The method of obtaining derivatives of morphinan, the method of obtaining derivatives of 14-hydroxymorphinone, and the method of obtaining derivatives oxymorphone


C07D489/06 - with a hetero atom directly attached in position 14

 

(57) Abstract:

The invention relates to a method for producing derivatives of morphinan, which are intermediate compounds for obtaining derivatives of 14-hydroxymorphinone, which, in turn, are used to obtain opiate antagonists derived Oxymorphone. The method of obtaining derivatives of morphinan includes the oxidation of salts of hypochlorous and bromoviridae acids morphine derivatives of General formula I:

where R is lower alkyl, C3-C6cycloalkyl, benzyl or substituted benzyl, cyan; R1- alkyl, benzyl or alkylaryl; R2is hydrogen, alkyl, benzyl or alkylsulphonyl. The oxidation is conducted salts of hypochlorous and bromoviridae acids, mainly obtained immediately before oxidation. For oxidation are preferably hypochlorites or hypobromites sodium and potassium. Opiate antagonists are important drugs for the treatment and diagnosis of addiction. 3 S. and 4 C.p. f-crystals.

The invention relates to a method for producing derivatives of morphinan, which are intermediate compounds for obtaining derivatives of 14-hydroxymorphinone, which, in turn, ispolschovaniem means for the treatment and diagnosis of addiction.

The most widely used method of production of opiate antagonists derived Oxymorphone, 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 with getting 14-hydroxycotinine, its hydrogenation, serial dealkylation of methyl groups at the phenyl ring and the nitrogen processing of the received noroxymorphone appropriate alkylhalogenide. The main disadvantage of this method of production is the need to use as feedstock expensive thebaine, because the amount of thebaine limited due to its very low content in opium resin.

In U.S. patent No. 5922876 and No. 6008355 disclosed methods of obtaining derivatives Oxymorphone and oxycodone, including the production of derivatives of morphinan of morphine and codeine by direct oxidation in Turn, namely the action of DMSO with oxalylamino in methylene chloride at-S obtaining technical product followed by treatment with acetic anhydride and receiving danilatos, their secondary oxidation by peroxide or nagkalat obtaining derivatives of 14-hydroxymorphinone that gdny, which alkylate with obtaining opiate antagonists. The main disadvantage of this method is carrying out the oxidation of morphine and codeine derivatives in morphinone in harsh environments, making this method unsuitable for use in industry.

In addition to the method of obtaining derivatives of morphinan oxidation of codeine and morphine, which is described above as one of the stages of the method of obtaining derivatives Oxymorphone and oxycodone, the most widely applicable may be considered a method of obtaining data products from thebaine reaction halogenation in the presence of a catalyst followed by hydrolysis as described in U.S. patent No. 4052402. The disadvantage of this method is the use of expensive thebaine.

Derivatives of morphinan can also be obtained by oxidation of morphine and codeine various strong oxidizers, however, the selectivity of the oxidation is low, and in some cases, the oxidation goes towards the education of other products (Beilstein, 27 II 136).

The present invention is to develop a simpler, high-tech, using more accessible and cheap source of raw materials method of obtaining derivatives of morphinan, prossa currently the main means of treatment of opiate dependence and the diagnosis of drug.

The authors of the present invention it has been unexpectedly discovered that the use of such strong not specific oxidizing agents like salts of hypochlorous and bromoviridae acids under mild conditions allows to obtain high yield and purity derivative of morphinone.

Thus, the present invention relates to a method for producing derivatives of morphinan, including oxidation of salts of hypochlorous and bromoviridae acids morphine derivatives of General formula I:

(I)

where K represents lower alkyl, C3-C6cycloalkyl, benzyl or substituted benzyl, cyan; R1represents alkyl, benzyl or alkylaryl; R2represents hydrogen, alkyl, benzyl or alkylsulphonyl.

Oxidation (Scheme 1) are preferably salts of hypochlorous and bromoviridae acids, mainly obtained immediately before oxidation. For oxidation are preferably hypochlorites or hypobromites sodium and potassium.

The oxidation is carried out by simple mixing of an aqueous solution of an oxidizer and the solution of the original substance or suspension in an organic solvent. Preferably the solvent used azet the product distinguish, using known techniques.

In a preferred embodiment of the invention the ratio of the organic solvent solution of the oxidizing agent is chosen so that the formed two-phase system in which the target product is in the organic phase, which facilitates its release. Preferably, the above ratio is 1:3.

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

Derivatives of morphine (I) are oxidized by hypochlorite or hypobromite with obtaining the compound (II), shown in figure 1. Further derivatives of morphinan (II) is treated with acetic anhydride to obtain the enol ether (III), which further oxidize hydrogen peroxide with obtaining derivatives of 14-hydroxymorphinone. The second and third stage of the method carried out by known methods, for example as described in U.S. patent 6008355.

Another object of the present invention is a method of obtaining derivatives Oxymorphone according to the General scheme presented in figure 3:

where R’ is substituted alkyl or alkylaryl.

The first stage of oxidation, the production is of skorpiona (IV) the process is conducted, as shown in Scheme 2. The transformation of the derivatives of 14-hydroxymorphinone (IV) derivative Oxymorphone (V) is produced by hydrogenation, next (V) deaccelerate nitrogen with getting necrosophic (VI), which alkylate with obtaining opiate antagonists (VII), as shown previously.

Below are some specific examples of embodiments of the invention, which are given for illustration.

Examples

Example 1. Getting codeinone (II; R=CH3, R1=CH3).

Prepare a solution of an oxidising agent, dissolving solid sodium hydroxide (3.0 g) in 25 ml of water, and cooled with a mixture of ice/water bubbled through the solution to chlorine gas, vaporizing 2 ml of liquid chlorine.

Separately preparing a suspension of codeine (5.0 g, 0,0168 mol) in acetonitrile (8 ml). To the suspension is added a solution of oxidizing agent, maintaining the temperature of the reaction mass 5-10C. The reaction mass is maintained at this temperature for one hour and then brought to room temperature. Separate the organic layer. To the organic layer was added methylene chloride (25 ml) and the resulting solution washed with water (ml). The solution is dried with sodium sulfate and evaporated. After recrystallization from ethyl acetate receive 4,96 g of the target product (the

To codeinone (4,96 g; 0,0158 mol), obtained according to the method described in Example 1, was added acetic anhydride (13,6 g; 0,158 mol) and toluene (5 ml) and refluxed for 3 hours. The resulting solution is cooled, diluted with methylene chloride and added dropwise an aqueous solution of sodium bicarbonate (27,72 g; 0.33 mol), maintaining the temperature of the reaction mass 5-10C, bring to room temperature, separate the organic layer, washed with water (250 ml) and dried with sodium sulfate. Then the solution is evaporated to dryness and the residue triturated with 50 ml of low-boiling petroleum ether and filtered. Received technical girolata of codeinone is a brown precipitate, which without further purification subjected to oxidation, mixing with formic acid (3.7 g; 0.1 mol), hydrogen peroxide solution (a 3.87 g of 30%) and water (10 ml) and maintained the reaction mass at 35-40C for 5 hours. The reaction mass was adjusted to pH 9 ammonia water and extracted with methylene chloride (225 ml). After evaporation obtain 3.55 g of the target product. Output 72,0%.

Example 3. Receiving naltrexone (VII; R’=cyclopropylmethyl, R1=H).

To 14-hydroxycotinine (3.55 g; 0,0114 mol), obtained according to the method described in examples is 24 hours at room temperature. The reaction mass is filtered and evaporated. The residue is mixed with 20 ml hexamethyldisilazane and refluxed for 2 hours. Excess hexamethyldisilazane distilled off in vacuum. The residue is recrystallized from hexane (25 ml). Received 14 trimethylsilyloxy compound is mixed with a solution of bromine cyan in chloroform (10 ml, 1M) and boil the mixture for 20 hours. The reaction mass is washed with water, dried with sodium sulfate and evaporated. To the resulting lanproton add a solution of acetic acid (60 ml, 80%) and the reaction mass is boiled for 2 hours. The mixture is alkalinized 25% ammonia solution to pH 9. The precipitation is filtered off, add klimatyzatory (7.0 g), potassium iodide (2.0 g) and ethanol (100 ml) and the reaction mass is heated to boiling. The reaction mass is then cooled, alkalinized ammonia water to pH 9, extracted with methylene chloride (225 ml) and dried with sodium sulfate. The solution is cooled to 0-5C and adds the solution tribromide phosphorus in methylene chloride (50 ml, 1M), the reaction mass is stirred at room temperature, alkalinized ammonia water to pH 9 and separated the organic layer, washed with water (230 ml), dried with sodium sulfate and evaporated in vacuum dosnon General formula (II)

where R represents lower alkyl, optionally substituted C3-C6cycloalkyl,3-C6-cycloalkyl, benzyl or substituted benzyl, cyan;

R1represents alkyl, benzyl or alkylsulphonyl,

including the oxidation of salts of hypochlorous or bromoviridae acid morphine derivatives of General formula (I):

where R and R1take the values defined above;

R2represents hydrogen, alkyl, benzyl or alkylsulphonyl.

2. The method according to p. 1, characterized in that the oxidation is carried out at a temperature of from 0 to 20C.

3. The method according to p. 1, characterized in that salts of hypochlorous or bromoviridae acid use salts of alkali metals.

4. The method according to p. 1, characterized in that the reaction is carried out in an organic solvent, preferably acetonitrile.

5. The method according to p. 1, characterized in that the volume ratio of organic solvent:solution of the oxidant is 1:3.

6. The method of obtaining derivatives of 14-hydroxymorphinone General formula (IV)

where R and R1take the values defined in paragraph 1,

including the oxidation of salts of hypochlorous or bromoacetone above,

R2represents hydrogen, alkyl, benzyl or alkylsulphonyl,

obtaining derivatives of morphinan (II)

where R and R1take the values defined in paragraph 1,

processing derivatives of morphinan (II) with acetic anhydride to obtain the enol ether (III)

where R and R1take the values defined above,

oxidation of the enol ether (III) hydrogen peroxide with obtaining derivatives of 14-hydroxymorphinone (IV).

7. The method of obtaining derivatives Oxymorphone General formula (VII)

where R’ - substituted alkyl or alkylaryl;

R and R1take the values defined in paragraph 1,

including the oxidation of salts of hypochlorous or bromoviridae acid morphine derivatives of General formula (I)

where R and R1take the values defined above;

R2represents hydrogen, alkyl, benzyl or alkylsulphonyl,

obtaining derivatives of morphinan (II)

where R and R1take the values defined in paragraph 1,

processing derivatives of morphinan (II) with acetic anhydride to obtain the enol ether (III)

where R and R1take the values defined above,

where R and R1take the values defined above,

hydrogenation of derivatives of 14-hydroxymorphinone (IV) to obtain the derivatives Oxymorphone (V)

where R and R1take the values defined above,

dealkylation nitrogen derivatives Oxymorphone (V) obtaining necrosophic (VI)

where R and R1take the values defined above,

alkylation necrosophic (VI) to obtain the derivatives Oxymorphone (VII).

 

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