RU2236412C2 - Method for preparing derivatives of morphinone, method for preparing derivatives of 14-hydroxymorphinone and method for preparing derivative of oxymorphone - Google Patents

Abstract

FIELD: organic chemistry, chemical technology, medicine, narcology.

SUBSTANCE: invention relates to a method for preparing derivatives of morphinone that are intermediate compounds used for preparing derivatives of 14-hydroxymorphinone that, in turn, are used for preparing antagonists of opiates - derivatives of oxymorphone. Method for preparing derivatives of morphinone involves oxidation of derivatives of morphine of the general formula (I):

with hypochlorous and hypobromous acid salts wherein in indicated formula (I) R means lower alkyl, (C₃-C₆)-cycloalkyl, benzyl or substituted benzyl, cyano-group; R₁ means alkyl, benzyl or alkylcarbonyl; R₂ means hydrogen atom, alkyl, benzyl or alkylcarbonyl. Oxidation is carried out with hypochlorous and hypobromous acid salts prepared preferably before oxidation immediately. For oxidation sodium and potassium hypochlorites or hypobromites are used preferably. Antagonists of opiates are important medicinal agents used for treatment and diagnosis of narcomania.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

7 cl, 3 ex

Description

The invention relates to a method for producing derivatives of morphinone, which are intermediate compounds for the preparation of derivatives of 14-hydroxymorphinone, which, in turn, are used to obtain antagonists of opiate derivatives of oxymorphone. Opiate antagonists are important drugs for the treatment and diagnosis of addiction.

The most widely used method for the production of opiate antagonists, oxymorphone derivatives, such as, for example, naltrexone, and naloxone is the method described in The Organic Chemistry of Drug Synthesis. Vol. 1 John Wiley & Sons, New York, 1990, p. 289-291, including the oxidation of thebaine to produce 14-hydroxycodeinone, its hydrogenation, sequential dealkylation of methyl groups on the phenyl ring and nitrogen with the treatment of the resulting noroxymorphone with the corresponding alkyl halide. The main disadvantage of this production method is the need to use expensive thebaine as a raw material, because the amount of thebaine produced is limited due to its very low content in opium resin.

US Pat. Nos. 5922876 and 6008355 disclose methods for preparing derivatives of oxymorphone and oxycodone, including the preparation of morphinone derivatives from morphine and codeine by direct Swern oxidation, namely, the action of DMSO with oxalyl chloride in methylene chloride at -78 ° C to obtain a technical product with subsequent processing acetic anhydride and obtaining dienolacetates, their secondary oxidation with peroxide or peroxyacid to obtain derivatives of 14-hydroxymorphinone, which are hydrogenated to obtain oxycodone and oxymorphone, which then alkalize with nitrogen to produce nor derivatives that alkylate to produce opiate antagonists. The main disadvantage of this method is the oxidation of morphine and codeine to derivatives of morphinone under stringent conditions, which makes this method inconvenient for use in industry.

In addition to the method for producing morphinone derivatives by oxidation of codeine and morphine, which is described above as one of the steps of the method for producing derivatives of oxymorphone and oxycodone, the most widely applicable method for producing these products from thebaine by the reaction of hydrogen halide in the presence of a catalyst followed by hydrolysis, described in US patent No. 4052402 The disadvantage of this method is the use of expensive thebaine.

Derivatives of morphinone can also be obtained by oxidation of morphine and codeine with various strong oxidizing agents, however, the selectivity of this oxidation is low, and in some cases the oxidation goes towards the formation of other products (Beilstein, 27 II 136).

The objective of the present invention is to develop a simpler, more technologically advanced, using more affordable and cheaper feedstock method for producing morphinone derivatives, 14-hydroxymorphinone derivatives, and a method for producing opiate antagonists - oxymorphone derivatives, which are currently the main means of treatment of opiate addiction and diagnosis of drug addiction.

The authors of the present invention unexpectedly found that the use of such strong nonspecific oxidizing agents as salts of hypochlorous and hydrobromic acids under mild conditions makes it possible to obtain morphinone derivatives with high yield and purity.

Thus, the present invention relates to a method for producing derivatives of morphinone, comprising the oxidation by salts of hypochlorous and hydrobromic acids of morphine derivatives of the general formula I:

(I)

where K represents lower alkyl, C ₃ -C ₆ cycloalkyl, benzyl or substituted benzyl, cyan; R ₁ represents alkyl, benzyl or alkylcarbonyl; R ₂ represents hydrogen, alkyl, benzyl or alkylcarbonyl.

The oxidation (according to Scheme 1) is preferably carried out with salts of hypochlorous and hydrobromic acids, mainly obtained immediately before oxidation. For oxidation, preferably sodium or potassium hypochlorites or hypobromites are used.

The oxidation is carried out by simply mixing an aqueous solution of an oxidizing agent and a solution of the starting material or its suspension in an organic solvent. Preferably, acetonitrile is used as a solvent. The process is carried out at a temperature in the range from 0 to 20 ° C for from 30 minutes to 2 hours. Next, the target product is isolated using known methods.

In a preferred embodiment of the invention, the organic solvent-oxidizer solution ratios are selected so that a two-phase system is formed in which the target product is in the organic phase, which facilitates its isolation. Preferably, the above ratio is 1: 3.

Another object of the present invention is a method for producing derivatives of 14-hydroxymorphinone. The general scheme of the method is presented in Scheme 2.

Derivatives of morphine (I) are oxidized with hypochlorite or hypobromite to obtain compound (II) by the method presented in Scheme 1. Next, derivatives of morphinone (II) are treated with acetic anhydride to obtain enol (III) ester, which is further oxidized with hydrogen peroxide to obtain derivatives of 14-hydroxymorphinone . The second and third stages of the method are carried out by known methods, for example, as described in US patent 6008355.

Another object of the present invention is a method for producing derivatives of oxymorphone according to the General scheme presented in Scheme 3:

where R ’substituted alkyl or alkylcarbonyl.

The first stage of the oxidation of derivatives of morphine (I) to derivatives of morphinone (II) is carried out as described above (Scheme 1). Next, to the derivatives of 14-hydroxymorphinone (IV), the process is carried out as shown in Scheme 2. The conversion of the derivatives of 14-hydroxymorphinone (IV) to the derivatives of oxymorphone (V) is carried out by hydrogenation, then (V) is dealkelated with nitrogen to obtain the nor derivatives (VI), which alkylate to obtain opiate antagonists (VII), as shown previously.

The following are a number of specific examples of embodiments of the invention, which are given to illustrate it.

Examples

Example 1. Obtaining codeinon (II; R = CH ₃ , R ₁ = CH ₃ ).

An oxidizing solution is prepared by dissolving solid sodium hydroxide (3.0 g) in 25 ml of water, and when cooled with ice / water, chlorine gas is bubbled through this solution, evaporating 2 ml of liquid chlorine.

Separately, a suspension of codeine (5.0 g, 0.0168 mol) in acetonitrile (8 ml) was prepared. An oxidizer solution is added to the suspension, maintaining the temperature of the reaction mass 5-10 ° C. The reaction mass is kept at this temperature for one hour and then brought to room temperature. Separate the organic layer. Methylene chloride (25 ml) was added to the organic layer and the resulting solution was washed with water (2 × 25 ml). The product solution was dried with sodium sulfate and evaporated. After recrystallization from ethyl acetate, 4.96 g of the expected product are obtained ( _mp = 184-185 ° C.). Yield 94.3%.

Example 2. Obtaining 14-hydroxycodeinone (IV; R = CH ₃ , R ₁ = CH ₃ ).

To codeinone (4.96 g; 0.0158 mol) obtained by the procedure described in Example 1, acetic anhydride (13.6 g; 0.158 mol) and toluene (5 ml) were added and refluxed for 3 hours . The resulting solution was cooled, diluted with methylene chloride and an aqueous solution of sodium bicarbonate (27.72 g; 0.33 mol) was added, maintaining the temperature of the reaction mixture 5-10 ° С, brought to room temperature, the organic layer was separated, washed with water (2 × 50 ml) and dried with sodium sulfate. Then the solution was evaporated to dryness and the residue was triturated with 50 ml of low boiling petroleum ether and filtered. The resulting technical codeinone dienol acetate is a brown precipitate, which is oxidized without further purification by mixing with formic acid (3.7 g; 0.1 mol), a solution of hydrogen peroxide (3.87 g 30%) and water (10 ml) and maintain the reaction mass at 35-40 ° C for 5 hours. The reaction mass was adjusted to pH 9 with ammonia water and extracted with methylene chloride (2 × 25 ml). After evaporation, 3.55 g of the expected product is obtained. Yield 72.0%.

Example 3. Obtaining naltrexone (VII; R '= cyclopropylmethyl, R ₁ = H).

To 14-hydroxycodeinone (3.55 g; 0.0114 mol) obtained by the procedure described in Example 2, placed in an autoclave, methanol (15 ml) and palladium on carbon (5%) (0.5 g) were added and hydrogenated at 20 ati for 24 hours at room temperature. The reaction mass is filtered and evaporated. The residue was mixed with 20 ml of hexamethyldisilazane and refluxed for 2 hours. Excess hexamethyldisilazane is distilled off in vacuo. The residue was recrystallized from hexane (25 ml). The resulting 14-trimethylsilyloxy compound was mixed with a solution of cyanogen bromide in chloroform (10 ml 1M) and the resulting mixture was boiled for 20 hours. The reaction mass is washed with water, dried with sodium sulfate and evaporated. A solution of acetic acid (60 ml, 80%) is added to the obtained cyano derivative, and the reaction mass is boiled for 2 hours. The mixture was made basic with a 25% ammonia solution to pH 9. The precipitate was filtered off, chloromethylcyclopropane (7.0 g), potassium iodide (2.0 g) and ethanol (100 ml) were added and the reaction mixture was heated to boiling. The reaction mass is cooled, alkalinized with ammonia water to pH 9, extracted with methylene chloride (2 × 25 ml) and dried with sodium sulfate. The solution is cooled to 0-5 ° C and a solution of phosphorus tribromide in methylene chloride (50 ml 1M) is added, the reaction mass is stirred at room temperature, alkalized with ammonia water to pH 9 and the organic layer is separated, washed with water (2 × 30 ml), dried with sodium sulfate and evaporated to dryness in vacuo. 2.17 g of the expected product is obtained in the form of a base. Yield 56.0%.

Claims (7)

1. The method of obtaining derivatives of morphinone of General formula (II)

where R is lower alkyl, optionally substituted with C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyl, benzyl or substituted benzyl, cyan; R ₁ represents alkyl, benzyl or alkylcarbonyl, comprising the oxidation by salts of hypochlorous or hydrobromic acid of morphine derivatives of the general formula (I):

where R and R ₁ are as defined above; R ₂ represents hydrogen, alkyl, benzyl or alkylcarbonyl. 2. The method according to claim 1, characterized in that the oxidation is carried out at a temperature of from 0 to 20 ° C. 3. The method according to claim 1, characterized in that as the salts of hypochlorous or hydrobromic acid use alkali metal salts. 4. The method according to claim 1, characterized in that the reaction is carried out in an organic solvent, preferably acetonitrile. 5. The method according to claim 1, characterized in that the volume ratio of the organic solvent: the oxidizing solution is 1: 3. 6. A method of obtaining derivatives of 14-hydroxymorphinone of General formula (IV)

where R and R ₁ take the values defined in claim 1, comprising the oxidation by salts of hypochlorous or hydrobromic acid of morphine derivatives of the general formula (I)

where R and R ₁ take the values defined above, R ₂ represents hydrogen, alkyl, benzyl or alkylcarbonyl, with the derivation of morphinone (II)

where R and R ₁ take the values defined in claim 1, treatment of morphinone (II) derivatives with acetic anhydride to obtain enol (III) ester

where R and R ₁ take the values defined above, oxidation of enol (III) ester with hydrogen peroxide to obtain derivatives of 14-hydroxymorphinone (IV). 7. A method of obtaining derivatives of oxymorphone general formula (VII)

where R ’is substituted alkyl or alkylcarbonyl; R and R ₁ take the values defined in claim 1, comprising the oxidation by salts of hypochlorous or hydrobromic acid of morphine derivatives of the general formula (I)

where R and R ₁ are as defined above; R ₂ represents hydrogen, alkyl, benzyl or alkylcarbonyl, with the derivation of morphinone (II)

where R and R ₁ take the values defined in claim 1, treatment of morphinone (II) derivatives with acetic anhydride to obtain enol (III) ester

where R and R ₁ take the values defined above, oxidation of enol (III) ester with hydrogen peroxide to obtain derivatives of 14-hydroxymorphinone (IV)

where R and R ₁ take the values defined above, hydrogenation of derivatives of 14-hydroxymorphinone (IV) to obtain derivatives of oxymorphone (V)

where R and R ₁ take the values defined above, Dealkylation with nitrogen of derivatives of oxymorphone (V) to obtain nor derivatives (VI)

where R and R ₁ take the values defined above, alkylation of nor derivatives (VI) to give derivatives of oxymorphone (VII).