DE1095277B - Process for the preparation of water-soluble derivatives of a steroid hormone - Google Patents

Description

The invention relates to a method for producing water-soluble derivatives of a steroid hormone, namely the alkali salts of 3,5-disulfamylbenzoate of testosterone the following general formula

(1 - 0 - C -

NH-SOoM

SO ₃ M

NH-

In this formula, M represents an alkali metal, e.g. B. sodium, potassium or lithium.

Such water-soluble derivatives are known to be of importance when higher hormone doses are to be administered quickly. In order to avoid the injection of large volumes, compounds are needed in these cases, the solubility of which in water is quite high. This is true for the disodium salt of 3,5-testosterone disulfamylbenzoats which is soluble at 20 ⁰ C to about 17% in water.

When carrying out the method according to the invention, testosterone 3,5-dinitrobenzoate is first prepared preferably by esterifying the hormone with a functional derivative of 3,5-dinitrobenzoic acid, z. B. its chloride, its anhydride or a mixed anhydride, and then treats the formed Ester with a mixture of sodium bisulfite and sodium sulfite in aqueous solution in the presence of a third Solvent, e.g. B. dimethylformamide, which serves to ensure that the testosterone-3,5-dinitrobenzoate goes into solution in the reaction medium. The reaction is in the heat, preferably carried out under reflux. The reduction of the nitro groups takes place at the same time Formation of the corresponding soluble disulfamate. According to a particular embodiment of the invention

CH,

CH,

Method of manufacture

water-soluble derivatives

a steroid hormone

Applicant:

Les Laboratoires Francais
de Chimiotherapy, Paris

Representative: Dr. F. Zumstein,

Dipl.-Chem. Dr. rer. nat. E. Assmann

and Dipl.-Chem. Dr. R. Koenigsberger, patent attorneys,

Munich 2, Bräuhausstr. 4th

Claimed priority:
France from August 4, 1958

Dr. Gerard Nomine, Noisy-le-Sec, Seine,

and Michel Vignau, Neuilly-sur-Seine (France),

have been named as inventors

according to the method is then to a quaternary ammonium salt, which by double conversion to Capable of forming an insoluble salt, e.g. B. benzyldimethyl 2 - [2 - (p -1,1,3,3 - tetramethylbutylphenoxy) ethoxy] ethylammonium chloride of the formula II, which is referred to below by its trade name "Hyamin 1622". The insoluble hyamin 1622 salt is separated of testosterone-3,5-disulfamyl-benzoate, takes it in a water-immiscible solvent, such as chloroform or methylene chloride, and cleans it by washing it with water.

CH,

Cm-C-CH ₉ -CC-Hi-O-CH ₉ -CH ₉ -O-CH ₂ -CH ₂ -N-CH ₂ -CH ₆

CH,

CH,

CH,

α

The hyamine salt is then made by reacting twice with a soluble potassium salt in a lower alcohol converted into the potassium salt. After releasing the acid groups of the testosterone-3,5-disulfamylbenzoate by acidification and extraction of the free acid or with the aid of an ion exchange resin, it is neutralized with Caustic soda. The sodium salt is made insoluble by adding a water-miscible solvent is, isolated and optionally purified by recrystallization from water.

The following examples explain the process according to the invention. The melting points given are those on instantaneous melting point determined by the block maquenne.

009 679/531

3 4

Example 1 3,5-disulfamylbenzoate is mixed with water up to the chlorine _{TT A} .,, "_ Τ-. . ^. _{, ^, freedom of washing water washed and dried} over magnesium production of the 3,5-dinitrobenzoate of testosterone sulfate. _{After d} ^S _em filtration, evaporate in

12 g of testosterone are dissolved to dryness with stirring in a vacuum under nitrogen.
Mixture of 48 ecm benzene and 12 ecm pyridine leads to 5

then, without exceeding 50 ° C and without stirring ^{Z B} * ^ld ™ g of the Kalmmsalzes
interrupting, 14 g dinitrobenzoyl chloride and sets The residue obtained heating to 50 ° C is continued another _^3/4 hour in anhydrous ethanol. After that from about 50 to 6O ⁰ C added. It is distilled, cooled to normal temperature, a little ethanol is added to remove benzene from the hyamine salt, it is washed with hydrochloric acid and maintained chloroform to remove the pyridine, and then made up of saturated aqueous sodium carbonate-ethanol with water Volume of about 300 ecm. After dissolving and again with water, the benzene solution is dried. Cooling to normal temperature is slowly poured over magnesium sulfate, filtered and evaporated to dryness with stirring without interruption of 160 ecm. This gives 19.2 g of crude testosterone dinotrobenzoat 10% solution of anhydrous potassium acetate in mp = 208-209 ⁰ C (95% yield), which absolute ethanol for 15 to. The mixture is stirred for a few minutes, the following reaction is sufficiently pure. Continue the analysis and then leave to stand overnight to the exclusion of cleansed by recrystallization from methanol and moisture. The crude dipotassium is then sucked out of acetone. F. = 217 ° C, [a] o "= 4-134 ° (c = 1% in the salt of testosterone 3,5-disulfamylbenzoate rapidly from chloroform). The product is in the form of a whitish cream- washes with ethanol first on the filter and then colored needles, which in dimethylformamide, chloro-20 by rubbing, sucks off again and dries in the form and dichloroethane highly soluble, soluble in benzene, in vacuo. It is cleaned by two or three times ether and acetone sparingly soluble and crystallize in water, acids, the first time being insoluble in 2.5 volumes and alkalis, warm water and then in the smallest possible amount Analysis: C ₂₆ H ₃₀ O ₇ N ₂ = 482.5. ^wa ™ absorbs ^what f ^rs and the crystallization at rt "w + r A4 vi υ α ο-? η ο-λ 91 μ ς" ίο /. 25 4-5 ⁰ C leads to the end. Calculated after suction and drying ... C 64.71, H 6.27, O 23.21, N 5.81%; _{If the dika] iumsa} i _{z of} testosterone-3,5-disulfamyl is found ... C 64.5, H 6.2, O 23.0, N 6.0% benzoate in the form of a water-solvated white D This compound is not yet described in the literature as a solid substance (water content determined according to Fischer. 9.4%). For the solvated product, _Example 2 is 30 [α] ί ^ο = + 109 ° (c == 0.7% in H ₂ O). The connection is

highly soluble in warm water, sparingly soluble in cold

Conversion of testosterone-3,5-dinitrobenzoate into water and insoluble in alcohol, ether and chloroform,

the sodium salt of testosterone 3,5-disulfamylbenzoate _analysis . C ₃₆ H ₃₂ O ₉ N ₂ S ₂ K ₂ = 658.86.

1. Formation of the hyamine salt Calculated: C 47.39, H 4.9, S 9.73, N 4.25, K 11.86%;

To 25 g of the testosterone obtained according to Example 1 found: C 47.7, H 5.0, S 9.9, N 4.2, K 11.6%.

3,5-dinitrobenzoate is added to 210 ecm of freshly distilled water that shows the UV spectrum determined in aqueous solution

Dimethylformamide, the mixture is heated to 95 ⁰ C and Xmax = 223 πιμ. (EJ * _m = 586) and X _max = 317 ηιμ.

then slowly add 550 ecm of water, adding the (E} * _m = 35.2).

Do not let the temperature of the solution fall below 90 ° C. Man 40 -d: "": 13

then added while maintaining a temperature _TT,. , ¹ L.

from 90 to 95 ° C at once with 104 ecm of an aqueous preparation of the Dmataum salt

Solution of sodium bisulfite and sodium sulfite, which one of ^the testosterone-3,5-d _1S ulfamylbenzoats

by adding 73 ecm of sodium bisulfite solution of 2.5 g of the dipotassium salt described above, in

35 ⁰ Be and 31 ecm of a neutralized sodium bisulfite 45 175 ecm of distilled water dissolved by weakly

solution is obtained, the latter being heated from 7.2 ecm 10 η-sodium bicarbonate. After cooling to 15 ° C., one sets by means of

lye and 24 ecm sodium bisulfite solution at 35 ° Be passed through an ion exchange resin (known

is being prepared. The mixture is heated with stirring and nitrogen under the trade name Dowex; acidic form) the acid

for gentle reflux, that one ¹ I ₂ hours free, for which a column of about 170 mm in height and

continues, gives 105 ecm of freshly distilled dimethyl 50 13 mm diameter used, which is then used

formamide is added and the reflux is continued for 3 ¹ _{2 2} hours and washes with water. The eluate is collected as soon as the

the away. The small amount of insoluble substance pn value has dropped to 3 and breaks off as soon as it does

containing yellow-orange solution is again reached 4 overnight. By adding n / 10 soda

ditched. Then the insoluble liquor is filtered off and the ρπ value of the eluate is kept between 3 and

from 1.47 g of unreacted testosterone dinitro 55 4 and finally neutralized with the help of n / 10 sodium bicarbonate

benzoate, and the filtrate is extracted with methylene liquor up to a ρπ value of 6.0 to 6.2, with a total of

chloride in order to be consumed by the last traces of the starting material including 58 ecm of sodium hydroxide solution. One constricts

to free. The aqueous layer is separated off and with a vacuum to a volume of about 5 ecm, whereby

Treated activated carbon. The activated carbon is mixed with water to keep the temperature below 60 ° C. After cooling down

washed, and the washing waters are gradually added to ordinary temperature with the filtrate 60

united. To this end, a 10% solution of 40 ecm of absolute ethanol is added. A low

Hyamin 1622 up to the formation of foam on the entire loft, which agglomerates when heated slightly.

Surface, for which about 500 ecm of this solution is required. After cooling to the usual temperature, suction is carried out

are. The hyamine salt precipitates in an oily form and is washed off and washed by rubbing with absolute ethanol,

solidifies when crushed ice is added. It is poured 65. After suctioning off, 1.82 g of the disodium

the supernatant liquid in which by adding salt of testosterone-3,5-disulfamylbenzoats; [α] "=

Hyamin no more precipitation may be caused. 4-104.5 ° C (c = 0.65% in water). The product is with

The solidified precipitate is washed with ice water, water solvated (water content, determined according to

and then taken up in 250 ecm chloroform. The fishermen, 10.5%). Its solubility in water is

Chloroform solution of the hyamine salt of testosterone 70 at 20 ° C 17.5% and at 30 ° C 25%. It is insoluble in

Alcohol, ether and chloroform are decomposed by aqueous acids and alkalis and can be made up of 2 volumes recrystallized warm water; white leaflets.

Analysis: C ₂₆ H ₃₂ O ₉ N ₂ S ₂ Na ₂ = 626.66.
Calculated: C49.83, H5.15, S 10.23, N4.47, Na 7.34%; found: C50.0, H5.2, S 10.2, N4.3, Na7.3%.

This connection has not yet been described in the literature.

The tempo specified in the preceding examples temperatures and solvents are not critical. Instead of hyamin one can also use other quaternary Use ammonium salts, e.g. B. Hyamin-2389, published in "Index des huiles sulfonees et detergents modern", Vol. 2, by J. P. Sisley, p. 373, is referred to as the chloride of a quaternary ammonium base, and furthermore »Cequartyl BE ", of which it says on page 287 of the above-mentioned index:" a base de sels d'ammonium ", Arquad 2 C, das according to the same index (p. 261) represents Dilauryldimethylammoniumchlorid, and "Zephirol", which after the same manual (p. 286) an alkyldimethylbenzylammonium chloride should be; usable other solvents are those z. B. the hyamine salt, but not dissolve the alkali salts of testosterone 3,5-disulfamylbenzoate. You can finally get straight from the one in water get insoluble quaternary ammonium salt by double conversion to the sodium salt.

Claims (6)

Patent claims: 1. A process for the preparation of water-soluble derivatives of a steroid hormone, characterized in that the testosterone is esterified with the aid of a functional derivative of 3,5-dinitrobenzoic acid in a manner known per se, the testosterone dinitrobenzoate formed with a mixture of sodium bisulfite and sodium sulfite in the presence of a third solvent treated, the resulting testosterone-3,5-disulfamylbenzoate is isolated in the form of an insoluble salt of a quaternary ammonium base and this salt is converted into the sought alkali salt by double conversion, optionally first preparing the potassium salt from the quaternary ammonium salt to achieve greater purity the sodium salt is obtained by releasing the disulfamic acid, neutralizing it with sodium hydroxide solution and precipitating it with a water-miscible solvent. 2. The method according to claim 1, characterized in that there is dimethylformamide as the third solvent used. 3. The method according to claim 1, characterized in that the testosterone-3,5-disulfamylbenzoate isolated in the form of its "Hyamin-1622" salt. 4. The method according to claim 1, characterized in that there is the double reaction with Potassium acetate carried out in ethanol. 5. The method according to claim 1, characterized in that to release the testosterone-3,5-disulfamylbenzoate an ion exchange resin is used. 6. The method according to claim 1, characterized in that that ethanol is used to precipitate the sodium salt. © 009 679/531 12.