DE2131944A1 - Process for dehalogenation, as well as dehalogenation and simultaneous reduction in the case of C6-a 11a-chloro-6-deoxy-6-desmethyl-6-methylene tetracycline - Google Patents

Description

Dr. Ing. E. BERKENFELD · Dipl.-Ing. H. BERKENFELD, patent attorneys, Cologne Attachment file number

on the submission of July 23, 1971 VA./ Name d. Note ΙΥβΙ! V 1 1 1 Ά X

Process for dehalogenation and dehalogenation and simultaneous reduction at C6 of a Ha-chloro-o-deoxy-a-desmethyl-6-methylenetetracycline

The o-deoxy-ö-desmethyl-o-methylentetracycline and 6-deoxytetracycline are important antibiotics, of which the 6-deoxy-6-desmethyl-6-methylene-5-hydroxytetracycline (Methacycline) and the alpha-6-deoxy-5-hydroxytetracycline (Doxycyiin) the most important are.

The preparation of the o-deoxy-fr-desmethyl-o-methylentetracycline is known from Portuguese patent application 36,099, German patent 1,156,415 , British patent 951,663 and US patent 2,984,686.

The 6-deoxytetracyclines are known from US Pat. No. 3,019,260 by catalytic hydrogenation of tetracycline, oxytetracycline and chlortetracycline to obtain the beta-6 isomers be obtained, or, as known from Uü patent 3.200.149, by a catalytic hydrogenation of methacycline or Ha-halo-methacycline, a mixture of obtained alpha-6 and beta-6 isomers in various amounts will. From US patents 3,165,531 and 3,484,483 and the Portuguese patent 52,217 it is known the alpha isomers without obtaining the beta isomer that would otherwise occur at the same time.

The present invention relates to a process for producing the 6-methylenetetracyclines in almost stoichiometric yield

V 10/42 - 1 -

¹ 1091 * 4/1877

and in a satisfactory yield of the 6-deoxytetracyclines while avoiding the disadvantages occurring in the known processes.

For the process of the invention, the 11a - <^ lor-6-deoxy-6-desmethyl-6-methylenetetracyclines serve as starting compounds described for the first time in Portuguese patent application 36,099 dated May 19, 1959.

It has been found that the Ha-chloro-o-deoxy-ö-desmethyl-6-methylene tetracyclines easily dehalogenated by hydrazine if it is present in an equimolecular amount a catalytic amount of palladium-activated carbon in an inert reaction medium, using the same procedure the 6-methylentetracyclines and the 6-deoxytetracyclines can be obtained when the amount of hydrazine present is at least two equivalents and the catalyst is preferably platinum is.

A significant advantage of the process of the present invention is that the secondary product of the reaction is nitrogen which of course does not interfere with the separation of the end product in its pure form.

The 6-deoxy-6-desmethyl-6-methylenetetracyclines are produced according to the method of German patent specification 1.156.405 and British patent specification 951.663 obtained by acid dehydration of the 12-sulfuric acid ester of tetracycline; the hints are, however, because of a partial decomposition of the methylentene tracycline is relatively low in the strongly acidic medium. Portuguese patent application 36.099 describes dehalogenization the Ha-halogen-o-deoxy-ö-desmethyl-ö-methylentetracycline by hydrosulfite; according to the method of US Pat. No. 2,984,686, the dehalogenation is carried out by zinc and a mineral acid, iron and dilute hydrochloric acid, alkali metal hydrosulfite in an aqueous medium, sodium iodide in a halogen acceptor medium, like acetone, and by catalytic hydrogenation.

V 10/42 - 2 -

109884/1877

In these processes, with the exception of catalytic hydrogenation, By-products, such as zinc chloride, ferric chloride, free sulfur, often in colloidal form, sodium iodide and sodium chloride, which must be separated from the methylene tetracyclines, which however is a difficult process and the final yield is considerable decreased. Catalytic hydrogenation does not give secondary products as such, but it also leads to one considerable destruction of the molecules to be dehalogenized as well as, as has been established, simultaneous formation of alpha- and beta-deoxytetracyclines, even if the hydrogenation is interrupted if the hydrogenation is terminated when the exactly required for a dehalogenation equimolar amount of hydrogen has been absorbed.

Dehalogenation by hydrazine in the presence of palladium-activated carbon is more advantageous than direct catalytic hydrogenation, as pressure or special equipment is not required and it is less dangerous than catalytic hydrogenation, since the molecules to be dehalogenated are not are destroyed and the simultaneous formation of alpha- and beta-6-deoxytetracyclines can be neglected if no or only a small excess over the equimolecular amount of hydrazine has been used; as a catalyst is preferred Palladium activated carbon used.

If you have at least two equivalents of hydrazine or an excess is used, and especially if the catalyst is platinum, the dehalogenation occurs at the same time as the formation of the 6-deoxytetracyclines reduce the 6-methylene bond. It is surprising that the reaction according to the invention occurs simultaneously on the C11a and C6 and not in stages, as one would expect could, first at the C11a and then at the C6- entry. Since the production of the alpha- and beta-isomers depends on the pH, a slightly acidic pH range in the vicinity of the favors Neutral point the formation of the alpha isomer, but also at the same time the formation of degradation products. At a pH of 3, the proportion of alpha and beta isomers is about 1: 1, while at

V 10/42 - 3 -

109884/1877

even more acidic conditions result in the formation of the beta isomer grows. With the help of a few experiments, the optimal pH range for each starting compound can be determined and during the execution of the invention, the pH can be adjusted by the continuous addition of the hydrazine solution by neutralizing the during the dehalogenation formed hydrohalic acid are kept constant. Compared to catalytic hydrogenation, the formation of Degradation products at a given pH are much less pronounced when hydrazine is used as an agent for dehalogenation and reduction is used.

In the preparation of the 6-deoxytetracycline is in the reaction mixture also a certain amount of 6-deoxy-6-desmethyl-6-methylentetracyclines educated and considering the fact that these are also valuable antibiotics, sis can at the same time isolated with the 6-deoxytetracyclines and then according to the procedure of the Portuguese patent application 54,109 (same priority German application filed with the same post as this one) must be separated.

The starting compounds used for the process of the invention are the Ha-Cailor-e-deoxy-e-desmethyl-e-methylentetracyclines, in the form of their free base, an acid addition salt, such as the hydrochloride, hydrofluoride or p-toluenesulfonate or their molecular complexes with Ν, Ν'-dibenzylethylenediamine or N, N'-dibenzylethylenediimine. The diamine or Diimine can be prepared by adding an acid addition salt of the free base of 11a-chlorine derivatives with N, N'-dibenzylethylenediamine (DBED) or N, N'-dibenzylethylenediimine (Δ-DBED) in an inert solvent and the complex compounds falls by means of a nonsolvent such as a lower dialkyl ether. Examples of inert solvents for the implementation are lower aliphatic ^ alcohols and a lower dialkylformamide. When using a 5-hydroxy derivative, it is preferable to work under anhydrous conditions in order to produce 5-12a-lactone, a known degradation product avoid. The use of the molecular complexes in the manufacture

V 10/42 - 4 -

109884/1877

position of the 6-deoxytetracycline allows this in a simple way Maintain pH constant so that the highest yields of the alpha isomer are obtained. The new DBED and DBED complexes from iia-chloro-o-deoxy-ö-desmethyl-o-methylentetracyclines are also useful as starting compounds for a catalytic hydrogenation to obtain the 6-deoxytetracyclines.

A lower reaction medium is used for the hydrazine reduction alphatic alcohol, tetrahydrofuran, dioxane, a lower one Dialkylformamide, aoetone, water, or a mixture of these in Question. When Ha-chloro-ö-deoxy-e-desmethyl-ö-methylen - ^ - hydroxytetracycline the starting compound and the initial pH higher than 3, it is preferred to use an anhydrous medium for the reaction. To perform this procedure, one can use a hydrazine hydrate or a hydrazine acid addition salt, such as the hydrochloride or sulfate,

The reaction temperature is not critical; it can be in a range between -10 and + 50 ° C. When preparing the 6-deoxytetracyclines, however, a higher temperature range of 25 to 50 ° C is preferred.

Palladium is the preferred noble metal catalyst for the production of 6-methylenetetracyclines, and platinum is preferred for the production of 6-deoxytetracyclines; however, rhodium can also be used. The amount of catalyst used to prepare the 6-methylenetetracyclines is not critical; an amount as small as 0.001 part of 5 % palladium-activated carbon per part Ha-halo-tetracycline can be used to promote the dehalogenation even if the reaction is slow. To produce 6-deoxytetracyclines, approximately 0.1 part of platinum on a suitable carrier such as carbon is required. These amounts can be increased up to 2 parts without causing further destruction of the molecules.

The 6-methylenetetracyclines can be isolated in a known manner can easily be done, for example by filtering the conversion

V 10/42 - 5 -

109884/1877

mixed and acidification with an ethanolic or methanolic Hydrogen chloride, whereby the hydrochloride is obtained in a pure state. Any other acid addition salt can also be used 6-methylenetetracyclines by treating the filtered reaction mixture with the desired acid and crystallization can be obtained by adding a nonsolvent. A Procedure for the isolation and purification of 6-deoxytetracyclines is in the simultaneously filed Portuguese application 54,109 corresponding patent application.

For a better understanding of the invention, the preparation of the starting compounds is first described in the following the method of Portuguese patent application 36.099 (1959) taking into account further improvements and some practical ones Details described.

Preparation of 11a-chloro-5-hydroxytetracvcline

a) 0.7 g of anhydrous chlorine in 25 ecm of 1,2-dimethoxyethane were rapidly added to 9.5 g of high-purity oxytetracycline hydrochloride in 25 ecm of diethoxyethane containing 5.6 ecm of triethylamine at 0 ° C; then 125 ecm of a mixture of water and ice were added and after 12 minutes a further amount of 300 ecm of a mixture of water and ice. The precipitate was filtered off, washed with water and acetone and then dried at 10 ° C. and the ha-chloro-5-hydroxytetracycline was obtained in the form of the 6,12-ketal. The melting point with decomposition was 177 to 178 ° C; it had a specific rotation / oU-q -27.5 (c = 1 in methanol containing 1 % concentrated aqueous hydrochloric acid), E _1c jj 430 at 266 mu ± 2 in methanol containing 1 % concentrated hydrochloric acid. The infrared curve showed no absorption maximum in the 5 µ area at 5.9 p.

b) 13.5 g of N-chlorosuccinimide were obtained at 0 ° C. with vigorous stirring quickly added to a solution that was 46.5 g of anhydrous

V 10/42 - 6 -

109884/1877

Oxytetracycline base in 200 ecm diethoxyethane and 0.5 ecm triethylamine contained. After 6 minutes, 1000 ecm of water were added, the pH automatically adjusting to about the isoelectric Point set; a not quite white precipitate was obtained, which was filtered off and washed with water; 11.6 g of 1Ia-chloro-5-hydroxytetracycline were obtained as a 6,12-hemiketal obtain.

c) 25 g of oxytetracycline hydrochloride in 225 ecm of dimethylformamide were mixed with 7.1 ecm of triethylamine in 25 ecm of dimethylformamide and the mixture was cooled to -10 ° C. with vigorous stirring. 7 g of N-chlorosuccinimide were quickly added and, after 2.5 minutes, 750 ecm of a mixture of water and ice were added. After 12 minutes, the thick precipitate was diluted by adding 375 ecm of a mixture of water and ice, then filtered off and washed with water and acetone. After drying the precipitate, 11a-chloro-5-hydroxytetracycline-6,12-hemiketal was obtained, which had a melting point of 180 to 185 ° C. with decomposition; specific rotation / ct / _D -25 ± 2.5 (c = 1 % in methanol containing 1 % concentrated hydrochloric acid); E ^ j _c Jj 432 at 266 rough and 91 at 340 to 345 mu in methanol containing 1 % concentrated hydrochloric acid.

d) 5 g of the 11a-chloro-5-hydroxytetracycline obtained as 6,12-hemiketal base according to process steps a, b or c and 30 ecm of isopropyl alcohol were mixed and then 26 ecm of absolute ethanol containing 17% by weight of anhydrous hydrogen chloride , added. The product goes into solution, whereupon it begins to crystallize. After standing at room temperature for eighteen hours, the precipitate was filtered off and washed with isopropyl alcohol. The unreacted part of the ha-chloro-5-hydroxytetracycline present as the hydrochloride was removed from the mixture by filtration; Melting point 212 to 216 ° Cj / c (/ _n -22.5 (c = 1j6 in

1 9έ methanol containing 1 % concentrated hydrochloric acid); Ej Jz 400 at 266 to 268 mu and 85 at 337 to 341 mu. When

V 10/42 - 7 -

1Q988W1877

putting the filtrate with isopropyl ether fell 1.1 g of 11a-chloro-6-de soxy-6-de sme thyl-6-methylene-5-hydroxy te tracycline. Hydrochloride showing a single maximum in the 5 to 6 μ region at 5.72 μ.

There was added 3.3 g of the unreacted recorded as the hydrochloride Ha-Ghlorderivates with 10 cc of anhydrous hydrogen fluoride for 3 hours at -5 ° C treated, after which the hydrogen fluoride afcdestilliert and the residue was dissolved in ¥ anhydrous methanol, wherein the pH with triethylamine to 3 _f ^ was discontinued. The Ha-chloro-o-deoxy-ö-desmethyl-ö-methylene-5-hydroxytetracycline base slowly crystallized as a solvate. The anhydrous base had the following properties: decomposition at 176 ° C; jfö (/ _D +35 (c = 1 % in methanol containing 1 % concentrated hydrochloric acid); E ^ _c Jj 371 at 270 ιημ and 430 at 237 to 239 πμ in methanol containing 1 % hydrochloric acid; 100 mg went into 18 cc of ethanol, 440 cc methanol, 22 ccE dioxane _s 60 cc of acetone and 1 cc of dimethylformamide solution in. the infrared curve showed the main peaks at 2.8 μ, 2.98 μ, 3.25 μ, 5.72 μ, 6 , 08μ, 6.3μ, 7.8μ, 8.1μ, 8 ^, 42μ, 9.0μ, 9, ^ 18μ, 9.73μ, 10.6μ, 10.76μ , 10.82 µ, 11.6 µ, 12.1 µ and 12.3 µ.

e) 5 g of the unreacted iia-chloro-S-hydroxytetracyclin.Hydrochloride obtained in process step c were suspended in 15 ecm of a mixture of 1: 3 ethyl cellosolve and butanol, whereupon 15 ecm hydrogen fluoride were added at -18 ° C. After stirring for three hours at -4 ° to 0 ° C, the hydrogen fluoride was precipitated by a stream of nitrogen and the product was precipitated by adding isopropyl ether; 4.4 g of 11a-chloro-6-deoxy-6-desmethyl-6-methylene-5-hydroxytetracyclin.Hydrofluorid were obtained, which decomposed at 220 ° C .; E ^ JJjJ 421 at 235 πμ, 272 at 272 to 274 πιμ and 60 at 377 to 379 ιημ in methanol; the infrared curve showed a single maximum in the 5 to 6 µ range at 5.72 µ.

V 10/42 - 8 -

109884/1877

EXAMPLES

1. There were 2.5 g of 10 percent palladium activated carbon and 2 ecm of diluted hydrazine hydrate, 15 % _t to 5 g of 11a-chloro-6-deoxy-6-desmethyl-6-methylene-5-hydroxytetracycline.Hydrofluorid in 100 ecm Given ethanol. After 15 minutes, 2.7 ecm of 15 percent hydrazine hydrate were added and, after stirring overnight, the reaction mixture was filtered and then 5 g of 5-sulfosalicylic acid and 200 ecm of water were added. After stirring for one hour, it was filtered, washed and dried, and so 5.5 g of e-deoxy-ö-desmethyl-e-methylene-S-hydroxytetracycline were obtained as sulfosalicylate. Melting point at 189 to 193 ° C; specific rotation AV _n -220 (c = 1 in methanol containing 1 % concentrated hydrochloric acid); E, j _c JJ 397 at 238 mu and 219 at 345

2. There were 1.25 g of 5 percent palladium activated carbon in 15 ecm Suspended 70 percent aqueous dimethylformamide and then a solution of 5 g of Ha-chloro-ö-deoxy-e-desmethyl-e-methylene-5-hydroxytetraeycline-p-toluenesulfonate in 25 ecm of 70 percent aqueous dimethylformamide and 2 g of hydrazine sulfate were added. After stirring overnight, the reaction mixture was filtered and then 33 ecm of water and 5 g of 5-sulfosalicylic acid added; 4.9 g of methacycline sulfosalicylate, which is comparable to that of Example 1, were obtained.

3. There were 2 ecm of 15 percent hydrazine hydrate to 5 g of 11a-chloro-G-deoxy-e-desmethyl-e-methylene ^ -hydroxytetracycline. Hydrofluoride and 2.5 g of 10 percent palladium-activated carbon were added and then further amounts of 1 ecm each of hydrazine hydrate were added at intervals of 15 minutes until the total amount of 15 percent hydrazine hydrate was 8 ecm. After stirring for three hours, 5 g of sulfosalicylic acid and 200 ecm of water were added. After stirring for a further hour, 3.6 g of methacycline sulfosalicylate were separated off, which, as was shown by paper chromatography, contained 8 % alpha-doxycycline (Schleicher Schull Pa-

V 10/442 - 9 -

109884/1877

pier No. 2Q43bmgl-0 26.5, 'stationary solvent: McIlvain Buffer - pH 4.2} mobile phase: pyridine: benzene: nitromethane in a 3: 10: 20 ratio,

The crude sulfosalicylate thus obtained showed a shoulder at 10u in its infrared curve, which indicates the presence of doxycycline. The optical rotation was IdJ ^ -180 (c = 1 in methanol containing 1 % concentrated hydrochloric acid), Jv max. 238 ΐημ, 319 mu, 344 to 350 mu. Another 1.6 g of a precipitate fell out of the mother liquors overnight and, according to a paper chromatogram, consisted of 60 % methacyclla and 30 % doxycycline sulfosalicylate. The optical rotation of the crude product was JoCj _n -160 (c = 1 in methanol containing 1 % concentrated hydrochloric acid); EJ ₀ J 409 at 238 mu, 180 at 317 ψ, 194 at 340 mu, 195 at 349 mu.

4. Example 3 was repeated, but instead of palladium, platinum-activated carbon was used. 3.8 g of crude sulfosalicylate were obtained which, according to chromatography, contained 41 % methacycline, 53 % alpha-6-deoxy-5-hydroxytetracycline and 4 % beta-6-deoxy-5-hydroxytetracycline.

5. 5.1 g of the 11a-chloro-6-deoxy-6-desmethyl-6-methylene-5-hydroxytetracycline obtained as above under d) were neutralized in 45 ecm anhydrous acetone with 1.4 ecm triethylamine in 0 ecm acetone and then 1.2 g of N, N'-dibenzylethylenediamine in 5 ecm of acetone were added. After stirring for 2 to 3 minutes, isopropyl ether was added and in this way 5.5 g of the molecular complex compound Ν, Ν'-dibenzylethylenediamine. 1 la-chloro-ö-deoxy-ö-desmethyl-ö-methylene ^ - hydroxytetracycline (1 mole N, N ^f -dibenzylethylenediamine - 2 moles Ha-chlorine derivative) obtained. The infrared curve in mineral oil gauze did not show a maximum at 5.6 μ, which would have indicated a breakdown to the 5-12 lactone, but only a strong, thin maximum at 5.74 μj, further main maxima were at 2.95 μ , 6.1µ, 6.3µ, 6.4µ, 7.85µ, 9.5µ, 10.55µ, 11µ, 12.47µ, 13.3µ, 14.24µ.

V 10/42 - 10 -

109884/1877

6. Example 4 was repeated, but not N, N'-dibenzyläthylendiaatn, but N, N ^f -dibenzyläthylenediamine used and 5.3 g of the complex compound of Ν, Ν'-dibenzyläthylenendiimen and iia-Oilor-o ^ deoxy-ö- desmethyl-ö-methylene-S-hydroxytetracycline (1: 2 mol) was obtained. The infrared curve in the mineral oil gauze showed the following main maxima: 2.98 μ (sta, rk ), 5.73 μ, 6.1 μ, 6.3 μ, 6.6 μ, 7.82 μ, 8.12 µ, 8.46 µ, 9.1 µ, 9.76 µ, 10.05 µ, 10.55 µ, 11.5 µ. There was no maximum w at 5.6 μ.

The molecular complex compound of Ν, Ν'-dibenzylethylenediimine-calcium and Ha-chloro-δ-deoxy-o-desmethyl-o-methylene-5-hydroxytetracycline (1 mol: 1 atom: 2 mol) showed the following main maxiaa of the infrared absorption curve: 2.76 μ, 2.96 μ, 5.72 μ, 6.09 μ, 6.3 μ, 6.6 μ, 7.82 μ, 8.12 µ, 8.44 µ, 8.52 µ, 9.1 µ, 11.52 µ, 12.3 µ.

7. Example 3 was repeated, except that 5 g of the hydrofluoride were used instead of 6 g of the N, N ¹ -dibenzylethylenediamine complex obtained in Example 4. The crude sulfosalicylate contained 36 % methacycline and 40-56 alpha-6-deoxy-5-hydroxytetracycline, both as sulfosalicylate; the remainder consisted of impurities including the beta isomer.

Claims

V 10/42 - 11 -

1 Q9884 / 187 7

Claims (1)

21319U Dr. Ing. E. BERKENFELD · Dipl.-Ing. H. BERKENFELD, patent attorney ·, Cologne Tl Anlafl · file number 2urEin ₈ abevoni 23 JUOi 1971 VA / Nam. d. Note ΙνβΠ V I 1 1 B. X PATENT CLAIMS Process for dehalogenation and simultaneous dehalogenation and reduction aa C6- of a 11a-chloro-6-deoxy-6-deE-methyl-6-methylenetetracycline, characterized in that «an in the presence of catalytic amounts of a noble metal catalyst in an inert reaction medium, the 11a-chlorine derivative at C11a ~ dehalogenated by equimolecular amounts of hydrazine in order to obtain the corresponding S-deoxy-ö-desmethyl-ö-methylentetracyclines, and simultaneously by at least two equimoleculars Amounts of hydrazine dehalogenated at 11ad and reduced at C6- to obtain the appropriate 6-deoxytetracyclines, and then absorbs the compounds formed from the reaction mixture 2. The method according to claim 1, characterized in that aan as 11a-chlorotetracycline are the ha-chloro derivatives of 6-deoxy-6-desBethyl-6-ethylenetetracycline, δ-deoxy-o-desBethyl-e- ■ ethylene-5-hydroxytetracycline, e-deoxy-δ-desBethyl-o-ethylene -7-chlorotetracycline and e-deoxy-e-deeMethyl-e-methylene - ^ - hydroxy-7-chlorot "tracycline used, namely in the form of the free base, the acid addition salts, the molecular complex compounds of Ν, Ν'-dibenzylethylenediamine or · N, N «-dibenzylethylenediamine bxw. of the molecular complex compounds of N, N'-dibenzylethylenedi- or NfN'-dibenzylethylenediimine alkaline earth metal used 3. Process according to Claims 1 and 2, characterized in that the noble metal catalyst used is palladium, platinum or rhodium used 4. Process according to Claims 1 to 3, characterized in that V 10/42 - Hl - 10988A / 1877 bad original draws that the reaction is carried out at a temperature of -10 to + 50 ° C. 5.. Process according to Claims 1 to 4, characterized in that that the inert reaction solvent is a lower aliphatic alcohol, tetrahydrofuran, dioxane, a lower one Dialkylformarai d, acetone or a mixture of these is used. 6. Process according to claims 1 to 5, characterized in that the hydrazine is in the form of the hydrochloride, sulfate or hydrate is used. 7. A method for producing molecular complex compounds of Ha-chloro-ö-deoxy-e-desmethyl-e-methylentetracycline and N, N ^f -Qlbenzyläthylenediamine or Ν, Ν'-dibenzylethylenediamine according to claim 2, characterized in that a Ha- Chlore-desoxy-ö-desraethyl-o-methylentetracyelin with Ν, Ν'-dibenzylethylenediamine or Ν, Ν'-dibenzylethylenediamine in an inert reaction medium adjusted to a pH of 3.5 to 7-5 with ammonia or alkali hydroxide. 8. Process for producing the alkaline earth metal complex compounds according to claims 2 and 7, characterized in that the pH is adjusted with an alkaline earth metal hydroxide. 9. The method according to claims 7 and 8, characterized in that that the inert reaction solvent is a lower aliphatic alcohol, tetrahydrofuran, dioxane, a lower one Dialkylformamide, acetone or a mixture of these is used. 10. The method according to claims 7 to 9, characterized in that a reaction medium is used which also includes water contains, except when the Ha-chlorine derivatives have a hydroxyl group at C5-. 11. The method according to claims 1 to 6 for the production of mainly the alpha isomer having 6-deoxytetracycIi- V 10/42 - 13 - 109884/1877 «■ as- - - / ff nen, characterized in that the pH of the reaction mixture keeps constant to a value of 3 to 7 by gradually adding hydrazine slowly. V 10/42 - 14 - 109884/1877