DE2702807A1 - PROCESS FOR THE PRODUCTION OF RACEMIC OR OPTICALLY ACTIVE 5BETA-HALOGEN-2BETA-HYDROXYMETHYL-CYCLOPENTAN-3ALPHA-HYDROXY-1 ALPHA-ACETIC ACID (1 'ARROW TO RIGHT 3) DELTA-LACTONE - Google Patents

Description

50 725 - BR

Applicant; Carlo Erba SpΑ., Via Carlo Imbonati 1-20159 Milan / Italy

Process for the preparation of racemic or optically active 5ß-halo-2ß-hydroxymethyl-cyclopentane-3ahydroxy-1a-acetic acid (1 ¹ - * 3) 6 -lactone

The invention relates to a process for the preparation of racemic or optically active 5ß-halo-2ß-hydroxymethyl-cyclopentane-3a-hydroxy-1a-acetic acid (1'-► 3) <S - ~ lactone of the general formula

(I)

where X is chlorine or bromine,

and a method for the optical splitting of a diacetal a racemic 6-halobicyclo [2.2.1] heptan-3-one-7-carboxylic acid the general formula

HOO

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in which X has the meanings given above and Z is a radical of the formula _{v /} 0K

^{/ N} OH
in which R and R ¹ , which can be the same or different from one another, each represent a C ^ -Cg -alkyl group or together a radical of the formula - ( ^σ Η ₂ ) _η - »where η is the number 2, 3 or

4 represents, or a radical of the formula / _CH )

² ™ i

mean, in which m ^ j is the number _{1, 2 or 3 and m 2 is} the number O, 1, 2 or 3 and X has the meanings given above.

Both of the above compounds are valuable intermediates for the synthesis of natural prostaglandins or enantio-prostaglandins.

It is known that the bicyclic Corey lactone 2ß-hydroxymethyl-cyclopentane-3a, 5a-dihydroxy-1a-acetic acid (1 '- ^ 5) -. Y-lactone (see EJ Corey et al, "J. Am Chem. Soc. ", 92 , 397» 1970) and its enantiomer on a large scale for the synthesis of natural prostaglandins and synthetic ones

Prostaglandin analogs used and the high degree of their Suitability for further synthetic developments shows that it would be very desirable to develop new synthetic methods for economic Manufacture of the same to be found.

Recently, JS Bindra et al in "J. Am . Chem. Soc", 95 »7522 (1973), and R. Peel and JK Sutherland in" J. Chem. Soc. Chem. Commun. ", 15I (197 ^ 0 »published a new attempt to prepare the bicyclic intermediate (formula B) from bicyclic [2.2.1] hept-2,5-diene (formula A), in which

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R a general acyl means:

(A)

^CH 2 ^OH

This attempt is indeed interesting in terms of: the already known Corey process because it involves fewer "chemical steps, different reagents, and cheaper Reagents and Other Reaction Conditions Applied »The above procedure has however, with respect to the preparation of the important intermediate 5ß-halo-2ß-hydroxymethyl- 'cyclopentane-3a-hydroxy-1a-acetic acid (i' -> 3) <^ -lactone, from which the authors given above the compound of the formula (B) have serious drawbacks.

The method described in the publications cited above; drive to the production of 5ß-halo-2ß-hydroxymethyl-cyclopentane-3 <x-hydroxy-1a-acetic acid (1 '-> 3) «S -lactone consists of a Prins reaction with paraformaldehyde and formic acid with norbornadiene (A) below Formation of a tricyclic diformate (C), which is then oxidized to the tricyclic keto acid (D), which after splitting with L - (-) - cx-methylbenzylamine with boiling aqueous hydrochloric acid is converted into chloric acid (E), which in turn oxidized after the Baeyer-Villiger reaction to the 5-lactone (F) and then to the primary alcohol (I), ie the 5ß-halo-2ß-hydroxymethyl-cyclopentane-3a-hydroxy-1a-acetic acid (1 ' - > 3) 6 "-lactone, is reduced by reduction with ethanolic NaBH ^ or with ZnBH ^ in tetrahydrofuran of the mixed

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hydrids (G), which has been produced from the acid (F) by successive treatment with ethyl chlorocarbonate and triethylamine.

HCOOH

-OH

HOOC

(D)

'Splitting up

X = Cl, Br,

ItO-CO-O-CO

(G)

(I)

In the same series of reactions, treatment of (D) with HBr / acetic acid gives the corresponding bromo derivative of (E) which, when subjected to the remainder of the series of reactions, yields (I) which contains bromine in place of chlorine.

This synthetic scheme has clear advantages over the other known methods, mainly because of the

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easily accessible starting materials and the low Cost of the reagents used. Nevertheless, a critical examination shows that the splitting into the optical antipodes of the Cyclopropyl ketone (D) with a stated yield of about 75% after 2 or 3 recrystallizations in particular then when they are done on a very large scale does not give the same yield, and the extremely expensive base L - (-) - a-methylbenzamine used in the cleavage is a synthetic product, which during its synthesis is also split into the optical antipodes must become.

Attempts to split the chloric acid (E) and the analogous bromine derivative into the optical antipodes have quickly shown that the process does not work because of the considerable predisposition of (E) to regenerate the cyclopropyl ketone (D) when treated with a base.

The lability of the halogen, which in the presence of bases gives the corresponding cyclopropyl derivatives, a characteristic of all intermediates from (E) to (I), is another negative aspect of this synthesis scheme. In addition, in the conversion of (E) into (F) by Baeyer-Villiger oxidation with a peracid, a major disadvantage is the fact that at least 1 mole of peracid per mole of (E) is required for the conversion to produce the S -lactonic acid ( P), so that in the final purification process the compound must be removed from the peracid by at least one acid equivalent. This process can be facilitated by using the very expensive m-chloroperbenzoic acid, but there is a problem of manufacturing cost which must be solved.

Finally, the reduction of the carboxylic acid (F) makes for production of the corresponding primary alcohol (I), although the yields are good, difficult to purify them

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Connection of the anhydride or the starting acid required, which is not possible chemically because of the tendency of 6-lactone alcohol to be treated with a Base to be split hydrolytically, or because of the tendency of the unreacted δ-lactone halocarboxylic acid, to be converted by a base into the cyclopropane derivative with the consequent decrease in the overall yield of the procedure.

It has now been, and this is an aim of the present invention, found a new process for the preparation of the compound of the formula (I) given above, which is free from those given above Disadvantages and has notable advantages over the method described above, in particular the following:

1.) the yields in each stage are practically quantitative and they are on average about 90 to about 95 % and only in the worst case they are about 8 to about 80 % \ in all stages the unreacted starting material can easily be recovered and this increases the yields to 100 % ;

2.) The reaction times are very short, as they usually never exceed 2 hours, and they are around 15 to about 3 minutes;

3.) The end products can be separated off and purified without difficulty, in particular crystalline compounds are obtained or easily crystallizable compounds and you get no undesirable by-products due to the special reaction conditions used.

These features of the new method forming the subject of the invention allow it to be used on an industrial scale

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AO

Production. The new process according to the invention comprises the following stages:

a) acetalization of a compound of the general formula

Y ^

wherein X is chlorine or bromine and Y is a carboxy group or a functional derivative thereof,

with formation of a compound of the general formula

(III)

in which X and Y have the meanings given above and Z is a radical of the formula ^OR

in which R and R ¹ , which can be the same or different from one another, are each a C 1 -C 4 -alkyl group or together a radical of the formula - (CHp) -, in which η is the number 2, 3 or 4
represents, or a radical of the formula - (CH-) -CH-

¹ CHX- (CH ₀ ) -H

mean in which m ^ the number _{1, 2 or 3 and m o} the number O, 1, 2 or 3, and X has the meanings given above;

b) reduction of the compound of the formula (III) to form a compound of the general formula

HOH ₂ C

709

(IV)

wherein X and Z have the meanings given above;

c) Ent.acetalisierung the compound of formula (IV) under Formation of a compound of the general formula

HOH ₂ C

CV)

0
wherein X has the meanings given above; and

d) oxidation of the compound of formula (V) according to Baeyer-Villiger to form the compound of Formula (I).

All of the compounds of the formulas (II) to (V) given above can be either racemic or optically active compounds be. When it comes to optically active compounds, it can either be nat derivatives, i.e. those _ those for the production of prostaglandins of the natural series are suitable, or to ent-derivatives, i.e. those that are used for the production of prostaglandins of the Enantio series, i.e., 8,12-diiso-prostaglandins, are suitable. Functional derivatives of the compounds of the formulas (II) and (III) can, for example, be the esters, the anhydrides or the mixed anhydrides; they can be made by conventional methods. In connection with the above Formulas (III) and (IV), Z preferably represents a group of the formula

S \

0 0

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The acetalization reaction of the compound of formula (II) is carried out using the conventional ones in organic chemistry Procedure carried out. For example, the compound of formula (II) with a mono- or dihydroxy alcohol in The presence of catalytic amounts of an acid and an organic solvent, for example benzene, reacted will. The acid can be either a Lewis acid or an organic acid such as p-toluenesulfonic acid, or an inorganic acid such as anhydrous hydrohalic acid such as HCl but it can also be an ion exchange resin in the acid form, "such as a styrylsulfonic acid resin.

The solvent used in the reaction is preferably an inert solvent, e.g. as indicated above Benzene, and one which allows the water formed to be removed as an azeotrope.

The acetalization reaction can also be carried out by implementing the * Compound of the formula (II) with a mono- or dihydroxy alcohol and with an orthoester of a lower aliphatic Alcohol, such as methyl or ethyl orthoformate, performed , the lower aliphatic alcohol formed being distilled off. In this case too, the reaction will be preferably carried out in the presence of catalytic amounts of an acid such as one of the acids indicated above. In addition, the acetalization reaction can be carried out by reacting the compound of the formula (II) with a mono- or dihydroxy alcohol and with the dialkyl acetal of a ketone of the formula? i-OR-j

wherein the radicals R ^, Rg, Rz and R ^, which are the same or from each other can be different, each represent a C ^ -Cg -alkyl group, in the presence of catalytic amounts of an acid,

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e.g. one of the acids indicated above, the formed lower aliphatic ^ alcohol is distilled off. In the reactions in which the orthoester of a lower aliphatic Alcohol or the dialkyl acetal of a ketone is used with the formula given above, they also function as a solvent, even if there are other solvents such as aromatic hydrocarbons, e.g. benzene and toluene, or linear ethers, such as ethyl ether or isopropyl ether, or cyclic ethers such as tetrahydrofuran or dioxane can be added.

If the acetalization is carried out with the monohydroxy alcohol, there must be at least 2 moles of alcohol per half of the compound the formula (ΙΓ) can be used, while if it is carried out with a dihydroxy alcohol, e.g. ethylene glycol, at least 1 mole of alcohol per mole of the compound of formula (II) is sufficient. The acetalization reaction is carried out at a temperature performed, preferably within the range of. From room temperature to the boiling point of the solvents used; the response times vary from about 15 to ' 30 minutes to about 2 hours. As indicated above, catalytic amounts of an acid are used, e.g., about 0.05 to about 0.5 »preferably 0.05 to 0.1 mol of acid per MbI of Compound of formula (II).

The reduction of the compound of the formula (III) is also carried out by conventional methods. For example, if a mixed anhydride is reduced which has been prepared, for example, by treating the compound of the formula (III) with an alkyl chlorocarbonate, such as ethyl chlorocarbonate, in the presence of a base, such as triethylamine or sodium bicarbonate, the reaction is carried out using hydrides such as sodium borohydride, LiAlH ^ or tetrabutylammonium borohydride, in halogenated solvents such as CH2Cl2 and

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CHCl3, or in ethereal solvents such as tetrahydrofuran, or in alcoholic solvents such as ethanol. The reduction can also be carried out with the acid by treatment, for example, with LiAlH ^ in an inert ethereal solvent such as tetrahydrofuran or dimethoxyethane, or with borane in an inert ethereal solvent such as tetrahydrofuran or dimethoxyethane

The compound of the formula (IV) can either be isolated or can be used directly for the subsequent deacetalization reaction. In particular, it is not necessary that the To isolate compound of formula (IV) if the solvents used in the reduction reaction are also used for the deacetalization reaction are suitable, e.g. when the solvents are water-miscible, such as tetrahydrofuran and dimethoxyethane.

The deacetalization reaction is preferably carried out in an acidic medium, i.e. in the presence of organic acids, such as Acetic acid, oxalic acid, p-toluenesulfonic acid, benzenesulfonic acid, or

. inorganic acids, such as hydrochloric acid or sulfuric acid, or an ion exchange resin in the acid form, e.g., a styryl sulfonic acid resin, and in aqueous organic Solvents such as ketones, e.g. acetone, lower aliphatic alcohols, e.g. ethanol and methanol, or in with water-miscible solvents such as tetrahydrofuran and dimethoxyethane carried out.

The temperature and the reaction times can be within the range from room temperature to the reflux temperature vary from about 15 minutes to about 2 hours.

The acetalization or the reduction or the deacetalization are carried out in an acidic medium, which means that the

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Avoided formation of undesirable cyclopropane derivatives.

The oxidation reaction according to Baeyer-Villiger is carried out under conditions carried out as they are usually used for this type of reaction, using a peracid, "which is preferably monoperphthalic acid acts, in an organic solvent such as ethyl acetate, in the presence of at least one equivalent of one inorganic base, such as an alkali bicarbonate, e.g. sodium or potassium bicarbonate, per mole of peracid.

• The use of monoperphthalic acid is advantageous in that than the phthalic acid obtained at the end of the oxidation reaction in organic solvents such as ethyl acetate, which are used in the oxidation reaction, is insoluble and the addition of a base such as sodium or potassium bicarbonate to the reaction mixture causes the precipitate of all phthalic acid in the form of the insoluble alkali phthalate permitted. In fact, even if a base such as an alkali metal is used during the oxidation reaction tall bicarbonate, the formation of undesirable cyclopropane derivatives is avoided, since the alkali metal bicarbonate is insoluble in the solvents used, such as ethyl acetate, which are practically anhydrous.

The addition of the alkali metal bicarbonate to the reaction mixture results in precipitation of all of the acid obtained in the reduction of the peracid, as well as all of the unreacted peracid, in the form of insoluble alkali metal salts. By treating the organic phase containing the final product with a buffer such as & B. 20% NaH2P0 _/ p gives a solution that is completely free of bases, which avoids the formation of the undesired cyclopropane derivatives.

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In addition, it has been found, and this is a further object of the present invention, that when the compound of formula (III) wherein Y is carboxy is in the racemic form, it can be used at low cost and in high yields (about 70 to about 80 %) can be split into the optical antipodes by treatment with ephedrine, the pure optically active salt of the compound of the formula (III), in which Y is carboxy, being obtained with ephedrine, from which the pure optical antipode is obtained by conventional methods can be.

When 1-ephedrine is used it is used for manufacturing optical antipode suitable for natural prostaglandins in the form of a salt with 1-ephedrine, while then, if d-ephedrine is used, the optical enantio-antipode suitable for the production of the enfc prostaglandins in Is obtained in the form of a salt with d-ephedrine "

The conversion of the compound of formula (III) wherein Y ' Carboxy means with ephedrine (1-ephedrine or d-ephedrine) in a salt is preferably carried out by treatment a solution or a suspension of the compound of the formula (III), in which Y is carboxy, in an organic solvent, such as benzene, acetone, acetonitrile, with a solution of ephedrine (1-ephedrine or d-ephedrine) in an organic Solvents such as benzene, acetone, acetonitrile, the optically pure salt of ephedrine crystallizing out directly.

The pure optically active compound of the formula (III), in which Y is carboxy, can be obtained from the ephedrine salt, for example by acidifying the aqueous solution of the salt to a pH value of about 3 to 4 or by making it alkaline the aqueous solution of the salt with a stronger base

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as ephedrine, such as sodium or potassium hydroxide, and subsequent removal of the ephedrine by extraction with an organic solvent such as benzene, Ethyl acetate or ethyl ether, and by subsequent acidification of the remaining aqueous solution to form the pure optically active compound of formula (III) in which Y is carboxy which precipitates or with an organic Solvent, such as ethyl acetate, chloroform or benzene, is extracted, in the latter case the pure optical active compound of formula (III) in which Y is carboxy, by evaporating the organic phase to dryness is obtained.

The invention is illustrated in more detail by the following examples, without, however, being restricted thereto.

example 1

To a suspension of 169.3 g of dl-syn-ö-exo-chloro ^ -carboxy-bicyclo [2.2.1] heptan-3-one in 1.7 l of benzene, 57 g of ethylene glycol and 1.7 g of p-toluenesulfonic acid were added. the The mixture was refluxed for 2 1/2 hours, the water formed during the reaction (about 17 ml) by azeotropic distillation in a Marcusson apparatus was removed. The reaction was stopped by adding 1.2 ml of pyridine and the mixture was brought to room temperature cooled down.

The crystalline precipitate (188.74 g) was filtered off. The benzene layer was washed with a saturated ammonium sulfate solution washed, evaporated to dryness and the residue was crystallized in CI ^ ClVAceton, whereby one another 17.51 g of product, mp 160-162 ° C, was obtained; the total yield was 206.25 g (99%) dl-syn-6-exo-chlorine-

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7-carboxy-bicyclo [2.2.1] heptan-3-one-3,3-ethylene dioxide. Example 2

A mixture of 110g dl-syn-ö-exo-chloro - ^ - carboxy-bicyclo [2.2.1] heptan-3-one, 70 ml of ethylene glycol and 195 ml of triethyl orthoformate was in the presence of 2.15 g of p-toluenesulfonic acid for 1 hour heated to 90 ^° C. for a long time and to 120 ^° C. for 2 hours, the ethanol formed being distilled off. The reaction was stopped by adding 1.8 ml of dry pyridine and the mixture was cooled to 0-5 ° C. The precipitated crystalline product was filtered off and 110.2 g of dl-syn-e-exo-chlorine - ^ - carboxy-bicyclo- [2.2.1] heptan-3-one-3,3-ethylene dioxide, mp 162 bis 165 ° C.

The piltrate was diluted with benzene, washed with water and evaporated to dryness in vacuo. After crystallization in CH ₂ Cl ₂ ZAcCtOn, the residue gave a further 14.1 g

Product, m.p. 160 to 162 ° C, so that the overall yield was 91.66 % .

Example 3

To a stirred suspension of 18.5 g of dl-syn-6-exo-chloro-7-carboxy-bicyc Io [2.2.1] hept an_3-on-3 «3-ät hy le ndi oxide in 150 ml of dichloromethane, the had been cooled to -15 ° C., 8.3 ml of ethyl chlorocarbonate were added in succession and then a solution of 12.1 ml of triethylamine in 30 ml of dry dichloromethane was added dropwise. Stirring was continued for 30 minutes to give a solution of the acid and a precipitate from the triethylamine hydrochloride. The mixture was then warmed to 0-5 ° C. with a solution of 12.5 S sodium borohydride in 200 ml of ethanol for 1 hour at this temperature and then for 2 hours

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treated at room temperature. After careful addition of 12 ml of water to decompose the excess borohydride, most of the solvent became in vacuo evaporated. The remaining aqueous alcoholic solution was with 30 ml of 2 η NaOH for 30 minutes at the reflux temperature treated, cooled and extracted repeatedly with dichloromethane.

After acidifying the aqueous alkaline extract and then filtering off the precipitate, 2.9 6 of the starting material dl-syn-ö-exo-chloro ^ -carboxybicyclo [2.2.1] heptan-3-one-3,3-ethylene dioxide, F. 159 to 161 ^° C. After evaporation of the dichloromethane, 14.4 g of dl-syn-δ-exo-chlorine - ^ - hydroxymethylbicyclo [2.2.i] heptan-3-one-3 were obtained , 3-ethylene dioxide, P. 50 to 52 ⁰ C (from isopropyl ether), in a yield of 99 % _t based on the converted starting material.

A solution of 14.4 g of the reduced compound in 100 ml Acetone was added for 3 hours at the reflux temperature. 40 ml of 4 η sulfuric acid treated. The acetone was evaporated, the aqueous phase was saturated with ammonium sulfate and extracted with dichloromethane, 11.7 g of crude dl-syn-6-exo-chloro-7-hydroxymethyl-bicyclo [2.2.1] heptan-5-one being obtained received. After crystallization from isopropyl ether, 10.8 g were obtained of the pure dl compound, m.p. 76 to 78 ° C, in one yield as a crystalline product of 92%, based on the converted Source material.

Example 4

865 ml of a 1 M borane solution in tetrahydrofuran was cautiously to a stirred solution of 193.06 g (0.83 M) dl-syn-6-exo-chloro-7-carboxy-bicyclo [2.2.1] heptan-3-one-3,3-ethylene dioxide in 765 ml of tetrahydrofuran at 0 to 5 ° C

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had been cooled, added. After 1 hour the reaction mixture was warmed to skin temperature and left to stand for 3 hours, then the excess reagent was decomposed by adding 190 ml of water and 400 ml of 4 η sulfuric acid. The mixture was refluxed for 2 hours and the tetrahydrofuran was distilled off. The aqueous phase was cooled and extracted with dichloromethane. The combined organic phases were washed with ammonium sulfate until neutral, dried and concentrated to a small volume (40 to 50 ml) and then diluted with 100 to 140 ml of isopropyl ether. After 2 hours cooling at 0 ⁰ C was a crystalline product that g dl-syn-e-exo-chloro-y-hydroxymethyl-bicyclo [2.2.1] heptan-3-one after filtration 120.73, F 80 to 83 ° C. Concentration of the aqueous mother liquors gave a further 15.28 g of product, mp 79 to 80 ° C., corresponding to a total yield of 133.01 g or 92%.

Example 5

A solution of 207 g of monoperphthalic acid in 1.5 l of ethyl acetate became a solution of 132.42 g of dl-syn-6-exo-chloro-7-hydroxymethyl-bicyclo [2.2.1] heptan-3-one in 0.6 l of ethyl acetate, which had been cooled to 0 to 5 ° C., was added. While stirring 67 g of sodium bicarbonate were added to the mixture, which after warming to room temperature, the mixture was stirred for 6 hours before 67 g of sodium bicarbonate were then added became.

Stirring was continued for 2 hours, then the precipitate was removed by filtration and washed with ethyl acetate. The combined filtrates were mixed with 80 ml of a 30% strength aqueous NaH ₂ PO ^ solution, with 80 ml of a 10% strength aqueous Na ₂ S0 solution (which had been buffered to pH 7 with a NaH ^ PO ^ solution ) and then one with 80 ml

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Washed solution and _{dried over Na 3} SO ^. After evaporation of the solvent in vacuo, 143 »2 g of crude 6-lactone were obtained, which after crystallization in isopropyl ether 126.2 g (yield 88 %) of dl-5β-chloro-2β-hydroxymethylcyclopentane-3a-hydroxy-1a-acetic acid (1 ¹ -> 3) α-lactone, m.p. 93 to 95 ° C.

Example 6

A 1.5 M borane solution was added over a period of 30 minutes in 432 ml of tetrahydrofuran to a stirred solution from 115 »94 g (-) - syn-6-exo-chloro-7-carboxy-bicyclo [2.2.1] -

heptan-3-one-3,3-ethylene dioxide in dry tetrahydrofuran which had been cooled to 0-2 ° C. was added. The mixture was allowed to warm to room temperature and then stirred for 3 hours. The excess reagent was decomposed by carefully adding 580 ml of an aqueous 2η NaOH solution and the tetrahydrofuran was distilled off in vacuo. The remaining aqueous phase was extracted repeatedly with dichloromethane. The organic extracts were combined with one another, washed until neutral, dried and evaporated to dryness, giving 106 g of (-) syn-6-exo-chloro-7-hydroxymethyl_bicycIo [2.2.1] heptan-3-one-3,3 -äthylendioxid (yield 97.3%), mp 68 to 7O ⁰ C (from isopropyl ether), Ca] _D = -3.8 (MeOHJ, [a] _D = -12.5 ° (CHCl ₃₎ received.

When the aqueous alkaline phase was acidified, no appreciable amount of the starting material was obtained.

Example 7

To a solution of 18.5 g of (-) syn-6-exo-chloro-7-carboxybicyclo [2.2.1] heptan-3-one-3,3-ethylene dioxide in 120 ml of dichloromethane, which has been cooled to ^{0 ° C} was, were admitted one after the other:

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1.) a solution of 12.1 ml of triethylamine in 10 ml of dichloromethane and 2.) then a solution over a period of 10 minutes of 8.3 ml of ethyl chlorocarbonate in 30 ml of dichloromethane.

The mixed anhydride formation was complete within 20 minutes from the time the last reagent was added. The mixed anhydride solution v / urde then over a period of 20 minutes (5 ml / min, within the first 10 minutes and then 15 ml / min.) To a suspension of 13 g of sodium borohydride in 90 ml of ethanol, which to about -5 to O ⁰ C had been cooled, added. The mixture was stirred for 2 1/2 hours at ⁰ ° C. and then the excess NaBH ^ was destroyed by adding 20 ml of 7 / water and the reaction mixture was evaporated to dryness. 80 ml of 2η NaOH were added and the mixture was heated to 60 to 65 ° C. for 30 minutes. After extracting with 300 ml of methylene chloride (3 × 100 ml) and washing the extract with water until neutral and evaporating to dryness, 15-64 g of (-) syn-6-exo-chloro-7-hydroxymethylbicyclo [ 2.2.1] heptan-3-one-3,3-äthylendioxid, Cal _D = -3.7 ° (MeOH), [a] _D = -12.4 ° (CHCl _5), mp 67-68 ⁰ C (from isopropyl ether).

After acidification and extraction, the aqueous alkaline phase gave 0.7 S of the starting material (-) syn-6-exo-chlorine 7-carboxy-bicyclo [2.2.1] hept an-3-one-3,3-ethylene dioxide, see above that the overall yield of the process was 93 % .

Example 8

A solution of 103 g of (-) syn-6-exo-chloro-7-hydroxymethylbicyclo [2.2.1] heptan-3-one-3,3-ethylene dioxide in 0.4 l of acetone was treated with 0.2 l of an aqueous 4 η sulfuric acid for 2 hours at the reflux temperature. The biggest part the solvent was evaporated in vacuo and after

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Addition of 40 g of (NH ^^ SO ^ the aqueous phase was extracted with llethylene chloride. The organic extracts were combined, washed until neutral, dried over sodium sulfate and evaporated to dryness, giving 81.89 g of crude (-) syn-6 -exo-chloro-7-hydroxymethyl-bicyclo [2.2.1] heptan-3-one, Ca] _D - + 36 ° (MeOH), was obtained, which was crystallized in ethyl ether / isopropyl ether, 76 g of the pure compound, P. 77 to 79 ° C, CaD ₁ J = + 39.2 ° (MeOH), Ca] _D = + 37.4 ° (CHCl ₃ ).

Example 9

0.51 l of a 0.95 M borane solution in tetrahydrofuran was added to a stirred solution of 87.18 g of (-) syn-6-exo-chloro-7-carboxy-bicyclo [2.2.1] heptan-3-one-3 , 3-Ethylene dioxide (0.374 mol) in 350 ml of tetrahydrofuran, which had been cooled to 0 to 5 ° C., was added, the addition initially having to be carried out carefully because of the evolution of gas. Stirring was continued for 4 hours at room temperature, then the excess reagent was destroyed by adding 87 ml of water and 180 ml of aqueous 4 HgSO ^. The mixture was refluxed for 2 hours, most of the tetrahydrofuran was evaporated in vacuo and the aqueous phase was extracted with dichloromethane. The combined organic extracts were washed to neutrality with a 20% ammonium sulfate solution, dried over sodium sulfate and evaporated to dryness, 65.6 g of crude product being obtained. After crystallization in isopropyl ether, 61.5 g of pure (+) syn-6-exo-chloro-7-hydroxymethyl-bicyclo [2.2.1] heptan-3-one, melting point 79 to 81 ^° C., [alp = +] were obtained 37.5 ° (chloroform, C = 1 %) (theoretical 65.2 g, yield 94.5%).

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Example 10

With vigorous stirring, a solution of 12D, 5 6 monoperphthalic acid in 0.74-1 ethyl ether was added to a suspension of 36.5 g of anhydrous NaHCO ₅ in a solution of 72.4-2 g of (+) syn-6-exo-chlorine- 7-hydroxymethyl-bicyclo [2.2.1] heptan-3-one in 1.09 l of dry dichloromethane was added, the temperature of the reaction mixture being kept ^{at about 20 ° C. with external cooling.} After 5 hours an additional 36.8 g of anhydrous NaHCO _{5 was} added and stirring was continued for an additional 2 hours. The precipitate was filtered off, washed with 50 ml of dichloromethane and 50 ml of dry ethyl acetate. The filtrates were combined, washed with 3 x 20 ml of a 10% Na ^ CO, solution and 3 x 4-0 ml of a 10% solution of monobasic phosphate, dried over NapSO ^ and evaporated to dryness, whereby 78 g of crude 6-lactone was obtained in 96.5 % yield. After crystallization in methylene chloride, 65 6 pure (-) 5β-chloro-2β-hydroxymethyl-cyclopentane-3a ~ - hydroxy-1a-acetic acid (1'- »3) S-lactone, mp 127 to 129 ° C, . [oc] _D = -63 ° (CHCl ₅ ). After concentrating the mother liquors, a further 5.23 g of product were obtained, melting point 124 ° to 127 ° C., CaDp = -62 ° (CHCl ₅ ).

Example 11

0.23 l of a 0.95 M borane solution in tetrahydrofuran were converted into a solution of 4-0.3 β (+) enant-syn-δ-exo-chloro-carboxybicyclo [2.2.1] heptan-3-one-3 , 3-ethylene dioxide, Ca] _D = +11 ⁰ C (MeOH, C = 1 %) ^ in 0.1 l of tetrahydrofuran, which had been cooled to 0 to 5 ⁰ C, was added. After 1 hour the reaction mixture was warmed to room temperature. After 3 hours the excess reagent was destroyed with 20 ml of water. Most of the solvent was evaporated off in vacuo, the aqueous phase was treated with 70 ml of 4-η NaOH and

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is

extracted with dichloromethane. The combined organic extracts were washed to neutrality, dried over ^ 280 ^, evaporated to dryness, giving 36.90 g of (+) enant -syn-ö-exo-chloro ^ -hydroxymethyl-bicyclo [2.2.1] - heptan-3-one-3,3-äthylendioxid, [oc] _D = + 12 ° (CHCl _5), mp 61 to 62 ⁰ C, obtained. A solution of this product in 140 ml of acetone was treated with 70 ml of 4 η sulfuric acid for 2 hours at the reflux temperature. After the usual work-up, 27.41 g of (-) enant. -Syn-ö-exo-chloro -? - hydroxymethyl-bicyclo [2.2.1] heptan-3-one, ^{mp 77 to 78 0} C ₁ [odjj = -37.5 ° (chloroform).

A solution of 22.24 g of this product in 310 ml of methylene chloride was treated at room temperature with stirring with 28.7 g of 85% strength n-chloroperbenzoic acid in the presence of 14.1 g of anhydrous NaHCO 3. After 2 hours the precipitate was filtered off and washed repeatedly on the filter with dichloromethane. The filtrates were combined, washed with 3 × 5 ml of a 10% strength Na ₂ CO 2 solution and then dried over sodium sulfate. After evaporation of the solvent, 24.1 g of crude product were obtained which, after crystallization in isopropyl ether, 21.2 g of pure 5α-chloro-2a-hydroxymethylcyclopentane-3β-hydroxy-1β-acetic acid (1'- > 3) 8- lactone, M.p. 121 to 124 ⁰ C, [a] _D = + 62 ° (chloroform).

Example 12

A mixture of 23.3 g of dl-syn-e-exo-bromine ^ -carboxy-bicyclo- [2.2.1] heptan-3-one (M.p. 179 to 181 ° C), 0.25 l dry benzene, 6.3 ml dry ethylene glycol and 180 mg p-toluenesulfonic acid was heated at reflux temperature while azeotropically removing the water formed during the reaction. After 2 1/2 hours, the reaction was stopped by adding 0.4 ml of pyridine. After cooling, 25.48 g crystallized dl-syn-6-exo-bromo-7-carboxy-bicycloC 2.2.1] hept an-3-one-3,3-

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ethylene dioxide, m.p. 154 to 155 ° C, and it was through Filter collected.

Example 15

A solution of 27.6 g of dl-syn-e-exo-bromine ^ -carboxy-bicyclo- [2.2.1] heptan-3-one-3,3-ethylene dioxide in 1OC jnl dry tetrahydrofuran was at ⁰ ° C. with 105 ml of a 1 M borane solution in tetrahydrofuran, left to stand for 4 hours at room temperature, then the excess reagent was destroyed by adding 20 ml of water and 40 ml of 4 η sulfuric acid. The mixture was refluxed for 3 hours during which time most of the tetrahydrofuran was distilled off, the residue was cooled, and the inorganic material which precipitated was removed by filtration. The aqueous piltrate was extracted with dichloromethane, 20.2 g of dl-syn-e-exo-bromo-hydroxymethylbicyclo [2.2.1] heptan-3-one being obtained.

A stirred solution of this compound in 200 ml of methylene chloride, which ^{had been cooled to 0} ° C., was treated first with a solution of 25.11% monoperphthalic acid in 180 ml of ethyl ether and then with 7.8 g of sodium bicarbonate. Stirring was continued for 3 hours at room temperature, then an additional 3.9 g of sodium bicarbonate was added and the mixture was stirred for an additional 2 hours. The precipitate was removed by filtration, washed with ethyl acetate and the combined filtrates were washed with 3 x 10 ml of a 5% Na ^ CO, solution and with 3 x 15 ml of a saturated NaHoPO ^, solution, dried and evaporated to dryness . After crystallization in isopropyl ether, 19.8 g of dl-5ß-bromo-2ß-hydroxymethyl-cyclopentane-3a-hydroxy-1 <x ^{-acetic acid (1 1} -> 5) ^ -lactone were obtained.

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2707807

Example 14

The products according to the invention were examined for purity using gas chromatographic methods and these tests showed that the individual products had a purity of at least 98%. The products were chromatographed in the form of the silyl derivatives and these were prepared by treating 5 large of each intermediate product (or a volume of solution equivalent to 5 mg) with 1 ml of CHCl by 0.2 ml of bistrimethylsilylacetamide. After 20 minutes at 50 ° C. on a water bath, 1 ml proportions were measured in a Fractovap ^ gas chromatograph, model GI, with a 2 m long glass column (diameter 3 mm) and a stationary phase of 3% OV 225 with gas chromium P (particle size 0.15 to 0.125 mm (100 to 120 mesh)), washed with an acid and silanylated. The transport _{gas was N 2} at a flow rate of 37 ml / min and the auxiliary gases were hydrogen at 40 ml / min and air at 250 ml / min. The detector had a temperature of 260 ⁰ C and the Rekorrder had a recording velocity of 0.64 cm (0.25 inches) / min. on. The following characteristics were obtained:

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- dfir-

link Column temp.
⁰ C Retention time
(Min.) syn-6-exo-chlorine -7-carboxy-
bicyclo Γ2.2.1J heptan-3-one 190 10.39 syn-6-exo-chlorine -7-carboxy-
bicyclo [p. 2. i] heptan-3-one -
-313-ethylene-dioxide 190 13.56 syn-6-exo-chloro ^ 7-hydroxy-
methj'l-bicyclo | 2.2.1 ~ 1 heptan-
-3-on -3 _t 3-ethylene-dio; cid \ 190
j 180 6.15
8.28 8yn-6-exo-chlorine -7-hydroxy-
methyl-Mcyclo А2.2. ί \ heptan-
-3-on I 180
J 200 6.93
3.90 5? -Chlor - 2ß-hydroxynethyl-
-cyclopentane-3ΰ ^ - ^ 0 ■ droxy-1c | -
acetic acid- (1'- > 3) <i-lactone 200 December 18

Similar characteristics were found for the analogous bromine derivatives.

Example 1 ^

A mixture of 189 g (1 mol) of dl-syn-6-exo-chloro-7-carboxy-bicyclo [2.2.1] heptan-3-one, 63 ml of dry ethylene glycol and 2.5 1 of dry benzene was in the presence of I *? ² S P-toluenesulfonic acid heated to reflux temperature, the water formed during the reaction (18 ml)

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27Π2807

was removed. At this point (after 1 hour) a solution of 167 g of 1-ephedrine in 2 liters of dry benzene was added to the reaction mixture, which was cooled to 25-30 ° C, and allowed to crystallize. The crystalline product was filtered off, 151 g of nat-syn-6-exo-chloro-7-carboxy-bicycIo [2.2.1] heptan-3-one-3,3-ethylenedioxy-1-ephedrine salt, P. 170 bis 172 ⁰ C, Ca3 _D = -33.05 °, -97 ° (MeOH, C = 1%).

Example 16

A solution of 10Og dl-syn-ö-exo-chloro ^ -carboxy-bicyclo- [2.2.1] heptan-3-one-3,3-ethylene dioxide in 4.5 1 acetonitrile was mixed with 70.8 g 1- Treated Ephedrine. After 4 hours, the crystalline precipitate was filtered off, 62.3 g of nat-syn-6-exo-chloro-7-carboxy-bicyclo [2.2.1] hept an-2-one-3,3-ethylene dioxide-1- ephedrine salt, mp 174- 173 ⁰ C, [ou _D = -33.5 °, Ca] ₃₆₅ = -97.8 ° (MeOH, C = 1%), obtained.

39.7 g of this salt were dissolved in 50 ml of water and treated with 4.2 g of sodium hydroxide. The solution was extracted with benzene to remove the ephedrine. The organic extract was backwashed with 3 5 ml of 1 η NaOH and with 3 χ 5 ml of water. The aqueous phases were then combined with one another, acidified to pH 4 and extracted with ethyl acetate. After evaporation of the solvent, 22.1 g of (-) syn-6-exo-chloro-7-carboxy ~ bicyclo [2.2.1] hept were obtained an-3-one-3,3-ethylenedioxiu, mp 128 to 129.2 ° C, [oc] _D = -10.2 °, -19.6 ° (MeOH, C = 1%).

If 2.33 g of this compound by treatment with 4 ml of an aqueous 4 η sulfuric acid and 20 nl acetone for a Decetalized for a period of 1 hour at reflux temperature and by customary work-up, were obtained

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2709807

1.75 6 pure (+) syn-6-exo-Cblor-7-carboxy-bicyclo [2.2.1] -heptan-3-one, P. 157 to 158 ⁰ C, [a] _D = + 14 °, Ca] ₅₆₅ = + 200 ° (MeOH).

Example 17

A solution of 23.3 g of dl-syn-6-exo-chloro-7-carboxy-bicyclo- [2.2.1] heptan-3-one-3,3-ethylene dioxide and 16.5 g of d-ephedrine in 400 ml Benzene was allowed to cool down ^{to 20 ° C.} The crystalline precipitate was filtered off and 14.72 g of enant -syn-ö-exo-chlorine - ^ - carboxy-bicycloC ^^. I] -heptan-3-one-3,3-ethylenedioxide-d-ephedrine salt, F. 17I "to 172 ⁰ C, [a] _D = + 33.2 ° (MeOH, C = 1 %) .

Example 18

A solution of 100 g of dl-Tsyn-G-exo-chlorine - ^ - carboxy-bicyclo- [2.2.1] heptan-3-one-3,3-ethylene dioxide in 5 l of dry acetonitrile was treated with 70 »8 g of dry d-ephedrine and after 3 hours the crystalline precipitate was filtered off, leaving 69.8 g of a salt with a rotating power of + 32.8 ° (MeOH). After recrystallization of this compound from acetonitrile (1.75 liters), 59.4 g of pure was obtained

enant-syn-6-exo-chloro-7-carboxy-bicyc Io [2.2.1] heptan-3-one-3,3-ethylenedioxide-d-ephedrine salt, P. 174 to 174.5 ° C [a] _D = + 34.1 °, Ca] ₃₆₅ = + 100.75 ° (MeOH).

4 g of this compound was dissolved in water, there were 0.44 g of sodium hydroxide was added and the mixture was extracted with ethyl ether to remove the d-ephedrine. the Ether extracts were backwashed with 2 χ 3 ml 1 η NaOH and the combined aqueous phases were, after acidification to pH 4.8, extracted with ethyl acetate. These organic extracts were dried and evaporated to dryness, whereby one

709831/0975

2.21 g of enant-syn-6-exo-chloro-7-carboxy-bicyclo [2.2.1] -heptan-3-one-3,3-ethylene dioxide, P. 124 to 126 ° C, [<x] _D = + 11 ° (MeOH).

After decatalization, 1.71 g of enant-syn-6-exo-chloro-7-carboxy-bicyclo [2.2.1] heptan-3-one, P. 156 to 157 ° C., Ca] _n = -1 ^ , 5 ° (MeOH).

709831 / 097S

Claims (5)

50 725 - DR applicant; Carlo .Erba S.p.A., Via Carlo Imbonati 24, 1-201-59 Milan / Italy 2702807 claims 1. Process for the preparation of racemic or optically active 5ß-halo-2ß-hydroxymethyl-cyclopentane-3a-hydroxy-1a-acetic acid (1'- > 3) c-lactone of the general formula HOH ₂ C ^^ H wherein X is chlorine or bromine, characterized in that one a) a compound of the general formula (H) where X is chlorine or bromine and Y is a carboxy group or a functional derivative thereof, acetalized to form a compound of the general formula (III) wherein X and Y have the meanings given above and Z 709831/0975 INSPECTEO represents a remainder OR X OR in which R and R ¹ , which can be the same or different from one another, each represent a C 1 -C 4 -alkyl group or together a radical of the formula _{- (CH 0} ) -, in which η is the number 2, 3 or 4, or one Radical of the formula _ (cH) - CH -. 2 V, CKX- (CH ₂ J _n -H mean in which m ,, the number 1, 2 or 3 and m _o the number 0, 1, 2 or 3, and X has the meanings given above; b) the compound of the formula (III) is reduced to form a compound of the general formula H
\ (IV) wherein X and Z have the meanings given above; c) the compound of the formula (IV) is deacetalized to form a compound of the general formula HOH ₂ C (V) wherein X has the meanings given above; and d) the compound of formula (V) is oxidized according to Baeyer-Villiger to form the compound of formula (I) given above. 709831/0976 2. The method according to claim 1, characterized in that it is for all compounds of formulas (I) to (V) are racemic or optically active compounds. 3. Process for the optical resolution of a racemic compound of the general formula wherein X is chlorine or bromine and Z is a radical of the formula ^s oa denote in which R and R ¹ , which can be the same or different from one another, each represent a Cj-Cg-alkyl group or together a radical of the formula - (CHp) _n -, in which η denotes the number 2, 3 or 4, or a radical the formula . (CH ₂ ) approx. ¹ CHX- (CH J - H 2, where m ^ is the number 1, 2 or 3 and m _{2 is} the number O, 1, 2 or 3, and X has the meanings given above, characterized in that the above-mentioned racemic compound is converted into a salt with ephedrine and according to conventional methods Process from the ephedrine salt then wins the pure optical antipode. 4-, method according to claim 3 »characterized in that one uses 1-ephedrine. 5. The method according to claim 3, characterized in that d-ephedrine is used. 709831/0975