SU1362734A1 - Method of obtaining n-cyclopropylmethyl-6,14-endoethano-7-(2-oxy-2-methyl-2-tertabutyl)tetrahydronororipavine - Google Patents

Abstract

N-(cyclopropyl-methyl) -6,14-endo-ethano-7-(1-hydroxy -1, 2, 2-trimethyl-propyl)-dihydro -normorphine-6-methylester is prepd. from the Diels-Alder reaction prod. of thebaine with acrolein by reacting the resulting 6, 14-endo-etheno -7-formyl-tetrahydro -thebaine with methyl-magnesium-iodide, oxidizing the resulting 6, 14-endo-etheno-(1-hydroxy -ethyl) -tetrahydro -thebain with potassium-permanganate, hydrogenating the resulting 6, 14-endo-etheno-7-acetyl -tetrahydro-thebaine on a palladium catalyst, reacting the resulting 6, 14-endo-ethano-7-acetyl -tetrahydro-thebaine with tert. -butyl-magnesium-chloride, reacting the resulting 6, 6,14-endo-ethano-7-(1-hydroxy - 1, 2, 2-trimethyl -propyl) -tetrahydro-thebaine with cyanogen-bromide, reacting the resulting N-cyano-6,14-endo-ethano -7-(1-hydroxy-1, 2, 2-trimethyl-propyl) -tetrahydro-thebaine with potassium-hydroxide at 210 deg. C, andreacting the resulting 6,14-endo-ethano-7-(1-hydroxy -1, 2, 2-trimethyl -propyl)-dihydro -normorphine-6-methylester with bromo-methyl-cyclopropane.

Description

1 13 The invention relates to an improved process for the preparation of a known oripavine derivative, namely N-cyclopropylmethyl-b, 14-endoethano-7- (2-hydroxy-2-methyl-2-tert-butyl) tetrahydronororipavine of the general formula

1СНН2-

where t-Bu is tert-butyl with pharmacological activity, in particular, the ability to affect the central nervous system.

The purpose of the invention is to simplify the process by using as a non-starting material more available than methyl vinyl ketone acrolein to obtain more pure intermediate products.

Example 1. 6,14-Endoetheno-7-formyl-tetrahydrotebaine.

A mixture consisting of tebaine in the amount of 6 g and acrolein in the amount of 20 ml in benzene (25 ml) is refluxed in a water bath for 12 liters. The solvent and unreacted acrolein are then removed by distillation. The resulting solid material is washed several times with hexane. Having formed

to time

The shys adduct is separated from tebaine by recrystallization from ethanol. As a result, the tebai-on-acrolein adduct was obtained as a colorless crystalline solid with a melting point of 109 ° C in the amount of 6 g (85% of the theoretical yield) M: 367, M 367.

Example 2. 6,14-Endoetheno-7- (2-Oxy-2-metsh) tetrahydrotebain. A solution of methylmagnesium iodide was obtained from magnesium in an amount of 38.1 g in ether in an amount of 300 ml and methyl iodide in an amount of 1.94 g in ether (200 ml) and benzene (20 ml). The mixture thus obtained is stirred for 2 hours and then added to the stirred mixture for 1 hour, 6.14-endoetheno-7-formyl tetrahydrotebaine in an amount of 100 g in benzene (500 ml). After standing overnight, the mixture thus obtained is added to sat

1G

20

5 ml of ammonium chloride water. The organic layer is separated, and the aqueous layer is further subjected to extraction with ether. After removal of the solvent, 40 g of the expected product were obtained. As a result of a simple pe1: uninstallation, the product indicated in the title, characterized by a melting point of 140 ° C, M, was obtained from methanol: 397.47; M 298.5.

Example 3. 6,14-zdoeteno-7- (2-hydroxy-2-methyl) tetrahydrotebaine in the amount of 10 g is dissolved in 160 ml of acetone. Next, potassium permanganate is added in portions with stirring and at room temperature, the total amount of which is 7.93 g. Each subsequent amount of potassium permanganate is added only after the previously added amount of manganate is consumed. Stirring is carried out for 6 hours, after which the addition of potassium permanganate is stopped.

The reaction thus obtained

30 nyu mixture is filtered from MnO and

rinse thoroughly with hot acetone. The solvent is then removed with a water bath and 9 g of the desired product are obtained (95% of the theoretical yield), and the melting point is 120 ° C, M: 381.47;

,five.

Example 4. 6,14-endoethano-7-adyltetrahydrothebaine in the amount of

0 25 g in ethanol (500 ml) is subjected to mixing with a 10% palladium catalyst in an amount of 2.5 g in a nitrogen atmosphere at a pressure of 85 pounds / / KS-inch (i.e., 5.976 kg / cm-q) at

5 for 10-12 hours. The solution thus obtained is filtered from the catalyst and evaporated. The residue is recrystallized from methanol, thereby obtaining the desired product in an amount of 20 g, characterized by a melting point, equal to 134 ° C. M .: 383; M- 383.

Example 5. 6,14-Endoethanoc 7- (2-hydroxy-2-metsh1-2-tertbutyl) tetrahydrothebaine. 10.0 g of 6.14-endoethano-7-acetyltetrahydroprotein dissolved in 500 ml of benzene is added dropwise to the solution of t-butyl magnesium

chloride, get {1 out of 85 g of magnesium, 275 g of t-butyl chloride and 1 l of anhydrous ether. Thus obtained, the reaction mixture is stirred at room temperature for 8 hours and then decomposed, with cooling, with a saturated ammonium chloride solution. The ether layer is separated, dried with magnesium sulfate and evaporated to give a residue, in an amount of 16 g, which is 6.14-endoethano-7- (2-hydroxy-2-methyl-2-tert-butyl) tetrahydrotebaine characterized by a melting point of 180-189 ° C.

Example 6. N-Cyano-b, 14-anddo-ethano-7- (2-hydroxy-2-methyl-2-tert-butyl) tetrahydrotebaine. The product obtained as indicated in Example 5, in an amount of 50 g, is dissolved in 250 ml of chloroform. 30 g of bromide is added to the resulting mixture, and then the mixture is subjected to

reflux for 8 hours. Next, the chloroform is evaporated, and the residue is subjected to recrystallization from alpha ethoxy ethanol, resulting in the result of the N-cyanonor compound indicated in the title of the example in an amount of 38 g.

characterized by a melting point of 205 C.

Example 7. 6,14-Endoethano-7- (2-hydroxy-2-methyl-2-tert-butyl) tetra-hydronori-pavine. The product obtained as indicated in Example 5, in an amount of 50 g, is dissolved in 250 ml of chloroform. Next, 30 g of cyanbromide is added to this mixture, and the mixture thus obtained is refluxed for H. Chloroform is evaporated and the residue is recrystallized from alpha ethoxy ethanol. The result was an N-cyano-nor-compound in an amount of 38 g, characterized by a melting point of 205 ° C, which was then added to the vigorously stirred mixture consisting of 30 g of potassium hydroxide in 300m diethylene glycol at 210 ° C. The reaction mixture thus obtained is maintained at 210 ° C for 8 hours. The reaction mixture is further decomposed by diluting it tenfold (by volume) with cold water. The precipitated solid material is filtered off, washed with water and

dried. As a result, the target product was obtained in an amount of 12 g, characterized by a melting point of 1–2-169 ° C.

I

Example 8. N-Cyclopropylmethyl-6, 14-zdoethane-7- (2-hydroxy-2-methyl-2-tert-butyl) tetrahydronororipavin.

6.14-Endoethano-7- (2-hydroxy-2-methyl-2-tert-butyl) tetrahydronororipavin in an amount of 4 g is dissolved in dimethylformamide (150 ml) and then 8 g of anhydrous are added.

potassium carbonate. Then 7.5 g of cyclopropylmethyl bromide is added dropwise. The reaction temperature is slowly raised to 80 ° C. Heating process at 80 ° C

with stirring, continue for 4 hours. Next, the dimethylformamide is evaporated under vacuum, water is then added and the resulting product is extracted with ether.

As a result of evaporation of the solution

2.5 g of the above temperature product are obtained.

melting point of 209 C.

Claims (1)

Invention Formula The method of producing N-cyclopropylmethyl-6,14-endoethano-7- (2-hydroxy-2-methyl-2-tert-butyl) tetrahydronori-pavine from thebaine, including Grinir alkylation with alkyl magnesium halide, hydrogenation double bond on a palladium carbon-based catalyst, caustic demethylation potassium when heated and cyanidation with bromine cyanide, characterized in that, in order to simplify the process, thebaine is reacted with acrolein to form 6,14-endoetheno-7-formyl tetrahydrotebaine, which is then treated with methyl magnesium iodide and the d; 14-endo etheno-7- (2-hydroxy-2-metsh1) - tetrahydrotebaine obtained is oxidized with potassium permanganate, after which in the resulting 6, 14-endoetheno-7-acetyl-tetrahydro-. thebaine is hydrogenated with a double bond to give 6,14-endoethano-7-acetyl-tetrahydrotebaine, which is then treated with tert-butyl magnesium chloride, and the resulting 6,14-endo-ethano-7- (2-ox-2-methyl-2-tert-butyl ) -tetrahydrotebaine is treated with cyanogen c. 13627346 by the irradiation of the N-cyano derivative, which is at 210 ° C in diethylene glycol, and then the demethimethylated derivative is subjected without treatment to treatment with hydroxide, the cyclopropylmethyl bromide is rolled.