SU543347A3 - Preparation method - (heteroaryl-methyl) benzomorphans or = morphinans - Google Patents

Description

one

This invention relates to a process for the preparation of new compounds of the benzomorphane polyphosphine category with valuable therapeutic properties.

The proposed method is based on the reaction of obtaining amines by reducing the corresponding quaternary ammonium salts.

By applying the known reaction to the quaternary ammonium salts of the benzomorphap or morphinan range, the applicants obtained new L- (heteroaryl-methyl) -benzomorphans or morphinans with high physiological activity.

In accordance with the invention, a process for the preparation of L- (heteroaryl-methyl) -benzomorphanes or morphinans of the general formula (1) is described.

R5 and R- are the same or different, are hydrogen or alkyl with 1-4 carbon atoms, or a 1,4-butylene chain;

R

hydrogen, methyl or ethyl;

X is an oxygen atom of sulfur or

or their salts, which is that

quaternary ammonium salt of the formula (2)

if)

(2)

BUT

t

these radicals are in the CISS, i.e., the a-benzomorphane series, or in the trans position, i.e. the p-benzomorphane series.

Recovery can be carried out with the help of complex metal hydrides. Lithium aluminum hydride, which is used either in a calculated amount or preferably in excess, is particularly suitable and easily obtained. The reaction is carried out in inert solvents, for example, in ethers, preferably diethyl ether, tetrahydrofuran or dioxane. The reaction temperature can be varied over a wide range, preferably between 0 ° and the boiling point of the solvent. Sodium borohydride also reacts without difficulty with quaternary ammonium derivatives of formula II, which can therefore be recovered with the help of this less flammable hydride. Sodium borohydride is used in a calculated amount or preferably in excess. Of the solvents, preferred are alcohols, in particular methanol or ethanol, if necessary mixed with water. The reaction temperature can be varied over a wide range, preferably it is maintained in the range from 20 ° C to the boiling point of the solvent or mixture of solvents ..... J

The reduction of derivatives of the formula II can also be carried out with the aid of hydrogen at the time of its release, and it is obtained in situ, for example, from base metals, preferably from zinc or iron and acids, such as hydrochloric, sulfuric or acetic acid. If necessary, to increase the reducing ability according to the Clemensen method, zinc can be amalgamated by treatment with mercury chloride. When using sodium amalgam, aluminum or other amalgam, and water or alcohol, it is also possible to work in the host medium. For carrying out such reductions, there are a variety of solvents, preferably those which, as a result of undesirable side reactions, do not decompose the compounds used. Depending on the starting compound and the reaction conditions, for example, alcohols, in particular ethanol and methanol or tetrahydrofuran and dioxane, can be used, if appropriate in a mixture with water. It is recommended to work at a temperature between room temperature and the boiling point of the solvent.

Compounds of formula II, in which Y represents a sulfur atom, can be desulfurized by reduction with Raney nickel. Rene nickel is preferably used in large excess, from about 10 to about 100 times the weight by weight of the substance to be desulfurized. It is better to add Rene nickel during the reaction in portions. It is possible to use a variety of solvents, however, alcohols, in particular, methanol and ethanol are preferred. During the reaction, hydrogen can be passed through the reaction mixture; desulfurization, however, occurs without hydrogen. The reaction is best carried out with vigorous stirring.

Compounds of formula II can be reduced electrochemically.

The method of producing compounds of formula I by reducing compounds of formula II compared to obtaining these compounds by reducing the corresponding amides is that reduction is facilitated and, consequently, the choice of reducing agents is wider. Thus, for example, carboxylic acid amides, as opposed to ammonium derivatives of formula II, cannot be reduced using sodium borohydride, hydrogen at the time of its release, Raney nickel or catalytically, but only with the help of special complex hydrides.

The starting compounds of formula II in which Y represents a sulfur atom (imidothioether salts) can be obtained, for example, by alkylation of the corresponding thioamides, and compounds of formula II, in which Y means an oxygen atom (imidoester salts) can be obtained by alkylation of the corresponding carbonamides with oxonium salts.

Example 1. 2-Furfuryl-2-hydroxy-5,9a-dimethyl-6, 7-benzomorfan.

a) 2- {2-Furoyl) -2- (2-furoyloxy) - 5.9 dimethyl-b, 7-benzomorfan.

In a suspension of 21.7 g of 2-hydroxy-5.9sb-dimethyl6, 7-benzomorfana (0.1 mol) in 217 ml of absolute methylene chloride and 40 ml of triethylamine, placing and cooling with reverse holo

Add a drop of 28.7 g (0.22 mol) of furan-2-carboxylic chloride to 109 ml of absolute methylene chloride. Then the reaction mixture was heated under reflux for 4 hours. Then cooled and in the presence of ice, washed twice each time with 100 ml of 2 n HCl and then three times with water. After drying with sodium sulfate, the methylene chloride solution is evaporated in vacuo. The residue is crystallized

by repeated mixing with 250 ml of hot ethanol. Stir until cooled and allow to stand overnight in the refrigerator. Then sucked off, washed with absolute simple ether and dried at 80 ° C.

Yield 38.5 g (95% of theory); m.p. 176-177 ° C. The recrystallized sample has an mp. 177-178 ° C.

The above-described amide crystallization is not required for subsequent thionization. AT

In general, the remainder of the methylene chloride solution is reacted without further purification.

b) 2- (2-Thiofuroyl) -2- (2-furoyloxy) -5,9-dimethyl-6, 7-benzomorfan. 10.1 g (0.025 mol)

2- (2-furoyl) -2- (2-furoyloxy) -5.9a-dimethyl6, 7-benzomorfana is dissolved in 125 ml of absolute pyridine. The solution, after adding 3.2 g of semi-phosphorous phosphorus, stirring and removing moisture, is boiled for 3 hours.

with reflux. Pyridine is removed.

under vacuum, and the residue is shaken with 100 ml of methylene chloride and 100 ml of water. The aqueous phase is again extracted with 50 ml of methylene chloride, the combined methylene chloride solutions are washed with 50 ml 2 and. HC1 in the presence of ice, then 3 times with water, dried with sodium sulfate and evaporated in vacuo. The yellow residue (10.6) consists of 2- (2-thiofuroyl) -2- (2-furoyloxy) -5.9a-dimethyl-6.7 benzomorphan.

c) Metoiodide 2- (2-thiofuroyl) -2- (2-furoyl .xy) -5.9a-dimethyl-6,7-benzomorpha.

The thioamide obtained in the previous reaction step is dissolved in 150 ml of absolute acetone, and the solution, after adding 17.8 g (7.85 ml) of methyl iodide, is refluxed. The yellow solution then becomes yellow-red and after about an hour, the reaction product begins to precipitate as crystals. The mixture is generally boiled for 2 hours, then allowed to cool and, after placing, 450 ml of absolute ether are gradually added. In order to complete the crystallization, it is left to stand overnight, sucked off with the prevention of air humidity, washed with absolute ether and dried in a vacuum desiccator over concentrated sulfuric acid until constant weight. The total yield of reaction steps a) and b) is 11.0 g (78% of theory), so pl. 125-130 ° C. The sample recrystallized from acetone / ether also has a melting point of 200 ml. 125-130 ° C.

d) Methanesulfate 2-furfuryl-2-hydroxy-5,9-dimethyl-6, 7-benzomorfana.

To a suspension of 0.6 g of LiAIH4 in 20 ml of absolute tetrahydrofuran, placing and cooling with ice, was added 2.82 g (0.005 mol) of metoiodide 2- (2-thiofuroyl) -2- (2-furoyloxy) 5.9a-dimethyl -6,7-benzomorfan (previous step of the reaction). The yellow color of the salt disappears immediately. After 15 minutes, the ice bath is removed and the reaction mixture is stirred for one hour at room temperature. Then, while stirring, 2 ml of water are added dropwise and then 50 ml of a saturated solution of diammonium tartrate is added. Shake vigorously for some time and then separate in a separatory funnel. The tetrahydrofuran solution (upper layer) is evaporated in vacuo, the aqueous layer is extracted three times with 40 ml of chloroform each time. The combined chloroform extracts dissolved the residue by evaporation of the tetrahydrofuran solution, washed with water, dried with sodium sulfate, and evaporated in vacuo. The residue was dissolved in 5 ml of ethanol and absolute ether was added to the solution after acidification with 0.5 g of methanesulfonic acid until cloudy. The methanesulfonate crystallizes, which is left to stand in the refrigerator to complete the crystallization overnight. Then sucked off and washed with ethanol / ether and then ether. After things get

1.2 g of substance (61% of theory) with m. Pl. 163-165 ° C, which, after recrystallization from ethanol / ether, is 165-168 ° C.

Example 2. Methanesulfonate 2-furfuryl-2-hydroxy-5, 9a-dimethyl-6,7-benzomorfana.

1 g of sodium borane is dissolved in 10 ml of water, and to the solution, after dilution with 20 ml of ethanol, stirring, 2.82 g (0.005 mol) of 2- (2-tfofuroyl) -2-2-furoyloxy-metoiodide (5-furoyloxy-5 , 9a-dimethyl-6,7-benzomorfan (see example 1, reaction stage c). The temperature rises to 45 ° C and the yellow color of the salt disappears almost immediately. Continue to place for an hour and then added dropwise just 25 ml of 2N HC1 and boil for 15 minutes under reflux.Then, cool, add 25 ml of 2N ammonia and extract three times with 50 ml of chloroform each time. The combined chloroform solutions are washed with water, dissolved in sodium sulfate and evaporated in vacuo. The residue is described in Example 1, g is crystallized by the method as methanesulfonate. Yield 1.5 g (76% of theory); mp 164-167 ° C, after recrystallization from ethanol / ether 166-168 ° C.

Example 3. 2-Furfuryl-2-hydroxy-5.9a-dimethyl-6, 7-benzomorfai.

2.82 g (0.005 mol) of 2- (2-thiofuroyl) -2- (2-furoyloxy) -5.9a-dimethyl-6.7-bessomorphane metoiodide (see example 1, reaction step c) is added to the suspension 10 g of Rene nickel in 100 ml of methanol and the reaction mixture for 30 min under reflux. Then cooled and filtered over kieselguhr. The filtrate is evaporated in vacuo and the residue is boiled in 50 ml of methanol and 12.5 ml of 2 N for complete cleavage of the 2-furoyloxy group for 15 minutes. NaOH. Then cooled, add 25 ml of 2 n. ammonium chloride and evaporated in vacuo. The residue is shaken with 50 ml of water and 50 ml of chloroform and the aqueous phase is extracted twice more with 25 ml of chloroform each time. The combined chloroform extracts are washed with water, dissolved in sodium sulfate and evaporated in vacuo. The residue is purified by chromatography on silica gel and crystallized from benzene / petroleum ether. The yield is 0.2 g, m.p. 103 ° C.

Example 4. 2-Furfuryl-2 - hydroxy-5,9a - dimethyl-6, 7-benzomorfan.

a) It is ethyl ethylsulfate 2- (2-thiofuroyl) -2- (2furoyloxy) -5,9a-dimethyl-6,7-benzomorfana.

Starting from 4.0 g (0.01 mol) of 2- (2-furoyl) 2- (2-furoyloxy) -5.9a-dimethyl-6.7-benzomorphane through the corresponding thioamide, which in acetone is reacted with diethyl sulfate , and obtained as in Example 1, said compound in the form of a non-crystallizing syrup.

b) 2-FURFURIL-2 - hydroxy - 5.9 a - dimethyl-6.7 benzomorphan.

Start from the reaction product of the previous reaction step and are obtained by reduction

using sodium borane, analogously to example 2, said compound. The total yield of all reaction steps from a to g is 1.7 g (57% of theory), m.p. 97-98 ° C, after recrystallization from beizol / petroleum ether 103-105 ° C.

Example 5. 2- (3 - Methyl-fluoryl) -2-Oxy-5-ethyl-9a-methyl-6, 7-benzoforfan.

Starting from 2.3 g (0.01 mol) of 2-hydroxy-5-ethnl9a-methyl-6, 7-benzomorphan, similar to irimer 1, a) and 1.6), 2- (3-methyl-furfuryl ) -2- (3-methyl-2-furoyloxy) -5-ethyl-9a-methyl-6, 7-benzomorphan and from it 2- (3-methyl-2-tofuroyl) -2 (3-methyl-2-furoyloxy) -5-ethyl9a-methyl-6,7-benzomorphan. From the latter, by alkylation with methyl iodide, analogously to example 1, c), the corresponding metoiodide is obtained in the form of non-crystallizing syroy, which is analogously to example 2 is reduced with sodium borane. The reaction product is crystallized from aqueous methanol. The total yield of the four stages of synthesis of 0.25 g (7.7% of theory); m.p. 178 ° C, unchanged after recrystallization from methanol.

Example 6. (-) - M-Furfuryl-3-hydroxy-morphinan.

Outcome of 2.43 g (0.01 mol) of 3-hydroxy-morphian and is obtained, similarly to nimers 1, a) and 1.6) 2- (2-furoyl) -3- (2-furoyloxy) morphinan, and from 2- (2-thiofuryl) -3- (2-furoyloxy) morphinane. From the latter, by alkylation with methyl iodide, analogously to example 1, c), a crystallization syrup is obtained, which is analogously to example 2 reduced with sodium borane. The reaction product is crystallized from acetone. The total yield of the four synthesis steps is 1.4 g (43% of theory); m.p. 205-206 ° С, after recrystallization from ethyl acetate 207 ° С.

Example 7. 2- (3-furylmethyl) -2-hydroxy-5-ethyl-6,7-benzomorfana hydrochloride. Starting from 2.17 g (0.01 mol) of 2-hydroxy-5-ethyl-6,7-benzomorfan and is prepared analogously to examples 1, a) and 1.6) 2- (3-furoyl) -2- ( 3 - furoyloxy) 5-ethyl-6, 7-benzomorfan and from it 2- (3-thiofuroyl) -2- (3-furoyloxy) -5-ethyl - 6,7-benzomorfan. From the latter, 4.2 g of the corresponding metoiodide is obtained by alkylation with methyl iodide, which is reduced by sodium borane in the same way as in Example 2. Product reactions crystallized from ethanol / simple ether in the form of hydrochloride. The total yield of the four synthesis steps is 1.5 g (44% of theory); m.p. 212 ° С, after recrystallization 223 ° С.

Example 8. 2- (2-Met11L-3-furylmethyl) -2oxy-5, 9a-dimethyl-6,7-benzomorfan.

a) 2- (2-Methyl-3-furoyl) -2 - hydroxy-5,9a-dimethyl-6, 7-benzomorfan.

43.4 g (0.2 mol) of 2-hydroxy-5,9a-dimethyl-6.7 benzomorphane was dissolved in 1400 ml of methanol and 50 g carbonate of carbonate in 80 ml of water was added to the solution, vigorously stirring. Suspension, mind, i. 32 g (0.22 mol) of 2-methylfuran-3-carboxylic acid chloride are added over an hour and stirring is continued for another hour at room temperature. Then it is evaporated and the residue is shaken with 300 ml of chloroform and 150 ml of water. The aqueous phase is separated and extracted once more with 150 ml of chloroform. The chloroform extracts are combined and washed successively with 150 ml of 2N. HC1, 150 ml of water and 150 ml of sodium bicarbonate. Then it is dissolved in sodium sulfate and evaporated in vacuo. The residue is crystallized from toluene. Yield 58.5 g (90% of theory); m.p. 157-159 ° C.

b) 2- (2-Methyl-3-furoyl) -2 - acetoxy-5,9-dimethyl-6, 7-benzomorfan.

32.5 g (0.1 mol) of 2- (2-methyl-3-furoyl) -2oxy-5, 9a-dimethyl-6,7-benzomorphan together with 325 ml of anhydrous acetic acid is heated in boiling for 2 hours water bath. It is then evaporated in vacuo and the residue is shaken with ice and water for one hour. Then the reaction product is extracted 3 times with chloroform (200 ml and 2 times with 100 ml) and the combined chloroform extracts are sprayed with water. After drying with sodium sulfate, the solution is evaporated in vacuo. A reaction product is obtained in the form of a syrup, which reacts further in the next reaction step.

c) 2- (2-methyl-3-furoyl) -2-acetoxy-5, 9a-dimethyl-6,7-benzomorfana etofluoroborate. The residue from the previous reaction step, in 100 ml of absolute methylene chloride together with 19 g (0.1 mol) of triethyloxon fluoroborate, is stirred for 24 hours with elimination of humidity at room temperature. After evaporation under vacuum, a viscous residue of the reaction product remains, which, due to the danger of decomposition, is expediently processed in this form.

d) 2- (2-Methyl-3-furylmethyl) -2-hydroxy-5,9-dimethyl-6, 7-benzomorfan.

The residue from the previous reaction step is dissolved in 100 ml of absolute ethanol and to the solution, stirring and cooling, 5.5 g (0.15 mol) of sodium borane are added in portions. Continue to stir overnight, then pour in 300 ml of water and extract with ether. After evaporation of the ether extracts, the residue was dissolved in 300 ml of methanol and the solution after the addition of 100 ml of 2 n. The NaOH was refluxed for 30 minutes. Then the main amount of methanol was removed in vacuo, 120 ml of 2N was added to the residue. ammonium chloride and extracted with chloroform (200, 100, 100 ml). The combined extracts are washed with water, dried with sodium sulfate and evaporated in vacuo. The residue is crystallized from aqueous isopropanol. Yield 22 g - 70.5% of the theory (total yield from reaction steps b) - d), so pl. 138-140 ° C.

Example 9. 2- (Furfuryl) -2-hydroxy-5,9-dimethyl-6 .7-ben omopfan.

The outcome is 21.7 g (0.01 mol) of 2-hydroxy-5,9adnylmethyl-6 .7-benzomorsane and, similarly, as described above, 8 are obtained. Obctions exit from reaction steps a) -d)

9

65% of theory (crystallized from aqueous isopropanol); m.p. 119-120 ° C.

Claims (1)

Invention Formula The method of obtaining M- (heteroaryl-methyl) benzomorphans or morphinans of the general formula (1) / cH, . "V (l) in which R is a hydrogen atom, a methyl acetyl group; and - may be the same or different, denote a hydrogen atom or an alkyl group with 1-4 carbon atoms or a 1,4-butylene chain. ten R is a hydrogen atom, methyl or an ethyl group and X represents an oxygen or sulfur atom, or salts thereof, characterized in that the quaternary ammonium salt of the formula (2) W ./ Cr N 2 (VJ in which RR and X have the indicated values; Y is an oxygen or sulfur atom; R is a lower alkyl radical with 1-4 carbon atoms; AW is an anion of an inorganic or organic acid, subjected to reduction, followed by isolation of the target product in free form or in in the form of salt by the well-known techniques.