methyl} ether by racemic PGF _2-15-methyl ether, to give the corresponding racemic product.

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BAD ORIGINAU

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Example 15

PGE ..- 15-methyl ether, free acid (by enzymatic hydrolysis)} (formula II: R, ■ «hydrogen, H ₂ ^β methyl).

A. Enzyme manufacture.

A medium as 2 ^a / -> Corn Steep Liquor (mixture of equal parts of corelose and glucose) in tap water is adjusted to pH 4.5 with hydrochloric acid, then 1 $ methyl oleate is added. 4 5oo ml flask, of which each 1oo ml of this medium containing, Cladosporium resinae be with (01-11, ATCC 11274) was inoculated and treated at room temperature (about 28 ⁰ C) for 4 hours. On a shaker. The cultures ground

then filled into 40 ml centrifuge tubes and centrifuged at about 2,000 revolutions per minute in a clinical centrifuge. The supernatant liquid is decanted off and the cells are washed with cold water, the grown cells from two centrifuge stirrers are suspended in 50 ml of ice-cold 0.05 in-phosphate buffer solution of pH 7.0 and transferred to a Waring mixing beaker cooled with Ms. Then ^u lase spheres are added and the suspended cells are treated in the mixer for 15 minutes. The resulting suspension of disrupted cells is centrifuged in a clinical centrifuge at about 2,000 revolutions per minute and room temperature for 15 minutes, then the supernatant liquid is collected. This contains the acylase from Cladosporium resinae, it is used directly for the hydrolysis of the alkyl esters or stored until required, preferably in the frozen state.

B. Esterase hydrolysis.

1ο nil of the above, containing the acylase of Cladosporium resinae Liquid and 5o mg PGiL-15-methyl ether-methyl ester are at room temperature under nitrogen at about 19 hours shaken, then .7 o ral acetone are added and that The mixture is filtered to give the filtrate and insoluble residue. The filtrate is concentrated under reduced pressure, the residue is chromatographed on silica gel, eluting with 50-100 $ ethyl acetate / Skellysolve B. Those fractions according to the thin-layer chromatogram containing the product free of starting material and impurities are combined and concentrated to give the free acid of formula II.

Following the procedure of Example 15 are also all of the methyl, ethyl and other alkyl esters and in accordance with Examples 3, 5, 5A, 5B, 6, 6A, 7, 8, 8A, 9, 1o and _f 11 mentioned are enzymatically hydrolyzed to form the corresponding free acids.

Example 16

PGA.j-methyl ether ethyl ester.
(Formula XIII: R ₁ and R ₂ = methyl).

A solution of diazomethane (about 5o excess) in 25 ml Ethyl ether becomes a solution of 5o mg PGA ^ -15-methyl ether (see Example 9) in 25 ml of a 1: 1 Geirdsch Methanol and ethyl ether were added. The mixture is left to stand at 25 ° C. for 5 minutes and then evaporated, whereby the title compound XIII is obtained.

BATH ORIGINAL

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222UO

Following the procedure of Example 16, all PGE, PGP, PGA and PGE-15 alkyl ethers with a free acid group converted into the corresponding methyl ester.

The procedure of Example 16 is also repeated, however by replacing the diazomethane with diazoethane, diazobutane, 1-diazo-2-ethylhexane and diazocyclohexane, the Ethyl, butyl, 2-ethylhexyl and cyclohexyl esters of PGA ..- methyl ether All other PGE, PGF, PGA and PGB-15 alkyl ethers mentioned above are similarly grounded with free acid group converted into the corresponding lister.

Example 17

PGE _o -15-methyl ether, sodium salt (i'ormel Uli H. = sodium, R ₂ = methyl).

A solution of 1oo mg PGE ^ -I5 methyl ether (see Example 3) in 5o ml of a 1: 1 mixture of ethanol and Vasser is cooled to 5 ⁰ C and neutralized with the equivalent amount of o, ^ s 1nv.ässrig sodium hydroxide . The neutral solution gives the title compound on evaporation.

If the procedure of Example 17 is repeated, but below Replacement of the sodium hydroxide by potassium hyaroxide, calcium hydroxide, Tetramethylar.jnonium hydroxide or benzyltrimethylammonium hydroxide, this gives the corresponding salts of PGEp-15 methyl ether.

Likewise, according to the formula of Example 17, all -, PGP ₂ -, PGA ₂ - and PGB ₂ -15-alkyl ethers with free acid * -

209847/1190

BATH ORIGINAL

group into the sodium, potassium, calcium,! Tetramethylanmcniuni- and eenzyltrimethylanjaonium salts.

In the above. Examples, for example in Examples 5. to 1o, which indicate that ü. = -CII = CH-, the Sj means that E is a trans-Cri = CH- group within the scope of the definition of E. The specification V »-CH = CH- (CH ₂ K- says that V is a CiS-CII = CH- (CH ₂ ) group within the scope of the definition of V.

Claims (2)

Patent claims: 1 .. Optically active compound of the general formula CH ₂ -V-COOR ₁ OR or a racemic compound of this formula and its mirror image, in which one of the following four represents carbocyclic radicals or E is a -CH ₂ CH ₂ - or trans-CH = CH-ReSt, R _{1 is} a hydrogen atom, an alkyl group with 1 to 8 carbon atoms or a pharmacology cn acceptable Katojln, R _{2 is} an alkyl group with 1 to 5 carbon atoms, V either a - (CHg) ₅ - or CiS-CH = CH- (CH ₂ ), - radical, provided that E only means a -CH ₂ CH ₂ radical if V is a - (CH ₂ ), - radical , W denotes a 1-pentyl or cis-l-pent-2-enyl radical, provided that W denotes a cis-l-pent-2-enyl radical only when E «» denotes a trans-CHsCH radical and V denotes a -CH * CH- (CH ₂ ) - remainder be 2098O / 1 196 indicate, and where ^ - 'the bond of the hydroxyl radical indicates the cyclopentane ring in alpha or beta configuration. 2. Optically active "compound according to claim 1, 3. Razemiache compound according to claim 1. 4. Optically active or racemic compound after Claim 1, characterized in that3) of the formula has the following meaning: 5. Optically active or raceric compound according to claim 1, characterized in that <£) of the formula has the following meaning: HO ι HO \ and <^ the alpha or beta bond of the hydroxyl group / on the cyclopentane ring. 6. Optically active or racemic compound after : Claim 1, characterized in that ^ P of the formula \ has the following meaning: 209847/1196 7. Optically active or racemic compound according to claim 1, characterized in that dap "J) of the formula has the following meaning: 8. Optically active or racemic compound according to claim 4, characterized in that E of the formula is a trans-CH = CH radical, V is a - (CH ₂ ), - radical and W is a 1-pentyl radical. 9.. Optically active or racemic compound according to claim 4, characterized in that E of the formula denotes a trans-CH = CH-Reet, V denotes a cia-CH = CH radical and W denotes a 1-pentyl radical. 10. Optically active vein racemic compound according to claim 4, characterized in that E of the formula is a trans-CH = CH radical, V is a cis-CHsCH- (CH ₂ )., - radical and W is a cis-l-Pent- 2-enyl radical. 11. Optically active or racemic compound according to claim 4, characterized in that E of the formula is a -CH ₂ CH ₂ radical, V is a - (CHg) ₅ radical and W is a 1-pentyl radical. 12. Optically active or racemic compound according to claim 5, characterized in that E of the formula is a trans-CH = CH radical, V is a • (CH ₂ ) _I radical and W is a 1-pentyl radical. 209847/1 196 13. Optically active or racemic compound according to claim 5, characterized in that E of the formula is a trans-CH = GH radical, V is a CiS-CH = CH- (CH ₂ ) radical and W is a 1-pentyl radical mean. 14. Optically active or racemic compound according to claim 5, characterized in that E of the formula
a trans-CH = CH radical, V a -CH = CH- (CH ₂ ), - radical and W a cis-1-pent-2-enyl radical. 15. Optically active or racemic compound according to claim 5, characterized in that E of the formula is a -CHgCHg radical, V is a - (CH ₂ ), - radical and W is a 1-pentyl radical. 16. Optically active or racemic compound according to claim 6, characterized in that E of the formula is a trans-CH = CH radical, V is a - (CHg) ₅ radical and W is a 1-pentyl radical. 17. Optically active or racemic compound after
Claim 6, characterized in that E of the formula is a trans-CH = CH radical, V is a cis-CH = CH- (CH ₃ J ₃ radical and W is a 1-pentyl radical. 18. Optically active or racemic compound according to claim 6, characterized in that E of the formula is a trans-CH = CH radical, V is a -CH = CH- (CH ₂ ), radical and W is a cis-l-Pent- 2-enyl radical. 19. Optically active or racemic compound according to claim 6, characterized in that E of the formula is a -CHgCHg radical, V is a - (CH ₂ ), - radical and W is a 1-pentyl radical. 209847/1196 ORIGINAL INSPECTED -96- 2221U3 20. Optically active or racemic compound according to claim 7, characterized in that E of the formula is a trans-CH = CH radical, V is a - (CH ₂ ) ^ - ReSt and W
mean a 1-pentyl radical. 21. Optically active or racemic compound according to claim 7, characterized in that E of the formula is a trans-CH = CH radical, V is a cis-CH = CH- (CH ₂ ) radical and W is a 1-pentyl radical mean. 22. Optically active or racemic compound according to claim 7, characterized in that E of the formula is a trans-CH = CH radical, V is a -CH = CH- (CH ₂ ), radical and W is a cis-l-Pent- 2-enyl radical. 23. Optically active or racemic compound according to claim 7, characterized in that E of the formula
a -CH ₃ CH ₂ radical, V a - (CH ₂ ), - radical and W a 1-pentyl radical. 24. PGE ₁ -15-methyl ether as an optically active compound according to claim 8, characterized in that R _{1 is} the
Formula is a hydrogen atom and R _{2 is} a methyl radical. 25. PGEj-methyl ester-15-methyl ether as an optically active compound according to claim 8, characterized in that R ₁ and R _{2 of} the formula represent methyl radicals. 26. PGF ₁ -15-methyl ether as an optically active compound according to claim 12, characterized in that R _{1 of} the formula is a hydrogen atom and R _{2 is} a methyl radical and indicates how an alpha bond. 209847/1196 ) "" - 2221U3 27. PGF _{lß -15-methyl ether} as an optically active compound according to claim 12, characterized in that R _{1 of} the formula is a hydrogen atom and R _{3 is} a methyl radical and r ^ indicates the beta bond. . 28. PGF _oo -15-methyl ether as an optically active compound there according to claim 13 »characterized in that R _{1 of} the formula is a hydrogen atom and Rp is a methyl radical and indicates a beta bond. 29. PQAj-15-methyl ether as an optically active compound according to claim 16, characterized in that R _{1 of} the formula is a hydrogen atom and R _{2 is} a methyl radical. 30. PGA ₁ -raethylester-15-methyl ether as an optically active compound according to claim 16, characterized in that R ₁ and Rp of the formula represent a methyl radical. 31. PGA ₂ -15-methyl ether a3 ^ 3 optically active compound according to claim 17, characterized in that R _{1 of} the formula is a hydrogen atom and R _{2 is} a methyl radical. 32. PGA ₂ -methylester-15-methyl ether as an optically active compound according to claim 17 *, characterized in that R ₁ and R _{2 of} the formula represent methyl radicals. 33. PGB ₁ -IS-JBe thy lather as an optically active compound according to claim 20, characterized in that R _{1 of} the formula is a hydrogen atom and R _{2 is} a methyl radical. 3 ^. PGB ₁ -ethyl ester-15-methyl ether as optically active compound according to Claim 20, characterized in that R and R _{2 of} the formula represent methyl radicals. 209847/1 196 -98- 222U43 35. PGBp-15-methyl ether as an optically active compound according to claim 21, characterized in that IL of the formula is a hydrogen atom and FL is a methyl radical. 36. PGB ₂ methyl ester-15-methyl ether as optically active compound according to claim 21, characterized in that R ₁ and R _{2 of} the formula represent methyl radicals. 37. Optically active compound of the general formula or a racemic compound of this formula and its mirror image, where R _{2 is} an alkyl radical having 1 to 5 carbon atoms and Rg is a hydrogen atom, a tetrahydropyranyl radical, a benzoyl radical or an acetyl radical. 38. Optically active or zrazemische compound according to claim 37, characterized in that Rg of the formula means a hydrogen atom. 39. Optically active or racemic compound according to claim 37, characterized in that R _{2 of} the formula is a methyl radical and Rg is a hydrogen atom. 40. Process for the preparation of an optically active compound represented by the following formula: 209847/1196 HO j OR ₂ or a racemic compound of this formula and its mirror image, where R ₃ denotes an alkyl radical having 1 to 5 carbon atoms inclusive, characterized in that the starting material used is an optically active reagent of the general formula or a racemic reagent of this formula and its mirror image are used, where R _{2 has} the meaning given above, and this reagent is successively subjected to the following reactions: a) Replacement of the free ring hydroxyl radical by a tetrahydropyranyloxy radical, b) reduction of the lactone oxo radical to a hydroxy radical, c) Wittig alkylation with a compound of the formula Hal- (CHp) ij-COOH, where Hai is a bromine or chlorine atom means; d) Oxidation of the 9-hydroxy group to an oxo group and e) Conversion of the tetrahydropyranyloxy radical into a hydroxy radical. 209847/1 196 -loo- 41. Process for the preparation of an optically active compound of the general formula COOH or a racemic compound of this formula and its Mirror image, where FL denotes an alkyl radical having 1 to 5 carbon atoms, characterized in that one as a starting material an optically active reagent of the general formula or a racemic reagent of this formula and its mirror image is used, where R _{2 has} the meaning given above, and this reagent is successively subjected to the following reactions a) Replacement of the ring hydroxyl radical by a tetra / oxy
hydropyranyrrest, b) reduction of the lactone oxo radical to a hydroxy radical, c) Wittig alkylation with a compound of the formula HaI- (CH ₂ ) ^ - COOH, where Hai is a bromine or chlorine atom, 209847/1196 222H43 d) Conversion of the tetrahydropyranyloxy radical into a Hydroxy radical. 42. Process for the preparation of an optically active compound of the general formula HO or a racemic compound of the formula and their mirror image, where R ₂ denotes an alkyl radical with 1 to 5 carbon atoms, characterized in that the starting material is an optically active compound of the general formula or a raceric compound of this formula and its mirror image is used, where R denotes a benzoyl or acetyl radical, _{replacing the hydroxyl group by the -OR 2} group, where R ₂ denotes an alkyl radical containing I up to and including carbon atoms, and then the -OR --Rest replaced by the hydroxy residue. 43. Process for the production of an optically active Compound of the general formula 209847/1196 - Ιο * - 222Η43 CH ₀ -V-COOR, E-CH-If ι OR ₂ or a racemic compound of this formula and its Mirror image, where J) is one of the following four ear- -bocyclic radicals or E is a -CH ₂ CH ₂ - or trans-CHsCH radical, R _{2 is} an alkyl radical with 1 to 5 carbon atoms, and Rc is an alkyl radical with 1 to 8 carbon atoms, V either a - (CH ₂ ), - or a CIs -CH = CH- (CH ₂ ) radical, provided that E is a -CH ₂ CH ₂ radical only when V is a - (CH ₂ ) ^ - radical, W is a 1-pentyl or cis -l-Pent-2-enyl radical means, provided that W means a cis-l-pent-2-enyl radical only if E is a tAs-CH = CH-ReSt and V is a -CH «CH- (CH ₂ ), - radical, und'vräie binding of the hydroxyl radical to the cyclopentane ring in the alpha or beta configuration, characterized in that an optically active reagent of the general formula is used as the starting material CH _n -V-COOR ₁ BC ^^ ^ E-CH-W 2 0 9 8 4 7/1 1 9 6 BATH ORIGINAL ~ ^lo3 ~ 222UA3 or a racemic reagent dfeser formula and its mirror image used, where D, E, V, W and ~ »have the meaning given above and R ₁ ^ means a hydrogen atom or an alkyl radical with 1 to 8 carbon atoms, the side chain hydroxy radical by the - OR ₃ radical replaced, where R _{2 is} an alkyl radical having 1 to 5 carbon atoms, and separates the alkyl ether product from the reaction mixture. 44. Process for the preparation of an optically active compound the general formula , CH ₂ -V-COOR ₁₁ OR ₂
or a racemic compound of this formula and its Mirror image, where E is a -CHpCHp- or trans-CH = CH radical, Rp is an ¹¹ alkyl radical with 1 to 5 carbon atoms, R ₁ J is a hydrogen atom or an alkyl radical with 1 to 8 carbon atoms and V is either a - (CHp) ₁ - or a CiS-CH = CH- (CH ₂ ) -χ- radical, provided that E only means a -CH ₂ CHp-ReSt when V is a - (CH ₂ ), - radical, Vf represents a 1-pentyl or a cis-1-pent-2-enyl radical, provided that W represents a cis-1-pent-2-enyl radical only when E is a trans-CH = CH radical and V is a -CH = CH- (CH ₂ ), - radical, and ^ indicates the bond of the hydroxyl radical to the cyclopentane ring in the alpha or beta configuration, characterized in that an optically active reagent of the general formula is used as the starting material 2 0 9 ίί /, 7/1 1 9 6 - Ιο * - 222U43 CH ₀ -V-COOR, - / 2 b E-CH-W
ι OR ₂ or a racemic reagent of this formula and its mirror image is used, where R ^ is either an alkyl radical having 1 to 8 carbon atoms or an (A), - Si radical, where A is an alkyl radical having 1 to 4 carbon atoms, a phenyl radical, a by 1 or 2 fluorine or chlorine atoms or alkyl radicals with 1 to H carbon atoms substituted phenyl radical, or an aralkyl radical with 7 to 12 carbon atoms and R _{7 is} either a hydrogen atom or an (A) -z-Si radical as defined above, and E, R _? , V and W have the meanings given above, and this reagent is subjected to the following process steps: (1) reduction of the ring carbonyl radical with a reducing agent which does not change the ester or ethylenic groups, (2) replacement of the trisubstituted silyl radicals with hydrogen atoms and (3) Separating the 9a-hydroxy product from the reaction mixture. For The Upjohn / tompany (Dr. H.J. Wolff) Lawyer ή ο · · _: 7/1 1 $ 3