CH617176A5 - Process for the preparation of new cyclopentanone derivatives - Google Patents

Abstract

Compounds of formula I are prepared by ozonolysis and reduction in the presence of alcohols of a compound of formula II. This compound II can be obtained from a compound of formula III' which, in its turn, can be obtained from a tropolone of formula V'. The meaning of the various symbols is given in Claim 1. The compounds of formula I are useful as synthetic intermediates in the preparation of prostaglandins. <IMAGE> <IMAGE> <IMAGE> <IMAGE>

Description

The present invention relates to the preparation of new chemical compounds useful in particular as synthesis intermediates in the preparation of known or new prostaglandins.

Prostaglandins constitute a large family of substances which can be identified by the variety of their biological actions in mammals and in particular in humans.

Although these compounds have been extracted from many tissues, organs or body fluids of mammals, the amounts thus extracted remain very small, except for the methyl ester of prostaglandin A2 extracted from Plexaura homomalla corals. Thus A.J. Weinheimer et al. ["Tetrahedron Letters", 5183 (1969)] reported that the corals of the family Plexaura homomalla, found in the Caribbean Sea, contain large quantities of prostaglandins of the family PGA2 whose C-15 hydroxyl has the configuration absolute (R). W.P. Schneider et al. [“J. Amer. Chem. Soc. ”, 94, 2122 (1972)], and A. Prince et al. ["Prosta-

5

10

15

20

25

30

35

40

45

50

55

60

65

617,176

4

glandins ”, 3,531 (1973)] reported that certain forms of Plexaura homomalla contain prostaglandins A2 whose absolute configuration of the C-15 hydroxyl is (S), that is to say identical to that of the prostaglandins present in mammals.

Recent research has therefore aimed to achieve a chemical synthesis of prostaglandins which would produce these compounds in sufficient quantity to be marketable in good conditions. [See for example: "Tetrahedron Letters", 2093 (1967); "J. Bitter. Chem. Soc. ”, 90, 3245 (1968); 91, 5364 (1969); 91.5675 (1969); 92, 2586 (1970); 93.1489 (1971); 93, 5594 (1971); 94.4342, 4343 (1972); 95.1676 (1973); 95, 6853 (1973); 96, 6764 (1974); 97,857, 865 (1975).]

However, the total syntheses proposed in the prior techniques require a large number of synthesis stages (of the order of 20 to 25 stages). It is therefore understandable that, even with good partial yields, the overall yield of these syntheses remains very low: thus, overall yields are commonly obtained much less than 1%.

It is therefore interesting to propose a synthesis of prostaglandins which requires a small number of steps (of the order of ten) because, regardless of the improvement in overall yield that can be expected, this leads to a saving of time in the synthesis which constitutes a considerable advantage from the industrial point of view.

The present invention therefore provides a process for the preparation of new compounds intended in particular to serve as a basis for the synthesis of prostaglandins in the context of a fairly rapid process which, by its flexibility, also makes it possible to prepare new prostaglandins in excellent conditions.

It may be useful to remember that prostaglandins belong to a group of fatty acids with 20 carbon atoms having a bond between the carbons in position 8 and in position 12, thus forming a cyclopentane radical having two contiguous aliphatic chains variously unsaturated.

The numbering of prostaglandins derives from the skeleton of prostanic acid which has the following structure:

COOH

The following journals define natural prostaglandins and discuss their main activities: U.S. von Euler and R. Eliasson (ed.), "Prostaglandins", Academic Press, London 30 (1967); S. Bergström, "Recent Progress in Hormone Research", 22.153 (1966); "Science", 157.382 (1967); P. Ramwell and J.E. Shaw (ed.), "Prostaglandin", "Ann. N.Y. Acad. Sci. ”, 180, pp. 1-568 (1971); P.W. Ramwell (ed.), "The Prostaglandins", Plenum Press, London (1973). 35

In what follows and in accordance with the practice, the substituents at a will be indicated by dotted connections, that is to say the substituents situated behind the plane defined by the cyclopentane ring and by A the connections corresponding to β substituents, i.e., substituents located in front of the plane of the cyclopentane ring. The links in sinuous lines (-) indicate that the substituent can be in position a or ß; as for the links in solid lines, they in no way presume the position of the substituent which is attached thereto. The dotted lines represent a possible double bond. 45

The present invention relates more particularly to a process for the preparation of acetals derived from cyclopentan-2-one carboxylic acid of formula I:

O r, 0

Ra he

(i)

phatic, or taken together an unsubstituted or substituted alkylene or alkenylene radical;

R7 represents a hydrogen or halogen atom, an aliphatic radical, a substituted or unsubstituted aryl, cycloaliphatic radical, a terpene radical, a substituted silyl radical or a metal cation,

which is characterized in that the ozonolysis of a compound of formula II is carried out:

(II)

in which

Ri, R'i, R2i R'2> R3, R4 and Rg independently represent a hydrogen atom, a halogen atom, a radical of aliphatic nature, a free or protected hydroxymethyl radical or a cyano radical;

R'2 can also be an aryl, cycloaliphatic radical or a free or protected hydroxy radical;

R't and R'2 taken together can represent a double bond or a substituted or unsubstituted alkylene or alkenylene radical;

R5 and R6 separately represent a radical of ali character

in which Rt, R'j, R2, R'2, R3, R4, R7 and Rg have the meanings given above and the ozonide is reduced in the presence of sulfur dioxide and at least one alcohol fixing the radicals R5 and R6 by acetalization.

By radical of an aliphatic character is meant a radical whose carbon atom ensuring the bond is not part of a cycle. Among these radicals, mention should be made very particularly of aliphatic radicals: alkyl, alkenyl, alkynyl radicals, araliphatic radicals, in particular aralkyl radicals and (cycloaliphatic) aliphatic radicals, in particular (cycloalkyl) alkyl and (cycloalkenyl) alkyl radicals .

Among the alkyl radicals which have been mentioned above, mention should be made very particularly of lower, normal or branched alkyl radicals having less than 10 carbon atoms and, preferably, less than 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or terbutyl.

Likewise, the alkenyl radicals are preferably lower, normal or branched alkenyl radicals, mono- or diunsaturated having from 2 to 10 carbon atoms, but preferably from 2 to 4 carbon atoms, such as the vinyl radical.

5

617,176

The alkyl or alkenyl radicals can also be substituted by halogen atoms and are, for example, mono-, di- or trifluoromethyl or mono-, di- or trichloromethyl radicals, or else these radicals can be substituted by various functions such as hydroxy, ketone, etc.

Among the aryl radicals, particular mention must be made of monocyclic radicals, such as the phenyl radical and the phenyl radicals substituted by halogen atoms or hydroxy or alkyl groups.

The aralkyl radicals are preferably groups having in their arylated or alkylated portion the characteristics mentioned above for the alkyl and aryl radicals such as the benzyl radical.

The cycloalkyl and cycloalkenyl radicals preferably contain from 3 to 6 members, such as the cyclobutyl, cyclo-pentyl or cyclohexyl groups and are preferably the cyclopropyl or cyclopropylidene radical.

These cycloaliphatic radicals can be substituted by aliphatic radicals or be carried by alkylene or alkenylene carbon chains described below.

The cycloalkylalkyl radicals are preferably formed in their cyclic part, as has been said previously for the cycloalkyl radicals, and in their alkyl part, as has been said for the alkyl radicals.

The alkylene or alkenylene chains preferably contain between 2 and 5 carbon atoms such as the ethylene, propylene, butylene, ethenylene, propenylene or but-2-enylene chains. These chains can be substituted by alkyl radicals or can be bridged by unsubstituted or variously substituted alkylene or alkenylene chains.

The terpene radicals are preferably menthyl, bornyl or isobornyl radicals attached to any carbon atom of the radical.

Among the silyl radicals, mention should be made very particularly of the trimethylsilyl radical. The metal cations in question are more particularly cations originating from alkali or alkaline-earth metals such as sodium, potassium or calcium.

The hydroxy functions can be protected by any of the known methods, in particular by esterification or etherification, the esterification preferably taking place with carboxylic acids such as alkanecarboxylic acids.

The halogens which may be present as substituents are fluorine, bromine, chlorine and iodine, but are preferably chlorine.

The compounds of formula I which are particularly interesting are the compounds of formula la:

0

COOR.

(the)

55

variously substituted, which are intermediates more particularly usable in the synthesis of prostaglandins of the E series and of the F series.

The compounds of formulas Ib and the:

(Ib)

.COOR

(the)

variously substituted, are also interesting compounds, because they are intermediaries in the synthesis of prostaglandins of the A series.

The ozonolysis is preferably carried out in the presence of ozone at low temperature in a solvent to prepare the ozonide, then reduction of the ozonide in a solvent in the presence of sulfur dioxide [see for example: R. De Master, "Diss. Abst. Int. B. ”, 31, 5871 (1971)].

The solvent used in the step for preparing the ozonide is preferably a mixture of methylene chloride methanol and the reaction is carried out at -77 ° C (for example in a dry ice / acetone mixture). The reduction of the ozonide is carried out for example by adding liquid sulfur dioxide and a polar solvent to the solution obtained previously. This polar solvent can in particular be an alcohol or a mixture of alcohol such as methanol, ethanol or glycol. The use of sulfur dioxide with a boiling point of -10 ° C requires operating at a low temperature of the order of - 20 ° C. The sulfur dioxide used preferably is anhydride double sulfurized sulfur. Sulfur dioxide plays the role of ozonide reducer and catalyzes the formation of acetal.

The compound of formula II is preferably prepared by one of the following methods:

a) From a compound of formula III:

35 O

(III)

in which R7 has the meaning given for formula I, by selective reduction of the 3-position double bond of 3,6-bicyclo- [3,2,0] -heptadien-2-one, in particular using hydrogen in the presence of a selective catalyst, such as platinum; a compound of formula lia is thus obtained, in which R't and R'2 represent a hydrogen atom:

0

HE . OR7

./ I (Ha)

and H,

in which R7 has the meaning given for formula I.

b) From a compound of formula III given above by epoxidation of the double bond in position 3 [see A. Guzman et al., “Prostaglandins”, 8, 85 (1974)], followed by a reduction in the epoxy bond to obtain a compound IIb of formula:

0Rr

(IIb)

HO '

617,176

in which R7 has the meaning given for formula I, the hydroxy radical being able to be protected by any of the known methods, such as esterification. The epoxidation is preferably carried out in the presence of hydrogen peroxide in an alkaline medium, in a solvent such as methanol, when cold at a temperature of the order of -15 to -20 ° C; the reduction of the epoxide is carried out selectively, for example using aluminum amalgam in a polar aprotic solvent, such as dimethylformamide, under an inert atmosphere, for example under argon. The hydroxy function thus obtained is fixed in position a for steric reasons.

c) From the compound of formula III, by the action of a conjugated diene compound to form, for example, a compound of formula Ile

GOLD,

in which R 7 has the meaning given for formula I. In fact, the double bond in position 3 of compound III is activated by the presence of the keto group at a and thus constitutes a dienophilic compound on which cycloadditions 1,4 of type Diels and Help; these reactions, which are well known, can be carried out in an alcoholic solvent under mild conditions. In particular, dimethylfulvene can be reacted as a diene compound; the compound thus obtained is particularly advantageous, because it protects the double bond in position 3 of the cyclo-pentanone, which can be reconstituted at the end of the synthesis by a reaction of retro type Diels and Help by treatment in the diglyme, benzene , toluene or tetrahydrofuran at around 150-190 ° C [see A. Ichihara et al, "Tetrahedron Letters", 4231 (1974)].

d) From the compound of formula III, by addition reactions on the double bond of the Michael 1,4 addition type, for example to fix alkyl radicals on the double bond by the action of alkylithium, dipolar additions 1 , 3 or photochemical additions, such as that described by B. Graser-Reid et al. [“Tetrahedron Letters”, 297 (1975)], which make it possible to introduce substituents on either side of the double bond and lead to prostaglandins substituted at 10 and 11.

e) From the compound of formula III, by alkylation or halogenation of the positions located on either side of the ketone function by known methods.

The same reaction sequences can be used on compounds of formula III 'already having substitutions:

GOLD,

R

R

R

in formula III ', Rlf R2, R3, R4, R5, R6, R7 and Rg have the meanings given in formula I.

These compounds III and III ′ can be prepared by methods which will be described below.

Some of the compounds of formulas III and III ′ are already known and have already been prepared [see for example: W.G. Dauben et ai,

"J. Bitter. Chem. Soc. ”, 85.2616 (1963); K.F. Koch, "Adv. Alicycl. Chem. ”, 257 (1967)].

They are preferably prepared by treatment of a derivative

of a-tropolone of formula V:

GOLD,

by irradiation.

The irradiation is preferably carried out in a solvent such as methanol at a temperature close to 0 ° C., the irradiation being provided by a Hanau TQ150 high pressure ultraviolet lamp. In order to ensure a practically quantitative yield, it is essential to monitor the temperature and to use double-distilled methanol, the concentration of product V must also be between 10 and 40 mM / 1.

Tropolones of formula V are known or can be prepared, for example, by adding cyclopentadiene to dichloroketene [H.C. Stevens et al, "J. Bitter. Chem. Soc. ”, 87.5257 (1965); L. Ghosez et al, "Tetrahedron Letters", 135 (1966)], which leads to a bicyclic compound of formula VI:

Cl

Cl

This compound is transformed into a-tropolone by the Stevens method (see previous reference).

Then the a-tropolone obtained from formula Va:

0

OH

(Go)

is etherified or esterified by conventional methods. For example, a-tropolone can be methylated by the action of diazomethane in methyl ether [J.W. Cook et al, "J. Chem. Soc. ”, 503 (1951); W.E. Doering et al, “J. Bitter. Chem. Soc. ”, 73, 828 (1951)].

The terpene ethers of a-tropolone have the advantage of leading to products resolved from the start of the synthesis; this is the case for ethers of menthyl, borneol, isobornéol, for example. As for the ethers in which R7 represents a halomethyl or trimethylsilyl radical, these have the advantage that they are more labile and will lead to compounds I which are advantageous for the synthesis of prostaglangins.

Substituted tropolones of formula V ′ are also known.

0

GOLD,

2

6

5

10

15

20

25

30

35

40

45

50

55

60

65

7

617,176

in which the different substituents of the tropolone have the meanings given in formula I and are in particular alkyl groups, halogen atoms or hydroxy-methyl or cyano radicals (see the references cited above), or these are prepared by methods analogous to those described for the compounds of formula V using substituted compounds. These compounds will lead to compounds of formula I substituted, by the same reaction sequences as those described above.

A reaction scheme for the preparation of compounds I can be illustrated as follows:

or alternatively from compound III

Q

617,176

In these formulas, the substituents have the meanings given starting from substituted compounds Va or V and one obtains for for formula I, of course, the reaction sequence is the same compounds I having substituents R 1, R 2, R 3, R * and Rg different from hydrogen.

The products of formula I make it possible to prepare prostaglandins substituted in various ways, in particular by the following reaction sequence:

Q

OOpRr ^

+ Hal [0H2] 6C02Alk (i)

0

CH2 [cH2] 5co2A1k li CH2 [cHg] ^ CC> 2Alk

GH,

C5H11

he

0

0 0 /

° / CH2 [CH2] 5C02Alk 'CH2 [CK2] 5CC2Alk

(XII)

CH2 [CH9] 5C02H

OH

i

9

617,176

In these formulas, R5, Rö and R7 have the meanings given for formula I, Hai represents a halogen atom and Alk an alkyl radical.

In this reaction scheme, for the sake of simplification, unsubstituted cyclopentane rings have been shown; of course, the reaction sequences are the same starting from compounds of formula I having the substituents Rj, R'j, R2, R'2, R3, R4 and Rg.

In order to simplify the nomenclature, the carbon atoms of the pentane rings will be numbered, as indicated for prostanic acid.

The compound of formula I is transformed into diester VII by an alkylation followed by the addition of a halide corresponding to the chain of aliphatic character which it is desired to fix in position 8 of the prostaglandin. In the present case, in order to prepare a natural prostaglandin, the fixed compound is the ethyl ester of heptyl-iodide-7.

The alkylation in position 8 of compound VII is carried out in the presence of potassium hydride in anhydrous dimethyl sulfoxide [D.M. Pond et al, "J. Org. Chem. ", 32.4064 (1967); C.A. Brown, "J. Org. Chem. ”, 39, 3913 (1974)], then adding the preceding ethyl ester prepared for example from tetrahydropyran [M.E. Synerholm, "J. Bitter. Chem. Soc. ”, 69.2581 (1947); D.E. Ames et al, “J. Chem. Soc. ”, 174 (1950)].

The diester VII thus obtained is decarboxylated to obtain the; compound VIII by treatment with potassium cyanide in the triamide of hexamethylphosphoric acid (HMPT)

[P. Müller et al, "Tetrahedron Letters", 3565 (1973)].

Acetal VIII is transformed into an aldehyde of formula IX by an acid treatment. :

The aldehyde IX is then alkylated to give the compound of formula X, either by treatment with heptyl dimethyloxo-2-phosphonate in dimethoxymethane in the presence of sodium hydride [E.J. Corey et al, "J. Bitter. Chem. Soc. ”, 91, 5675 (1969); 92, 397 (1970); 93,1491 (1971)], or by aldolic condensation: regiospecific of kinetic lithium enolate generated from methylpentylketone [G. Stork et al, "J. Org. Chem. ”, 39.3459 (1974)].

The enone of formula X is transformed into a monocetal of formula XI by treatment with ethylene glycol in the presence of a trace of p-toluenesulfonic acid.

The reduction of the carbonyl function in position 15 of the compound XI is carried out either by sodium borohydride or by zinc borohydride [P. Crabbé et al, "J. Chem. Soc. Perkin I ", 810 (1973)] and leads to a mixture of alcohol in 15a and 15 p, which are separated by preparative chromatography on silica gel.

1 The acid hydrolysis of the compound of formula XII having the alcohol function in position 15 a regenerates the ketone function in position 9, then the alkaline hydrolysis in position 1 leads to 11-dehydroxy PGEi.

Of course, starting from a compound in which R'i and R'2 represent a double bond like compound Ib, we would have obtained in the same way Prostaglandin Ai.

Starting from a compound le and, at the end of the reaction, by practicing a retro Diels and Help reaction, one also obtains a Prostaglandin Ai.

Starting from a compound in which R′2 is a hydroxyl function which one would have taken care to protect, for example by esterification, one would have obtained a prostaglandin of the Ei type by releasing the hydroxyl function.

Although, in this reaction scheme, we started by fixing the chain in position 8, it is possible, by following the same reaction sequences, to start by fixing the chain in position 12.

One of the advantages of this synthesis, in addition to the fact that it is rapid, is to allow the preparation of prostaglandins carrying various substituents in position 8, 10, 11 and 12 starting from a suitable compound of formula I and, in addition, it is possible to fix in position 8 chains of various structures, in particular chains comprising several unsaturations or chains containing 1,2-cyclopropylene or cyclopropyl-1-ylidene-2 radicals or, for example, radicals of type furan, tetra-hydrofuran, pyranne variously substituted.

However, from the compounds of formula I, it is also possible to synthesize prostaglandins by another reaction scheme illustrated below:

co2R7

(CH2) 4C02And

617,176

10

(CH2) 6C02And

In these formulas, R5, R6 and R7 have the meanings given for the formula I and Rg is a protective radical of the hydroxy function, for example an alkyl group, and Et is the ethyl radical.

Compound I is transformed into an alcohol mixture in position 9 of formula XlIIa by reduction of the carbonyl function in position 9.

The alcohol function of compound XlIIa is protected by etherification to form the compound of formula XIII.

Compound XIII is transformed into compound XIV by reduction of the ester in position 8 in the presence of diisobutyl aluminum hydride in toluene at -70 ° C. [L.I. Zakharkin et al, "Tetrahedron Letters", 619 (1962)].

Aldehyde XIV is transformed into compound XV by reaction

(XVI)

sodium salt, triphenylphosphoniohexanolque acid in anhydrous dimethyl sulfoxide.

The compound XV is transformed into the compound XVI precursor of the prostaglandins of the series 1 by catalytic reduction.

The chain at position 12 is fixed in the same manner as that described above for the compound of formula VIII, with the only difference that it is not necessary to pass through the intermediary of a compound of type XI, since the function in position 9 is already protected. This will give an 11-dehydroxy PGFi compound. As mentioned above, many other prostaglandins can be obtained by the same reaction scheme, in particular prostaglandin fi.

To prepare prostaglandins of series 2, one can operate according to the following reaction scheme:

CH = GH - S

C3H6C02And

Starting from compound XIV, compound XVII is prepared by treatment with triphenylphosphoranilidenephenylmercaptomethane in dimethylsulfoxide, which leads to a mixture of eis- and vinyl transthioether [N. Finch et al, "J. Org. Chem., 38.4412 (1973)].

The reaction of product XVII with mercuric acetate in acetonitrile, followed by the reductive cleavage of the organomercuric addition compound by aluminum amalgam in tetrahydrofuran and the hydrolysis of acetoxyphenylmercaptoacetal with carbonate potassium in methanol, leads to aldehyde XVIII.

The treatment of compound XVIII with the sodium salt of triphenylphosphoniopentanoic acid in anhydrous dimethylsulfoxide ■ leads to compound XIX, precursor of prostaglandins

55 of series 2 [I. Vlattas et al, "Tetrahedron Letters", 4451 (1974)], which can be treated as discussed above.

Although, in the two preceding reaction schemes, we started by fixing the chain in position 8, it is possible to carry out the same sequence of reactions by starting by fixing the chain in 60 position 12.

The examples below are intended to illustrate certain embodiments of the method according to the present invention.

Preparation

65 To a solution of 20 ml of 30% sodium hydroxide and 15 ml of diethylene glycol monomethyl ether, kept at 0 ° C., 100 ml of ether are added, then 6 g of bis- (N-methyl N-nitroso) terephtala -mide (with magnetic stirring). Maintained at 0 ° C (

11

617,176

ice) and distill the diazomethane in a container containing ether. The diazomethane solution is added to a solution of 50 ml of ether containing 1.25 g of a-tropolone (Va). The reaction mixture is stored for 1 hour at 0 ° C, then 2 hours at room temperature. The excess diazomethane is destroyed by a few drops of acetic acid. The ether is evaporated under vacuum, delivering the methyl ether of a-tropolone (V).

Example 1

A solution containing 0.9 g of the methyl ether of a-tropolone (V) in 240 ml of anhydrous redistilled methanol is cooled to 0 ° C. and stored under an argon atmosphere. This solution is irradiated by a Hanau TQ-150 high pressure ultraviolet lamp at 0 ° C for 6 h. The solvent is removed by rotary evaporator under reduced pressure. The oily residue is distilled under high vacuum E <80 ° giving 7-methoxy-3,6-bicyclo- [3,2,0] -heptadiene-2-one (III).

Example 2

80 mg of platinum oxide is added to 30 ml of distilled ethyl acetate. After evacuation of the air, place in a hydrogen atmosphere and reduce the platinum catalyst. 580 mg of the compound of Example 1 (III) are dissolved in 75 ml of distilled ethyl acetate and the perhydrogenated platinum is added. The mixture is hydrogenated at ordinary pressure and room temperature until absorption of hydrogen corresponding to an equivalent. After absorption, the catalyst is filtered, the solvent is evaporated in a rotary evaporator and the product is distilled under vacuum at 60 °. 7-methoxy-3,6-bicyclo- [3,2,0] -heptene-2-one (IIa) is thus obtained: colorless liquid, vraax 3070.1730 and 1625 cm-1, NMR 4.75 (s , vinyl H), 3.60 ppm (s, Me).

Example 3

5.7 ml of methanol are added to a solution containing 1.62 g of the compound of Example 2 in 29 ml of methylene chloride. The mixture is cooled to - ITC (CO2 + acetone) and the cooled solution is subjected to a stream of dry ozone. After a few minutes a slight blue color appears. It is dissipated by passing a stream of dry argon for a few seconds. To the solution thus obtained, 2 ml of sulfur dioxide are added by distillation (-10 ° C). After 5 min at -77 ° C, 4 h at -20 ° C, 1 h at 0 ° C and 1 h at room temperature, the solvents are evaporated under vacuum, with a rotary evaporator and, by extraction according to the usual technique, we obtain 5- (dimethoxymethyl) cyclopentan-2-on- acid methyl ester

1-oic: colorless oil, vmax 1750-1J30 cm "\ NMR 4.25 (d, J = 5 Hz, acetal H), 3.70 (s, Me ester), 3.35 ppm (d, J = 1 , 5 Hz, 2 x OME), FeCl3 test: positive.

Example 4

The procedure is as in Example 3, starting from the compound of Example 1, 7-methoxy-3,6-bicyclo- [3,2,0] -heptadiene-2-one; 'we obtain the 5- (dimethoxymethyl) -cyclopent-3-en-2-on-l-oic acid methyl ester.

Use of the product of example 4:

To a solution of lithiumdimethylcopper prepared from 950 mg of copper iodide in 20 ml of anhydrous ether, cooled to -10 ° C., a solution of methyllithium is added dropwise.

2-molar, under argon, until discoloration. This solution is added dropwise to 220 mg of the cyclopentenone obtained in Example 4 in 15 ml of anhydrous ether, keeping the temperature between -20 and -25 ° C for 15 min. An aqueous ammonium chloride solution is then added and 1 hour is added at room temperature. Extracted with ether, washed and dried over anhydrous sodium sulfate. It is filtered, the solvent is evaporated in vacuo and chromatography on 25 g of Florisil. The methyl ester of 5- (dimethoxymethyl) -4-methylcyclopentan-2-on-1-oic acid is thus isolated.

By using the compound of Example 4 and ethyllithium as reaction product, the methyl ester of 5- (dimethoxymethyl) -4-ethylcyclopentan-2-on-1-oic acid is obtained.

By using the compound of Example 4 and vinyllithium as reaction product, the methyl ester of 5- (dimethoxymethyl) -4-vinylcyclopentan-2-on-1-oic acid is obtained.

By using the compound of Example 4 and cyclopropyllithium as reaction product, the methyl ester of 5- (dimethoxymethyl) -4-cyclopropylcyclopentan-2-on-1-oic acid is obtained.

By using the compound of Example 4 and butyllithium as reaction product, the methyl ester of the acid is obtained.

5- (dimethoxymethyl) -4-butylcyclopentan-2-on-l-oïque.

By using the compound of Example 4 and phenyllithium as reaction product, the methyl ester of 5- (dimethoxymethyl) -4-phenylcyclopentan-2-on-1-oic acid is obtained.

Preparation 2

Starting from the compound of Example 1, on which the corresponding lithium-copper derivative is reacted, 7-methoxy- is obtained.

Corresponding 6-bicyclo- [3,2,0] -heptene-2-one-4-substituted which is ozonolysed by the method of Example 3.

To a solution of 0.068 g (0.50 mmol) of 7-methoxy-3,6-bicyclo- [3,2,0] -heptadiene-2-one in 5 ml of methanol, 0.042 g of acetonecyanohydrin ( Aldrich) and two drops of a 10% aqueous potassium carbonate solution. After stirring at 50 ° C for 2 h, the ethanol is removed and ether is added and the solution is washed with distilled water and dried over sodium sulfate to give 0.05 g of 4-cyano-7 -methoxy-3,6-bicyclo- [3,2,0] -heptadiene-2-one as a yellow oil after column chromatography (Si02 Merck / n-hexane 60:40 benzene).

Preparation 3

Treatment of 10 g of tetrahydropyran with acetyl chloride at reflux in anhydrous benzene, in the presence of zinc chloride, provides the methyl ester of 5-chloropentyl alcohol. The reaction of this chlorinated derivative with ethyl malonate, in the presence of sodium and sodium iodide, at reflux in ethyl alcohol, gives the lactone ester of co-hydroxyheptanoic acid. This is converted to the ethyl ester of bromo-7-heptanoic acid by treatment with hydrobromic acid and sulfuric acid in solution in acetic acid. The ethyl ester of bromo-7-hepta-noic acid is converted into the iodo-7-heptanoic derivative by reaction with sodium iodide in anhydrous acetone, 2 h at ordinary temperature.

Use of the product of Example 3:

328 mg of the ketoester obtained in Example 3, dissolved in 3 ml of anhydrous dimethyl sulfoxide (distilled on calcium hydride), are rapidly added under argon to an oily dispersion of 75 mg of potassium hydride (330 mg mixture at 22.5 %). After stirring at ordinary temperature for 15 min (cessation of the evolution of hydrogen), 900 mg of the pure compound obtained is added to preparation 2 and the reaction mixture is stirred for 27 h at ordinary temperature. Then poured into a water / hexane mixture, extracted with hexane, dried over anhydrous sodium sulfate, filtered and obtained, after chromatography, the diester of formula VII in which R5, R6 and R7 represent the methyl radical and Alk the radical ethyl: oil, vmax 1745-1730 cm "S NMR ca. 4,12,4,16 (acetal H), 3,95 (q, J = 7 Hz, CH2Me), 3.55 (s, Me ester), 3.25 (s; OMe), 1.20 ppm (t, J = 7Hz, CH2Mê); m / e 340 (M + —MeOH).

A mixture containing 37 mg of this diester, 10 mg of sodium cyanide and 1 ml of hexa-methylphosphotriamide (redistilled over sodium) is added under an argon atmosphere at 75 ° C. during A h, then overnight at temperature. ordinary. The reaction mixture is then added, under a hood, to a mixture of 10% hydrochloric acid in water and hexane. Then we extract and dry

5

io

15

20

25

30

35

40

45

50

55

60

65

617,176

12

on sodium sulfate and potassium carbonate. After filtration and evaporation of the solvents under vacuum, the monoester of formula VIII is obtained in which R5 and R6 represent the methyl radical and Alk the ethyl radical: liquid, vmax 1730 cm ~ NMR ca. 4.12, 4.16 (acetal H), 4.05 (q, 7 Hz, CH? Me). 3.35 (s, 2 x OMe); 1.2 ppm (t, J = 7 Hz, CH? Me).

A solution containing 50 mg of the acetal of the monoester thus obtained is stirred in 4 ml of acetone and 4 mg of p-toluene sulfonic acid monohydrate, for 62 h at room temperature, under argon. Thrown into water, extracted with ether, washed with a bicarbonate solution, dried over sodium sulfate, filtered, and evaporated in vacuo. The aldehyde of formula IX is thus isolated in pure form.

368 mg of heptyl dimethyloxo-2-phosphonate in 10 ml of dimethoxyethane (redistilled on double lithium and aluminum hydride) are stirred under dry argon, to which 68 mg of sodium hydride (oily solution at 55-60%) in 11 ml of dimethoxyethane. After 1 h at room temperature, the mixture is cooled to -15 ° C and rapidly added 400 mg of the aldehyde of formula IX in 6 ml of dimethoxyethane. After 2/4 h between -10 and 0 ° C, the mixture is stored overnight at room temperature. About 0.1 ml of acetic acid is added to dissolve the solids. Then evaporated to dryness with a rotary evaporator, then chromatographed on a column of 60 g of silica gel, eluting with methylene chloride and ethyl acetate. A purified lightly colored oil is collected by preparative chromatography on silica gel. The enone of formula X is thus obtained in pure form.

A solution containing 200 mg of the enone of formula X obtained in 100 ml of anhydrous benzene, 25 ml of ethylene is heated.

glycol and 10 mg p-toluenesulfonic acid. The water is removed by azeotropic distillation. The reaction is followed by chromatography and the heating is continued until the intensity (coefficient of molecular extinction) of the enone in ultraviolet is reduced. It is cooled, thrown into water, washed with sodium bicarbonate and extracted with ethyl acetate. It is dried over sodium sulfate and the solvents are distilled under high vacuum. The monocetal of formula XI is purified by preparative chromatography on silica plates.

120 mg of the monocetal of formula XI are dissolved in 20 ml of distilled dimethoxymethane. A solution of zinc borohydride in dimethoxyethane is added, prepared by reaction between sodium borohydride and zinc chloride. It is left to react for 2 h at ordinary temperature. Poured into water, extracted with ethyl acetate, washed and dried over anhydrous sodium sulfate. The solvents are filtered and evaporated in vacuo.

The alcohol mixture of formula XII is separated by preparative thin layer chromatography on silica gel. The (R) and (S) isomers are thus isolated in pure form.

a, 75 mg of the β alcohol thus obtained are treated with a solution containing 5 mg of p-toluenesulfonic acid in 5 ml of acetone overnight at room temperature. Then add an excess of sodium bicarbonate solution and evaporate 4/5 of the volume. 10 ml of a methanolic solution containing 200 mg of potassium carbonate are then added and stored overnight at ordinary temperature to hydrolyze the ester to C-1. The course of the reaction is followed by thin layer chromatography, and the 11-dehydroxy-PGEi is isolated.

The references given in parentheses are intended to illustrate certain analog processes.

R

Claims (19)

617,176 1 by irradiation, into a compound of formula III ' ° Il ° ORf Ll ^ air) ß1 - V l * r rji and in that the compound thus obtained is transformed according to the method of claim 8 into a compound of formula I. * 1 - ß <- (III ') (III ') 65 by addition 1.4 of Michael by action of an alkylllithium, of phenyllithium or of a cycloalkylllithium to a compound of formula II, in which R't is hydrogen and R'2 is an alkyl, phenyl or cycloalkyl radical , and in that we transform the 2 by irradiation, into a compound of formula III ' (III ') and in that the compound thus obtained is transformed according to the process of claim 10 into a compound of formula I. '2 by irradiation, into a compound of formula III ' (III ') ~ \ and in that the compound of formula III 'thus obtained is transformed according to the method of claim 4 into a compound of formula I. 2. Method according to claim 1, characterized in that the ozonolysis is carried out in the presence of ozone in a solvent. * 2 T? 3 by epoxidation of the double bond in position 3, followed by a reduction of the epoxide bond, into a compound of formula n with R \ = hydrogen and R'2 = a hydroxy radical, and in that the compound II is transformed thus obtained according to the process of claim 25 cation 1 to a compound of formula I. 2 CLAIMS 1. Process for the preparation of a compound of formula I (I) by selective reduction into a compound of formula II with R'x and R'2 = hydrogen, and in that the compound II thus obtained is transformed according to the process of claim 1 into a compound of. formula I. 3 617,176 compound II thus obtained according to the process of claim 1 into a compound of formula I. 3. Method according to claim 2, characterized in that the solvent used is a mixture of methylene chloride and methanol and in that the reduction of the ozonide is carried out in the presence of an alcohol. 4. Process for the preparation of a compound of formula I, characterized in that a compound of formula III 'is transformed by reaction with a conjugated diene compound, to a compound of formula II with R'x and R'2 taken together representing a substituted or unsubstituted alkylene or alkenylene radical, and in that the compound II thus obtained is transformed according to the the process of claim 1 into a compound of formula I. 5. Method according to claim 4, characterized in that the selective reduction of the double bond in position 3 is carried out using hydrogen in the presence of platinum. 6. Process for the preparation of a compound of formula I, characterized in that a compound of formula III 'is transformed 0R7- Tti in which ®-l> R'ii ®-2 »^ '21 R3) R4 and R8 separately represent a hydrogen atom, a halogen atom, a radical of aliphatic nature, a free or protected hydroxymethyl radical or a cyano radical; R'2 can also be an aryl, cycloaliphatic radical or a free or protected hydroxy radical; R'j and R'2 taken together may represent a double bond or a substituted or unsubstituted alkylene or alkenylene radical; R5 and R6 represent independently an aliphatic radical, or taken together an unsubstituted or substituted alkylene or alkenylene radical; R7 represents a hydrogen or halogen atom, an aliphatic radical, a substituted or unsubstituted aryl, cycloaliphatic radical, a terpene radical, a substituted silyl radical or a metal cation, characterized in that the ozonolysis of a compound of formula II is carried out: (II) (III ') 7. Method according to claim 6, characterized in that the epoxidation is carried out in the presence of hydrogen peroxide in an alkaline medium and in that the reduction of the epoxide is carried out by aluminum amalgam. 30 8. Process for the preparation of a compound of formula I, characterized in that a compound of formula III 'is transformed GOLD- (III ') in which R1; R'j, R2, R'2, R3, R4, R7 and R8 have the meanings given above, and the ozonide is reduced in the presence of sulfur dioxide and at least one alcohol fixing the radicals R5 and R6 by acetalysis . 9. Method according to claim 8, characterized in that the 50 conjugated diene compound used in the reaction is dimethyl-fulvene. 10. Process for the preparation of a compound of formula I, characterized in that a compound of formula III 'is transformed OR7- 11. Process for the preparation of a compound of formula I, characterized in that a tropolone of formula V 'is transformed O Vl 12. Process for the preparation of a compound of formula I, characterized in that a tropolone of formula V 'is transformed O Ö * 13. Process for the preparation of a compound of formula I, characterized in that a tropolone of formula V 'is transformed O 14. Method according to one of claims 11 to 13, characterized in that the irradiation is provided by a high pressure ultraviolet lamp. 15. The method of claim 1, characterized in that a product of formula I is prepared in which R't and R'2 together represent a double bond. 16. Method according to claim 1, characterized in that a product of formula I is prepared in which R'2 represents a hydroxy radical. free or protected. 17. Method according to claim 1, characterized in that a product of formula I is prepared in which R5, R6 and R7 represent an alkyl radical. 18. Method according to claim 1, characterized in that a product of formula I is prepared in which R5, R6 and R7 represent a methyl radical. 19. The method of claim 1, characterized in that a product of formula I is prepared in which R'2 represents an alkyl radical, a vinyl radical, a cyclopropyl radical or a phenyl radical.