DE1170943B - Process for the preparation of [2, 3-d] -triazolo-steroids of the 5ª ‡ -Pregnan-, -Androstan- and -Cholestanreihe - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Boarding school Class: C 07 c

GERMAN

PATENT OFFICE

EDITORIAL

German KL: 12 ο - 25/02

Number: 1170 943

File number: L 40751IV b / 12 ο

Filing date: December 20, 1961

Opening day: May 27, 1964

The invention relates to a process for the preparation of therapeutically active [2,3-d] -triazolosteroids the 5a-pregnane, -androstane and cholesterane series, that of the general sub-formula (I)

(D

in which R is hydrogen or an aryl radical, correspond.

According to the invention, these steroid compounds are obtained when using a 3-ketosteroid

(Π)

the 5a-pregnan, -androstan or cholesteran series treated with a secondary amine in a manner known per se and the 3-enamine obtained in an inert organic solvent either a) with an azide of the formula N ₃ R "(R" = a) Aryl radical) or b) with an azide of the formula YO-CO-N ₃ (Y = an aralkyl radical) reacts and the compound obtained last is hydrogenated or alkaline hydrolyzed by methods known per se.

When using an azide of the formula N3R ", the process proceeds according to the following reaction scheme, in which R 'is the morpholyl or pyrrolidyl radical is:

II

Of the azides of the formula YO-CO-N ₃ , the benzyl azidoformate CeHsCHfeOCONg, a compound not previously described, was found to be particularly suitable for the process of the invention.

When using azides of the formula N ₃ R ″, the reaction takes place in an inert anhydrous high-boiling solvent, such as toluene or xylene, at its boiling point. The azides of the formula Y - O - CO - N ₃ are more reactive. Processes for the preparation of f2,3-d] -triazolosteroids of the 5a-pregnan, -androstan and
-Cholestane range

Applicant:

LEPETIT S. p. A., Milan (Italy)

Representative:

Dr. W. BeU, A. Hoeppener and Dr. H. J. Wolff,

Lawyers,

Frankfurt / M.-Höchst, Antoniterstr. 36

Named as the inventor

Giangiacomo Nathansohn, Milan (Italy),

Emilio Testa, San Simone (Switzerland)

Claimed priority:

Great Britain January 18, 1961 (2096)

therefore at lower temperatures in a low-boiling solvent such as chloroform or diethyl ether or tetrahydrofuran. The following examples explain the process according to the invention.

example 1

17 ^ -Hydroxy-l 7a-methyl-5a-androst-2-ene- [2,3-d] -N ³ -phenyltriazole

A mixture of 10 g of Sa-androstan-na-methyl- Πβ-όΙ-3-οη, 12 g of morpholine, 0.1 g of p-toluenesulfonic acid and 180 ecm of toluene is heated under reflux for 8 hours, the continuously formed during the reaction Water removed. The morpholine-enamine crystallizes out on cooling; M.p. = 209 to 216 ° C; [a] f ° = 6.6 (c = 2; CHCl ₃ ). g of the enamine obtained are refluxed with 6.4 g of phenyl azide in 165 ecm of anhydrous toluene for 4 hours. After concentration to half its volume and subsequent cooling, a crystalline product is obtained which is recrystallized from methanol-chloroform. M.p. = 288-291 ° C; [a] f ° = 53 (c = 1; CHCl ₃ ).

Analysis for C26H35N3O:

Calculated ... C 76.99, H 8.7, N 10.36;
Found ... C 76.95, H 8.57, N 10.18.

409 597/457

Example 2

17jS-Hydroxy-17a-methyl-5a-androst-2-ene- [2,3-d] -triazole

For the production of the benzyl azidoformate used as starting material C6H5CH2OCON3 a solution of 4.6 g of benzyl chloroformate in 20 ecm of acetone with cooling 2 g of sodium azide in 10 ecm Water added. After stirring for a few minutes, the acetone is in vacuo at Distilled off at room temperature. The residue is diluted with water and the benzyl azidoformate formed is extracted with 100 ecm chloroform.

a) 17 / S-Hydroxy-17a-methyl-3- (N-morpholyI) -5a-androstan- [2,3-d] -N ³ -carbobenzyloxytriazole

The chloroform solution prepared as described above, which contains 4 to 4.8 g of benzyl azidoformate, is dried with anhydrous sodium sulfate. 6.8 g of the morpholino-enamine of 17a-methyl-5a-androstan-17j3-ol-3-one obtained according to Example 1 are then added. After standing for a long time at room temperature, the mixture is concentrated to about 10 to 15 ecm and ethyl ether is added until a crystalline product has completely precipitated. The precipitate is recrystallized from acetone. F. = 140 ⁰ C (decomposition).

b) 17ß-Hydroxy-17a-methyl-5a-androst-2-en-

[2,3-d] triazole

A suspension of 5 g of 17 /? - Hydroxy-17a-methyl-3 - (N - morpholyl) - 5a - androstane - {2,3 - d] - N ³ - carbobenzyloxytriazole in 500 ecm of anhydrous methanol are stirred under normal pressure and while passing in hydrogen, 1.3 g of 10% palladium black were added until the evolution of carbon dioxide ceased. The methanol solution is filtered off the catalyst and concentrated to a small volume, whereupon a crystalline product separates out. Mp = 258-261 ° C. Recrystallization from methanol and dried at 140 ⁰ C in vacuo, the melting point is increased to 270-271 ⁰ C.

This compound can also be prepared by reducing the 17j3-hydroxy-17a-methyl-3- (N-morpholyl) -5a-androstane [2,3-d] -N ³ -carbobenzyloxytriazole with LiAlH ₄ . [2,3 - For this purpose, a suspension of 2.2 g _LiAlH4 in 80 cc of tetrahydrofuran with stirring and cooling 10.7 g to 17 / J-hydroxy-17a-methyl-3 - (N - morpholyl) - 5a - androstan - d] - N ³ - carbobenzyloxytriazole in 130 ecm tetrahydrofuran was added. The reaction mixture is then refluxed for 8 to 10 hours. The LiAlH ₄ is decomposed with 10 ecm of water, the solution of lithium salts is filtered and concentrated in vacuo. The deposited precipitate is recrystallized from methanol and ^{dried in vacuo at 140 °} C .; F. = 269 to 270 ° C. The product obtained is identical to that obtained by treatment with hydrogen in the presence of palladium black and, as can be seen below, can also be obtained by alkaline hydrolysis.

c) A suspension of 5.5 g of 17ß-hydroxy-17a-methyl-5a-androstane-3- (N-morpholyl) - [2,3-d] -N ³ -carbobenzyloxytriazole in 250 ecm of methanol are 16 ecm 10% ige NaOH added. The mixture is left to stand for 12 hours at room temperature, the unreacted material is filtered off and the solution is neutralized with 1 ecm acetic acid. It is then concentrated to a small volume in vacuo and diluted with water. The aqueous solution is added to pn 4 to 5 with cold acetic acid, diluted with water and heated for 10 minutes from 60 to 7O ⁰ C. Upon cooling a white precipitate which is recrystallized from methanol forms, 2.6 g of a melt at 265 to 27O ⁰ C compound is obtained.

17 / S-Hydroxy-17a-methyl-5a-androst-2-en- [2,3-d] -triazole hydrochloride melts at 225 to 229 ° C (decomposition); [a] ² _a ⁰⁰ = 40.2 (c = 1.044; CHCB).

Analysis for C ₂ UH ₃₂ N ₃ OCl:

Calculated ... C 65.65, H 8.82, N 11.50, Cl 9.69; Found ... C 65.41, H 8.47, N 11.72, Cl 9.45.

Example 3

17 / i-Hydroxy-5a-androst-2-en- [2,3-d] -N ³ -phenyltriazole

A mixture of 65.5 g of androstan-17 / i-ol-3-one, 78.5 g of morpholine and 0.3 g of p-toluenesulfonic acid in 980 ecm of anhydrous toluene is refluxed for 8 hours, this being the case during the reaction resulting water is continuously removed. Then 300 ecm of toluene are distilled off. Then it is cooled. 76 g (94% of theory) of morpholino-enamine are obtained; M.p. = 180 to 190 ^° C; [a] ° ^o l = 31 (c = 2; CHCl3). 3.6 g of this enamine in 65 ecm of toluene are refluxed with 2.38 g of phenyl azide for 4 hours. The toluene is completely distilled off under normal pressure and the residue is heated ^{to 120 to 130 ° C. in vacuo.} It is then taken up with diethyl ether and the mixture is left to stand for a few hours. A white crystalline product separates out. F. = 270 ° to 290 ⁰ C. By recrystallization from chloroform-petroleum ether, the melting point is increased to 306-311 ° C. [a] f ° = 74 (c = 1.109; CHCb).

Analysis for

Calculated
found

C 76.7, H 8.5, N 10.73; C 76.49, H 8.21, N 10.41.

Example 4

a) 17β-Hydroxy-3- (N-morpholyl) -5tt-androstan- [2,3-d] -N ³ -carbobenzyloxytriazole

This compound is obtained by the process of Example 2 from the enamine prepared according to Example 3. The product melts at 153 to 154 ° C (decomposition); [a] f ° = 177 (c = 1.017; CHCl ₃ ).

Analysis for C ₃ IH ₄₄ N ₄ O ₄ :

Calculated ... C 69.37, H 8.26, N 10.44; »Found ... C 69.67, H 8.44, N 10.51.

b) 17 /? - Hydroxy-5u-androst-2-ene- [2,3-d] -triazole

The product obtained according to a) is hydrogenated with hydrogen in the presence of palladium black or with LiAlH ₄ . The androstene-triazole obtainable by both processes melts after the conversion

crystallization from ethanol at 237 to 242 ° C; [α] Γ = 65 (c = 0.75; CHCl ₃ ).

Analysis for C19H29N3O:

Calculated ... C 72.34, H 9.26, N 13.32; Found ... C 72.50, H 9.21, N 13.18.

The hydrochloride melts at 258 to 266 ° C; [a \ f ° = 94 (c = 1.122; CH ₃ OH).

10

Example 5
5a-Cholest-2-ene- [2,3-d] -triazole

a) 3- (N-Morpholyl) -5a-cholestan- [2,3-d] -

N'-carbobenzyloxytriazole

A mixture of 11.6 g of Sa-cholestane, 10.4 g of morpholine, 0.1 g of p-toluenesulfonic acid and 175 ecm of anhydrous toluene is refluxed for 8 hours under nitrogen while the water formed during the reaction is continuously removed. The solvent is distilled off until the morpholine-enamine crystallizes; Mp = 124-133 ⁰ C. 4.56 g of this enamine in 35 cc of chloroform are added to 2.65 g Benzylazidocarbonat. The mixture is left to stand at room temperature for 90 minutes. It is then concentrated to a small volume in vacuo, the residue is crystallized from diethyl ether and washed with methanol. The product obtained melts at 135 ^° C. (decomposition). [a] ² o °° = -61.5 (c = 1; CHCl ₃ ). The addition of ethyl alcohol results in precipitation in the ethereal mother liquors, melting at 108 ⁰ C. [a] 1 °° = 125.2 (c = I; CHCl ₃ ). The IR spectra and the microanalysis of the two products gave the values expected for 3- (N-morpholyl) -5a-cholestan- [2,3-d] -N'-carbobenzyloxytriazole. The different physical data are based on the different steric orientations of the N-morpholyl group.

b) 5a-Cholest-2-en- [2,3-d] -triazole

The same product is obtained by reduction or alkaline hydrolysis of the two compounds. 2.2 g of 10% palladium black become 7.5 g of 3- (N-morpholyl) -5a-cholestan- [2,3-d] -N under normal pressure with stirring and the introduction of hydrogen until the evolution of carbon dioxide ceases '-carbobenzyloxytriazole given in 700 ecm of anhydrous methanol. The methanol solution is filtered off the catalyst and concentrated to a small volume in vacuo. A crystalline product separates out. M.p. = 212 to 216 ° C; [a \ l ^oa = 61.8 (C = 1; _CHCl3).

Analysis for

Calculated
found

15th

C 78.77, H 11.02, N 10.21;
C 78.77, H 10.92, N 10.38.

Example 6

a) 3- (N-Morpholyl-5a-pregnan- [2,3-d] -N'-carbobenzyloxytriazole

A mixture of 12.66 g of allopregnan-3,20-dione, 13.94 g anhydrous morpholine, 0.15 g p-toluene

25th

30th

35

40

45 sulfonic acid and 200 ecm of anhydrous toluene is heated under reflux for 7 hours under nitrogen with continuous removal of the water formed during the reaction. The solvent is distilled off in vacuo until the 3- (N-morpholyl) -5a-pregn-2-ene has crystallized. Mp = 164-173 ⁰ C. 11g of this dissolved in 130 cc of anhydrous chloroform is added to 7.6 g of enamine Benzylazidocarbonat. The mixture is stirred for 1.5 hours at room temperature, concentrated to a small volume and treated with diethyl ether. The crystalline product melts at 137 ° C (decomposition); [a] ⁰⁰ l = 182 (c = 1; CHCl _3). The mother liquors are evaporated and the oily residue is treated with methanol. The product obtained melts at 141 ^° C. (decomposition); [a] S °° = -59.4 (c = 1; CHCl ₃ ). The IR spectra and the microanalysis gave the expected values. The different physical data are based on the different orientations of the N-morpholyl group.

b) 5a-Pregn-2-ene- [2,3-d] -triazole

1.2 g of palladium black are added to a solution of 4.2 g of 3- (N-morpholyl-5a-pregnan- [2,3-d] -N'-carbobenzyloxytriazole in 400 ml of anhydrous methanol. Hydrogen is passed into the mixture, Kohleridioxydentwicklung until the stop is then filtered from the catalyst and concentrated in vacuo to a small volume the crystalline product obtained melts at 275 to 28O ⁰ C: [a] T = 146.6 (c = 1; _CHCl3) analysis for... C2iH ₃ iN ₃ O:

Calculated ... C 73.87, H 9.15, N 12.40; Found ... C 73.76, H 9.19, N 12.37.

Claims (1)

Claim: Process for the preparation of [2,3-d] -triazolosteroids of the 5a-pregnan-, -androstan- and -Cholestane series, that of the general sub-formula 55 60 in which R denotes hydrogen or an aryl radical, characterized in that a 3-ketosteroid of the 5a-pregnane, -androstane or -cholestane series is treated with a secondary amine in a manner known per se and the enamine thus obtained in an inert one organic solvent either a) with an azide of the formula N ₃ R ", in which R" represents an aryl radical, or b) _{reacts with an azide of the formula YO - CO - N 3} , in which Y is an aralkyl radical, and the compound obtained last is hydrogenated or alkaline hydrolyzed by methods known per se.