CH615658A5 - Process for the separation of a racemic mixture of chiral compounds - Google Patents

Description

The present invention relates to a method for separation (referred to in the following description with “PGE2”, “PGF2” etc.) of a racemic mixture of chiral compounds) are usable.

which as intermediates for the presentation of prostaglandins 20

The compounds mentioned have the following formulas

CHO

Mirror plane

0 //

r \

cho

OHC

or

0 !!

H

\

- ~ v / v i-.T

or.

-UH,

Mirror plane

I.

R, 0

RpO

Mirror plane

5

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into which of the formulas

R, and R2 individually alkyl radicals having 1 to 4 carbon atoms or taken together a radical of the formula

PGE3:

.'3

-u-

R.

R

R,

R,

-C-

xR,

represent in which R3, R4, Rs, R6, R7 and Rs are hydrogen atoms, alkyl radicals having 1 to 4 carbon atoms or phenyl, provided that no more than one of the radicals R is phenyl and the total carbon number is 2 to 10 and x the Number 0 or 1, and ^ denotes the binding of the side chain to the cyclopropane ring in exo or endo configuration.

Recently, the preparation of a racemic bicyclic lactone diol of the formula n ~ C5H11

by E.J. Corey et al., J. Am. Chem. Soc. 91, 5675 (1969) and an optically active form thereof [see E.J. Corey et al., J. Am. Chem. Soc. 92, 397 (1970)]. The conversion of this intermediate into PGE2 and PGF2a both in the dl and in the optically active form is known from the above publications.

As is known, the prostaglandins have several centers of asymmetry and are therefore present as stereoisomers [see Nugteren et al., Nature 212, 38 to 39 (1966); Bergstrom et al., Pharmacol. Rev. 20, 1 (1968)]. Each of the formulas for PGE2, PGF2a, PGE3 and PGF3a given here represents a molecule of the optically active, naturally occurring form of prostaglandin.

Known prostaglandins have the following structures:

PGE:

COUH

PGF2o:

COOH

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60

65

! "PGF3

15

OH

JOÖH

See also formulas XVI, XXII, XXIV and XXVI, which are identical to the above formulas if the binding of the hydroxyl group is in a (S) configuration. The mirror image of each of these formulas denotes a molecule of the enantio-morphic form of the respective prostaglandin. For example, “ent-PGE3” refers to the enantiomorph of PGE3. The racemic or dl form of prostaglandin consists of an equal number of the two types of molecules, e.g. B. a prostaglandin with a natural configuration and its enantiomorph. If one of the optically active isomers is clockwise, the other is equally clockwise. A racemic mixture of equal amounts of the 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, e.g. B. different solubility in a solvent. Another name used in this description 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 designation “15/3-PGE3” therefore applies to a product which has a 15 β (R) configuration at the carbon atom instead of the “^ -Configuration of the PGE3.

PGE2, PGF2ct, PGF2 / 3 and PGA2, their esters, acylates and pharmacologically acceptable salts, are extremely effective in eliciting various biological reactions and are therefore suitable for pharmacological purposes, [see e.g. B. Bergstrom et al., Pharmacol., Rev. 20, 1 (1968)] and literature references there. Such biological effects are e.g. B. Systemic lowering of arterial blood pressure by PGE2, PGF2 (3 and PGA2 compounds, measured in rats anesthetized with pentobarbital sodium and treated with PentoHnium, with an introducing cannula in the aorta and right ventricle; blood pressure activity, measured analogously, by PGF2tt -Connections; stimulation of the smooth muscles, demonstrated, for example, on strips of guinea pig ileum, rabbit duodenum or colon of voles; enhancement of other smooth muscle stimulants, the antilipolytic effect, demonstrated by the antagonism of the mobilization of free fatty acids induced by epinephrine or the inhibition of spontaneous glycerin release from isolated rat fat pads; the inhibition of gastric secretion by PGE2 and PGA2 compounds, detected in dogs whose secretion was stimulated by feed or histamine infusion; the effect on the central nervous system, reduction in the adhesion of the Platelets, ed instructed on the adherence of platelets

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Glass, and the inhibition of physical effects, e.g. B. arterial injury, or biochemical exposure, e.g. B. induced by ADP, ATP, serotonin, thrombin and collagen platelet aggregation and thrombosis. PGE2 compounds also promote skin growth and keratinization, as demonstrated by application to segments of embryonic chick and rat skin.

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

For example, the compounds, particularly the PGE2 compounds, can be used in mammals, including humans, to pull the skin out of the nose. For this purpose, the compounds are used in doses of about 10 fxg to about 10 mg per ml of a pharmacologically suitable liquid carrier or as an aerosol spray for topical use.

The PGE2 and PGA2 compounds are also useful in mammals including humans and certain farm animals such as dogs and pigs to reduce and control excessive gastric juice secretion, thereby reducing or avoiding the formation of gastrointestinal ulcers and accelerating the healing of such existing ulcers . For this purpose, the compounds are injected or infused intravenously, subcutaneously or intramuscularly, at an infusion dose of about 0.1 to about 500 fig per kg of body weight per minute, or at a total dose per day by injection or infusion of about 0.1 to about 20 mg per kg body weight, the exact amount depending on the age, weight and condition of the patient, the frequency and type of administration.

The PGE2, PGF2 "and PGF2 / 3 compounds are useful for inhibiting platelet aggregation, reducing platelet adhesion, and eliminating or preventing thrombosis in mammals including humans, rabbits and rats. For example, the compounds are useful for the treatment and prevention of myocardial infarctions, for the treatment and prevention of post-operative thrombosis, for accelerating the opening of vascular grafts after surgery and for the treatment of conditions such as atherosclerosis, arteriosclerosis, blood clotting due to lipemia, and against other clinical disorders Conditions in which the underlying etiology is related to lipoid imbalance or hyperlipidemia. For the purposes mentioned, the connections are systemic, e.g. B. administered intravenously, subcutaneously, intramuscularly and in the form of sterile implants for long-term effect. For rapid uptake, especially in emergency situations, intravenous administration is preferred. Doses of from about 0.005 to about 20 mg per kg of body weight per day are used, the exact amount also depending on the age, weight and condition of the patient and the frequency and type of administration.

The PGE2, PGF2a, and PGF2 / J compounds are also useful as additives to blood, blood products, blood substitutes, and other liquids used for artificial, out-of-body circulation and perfusion of isolated body parts, e.g. B. limbs and organs are used that are still on the donor body, separated from it and preserved or prepared for transplantation or are already on the body of the recipient. During these circulations, aggregated platelets tend to block the blood vessels and parts of the circulation device. These

Blocking is avoided in the presence of the above compounds. For the stated purpose, the compounds are added gradually or in one or more portions to the circulating blood, the donor's blood, the perfused part of the body, the recipient or both or all in a steady total dose of about 0.001 to 10 mg per liter of circulating liquid. The compounds are particularly useful when administered to laboratory animals such as cats, dogs, rabbits, monkeys and rats to develop new methods and techniques for organ and limb transplantation.

The PGE2 compounds are extremely effective smooth muscle simulators, and they are also highly active in enhancing other known smooth muscle stimulators, for example oxytocin agents such as oxytocin and the various ergot alkaloids including their derivatives and analogs. PGE2, for example, is therefore useful in place of, or in combination with, less than the usual amounts of these known stimulators, for example, to relieve the symptoms of paralytic ileus or to combat or prevent atonic uterine bleeding after miscarriage or delivery, or to facilitate placental rejection as well as during the puerperium. For the latter purposes, the PGE2 compound is administered by intravenous infusion immediately after the miscarriage or delivery at a dose of about 0.01 to about 50 µg per kg of body weight per minute until the desired effect is achieved. Subsequent doses are injected intravenously, subcutaneously or intramuscularly or infused during the puerperium in an amount of 0.01 to 2 mg per kg body weight per day, the exact dose depending on the age, weight and condition of the patient.

The PGE2, PGF2 / j and PGA2 compounds are also useful as hypotensive agents for lowering blood pressure in mammals, including humans. For this purpose, administration is by intravenous infusion in an amount of about 0.01 to about 50 µg per kg of body weight per minute or in one or more doses of about 25 to 500 / µg per kg of body weight per day.

The PGE2, PGF2 (, - and PGF2 / 3 compounds are also useful in place of oxytocin to induce labor in pregnant females such as cows, sheep and pigs, and in humans, at or near the time of birth, or in the event of intrauterine death of the fetus from about 20 weeks before the time of birth, for this purpose the compounds are infused intravenously at a dose of 0.01 to 50 g per kg of body weight per minute, or almost until the end of the second stage of labor, ie the expulsion of the fetus. The compounds are particularly useful if the natural contractions have not started one or more weeks after the time of birth, or 12 to 60 hours after the membrane has torn without the natural contractions having started.

The PGE2, PGF2tt and PGF2 (3 compounds are also useful for controlling the conception cycle in ovulating-female mammals such as monkeys, rats, rabbits, dogs, cattle, and the like, and in humans. For this purpose, for example, PGF2a becomes systemic administered in a dose of 0.01 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. The expulsion of an embryo or fetus by similar Administration of the compound caused during the first 3 months of gestation or pregnancy.

Since the PGE2 compounds are effective antagonists of the mobilization of free fatty acids induced by epinephrine, these compounds are used in experiment5

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len medicine useful for in vitro and in vivo studies in mammals including humans associated with abnormal lipoid mobilization and high levels of free fatty acids for understanding, preventing, relieving and curing diseases, e.g. B. Diabetes mellitus, vascular diseases and hyperthyroidism.

The PGE2 compounds promote and accelerate the growth of epidermal cells and keratin in animals, including humans. For this reason, the compounds are used to promote and accelerate the healing of damaged skin, for example in the case of burns, wounds, abrasions and after surgical interventions. The compounds are also useful for promoting and accelerating the growth of skin pieces (auto-grafts), in particular small deep (Davis) inserts, which are intended to cover skin-free areas by subsequent growth to the outside, with a delay in the rejection of one's own skin (homografts).

For the above purposes, the compounds are preferably topically or near the location where cell growth or keratin formation is desired, preferably as an aerosol liquid or finely divided powder spray, as an isotonic solution in the case of moist envelopes or as a lotion, cream or ointment together with conventional ones pharmaceutically acceptable diluents. In some cases, for example in the event of severe fluid loss as a result of extensive burns or for other reasons, this is recommended

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systemic administration, for example by intravenous injection or infusion, alone or in combination with the usual infusion of blood, plasma or blood substitute. Other routes of administration are subcutaneous or intramuscular administration near the site to be treated, oral, sublingual, rectal or vaginal administration. The exact dose depends on the type of administration, age, weight and condition of the patient. For example, an isotonic aqueous solution containing 5 to 1000 g per ml of the PGE2 compound is expediently used in a wet envelope for topical use in second and / or third degree burns with areas of 5 to 25 cm 2. Particularly when used topically, these prostaglandins are expediently used in combination with antibiotics such as gentamycin, neomycin, polymyxin B, bacitracin, spec-tinomycin and oxytetracycline, other antibacterial agents such as mafenide hydrochloride, sulfadiazine, furazolium chloride and nitrofurazone, and with corticoid steroids, e.g. B. hydrocortisone, prednisolone, methylprednisolone and flupredniso-lon used. The latter components are used in the concentration customary when used alone.

The process according to the invention is characterized in that a) the racemic mixture of the corresponding compounds with an optically active ephedrine is converted into a mixture of oxazolidine diastereomers of the formulas or

and and

CHs CH3

and

CHs ch3—

C —ö

r.

OR

OR;

CH <

/

transferred.

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b) at least one corresponding oxazolidine diastereomer is separated from the mixture,

c) this oxazolidine diastereomer hydrolyzes to form the free, optically active isomeric compound and d) the optically active isomeric compound obtained is isolated.

The method according to the invention can be carried out as follows:

In the decomposition of a bicyclic aldehyde of the formula I, the reaction of the aldehyde with an optically active ephedrine, e.g. B. d- or 1-ephedrine or d- or 1-pseudoephedrine, an oxazolidine. Almost equimolar amounts are used in a solvent such as benzene, isopropyl ether or dichloromethane. Although the reaction proceeds smoothly in a wide temperature range of, for example, 10 to 80 ° C., temperatures of 20 to 30 ° C. are preferred in order to keep side reactions low. The reaction with compounds of formula I proceeds rapidly in the course of minutes, after which the solvent is removed, preferably under vacuum. The product consists of the diastereomers of the aldehyde-ephedrine reaction product, i.e. H. the oxazolidines. At least one of the diastereomers is separated in a known manner, for example by crystallization and chromatography. Crystallization is the preferred method. By repeatedly recrystallizing the solid oxazolidine thus obtained from a suitable solvent, e.g. B. isopropyl ether, you get one of the diastereomers in practically pure form. This oxazolidine xo

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is then hydrolyzed in a manner known per se, the aldehyde being released. Silica gel wetted with water is also surprisingly effective, the silica gel being used in a column. Another advantage of the column is that it separates the ephedrine from the aldehyde. The eluted fractions are then evaporated to give the desired decomposed aldehyde of Formula I.

The mother liquor from the recrystallizations contains the optical isomer of opposite configuration. A preferred method for isolating this second diastereomer is, however, that the oxazolidine of the racemic aldehyde is prepared with an ephedrine of opposite configuration and then recrystallized as described above. Hydrolysis and isolation then give the aldehyde of the formula I with the opposite configuration to that described above.

It has been found that this method is generally suitable for the decomposition of aldehydes and ketones, ie not only for the separation of the aldehyde of the formula I, but also for the separation of the lactonaldehyde of the formula VI and the acetalketone of the formula IV.

The new compounds obtainable according to the invention are useful intermediates for the production of prostaglandins, namely the bicyclic aldehyde I in optically active form, the ketone IV and the lactonaldehyde VI.

A preferred embodiment for the preparation of the starting compounds of the process according to the invention is described in scheme A below:

(a)

>

CHO

IX

XXX

"^ -OR,

(e)

CH

OR,

O

CHO

IV

VI

The various implementations can be carried out as follows:

The bicyclic aldehyde of the formula I according to scheme A is available in various isomeric forms. With regard to the binding of the aldehyde group, there are two isomeric forms, namely exo and endo. With regard to the position of the cyclopentene double bond relative to the aldehyde group, the exo and endo forms also provide two optically active (d or 1) forms, which results in a total of 4 isomers. All of these isomers

60 individually or in a mixture undergo the reactions described for the preparation of the prostaglandin intermediates. The non-separated isomers are used to produce racemic products. To produce optically active prostaglandins, the aldehyde or later intermediate products of the process described below are separated and used in the form for the production of optically active products. The preparation of the exo and endo aldehydes is also explained later.

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When stage (a) is carried out, a bicyclic aldehyde I is converted into an acetal of the formula II in a manner known per se. The aldehyde I is either with an alcohol having 1 to 4 carbon atoms, e.g. B. methanol, ethanol, propanol, butanol or their isomers, or a corresponding alcohol mixture or preferably with a glycol of the formula

* 3

HO-C-I

R,

R

C!

R,

I7

-C-OH

I.

Ro x 8

15

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40

in which R3, R4, Rs, R6, R7 and Rg represent hydrogen atoms, alkyl radicals having 1 to 4 carbon atoms or phenyl, provided that no more than one of the radicals R is a phenyl radical and the total number of carbon atoms is 2 to Is 10, and x is the number 0 or 1, implemented. Examples of suitable glycols are: ethylene glycol,

1,2-propanediol, 1,2-hexanediol, 1,3-butanediol, 2,3-pentanediol, 2,4-hexanediol, 3,4-octadiol, 3,5-nonanediol, 2,2-dimethyl-25

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 according to methods known per se under different conditions. For example, the reactants are dissolved in benzene and the mixture is heated to remove the water formed azeotropically. To accelerate the reaction, an acidic catalyst such as p-toluenesulfonic acid, trichloroacetic acid, zinc chloride or the like can be added. Furthermore, the starting materials can be heated to 40 to 100 ° C. together with the acid catalyst and a water scavenger such as trimethyl orthoformate in an inert solvent such as benzene, toluene, chloroform or carbon tetrachloride. 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 step (b), the acetal II is reacted with a ketene of the formula Ri0RnC = C = O, for example with HBrC = C = 0, HC1C = C = 0, Br2C = C = 0 or C12C = C = 0. For reasons of convenience, ketene C12C = C = 0 is preferred. It is conveniently prepared in situ by using a 0.5- to 2.0-fold excess of dichloroacetyl chloride in the presence of a tertiary amine, e.g. B. triethylamine, tributylamine, pyridine or 1,4-diaza-bicyclo- [2,2,2] octane in a solvent such as n-hexane, cyclohexane or mixtures of isomeric hexanes (Skellysolve B) at a temperature of 0 to Treated at 70 ° C (see e.g.

Corey et al., Tetrahedron Letters No. 4, pp. 307 to 310, 1970). The ketene C12C = C = 0 can also be obtained by adding a trichloroacyl halide to zinc dust suspended in a reaction vessel, the tertiary amine being eliminated.

When stage (c) is carried out, the mono- or dihalo-ketone of the formula III is 60 to 60 times

Excess zinc dust reduced over the stoichiometric ratio of Zn: Cl in methanol, ethanol, ethylene glycol or the like in the presence of acetic acid, ammonium chloride, sodium bicarbonate or sodium dihydrogen phosphate. This reduction can also be carried out with aluminum amalgam in a water-containing solvent such as methanol-diethyl ether water, tetrahydrofuran water or dioxane water at about 0 to 50 ° C.

In step (d), the tricyclic acetalketone IV is converted into a lactone in a manner known per se, for example by reaction with hydrogen peroxide, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid or the like, in the presence of a base such as, for. B. an alkali metal hydroxide, bicarbonate or orthophosphate, preferably a molar ratio of oxidizing agent to ketone of 1: 1 is used.

In step (e), the lactone acetal of the formula V is converted into the aldehyde VI by acid hydrolysis in a manner known per se, dilute mineral acids, acetic acid, formic acid or the like being used. Acetone, dioxane, tetrahydrofuran and the like are suitable as solvents. the like

In the following examples, the infrared spectra were measured with a Perkin-Elmer Model 421 spectrophotometer. Unless otherwise specified, undiluted samples were used. The NMR spectra were measured with a Varian A-60 spectrophotometer in deuterochloroform with tetramethylsilane as the internal standard (downfield). The curves of circular dichroism were determined using a Cary 60 spectro-polarimeter.

Chromatography started collecting the eluate fractions as soon as the front of the eluent reached the bottom of the column.

Preparation 1

Endo-bicyclo [3, 1,0] hex-2-en-6-carboxaldehyde (formula I: ^ = endo).

To a vigorously stirred suspension of 318 g of anhydrous sodium carbonate in a solution of 223.5 g of bicyclo [2.2, l] hepta-2,5-diene in 1950 ml of methylene chloride, 117 ml of 25.6% peracetic acid are added Contains 6 g of sodium acetate. The addition time is about 45 minutes, the temperature is 20 to 26 ° C. Then the mixture is stirred for a further 2 hours, then filtered and the filter cake is washed with methylene chloride. The filtrate and washing solutions are concentrated in vacuo. About 81 g of the resulting liquid is stirred with 5 ml of acetic acid in 200 ml of methylene chloride for 5 hours, then is concentrated and distilled. The fraction boiling at 30 mm at 69 to 73 ° C consists of the desired aldehyde of formula I, yield 73 g, NMR peaks at 5.9 and 9.3 (doublet) ó.

The various intermediates of formulas I to VI can be in exo and endo form. A preferred method for producing the exo form of the bicyclic aldehyde of the formula I consists of the steps shown in Scheme G, which use procedures known per se (see South African patent specification 69-4809).

Scheme G

50

55

XXYII

NI /

XXVIII

CoEOH

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V

XXIX

CH20H

XXX

Oi-jO

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In formulas XXVII to XXXVII, the exo configuration is represented by the straight line running downwards at an angle. Diazoacetic acid is added to a double bond of cy-clopentadiene, an exo-endo mixture of bicyclo [3, 1,0] hexene of the formula XXVIII substituted in the 6-position by a carboxyl group being obtained. This mixture is treated with a base, the endo isomer being isomerized to form further exo isomer. Then the carboxyl group in the 6-position is converted into a hydroxyl group, whereupon the exo-aldehyde of the formula XXX is formed.

Preparation 2

dl-Endo-bicyclo [3, 1,0] hex-2-en-6-carboxaldehyde, acetal with ethylene glycol (formula II: Rj and R2 together = -CH2CH2- -, 'v, = endo) (see scheme A) .

A solution of 216 g of endo-bicyclo [3, 1, 0] hex-2-en-6-carboxaldehyde (see preparation 1), 150 g of ethylene glycol and 0.5 g of p-toluenesulfonic acid in 1 1 of benzene is refluxed cooked. The azeotropically distilled water (29 ml after 20 hours) is collected in a Dean-Stark trap.

Then the reaction mixture is cooled, treated with 0.3 g of sodium carbonate and distilled under reduced pressure. The fraction passing at 3 to 4 mm and 55 to 60 ° C is distributed between ether and water. The ether phase is extracted with water, dried over anhydrous magnesium sulfate and concentrated to give the bicyclic acetal of the formula II in the form of a light brown oil, yield 70 g, NMR peaks at 1.1, 1.6 to 2.9, 3 , 5 to 4.2, 4.42 and 5.3 to 6.0 ó.

If the process of preparation 2 is repeated, but using the exo compound of the formula I (XXX), the corresponding exo acetal of the formula II is obtained.

Furthermore, the procedure of preparation 2 using the endo and exo form of the aldehyde of the formula I is obtained, but the ethylene glycol is replaced by 1,2-propanediol, 1,2-hexanediol, 1,3-butanediol, 2,3 -Pentanediol, 2,4-He-xanediol, 3,4-octanediol, 3,5-nonanediol, 2,2-dimethyl-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 corresponding acetals of formula II.

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55

Furthermore, the corresponding acetals of the formula II are obtained by the procedure of preparation 2 using the endo or exo form of the aldehyde I and replacement of the ethylene glycol by methanol, ethanol, 1-propanol or 1-butanol.

Preparation 3

dl-tricyclic dichloro ketone (formula III: Ri and R2 together = -CH2CH2-, -x, = endo) (see scheme A).

A solution of 56 g of the bicyclic acetal II according to Example 1 and 80 g of triethylamine in 300 ml of Skellysolve B is boiled under reflux with stirring, 100 g of dichloroacetyl chloride in Skellysolve B being added dropwise over the course of 3 hours. The mixture is then cooled and solids are filtered off. The filtrate and Skellysolve-B wash solution are washed with water, 5% aqueous sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give the title compound in the form of 91 g of a dark brown oil. Another 13 g are obtained from the filter cake and the aqueous washing solutions. According to a variant, the triethylamine is added to a solution of bicyclic acetal and dichloroacetyl chloride, or the triethylamine and dichloroacetyl chloride are added in separate solutions, but at the same time to a solution of the bicyclic acetal in Skellysolve B.

If the process of preparation 3 is repeated, but using the exo compound of the formula II, the corresponding exo-dichloro ketone of the formula III is obtained. Furthermore, the corresponding derivatives of the formula III are obtained by the process of preparation 3 using the compounds described in connection with example 1.

Preparation 4

dl-tricyclic ketone (formula IV: Ra and R2 = methyl, 'x- = endo).

A solution of 104 g of the dichloro ketone III obtained according to preparation 3 in 1 l of dry methanol is treated with 100 g of ammonium chloride and small portions of zinc dust. The temperature is allowed to rise to 60 ° C. After adding 200 g of zinc, the mixture is refluxed for a further 80 minutes, then cooled, the solids are filtered off and the filtrate is concentrated. The residue is treated with ethylene chloride and 5% aqueous sodium bicarbonate solution and the mixture is filtered. The methylene chloride phase is washed with 5% aqueous sodium bicarbonate solution and with water, dried and concentrated to give the title compound in the form of 56 g of a dark brown oil; Infrared absorption at 1760 cm "1.

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

Furthermore, the corresponding derivatives of the formula IV are obtained by the process of preparation 4, but using the compounds of the formula III mentioned after example 2.

Preparation 5

dl-tricyclic lactone acetal (formula V: R, and R2 = methyl, = endo) and tricyclic lactone aldehyde (formula VI: 60 = endo) (see scheme A).

A solution of 56 g of the product of formula IV obtained according to preparation 4 in 400 ml of methylene chloride is treated with 40 g of potassium bicarbonate and cooled to 10 ° C. A solution of 55 g of 65 m-chloroperbenzoic acid (85%) in 600 ml of methylene chloride is then added over the course of 40 minutes. The mixture is stirred at 10 ° C for 1 hour, then refluxed for 40 minutes. Then it is cooled and filtered, and the filtrate is washed with 5% sodium bicarbo-

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nat solution containing 60 g of sodium thiosulfate per liter and washed with water. The methylene chloride phase is dried over anhydrous sodium sulfate and concentrated to give 61 g of the acetal V. A portion (58 g) is chromatographed on 2 kg of silica gel, which is packed with ethyl acetate-Skel 5 lysolve B (50:50). Elution with 50-50, 70-30 and 80-20 ethyl acetate-Skellysolve B gives a fraction of 24.9 g, which according to the NMR spectrum consists of a mixture of dimethyl acetal V and aldehyde VI. A portion of the mixture (22.6 g) is dissolved in 100 ml of a 60:40-10 formic acid-water mixture and left at 25 ° C. for 1 hour. 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 bicarbonate 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 the form is obtained.

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with VI in crystalline form (9.9 g). An analytically pure sample is obtained by recrystallization from tetrahydrofuran, melting point 72 to 74 ° C. (corr.); IR absorption peaks at 2740, 1755, 1710, 1695, 1195, 1165, 1020, 955 and 910 cm "1; NMR peaks at 1.8 to 3.4, 5.0 to 5.4 and 9.92 ó.

If the process of preparation 5 is repeated, but using exo-lactone acetal IV, the corresponding exo-lactone acetal V is obtained.

Likewise, according to the procedure of preparation 5, when using exo compound V, the corresponding exo-lactonaldehyde VI is obtained.

If the process of preparation 5 is repeated, but using the compounds IV mentioned after preparation 4, the corresponding products of the formula V and the corresponding lactone aldehydes VI are obtained.

A preferred way to prepare the exo form of the tricyclic lactonaldehyde VI is shown in Scheme H.

•>

Scheme H

XXVII

COOR

14

XXXI

0 R.

// / 1 °

Ç-Ç-Âiî

COOIi

14

XXXII

COOK

14

-7

COOK.

14

: cch

-7

XXXIII

XXXIV

XXXV

xxxvi

XXXYll

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In this scheme, R14 represents an alkyl group with 1 to 4 carbon atoms. Diazoacetic ester is attached to a double bond of cyclopentadiene, an exo-endo mixture of the 6-position being substituted by an esterified carboxyl group, e.g. B. a methyl ester group, substituted Bi-cyclo [3, 1, 0] hexene of the formula XXXI. The exo-endo mixture is treated with a base to isomerize the endo isomer to form further exo isomer.

Then the hexene is reacted with C12C = C = 0, which has been prepared in situ from dichloroacetyl chloride and a tertiary amine or from trichloroacetyl chloride and zinc dust, the dichloro ketone of the formula XXXII being obtained. The dichloroketone is then reduced as in step (c) of scheme A. The resulting tricyclic ketone XXXIII is converted to a lactone ester as explained in step (d) of Scheme A, the lactone is saponified, then acidified to give the compound of formula XXXV with a carboxyl group in the 6-position. The carboxyl group is then converted to a hydroxymethyl group and then the exo aldehyde of formula XXXVII is formed.

Preparation 6

dl-Endo-bicyclo [3,1,0] hex-2-en-6-carboxaldehyde, acetal with 2,2-dimethyl-1,3-propanediol (Formula II: Ra and R2 together = -CH2-C (CH3 ) 2-CH2 -, = endo) (see scheme A).

A solution of 48.6 g of endobicyclo [3, 1,0] hex-2-en-6-carboxaldehyde of the formula I, 140.4 g of 2,2-dimethyl-1,3-propanediol and 0, 45 g of oxalic acid in 0.9 l of benzene is boiled under reflux for 4 hours. The azeotropically distilled water is removed by a water separator. The reaction mixture is cooled, then washed with 5% sodium bicarbonate solution and with water. The benzene solution is dried over sodium sulfate, concentrated to an oil (93 g) and distilled under reduced pressure. The fraction boiling at 0.4 mm at 88 to 95 ° C consists of the desired title compound, yield 57.2 g, melting point 53 to 55 ° C, NMR peaks at 0.66.1.2, 3.42, 3 , 93 and 5.6 Ó; IR absorption at 1595, 1110, 1015, 1005, 990, 965, 915 and 745 cm-1.

If the procedure of preparation 6 is repeated, but using exo compound I, the corresponding exo acetal II is obtained.

Preparation 7

dl-Tricyclic dichloro ketone (formula III: Ri and R2 together = -CH2-C (CH3) 2-CH2-and -x- = endo) (see scheme A).

According to the procedure of preparation 3, compound II according to preparation 6 is converted into the title compound from melting point 97 to 100 ° C., NMR peaks at 0.75, 1.24. 2.43 (multiplet), 3.42, 3.68 and 3.96 (doublet) Ó; IR absorption at 3040, 1810, 1115, 1020, 1000, 980, 845 and 740 cm-1.

Preparation 8

dl-tricyclic ketone (formula IV: R] and R2 together = -CH2-C (CH3) 2-CH2—, --v- = endo) (see scheme A).

According to the procedure of preparation 2, dichloroketone III according to preparation 7 is converted into the title compound, which is an oil, NMR peaks at 0.75, 1.25, 3.0 (multiples) and 4.0 (doublets) ó; IR absorption at 1770 cm-1.

Furthermore, the corresponding tricyclic exo-ketone IV is formed by the process of preparations 4 and 8, but using the corresponding exo compound III.

Preparation 9

dl-tricyclic lactone acetal (formula V: R, and R2 together = -CH2-C (CH3) 2-CH2- • -v, = endo) and tricyclic lactone aldehyde (formula VI: '-v, = endo) (see Scheme A).

12 g of the tricyclic ketone IV (preparation 8) and 6.1 g of potassium bicarbonate in 100 ml of methylene chloride are cooled to about 10 ° C. Then 12.3 g of m-chloroperbenzoic acid (85%) are added in portions at such a rate that the reaction temperature remains below 30 ° C. Then the mixture is stirred for 1 hour and treated with 150 ml of 5% aqueous sodium bicarbonate solution containing 9 g of sodium thiosulfate. The methylene chloride layer is dried over sodium sulfate 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) ó; IR absorption at 1760 cm-1.

About 4.4 g of the lactone acetal V in 60 ml of 88% formic acid are left to stand at 50 ° C. for 1 hour. Then the solution is cooled, diluted with 60 ml saturated with sodium chloride in sodium hydroxide solution and extracted with methylene chloride. The combined extracts are washed with 1 sodium carbonate solution above, dried over sodium sulfate and 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 ° C., NMR peaks at 5.2 (multiplet) and 10.0 (doublet) ò \ IR absorption at 1755 cm-1.

If the process of preparation 8 is repeated using the corresponding exo-ketone IV, the corresponding products V and VI are obtained.

example 1

Separation of the endo-bicyclo [3, 1,0] hex-2-en-6-carboxal dehydes (formula I: 'x. = Endo).

A. 12.3 g of endo-bicyclo [3, 1,0] hex-2-en-6-carboxalde-hyd I and 16.5 g of 1-ephedrine are dissolved in about 150 ml of benzene. The benzene is removed in vacuo and the residue is taken up in about 150 ml of isopropyl ether. The solution is filtered and then cooled to -13 ° C, giving 11.1 g of crystalline 2-endo-bicyclo [3, 1,0, hex-2-en-6-yl-3,4-dimethyl-5- phenyl-oxazolidine of melting point 90 to 92 ° C. After three recrystallizations from isopropyl ether, each with cooling to −2 ° C., 2.2 g of the crystalline oxazolidine with a melting point of 100 to 103 ° C. are obtained, which, as can be seen from the NMR spectrum,

is essentially in a single isomeric form.

1.0 g of the recrystallized oxazolidine is dissolved in a little ml of methylene chloride, the solution is applied to a 20 g silica gel column and eluted with dichloromethane. Silica gel is used for chromatography (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 fractions containing the desired compound according to the thin layer chromatogram are combined and evaporated to give 360 mg of an oil. According to the NMR spectrum, this consists of the desired compound I, the endo-bicyclo [3, 1,0, hex-2-ene-6-carboxaldehyde, which is practically free of ephedrine and essentially in the form of a single optically active one Isomer is present. The points on the circular dichroism curve are at /. in nm, 0: 350, O; 322.4, -4 854; 312, -5 683; 302.5, -4 854; 269, O; 250, 2 368; 240, O; and 210, -34 600.

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

C. A preferred method for producing the isomeric oxazolidine, which gives the aldehyde with reverse optical rotation as the isomer mentioned, is carried out as follows: According to method A, the racemic aldehyde is reacted with d-ephedrine, whereby the oxazolidine in the

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receives diastereomeric forms. Upon recrystallization, the desired oxazolidine is then obtained, which provides the desired optically active aldehyde by hydrolysis.

According to the procedure of Example 1, the exo-bicyclo- [3, 1,0] hex-2-en-6-carboxaldehyde I is converted into the oxazolidine with d- or 1-ephedrine and broken down into the optically active isomers.

Example 2

Separation of the acetal ketone (formula IV: R, and R2 together = -CH2C (CH3) 2-CH2 -, ^ = endo).

A. A solution of 2.35 g of the acetal ketone IV according to preparation 8 (preparation of the acetal with 2,2-dimethyl-1,3-propanediol) and 1.65 g of 1-ephedrine in 15 ml of benzene is followed Add a drop of acetic acid to reflux for about 5 1/2 hours, removing the water with a Dean-Stark trap. The benzene is then evaporated, leaving the oxazolidine as a solid which is dissolved in methanol. When the methanol solution is cooled, one of the diastereomeric oxazolidines is obtained in a yield of 1.57 g, melting point 161 to 166 ° C., [a] D25-7.5 ° (chloroform). The product consists essentially of a single isomeric form, as evidenced by the NMR spectrum; NMR peaks at 0.63 (doublet), 0.72, 1.23, 2.38, 3.52, 3.95 (doublet) and 4.94 (doublet) ò.

According to the procedure of Example 1, the above crystalline oxazolidine is converted into the optically active isomer on a silica gel column. The yield is 0.56 g, melting point 43 to 47 ° C, [a] D25 + 83 ° (chloroform). This compound is referred to as the "isomer according to Example 14a".

B. The mother liquors of A are concentrated and cooled to -13 ° C., the other diastereomeric oxazolidine being obtained in a yield of 1.25 g, melting point 118 to 130 ° C., [a] D25 + 11.7 ° (chloroform) , NMR peaks at 0.63 (doublet), 0.72, 1.23, 2.38, 3.52, 3.99 (doublet) and 5.00 (doublet) ó. This compound is referred to as the "isomer according to Example 14B". According to the procedure of Example 13, the crystallized oxazolidine is converted on a silica gel column into an optically active isomer of the compound IV.

C. The reaction of the isomer according to Example 2B with d-ephedrine according to the instructions in Example 2A gives the enantiomorph of the oxazolidine according to Example 14A with a melting point of 165 ° C., [a] D2S + 7.5 ° (chloroform).

Following the procedure of Example 1, the crystallized oxazolidine is converted on a silica gel column into an optically active isomer of the compound IV, which is identical to the product according to Example 2B.

615 658

According to the procedure of Example 2, the exo form of the acetalketone IV according to preparation 8 is converted into the oxazolidine with d- or 1-ephedrine and broken down into the optically active isomers.

The oxazolidines separated in the above manner are hydrolyzed by contact with water, preferably in the presence of an acid catalyst, in a manner known per se to give oxo compound and ephedrine (see Elderfeld, Heterocyclic Compounds, Vol. 5, p. 394, Wiley, N.Y., 1957). For example, the oxazolidine from 1-ephedrine and the acetal ketone IV (Example 2A, 5.0 g) is stirred in a solution of 25 ml of tetrahydrofuran, 25 ml of water and 5 ml of acetic acid at about 25 ° C. under nitrogen. The solvents are removed under 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 concentrated under reduced pressure, giving the optically active acetalketone IV, which has the same properties as the product according to Part A. Another method for the hydrolysis of the oxazolidine consists in using a column with silica gel and water according to Example 13, from which the oxo compound is eluted and isolated in a conventional manner.

Example 3

Separation of the tricyclic lactonaldehyde (formula VI: -x, = endo).

A. A solution of 0.5 g of the endo-lactonaldehyde VI according to preparation 5 and 0.5 g of 1-ephedrine in 20 ml of benzene is concentrated to dryness in vacuo. The residue is treated with diethyl ether, whereby crystals are obtained from an oxazoli-din mixture. When the mixture is recrystallized from methanol, an oxazolidine of melting point 133.5 to 134.5 ° C. is obtained. The hydrolysis of the oxazolidine on silica gel according to the procedure of Example 13 gives an optically active isomer which corresponds to the mirror image of the formula VI; this product is worked up in a conventional manner and is subsequently referred to as the "isomer according to Example 3".

B. Using the method of Example 3, replacing the 1-ephedrine with d-ephedrine, the optically active isomer of lactonaldehyde VI is prepared, which is referred to below as "isomer according to Example 3B".

The exo-lactone aldehyde VI is broken down into the optically active isomers by the process of Example 3.

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Claims (10)

615 658 1 XK3 represent in which R3, R4, Rä, R6, R7 and Rs are hydrogen atoms, alkyl radicals having 1 to 4 carbon atoms or phenyl, provided that no more than one of the radicals R is phenyl and the total carbon number is 2 to 10 and x the number is 0 or 1, and <- \. denotes the binding of the aldehyde group or acetal group to the cyclopropane ring in the exo or endo configuration, characterized in that a) the racemic mixture of the corresponding verbin-55 is fertilized with an optically active ephedrine in a mixture of oxazolidine diastereomers of the formulas and V-N y \ CH < CHi 1 R "" 6 1 y 1 r _ I. 2. The method according to claim 1, characterized in that the racemic mixture of optically active chiral aldehydes of the forms / "X / CHO OHC Mirror level exists, in which the binding of the aldehyde group to the cyclopropane ring denotes in exo or endo configuration. CH OK. •OK, 2nd PATENT CLAIMS 1. Process for the separation of a racemic mixture of chiral compounds of the formulas v ~ v / CHO Mirror plane OMC Mirror plane or V / '// -S »/ / "S OR. "^ UrL, RjO RpO Mirror level in what formulas R) and R2 individual alkyl radicals having 1 to 4 carbon atoms or taken together a radical of the formula • K. ■ R I5 | ' 3. The method according to claim 1, characterized in that the racemic mixture of optically active, 35 chiral aldehydes of the formulas 45 CHO OHC Mirror level consists in which the binding of the aldehyde group to the Cy-50 clopropane ring denotes in exo or endo configuration. 4. The method according to claim 1, characterized in that the racemic mixture of optically active, chiral ketones of the formulas Mirror plane 615 658 3rd 615 658 transferred. b) at least one corresponding oxazolidine diastereomer is separated from the mixture, c) this oxazolidine diastereomer hydrolyzed to form the free, optically active, isomeric compound and d) the optically active, isomeric compound thus obtained isolated. 4th exists, wherein Ri and R2 have the meaning given in claim 1 and denotes the binding of the acetal group to the cyclopropane ring in exo or endo configuration. 5. The method according to claim 4, characterized in that Ri and R2 together form the radical -CH2-C (CH3) 2-CH2—. 6. The method according to claim 1, characterized in that the racemic mixture is reacted with d-ephedrine. 7. The method according to claim 1, characterized in that the racemic mixture is reacted with 1-ephedrine. 8. The method according to claim 1, characterized in that the separation is carried out by fractional crystallization from isopropyl ether. 9. The method according to claim 1, characterized in that the separation is carried out by fractional crystallization from methanol. 10. The method according to claim 1, characterized in that the hydrolysis with water and an acid ka 10 talysator or with water in the presence of silica gel.