DE2321984A1 - PROCESS FOR THE PREPARATION OF 3HYDROXY-5-OXO-1-CYCLOPENTEN-1-ALKANIC ACIDS AND THEIR ESTERS - Google Patents

Description

LAWYERS

DR. JUR. DiPL-CHEM. WALTER BEIL ALFRED KOEPPENER
DR. JUR. DIPL-CHEM. H.-J. WOLFP DR. JUR. HANS CHR. AX

623 FRANKFURTAM MAIN-HOCHS?

AMlONSTRASä »

April 26, 1973

Our No. 18 65I

Pr / br

G.D. Searle & Co. Skokie, 111, V.St.A.

Process for the preparation of 3-hydroxy-5-oxo-1-cyclopentene-1-alkanoic acid-n and their esters.

The invention relates to a process for the preparation of 3-hydroxy-5-oxo-1-cyclopentene-1-alkanoic acids and their Esters of the general formula

(CH ₂ ) _m COOR.

(D

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-2- 2321384

wherein R is a hydrogen atom. or an alkyl radical with 1 to 7 carbon atoms and m 5, 6 or 7 mean. The inventive method consists in that one Compound of the general formula

(CH ₉ ) COOR

Ui)

in which R and m have the above meaning and R ¹ denotes an alkyl radical having 1 to 7 carbon atoms, brings into contact with a hydride reducing agent in a "suitable inert solvent and the resulting 5-hydroxyenol ether with a suitable acidic agent that Hydrolysis and dehydrogenation caused, treated, with the corresponding compounds of the formula I being formed.

The alkyl radicals represented by R and R ¹ in the above formulas can be methyl, ethyl, propyl, butyl, pentyl, hexyl and heptyl radicals and their branched-chain isomers. -

Examples of hydride reducing agents that are suitable for the Processes according to the invention are suitable, aluminum hydrides, such as aluminum hydride, lithium aluminum hydride, sodium di-

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hydro-bis- (2-methoxyethoxy) -aluminate and borohydride lithium borohydride, borane and similar reagents Aluminum hydrides are preferred, with sodium dihydrobis (2-methoxyethoxy) aluminate is particularly preferred.

Effective acidic agents for use in the hydrolysis-dehydrogenation step are for example the mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and perchloric acid as well as the strong organic acids such as malonic acid, oxalic acid or perchloracetic acid.

Typical inert solvents are, for example, tetrahydrofuran and toluene. The choice of solvents is made in general by solubility points of view, which the expert are known, determined.

The process is carried out at temperatures below 10 ⁰ C with a temperature range between about -90 ⁰ C to +10 ⁰ C as an example. A particularly preferred temperature range is between -60 ° C and -40 ⁰ C. The reaction times are not critical, but times between 1 to 16 hours are typical.

The invention compounds can be prepared according to by extraction ⁵ - and chromatographic methods which are known in the art, isolate. For example, extractions with ethyl acetate and chromatographic separation on silica with ethyl acetate-benzene as the eluent are typical.

In a preferred embodiment of the invention, 2-methoxy- ⁱ ^ -hydroxy-5-oxo-1-cyclopentene-lheptanoic acid and its alkyl ester are allowed to react with an aluminum hydride reducing agent and then with a mineral acid, the corresponding 3-hydroxy-5 ~ oxo-

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l-cyelopenten-l-heptanoic acid and its esters are obtained.

In a particularly preferred embodiment of the invention becomes 2-methoxy-4 ~ hydroxy-5-oxo-1-cyelopenten-lheptanoic acid and their AlkyIester with sodium dihydro'-bis- {2-methoxyethoxy) aluminate and then with hydrochloric acid to form 3 ~ hydroxy-5-oxo-l-cyelopenten-l-heptanoic acid or their esters treated.

The starting materials used in the process according to the invention can be prepared by methods as described by Fappo, Collins and Jung, Annals NY Academy of Sciences, ISO, 64 (1971). For example, 2-methoxy-4-hydroxy-5-oxoeyclopent-1-enoctanoic acid and its lower alkyl esters are prepared by the methods described therein, 10-oxoundecanoic acid being used as the starting compound instead of 9-oxodecanoic acid. In addition, the 2-alkoxy derivatives are prepared by reacting, instead of 2, 2-dimethoxypropane reagents, the appropriate 2,2-di (lower alkoxy) propane used and that instead of the methanol solvent described therein uses the appropriate alkanol solvent.

The treatment of a solution of methyl 2-methoxy-4-hydroxy-5-oxocyclopent-1-enheptanoate in toluene with a toluene solution of sodium dihydro-bis- (2-methoxyethoxy) -aluminate at a temperature of -70 is typical of the process according to the invention C to -60 C and subsequent heating to 0 ⁰ C and treatment of the methyl ^ jS-dihydroxy-2-methoxy-l-cyclopentene-l-heptanoate with hydrochloric acid, whereby one methyl ^ -hydroxy-S-oxoeyclopenten-l-heptanoate receives.

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The compounds which can be prepared according to the invention are suitable for the preparation of pharmacologically active prostaglandins derivatives that have antiulcerogenic effects and act as prostaglandin antagonists.

Prostaglandin derivatives are prepared, for example, in that the compounds according to the invention with an alkenyl copper, trialkiny, aluminum or trialkinyl boron compound be brought into contact. These connections can be made through the. below general formulas

CH ₃ (CH ₂ ) _n CH = CH-Cu

₃₃
/ CH ₃ (CH ₂ ) _n C = c £ 7 ₃ B

represent where η is an integer greater than 2 and less than 6.

The "trans-1-alkeny! Copper compounds are made by adding from copper-I-iodide to the appropriate trans-1 / alkenyl magnesium chloride in a suitable solvent such as tetrahydrofuran. The t'rans-l7Alkeny! Magnesium chloride are made by using mercury-II chloride activated magnesium with trans-1-alkenyl mercury-II chloride is brought into contact, which in turn is produced by first the 1-alkynes with pyrocatechol, catecholborane are brought into contact and the product is then treated with mercury (II) chloride.

The cis-1-Alkeny! Copper compounds are ^ from the c is-1- AlkenyIbromiden produced by these one after the other treated with lithium and copper-i-iodide.

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The process for the preparation of the is-1-alkenyl bromides was made by Q.B. Bachmann in Journal Amer. Chem. Soc. 55, 4279 (1933).

The Trialkiny! Aluminum compounds are made by the appropriate 1-alkyne with butyllithium and then treated with aluminum trichloride. The trialkiny! Boron compounds are made in the same way made with the difference that boron trichloride, boron tribromide, boron trifluoride or boron trifluoride etherate is used will. The reactions are generally carried out in a suitable solvent such as ethyl ether or tetrahydrofuran or toluene. The copper, boron and aluminum compounds are generally used in situ.

The, trans-l-: H5xenylmercury-II chloride is typically produced by 1-hexyne with pyrocatechol and then with mercury (II) chloride in Contact is brought. The t.'rans-1-kexenylmercury-II-chloride is then added to a suspension of magnesium powder and tetrahydrofuran. The resulting "trans-1-liexeny! Magnesium chloride is not isolated, but treated with copper-I-iodide, whereby t.'rans-l-hexeny! copper is obtained, which is used in situ and with _ tetrahydrofuran ^ -yl-S-oxocyclopent-l-enheptanoate treated to obtain 2- (1-hexenyl) -5-oxocyclopentanheptanoic acid.

The preparation of the 2-alkynylcyclopentanalkanecarboxylic acid derivatives takes place, for example, by treating 1-octyne with butyllithium and then adding Alurainium trichloride, whereby trioctinyl aluminum is obtained that is used in situ and that with methyl 3 ~ hydroxy-5-oxocyclopent-1-enheptanoate is implemented, whereby

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the prostaglandin derivative is methyl 3-hydroxy-2- (loctinyl) -5-oxocyclopentane heptanoate receives *

The following examples serve to further illustrate the invention. The quantities are given as parts by weight unless parts by volume are named as such. The ratio between parts by weight and parts by volume is the same as between grams and milliliters. The infrared maxima were determined in chloroform solution and are given in reciprocal centimeters (cm). the NMR spectra were recorded on a 100 mega Hertz instrument using tetramethylsilane as a reference material and are reported as Hertz.

example 1

87 parts of dry toluene, which had been cooled to -70 ° C, were simultaneously with a solution of 15.5 VolI, parts of a 1.83. M sodium dihydrobis (2-methoxyethoxy) -aluminate-benzene solution in 87 parts of toluene and a solution of 6.92 parts of methyl 2-methoxy-4-hydroxy-5-QXO-1-cyelopenten-1-heptanoate in 176 parts of toluene were added dropwise . The addition was carried out at a rate which was set so that the temperature did not rise above -6O ⁰ C and that the sodium dihydro-bis (2-methoxyethoxy) aluminate was added somewhat faster than that. The addition took place over a period of about 15 minutes, and then 15 by stirring the reaction mixture for 3.5 hours at -7O ⁰ C. After this time, the temperature at O was allowed to rise ⁰ C, and the reaction mixture was further at this temperature Minutes stirred. Then 4 parts of methanol in 8.7 parts of toluene and then 150 parts by volume of 1N hydrochloric acid were added. The forming

Λ changed dispatched on

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aqueous and organic layers were separated from each other separated, and the organic layer was sequentially washed with aqueous potassium bicarbonate and water and dried over anhydrous sodium sulfate. The solvent was stripped off under reduced pressure, giving methyl 3 "" hydroxy-5 "" oxo-1-cyclopentene-1-heptanoate The crude product was then dissolved in 222 parts of tetrahydrofuran and treated with 30 parts by volume of an 1-in hydrochloric acid solution. The total mixture was left about Stand for 16 hours at about 4 ° C and then removed the tetrahydrofuran under reduced pressure. The residual substance was diluted with ethyl acetate, and the organic layer was washed with potassium bicarbonate and water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residual crude product from diethyl ether crystallized, pure methyl 3 "-hydroxy-5'-oxo-eyclopenten-1-heptanoate received; Melting point about 50 - 51 C and -, IR spectrum maxima in chloroform at

about 3,600, 3 020, 2 930, 2860, 1 720, 1 44O _? 1 20, 1 100, 1 030 and 790 cm * " ¹ .

Example 2

222 parts of redistilled tetrahydrofuran * were ^{cooled to 0} ° C. and then treated with 15.6 parts by volume of a solution of lithium aluminum hydride in tetrahydrofuran. The temperature of this mixture was lowered to -70 ⁰ C, and there were 6.92 parts of methyl 2-methoxy-4-hydroxo-5-ox <> ~ 1-eyclopenten-i-heptanoate, dissolved in 53 parts of tetrahydrofuran, was added . The addition took place over a period of 2 minutes j and not allowing the temperature of the Reaktionsgemisehs about -60 ⁰ C to rise. After the addition

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- y -

was ended, the temperature was ^{lowered to -70 0} C, and the reaction mixture was stirred for 4.5 hours. Thereafter, 4 parts of methanol and 8.9 parts of tetrahydrofuran were added and the temperature was allowed the reaction mixture to -20 ⁰ C to increase, after which 6o parts by volume were in hydrochloric acid solution was added slowly a. The resulting mixture is allowed to stand at a temperature of about 4 ° C. for 16 hours. Then the solvent was removed under reduced pressure and the remaining residue was diluted with ethyl acetate. The aqueous and organic layers that formed were separated and the organic layer was washed with water,

washed over potassium bicarbonate and water and / anhydrous Dried sodium sulfate. After the solvent was removed under reduced pressure, the residual one became Substance chromatographed on silica with ethyl acetate / benzene (1: 4) as the eluent, whereby one Received methyl S-hydroxy-S-oxo-l-cyclopentene-l-heptanoate, which was identical to the product of Example 1.

Example 3

222 parts back distilled tetrahydrofuran was cooled to 0 ⁰ C and then 23 parts by volume ** treated in a solution of lithium aluminum hydride in tetrahydrofuran. The temperature of the mixture was lowered to ~ 70 ° C, and it. 6.9 parts of 2-methoxy-4-hydroxylc-5-oxo-1-cyclopentene-1-heptanoic acid, dissolved in 53 parts of tetrahydrofuran, were added. The addition took place over a period of 2 minutes and the temperature of the reaction mixture was not allowed to rise above -60 ° C. After the addition was over,

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the temperature at -70 ⁰ C was lowered, and the reaction mixture was stirred for 4.5 hours. Thereafter, 4 parts of methanol and 8.9 parts of tetrahydrofuran were added, and the temperature of the reaction mixture was allowed to rise to -20 ° C., after which 60 parts by volume of an 1 N hydrochloric acid solution were slowly added. The resulting mixture was allowed to stand at a temperature of about 4 ° C for 16 hours. The solvent was then removed under reduced pressure and the remaining residue was diluted with ethyl acetate. The resulting aqueous and organic layers were separated, and the organic layer was washed with water, potassium bicarbonate and water and dried over anhydrous sodium sulfate. After the solvent had been removed under reduced pressure, the residue was chromatographed on silica with ethyl acetate / benzene (1: 4) as the eluent, 3-hydroxy-5-oxo-1-cyclopentene-1-heptanoic acid being obtained in the form of an oil which was characterized by IR maxima in chloroform at about 3,000, 1,730, 1,460, 1,300 and 1,060 cm.

Example 4

10 parts of sulfuric acid were mixed with 9 parts of a 20 # igen treated fuming sulfuric acid and allowed to stand for 10 minutes at room temperature. 1.25 parts by volume of this Solution was then added dropwise to 28.5 parts by volume of a solution of lithium aluminum hydride in tetrahydrofuran added. After the addition was complete, the temperature was held at -60 ° C. for 15 minutes and then left rise to room temperature. The aluminum hydride solution obtained was cooled to -60 ° C and quickly one

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Solution of 6.92 parts of methyl 2-methoxy-4-hydroxy-5-oxol-cyclopentene-1-heptanoate, redistilled dissolved in 10 parts Tetrahydrofuran, which had cooled to -40 ° C., was added. The temperature was up after the addition had ended, reduced to -70 .C, and the reaction mixture was stirred at this temperature for 3.75 hours. Then 7 * 9 parts of methanol in 17.8 parts of tetrahydrofuran were slowly added and the temperature was released -20 ° C rise and then put 120 parts by volume of an In hydrochloric acid solution. The mixture was left for about 16 hours stand at 4 ° C and then removed the solvent under reduced pressure. The remaining aqueous residue was diluted with ethyl acetate and the organic and aqueous layers separated. the organic layer was made with water, potassium carbonate and Water washed. Then it was dried over anhydrous sodium sulfate and the solvent was reduced under reduced pressure Pressure removed, methyl-3-hydroxy-5 ~ ox <-> ~ l-cyclopentene-l-heptanoate received what with the product of Example 1 was identical.

Example 5

The procedure of Example 1 was followed using an equivalent amount of ethyl 2-ethoxy-4-hydroxy-5-oxo-lcyelopenten-1-heptanoate, and ethyl 3-hydroxy-5-oxo-1-cyclopentene-1-heptanoate was obtained marked by IR maxima in chloroform at about 3,600, 3,020, 2,930, 2,860, 1,720, 1,260, 1,100, 1,030 and 790 cm " ¹

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Example 6

The procedure of Example 2 was carried out using one equivalent amount of lithium borohydride and received methyl 3-hydroxy-5-oxo-l-cyabpentene-l-heptanoate, which was identical to the product of Example 1.

Example 7

The procedure of Example 1 was followed using an equivalent amount of methyl 2-methoxy-4-hydroxy-5-oxo-1-cyclopentene-1-octanoate and received methyl ~ 3 ~ hydroxy-5-oxo-1-cyclopentene-1-octanoate, that by IR maxima in chloroform at about 3,600, 3,020, 2,930, 2,860, 1,720, 1,440, 1,260,

mm A

1 100, 1 030 and 790 cm. Example 8

A solution of 10.0 parts of methyl 2-methoxy-4-hydroxy-5-oxo-1-cyclopentene-1-heptanoate in 450 parts of redistilled tetrahydrofuran was cooled to 39.degree. To this solution, 65.7 parts by volume of O ₉ 56M borane in a tetrahydrofuran solution were quickly added with stirring and under a nitrogen atmosphere. The reaction mixture was stirred at -40 ° C. for 2.5 hours and 248 parts of acetone were added. The solution was stirred for an additional hour, then acidified with dilute aqueous hydrochloric acid and allowed to warm to room temperature. After standing for several hours at room temperature, the acetone and the tetrahydrofuran were removed by heating to 40 ° C., and the residual material was extracted with ethyl acetate.

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The ethyl acetate extract was diluted with potassium carbonate washed and dried over anhydrous sodium sulfate. Thereafter, the solvent was reduced under reduced pressure removed, and the crude product was on silica using ethyl acetate / benzene (1: 4) as the eluent chromatographed, giving methyl 3-hydroxy-5-oxo-1-cyclopentene-1-heptanoate, which was obtained with the product of Example 1 was identical.

Example 9

A mixture of 0.24 parts of methyl 3-hydroxy-5-oxo-lcyclopenten-1-heptanoate, 10 parts by volume of sodium hydroxide and 7> 9 parts of methanol were left for 16 hours stand at room temperature, then diluted it with water and extracted it with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulfate and the solvent stripped off under reduced pressure. Chromatography of the crude product on silica gel with 50 # strength ethyl acetate / benzene gave 3-hydroxy-5-oxo-lcyclopenten-1-heptanoic acid with a melting point of about 47 - 48.5 ° C. The connection continues through absorption in the UV spectrum at about 222 mu with-a molecular Characterized extinction coefficients of about 7,700.

Example 10

A solution of 200 parts by volume of borohydride in tetrahydrofuran was added dropwise at 0 ° C with stirring under a nitrogen atmosphere over a period of 13 minutes

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22 parts of catechol in 44 parts of tetrahydrofuran are added. This solution was stirred for one hour at room temperature. Then 16 parts of 1-hexyne were added and the solution was refluxed for 2 hours. The reaction mixture was ^{cooled to 0 °} C. and treated with 54 parts of mercury (II) chloride. The resulting mixture was ^{stirred for one hour at 0 °} C. and allowed to warm to room temperature. After 16 hours. Standing at room temperature, the mixture was poured into a ~ 5'.l water / acetone mixture and the white precipitate that formed was collected and washed with water. Then, the precipitate was dissolved in boiling hexane and the, solution was while it was still hot, filtered and cooled to 0 ⁰ C to give white crystals of trans-1-Hexenylquecksilber-II-chloride having a melting point of about 111 ° C formed.

Example 11

Example 10 was repeated using an equivalent Amount of 1-octyne and received trans-1-octenylqueekilver-II-chloride with a melting point of about 1O4-1O5 ° C.

Example 12

A suspension of 1.6 parts of magnesium powder and 27 parts Tetrahydrofuran obtained from a solution of ethyl magnesium bromide Was distilled off, was mixed with a part of Queefcsilber (II) chloride treated. After stirring the mixture for 15 minutes, it became 5.1 parts of trans-1-hexenylmercury-II chloride was added and the mixture was stirred at room temperature for about 16 hours. The supernatant liquid was decanted from the excess magnesium and d'anr stirred and in an isopropanol / dry ice bath to -60 ° C

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cooled down. Thereafter, 3 _} 0 parts of copper I-iodide were added in one portion, and the mixture was allowed to warm to -30 ° C. and held at this temperature for 10 minutes. The mixture was cooled to -60 ° C. and 1.47 parts of methyl 3-hydroxy-5-oxo-1-cyclopentene-1-heptanoate dissolved in tetrahydrofuran were added dropwise to the reaction mixture. This mixture was stirred for 30 minutes and then poured into a mixture of 140 parts of ethyl ether and 100 parts by volume of 0.5N hydrochloric acid. The ether layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure and the residue was dissolved in 40 parts of acetone containing 10 parts by volume of hydrochloric acid. The mixture was allowed to stand at room temperature for 1 hour, diluted with water and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and the solvent stripped off. The remaining residue was chromatographed on silica gel using ethyl acetate / benzene as the eluent and gave racemic methyl 2ß- (1-hexenyl) -3o £ - hydroxy-5-oxocyclopentane-Kfc.-heptanoate, racemic methyl-206- (l- hexenyl) -3 ^c C-hydroxy-5-oxocyclopentane-lßheptanoat and racemic methyl 2ß- (l-hexenyl) -3C £ - hydroxy-5 ~ oxocyclopentane-lßheptanoat as yellow oils. These compounds showed absorption maxima in the IR spectrum at 1,744 cm " ¹ .

Example 13

The procedure according to Example 12 was carried out using equivalent amounts of trans-l-octenylmercury-II chloride and methyl ^ -hydroxy-S-oxo-l-cyclopentene-l-heptanoate and received

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racemic methyl 2 & e- (l-octenyl) -3c (rhydroxy-5-oxocyclopentane-lß-heptanoate, which is characterized by NMR peaks in deuteriochloroform at about 559 (multiplet) and 430 (complex) Hertz; racemic methyl-2ß- (loctenyl) -3Ctrhy ^drox y ~ 5 ~ oxocyclopentane-dc6-heptanoate _i which is characterized by NMR peaks in deuterio-chloroform at about 567 (multiplet), 530 (douplet) and 403 (complex) Hertz, and racemic methy 1 -2Qi- (I-octenyl) - ~ $ O & hydroxy-S-oxocyclopentane-lß-heptanoate, which by IR-Ab-

sorption maximum is marked at about 1 7 ^ 8 cm.

These substances were in the form of yellow oils.

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Claims (6)

Patent claims: 1. Process for the preparation of 3-hydroxy-5-oxo-lcyclopenten-1-alkanoic acids and their esters of the general formula (CH ₂ ) _m COOR (I) H ' wherein R is a hydrogen atom or an alkyl radical having 1 to 7 carbon atoms and m 5> 6 or 7 mean, characterized in that a compound of the general formula (CH ₂ ) _m C00R (II) )H 309846/1160 wherein R and m are as defined above, and R ^T is alkyl of 1 to 7 carbon atoms, first with a hydride reducing agent and then with an acidic medium at a temperature of -90 ⁰ C to +10 ⁰ C in contact brings . · 2. The method according to claim 1, characterized in that an aluminum hydride derivative or a borohydride derivative is used as the hydride reducing agent and a mineral acid is used as the acidic agent and that temperatures of -60 to -40 ° C are used \ 3. The method according to claim 1, characterized in that the hydride reducing agent used is aluminum hydride, Lithxum aluminum hydride, sodium dihydro bis (2-methoxyethoxy) aluminate, sodium borohydride or borane and a mineral acid is used as the acidic agent. 4. The method according to claim 1, characterized in that a compound is used in which m 6 and R ¹ mean the methyl radical and that the hydride reducing agent aluminum hydride, lithium aluminum hydride or sodium dihydro-bis (2-methoxyethoxy) aluminate and as acidic means mineral acid used. ^ 5. The method according to claim 1, characterized in that a compound is used in which m 6 and R ¹ denote the methyl radical that is used as the hydride reducing agent 308846/1160 Sodium dihydro bis (methoxyethoxy) aluminate and as acidic agent used hydrochloric acid. 6. The method according to claim 1, characterized in that a compound is used in which m is 6 and R and R * Methyl radicals are used as the hydride reducing agent sodium dihydro-bis (methoxyethoxy) aluminate and as acidic agent used hydrochloric acid. For:, G. D. Sear le & Co. Dr W. Beil Lawyer 309846/1160