MXPA00010964A - Improved method for preparing pharmaceutically valuable norbenzomorphane derivatives - Google Patents

Abstract

The invention relates to a new method for preparing norbenzomorphane derivatives of general formula (1).

Description

IMPROVED METHOD FOR THE PREPARATION OF NORBENZOMORPHAN DERIVATIVES, VALUABLE PHARMACEUTICAL MEANS The present invention relates to a new method for the preparation of norbenzomorphan derivatives of general formula 1 (the corresponding stereoisomers are represented in the figures la and Ib, only the R enantiomer preparation is addressed in the text, the preparable S enantiomers being similarly): 1a 1b Ref .: 124172 in which R1 can mean H, alkyl (Ci-Cß), alkoxy (Cj.- C8) hydroxy or halogen.

Insofar as there are no indications for discrepant particular cases, the general definitions are used in the following sense: alkyl (Ci-Cß) represents, in general, a branched or unbranched hydrocarbon group with 1 to 8 carbon atom (s) which they may optionally be substituted with one or more halogen atom (s) - preferably fluorine - which may be the same or different from each other. As examples, the following hydrocarbon radicals are to be mentioned: methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1, 1-dimethyl-propyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethyl-propyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methyl-pentyl, 4-methyl-ethylpentyl, 1,1-dimethylbutyl, 1,2 -dimethyl-butyl, 1,3-dimethyl-butyl, 2,2-dimethylbutyl, 2,3-dimethyl-butyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Preferred - unless otherwise indicated - lower alkyl radicals with 1 to 3 carbon atoms such as methyl, ethyl, propyl, isopropyl.

Alkoxy (Ci-Cß) represents, in general, a branched or unbranched hydrocarbon radical, linked through an oxygen, with 1 to 8 carbon atom (s) which may optionally be substituted with one or more carbon atom (s). halogen preferably fluorine - which may be the same or different from each other. As examples, the following hydrocarbon radicals are to be mentioned: methoxy, ethoxy, propoxy, 1-methylethoxy (isopropoxy), butoxy, 1-methylpropoxy, 2-methylpropoxy, 1, 1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1, 1-dimethyl-propoxy , 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-yl-propoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methyl-pentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2- dimethyl-butoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethyl-butoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1-trimethylpropoxy, 1,2, 2-trimethylpropoxy, 1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy. Preferred - unless otherwise indicated - lower alkoxy groups with 1 to 3 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy.

Halogen, in the sense of the present invention, means fluorine, chlorine, bromine, iodine, among which fluorine and chlorine are preferred as substituents. As anions in aluminum compounds, bromine and chlorine are preferred - especially the latter.

The process can be used for the synthesis of the racemic compounds as well as for the synthesis of the corresponding pure compounds with respect to the enantiomers. In front of the procedure described in the German publication memory 195 28 472, the process according to the invention has the advantage that two steps are saved - namely the introduction of the N-formyl protecting group and its subsequent dissociation. In the case of the norbenzomorphane substituted with 4'-methoxy (R1 = 4'-OMe), which represents a valuable intermediate product for pharmaceutically active norbenzomorphan derivatives, clearly higher desired yields of the desired compound are also obtained.

In the state of the art mentioned at the beginning, a process is described in which the corresponding 4-methylene-piperidine derivatives 2, after the introduction of a N-formyl-3 protecting group, are cyclized to provide the corresponding benzomorphan derivatives 4_. However, to access the corresponding norbenzomorphan 5_, the formyl protecting group must be dissociated again, in another step.

Then - if desired - the substituent R2 can be modified in a known manner to R1, according to the desired compound 1. Thus, in the case that R2 has the meaning of an alkoxy group such as, for example, methoxy, ethoxy, n-propoxy or isopropoxy - through a dissociation of the ether - for example by reaction with a hydrogen halide as HBr - the corresponding hydroxy compound can be generated (R1 = OH).

It was now found, surprisingly, that from now on, with the process according to the invention, the introduction of a formyl protecting group can be dispensed with. According to the invention, the piperidine derivative _2, in the protonated form, can be cyclized directly with A1C13, providing the benzomorphan derivative 5_. The synthesis is represented in scheme 1 for the corresponding IR enantiomers. However, it can also be carried out analogously with the corresponding ISS enantiomers or with the racemic starting compounds.

Scheme 1 Thus, according to the process described in the state of the art, in the case of 2- (2-methoxy phenyl) -methyl-3, 3-dimethyl-4-methylene-piperidine 2_a (R2 = 2-OMe) , the desired benzomorphan derivative is obtained only by 20%. The new method, on the other hand, provides the desired benzomorphan derivative of type 5_ - in the example with R2 = 0CH3 - isolated with a yield of more than 80%.

Variations of the test conditions (Table 1) show that for an efficient cyclization, the 4-methylene-piperidine 2_ should simply be transformed into a salt, since the cyclization of the free base predominantly provides decomposition products of unknown nature.

The process according to the invention is conveniently carried out in a reaction medium. For this purpose, aliphatic or aromatic halogenated hydrocarbons or, alternatively, acid amides are particularly suitable as a reaction medium, with mono- or polychlorinated alkanes having 1 to 3 carbon atoms or ) chlorinated benzene (s) or carboxylic acid amides with 1 to 3 C atoms in the carboxylic unit. Especially preferred are dichloromethane (methylene chloride), 1,2-dichloroethane, chlorobenzene and dimethylacetamide. However, mixtures of the solvents mentioned can also be used.

The reaction temperature, within a wide range, is not critical for the reaction according to the invention. Firstly, it is governed by the reactivity of the reaction participants, the upper limit being set by the boiling point of the solvent - as long as the reaction is not carried out in an autoclave. Therefore, the reaction according to the invention, depending on the solvent used, can be carried out in a temperature range of 0 to 150 ° C. A range of 20 to 100 ° C is preferred, a range of 40 to 70 ° C being especially preferred.

The amount of aluminum halide (III) used preferably aluminum tribromide and, especially preferably, aluminum trichloride, is also variable over wide ranges. It is typically located in a range of 2 to 12 equivalents of aluminum chloride, based on the starting material. Particularly preferably, a ratio in the range of 3 to 10 equivalents is used, a ratio comprised in a range of 3 to 5 equivalents being particularly preferred.

The salt form used is also not critical in terms of the advantageous viability of the reaction according to the invention. The salts of the piperidine derivative of type 2 are preferably used with inorganic acids, especially with mineral acids. Preferred are neutral salts with hydrogen halides or sulfuric acid. Along with neutral sulfates (abbreviated "SU1" in Table 1), hydrochlorides (Cl) or hydrobromides (Br) are particularly preferred.

The invention described above is further explained by the method described in the following examples. From the present specification, other executions of various nature of the method according to the invention are evident to the specialist. It is expressly stated, however, that the examples and the specification are merely intended for explanation and should not be considered as limiting the invention.

Eg emplos Example 1: (-) -4 '-methoxy-5, 9, 9-trimethyl-6,1-benzo orphan-tartrate ((-) -5aTA) 4.9 g (20 mmol) of (+) -2- (2-methoxyphenyl) -methyl-3, 3-dimethyl-4-methylene-piperidine (2a.) Are dissolved in 20 ml of acetone and mixed with 1 g of concentrated sulfuric acid. The precipitating crystals are separated by filtration with suction and suspended in 6 ml of dichloromethane 1), 2). To this is added, with cooling, to 10-20 C, 9 g (68 mmol) of A1C13. A clear solution is produced which is then boiled for 2 hours (inside temperature, 46 ° C). The brown-red reaction mixture is cooled to room temperature, diluted with 25 ml of dichloromethane and poured onto about 100 and ice. At 20-25 ° C, with cooling, 100 ml of 20% NaOH are added dropwise, the organic phase is then separated and the aqueous phase is extracted with 25 ml of dichloromethane. The combined organic extracts are dried over magnesium sulfate and the solvent is distilled off in vacuo. The residue is taken up in 10 ml of methanol and mixed with 3.1 g of L- (+) - tartaric acid 3 'in 2 ml of H20. It is left to crystallize in an ice bath for 10 min, diluted with approximately 40 ml of acetone and filtered with suction. Yield: 6.5 g (82.3%). Melting point: 236 ° C. i) The alternative use of 1,2-dichloroethane provides, after inverted addition of A1C13 and after 30 min at 55 ° C, 78% benzomorphan. 2! The reaction in dichloromethane at 55 ° C, under pressure, gives the benzomorphane after 1.5 hours with a yield of 82%. 3) Alternatively, 62% HBr can be used for crystallization. The corresponding hydrobromide is isolated with a yield of 77%.

Table 1 Example 2: (-) -3'-methoxy-5, 9, -trimethyl-6, 1 -benzomorphan-tartrate ((-) - 5bTA) 8.6 g (35 mmol) of (+) -2- (3-methoxyphenyl) -methyl-3, 3-dimethyl-4-methylene-piperidine (2b) are dissolved in 35 ml of acetone and mixed with 1.8 g of acid concentrated sulfuric The crystals that precipitate are separated by filtration. with suction and suspended in 10.5 ml of 1,2-dichloroethane. To this is added, with cooling, at 20-30 ° C, 16 g (120 mmol) of A1C13. The mixture is heated rapidly to 55-70 ° C. After 30 min it is left to cool to room temperature, diluted with 100 ml of dichloromethane and mixed with 200 g of ice water. At 20-25 ° C, with cooling, 300 ml of 20% NaOH are added dropwise, the organic phase is then separated and the aqueous phase is extracted with 150 ml of dichloromethane. The combined organic extracts are dried over magnesium sulfate and the solvent is distilled off in vacuo. The residue is taken up in 20 ml of methanol and mixed with 5.4 g of L- (+) - tartaric acid in 3 ml of H20. It is left to crystallize in an ice bath for 10 min, diluted with approximately 40 ml of acetone and filtered with suction. Yield: 10.9 g (79%). Melting point 186 ° C.

It is noted that in relation to this date, the best method known to the applicant, to implement said invention is that which is clear from the manufacture of the objects to which it refers.

Having described the invention as above, the content of the following is claimed as property.

Claims (14)

1. Method for the preparation of R- or S-norbenzomorpanos of general formula 1 wherein R 'can mean H, (C? -C8) alkyl, (Ci-C?) alkoxy hydroxy, halogen, characterized in that a 4-methylene-piperidine derivative of general formula 2 it is reacted with an acid, providing the corresponding salt by addition of acid, and the salt is reacted in a reaction medium with an aluminum (III) halide, preferably aluminum tribromide or aluminum trichloride, at a temperature ranging from 0 to 150 ° C and, after the transformation has been carried out, the reaction product is isolated.

2. Process according to claim 1, characterized in that an aliphatic or aromatic halogenated hydrocarbon or an acid amide or mixtures of the solvents mentioned are used as the reaction medium.

3. Process according to claim 2, characterized in that a mono- or polychlorinated alkane with 1 to 3 carbon atoms, a benzene or chlorinated benzene derivative or an amide of a carboxylic acid with 1 to 3 carbon atoms is used as the reaction medium. C in the carboxyl radical or mixtures of the solvents mentioned.

4. Process according to claim 3, characterized in that dichloromethane, 1,2-dichloroethane, chlorobenzene or dimethylacetamide or mixtures of the aforementioned solvents are used as the reaction medium.

5. Process according to one of claims 1 to 4, characterized in that the reaction is carried out in a temperature range of 20 to 150 ° C

6. Process according to claim 5, characterized in that the reaction is carried out in a temperature range of 40 to 70 ° C.

7. Process according to one of claims 1 to 6, characterized in that 2 to 12 equivalents of aluminum halide (III) are used, based on the starting material.

8. Process according to claim 7, characterized in that from 3 to 10 equivalents of aluminum halide (III) are used, based on the starting material.

9. Process according to claim 8, characterized in that 3 to 5 equivalents of aluminum (III) bromide or aluminum (III) chloride are used, based on the starting material.

10. Process according to one of claims 1 to 9, characterized in that (+) - 2- (3-methoxyphenyl) methyl-3,3-dimethyl-4-methyl-piperidine is used as the piperidine derivative.

11. Process according to one of claims 1 to 9, characterized in that (-) - 2- (3-ethoxy phenyl) met i 1-3, 3-dimeti-4-methylene-piperidine is used as the piperidine derivative.

12. Process according to one of claims 1 to 11, characterized in that the piperidine derivative is used in the form of an addition salt with a mineral acid.

13. Process according to claim 12, characterized in that the piperidine derivative is used in the form of an addition salt with a hydrogen halogenide or sulfuric acid.

14. Process according to claim 13, characterized in that the piperidine derivative is used in the form of an addition salt with hydrochloric acid, hydrobromic acid or sulfuric acid.