DE2166796A1 - OXAZOLIDINE - Google Patents

Description

^; '.- \ rt not

LAWYERS

RECHTSANWÄLTE P _-1 .. ".._-

DR-JUR-OiFI-CHEAA-WALTERBEIIb 7. Matt 19/0

DR. J'iR. ;:!: ■ -.- '- · M. Γ.-J. WQLFP

FRAMKFUIiT AM MAiN-HOCHSf

Our no. 19 739 Pr / br

The Upjohn Company KalamazoQ, Mich ,, V, St, A,

Öxaz O- lidin

The invention relates to oxazolidines, which can be used as intermediates for the production of prostaglandins suitable.

Recently, the preparation of a racemic bicyclic lactone diol of the formula

50984 2/0935

11

by -JS.J. Corey et al., J. Am. Chem. Soc. 91, 5675 (1969) "and also an optically active form thereof, see E.J. Corey et al., J. Am. Chem. Soc. 92, 397 (197ο). Also the conversion of this intermediate into PGJSp and both in the dl and in the optically active form is known from the above publications. . '

It is known that the prostaglandins have several centers of asymmetry and are therefore present as stereoisomers (see ITugteren et al., Uature 212, 38-39 (1966) and Bergstrom et al., Pharmacol, Rev. 2o, 1 (1968)), each of those given here Formulas for PGS ₂ , PG ^ cl> PGE ₃ and ΐ & Έ ^ represent a molecule of the optically active, naturally occurring form of prostaglandin.

Known prostaglandins have the following structures:

BATH ORIGINAL

509842/0935

PGE ₂ :

COOH

PGP

OH

COOH

PGE ₅ :

OH

COOH

PGF COOK

509842/09

See also the formulas XVI, XXII, XXIV and XXVI, which are identical to the above formulas if r * J represents the bond of the hydroxyl group in the <Χ (s) configuration. The base of each of these formulas denotes a molecule of the enantiomeric form of the prostaglandin in question. For example, "ent-PGE ~" denotes the enantioraorph of PGE-. The racemic or dl ~ form of prostaglandin consists of an equal number of the two types of molecules, for example a prostaglandin with a natural configuration and its enantiomorph. If one of the optically active iso '■ · mers is dextrorotatory, and the other to the same extent is levorotatory. A racemic mixture of equal amounts of the W d and 1 isomers shows no optical rotation. The reaction of the components of a racemic mixture with an optically active substance leads to the formation of diastereoisomers with different physical properties, for example; different solubility in a solvent. Another term used in this specification is "15-epimer". With respect to one of the above prostaglandins, this term designates a molecule with an opposite configuration at the carbon atom "15. The term" 15β-PGE "therefore applies to a product , which has ß (ü) configuration at carbon atom 15, instead of the 0 ((S) configuration of the PGE ^.

»■ ^Ε>&ϊ> 2β ¹ ^ ⁴ ^^ 2» ^their esters, acylates and pharmacologically acceptable salts are extremely effective in producing various biological reactions and are therefore suitable for pharmacological purposes, see, for example, Bergstrom et al., Pharmacol ., ilev. 20, 1 (1968) and there. References. Such biological "effects are, for example, the systemic lowering of arterial blood pressure by. PGE ^, PGFpß and PGA ₂ compounds, measured in rats anesthetized with pentobarbital sodium and treated with pentolinium, with introducing cannula in aorta and right ventricle;

BADORlGiNAL 50984 2/0935

Blood pressure activity, measured analogously, of PGFp ₀ / compounds; The stimulation of the smooth musculature, demonstrated, for example, on strips of keypig ileum, rabbit duodenum or colon of voles; the strengthening of other stimulants, the smooth muscles, the antilipolytic effect, demonstrated on the antagonism of the mobilization induced by epinephrine Fatty acids or the inhibition of spontaneous glycerol release from isolated rat fat pads; the inhibition of gastric secretion by PGEp and PGA ₂ , compounds, demonstrated in dogs whose secretion was stimulated by putter or histamine infusion; the effect on the central nervous system, reduction of adhesion the platelets, demonstrated by the adhesion of platelets to glass, and the inhibition of the platelet aggregation and the formation of herombosis induced by physical effects, e.g. damage to the arteries, or biochemical effects, e.g., ADP, ATP, serotonin, yourombin and collagen . Through PGE "connections v / ir d also promoted skin growth and keratinization, as demonstrated by application to segments of embryonic chick and rat skin.

Because of their biological effects, they are known Prostaglandins useful for investigating, preventing, controlling, or relieving numerous diseases and undesirable ones 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, in particular the PGE "compounds _; eiHBeklä: eSiieti can be used in mammals, including humans, for deducting the haulage from the rabbit. For this purpose, the connections are made in lots from about 1o / Ug to about

509842/0935

BATH ORIGINAL

10 mg per nil of a pharraaco logically suitable liquid carrier or used as an aerosol spray for topical application. -

The P6E and PGAp lesions are also useful in mammals, including humans, as well as certain livestock animals such as dogs and pigs, to reduce and control excessive secretion of gastric juice, thereby reducing or avoiding the formation of ulcers and the healing of such. pre-existing ulcers-can be accelerated. For this purpose, the compounds are injected intravenously, subcutaneously or intramuscularly, or infused, at an infusion dose of about 0.1 / µg to about 500 / µg per kg of body weight per minute, or at a total dose per day by injection or infusion of ·. o about 1 mg per kg of body weight to about 2o the precise amount again depends on the age, weight and condition of the patient, the frequency and route of administration. \\

The -PGBp, PGJiV ₀ * and PG-Fp _ß compounds are useful for inhibiting platelet aggregation, reducing the tendency of platelets to adhere, and for eliminating or preventing shrombosis in mammals including human beings, rabbits and Rats. For example, the compounds are useful for the treatment and prevention of Kyocard infarcts, for the treatment and prevention of post-operative "clock eruptions, for accelerating the opening of." Vascular plugs after surgical singing and for the treatment of disease states such as atherosclerosis, arteriosclerosis, blood coagulation due to lipemia, as well as against other clinical conditions in those with the underlying iltiology. is associated with a lipoid imbalance or with hyperlipidaenia. For the purposes mentioned, the connections S3 ^{r are} systemically, z.3. administered intravenously, subkuta.n, intramuscularly and in the form of sterile implants for permanent action. For quick absorption, especially

509842/0935 BADORtGINAL

In liot situations, intravenous administration is preferred. Doses of about 0.05 to about 20 rug per kg of body weight per day are used, depending on the age, weight and degree of the exact amount Depends on the patient and the frequency and route of administration. , '■ ■ ·

The PGSp, PGPp ₀ / - .. and PGj? _β- compounds can also be used as additives to blood, blood products, blood substitutes and other liquids that are used for artificial, external stimulation and perfusion of isolated body parts, such as limbs and organs, which are still on the donor body be separated and preserved or prepared for transplantation or are already on the recipient's body, ". During these circulations, aggregated blood platelets tend to block the blood vessels and prevent the flow of circulation. This blockage is avoided in the presence of the above compounds For the stated purpose, the compounds are gradually or in one or more portions of the circulating blood, the blood of the donor, the perfused body part, the recipient or both or all in a steady total dose of about 0.01 to 10 mg per liter circulating Liquid added. Dife compounds are particularly useful r with administration 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 PGS ' ₂ compounds are extremely effective stimulators of the smooth muscles, and they are highly active in enhancing other known stimulators. the smooth muscles, for example from Cbcytoein shakers such as Gxytocin and the various I ^ utter corn alkaloids including their derivatives and analogues. PGE, for example, can therefore be used instead of or in conjunction with less than the usual length of these

50 98 42/09 3 B "BAD ORIGINAL

known stimulators, for example to relieve the symptoms of paralytic hay or to combat or prevent atonic uterine bleeding after miscarriage or childbirth, or to facilitate the rejection of the placenta, as well as during the puerperium. For the latter purposes, the PGE ₂ compound is administered by intravenous infusion immediately after the miscarriage or delivery in a dose of about 0.1 to about 50 / Ug per kg body weight per day until the desired effect is achieved. Subsequent doses are injected intravenously, subcutaneously, or intramuscularly or infused during the puerperium in an amount of 0.1 to 2 mg per kg body weight per day, the exact dose depending on the age, weight and condition of the patient.

The PGE ₂ , PGF _2β and PGAp compounds are also useful as hypotensive agents for lowering blood pressure in mammals, including humans. For this purpose, the administration is carried out by intravenous infusion in an amount of about 0.5 to about 50 / g per kg of body weight per minute, or in one or more doses of about 25 to 500 / ug per kg of body weight per day .

The PGB ₂ -, PGF ₂₀ , - and PGF _{2ß -compounds} can also be used instead of üxytocin to initiate v / marriages in pregnant females such as cows, sheep and sheep as well as in Ilens, at or near the time of birth, or at intrauterine death of the fetus from about 2o V / ochen before the time of birth. For this purpose, the compounds are infused intravenously at a rate of 0.1 to 50 / µg per kg of body weight per minute, until or almost to the end of the second stage of labor, that is, the expulsion of the fetus . The connections are especially available if one or more - "ochen after the time of birth have not yet started the natural marriage, or 12 to 60 hours

BATH ORIGINAL 509842/0935

after rupture of the membrane, without the natural Y / ehen "have started.

The PGE ^ -, PGi ^ oi - and PGF _{2ß compounds are also useful for controlling the conception cycle in ovulating} female mammals such as monkeys, rats, rabbits, dogs, cattle and the like, as well as in humans. For this purpose, for example, PGIPpQ is administered systemically in a dose of 0.1 to about 20 mg per kg of body weight, expediently during the period that begins approximately with the period of ovulation and ends approximately at the time of the menses or shortly before. Further, the expulsion of an embryo or fetus is caused by similar administration of the compound during the first three months of gestation or pregnancy.

Since the PGEp compounds are effective antagonists of the Representing epinephrine-induced free fatty acid mobilization, these compounds are used in experimental medicine for studies in vitro and in vivo in mammals including People useful for understanding, for prevention. Relief and healing of diseases with abnormal xipoid mobilization and high content of free fat

sand -

related to acids e.g. diabetes mellitus, vascular diseases and hyperthyroidism · ■ ''

The PGE ₂ compounds promote and accelerate the growth of epidermal cells and keratin in animals including humans. For this reason, the connections to the conveying. tion and acceleration of the healing of damaged skin are used, for example for burns, v / unden, abrasions and after surgical procedures. The compounds are also useful for promoting and accelerating the growth of pieces of skin (autografts), especially small ones

deep (Davis) inserts that cover skin-free areas

5Q9g42 / 0935 ' ^ßAD

- 1ο -

should be delayed by subsequent growth to the outside world the rejection of one's own skin (homografts).

For the above purposes, the compounds are preferred topically or near the point where cell growth or keratin formation is desired, preferably as an aerosol liquid or! "one-part powder spray, as an isotonic solution in the In case of moist compresses or as a lotion, cream or ointment together with common 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, systemic administration is recommended, for example by intravenous injection or infusion, alone or in combination with usual infusions of blood, plasma or blood substitutes. ¥ other routes of administration " are subcutaneous or intramuscular administration "near the site to be treated, oral, sublingual, rectal or v-aginal administration. The exact dose depends on the route of administration, age, weight and condition of the patient a%. For example, in a wet - Envelope for typical use in burns second and / or or third degree with areas of 5 "to 25 cm appropriate an isotonic aqueous solution with 5 to 100 / ug / ml of the PGEg connection. Especially when applied topically these prostaglandins expediently in combination with antibiotics such as gentamyein, neomycin, polymyxin B, bacitracin, speetinomycin and Qxytetracyelin, other antibacterial agents such as Mafenid-hydrοChlorid, Sulphadiazine, Furazoliumchlorid and Nitrofurazone, and with gorticoid steroids, e.g. hydrocortisone, Prednisolone, Methy! Prednisolon and Fluprednisolon are used. The latter components are used in the

used in the usual concentration.

The present invention aims to provide methods

BAÖ ORIGINAL 509842/0935 '.

Intermediate products for technical prostaglandin preparation, which are obtained in an optically active form.

The intermediate products obtainable according to the invention can be used for the production of PGEp, PGiVw, ^1>&1> 2β ¹ ^ ¹ * ^{1 1} ^? ' ^{And their} racemates, which are known to be useful for the pharmacological purposes described above. Further, the Z \ i ± obtainable according rule for the preparation of

enantiomorphic PGE ₂ , P ^ ₂ (V » ^{PG: P} 2ß" ¹ ^ ^{Ρ & Λ} 2 ' ^also from PGS ₅ , PGF ^ _0. , TG'Fq and PGA ^ and their enantioinorphs and their.
15β-epimers are used, all of which are also used for
the pharmacological purposes described above are useful. These new compounds are much more specific at causing prostaglandin-like biological reactions.
These new prostaglandin-like compounds are therefore surprisingly effective for at least one of the abovementioned
pharmacological purposes more useful than the corresponding, above-mentioned known prostaglandins, since they are a
have a different and narrower spectrum of effects than the known prostaglandins and are therefore more effect-specific, ie fewer and fewer undesirable side effects than
evoke the well-known prostaglandin when used for the same purpose.

^; The present invention relates to oxazolidine from an optically active compound of the formula.

BAD ORIGINAL 509842/0935;

or their mirror image and an optically active ephedrine, which at the resolution of a racemic mixture of an oxo compound of the formula.

and their mirror image, in which R ₁ and R ₂ together represent a radical of the formula

R ₃

-C-

• I

R,

R ₇

-Οι

xR

represent, wherein R ,, R ₂ J, R ₅₉ Rg, R ₇ and R _{g are} hydrogen atoms, or phenyl, with the proviso that not more than one of the radicals R is a phenyl radical and the total carbon number is 2 to 10, χ the number is 0 or 1 and r * ~ * denotes the bond to the cyclopropane ring in the exo or endo configuration, ge. is won, whereby one

a) converts the oxo compound with an optically active ephedrine to a mixture of oxazolidine biastereomers,

b) at least one oxazolidine diastereomer from the mixture dismantled,

c) this oxazolidine hydrolyzes to form the free, optically active oxo compound and. .

d) this isolated.

- BATH

50984 2/0935

In the decomposition of an acetal ketone - of the formula, a reaction of the - ketone gives ~. With an optically active ephedrine, for example d- or 1-ephedrine or d- or 1-pseudoephedrine, an oxazolidine is produced. Almost equimolar amounts are used in a solvent such as benzene, isopropyl ether or Dj, chlorine than. Although the reaction is broad temperature range extends, for example, Io to 80 ⁰ C smoothly, it is preferred temperatures of from 2o to 3o _f to side. reactions to minimize. the reaction proceeds with compounds of formula IV rapidly over the course of minutes, after which the is solvent removed!, preferably The product consists of the diastereomers of the ketone-ephedrine reaction product, ie the oxazolidines. At least one of the diastereomers is separated off in a known manner, for example by crystallization and co-chromatography. Crystallization is the preferred method. Repeated recrystallization the solid oxazolidine obtained in this way from a suitable solvent, e.g. isopropyl ether, is obtained to one of the diastereomers in practically pure form. This oxazolidine is then hydrolyzed in a manner known per se, the aldehyde being released. Even silica gel wetted with water is surprisingly effective, the silica gel being applied in a column. Another advantage of the column is "is that it separates the ephedrine aldehyde · The eluted fractions are then evaporated and give dos desired ketone dismantled. -Formula of IV

The mother liquor of the recrystallizations contains the optical Isomer of opposite configuration. A preferred method of isolating this second diastereomer is pedoch in that the oxazolidine of the racemic aldehyde with an ephedrine of opposite configuration and then recrystallized as described above. ^ Hydrolysis and isolation are then obtained as a ketone Formula Itf with opposite configuration to the first chri levels.

509842/0935

BATH ORIGINAL

The ketone IV, where R ₁ and R _? Have the above meaning can be prepared by

(a) an optically active or racemic bicyclo- / "^. 1 .o / hex-2-en-6-carboxaldehyde into an optically active acetal of the formula

or a mirror image thereof, or a corresponding Raeemat, wherein R _{1 and} R ν taken together -a radical of the formula

BAD OR / G / NAL 50984270935

-C-

-C- t

^R 8

represent, wherein R ₅ , R., R ₅ , Rg, R ₇ and R _{g are} hydrogen atoms,

-, - - ... ζ · or mean phenyl,

with the proviso that no more than one radical R is a phenyl radical and the total number "of carbon atoms is 2 to to and χ represent the number ο or 1, converts,

(B) this optically active or racemic acetal into an optically active tricyclic mono- or dihaloketone of the formula

O
//

CH

OR.

■ OR,

or their mirror image, or a corresponding racemate, in which R .. are bromine or chlorine and R ^ _{1 represent} a hydrogen atom, bromine or chlorine, and

(c} the optically active or racemic tricyclic mono- or Dihaloketone into the optically active, tricyclic ketone

the formula.

50 98A2 / 09 35

OR ₅ GlNALiHSPECTED

or their mirror image or a corresponding racemate transferred, . . -

The optically active or racemic ricyclic ketone can be then on to an optically active tricyclic lactone acetal of the formula

ι ■■■ "- '■.

CH

or their mirror image or a corresponding racemate oxidize,

(e) this optically active or racemic tricyclic lactone acetal to an optically active tricyclic lactonaldehyde the formula

ORIGINAL INSPECTED

509842/0935

CHO

or its mirror image or to a corresponding Raeemat hydrolyze,

(f) ^the i optically active or racemic ^! tricyclic: ·, laetonaldehyde into an optically active tricyclic lactone alkene or alkenine of the formula *

CH = CH-X

or their SpiegelMlds or in a corresponding piacemat convict and

(g) the optically active or racemic tricyelic lacton alkene or hydrolyze alkenine to form: an "optically active, or racemic tricyclic itactone glycol." the formula

5 0 9 8 4 2/09 3 5 Often INSPECTED

CH-CH-Y
OH OH

or its "mirror image, or a racemic compound according to this formula and its mirror image, in which Y /" is 1-pentyl or 1-pent-2-ynyl radical and ru is the bond of the respective radical to the cyclopropane ring in the xixo or endo configuration and to denote the side chain in 0 (- or ß-configuration.

Scheme A explains the conversion of the s · bicyclic aldehyde -1 "into the tricyclic lactone glycol VIII via the stages ag. In the formulas Γ to X of scheme A, R 1 and R 4 denote

- - "- .-" ^: - carbon atoms or taken together a radical of the formula

ORIGINAL INSPECTED

50984 2/09 3 5

C- R,

- 19 -

—Ο

wherein R _5, R, R ₁ -, Rg, R _7, and R "is _hydrogen; - _s

: * or phenyl, provided that

no more than one of the radicals is a phenyl radical and the total number of carbon atoms is 2 "to to", χ means the number ο or t, R <? denotes an alkyl radical having 1 to 5 carbon atoms. R ^ is bromine or chlorine and R ... represents a hydrogen atom, bromine or chlorine. Y is the 1-pentyl or 1-. Pent-2-inyl radical, \ I 1-pentyl, i-cis-pent-2-enyl or 1-pent-2-inyl radical. r «J denotes the bond of the respective radical to the cyclopropane ring in the exo or endo configuration. or the bond of the hydroxyl group to the side chain in oC or ß configuration. .

In the following formulas, dashed lines denote am Ring substituents in oil configuration, i.e. below the Paper plane. I) the serpentine line denotes the attachment of a group to the cyclopentane or lactone ring in the 0 (~ or ß-configuration or to the cyclopropane ring in exo or endo configuration, or it relates to the bond at carbon atom t5 of the prostanoic acid skeleton in C ((S) - or ß (R) -configuration. The formula drawn by jev / eils is supposed to be optical Represent isomer, which leads to an optically active prostaglandin of the configuration as it is in natural- -gev / ebe '-

prostaglandins obtained from mammals ^ is present. The mirror image each ^ 'ormel then gives a molecule of enantiomorph Porm this intermediate again. Under "racemic compound" becomes a mixture of the optically active isomer, · which the prostaglandin supplies natural configuration, and its enantiomorph is understood.

.509842 / 0935.

. BATH ORIGINAL

Scheme A

(a)

CHO

-OR.

CH

NO,

II

(e) _v

CH-

.OR.

III

(e)

CH

(f)

CHO

(G)

CH = CH-Y

VII

(i)

CH-CH-W

R ₉ O ₂ SO OSO ₂ R ₉ ,

IX

•. 509842/0935

*

(H)

CH-CH-V /

OH OH

VIII

OH

ORIGINAL iNSPECTED

The "bicyclic aldehyde of the formula I according to scheme A is in different isomeric forms. With regard to the binding of the aldehyde group, there are two isomeric forms, namely Exo- and Endo. "Also with regard to the location of the cyclopentene double bond to the aldehyde group give exo- and endo-form zv / ei optically active (d- or l-) forms, - * t £ oraus ij ^ esamt 4 Iso—

mers result. All of these isomers go individually or im Mixture eitt the reactions described for the preparation of the prostaglandin intermediates. For the production of racemic products the isomers that are not separated are used. Aldehyde is used to produce optically active prostaglandins or later intermediates of that described below Process separately and in the form of manufacture optically more active products used. The production of the exo- and endo-aldehydes will also be explained later.

When performing step (a), a bicyclic aldehyde is used I in a manner known per se into an acetal of the formula II convicted. The aldehyde I is made with a glycol of the formula

^R 7

t

-C-OH

Ä ■

in which R- ,, R., R ₁ -, Rg, R ₇ and R _g hydrogen atoms, ^

- · - ■ '-. 'or phenyl, among which Provided that no more than one of the radicals R is a phenyl radical and the total number of carbon atoms is 2 to 1o, and χ the number ο or T means implemented. As examples suitable glycols include: ethylene glycol, 1,2-propanediol, 1,2-hexanediol, 1,3-butanediol, 2,3-pentanediol, 2,4-hexane

I. I. HO-C-
I. C. ^H 4

5098A2 / 093 5 "" BADORiGlNAL

dioi, 3,4-octanediol, 3,5-lionanediol, 2,2-diethyl-1,3-propanediol, 3,3-dimethyl-2,4-heptanediol, 4-ethyl-4-methyl-3,5-heptanediol, Phenyl-1,2-ethanediol and 1-phenyl-1,2-propanediol.

The reaction can be carried out by various methods known per se Conditions carried out. For example, the reactants are dissolved in benzene and the mixture is grounded is heated to azeotropically remove the water formed. To speed up the implementation, an acidic Catalyst such as p-toluenesulfonic acid, trichloroacetic acid, Zinc chloride or the like is added. Furthermore, you can use the starting materials together with the acid catalyst and a water scavenger such as trimethyl orthoformate in an inert Solvents such as benzene, toluene, chloroform or carbon tetrachloride " heat to 40 to 100 g. The ratio of Aldehyde to glycol is preferably between 1: 1 and 1: 4.

To convert the acetal II into the ketone of the formula IV, reactions are used which are known from the preparation of analogous compounds. In stage (b ~) the acetal II '"~" with a ketene of the formula R> R ₁₁ C = C = O, for example with EBrC = C = O, HClC = C = O, Br ₂ C = C = O or Cl ₂ C = C = O implemented. For reasons of expediency, preference is given to the ketene CIpC = C = O. Bs is expediently prepared in situ by adding an 0.5-2% excess of dichloroacetyl chloride in the presence of a tertiary amine, for example triethylamine, tributylamine, pyridine or 1,4-diaza-bicyclo / 2.2.27octane in a solvent such as η -Hexane, cyclohexane or mixtures of isomeric hexanes ^ (Skellysolve B) treated at a temperature of ο to 70 ° C (see, for example, Corey et al., Tetrahedron Letters No. 4 _f pp. 3o7-31o, 197o). The ketene CIpC = C = O can also be obtained by adding a trichloroacyl halide to zinc dust suspended in a reaction vessel, the tertiary amine being omitted.

BATH ORIGINAL 509842/0935

When carrying out stage (c), the mono- or dihalo ketone of the formula III is mixed with a 2- to 5-fold excess of zinc dust over the st δchiometrisehe ratio of Zn: 2 Cl in! -! Ethanol, ethanol, ethylene glycol or the like . reduced in the presence of acetic acid, ammonium chloride, sodium bicarbonate or sodium dihydrogen phosphate. This reduction can also with aluminum amalgam in an aqueous solvent such as methanol-diethyl ether-water, water-letrahydrofuran made or dioxane-water at about ο bis5o C ^Q v / ground.

In stage (d) the tricyclic acetalketone IV is in itself converted into a lactone in a known manner, for example by reaction with hydrogen peroxide, peracetic acid, per- " benzoic acid, m-chloroperbenzoic acid or. Like., in the present a base such as an alkali hydroxide, bicarbonate or orthophosphate, preferably in a molar ratio of Oxidizing agent to ketone of 1: 1 is applied.

In stage (e) the lactone acetal of the formula V is replaced by acid Hydrolysis is converted into the aldehyde VI in a manner known per se, using dilute mineral acids, acetic acid, formic acid or the like. Suitable solvents are Acetone, dioxane, tetrahydrofuran and the like.

In stage (f) v / ird the aldehyde VI is converted into an alkene or alkenine of the formula VII, for example with the aid of a Tlids, as in the Wittig reaction. For the preparation of the Wittig reagent becomes a 1-hexyl halide or i-hex-3-ynyl halide ^, · preferably the bromide is used, e.g., hexyltriphenylphosphonium bromide or (hex-3-ynyl) triphenylphosphonium bromide.

In stage (g) the alkene or alkenine VII is known per se Way, see e.g. South African patent specification © -48o9, with formation of the glycol, which is hydroxylated by orniel VIII.

'BAD ORIGINAL 509842 / 0-9 35

In the hydroxylation of the endobsw. Exo-alkenes are different isomeric glycols are obtained, depending on factors such as the cis or trans persistence of the grouping -CH = CH- in compound VII, or the use of a cis or trans hydroxylating agent. Endo-cis-olefins result with a cis-hydroxylating agent such as osmium tetroxide a mixture of two isomeric erythroglycols of the formula VIII, analogously result in the endo-trans-olefins with a trans-hydroxylating agent, E.g. hydrogen peroxide, a mixture of the same two Eryh ^ troglycols. The endo-cis-olefins and the Endo-trans-olefins produce identical mixtures of the two threoglycols with trans and with cis hydroxylating agents. The various glycol genes are determined by chromatography is broken down into the individual isomers on silica gel isomeric erythroglycol and any isomeric threoglycol as an intermediate in the further process steps according to scheme Ä for the production of products of the ^ 'ormel X and then according to the Schemes C to F are suitable for the production of other end products. Thus, the various isomeric glycol mixtures are "der Formula VIII obtainable from various isomeric olefins of Formula VII, all for the same purposes useful. .

An optically active, bicyclic lactone diol of the formula

BAD OR / G / _NAL

509842/0 9-3

- '25 -

or its mirror image or a corresponding räcemat, in which W denotes the 1-pentyl, cis-i-pent-2-enyl or 1-pent-2-ynyl radical and f * -t the bond of the hydroxyl group to the side chain in oC - or Designated ß-configuration, can be produced by .— * a that one. '· -R

-r

a) the glycol hydrogen atoms of an optically active tricyclic formula lactone glycols

CH-CH-W OH OH

or its mirror image or a corresponding racemic compound replaced by an alkanesulfonyl group of the formula RqOpS-, Ä> rin Rg represents an alkyl radical having 1 to 5 carbon atoms and ** - * the bond of the corresponding radical to the cyclopropane ring in the exo or eno configuration and denoted on the side chain in tX or ß configuration, and

b) the compound thus obtained in one stage with water Mixes from 0 to 6o C, using the optically active or räcemisc bicyclic lactone diol is obtained.

The glycol of formula VIII is according to steps h) and i)

509 84 2/0 9 3 S BAD ORiö / MÄL

from scheme A into the diol of the ^ c-sleeve X converted. Methods for Production of the bis-alkanesulfonic acid ester of ^ drmel IX by replacing the glycol hydrogen atoms with an alkanesulfonyl radical and the hydrolysis of the ester thus obtained to the diol X are known per se (see the South African patent 69-4809).

Scheme A shows different groups of other side chains in the formulas YII and YIII. In formula YII, X is limited to the 1-pentyl or 1-pent-2-ynyl radical, while in formula VIII \ I the 1-pentyl, cis-i-pent-2-enyl and i-pent-2- inyl radical |, includes. The compounds of the ^x formulas VIII, IX or X, v / orin W is a cis-1-pent-2-enyl radical, v / earthed by reduction of the. Acetylene bond to the grouping cis-CH = CH-, before or after stages h) or i), ie at any point in time after the hydroxylation in stage g). Any known reducing agents which reduce an acetylene bond to a cis -ethylene bond are used for this purpose. Diimide or hydrogen and a catalyst, for example palladium (5/0 on barium sulfate, in particular in opposition to pyridine, see Fieser et al., "Reagents for Organic Synthesis", pp. 566-567, John Wiley & Sons) are particularly preferred , "Inc., Few York, KI '(196?).

The optically active bicyclic lactone diol of Pormel_. -

BATH ORIGINAL 509842/0935

or their mirror image or a corresponding racemate, in which W denotes the 1-pentyl, cis-i-pent-2-enyl or 1 ~ pent-2-ynyl radical <^ s the bond of the hydroxyl group of ^the side chain in oi- or ß- Designated configuration, can also be prepared by having an optically active tricyclic lactone or alkene in the formula

CH = ^ CH-X

or its mirror image or a corresponding racemate, v / orin Y represents the 1-pentyl or 1-pent-2-ynyl radical and r-> u the bond of the radical to the »cyclopropane ring in Exo ~. or endo-configuration, subjecting successively the following reactions:

a) oxidation of the -CH = CH group to form a _r Ep oxyrings,

Id) hydrolysis of the resulting epoxide to form a Ge misehs from bicyclic lactone diol and tricyclic laetone glycol,

c) Pormolysis of the mixture to form the Diformate des "bicyclic xactone diols, and

50984 2/0935 ^ßAD ORIG / nal

d) hydrolysis of the Dianjeisenctoireester to the Mcyclischen lactone-

with the proviso that, if \ I is the cis-1-pent-2-enyl radical, the acetylene group is reduced to the cis-GH = CH group before or after one of steps b) to d).

BAD ORIGfNAL

b Γι 'i HA? / fj ' \ 3 b

- 29 ₃ -

Scheme B

CH = CH-Y

VII

- = 7

/ V

CH-CH-W

XXXVIII

OE CH

XXXIX

OCHO OCHO

Xl

OH

OH

^r i O 9 8 -L ') ^ι Γ.-

In the formulas VII, X ^, X XXXVIlI, XXXIX and XL, E and M both denote hydrogen, or one substituent denotes hydrogen and the other denotes the formyl radical, T denotes the 1-pentyl or 1-pent-2-ynyl radical and rw denotes the bond to the cyclopropaiiring in exo or endo configuration, or the bond of the residues OE and OM in threo or erythro configuration, or the bond to the side chain in el or β configuration, and ^ \ ^ refers to the binding of the epoxy oxygen to the side chain in δ (- or ß-configuration.

The Alken or Alkenln of ^ 'ormel VII, v / elches through the Steps a) to f) of scheme A are obtained, v / is in the epoxy der ^ ormelXXXVIII by converting the compound VII with a peroxy compound v / ie hydrogen peroxide or preferably an organic percarboxylic acid. Suitable Percarboxylic acids are e.g. performic acid, peracetic acid, perlauric acid, peracid, perbenzoic acid, m-chloroperbenzoic acid and the like. Peracetic acid is particularly preferred.

The peroxidation v / ird expediently carried out by the starting material VII with about 1 equivalent of peracid or Hydrogen peroxide, expediently in a diluent, e.g. chloroform, mixes. The reaction is usually rapid and the epoxy of Formula XXXVIII is conventional Manner isolated ', for example by evaporating the diluent and optionally removing the corresponding to the peracid Acid. It is usually not necessary to purify the oxide before it can be used in the next stage of the process.

• To convert the epoxy of the ^x 'ormel XXXVIII into the diol formate XL, two methods are possible. According to one, the epoxy is hydrolyzed to form a mixture of glycol XXXIX, where E and H are hydrogen, and DIoI X, + _β . Kan works with a dilute solution of formic acid In an inert miscible solvent v / Ie acetone, dimethyl

5098 *? '-Π A3 6 BADORIGIWAL

sulfoxide, ethyl acetate or tetrahydrofuran. You can get temperatures of ~ 20 Ms 100 ° C, although et v / a 25 C are preferred. At lower temperatures, the desired Mixture formed very slowly. At higher temperatures v / ird the yield is worsened by unpredictable side reactions. Then the mixture of glycol diol with formic acid, preferably practically 1 ο above formic acid, at about 25 ° C brought into contact, the diol formate being " holds. Under "practically 100% formic acid" there is a purity understood by at least $ 99.5. .

According to the further method, the epoxy of the formula XXXVIII directly subjected to formolysis. It is preferable to work with practically 100% formic acid at about 25 C, An inert solvent such as dichloromethane, benzene or diethyl ether can be used / ended.

In both cases the glycol monoformate lies in the ormel XXXIX, in which one of the substituents E and M is selected from hydrogen and the other is the formyl radical, often as an intermediate before. It is usually not isolated, but is converted into the diol diformate with the practically 100% formic acid XL converted.

The diol formate XL is obtained as a mixture of isomers in which the ^ _ΟΓΐη - ^^ _Γΐ1 ρρ _{ΘΙ1 of} the side chain are in the 0 (- / and ß-configuration. The mixture is converted directly into the diols X ^ and X _ß without separation. For this purpose, the diol formates are reacted with a weak base such as an alkali metal carbonate, bicarbonate or phosphate, preferably with sodium or potassium bicarbonate in a lower alkanol, such as methanol or ethanol up to 5o C suitable, preferably one works at about 25 C. The product consists of one

50984? / OSi6 BADOBiQBW ..

Mixture containing the diols X_ / and X _ß , in which the hydroxyl group of the side chain is in ^ - or ß-configuration. The separation of the diols can be carried out in a known manner, expediently by chromatography, for example on silica gel or alumina. .

• *

Scheme B shows differences in the end groups of the side chains of sleeves VII, XXXVIII, XXXIX, XL, X ^ and X _ß . In formula VII, Y is restricted to the 1-pentyl or 1-pent-2-ynyl radical, while in the other formulas the 1-pentyl, cis-1-pent-2-enyl and 1-pent-2- Inyl radical comprises »Analogously to scheme A, the compounds in which W represents a cis-1 ~ pent-2-enyl radical are obtained by reducing the acetylene group to the cis-CK = CH group, this reduction being in a manner known per se can take place at any time after the epoxidation of compound VII «,. '

The manufacture of PGE _? or PG-Pp ^, from the xactone diol intermediate of the formula X ^ takes place according to the reactions known per se, which can be seen from schemes C and E (see EJ Corey et al., J. Am. Chem. Soc. 91, 5675 (1969).

. BATH ORIGINAL

! 509847/093 I.

Scheme C

-7

OH

OTHP

XI

XII

OTHP

OTHP OH

OTHP

OTHP

COOH

XIII XIV

XV COOH

XVT

/ ο μ a β

Scheme D.

OTHP

XYIII

OTHP

XIX

OTHP OTIIP

XX

COOH

■ f

OTHP

OTKP

XXI

COOH

COOH

XXII

5 09.8.42 / 0935

Scheme B

OH -

XI ■

OH

COOH

OH

XXIY

509842/0 9-3

ΟΟ / 30

The connection of the """'Ornel XI corresponds to the diol of ^x Ormel X, v / orin V, the radical nC ^ H .. is. The production of PG? _2ß by carbonyl reduction of PGEP is known. In the case of this reduction, any known reducing agents for ketonic carbonyl groups are used which do not reduce ester or acid groups and carbon-carbon double bonds, if the latter is undesirable. Examples of such reducing agents are the metal borohydrides, in particular sodium, potassium and zinc borohydride, lithium (tri-tert .-butoxy) aluminum hydride, metal trialkoxy borohydrides, for example sodium oximethoxyborohydride, lithium borohydride, diisobutylaluminum hydride.

It is known that this method gives a mixture of and PGFp _R , these compounds can easily be separated by chromatography. "^ The formation of PGAp by acidic dehydration of PGSp is also known, see, for example, Pike et al., Proc. Hobel Symposium II, Stockholm (1966), Interscience Publishers, New York, p. 162 (1967), and British Patent 1,097,533. Alkanecarboxylic acids having 2 to 6 carbon atoms, "especially acetic acid", are preferred for carrying out this acidic dehydration. Dilute aqueous mineral acid solutions, for example dilute hydrochloric acid, in particular in the presence of a solubilizing diluent such as, for example, tetrahydrofuran, can also be used for this purpose. -

Examples of alkyl radicals with 1 to 4 carbon atoms in the formulas II to XXXIV are methyl, ethyl, propyl,

i ■, _Λ

Butyl radical and its isomeric forms called. Examples for.

I /

Alkyl radicals having 1 to 8 carbon atoms are the above as well as the pentyl, kexyl, heptyl, octyl radical and their isomeric orraen.

BATH 509842/0 9-3 5

In. the formulas XI Ms XVI denotes "n-C ^ H ^" the straight chain « Pentyl group and "THP" the tetrahydropyranyl radical.

PGE ,, dl-PGE., And their 15 epimers can thereby be produced ^ that you have an optically active glycol of the Pprmel

OH OH

or a corresponding racemic compound wherein <^ y - the bond to. the cyclopropylan ring in exo or sndο configuration and on the side chain ^ in 0 (- or ß-configuration), subjecting successively the following reactions:

a) Replacement of the glycol hydrogen atoms by an alkanesulfonyl group the formula RqO-S-, in which Rq is an AlleyIrest with 1 represents to 5 carbon atoms,

b) Mixing with water at a temperature of ο to 60 ° C with formation of a bicyclic laptone diol of S and R configuration,

c) Treixation of the diols of the S and R configuration, ά) Conversion into a bis-tetrahydropyranyl ether,

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

f) alkylation according to "Wittig with a compound of the formula Hal- (CH ₂ ) .- COOH, where Hai denotes bromine or chlorine,

BATH ORIGINAL 509842/0935 _: ■ ■ ■

g) Oxidation of the 9-hydroxy group to the oxo group and

h) Conversion of the two letrahydropyranyloxy groups into Hydroxyl groups,

with the hatred that, before or after any of the steps a) Ms h), the acetylene group is reduced to a ci £ ~ CH = CH group.

The conversion of the bicyclic aldehyde of the formula I into PGE ₅ , ent-PGE ₅ , dl-PGE ₅ or their 15-epimers is illustrated in Schemes A and D. In scheme JD, Z denotes the cis-1-pent-2-enyl or 1-pent-2-ynyl radical and rJ and THP have the above meanings. A key compound in this reaction sequence is the racemic or optically active xactonaldehyde VI. The compound of the formula VI is prepared from the racemic bicyclic aldehyde V-HI according to steps a) to e) of scheme A, then it is broken down into the optically active forms via the oxazolidine, as explained in Example 15 below. If appropriate, the aldehyde of the formula I can also be broken down as described in Example 13, whereupon the conversion into the optically active compound of the formula VI takes place. ;

In step f) of Scheme A, the Wittig reaction is using a l-hex-2-ynyl chloride, bromide or iodide, preferably of the bromide, used to produce the required Vittig reagent. . ·

The methods for hydroxylating the alkenine of formula VII, in which T represents the 1- pent-2-ynyl radical, for preparing the bis-alkanesulfenic acid ester of formula IX and for hydrolyzing this ester to form the lactone diol of formula X are known per se, see the South African patent 69-48o9. The lactone diol of the formula X, which contains both ¹ U- and ß-Spinier, results in a mixture of PGE and its 15-epimer as the end product. Preferably the QC and β epimers of the diol and not ground

509842/0935

_ 39 - '.2156796

separated the epimers of the final product. Chromatographed for this purpose one on silica gel. From the ß-epimer of the formula X you then get the dl-15ß-PGE.

3 "

To convert the glycol of the formula VIII, in which 1 represents the 1-pentynyl radical, with the formation of a product of the formula XXII, the acetylene group is reduced in any process stage to the cis-CH = CH group. In this way, the glycol VIII can be reduced before the glycol hydrogen atoms are replaced by an alkahsulfonyl group. Any intermediate products of the formulas IX, -X, -XVIII, -XIX, -XX or -XXI can also be reduced. Reagents, catalysts and reaction conditions which do not reduce the ethylene bond significantly are used. Hydrogenation is expediently carried out over a Lindlar catalyst , ie a catalyst of 5 / »palladium on barium sulfate, in the presence of quinoline. The diluent used is methanol or similar inert solvents, the pressure is low, suitably slightly above atmospheric pressure and is usually not more than about 2 atmospheres isolated by chromatography on silica gel.

The formation of PGE, from the diol intermediate of the formula XVII according to scheme D generally follows known methods which are discussed above using the example of the formation of 1 "GEp became. ·. ·

e. ■
According to a further process for the production of PGF ,. , dl-PGF,. and their 15-epimers, the glycol of ^ 'prmel VIII, vorin a 1-Pentinylrest is \ _l; converted to diol XVII, in which Z represents the cis-i-pent-2-enyl or 1-pent-2-ynyl radical, from which the products of the formula XXVI according to scheme F are obtained.

BATH ORIGINAL 509842/0935

- Ho -

Scheme 3?

OH.

XXV

COOH

. XXVI

509842/0935

- Ill -

The diol XVII is reduced to the lactol XXV-which is alkylated according to Wittig. As in the production of PGE_v / the acetylene group is reduced to the cis-CH = CH group in "any stage between glycol and end product. As in the production of PGE., The optical isomers of the intermediate products give the corresponding PGF.,, - or ent-PGF., compound, the racemic intermediates give racemic PGF, ^. and the optically active intermediates with <U- or ß-configuration give PGF., .., ent-PGF ", or their 15- Epimers,. ~

The preparation of optically active or racemisehem ^ ₀ from racemic or optically active PGE is generally carried out by known methods, eg, "by reduction with borohydride, j 'see' the foregoing description of the preparation of _{PGP? Ss.} The formation 'of racemic and Optically active PGA ^, from racemic and optically active PGE ^ is also carried out by known methods, for example by acidic dehydration, see above for the preparation of PGA

2 *

In the following examples the infrared spectra were measured using measured on a Perkin-Elmer Model 421 spectrophotometer. If unless otherwise stated, undiluted samples were used. The NMR spectra were recorded on a Varian A-60 spectrophotometer in - "uterochloroform with tetramethylsilane as the inner

Circular dichroism curves Standard (downfield) measured. Diefea- were determined with a Gary 60 spectropolarimeter.

The eluate fractions were collected during chromatography - started as soon as the front of the eluent hit the bottom the column has reached.

BÖ9 84 2/093

Preparation 1

Endo-bicyclo / ~ 3.1. £ 7hex-2-en-6 ~ carboxaldehya (Formula I: Endo).

To a vigorously stirred suspension of 518 g of anhydrous sodium carbonate in a solution of 223.5 g of bicyclo / 2.2.f7-hepta-2,5-diene in 195o ml of methylene chloride ground 177 ml of 25.6% peracetic acid, the 6g Contains sodium acetate, added. The addition time is about 45 Hinuten, the temperature 2o to 26 C. Then, it is still the mixture was stirred for 2 hours, then filtered, and 'the filter cake is washed with methylene chloride P. The filtrate and / or washing solutions are concentrated in vacuo. About 81 g of the resulting liquid are stirred with 5 ml of acetic acid in 2oo ml of methylene chloride for 5 1/2 hours, then it is concentrated and distilled. The fraction boiling at 69 "to 73 ° C. at 50 mm consists of the desired aldehyde of the formula I, yield 73 g * MMR peaks at 5.9 and 9.3 (doublet) 6".

The various intermediates of the formulas I to IX can. exist in exo and endo form. His preferred method for the production of the Ξχο form of the bicyclic aldehyde Formula 1 consists of the stages shown in Scheme G, * which use procedures known per se, (see South African Patent specification 69-48o9).

509842/0935

- 43 Scheme G

XXVII

XXVIII

COOH

XXIX

CH ₀ OH

XXX

CHO

5.0.9 84 2/093

In the formulas XZVII to ZZXVII, the exo configuration is represented by the straight line running downwards at an angle. Diazoacetic acid is added to a double bond of cyclopentadiene, thus obtaining an exo-endo mixture of the bicyclo / 3-1 / 3-hexene of l'orrnel XXVIII, which is substituted in the 6-position by a carboxyl group. This mixture v / ill be treated with a base, v / obei the endo-isomer formation untei ^ / ori further exo-isomer is isomerized. Then the carboxyl group in the 6-position is converted into a hydroxyl group before the exo-aldehyde of the formula XXX is formed.

example 1

dl-Endo-bicyclo ^ J. 1 . cj7hex-2-en-G-carboxaldehyde, acetal with ethylene glycol (formula II: R ₁ and R_ together = -CHpCHp-, rJ = endo) (see scheme A).

A solution of 216 g of Endo-bicyclo / ~~ 3.1. £ 7hex-2-en-6-carboxalde · hyd (see preparation 1), 150 g Ethylene Glycol and 0.5 g p-Ioluenesulfonic acid in 1 l of benzene is refluxed. The azeotropically distilled water (29 nl after 20 hours) is in caught in a Dean Stark trap. Then there is the reaction mixture cooled, treated with 0.3 g of sodium carbonate and distilled under reduced pressure. The ones at 3 to 4 now and 55 to 60 ° C passing fraction is added to ether and water distributed. The ether phase is extracted with water, over Dried anhydrous magnesium sulphate and concentrated, "v / obei the bicyclic acetal of the formula II is obtained in the form of a light brown oil, yield 70 g, lli'iit peaks at 1.1, 1.6-2.9, 3.5-4.2, 4.42 and 5.3-6, o <p.

. '' iedez'holt can follow the procedure of example 1, but under

BATH ORIGINAL

50 9 842/093 5

_ ij.c -

Using the Zxo compound of the formula I (XZX.), the corresponding Bxo acetal of the ¹ OmIeI "II is obtained.

A,

Furthermore, after the working method, nan receives ύοώ. Example / using the endo and exo form of the aldehyde of formula I, however. Replacement of ethylene glycol with 1,2-JPropanediol, 1,2-hexaridiol, 1,3-butanediol, 2,5-pentanediol, 2,4-hexanediol, 3,4-octanaiol, 3,5-l « ^t onanediol, 2 , 2-dimethyl-1, '3-propanediol, 3,3-I> imethyl-2,4-heptanediol, 4-ethyl-4-methyl-3,5-h.eptanediol, phenyl-1,2-ät' handiol and 1-phenyl-1, 2-propanediol, the corresponding acetals of the formula II.

Furthermore, according to the procedure of Example 1, using the Endo- or Exo-Porra of aldehydes I and Replacement of ethylene glycol with Hethanol, Ethanol, 1-Propanol or 1-butanol the corresponding acetals of the ormel II "

Example 2

dl-Iricyclic dichloroketone (Formula III: R. and R "together = -CHpGHp -, / v = endo) (see scheme A).

A solution of 56 g of the bicyclic acetal II according to Example 1 and So g of triethylamine in 300 ml of Skellysolve B. v / is refluxed with stirring, wherein in the course of 3 hours too g of dichloroacetyl chloride in Skellysolve B draws ■ drops v / earth. Then the mixture is cooled and solids are filtered off. Dilute the filtrate and Skellysolve B wash solutions with water, Seiger aqueous liatric bicarbonate solution and saturated sodium chloride solution, washed over anhydrous Sodium sulfate dried and concentrated, the oil compound being obtained in the form of 91 g of a dark brown oil receives. Another 13 g are from the filter cake and the aqueous

BATH ORIGINAL

503842/0935

- K6 - 2 ^ 65796

for washing solutions. According to a variant, this will be Triethylamine to a solution of bicyclic acetal and Li- chloroacetylchlarid added, or the triethylamine is added and dichloroacetyl chloride in separate solutions, however at the same time to a solution of the bicyclic acetal in Skellysolve B.

If the process of Example 2 is repeated, but using the exo compound of the formula II, nan. the corresponding exo-dichloroketone of ^f Ormel III. In addition, using the compounds described in connection with Example 1, the process of ^{Example 2 gives the corresponding derivatives of the x} 'oreiel III.

Example 3

dl-Tricyclic ketone (Formula IV: R. and R "= llethyl endo). ■

A solution of 10 4 g of the bichloroketone III obtained according to Example 2 in 1 1 of dry liethanols v. ^It is made with 100 g of arronium chloride and small portions. Zinc dust treated. The temperature is allowed to rise to 60 ° C. After adding 2oo g. Zinc is refluxed for 80 minutes, the mixture is then cooled, the solids are filtered off and the filtrate is concentrated. The residue is treated with ethylene chloride / aqueous sodium bicarbonate solution and the mixture is filtered. The methylene chloride phase is washed with 55% aqueous sodium bicarbonate solution and with water, dried and concentrated, the bond in the form of. 56 g of a dark brown oil are obtained; Infrared absorption at 176o cm ".

BATH ORIGINAL

509042/0935

If the procedure of Example 3 is repeated, but using the exo compound from Pornel III, the corresponding Lxo-ketone IV is obtained.

Furthermore, following the procedure of Example 3, however, is obtained using the compounds of ^ ormel III mentioned in connection with Example 2, the corresponding derivatives of Formula IV.

Example 4

dl-Tricyclic lactone acetal (formula V: R. and R ~ = methyl, r ^ = endo) and iricyclic lactonaldehyde (formula VI: / v = endo) (see scheme A).

A solution of 56 g of the product obtained according to Example 3 the i'ormel IV in 400 ml of methylene chloride is mixed with 40 g of potassium bicarbonate treated and cooled to 10 G. Then it is in progress a solution of 55 g of m-chloroperbenzoic acid for 40 minutes (85 ^) in 600 ml of methylene chloride was added. The mixture is stirred at 10 ° G for 1 hour, then 40 minutes on Refluxed. Then it is cooled and filtered and the filtrate is mixed with 5% sodium bicarbonate solution, the 60 g Contains sodium thiosulphate per liter and washed with water. The ethylene chloride phase is poured over anhydrous sodium sulfate dried and concentrated, 61 g of acetal V being obtained. Part (58 g) is chromatographed on 2 kg silica gel, which is packed with ethyl acetate Skellysolve B (5o: 5o). Etching with 5o-5 °, 7o-3o and 8o-2o ethyl acetate-kellysol B gives a fraction of 24.9 g, which according to the IiIiR spectrum from a mixture of the dircethylacetals V and 'of the aldehyde VI consists. A part of the Geraisch (22.6 g) becomes · in 1oo 'nl one 6o: 4o Arrieisencäure-V / water Geiairjchs dissolved and 1 hour with

BATH ORIGINAL

5098 ^ 7 / 0-9: 35; ■

Left to stand at 25 C. The solution is then concentrated in vacuo and the residue is taken up in methylene chloride. The methylene chloride solution is washed with 5% aqueous sodium M-carbonate solution and water, dried over sodium sulfate and concentrated to 17.5 g of a brown oil, which crystallizes on seeding. When the crystals are triturated with benzene the aldehyde of formula VI is obtained in crystalline form (9.3 g). An analytically pure sample is obtained by recrystallization from tetrahydrofuran, melting point 72-74 ° C (corr.); IR absorption peaks at 274o, 1755, 171o, 1695, 1195, 1165, 1020, 955 and 91 ^{o cm ""1}; NMR peaks at $ 1.8-3.4, 5, o-5.4 and $ 9.92.

If the procedure of Example 4 is repeated, but under Ver Turning the exo-lactone acetal IV, you get the corresponding one Exo-lactone acetal V.

The procedure of Example 4 is also obtained when using the Exo connection V the corresponding Exo

Lactonaldehyde VI. ■.

Repeating the procedure of Example 4, but Vei turn of following Example _3: compounds IV-mentioned, we obtain the corresponding products of formula V and the corresponding Lactonaldehyde VI.

Example 5

dl-Tricyclic lactone-heptene (formula VII: Y = 1-pentyl and ro ■ = ■ endo) (see scheme A).

A suspension of 6.6 g of n-hexyltriphenylphosphine bromide in 20 ml of benzene is stirred under nitrogen and with 10 ml

BAD ORIGINAL 509842/0935 '· · ■

1,6m-n-Butyllithiuni added in η-hexane .. Hach 10 minutes we a "Bengali solution of 1.66 g of the tricyclic aldehyde VI according to Example 4 was added dropwise in the course of 15 minutes, The reaction mixture is then heated to 65 "to 70 ° C. for 2 1/2 hours. The solids are then cooled wird.ri filtered off and washed with benzene and entered and washing solutions v / earth with dilute e> l hydrochloric acid and Water extracted. The solution is dried over sodium sulfate and concentrated in vacuo to an oil (5.17 g). The crude product of the formula VII is chroma on 400 g of silica gel tographiert, 'which packed with 3o: 7o ethyl acetate: cyclohexane is, whereupon it is eluted with the same mixture. Fractions of 20 mil are collected. The fractions 47 his 5o skin 0.8 g of the tricyclic Laetonheptens of formula VII ,. KtIR peaks at o, 6-3, o, 4.4-5.1 and 5.4 £ ,. In order to keep side reactions to a minimum, this is preferred that made from phosphonium bromide and n-butyllithium Wittig reagent filtered to remove lithium bromide, Furthermore, the resulting solution / the benzene solution of the tricyclic aldehyde is added in an equivalent amount *

Following the procedure of Example 5, when using the exo-compound VI the corresponding exo-Lactonhepte VII. A preferred Meg for producing the exo-form of the tricyclic Lactonaldehyds .VI is shown in. Scheme H.

BATH ORIGINAL

509 8 42/093 5

Scheme H

XXVII

GOOR

XXXI

0 R "

Ji / ^1O

CCR ₁₁

COOR

14th

XXXII

COOR

14th

GOOR

¹ /

COOH

XXXIII

. XXXIV

XXXV

GH ₂ OH

XXXVI

CHO XXXVII

509842/0935

In this scheme "R. means an alkyl radical with 1" to 4 carbon atoms. Diazoacetic ester is added to a double bond of cyclopentadiene, giving an exo-endo mixture of the bicyclo- / 3.1. The exo-endo mixture is treated with a base "in order to isomerize the endo isomer with the formation of further exo isomer. Then the hexene is reacted with CIpC = C = O, which is formed in situ from dichloroacetyl chloride and a tertiary amine has been produced or trichloroacetyl chloride and zinc dust, to yield the dichloroketone of formula XXXII '. Anschlies send v / ith the dichloroketone as in step c) of- scheme A reduced. the resulting tric3 ^r clische. ketone XXXIII v / ill be as shown in Step & -) of Scheme A is converted into a lactone ester, the lactone is saponified, then acidified to give the compound of the formula XXXV with a carboxyl group in position 6. The carboxyl group is then converted into a hydroxymethyl group and then the exo-aldehyde of formula XXXVII is formed.

Example 6 '* ■

dl-Tricyclic glycols (formula VIII: W = VPentyl and • ^ = endo) (see scheme A). . · _F - ^

Method A. A solution of 0.8 g of the tricyclic lactone ~ heptens VII according to Example 5 in 1.o ml of benzene v / ird with 1.0 g Osmium tetroxide in 15 ml benzene. Treated. After 24 hours The mixture is left to stand for 30 minutes with hydrogen sulfide treated, then a black solid is filtered off. The filtrate is concentrated to an oil (393 mg). Further mg of oil are obtained by filtering off the

BAD ORIGINAL 5 0 9842/0935

black solid suspended in ethyl acetate and treated again with hydrogen sulfide. The oil is an 1όο g
Chromatographed silica gel, eluting with 40-60 acetone-methylene chloride to collect 20 ml fractions. Two erythroglycols of the formula VIII are obtained, one of which is more polar (moving more slowly in the column) than the other. The faster moving glycol, ο, 5 g, is in fractions 2o to 3o, the slower moving glycol, ο, 28 g, is in fractions 31 "to 40".

Method B. A mixture of 7 ml of the N-methylmorpholine oxide V / water substance per oxide complex (see Fieser et al., "Reagents, for Organic Syntheses ", p. 6 So, John Wiley and Sons, Inc., New York, H.Y. (1967)), 8 ml tetrahydrofuran, 14 ml tert Butanol and 2 mg Qsmiumtetroxyd in 2 ml tert-butanol cooled to about 15 ° C.

A solution of the tricyclic lactone heptene VII according to Example 5 (3.95 g) in 12 ml of tetrahydrofuran and 12 ml of tert-butanol is then slowly added over the course of 2 hours
15 to 20 ° C added. The mixture is stirred for a further 2 hours, then a slurry of a filter aid (for example 0.8 g of magnesium silicate) in 14 ml of water containing 0.4 g of sodium thiosulphate is added, whereupon the solids are filtered off. The filtrate is concentrated to an oil under reduced pressure. Then 2oo ml of water are added and the oil-water mixture is extracted several times with methylene chloride. The methylene chloride solution is dried over magnesium sulfate and concentrated under reduced pressure, a mixture of the title compounds being obtained.

Following the procedure of Examples 6A and 6B, one obtains at Use of the exo-compound VII the corresponding tricyclic exo-glycol VIII.. ,,

BATH ORIGINAL

509842/0935

Example 7.

dl-bicyclic laetone bismesylate (formula IX: R _g = methyl, V / = '1-pentyl, ^ = endo), and bicyclic laetone diol (formula X: W = 1-pentyl, r ^ f means & configuration ) (see scheme A-).

277 mg of the more slowly migrating erythroglycol from Example 6 are dissolved in 5 ml of pyridine, the solution is cooled to Ö ° C under nitrogen and with. 89 g methanesulfonyl chloride treated. The mixture is left to stand at 0 20 hours, then 0.6 ml of ice water are added and the mixture is stirred for a further 20 minutes. The solution is then poured into methylene chloride and washed with ice-cold 1N hydrochloric acid, ice-cold 5% sodium bicarbonate solution and bis-water. The solution is dried and concentrated in vacuo to an oil (29o mg), which can be extracted from the Bis-mesylate _r IX consists of *

This product is dissolved in 10 ml of acetone and 5 ml of water And the solution is left to stand at .25 ° C. for 3 hours and then freed from acetone under reduced pressure »Then is diluted with water and extracted with .Methylene chloride The methylene chloride solution is made with Seiger sodium bicarbonate solution and saturated sodium chloride solution, dried and concentrated in vacuo to an oil (2oo mg), which from the product of the 'forme! X exists.

The compound X is used as a mixture of isomers with o (~ and ß Configuration received. These isomers are grounded by chroma tography on silica gel separately and reused separately, e.g. for the production of the bis-tetrahydrqpyranyl ether ΧΙΪ «The undesired isomer X v / is returned in the cycle.

BATH ORIGINAL

S09842 / -0935

It is isomerized and isomerized to form a mixture of off- and ß-porms. The 15-hydroxyl group is isomerized with a. selective oxidizing agent, e.g. 2, 3 -]> chloro-5, ö-dicyan-l, 4 - benzoquinone, activated manganese dioxide or nickel peroxide (see Fieser et al., "Reagents for Organic Syntheses", John.Wiley and Sons, Inc., New York, N.T., pp. 215, 637 and

731) is oxidized to the 15-keto group. Then the 15-keto compound is produced reduced with zinc borohydride in a manner known per se, a mixture of the o (- and ß-isomers being obtained, which are then separated by silica gel chromatography.

Bach of the working method of Example 7 is also the converted faster migrating glycol into compound X, which was identical to the above product

Furthermore, using the process toe Example 7, however, is obtained using the exo compound VIII the corresponding Exobismesylate IX. This is done in the manner of Example 7 converted into the corresponding X lactpenediol.

The Iiactondiol of the formula X »in which ¥ denotes the 1-pentyl radical, can be converted to dl-PGEp and dl-PGF- and their alkyl esters are further processed, for example according to the reactions of Schemes C -and E.

Example 8

, Acetal with

2,2-Dimethyl-1,3-propanediol (Formula II: IL and Rg together = -CH ₉ -, r ^ ~ endo) (see scheme A).

A solution of 48.6 g of endobicyclo / 3.1. £> 7b.ex-2-en-6-carboxaldehyde the formula I, 14o, 4 g ajZ-M

BAD ORiGiNAL 0 9 8 4 2/0935 ·

diol and 0.45 g of oxalic acid in ο.9 1 benzene is 4 hours cooked at the Poick river. The azeotropically distilled off water is removed by a water separator. The reaction mixture is cooled, then 5? Iger sodium bicarbonate solution and washed with water. The benzene solution is over Dried sodium sulfate, concentrated to an oil (93 g) and distilled at reduced pressure. The fraction boiling at 0.4 mm at 88-95 C consists of the desired title compound, Yield 57.2 g, melting point 53 to 55 / C, NMR peaks at o, 66, 1.2, 3.42, 3.93 and 5.6g; IR absorption at 1595,

mo, I0I5, I005, 99o, 965, 915 and 745 cm "" !. '

i ·

If the procedure of Example 8 is repeated, | however, using the exo-compound I, the corresponding exo-acetal II. I _{1 is obtained}

Example 9

dl-Tricy'elic dichloroketone (Pormel III: iL and Rp together. -CH ₉ -C (CH ^) ₉ -CH ₉ - and / ^ / = endo) (see scheme; A).

Following the procedure of Example 2, the compound II "according to Example 8 is converted into the Tite! Compound with a melting point of 97 to 100 ° C., NKR peaks at 0.75, <; 1.24, 2.43 ( Multiplet), 3.42, 3.68 and 3.96 (doublet) ß; IR absorption 3o4o, 181o, 1115, 1o2o, 1000, 98o, 845 and 74o cm "" ¹ .

Example 1o

dl-Ti'icyclisches ketone (formula IV: R. and R ₉ · together -CH ₂ -C (CH ₅ ) ₂ -GH ₂ -, rv = endo) (see scheme A).

. . BAD ORiGfNAL

509842/0935,

Following the procedure of Example 3, the diehlorketone III is converted according to Example 9 into the title compound, which is an oil, HMR peaks at ο, 75, 1.25, 3, ο (multiplet) and 4, ο (doublet) £; IR absorption at 1770 cm " ¹

Furthermore, following the procedure of Examples 3 and 1o, however using the corresponding exo compound III, the corresponding tricyclic exo-ketone IV is formed.

Example 1oA

f dl-Tricyclic lactone acetal (formula V: R. and R ~ together! = -CH _? -C (CH -,) ρ-CHp-, * ^ j = endo) and tricyclic lactonaldehyde (formula VI: r ^> = endo ) (see scheme A).

12 g of the tricyclic ICetone IV (Example 10) and 6.1 g of potassium bicarbonate in 100 ml of methylene chloride are ^{cooled to about T} "10 ° C. Then 12.3 g of m-chloroperbenzoic acid (85%) are added in portions at this rate that the reaction temperature remains below 30 ° C. The mixture is then stirred for 1 hour and 15 ml of 5% aqueous sodium bicarbonate solution containing 9 g of sodium thiosulphate is added. The methylene chloride layer is dried over sodium sulphate and evaporated under reduced pressure. The oily residue contains the lactone acetal V, NMR peaks at 0.75, 1.23, 3.5 (quartet), 3.9 (doublet) and 4.8 (quartet) £ ; IR absorption at 176o cm ",

About 4.4 g of lactone acetal V in 60 ml of 88 / Siger formic acid are left to stand at 5o C for 1 hour. Then the The solution was cooled, diluted with 60 ml of sodium chloride saturated in sodium hydroxide solution and treated with ethylene chloride extracted. The combined extracts v; earth with 1 above

509842/0935 BADOWGINAL

Washed sodium carbonate solution, getrocki over sodium sulfate Concentrated under reduced pressure. The product crystallizes on standing and gives the lactonaldehyde of the formula VI with a melting point of 69 to 73 ° G, MMR peaks at 5.2 (multi-

plett) and 1o, o (doublet) £>, IR absorption at 1755 cm.

The procedure of Example 10 is repeated under Yerwendui of the corresponding exo-ketone IV, the corresponding products V and VI are obtained. . '

Example 11

dl-PGE-, dl-15-EpI-PGS ₅ and their allyl esters. (Formula XXII, according to Scheme D: «-v / denotes 15 & (- or 15 [beta] configuration) (see Scheme A and D).

Following the procedure of Examples 1 to 4, the Bicyclb ~ hexenaldehyde I converted into the tricyclic lactonaldehyde VI.

According to the procedure of Example 5 v / ird under Ersatz'des n-Hexyltriphenylphosphine bromide by the unsaturated Phosphorus compound from 1-bromo-3-hexyne, i.e. 1-hex-3-i "nyl triphenylphosphine bromide, the heptenin compound of the ^ orjuel VII obtained, in which Y represents the 1-pent-2-ynyl radical and is endo.

Then, using the methods of Examples 6 and 7, the compounds of formulas VIII, IX and in which Yf represents the 1-pentynyl radical and r ^ denotes the endo configuration on the cyclopropane ring and <X or β configuration of the hydroxyl group in the side chain; The octenine

BATH ORIGINAL 5098A2 / 0935

- 5ο -

diol X is used as a mixture of isomers with Oi- and ß-Konfigu- ■ get ration. These are indicated by chrome etching Silica gel separated and used to prepare compounds of Formula XVIl. The unwanted isomer X v / ird im Recirculated and isomerized according to the procedure of Example 7. The "octeninediol X with ^ -configuration, ■ where. "W is the 1-pentynyl radical, the octadiene diol becomes the Formula XVII, in which Z is the 1-pent-2-enyl radical, reduced, by hydrogenating the acetylene group over a Iiindlar catalyst converted into the cis-CH = CH group. To a solution of 20 mg of compound X in 2 ml of methanol, 5 mg of 5 $ palladium / barium sulfate and 2 drops of synthetic Quinoline added. The mixture is stirred at about 25 ° C. and normal pressure. The reaction will stop as soon as 1 equivalent of hydrogen was absorbed. Then it will The mixture is filtered and the filtrate is concentrated in vacuo. Ethyl acetate is added and the solution is chromatographed on silica gel impregnated with silver nitrate. The column is developed with isomeric hexanes (Skellysolve B) containing increasing amounts of ethyl acetate. the The fractions containing the desired octadiene diol are combined and concentrated, the intermediate product of the Formula XVII receives.

According to the process steps of scheme D, the compound of formula XYII, in which Zn-pent-2-enyl radical and -v represent the O <- configuration, is converted into PGE in a manner known per se. In the process, the diol XVII is converted into the bis-tetrahydropyranyl ether XVIII. The oxo group of the lactone is reduced with formation of the lactol XIX. The supply _t connection XX v / ith by V / ittig reaction using Lu-chloro- or lO-Brompentancarbonsäure prepared. The hydroxyl group in the 9-position of the compound XX is oxidized to the 9-ICeto group of the compound XXI, and finally

• 'BAD ORIGINAL 5 0.9 842/0935.

2156796

the letrahydropyranyl protective group is removed by hydrolysis, the desired dl-PGE ~ of the formula XXII being obtained.

If the procedure of Example 11 is repeated, but below Replacement of the endo-aldehyde by the exo-aldehyde I, so obtained one the exo-compounds VI, VII, VIII and IX, which in, / the laetondiol X and then in dl-PGE, to be converted.

"If the process of Example 11 is repeated for the preparation of dl-PGE ,, but replacing the compound with the S configuration by the compound X with the 15 [beta] (R) configuration, the intermediates of the ^x formulas XVII to XXI _{1 are obtained} , in which rü denotes the ß-configuration, and from this the dl-15ß-PGE 'of the formula XXII, in which r ^ denotes ß-configuration ...

Although in Example 11 the acetylene group of the octeninediol X is reduced to the cis -CH = CH group immediately before the formation of the cis-tetrahydropyranyl ether ν, as shown in Schemes A and D, this reaction can also be carried out in any be - j any stage between the glycol VIII and the end product ^ dl-PGE_ or dl-15ß-PGE "can be carried out. . _u

Thus, a compound of the formula VIII, in which W / 1-pent-2 ~ ^ ynyl radical and * ^ denotes the bond to the cyclopropane ring in the Exo- _{J (} or Endo-configuration) is subjected to successive reactions.

a) Replacement of the glycol hydrogen atoms by an alkanesulfonyl group of the formula RqO ₂ S-, in which R _{g represents} an alkyl radical with 1 to 5 carbon atoms,

b) Mixing with Äiasser at a temperature of ο to 6o ° C with formation of a bicyclic lactone diol,

509842/0935 BATH ORIGINAL

c) Separation of the diols with C ((S) - and ß (R) -configuration,

d) conversion into a bis-tetrahydropyranyl ether,

e) Reduction of the lactone oxo group with formation of a hydroxyl group,

f) Wittig alkylation with a compound of the formula Hal- (CHp) ₄ -CpOH, in which Hal is bromine or chlorine,

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

h) Conversion of the "two letrahydropyranyloxy groups in Hydroxyl groups. Before or after one of these stages a) "to h). Is the acetylene group is reduced to a cis-CH = CH group, and the end product is then dl-PGE, or dl-15B-PGE ^. In this way the intermediates of the formulas are grounded t VIII, IX and X, where W is the eis-i-Eeirt-2-enyl or 1-pent-2-ynyl radical represents, as well as the intermediates of the 5'formulas XIII, XIX XX and XXI obtained, wherein Z is the cis-1-pent-2-enyl- or 1-pent-2-ynyl radical. -

Example 12

and dl-15-epi-PGI '^ -ester (Formula XXVI from Scheme E: = 15 & (S) or 15β (R) configuration) (see scheme E).

Following the procedure of Example 11, the Octadiendiol 'XVII is prepared in c (-configuration This diol is prepared according to Scheme E, v / obei ^ j otorhinolar configuration is in a known V / else in PGi ^1,.. -. The diol XVII is converted into the lactol XXV by reduction of the oxo group of the lactone. The lactol XXV is then converted to / dl- ^ (formula XXVI, v / obei Ky S configuration) by performing a Wittig reaction Use of UJ-chloro- or Lu-bromopentanecarboxylic acid applies.

BAD ORiG / NAL

5 0 9 8 4 2/093 5

- 6l -

If the procedure of Example 12 is repeated, but using the octadiene diol with the β configuration instead of the octadiene diol XVII with the o (configuration, the compound dl-15B-PGIV ₀ , (formula XXVt, where r ^ f β Configuration).

Although Example 12 is an embodiment of the method for; Production of PGF ^ ₀ . illustrated, in which the acetylene group -C ^ C- of the octeninediol X takes place directly before the reduction of the lactone-oxo group to the cis-CH = CH group, as can be seen from schemes A and F, this reduction of the acetylene group in any another stage between the glycol VIII and the end product dl ^ PGF ^ or dl-15ß-;,.

PGF, take place. For example, a connection of the

Formula VIII, in which W / 1-Pent ~ 2-ynyl radical and r * J denotes the bond to the cyclopropane ring in the exo or end o configuration - ■: denotes the following reactions in succession:

a) Replacement of the glycol hydrogen atoms by an alkarisulfo, -nyl group of the formula R _Q O ₉ S-, \ ^ orin R _{Q is} an alkyl radical with: 1 to 5 carbon atoms, j

* b) Mix with v / ater at a temperature between 0 and 60 ° C! to form a bicyclic lactone diol, * _v j. c) Separation of the diols with Of and ß configuration, · - I

d) Reduction of the lactone oxo group with formation of a hydroxyl ·! group and · ·,, ί

e) V / ittig-alkylation with a compound of the formula Hal- (CH ₂ ) - COOH, in which Hal is bromine or chlorine, with the caveat that before or after one of these steps a) to e) the acetylene group to cis -CH = CH group is reduced, finally obtaining dl-PGF, or dl-15ß-PGF ". This process steps gives an intermediate of the formula XXV, in which Z is the cis-1'-pent-2 -enyl or 1-pent-2-ynyl radical.

. BATH ORIGINAL

509842/0935

Example 13 ■

Separation of the

Endo-bicyclo / ~ 3.1., O / hex-Z-en-ö-carboxaldehyde (formula I: r <J = endo).

A · 12.3 g Endo-Mcyclo / ~ 3.1. £ 7hex-2-en-6-carboxaldehyde I. and. 16.5 g of 1-ephedrine are dissolved in about 150 ml of benzene. Das.Benzol is removed in vacuo and the residue is taken up in about 150 ml of isopropyl ether. ¹ The solution is filtered and then cooled to -13 ° C., 11.1 g of crystalline 2-endobicyclo _J £ ~ 3.1 .o / hex-S-en-ö-yl-Sj ^ dimethyl - 5-phenyl-oxazolidin of melting point ^9o: receives to 92 C. After three recrystallization from isopropyl ether, in each case under cooling to -2 ° C, 2.2 g of the crystalline melting point of the oxazolidine to To3 1oo ° C was obtained. which, as can be seen from the NKR spectrum, 'essentially' ^: · exists in a single isomeric form. '' ^{1? f ö}

1, og of the recrystallized oxazolidine is dissolved in a little ml of methylene chloride, the solution is applied to a 2o g silica column and eluted with dichloromethane. One uses silica gel for chromatography purposes (Merck) with a particle size of 0.05 to 0.2 mm, which contains about 4 to 5 g of water per 100 g. The eluate is collected in fractions, and the amount required according to thin-layer chromatogram / gev / desired '^; Fractions containing bond are combined and evaporated to give 360 mg of an oil. According to the NMR spectrum, this consists of the desired compound I, the endobicyclo / 3.1 .oThex - ^ - en-δ-carboxaldehyde, which is practically is free of ephedrine and is essentially in the form of a single optically active isomer, which is referred to as the "isomer of Example 13A." The points on the circular dichroism curve are at Λ. in mn, O: 35o, O; 322, 4, -4 854; 312, -5 683; 3o2.5, -4 854; .263, O; 25o, 2 368;

BATH ORIGINAL

50.984 2/093 5

21 £ 6796

24ο, 0; and 21ο, -34 6οο.

B. Me mother liquors are combined and evaporated and. give crystals which are taken up in methylene chloride. The solution is chromate on silica gel as described above »- graphed, with the enantiomorphic compound I with reverse optical rotation.

C. A preferred method for the preparation of the isomeric zolidine, which gives the aldehyde with reverse optical rotation as the isomer according to Example 13A, is carried out as follows: Bach of method A, the racemic aldehyde is reacted with d-ephedrine, where ~ one obtains the oxazolidine ''' in the diastereomeric forms. During recrystallization, "the desired oxazolidine is then obtained which, by hydrolysis, yields the desired optically active aldehyde."

's

Following the procedure of Example 13, the Exo-bicyclo / ~ 3.ΐ, ο hex - ^ - en-G-carboxaldehyde I into the oxazolidine with d- or 1-ephedrine over "leads and in'die optically active isomers zer- j lays. . 'I.

Example 14. '. . . '

Separation of the acetal-acetone (Formula IV: R. and R «together = () ₂ -CH ₂ -, r ^ f = endo). .

A, A solution of 2.35 g of acetalketone IV according to example (Production of the acetal with 2,2-dimethyl-1,3-propanediol) and 1.65 g of 1-ephedrine in 15 ml of benzene is added after adding a capped acetic acid refluxed for about 5 1/2 hours, The water is removed with a Dean-Stark trap will. Then the benzene is evaporated, leaving the oxazolidine

5 0 9 8 4 2/0935

remains as a solid which is dissolved in methanol. When the methanol solution is cooled, one of the diaaereomeric oxazolidines is obtained in a yield of 1.57 g, melting point 161-166 ° C., βO-Q ^ -7.5 ° (chloroform). The product consists essentially of a single isomeric form, as evidenced by the HKR spectrum; ISMRA peaks at o, 63 (doublet), --- ¹ - o, 72, 1.23, 2.38, 3.52, 3.95 (doublet) and 4.94 (doublet) ζ .

Following the procedure of Example 13, the above crystalline ^v oxazolidine line on a Silkagel column in the optically active isomer transferred. The yield is 0.56 g, melting point 43-47 ° C., / "OLTj) ²⁵ + 83 ° (chloroform). This compound is called the" isomer according to Example 14A ".

B. -The mother liquors of A are concentrated and cooled to -13 ° C, the other diastereomeric 'oxazolidine in a yield of 1.25 g, melting point 118-130 C,., ..., / oijp ⁵ +11 7 ° (chloroform), HMR-peaks at 0.63 (doublet), ^o, 72, 1.23, 2.38, 3.52, 3.99 (doublet), and 5.00. (ijublett) £ ,, _rl receives. This compound is referred to as the "Isomer of Example, 14B". Following the procedure of Example 13, the crystallized oxazolidine is converted into an optically active isomer of the compound IV on a silica gel column. .

C. The reaction of the isomer according to Example 14B with d-ephedrine according to the procedure of Example 14A gives the '.. Enantiomorph of the oxazolidine according to Example 14A with a melting point of 165 ° C, / ¹² LT ² ) ⁵ + 7.5 ° (chloroform) .

Following the procedure of Example 13, the crystallized Oxazolidine on a silica gel column into an e ^ psei converted optically active isomer of the compound IV, which is identical to the product according to Example 14B.

5 0 9842/0935

Following the procedure of Example 14, the exo form of the Acetalketons IV according to Example 1o into the oxazolidine with d- or 1-ephedrine and broken down into the optically active isomers.

The oxazolidines separated in the above manner are by Contact with water, preferably in the presence of an acid catalyst, hydrolyzed in a manner known per se to oxo compound and ephedrine (see Elderfeld, Heterocyclic Compounds, Vol. 5, p. 394, Wiley, H.Y., 1957). So will "For example, the oxazolidine from 1-ephedrine and the acetal- ketone IV (Example 14A, 5, ο g) in a solution of .25 ml Tetrahydrofuran,, 25 ml of water and 5, ml of acetic acid about 25 ° C under nitrogen. The solvents 'Are removed at reduced pressure and 25 to 40 ° C and the residue is mixed with 25 ml of water. The mixture is extracted several times with benzene and the combined «- ·« Benzene extracts are washed with water, dried over sodium sulfate and finally under reduced pressure. = « concentrated, v / obei one the optically active acetalketone IV * which gets the same. Properties shows how the product according to Part A. Sine another method for hydrolysis of the oxazolidine consists in the use of a column of silica gel and water according to Example 1.3, from which the oxo compound eluted and isolated in a conventional manner "Will.

Example 15

Separation of the tricyclic lactonaldehyde (Formula VI: endo). . "

A. A solution of 0.5 g of endo-lactonaldehyde VI according to

50 9.8 42/0935

Example 4 and 0.5 g of 1-ephedrine in 20 ml of benzene and concentrated to dryness in vacuo. The residue v / ill with Diäthylather "treated to give crystals obtained from a oxazolidine mixture. Recrystallization of the mixture from methanol Oxoazolidin a melting point of 133.5 to 134.5 C ^O is obtained. The hydrolysis of the oxazolidines on silica gel after The procedure of Example 13 results in an optically active isomer which corresponds to the mirror image of the formula VI; this product is "worked up in a conventional manner and then referred to as the" isomer according to Example 1_5A ".

B. Using the method of Example 15Λ v / ird, replacing the ¹ - *. 1-ephedrine produced by d-ephedrine, the optically active isomer of laetonaldehyde VI, which is hereinafter referred to as "isomer according to Example 15B".

The exo-lactonaldehyde> VI is broken down into the optically active isomers according to the method of Example 15. ■ "■ '■

Example 16 ..., _ - ■

- - ti ■

An optically active tricyclic ^j Glycol (Formula / VIII according to 'Scheme A: W = 1-pentyl, and / ^ = endo.) - PGE _2. PGF _{2o {} , their ¹ ent derivatives and 15-epimers (sw scheme Ö). .

If the reactions of Examples 1 "to 6 are repeated using the endobicyclo / ~ '3 ί 1 • _i o_7hex-2 ~ en-6-carboxaldehyde isomer I according to Example 13A, the tricyclic glycol of the formula is obtained VIII, v / or in W / 1-pentyl radical and pj endo configuration designated form of an optically active isomer Following the procedure of Example 7, this isomer is converted into the optically active compounds of the formulas

50 98 42/0935

-. . - 67 - -; ■ . ■■■■■. - - j

»Ν

IX and X converted, in which W represents the ΐ-pentyl radical.

Analogously, "when using the isomer of the formula I" is obtained according to Example 130 the enantiomorphic compounds YIII, IX and.X,. -:

Each isomer of the formula X is converted into the compounds PGE 1, ent-PGE ₂ and their 15-epimers in a _{manner known per se, as shown in Scheme C. For example, PGE 2 is obtained} from the optically active diol X. , which is obtained from the isomeric aldehyde I according to Example 13A. ent-PGE "is ^{! produced} from the enantiomorphic Oiol X, which is formed from the aldehyde I according to Example 130."

Furthermore, when using the optically active yerbine--

formulas VIII, IX and X, according to the steps according to ■ ν t. Scheme E using: anisich known! Reactions the ί -ξϊι corresponding PGFp ₀ , - and ent-PGF2 _C j. Compounds * and their, 15-epimers. '"■'". · ·. · ■ "

If the processes of Examples 1 to 6 are repeated, but using the optical isomeric, exo-aldelium and I from Example 13 instead of the endo-AldBhydSj, one obtains'. ~ the optically active exo-glycols VIII and bis-r-mesylates IX, dier into the isomeric diols X and then into the compounds .. »· - ■ - ■ PGE ₂ and ent-PGS ₂ and their 15-epimers, ¹ PGF ₂ ,, H * ?? ^ ^ ²²¹⁰¹ whose 15-epimers are transferred. . * ■

Example 17

• -

PGE, ent-PGE, and their 15-epimers (formula XXII according to scheme.!): ^ / Denotes Ot or ß configuration) (see scheme D)

50 9842/093 5

According to the procedure of Example 15, the endo-bicyclohexenaldehyde I is broken down into the two optically active isomers. Following the procedure of Example 11, these isomers are converted into the corresponding dioil X in the (X - and β configuration and then into the compounds "PGE ₅ and ent-PGE" and their 15-epimers

Following the procedure of Examples 14 and 15, the endo-acetalketone IV or the lactonaldehyde VI broken down into the optically active isomers. Following the procedure of example the isomers of the formula IV and VI are then converted into the corresponding diol X in © (- and ß-configurations and then in the compounds PGE, and ent-PGE_ and their 15-epimers ■ convicted. . .

This is how PGE is made from the optically active diol X, which from the acetalketone IV according to Example 14A or the lactonaldehyde VI has been formed according to Example 15B. ent-PGE, is obtained from the enantioraorphic diol X, which has been prepared from the acetalketone IV according to Example 14C or the lactonaldehyde VI according to Example 15A.

The exo-forms of the compounds I, IV and VI broken down into the optically active isomers, - which then into the corresponding Diols X and then into the PGE-- and ent-PGE - V. compounds and their 15-epimers are converted,

According to the procedure of Example 11 and the following examples, the optically active glycol of the formula VIII, in which W denotes the 1-pent-2-ynyl radical and r * J denotes the bond to the cyclopropane ring in the Exd or Indo configuration, subjected to the following reactions in its isomeric porms:.

a) Replacement of the glycol hydrogen atoms by an alkanesulfo-

509842/0935

ny! group of the - "-" orrnel HqO "S-, where Rg is an alkyl radical with Represents 1 to 5 carbon atoms,

b) Mixing with water at a temperature between 0 and. 6o ° C with formation of a bicyelic lactone diol.

c) Separation of the diols with (^ - and .ß-configuration,

d) Conversion into a bis-tetrahydropyranyl ether ^

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

f) V / ittig alkylation with a compound of the formula Hal- (CH ₂ ) ^ - CQOH, in which Hal is bromine or chlorine ^. '

g) Oxidation of the S-hydroxyl group sur Oxqgruppe and

h) Conversion of the two letrahydropyranyloxyx-estes into. 'Hydroxyl groups, the acetylene group being reduced to the cis-CH = CH group before or after one of the stages a) to h), and PGS ,, ent-PGE «or their 15-epimers are ultimately obtained. '

Example 18

, ent-PGP _5i ^ and their 15-epimers (formula XXVI according to scheme Ϊ ¹ : ru denotes CX or ß-configuration) (see scheme F)

Subject _{t of} the procedure of Example 13, the endobieyclo- '- hexen-aldehyde I is broken down into the two optically active isomeric forms. According to the procedure of Example 12, the individual isomers are then converted into the corresponding diols X ^ in 0 (- and β-configuration and then converted into .the corresponding PGF ₅₀ ; - and ent-PGF ^ Q. Compounds and their 15-epimers. '"

Following the procedure of Examples 14 and 15, the endo acetalketone IV or the lactonaldehyde VI broken down into the optically active isomeric forms. Following the procedure of example 12 are then the individual isomers IV or VI in

509842/0935

the corresponding diol X in Oi _ or β configuration and then converted into the "products 2Gl ^ ₀ ,> ent-PGF., ^ ^{x> Jl} ^ their 15-epimers.

Analogously, the exoforms of the compounds I, IV and VI are broken down into the optically active isomers and then converted via the diol X into the PGF ₅₀ and ent-PGF-Qj compounds and their 15-epimers.

Also, the optically active glycol is the ^f Ormel VIII wherein \ i-Pent-2-inyl radical represents and RSJ signifies the bond to the cyclopropane ring in exo- or endo-configuration by the method of Example 12, successively in its isomeric forms following Subject to reactions:

a) Replacement of the glycol hydrogen atoms by an alkane sulfo

.. nyl group .the. F. Formula R ₀ OpS-, where Rq is an alkyl radical with ^Jl · - · '' ^ 1 to 5 carbon atoms,

b) Mixing with water at a temperature of ο to 60 ⁰ C with formation of a bicyclic iactondiols with S and R configuration, ■ -

c) separation of the diols from S and R configuration,

d) reduction of the oxo group of the lactone to the hydroxyl group and

e) -Wittig alkylation. with a compound of the formula Hal- (CHp) ₄ -COOH, in which Hal ^ is bromine or chlorine, with the disregard that before or after one of these stages a)

-bis e) the acetylene group is reduced to the cis -CH = CH group and finally the compounds PGF, ^, ent- or receives their 15-epimers.

Example 19

dl-tricyclic lactone epoxide (formula XXXVIII: Y = n-Pentj ^ l, denotes the bond to the cyclopropane ring in exo-

509842/0935 ^BAD original

y ° \ ■■■ · ■

or Endo-TConfiguration, r S denotes the binding of the Epoxy oxygen to the side chain in Oi or ß configuration) (see scheme B).

Peracetic acid (2 ml 40% in 8 ml methylene chloride) is added dropwise over 10 minutes to a mixture of 2.02 g of the tricyclic iacion YIII according to Example 5 and 0.8 g of potassium carbonate in 12 ml of methylene chloride. Once the product has been obtained (dünnschichtenchromatographisch ER -. Averages) (about 45 hours at 25 ⁰ G), the mixture is diluted 3o ml of methylene chloride and 2 χ 5 £ strength Watrium- biGarbonatlösung, the o, 5 g ο Hatriumthi? The ethylene chloride solution is dried over anhydrous sodium sulphate and evaporated under reduced pressure, giving 2.18 g of a residue from the 5% compound, NMR peaks at 0.6-3> 3, 4.8 (wide) ^.

Example 2o

ai-bicyclic lactone formate (JOrmel Xi: Y = n-pentyl, = ' 0 {or ß) (see scheme B).

Method A: A solution of 2.38 g of the glycol mixture ¥ 111 from Example 6 (formula XXXIX, M and E -hydrogen) in 40 ml loofaiger formic acid is left to stand at about 25 ° C for 5-1 / 2 hours. Then the mixture is concentrated to an oily solution under reduced pressure. This is treated with a solution of a phosphate buffer (pH 6.8) image of about 1 above sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulfate and concentrated under reduced pressure, 2.66 g of a residue from the filtered compound being obtained.

BATH ORIGINAL 509842/0935

Method B: Dine solution of 10.0 g of Bpoxide X] -CXVIII according to Example 19 in 8o ml of a mixture of acetone and water and formic acid (7o: 3o: 2 parts by volume) is left to stand at about 25 ° C for 55 minutes. Then the mixture is reduced at reduced Pressure evaporated to dryness. The residue is v / ird with 5 # sodium bicarbonate solution, which with sodium chloride is saturated, treated and extracted with ethyl acetate ■. The ethyl acetate solution is dried over magnesium sulfate and concentrated at reduced pressure, v / obei one a mixture of glycol XXXIX (M and E = hydrogen) and Diol X is obtained in an amount of 11.7 g.

k One solution to this glycol Diolgemisehs in 35o ml curly viird formic acid for 2 hours at etv / a 25 C allowed to stand. The mixture is then concentrated under reduced pressure and the residue is taken up in methylene chloride. The methylene chloride solution is washed with 5% sodium bicarbonate solution, dried over sodium sulfate and concentrated, 13.2 g of residue being obtained from the title compound. '

Method C: A solution of 2.18 g of the epoxide XXXVIII according to Example 19 in. 40 ml of 100% formic acid (see, for example, V / instein et al., J. Am. Chem. Soc. 74, 1.126 (1952)) is stirred under nitrogen at etv / a 25 ° C 2 '"-ψ hours, \ WO followed dünnschichtenchromatographisch in the reaction. the mixture is stirred at reduced pressure to dryness, evaporated. the residue v / ill be in 5o ml of methylene chloride was added and the solution is washed with 5% sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure, giving 2.92 g of residue from the compound XL.

BATH ORIGINAL

5098 A2 / 093 b

Example 21

dl-Bicyclic lactone diol (formula X: V = .1-pentyl, / ν / = "denotes οί or ß) (see scheme B).

A solution of 2.92 g of the Diformiate XL according to Example 2o in 10 ml of methanol is stirred with 0.2 g of potassium bicarbonate for 1/2 hour. The mixture is then filtered and the residue is diluted with 50 ml of methylene chloride. The solution is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue is chromatographed on 81 g silica gel, which is packed with acetone-methylene chloride (3o: 7o), v / if it is eluted with acetone-1-iethylene chloride (po-75 / ^ acetone) to collect 2oo ml fractions. The fractions containing the desired product without starting material and impurities according to thin layers are combined, "for example the fractions 2o" to 25 with the title _{compound X ß} and the fractions 26 to 35, which contain the title compound X ^ y. Concentration of the fractions gives d, 66 g of the diol X _ß and 0.76 g of the diol X. :.

Example 22

• dl-tricyclic lactone monoformate (formula X] CXIX: M and E = hydrogen or formyl, Y = 1-pentyl, ru denotes the bond to the cyclopropane ring in Endo ^ configuration and to the side chain in C (- or ß-configuration) .

A solution of 2.38 g of the glycol mixture VIII according to Example 6 (formula XXXIX, in which M and E = hydrogen). ird long at about 25 ⁰ C for 1/2 hour; in 4o ml of formic acid loojiiger v

BATH ORIGINAL 509842/0935

The mixture is then concentrated under reduced pressure. The residue is treated with a solution of a phosphate buffer (pH 6.8) and about 1 of the above sodium bicarbonate solution and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulfate The residue is worked up by chromatography on silica gel, the fractions containing the title compound according to the thin-layer chromatogram being combined. Concentration of these fractions gives the title _{compound, R f} = 0.2 in ethyl acetate Skellysolve B ( 4o: 6o) on thin-layer chromatogram plates.

Example 23

PGF-. and 15B-PGF ₂ ^ (see Scheme E).

A. Optically active tricyclic laetone acetal Y: A mixture of 12.0 g of the acetalketone isomer IV according to Example 14A and 6.1 g of potassium bicarbonate in 100 ml of methylene chloride in portions with stirring and cooling to maintain a temperature below 30 ° C treated with 12.3 g of m-chloroperbenzoic acid (855 »). After 2 hours, 150 ml of 57% sodium bicarbonate solution containing 9 g of sodium thiosulphate are added. The methylene chloride phase is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is recrystallized from ethyl acetate, it consists of the tricyclic lactone acetal of ^ ormel V, where R .. and R _? together form the residue -CHp-C (CH-) ₂ -CH ₂ - and ru denotes the endo configuration, the melting point of the product is 127 to 130 ° C, NMR peaks at o, So, 1.29, 3, 45, 3.72, 3.94, (doublet) and 4.89 (multiplet) & ; IR absorption peaks at 1765, 123o, 1185,

ORIGINAL BATHROOM 509842/093 5

• - 75 -; ■■ -. ·;

2166798

1i6o, 112ο, 11οο, 1ο95, 1 ο15, 1odo, S8o, 955 and 925 cm " ¹ βΧΐψ + 9 ° (methanol).

B. Optically active iricyelischer lactone aldehyde VI: 4.43 g of Acetalketons according to Example 23a is dissolved in 88 ^ formic Thus ml and maintained for 1 hour "at about 5o C. The solution is then cooled and saturated with 6ο ml with sodium chloride.. Diluted in sodium hydroxide solution, then extracted several times with diethylene chloride. The methylene chloride extracts are washed with 20 ml of the above sodium carbonate solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The oil that remains is rubbed in with isopropyl ether and impregnated , whereby crystals of the corresponding tricyclic lactonaldehyde VI with a melting point of 62.5 to 64 C are obtained, KtfR peaks at ■ 2.48 (doublet), 2.82 (doublet), 3.1 ο (multiplet), 5.12 ( Multiplet) and 9.84 (doublet) & ; IR absorption peaks at 1755, 171o and 1695 cm "¹; ßO ^ -3o ° (methanol).,

C. Optically active tricyclic lactone heptene VIII: Following the procedure of Example 5, the lactonaldehyde is converted into the corresponding optically active lactone heptene VII according to Example 23B, NKR peaks at 0.6-3.0, 4.5-5.2 xmd · 5.7 Sl IR absorption peaks at 17oo cm ".

D. Bicyclic Lactone Diol X:

Following the procedure of Examples 19 to 2fi, the tricyclic lactone heptene according to Example 23C is converted into the corresponding optically active lactone di-oils X ₀ . vind X _ß transferred. "

E. 2ite! Connections:

According to known methods v / ground, these diols in the corresponding 5G-P ₂ (V * ^{"undi 1} 50 ₂₀ PGP transferred -Endprodukte.

. - BAD ORIGINAL

5 O 9 8 U? I O 9 3 5

Following the process of the above steps C, D and E, the optically active isomers of Aldeyhds VI according to Example 15 are converted into PG ^ mixtures. Is obtained PGI ₂ * _(y-15SS and PGFpQ, from the isomer of Example 15B, and ent-pGFP "and corresponds 15B-PGi ¹ O ^{(from the} S ^isomer of Example 15A.

BATH ORIGINAL

5098A2 / 0935

Claims (3)

Patent claims: 1. Oxazolidine from an optically active compound of formula .O or their mirror image and an optically active ephedrine. 2. oxazolidine according to claim 1, wherein the optically active Ephedrine is d-ephedrine. 3. Pxaz01idin according to claim 1, wherein the optically active Ephedrine 1-Ephedrine is * For: The Upjohn Company Kalamazoo, Michigan, V.St.A. Dr.Ii ... T.Wolff Lawyer 5098 ^ 2/093