How to obtain tramadol

 

(57) Abstract:

Getting tramadol is performed in the Grignard reaction. The Grignard reaction between m-halogenation, magnesium and 2-(dimethylaminomethyl)cyclohexanone is carried out in a medium of an organic solvent with donor properties. As m-halogenase use m-bromoanisole or m-chloroanisole. The reaction is carried out with the activation of magnesium 1,2-dehalogenation. As 1,2-dehalogenating use 1,2-dibromoethane, 1,2-dichloroethane or 1-bromo-2-chlorate. Specified 1,2-dehalogenated take in the amount of from 0.01 to 0.95 molar amount of m-halogenase. As the organic solvent with donor properties use ethers or amines. The improved method provides a higher yield of the target product and expanding the resource base at the expense of use as the original m-halogenase m-chloroanisole. 14 C.p. f-crystals.

The invention relates to the chemistry of aminoalcohols, in particular, to an improved process for the preparation of tramadol - 2-dimethyl aminomethyl-1-(3-methoxyphenyl)cyclohexanol.

Tramadol (in the form of cleaners containing hydrochloride salt) is an effective analgesic with a low toxicity to warm-blooded animals (1).

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The described method is reorganizes compounds (Grignard reagent, derived from magnesium and m-bromoanisole) (1,2).

Getting substituted aminomethylphenol - tramadol by the Grignard reaction is presented in scheme 1 (see the end of the description).

Known for an improved method of obtaining aminoalcohols by the Grignard reaction and their separation from the reaction mixture (3). According to this method, the reaction mixture was subjected to acid and then alkali treatments, thereby increasing the yield of the target product.

However, according to patent documents the scope of the Grignard reaction is limited by the use of expensive product m-bromoanisole, which is several orders of magnitude more expensive than the corresponding chlorinated.

The number of known techniques to obtain a Grignard reagents from light aryl halides. So, when using the magnesium chloride-potassium iodide potassium Grignard reagents can be obtained with high yields (4), but the system with metallic potassium is flammable and explosive and may not be used to produce pharmaceutical substances in the industrial scale.

The use of the system magnesium-1,2-dibromethane allows you to get magyarkanizsa connections from and tend to the formation of insoluble deposits on the surface of magnesium and as a consequence, exhibit inertia (7). Therefore, even the approach formulated above with the above substituents interact with magnesium in the presence of 1,2-dibromethane only 36 - 56% (8-10).

As the closest analogue (prototype) the selected method of obtaining the tramadol, which consists in the interaction m-bromoanisole, magnesium and 2-dimethylaminomethylene in absolute tetrahydrofuran (THF) (2). According to example 1 of the said patent shavings of magnesium added in portions to a solution of m-bromoanisole in absolute tetrahydrofuran, maintaining the boil, and boil until dissolved magnesium. To the thus obtained Grignard reagent is added 2-dimethylaminomethylphenol, maintaining the temperature of the reaction mixture to -10...0oC. as a result, the output of the reasons tramadol is 78,6% in terms of 2-dimethylaminomethylene. The target product can be transferred to the cleaners containing hydrochloride salt in hydrochloric acid or gaseous hydrogen chloride in the presence of an organic solvent selected from ethers, ketones or aromatic esters.

Under these conditions, m-chloroanisole shows inert and does not interact with MAGN the AI known way for tramadol.

The technical result, which can be obtained by carrying out the invention is expressed in the increase in the yield of the target compounds in expanding the resource base through the use of a cheaper source connection, m-chloroanisole and expansion of the range of the used solvents.

The proposed method for obtaining the tramadol is in the interaction m-halogenase with magnesium and 2-dimethylaminomethylene in the environment of an organic solvent with donor properties in the presence of 1,2-dehalogenating, taken in an amount from 0.01 to 0.95 molar amount of m-halogenase. The target product is released in the form of a base or cleaners containing hydrochloride salt.

As m-halogenase used as m-bromoanisole and m-chloroanisole.

As 1,2-dehalogenating use 1,2-dibromethane in number, it is from 0.01 to 0.5, and preferably of 0.05 to 0.3 molar quantity of the specified m-halogenase.

As 1,2-dehalogenating use of 1,2-dichloroethane in number, preferably from 0.25 to 0.95 molar quantity of the specified m-halogenase.

As 1,2-dehalogenating you can use 1-bromo-2-chlorate.

As the solution is propyl ether, glyme or diglyme, or a cyclic ether, for example tetrahydrofuran. You can use as a solvent with donor properties of the amine, preferably a tertiary amine, such as triethylamine or pikolines.

In the absence of additives, activating the magnesium - specified 1,2-dehalogenating, the yield of the target compounds will be reduced to 10% when used as a solvent diethyl ether.

In the presence of 0.1-0.25 mol of 1,2-dibromethane when using as starting compound m-chloroanisole exit reasons tramadol is 50 to 75% depending on the solvent. When using m-bromoanisole output rises to 85% in diethyl ether, and slightly increased (up to 87-90%) when the number of 1,2-dibromethane. On the contrary, in the case of m-chloroanisole further increase in the amount of 1,2-dibromethane (from 0.25 to 0.95 moles) causes a gradual increase in the yield of the Foundation of tramadol.

The use amount of 1,2-dehalogenating more of 0.95 moles impractical because not lead to a noticeable increase in the yield of the target product.

Replacement 1,2-dibromethane 1-bromo-2-chlorate virtually no effect on the process, and the transition to a 1,2-dichloroethane leads to some reduction is of tramadol in the interval from -10 to 100oC.

Translation grounds of tramadol in cleaners containing hydrochloride salt is carried out by traditional methods.

The essence of this invention is illustrated by, but is not limited to the following examples.

Example 1. To 3.1 g (0.13 mol) of magnesium shavings add a solution of 18.7 g (0.1 mol) of m-bromoanisole and 4.7 g (0,025 mol) of 1,2-dibromethane in 60 ml of diethyl ether, so that the ether was quietly seething. Then boil for 1 hour, cooled to room temperature and added 12.4 g (0.08 mol) of 2-dimethylaminomethylene. Stirred for 0.5-1 hour and add 50 ml of saturated solution of ammonium hydrochloride. Layers divide, the water layer is extracted. The combined extract the solvent is distilled off, the residue is distilled in vacuum. Obtain 17.9 g (1), yield 85%, so Kip. 152-155oC/2 mm RT.art., so plvl. hydrochloride 177-178oC.

Example 2. Analogously to example 1 from 18.7 g (0.1 mol) of m-bromoanisole, 3.6 g (0.15 mol) of magnesium, 9.4 g (0.05 mol) of 1,2-dibromethane, 12.4 g (0.08 mol) of 2-dimethylaminomethylene and 60 ml of diethyl ether to obtain 18.7 g (1), yield 89 %, so Kip. 142-145oC/1 mm RT.article.

Example 3. Analogously to example 1 from 14.3 g (0.1 mol) of m-chloroanisole, 4.8 g (0.2 mol) of magnesium, 18,8 g (0,095 mol) of 1,2-dibromethane, 12.4 g (0.08 mol) of 2-dimethylaminomethyl is R 4. Analogously to example 1 from 14.3 g (0.1 mol) of m-chloroanisole, 3.1 g (0.13 mol) of magnesium, and 1.9 g (0.01 mol) of 1,2-dibromethane, 12.4 g (0.08 mol) of 2-dimethylaminomethylene and 80 ml of tetrahydrofuran gain of 12.6 g (1), yield 60 %, so Kip. 165-170oC/5 mm RT.article.

Example 5. Analogously to example 1 from 14.3 g (0.1 mol) of m-chloroanisole, 3.1 g (0.13 mol) of magnesium, 4.7 g (0,025 mol) of 1,2-dibromethane, 12.4 g (0.08 mol) of 2-dimethylaminomethylene and 60 ml of diethyl ether receive a 10.5 g (1), the yield is 50%, so Kip. 165-170oC/5 mm RT.article.

Example 6. Analogously to example 1 from 18.7 g (0.1 mol) of m-bromoanisole, 4.8 g (0.2 mol) magnesium, 18,8 g (0,095 mol) of 1,2-dichloroethane, 12.4 g (0.08 mol) of 2-dimethylaminomethylene and 60 ml of diethyl ether to obtain 16.6 g (1), yield 79%, so the bales. 142-145oC/1 mm RT.article.

The spectral parameters and physico-chemical constants of 2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol and its cleaners containing hydrochloride salt obtained in the examples are identical.

Thus, the proposed method allows to obtain higher outputs tramadol, based on both m-bromoanisole and m-chloroanisole using a wide range of organic solvents.

Sources of information

1. U.S. patent N 3652589, C 07 D 27/04, publ. 28.03.1972.

4. S. C. Welch, A. S. C. Prakasa Rao. J.Org. Chem., 1978, v. 43, p. 1957.

5. D. E. Pearson, D. Cowan, J. D. Beskler. J.Org. Chem., 1959, v. 24, N 4, p. 504.

6. M. S. Newman. J. Med. Chem., 1967, v. 10, p. 728.

7. L. Field. J. Am. Chem Soc., 1956, v. 78, No. 1, p. 92

8. G. R. Peftet, M. F. Bauman, K. N. Rangamnal. J. Med. Pharm. Chem., 1962, v. 5, p. 800.

9. G. W. H. Cheeseman, R. C. Poller. J. Chem. Soc., 1962, p. 5277.

10. A. Nudelman, D. J. Cram. J.Org. Chem., 171, v. 36, p.335.1

1. How to obtain tramadol - 2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol by the reaction of m-halogenase, magnesium and 2-(dimethylaminomethyl)cyclohexanone in the environment of an organic solvent with donor properties with the separation of the target product in the form of a base or cleaners containing hydrochloride salt, characterized in that as m-halogenase use m-bromoanisole or m-chloroanisole, and the reaction is carried out with the activation of magnesium 1,2-dehalogenation, taken in an amount from 0.01 to 0.95 molar quantity of the specified m-halogenase.

2. The method according to p. 1, characterized in that as 1,2-dehalogenating use 1,2-dibromethane.

3. The method according to p. 2, characterized in that the 1,2-dibromethane used in an amount of 0.01 to 0.5 molar quantity of the specified m-halogenase.

4. The method according to p. 3, characterized in that the 1,2-dibromethane used in quantities of 0.05 to 0.3 Molinos is ohinata use of 1,2-dichloroethane.

6. The method according to p. 5, characterized in that the 1,2-dichloroethane is used in amounts of from 0.25 to 0.95 molar quantity of the specified m-halogenase.

7. The method according to p. 1, characterized in that as 1,2-dehalogenation using 1-bromo-2-chlorate.

8. The method according to any of paragraphs.1 to 7, characterized in that the organic solvent with donor properties use the ether.

9. The method according to p. 8, characterized in that the ether used as an acyclic ether.

10. The method according to p. 9, characterized in that as the acyclic ether using diethyl ether, di-isopropyl ether, glyme or diglyme.

11. The method according to p. 8, characterized in that the ether used as a cyclic ether.

12. The method according to p. 11, characterized in that the cyclic ether used tetrahydrofuran.

13. The method according to any of paragraphs. 1 to 7, characterized in that the solvent with donor properties of the used amine.

14. The method according to p. 13, characterized in that used as an amine tertiary amine.

15. The method according to p. 14, characterized in that the tertiary amine using triethylamine or picoline.

 

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