PL155660B1 - Method of obtaining derivatives of 21-fluotopregnan - Google Patents

Description

REPUBLIC POLAND PATENT DESCRIPTION 155 660 Additional patent to patent No.-- Int. CL. ^s C07J 7/00 OFFICE Reported: 8® 06 24 / P. 273298 / Priority. ΕΖΥΤΕΙΒΗ 9 GÓLHU PATENT Application announced: 89 12 27 RP Patent description published: 1992 04 30

Creator of the invention: Marek M. Kabat

Authorized by the patent: Polish Academy of Sciences Institute of Organic Chemistry, Warsaw / Poland /

METHOD OF BACKGROUND OF 21-FIUOROPREGNANE DERIVATIVES

The subject of the invention is a method of heating 21-fluoropregnane derivatives, which are compounds with glucocorticoid and progestatic activity.

The 21-fluoropregnane derivatives produced by the process according to the invention have a total structure 1, in which the dotted lines indicate the possible presence of a double bond at the c / 1-2 / or C / 9-1l / or c / 1-2 / and c / 9- position. ll /.

Methods of obtaining compounds of general value 1 - due to their usefulness in medicine:

1. Βίϋπθόίοθΐ Aspects of Fluorine Chemiitry, ed. R. Filier and Y. Kabayysaki,

New York 1982;

2. H.E.Smlth, R.G. Smith, D.C. Taft, J.R. Neergaard, E.P.Bueeows and B.A. Oh'Maaiey,

J.Biol.Chem., 249, 5924/1974 / - have been the subject of many studies: / l. J.E. Herz,

J. Fried, P. Grabovich, E. F. Sabo, J. Am. Chem. Soc., 78, 4812 (1956); 2, P. Tannhauser, R. J. Pratt, E. V. Jensen, J. Am. Chem. Soc., 78, 2658 (1956); 3. H.M. Kissman, A.M.Srali, M.J.Aeiss, J.Am.Chem.Soc., 82, 2312/1960 /.

Among the 21-fluoropregnane derivatives produced according to the invention, two compounds are new, i.e. the compound of formula I in which the double bond is at the positions:

C (4-5) and C (1-2) and the compound of formula I in which the double bond is at the positions:

C / 4-5 /, C / 1-2 / and C / 9-11 /.

Known methods of obtaining 21-fluoropregnane derivatives consist in transforming 21-hydroxy pregnane derivatives in such a way that the 21-hydroxy group is protected in the form of an ester with acetic anhydride, toxic chlorides or mesyl chloride, and the obtained ester group is substituted with an iodide anion, thus obtaining a derivative 21-iodopregran, which in turn is converted by reaction with AgF to the 21-fluoropregnane derivative. / l. P. Tannhauser, R.J. Pratt, E.y. Jensen, J. Am. Chem. Soc., 78, 2658 (1956); 2. H. Reiman, D.H. Gould, U.S. Patent No. Zjddn.Am. 3 009 928, Chern.Astr., 56, P: 6049 c /.

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Another known method for the preparation of 21-fluoropregnane derivatives is the substitution of a fluoride ion derived from C104F, the reaction product of 21-methylpregnanes with oxalic acid esters / HMKissman, AMSmaai, MJWeiss, J.Am.Chem.Soc., 82, 2312/1960 /.

Both of the discussed known methods of obtaining 21-fluoropeggnane derivatives (croryite) use other pregnane derivatives as steroid substrates, which are expensive compounds and are synthesized separately in several passes. Influence of the fluorine atom takes an additional 2 to 4 steps. Known methods also use expensive sources of fluoride, such as: silver fluoride / AgF / or perchlorate fl ^ [mu] m ClO ^ F.

The process according to the mucilage is a new process for the preparation of compounds of general formula I from cheap 17-rxsoandrstaπl derivatives, which also allows the use of inexpensive sources of fluorine ion. In addition, in the process according to the invention, all reactions take place under very mild conditions.

The method according to the invention consists in that a 17-oxoandrostane derivative of general structure 2, in which the dotted lines indicate the presence of a double bond at the positions: C / 1-2 / or C / 9-11 /, or C / 1-2 / and c / 9-ll /, and Rj is a hydroxyl group optionally protected in the form of an airoxy group C 1 -C 4, methoxymeioxyl group, benzyloxy group, αlifa Z acylrxyl group Cj-Cj, binzoilrtyl group, tetrahydroirnoyloxy group, or trisyloxy group with the same C 1 -C 4 alkyl substituents, triphenylsirlrkxyO group or dlWllfitZorertbutylsiloyOoxy group, are subjected to addition reaction to the 17-oxo group with 1-mcealoorganic derivative of 1-trialkylsilioethane of general formula 3, in which Met is a metal atom from group I of the periodic table from group II of the Periodic Table combined with a halogen atom, such as chlorine, bromine or iodine, and R2 represents the same or different C1-, -C2 alkyl groups in an inert solvent or mixed other inert solvents, in the presence of a Lewis acid, and then in the obtained derivative of the general structure 4, in which all symbols have the meaning given above, the ethylene bond c (1'-2 ') is epoxidized in the presence of a catalyst with of the formula ΧΟΟΗ, in which X represents a hydrogen atom or an alkyl group C, -C 6, in an inert solvent or protractor, in the prepared derivative of the general formula 5. in which all symbols have the meaning given above, group 17/3 - The hydroxyl group is etherified with C1-C6 alcohol halide halides in the presence of a base, or esterified with apathetic C1-C4 carboxy acids, optionally substituted with 1-3 halogen atoms, their chlortomates or anhydrides, or else with sulfonic acid chlorides and anhydrides, to obtain a compound of formula general 6, where R 1, R g and dotted lines are as defined above, and R j is a Cy-C 1-4 alkoxy group, a C --- C acyirxyl group, optionally containing 1 to 3 halogen atoms a, such as Cl, Br, F, a meansulfonyloctyl group, a p-toluenesulfonyloxy group or a tΓflflroromitanesulfonyloxy group, which compound is reacted with a source of fluoride ions in an inert solvent to give the derivative of general formula 7 wherein R has the above-mentioned and then optionally deprotecting the 3/3-hydroxy group by hydrolysis and oxidizing the compound of the vane 7, wherein R 1 is hydroxy, it is converted to a 3-oxo group.

The starting compounds of the general formula 2, i.e. 17-oxoandrostanes, are known and can be easily obtained from cheap sieves by microbiological methods / 1. M.G. F.J. Antosz,

J.C.Knight, L.A. Fireplace, T.R. Pyke, BiochimBi.opl ^: ^^. A ^ -ta 538, 308/1978 /, 2. U. Eder,

G. Sauer, G. Haffer, G.Neef, R. Wiechert, A. Weber, A. Popper, M. Kennecke, R. Muller, Ger. Offen 2534911 /, and also on other roads, incl. total syntheses / e.g. A.R.Daniewski,

P. White, Z. Valenta, Can. J. Chem. 57, 1397/1919/11.

Compounds of general 3 can be obtained by halogen exchange in 1-halo-1-trialkyltyliroethene. The halogen can be chlorine or bromine.

The addition reaction to the 17-oxo group of a compound with general avulage of 2,1-organometallic derivative of 1-trialkylsilioeehm with a general avolume of 3 is carried out in an inert solvent,

Such as dimethyl ether, tetrahydrofuran, dimethoxyethane, pentane, hexane, especially tetrahydrofuran and hexane, or mixtures thereof, in the presence of a Lewis acid. Boron trifluoride complexes, e.g. BFj, can be used as Lewis acids. EtgO, halides of mgnesium, zinc, aluminum, titanium, tin, preferably AlCl3, ZmSB-, TiCl-, alkyl aluminum halides, preferably AlCl / Ett-. The addition reaction in the absence of Lewis karst proceeds with very low and / or yield, while producing a mixture of by-products that is difficult to separate. The addition reaction may be carried out over a wide range of temperatures, preferably from -78 ° ^C to reflux temperature to dissolve media. It is preferred to use a nadmeir of 2-6 equivalents of the compound of formula 3 and 2-6 equivalents of Lewis karst per equivalent of the compound of formula 3 and 2.

In the epoxidation step of the c / l′-2 "double bond of the compound of Raor 4, hydroonoxides of the general formula Χ-ΟΟΗ are preferably used, in which X m is defined as above, e.g. tert-butyl hydroperoxide.

The epoxidation reaction is conveniently carried out in inert solvents such as diethyl ether, tetahytroflum, hexane, pentane, benzene, toluene or in protic solvents such as methanol, ethanol, rhod3, tert-butanol or a mixture thereof, most preferably toluene. and benzene. Various catalysts for this type of reaction can be used as the catalyst, preferably so-called Sharpless epoxidation reactions, i.e. vanadyl acetylacetonate or titanium tetraisopropylate in the presence of chiral C6-C6 / A dialkyl tartrates. Phenninger, Synthesis, 89, 1986).

The tstrification of the 17/3-hydroxy group of the compound of the general formula is usually carried out with the aid of C1-6C2 aliphatic carboxylic acids, their anhydrides or chlorides, or with halogen atoms, preferably with karst anhydride.

In the esterification reaction, sulfonic acid chlorides and anhydrides can also be used, especially eethanesulfonyl chloride (meeyl chloride), p-toluenesulfonyl chloride (tosyl chloride), trifluoroethane sulfonic acid chloride or anhydride in the presence of an aliphatic Cy-C- or aromatic amine, preferably C-or aromatic. in an inert solvent such as diethyl ether, tetrahydrofuran, hexane, pentane, methylene chloride, chloroform. The reaction is carried out in a wide range of temperatures, preferably from -25 ° ^C to + 25 ° C. In the case of the formation of the ether of the 17/3 -hydroxy group, chlorides, bromides, iodides of the corresponding C1-C- α -phatic alcohols are used in an inert solvent such as diethyl ether, tetrahytrofurat, hexane, pentane, heptane, in the presence of a base such as NaH, KH, NaOH, KOH, C ^ H ^ Li, CH Li in a wide range of temperatures, preferably from ^-78 C to the boiling solvent destruction. In the esterification or etherification reaction of the 17 µl -hydroxy group, preferably 2 to 6 equivalents of the acylating or alkylating agent are used for 1 equivalent of the compound o: c ^ r'n5.

Compounds of general order 6 in which R.j, R2, Rj are as defined above are then reacted with fluoride ions. Fluoride ions are introduced in the form of metal fluorides of Group I of the Periodic Table or hydrogen fluoride, or C1-C6 α-quaternary ammonium anhydrous or rhodate salts, preferably KF, CsF, / C-Hg / -NF, / C-Hg / 4NF. 3H4 0; / CHj / -NF. The reaction is carried out in an inert solvent such as dimethyl ether, tetrahydrofuran, benzene, toluene, pentane, hexane, acetonitrile or a mixture thereof, preferably in tetrahydrofuran, over a wide temperature range, preferably at 25 ° C. You can also add a crown ether, e.g. 18-crown-6. In the reaction of the chip 6 compound with the fluoro ion, 2-6 equivalents of fluoride ions are used per 1 equivalent of the compound at 6.

Removal of the 3/3-hydroxy protecting group in the compound of Formula 7 is accomplished by hydrolysis.

Hydrolysis of the R · group, which is an aliphatic acyloxy% -C- group, or a benzooxy group, is carried out with sodium or potassium hydroxides in alcohol, preferably ethanol or methanol, with the addition of 20% water.

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Hydrolysis of the R- group representing the C1 -Cy alkoxy group, methoxyrethoxy, benzyloxy, tetaahydropyrayyloxy group, is preferably carried out with an alcoholic (methanol or ethanol) hydrogen chloride solution. In the case where Rj is a silyloxy group, the hydrolysis proceeds under the reaction conditions to convert the compound of Formula 6 to the compound of Formula 7 with a source of fluoride ions.

The oxidation reaction of the 3/3-hydroxy group to the 3-oxo group of the compound of formula VII is carried out with the aid of oxidizing agents such as inorganic chromium salts, e.g. chromium trinate in methylene chloride or in pyridine, by the Swrn method or by the Oppenauer method, i.e. aluminum isopropoxide in toluene and in the presence of a C 1 - C 6 ketone, especially cyclohexanone, preferably at a temperature from 0 ° C to the boiling point of the solvent.

The invention is illustrated in the following example without limiting its scope.

Example A. Preparation of compound of formula 4, wherein R = 3/3 tetrahydropyranyloxy, R ₂ = CH.

To a solution cooled to -25 ° C containing 1-bropyl-1-trimettylsilyletee / 537 mg, ϋ / in tetrahydrofurm / 10 ml / an added dropwise n-BuLi solution / 1.6 molar solution in hexane, 1.87 ml, 3 nM /.

A solution of 3'-terrayyrctopyranyloxy-5-andrlSten-17-one (372 mg -1 µl) and BFj was then added. EtGO / 420 mg, 3 nM / w / 5 ml /. The reaction mixture was kept at -25 ° C for 2 hours, then water (10 ml) was added and the product was extracted with dimethyl ether. The organic layer was washed with water (3 x 20 ml.) And dried over anhydrous magnesium sulfate. After evaporating off the solvent, the residue is chromatographed on a silica gel:> 0.063-2 mn; 15 g (using hexane-dimethyl ether (97: 3) as eluent. Afforded 17 (i -hydroxy, 17o £ - / 1'-trimethylsilyl-1'-etyll / -5-andrlsten-3/3 -tetrahydropiranylowy ether ^{/ 320} mg ^»63 8 / ^s in the form of colorless crystals, ch -temperaturze ¹⁵⁴ m.p. -16 ° C / hexane - dimethyl ether /.

¹ H NMR ^/ CDC1 ^{3 /} CT ^{/ pp} m / ^0, 14/9 ^ ^s ^ H ^ Si; ^0, 91 and ^1, 01 / 6H 2s, ^18-CH3 and 19-^ ° /; ^3, 50 / m, 2H, OCH /; 3.90 (m, 1H, 3-H); 4.71 (1H, brs, -OCHO-); 5.34 (1H, m, 6-H); 5.38 (iH, d, J -1.4 Hz, 2'-h);

IR / nujol /: 3640 / OH /,

MS: 472 (M +, 28),

Elemental aralysis: 029H4g02Si

Calculated: 73.68% C, 10, 2% 6H,

Found: 73.78 C, 10.08 H.

B. We will give a compound of formula 5, w klre, Rj = ³ 3> -tetrahdrlopireyyOoxy,

R2 = CH3.

For a solution containing Πβ-hydroxy, 17 ° C- (1'-triraethylsilyl-1'-ethyl-Z-S-androstene-3 (3-terrayydloprreyyl ether) (472 mg, 1nM) and acetylacetonirne in ^ n ^ and ^ y ^ lu / 5 mg in toluene (10 m), a solution of tert-butyl hydroperoxide (0.3 mL, 3.3 M solution in toluene, 1 nw) was added at room temperature. The reaction mixture was kept at 25 ° C for 30 minutes and then filtered through celite (3 g). After evaporation of the solvent, 17β-hydroxy-17 ° C- (1'-trimethylsilyl-1,2'-epoxyethyl) -O-andresiene-tetrahydropyranyl ether (465 mg, 958 L) as colorless crystals, m.p. m ^ 4 ^^ ° C / hexane - Et ₂ <- /.

¹ H NMR ^/ C Cl ^l / cT / ^pp m / ^{0, 18/7} O ^"s, Si / C ^o / ^/ 5 ^{/; 0,} 92 and ^1, 02/6 ^O, 2s, 18-C and 19-0 ° /;

2.54 (LH, d, J = 4.6 Hz, 2'-h); 3.00 (1H, d, J = 4.6 Hz, 2'-h); 3.50 (2h, m, -OCH); 3.90 (1H, m, 3-H); 4.72 (1H, brs, -OCHO); 5.34 (JH, m, 6-H);

MS: 386 (M ⁺ - 84-18.2%); 85/1008 /,

IR / nuj ^ /: 3500 / oh /.

Elemental aralysis: C29O4g ° 4Si.

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Calculated: 71.27% C, 9.90% HI,

Found: 71.36% C, 9.99% H.

C. Preparation of a compound of general formula 6 where R.j = 3/3-tetrahydropyranyloxy,

R2 = CHj, Rj = CFjCOO.

For a solution containing 17/3-hydroxy-17 <· - / 1'-trimethylsilyl-1 ', 2'-epoxyethyl / -5-androstene-3/3-tetahyyiropyayoyl ether / 488 mg, 1 mM / in pyridine / 10 ώ / at ⁰ ° ^{C d d} cyano anhydride trójflrtroocOow ^y / ⁰ 5 ^m / ^sec. The mixture rea tive utrz ^k ^ nywano at 0 ° C for 30 minutes, and then water / 50 m / sec and the product was extracted with ethyl acetate The ^ / 2 x 30 ml /. The organic layer was washed successively with water (3 x 30m), 5% HCl (3 x 30m,), water (30m), saturated NaHCO3 (3 x 30m) and dried with anhydrous Na2SOZ _| . After evaporation of the solvent, 17β-triflrtraceroxy-17oC - (1'-trimethylMiUlo-P, 2 ^, -eprxyethyl) -5-andrrsten-3/3-tetlayydiropilanyl ether (532 mg, 91%) was obtained as colorless oil IR / CHCl3 /: 1790 (C 0), MS: 584 (to *, 5%) which was used without further purification for the next reaction.

D. Obtaining compounds of general formula 7, in which R 14-3 β-tetrahydropyranyloxy.

Solution containing 17/3 -triflrtraaceroxy-17 ol - / 1'-trimethylsilyl-1 '^' - epokayethyl /

-5-andrasten-3 (i -tetrayydΓoptrazyrooz ether / 584 mg, lnM / in tetrahydrofuran / 15 m.1, at room temperature, treated once with the solution / l ^ Hg / ^ NF · 3-gO / 693 mg, 2.2nM / in THF / 5m / and held for 15 min. Water (50 ml.) Was then added and the product was extracted with ether (2 x 50 ml.). The organic vegetable was washed with 0/3 x 50m. / and dried over anhydrous MgSO 4. After evaporation of the ether, the residue was chtOMitogroupooranr on silica gel (0.063-0.2 mn, 50 g), using hexane-ethyl ether 96: 4 as eluent. Zl-fluoro-5-pregnen-20-one was obtained, 3 β-tetrhydropyrazine ether (288 mg, 69%) as colorless crystals, m.p. 118-122 ° 1 (hexane-ethyl ether).

¹ H NMR / ^ 400 MHz, .delta N, CDD ^{/ pp} m /: 0,75 and ^0, 98 / 2s, 6- 18-H and 19-H / ^2, 71 / H, dd, J | = 2.8 Hz, J2 = 9.3 Hz, 17 ° C h /; 3.48 (2h, m, -OCH-); 3.89 (m, 3-olH); 5.32 (- m, 6h); 4.71 / ω, dd, J- 3 16 Hz, 48 Hz, 1H-F /; 4.78 / lH, dd, Jh_h3 16Hz, J-_f = 48-z,

CH ₂ F /; 19 _f NMR / 400 Wiz, CDD11 /: cT -104.61 (t, J-, ^ 4.8 Hz)

IR / IHHCj /: 1730 / C = 0 /.

E. Preparation of a compound of general formula 7 where R 1 = 3 β -OH.

The solution containing 21-fluoro-5-pegnen-20-µm, 3β-tetraZydepyrazo Oowz ether (418 mg. InM) and p-toluenesulooz acid / 5 mg / ml in methanol / 5 mils was stirred at room temperature for 3 hours. Then water (30 m) was added and the product was recovered with ethyl acetate (50 m). The organic layer was washed with water (3 x 30 ml) and saturated NaHCO3 solution (3 x 30 m), and then dried with anhydrous Iragnezoozro sulfardane. Evaporation of the solvent gave 3β -hydroc: 3j ^ - ^; ^; ^ -: E 'luoro-5-i ^] ^ <^ g ^ nen-20-one / 301 mg, 90% mp 180-183 ° 1 (Et ₂ 0), IR (CHCCj): 36θθ / θΗ /, 173o (c = O), (HMKissman, AMSnmill, MMWwiss, J.Am.Chem.Soo., 82, 2312/1960 // melting point 184 ^The -185 C / CH2H2 - Et20 /.

F. Preparation of the compound of general formula 1.

Solution containing 3/3-hydroxy-2l-fluoro-5-pregnen-20-one / 334 mg, InM /, cyclohexanone / 2 m / and isoprop ^^ m aluminum / 1.5 g / in toluene / 50 m3 / mm5wlnr at reflux for 3 hours, then slowly dissolving off the oligo-toluene with toluene. Saturated clear NH-C1 solution (50 ml) was then added and the organic solvents were distilled off. The product was extracted with ethyl acetate (2 x 30 m) and dried with anhydrous MgNeosulfate. After evaporating the solvent, 21-ίΊuoro-ptogesteΓon (21-fluoro-S-pregnen-3 »20-dSrn) (295 mg, 89%) was obtained, with a melting point of 136-140 ^° C (pentane), / HMKissman» A. ^ Sma, MJWeess, J.Am.lhem. Soc., 82, 2312 (1960), m.p. 143-145 [deg.] 1 (Et2O).

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Claims (4)

Patent claims 1. The method of scalding 21-fluoro-pregnane derivatives with the general 1, where the dotted lines indicate the possible presence of a double bond with a position between C / 1-2 / or C / 9-H / »or C / 1-2 / and c (9-11), characterized in that the derivative of 1T-oxo-androstane of general order 2, in which the dotted lines have the meaning given, and R5 represents a hydroxyl group, which is voluntarily protected in the form of an alkoxy group methoxymethoxy, benzyloxy-oxy, aliphatic acyloxy C-C-benzoyloxy group, tetrahydropyranyloxy group, trialkylsilyloxy group with the same or different alkyl substituents of C-C-th, phenylsiloxylutenylysubstituted, ortho-phenylsiloxythenylethoxy group 1-trialOylsilitoethene of the general formula 3, where Met is a metal atom from Group I of the Periodic Table or a metal atom from Group II of the Periodic Table connected to a chlorine atom, such as chlorine, bromine or iodine, and R2 is for the same or different C - 4 alkyl groups, 'the presence of Lewis Ooas, with an inert solvent or a mixture of these solvent', and then with the obtained derivative with the general ozone 4, for which pure symbols have the meanings given above, are subjected to epoxidation and bonding to ethylenes c / l'-2 '/, in the presence of a catalyst, by means of an ohydroperoxide with the word Χ-ΟΟΗ, where X is a hydrogen atom or a C1-C6 alkali group, in an inert or protoooyl solvent obtained from a sea derivative general 5, in which all symbols have the same meaning, the 17/3-hydroxyl group is etherified with halides of aliphatic alcohols C - Cj, 'the presence of a base, or esterified with alffaSyzty oats Οβι ^ Ι ^^ ο ^! C - C-, ewenntai ^ l ^ ie substituted with 1-3 chloro ^ 'οθ atoms, their chlorides or hydrocarbons, or also chlorides and anhydrous k ^^ sulfonoic salts, and a compound of general formula 6, about which R-, R2 and Oropkooane lines have the same meaning as defined, R- is an alkoxy group C, -C4, acyloxyl group C-C- containing possibly from 1 to 3 chlorooc atoms, such as Cl, Br, F, a menansulfonyitxyl group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxyl group, are reacted with an inert solvent of a fluorine ion source to give a derivative of general ozone 7, where R is as defined above, and then monninically deprotected the 3/3-hydroxy group is converted to a 3-oxo group by hydrolysis and oxidation with the compound of the formula 7, wherein R- is a hydroxyl group. 2. The method of claims 1, characterized in that the epolissicization reaction of the C / l'-2 '/ compound with the tongue 4, in which' Quick symbols have the meaning given in claim 1, 1, the catalyst is acetsioacetothiat loanadyl or titanium tetrisopropylate with the presence of C, -C2 chiral dialkyl oatates. 3. A method according to claim The method according to claim 1, characterized in that the fluorides of group I metals of the Oresoo system, KF, CsF, / C-Hg / NF, / C-Hg / NF are used as the source of fluoride ions. 3H2O, / CHj / -NF, optionally in the presence of 18-croon-6 koh ether, with a stechtomethometic ratio of 2-6 Huokkoo ions per 1 humanoid compound with tongue 6, for which 'Quick symbols have the meaning given in claim . 1. 4. The method according to p. A compound according to claim 1, characterized in that, as the solvents for the transformation reaction of a compound with a general expression 6, in which the mean symbols have the meaning given in claim 1, 1, with the derivative of the general oz. 7, wherein R is the meaning given in claim 1, 1, ether for ethylene benzene, toluene, tetrahydrofuran, acetonitrile, pentane and hexane or mixtures thereof is used.