The method of obtaining 17-cyclopropylmethyl-6,14-endo-ethano-7-(2 - hydroxy-3,3-dimethylbutan-2-yl)tetr ahydro-17-notarialna

 

(57) Abstract:

The method of obtaining 17-cyclopropylmethyl-6,14-endo-ethano-7-(2-hydroxy-3,3-dimethylbutan-2-yl)tetrahydro-17-notarialna involves reacting thebaine with methyl vinyl ketone are the Diels-Alder reaction, hydrogenation of the double bond obtained 6,14-endo-etheno-7-acetyltryptamine in the column reactor type fixed bed of palladium catalyst on the corner at 3 to 3.5 MPa and high temperature, followed by alkylation of the obtained 6,14-endo-ethano-7-acetyltryptamine the Grignard using tributyltinchloride in the presence of equimolar quantities of butyl alcohol or anhydrous magnesium chloride, N-demethylation brown received 6,14-endo-ethano-7-(2-hydroxy-3,3-dimethylbutan-2-yl)tetrahydrofurane lead extract bromine cyan, directly obtained from Zinda sodium and bromine, and the resulting N-cyanoderivatives hydrolyzing potassium hydroxide and enter into interaction with cyclopropanecarbonitrile in the presence of anhydrous potassium carbonate, and without allocating product to restore lydialydia in THF. Achieved simplification of the synthesis of the target compounds by reducing the number of stages, improved security for schedulename way of getting from thebaine known derived oripavine General formula

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possessing pharmacological activity and is used in medicine as a strong analgesic with low potential for addiction and antishock tools.

A method of obtaining 17-cyclopropylmethyl-6,14-endo-ethano-7-(2-hydroxy-3,3 - dimethylbutan-2-yl)tetrahydro-17-notarialna from thebaine, which consists in the fact that thebaine is subjected to interaction with acrolein obtaining 6,14-endo-etheno-7-formyltetrahydrofolate, which is then treated with methylmagnesium, and received 6,14 - endo-etheno-7-(1-hydroxy-1-ethyl)tetrahydrofuran oxidized by potassium permanganate, then in the resulting 6,14-endo-etheno-7 - acetyltryptamine hydronaut double bond with obtaining 6,14-endo-ethano-7 - acetyltryptamine, which is then treated with tert - butylmagnesium, and received 6,14-endo-ethano-7-(2 - hydroxy - 3,3-dimethylbutan-2-yl)tetrahydrofuran treated with bromine cyan obtaining N-cyanoderivatives, which is further subjected to hydrolysis with simultaneous 3-O-demethylation using potassium hydroxide at 210oC diethylene glycol, and demetilirovanie derivative is treated with cyclopropanemethylamine

(ed. mon. USSR N 1362734, C 07 D 489/02, publ. 30.12.87 year).

the keys in 8 stages with the release of products at each stage, and low yield of the target product, consisting of not more than 4.9% in the calculation of the original thebaine.

A method of obtaining 17 - cyclopropylmethyl-6,14-endo-ethano-7-(2-hydroxy-3,3-dimethylbutan-2 - yl)tetrahydro-17-notarialna, taken as a prototype, according to which thebaine is subjected to interaction with methyl vinyl ketone are the Diels-Alder reaction, the resulting 6,14-endo - etheno-7 - acetyltryptamine hydronaut double bond at 10% platiunum catalyst coal at 60oC and a pressure of 45 ATM in acetic acid for 15 hours to obtain 6,14-endo-ethano - 7 - acetyltryptamine, which is then alkylate the Grignard using tert-butylacrylamide obtained 6,14-endo - ethano-7-(2-hydroxy-3,3-dimethylbutan-2-yl)tetrahydrofuran N - demetrious brown with bromine cyan in dichloromethane to obtain the 17-cyano-6,14-endo - ethano-7-(2-hydroxy-3,3-dimethylbutan-2-yl)tetrahydro-17 - northebaine, which is then subjected to hydrolysis of the cyano action of potassium hydroxide at 170oC diethylene glycol, and the resulting 6,14-endo-ethano-7-(2-hydroxy-3,3-dimethylbutan-2 - yl)tetrahydro-17-northebaine treated with cyclopropanecarbonitrile in dichloromethane for 48 h in the presence of triethylamine and restore po-dimethylbutan-yl)tetrahydro-17-northebaine 7 is subjected to a 6-O-demethylation using potassium hydroxide at 210 - 220oC obtaining the target product

(patent England N 1136214, 2, publ. 10.06.1966 year).

The disadvantage of this method is a multistage process, which is carried out in 7 stages, the need to use hazardous and toxic chemicals at stage N-demethylation and hydrogenation and low yield of not more than 5.8% in the calculation of the original thebaine.

The invention solves the problem of simplifying the process of obtaining 17 - cyclopropylmethyl-6,14-endo-ethano-7-(2-hydroxy-3,3-dimethylbutan-2 - yl)tetrahydro-17-notarialna by reducing the number of stages, enhance its security through the use of less hazardous and toxic chemicals and improve the yield of the target product.

The problem is solved in that the 17 - cyclopropylmethyl-6,14-endo-ethano-7-(2-hydroxy-3,3-dimethylbutan-2 - yl)tetrahydro-17-neurorepair derived from thebaine by the interaction of the latter with methyl vinyl ketone are the Diels-Alder reaction, hydrogenation of the double bond obtained 6,14-endo-etheno-7 - acetyltryptamine on palladium catalyst on coal with subsequent alkylation of the obtained 6,14-endo-ethano-7 - acetyltryptamine the Grignard using tert - butylaniline the formation of N-lanproton 6,14 - endo-ethano-7-(2-hydroxy-3,3-dimethylbutan-2-yl)tetrahydrofurane, while hydrogenation of 6,14-endo-etheno-7 - acetyltryptamine produced in the reactor column type with a fixed layer of palladium catalyst on coal at 3-3,5 MPa, the alkylation of 6,14-endo - ethano-7 - acetyltryptamine carried out in the presence of equimolar amount of tert-butyl alcohol or anhydrous magnesium chloride, N-demethylation 6,14-endo-ethano-7-(2-hydroxy - 3,3-dimethylbutan-2-yl)tetrahydrofurane lead extract bromine cyan in an inert solvent, directly derived from sodium cyanide and bromine, and the resulting N-cyanoderivatives subjected to hydrolysis by the action of potassium hydroxide, the resulting reaction mass is injected into the interaction with cyclopropanecarbonitrile in the presence of anhydrous potassium carbonate, and without allocating product restore with lithium aluminum hydride in tetrahydrofuran (see diagram at the end of the description).

The stage hydrogenation reactor column type 4-5% palladium catalyst on coal increases productivity and process safety, and reduces costs by saving palladium.

Alkylation of 6,14-endo-ethano-7 - acetyltryptamine in the proposed conditions leads to increased output from 25% to 30 the path of bromine cyan in an inert solvent instead of pure bromine cyan significantly reduces the explosion hazard and toxicity of the process.

Simplify the process of obtaining the final product is achieved due to the advanced stage of conversion of 17-cyano-6,14-endo - ethano-7-(2-hydroxy-3,3-dimethylbutan-2-yl)tetrahydro-17-northebaine in the target product, which is carried out without isolation of intermediate products.

The total yield of the target product, from thebaine, is the proposed method is not less 20,4%.

Example 1. 6,14-endo-Etheno-7 - acetyltryptamine (II). A mixture of 100.00 g of thebaine (I) and 300 ml of methyl vinyl ketone are, refluxed on an oil bath (bath temperature 100oC) for 1 hour. An excess of methyl vinyl ketone are distilled off. The viscous residue is recrystallized from methanol. Get 115,71 g (94.9%) product II with so pl. 122oC. Lit. data: so pl. 120oC.

Example 2. (6,14-endo-Ethano-7 - acetyltryptamine (III).

Hydrogenation of 6,14-endo-etheno-7 - acetyltryptamine (II) is carried out in the reactor column type (2000 x 40 mm) with a fixed catalyst bed brand IK-1 (4-5% Pd on coal) at 60-65oC. In the reactor to create a hydrogen pressure of 3 to 3.5 MPa (30 to 35 kgf/cm2and with the help of a plunger pump serves 20% solution II in acetic acid with speed 0,09-0,11 l/h. Conversion during these services the t replacement of the catalyst. Produce in quantity of 20 l evaporated in vacuum, the residue is dissolved in 3.0 liters of water and add 25% ammonia solution to pH 9-10. The precipitation is filtered off, washed with 2-2,5 l of water, dried at 40-50oC for 24 hours, is recrystallized from ethanol. Get the product III so pl. 135-136oC. Lit. data: so pl. 134oC.

Example 3. 6,14-endo-Ethano-7-(2-hydroxy-3,3-dimethylbutan-2 - yl)tetrahydrofuran (IV).

To a solution of tert-butylacrylamide obtained from 1.07 g of magnesium and 4.11 g of tert-butyl chloride in a mixture of diethyl ether/benzene, type of 0.82 g of tert-butyl alcohol. After stirring for 40 min to the mixture add a solution to 4.23 g 6,14-endo-ethano-7 - acetyltryptamine (III) in benzene. The mixture is boiled under stirring for 3 h, then cooled and treated with 40 ml of a saturated aqueous solution of ammonium chloride. The organic layer is separated, the aqueous layer was extracted with ether (CH ml). The organic solutions are combined dried with anhydrous sodium sulfate. The solvent is distilled off, the residue is recrystallized from methanol. Get 1,71 g (35%) IV so pl. 188oC. Lit. data: so pl. 188oC.

Example 4. 6,14-endo-Ethano-7-(2-hydroxy-3,3-dimethylbutan-2-yl)tetrahydrofuran (IV).

Example 5. 17-Cyano-6,14-endo-ethano-7-(2-hydroxy-3,3-dimethylbutan - 2-yl)tetrahydro-17-northebaine (V).

To the mixture 102,0 g of bromide and 40 ml of water, cooled to 10-15oC, was added dropwise a solution of 31.2 g of sodium cyanide in 480 ml of water until complete discoloration of bromine. To the mixture is added 300 ml of chloroform. The chloroform layer is separated, dried with anhydrous sodium sulfate, and dissolve in it 200,0 g 6,14-endo-ethano-7-(2-hydroxy-3,3-dimethylbutan-2 - yl)tetrahydrofurane (IV). After 40 h, the mixture is washed with a solution of 24 ml of HCl (conc.) in 300 ml of water, water (I ml) and dried with anhydrous sodium sulfate. The chloroform is distilled off. After recrystallization from ethanol 191,7 g (93,5%) V so pl. 207-208oC. Lit. data: so pl. 206-207oC.

Example 6. 17-Cyclopropylmethyl-6,14-endo-ethano-7-(2-hydroxy-3,3 - dimethylbutan-2-yl)tetrahydro-17-neurorepair (VIII).

A mixture of 250 ml of diethylene glycol and 70.0 g of KOH is heated on an oil bath to 140oC, stirred at this temperature arabain (V) and boiled for 50 hours The reaction mixture is cooled, treated with 900 ml of a saturated aqueous solution of NH4Cl and 100 ml of chloroform. The organic layer is separated, the aqueous extracted with chloroform (CH ml). The organic solutions are combined dried over K2CO3, filtered and evaporated to a volume of 400 ml. of this solution was added 50.0 g of calcined K2CO3and 17,25 g cyclopropanecarbonitrile and stirred for 30 minutes, the Reaction mixture was treated with 10% HCl to dissolve K2CO3. The organic layer is separated and evaporated to dryness. The residue is dissolved in 200 ml of THF and added dropwise with stirring to 12.0 g LiAlH4in 400 ml of THF. After you add all the mixture is boiled for 1.5 h, cooled and cooled with cold water is treated by adding dropwise 300 ml of a saturated aqueous solution of NH4Cl and extracted with ether (2x250 ml, then h ml). Extracts combine, dried over anhydrous Na2SO4, filtered and evaporated to dryness. After recrystallization of the residue from a mixture of benzene/hexane get 32,4 g (70%) VIII I. pl. 209oC. Lit. data: so pl. 209oC.

The method of obtaining 17-cyclopropylmethyl-6,14-endo-ethano-7-(2-hydroxy-3,3-dimethylbutan-2-yl)testirovanie double bond obtained 6,14-endo-etheno-7-acetyltryptamine on palladium catalyst on coal at elevated temperature and pressure with subsequent alkylation of the obtained 6,14-endo-ethano-7 - acetyltryptamine the Grignard using tert-butylmagnesium and N-demethylation (Braun received 6,14-endo-ethano-7-(2-hydroxy-3,3-dimethyl-but-2-yl)tetrahydrofurane with the formation of N-lanproton 6,14-endo-ethano-7-(2-hydroxy-3,3-dimethyl-but-2-yl)tetrahydrofurane, characterized in that the hydrogenation of 6,14-endo-etheno-7-acetyltryptamine produced in the reactor column type with a fixed layer of palladium catalyst on coal at 3-3,5 MPa, the alkylation of 6,14-endo-ethano-7-acetyltryptamine carried out in the presence of equimolar amount of tert-butyl alcohol or anhydrous magnesium chloride, N-demethylation 6,14-endoethano-7-(2-hydroxy-3,3-dimethylbutan-2-yl)tetrahydrofurane lead extract bromine cyan in an inert solvent, directly derived from sodium cyanide and bromine, and the resulting N-cyanoderivatives subjected to hydrolysis by the action of potassium hydroxide, the resulting reaction mass is injected into the interaction with cyclopropanecarbonitrile in the presence of anhydrous potassium carbonate, and without allocating product to restore lydialydia in tetrahydrofuran.

 

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