CZ20004323A3

CZ20004323A3 - Method for producing R- and S-norbenzomorphans

Info

Publication number: CZ20004323A3
Application number: CZ20004323A
Authority: CZ
Inventors: Matthias Grauert; Hanfried Baltes; Juergen Schnaubelt
Original assignee: Boehringer Ingelheim Pharma
Priority date: 1999-05-07
Filing date: 1999-05-07
Publication date: 2001-05-16

Abstract

Nový způsob výroby norbenzomorfanových derivátů obecného vzorce 1.A new method for the production of norbenzomorphan derivatives of general formula 1.

Description

Technical field

The present invention relates to a novel process for the production of norbenzomorphane derivatives of general formula 1 (corresponding stereoisomers are shown in Figures 1a and 1b;

where 1a 1b

R ¹ can be H, C 1 -C ₈ -alkyl, C 1 -C ₈ -alkoxy, hydroxy or halogen.

If different data are not provided on a case-by-case basis, common definitions are used with the following meaning:

C 1 -C ₈ -alkyl generally denotes a branched or unbranched hydrocarbon radical having 1 to 8 carbon atoms which may optionally be substituted by one or more halogen atoms, preferably fluorine, which may be the same or different. Examples which may be mentioned are the following hydrocarbon residues:

• 9 9999

- 2,999,9999,999

99999 99 9 99

9999 99

Methyl, ethyl, propyl, 1-methylethyl (isopropyl), butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1, 1-dimethylpropyl, 1,2-dimethylpropyl,

2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2, 3-dimethylbutyl,

3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,

1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Unless otherwise stated, lower alkyl radicals having 1 to 3 carbon atoms, such as methyl, ethyl, propyl, isopropyl, are preferred.

C 1 -C 5 -alkoxy generally denotes a branched or unbranched hydrocarbon radical attached via an oxygen atom having from 1 to 8 carbon atoms, which may optionally be substituted by one or more halogen atoms - preferably fluorine - which may be the same or different. Examples which may be mentioned are the following hydrocarbon residues:

methoxy, ethoxy, propoxy, 1-methylethyl (isopropyl), butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy,

1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, and 1-ethyl-2-methylpropoxy. Unless otherwise stated, lower alkoxy radicals having 1 to 3 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, are preferred.

Halogen is fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred as substituents. Preferred anions in aluminum compounds are bromine and chlorine, especially chlorine.

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The present method can be used to synthesize racemic compounds as well as to synthesize the corresponding enantiomerically pure compounds. In contrast to the method described in German Patent Application 195 28 472, the process of the present invention has the advantage of saving two steps, namely the introduction and subsequent removal of the Nformyl protecting group. In the case of 4'-methoxy substituted norbenzomorfanu (R ¹ = 4'-0Me), which is a valuable intermediate for pharmaceutically active norbenzomorfanové derivatives are moreover gained significantly improved yields of the desired compounds. The prior art discloses a process in which the corresponding 4-methylenepiperidine derivatives 2 are cyclized after the introduction of the Nformyl protecting group 3 into the corresponding benzomorphane derivatives 4. However, in order to obtain the corresponding norbenzomorphanes 5, the introduced one must be cleaved off again. a formyl protecting group.

In addition, R ² may be modified in a known manner, if desired, to R ¹ according to the target compound T. Thus, when R ² is an alkoxy group such as methoxy, ethoxy, n-propoxy or isopropoxy, it may be formed by ether cleavage. , for example by reaction with a hydrohalic acid such as HBr, corresponding to a hydroxy group (R ¹ = OH).

It has now surprisingly been found that the introduction of the formyl protecting group can be omitted in the process of the present invention. According to the invention, it is possible to cyclize the piperidine derivative 2 in protonated form directly with AlCl ₃ to the benzomorphane derivative 5. The synthesis is shown in Scheme 1 for the corresponding 1 enantiomer. However, it can be carried out analogously with the corresponding 1-enantiomers or with racemic starting compounds.

In the state of the art, the desired benzomorphane derivative is obtained in the case of 2- (2-methoxyphenyl) methyl-3,3-dimethyl-4-methylenepiperidine 2a (R = 2-OMe) with a yield of only 20%. In contrast, the novel process provides the desired benzomorphine derivative of type 5 - in the example with R ² = OCH ₃ - with an isolated yield of more than 80%. Changes in experimental conditions (Table 1) show that for successful cyclization, 4-methylenepiperidine 2 must first only be converted into a salt, since the cyclization of the free base predominantly provides degradation products of an unknown nature.

The process of the invention is suitably carried out in a reaction medium. Suitable reaction media are halogenated aliphatic

Or aromatic hydrocarbons or also acid amides, with mono- or polychlorinated alkanes having 1 to 3 carbon atoms or chlorinated benzene or derivatives or acid amides derived from carboxylic acids being particularly suitable. carbon atoms having from 1 to 3 carbon atoms. Very particularly preferred are dichloromethane (methylene chloride), 1,2-dichloroethane, chlorobenzene and dimethylacetamide. However, mixtures of the solvents mentioned may also be used.

The reaction temperature is not critical to the reaction of the invention over a wide range. It is primarily driven by the reactivity of the compounds involved in the reaction, whereas the upper limit is determined by the boiling point of the solvent - unless the reaction is carried out in an autoclave. Thus, depending on the solvent used, the reaction according to the invention can be carried out in a temperature range from 0 to 150 ° C. Preferably, a range of 20 to 100 ° C is used, with an interval of 40 to 70 ° C being particularly preferred.

The amount of aluminum halide used - preferably aluminum bromide and particularly preferably aluminum chloride - can also be varied within wide limits. This amount is typically in the range of 2 to 12 equivalents of aluminum chloride based on the starting material. Particularly preferred is a ratio of from 3 to 10 equivalents, with a range of from 3 to 5 equivalents being most preferred.

The salt form suitable for use is also not critical to the convenience of carrying out the reaction of the invention. Preference is given to using salts of the piperidine derivatives of type 2 with inorganic acids - in particular mineral acids. Preferably, neutral salts with hydrohalic acids or sulfuric acid are used. In addition to neutral sulphates (abbreviated as " SU1 " in Table 1), particularly preferably hydrochlorides (Cl) or hydrobromides (Br) can be used.

The present invention will be explained in more detail by the methods described in the following examples. Various other possible embodiments of the method of the invention will be apparent to those skilled in the art. However, it is explicitly indicated by the phone's call-through-the-phone that the examples and descriptions serve exclusively for illumination and should not be regarded as a limitation of the invention. .

EXAMPLES OF THE INVENTION

Example 1 (-) - 4'-Methoxy-5,9,9-trimethyl-6,7-benzomorphantartrate ((-) - 5a. TA)

4.9 g (20 mmol) of (+) - 2- (2-methoxyphenyl) methyl-3,3-dimethyl-4-methylenepiperidine (2a) are dissolved in 20 ml of acetone and 1 g of conc. sulfuric acid. The crystals formed are filtered off with suction and suspended in 6 ml of dichloromethane ^{1), 2)} ( ¹⁾ Alternative use of 1,2-dichloroethane yields 78% benzomorphane after 30 min at 55 ° C after inverse addition of AlCl 3. ²⁾ Reaction with dichloromethane at 55 ° C under pressure gives benzomorphane in a yield of 82% after 1.5 hours. 9 g (68 mmol) of AlCl 3 are added to the mixture while cooling to 10 to 20 ° C. A clear solution is formed which is then boiled for 2 hours (internal temperature 46 ° C). The reddish-brown reaction mixture was cooled to room temperature, diluted with 25 mL of dichloromethane and loaded onto approximately 100 g of ice. With cooling, it is added dropwise to a mixture of 100 ml of 20% NaOH at 20-25 ° C, the organic phase is separated off and the aqueous phase is extracted with 25 ml of dichloromethane. The combined organic extracts were dried over magnesium sulfate and the solvent was distilled off under vacuum. The residue is taken up in 10 ml of methanol and 3.1 g of L - (+) tartaric acid ( ^{3) is added} ( ³⁾ Alternatively, 62% HBr can be used for crystallization. The corresponding hydrobromide was isolated in 77% yield in 2 ml H2O. The mixture was allowed to crystallize in an aqueous bath for 10 min, diluted with approximately 40 mL of acetone and filtered off with suction.

Yield: 6.5 g (82.3%), mp: 236 ° C

- 7 · ΦΦΦΦ

Table 1

Salt Solvent AICI3 Temperature Time Yield Cl chlorobenzene 4.0 eq. 90 ° C 15 min 58.0% Cl chlorobenzene 4.0 eq. 75-80 ° C 2 hrs 61,7% Cl CH ₂ Cl ₂ 4.0 eq. 20-25 ° C 48 hrs 44,4% Cl ch ₂ ci ₂ 3.2 eq. 20-25 ° C 64 hrs 54.4% Cl c ₂ h ₄ ci ₂ 4.0 eq. 55-60 ° C 6 hrs 42.0% Cl c ₂ h ₄ ci ₂ 3.2 eq. High: 42 ° C 5 hrs 78,8% Br chlorobenzene 4.0 eq. 60 ° C 2 hrs 63.6% SU1 C ₂ H ₄ Cl ₂ 3.4 eq. 60-65 ° C 2 hrs 85.3% SU1 c ₂ h ₄ ci ₂ 3.4 eq. 55-60 ° C 30 min 91,1% SU1 c ₂ h ₄ ci ₂ 3.4 eq. 50-55 ° C 30 min 90.5% SU1 c ₂ h ₄ ci ₂ 3.4 eq. 55 ° C autoclave 1.5 hrs 82.0% SU1 ch ₂ ci ₂ 3.4 eq. 46-47 ° C slurry 2 hrs 90.3% SU1 DMAA 8.0 eq. 80-90 ° C 3 hrs 60%

Example 2 (-) - 3'-Methoxy-5,9,9-trimethyl-6,7-benzomorphantartrate ((-) - 5bTA)

8.6 g (35 mmol) of (+) - 2- (3-methoxyphenyl) methyl-3,3-dimethyl-4-methylenepiperidine (2b) are dissolved in 35 ml of acetone and 1.8 g of conc. sulfuric acid. The crystals formed are filtered off with suction and suspended in 10.5 ml of 1,2-dichloroethane. 16 g (120 mmol) of AlCl 3 are added to the mixture while cooling at 20 to 30 ° C. The mixture is rapidly heated to 55-70 ° C. After 30 min, allow to cool to room temperature, dilute with 100 mL of dichloromethane and add 200 g of ice water. Cooling at 20 to •

- 8 • 300 ml of 20% NaOH are added dropwise, the organic phase is separated and the aqueous phase is extracted with 150 ml of dichloromethane. The combined organic extracts were dried over magnesium sulfate and the solvent was distilled off under vacuum. The residue is taken up in 20 ml of methanol and mixed with 5.4 g of L - (+) tartaric acid in 3 ml of H ₂ O. The mixture is left to crystallize for 10 min in an ice bath, diluted with about 40 ml of acetone and filtered with suction.

Yield: 10.9 g (79%), m.p .: 186 ° C.

Represents:

- 9 00 0000 00 00 00 00 00 00 00 00 00 00 00 00

0000 000 00 0 * 0 0 · 0 * 00 0 * 000

Claims

PATENT CLAIMS

A process for the preparation of R- or S-norbenzomorphans of the general formula 1, wherein

R ¹ may be H, C 1 -C 5 -alkyl, C 1 -C 5 -alkoxy, hydroxy, halogen, characterized in that the 4-methylenepiperidine derivative of the general formula 2

1, HX

2. Al (Hal), converted by acid to the corresponding acid addition salt, and the salt is reacted in the reaction medium with aluminum halide, preferably aluminum bromide or aluminum chloride, at a temperature ranging from 8 to 150 ° C, and the reaction product is isolated after the reaction.

• · * <·· ··· ······

9 9 9 99 9 9 9 9 9 ·· · · · · · ·

- 10 - ·· ··· ·· ···· ·

Process according to claim 1, characterized in that a halogenated aliphatic or aromatic hydrocarbon or an acid amide or a mixture of said solvents is used as the reaction medium.

Process according to Claim 2, characterized in that the reaction medium used is a mono- or polychlorinated alkane having 1 to 3 carbon atoms, a chlorinated benzene or a benzene derivative or a carboxylic acid amide having 1 to 3 carbon atoms in the carboxyl radical or a mixture thereof. solvents.

Process according to Claim 3, characterized in that the reaction medium used is dichloromethane, 1,2-dichloroethane, chlorobenzene or dimethylacetamide, or mixtures of said solvents.

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

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

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

································

9

9 9 9 9 9 9 9 9 9

9 9 9 9 9

99,999 99,999 99 9

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

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

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

Process according to one of Claims 1 to 9, characterized in that (-) - 2- (3-methoxyphenyl) methyl-3,3-dimethyl-4-methylenepiperidine is used as the starting base.

Process according to one of Claims 1 to 10, characterized in that the piperidine derivative is used in the form of a mineral acid addition salt.

A process according to claim 12, wherein the piperidine derivative is used in the form of an addition salt with hydrohalic acid or sulfuric acid.

14. The process of claim 13 wherein the piperidine derivative is used in the form of a hydrochloride, hydrobromic or sulfuric acid addition salt.