RO112866B1 - PROCESS FOR PREPARING 1,2,3,4,4a,5,10,10a-OCTONHYDROBENZ(G)QUINOLINE - Google Patents

Description

The present invention relates to a process for the preparation of 1, 2, 3, 4, 4a, 5,1O, 1Oa-actahidrobenz [g] quinoline, compounds used as pharmaceuticals, in particular as a dopaminergic agent, and to obtain other compounds. with pharmacological properties.

A process for preparing the compound of general formula I is known:

in the form of racemates, racemic compounds can be separated by known separation methods, such as chromatography (EPO 077 754).

The present invention relates to a process for the preparation of 1, 2, 3, 4, 4a, 5, 10, 10a-octahydrobenz [g) quinoline of formula I:

wherein R ₁ and R ₂ independently represent hydrogen or methoxy, both not representing hydrogen, R ₃ and R ₄ independently represent one another with 1 to 4 carbon atoms, a process wherein -a first phase an anion of the compound of formula II is formed:

under very basic conditions, after which the obtained anion passes into a cetenacetal which in the second phase protonates.

Transformation into cetenacetal by direct deprotonation occurs in the same reaction medium.

By the process of the present invention, 6-methoxy-3-a-methoxycarbonyl-1-n-propyl-1,2,3,4,4aa, 5,10,1Oap-octahydrobenz [g] quinoline is prepared.

The process according to the invention has the advantage in that it allows an almost quantitative conversion of the compound of formula II into the epimer of formula I.

The passage of the compound of formula II into the corresponding anion can be done, in a known manner, under very basic conditions, for example by the action of a strongly nucleophile base. For example, lithium dicyclohexylamide, lithium tetramethylpiperidide, lithium isopropyl-cyclohexylamide or preferably lithium diisopropylamide, which can be prepared in situ, are used. It is used, preferably,

At least one basic equivalent for the proton to be removed.

Anion formation can be carried out in an aprotic polar solvent, for example, an ether such as tetrahydrofuran. The reaction temperature conveniently varies between -110 and + 50 ° C, preferably between -50 and -10 ° C.

The conversion of the anion into the cetenacetal can be achieved in itself known, for example, by reaction with a trialkylsilyl halide, preferably trimethylsilyl chloride. It is preferred that the cetenacetal passage be performed directly, after deprotonation, in the same reaction medium. Preferably at least one trialkylsilyl halide equivalent is used for a compound equivalent of formula II. The reaction temperature varies conveniently within the range specified above. Fixing the anion as cetenacetal contributes to the kinetic protonation, the proton being able to attack only from above, above the plane and thus, the axial compound is formed exclusively.

The following kinetic protonation can be done, either by rapidly adding a proton source, at low temperature, for example, at a temperature between -110 and -20 ° C, or conversely, by slowly adding cetenacetal to the proton source. at a temperature, for example, between -20 to + 25 ° C. As a proton source, for example, water, and / or methanol are used. An acid, such as acetic acid, hydrochloric acid or tartaric acid, may conveniently be used in aqueous medium and / or in an organic solvent, for example, in an ether as tetrahydrofuran or an alcohol as, for example, methanol, or in a mixture thereof.

The process according to the invention consists of an epimerization which practically allows the quantitative passage of the compounds of formula II into the epimer compound of formula I.

Initial compounds of formula II can be prepared, for example, by following the reaction scheme shown below:

r ₄ = is 1 to 4 carbon atoms (III) alkyl

RO 112866 Bl

Preparation of the compound of formula (II)

All these reactions can be carried out in a self-known manner. Thus, the preparation of the compound of formula IV, starting from the compound of formula III (process a), for example, with ammonium acetate (prepared from ammonia and acetic acid) can be done in the presence of a dehydrating agent, especially in the presence of molecular site.

Process b) is a conventional reduction of an amine and can be performed, for example, catalytic or with boron hydrides, such as sodium borohydride (NaBHJ.

The addition according to procedure c) can take place at room temperature.

The cyclization (process d) is itself known as Dieckman's reaction and can be achieved, for example, by heating to about 80 ° C, in the presence of a base, such as sodium methylate. By this, the compound of formula VII, in which cycles A and B are linked in trans, is practically formed exclusively.

For the reduction of 4-oxo compounds of formula VII to 4-OH compounds of formula VIII (process e) the NH group is first protected by a common amino protecting group, such as a benzyloxycarbonyl group (BOC), after which the oxo group is reduced to the OH group using a common reducing agent. The protecting group, for example the BOC group is then removed in a self-known manner, for example hydrogenolithic, using Pd / C as a catalyst.

Process f) represents a classical N-alkylation and can be carried out, for example with an alkyl halide in the presence of a base such as K ₂ CO ₃ .

Compounds of formula IX are typically dehydrated to compounds of formula X (process g), preferably using thionyl chloride as a dehydrating agent.

RO 112866 Bl

In compounds of formula X, the double bonds are hydrogenated with Ni Raney as a catalyst, yielding the racemate consisting of 3-α-alkoxycarbonyl-1,2,3,4,4a, 5,10,10a «octahydrobenz [g] quinoline and 3-. p-alkoxy-1,2,3,4,4a, 5,10,10ap-octahidrobenz [g] quinoline.

The compounds of formula II are themselves known or may be prepared according to methods known to those skilled in the art.

The compounds of formula I have, as indicated in the European patent application EPO 077 754 interesting pharmacological properties, such as for example PRL reduction properties, as well as dopaminergic properties. Also, these compounds can be used as starting materials for the preparation of other octahydrobenz [g] quinoline derivatives, also mentioned in the above material. These can be prepared by transforming the -C00R ₄ group as shown in the aforementioned patent application, as well as by another ordinary way, for example by reducing the -C00R ₄ group to a -CH ₂ 0H group or by converting it to an amide group. or in a nitrile group. For example, compounds of formula I may be used for the preparation of compounds

with the formula at: 0 ^S NHS0 ₂ N (R _g ) R ₁₀ ^R 'l ^R 'Z H complicated

in which:

R ₃ has the meaning above,

R \ and R ' ₂ represent independently of each other hydrogen, hydroxy or methoxy with the indication that R \ and R' ₂ cannot be both hydrogen and

R _q and R _in are independently of one another hydrogen or C ₃ alkyl or together - (CH ₂ ) ₄ - or - (CH ₂ ] ₅ -,

The compounds of formula Ia can be prepared according to the following reaction scheme:

RO 112866 Bl

NHSO ₂ N (R _g ) R _1Q

R t and R ₂ represent, respectively, independently of each other hydrogen or methoxy, with the mention that R ₁ and R ₂ cannot both be hydrogen. R / 'and R ₂ represent, respectively, independently of each other hydrogen or hydroxy, with the mention that R /' and R ₂ cannot both be hydrogen.

Phase (s) of the process can be performed according to known methods.

Phase (ii) of the process can be carried out for example by reaction with nitrosyl chloride. A solvent such as tetrahydrofuran is conveniently used and the reaction temperature is preferably between -40 and 0 ° C.

Phase (iii) of the process is accomplished by acylation with a suitable aminosulfonic acid, for example a compound of formula H0-S0 ₂ -N (R _g ] R _1o or a reactive derivative thereof. Suitable reactive derivatives thereof include acid chlorides. and the corresponding acid bromides The reaction is conveniently carried out in the presence of an organic base, such as triethylamine and in an inert organic solvent or in a diluent such as chloroform at or below the desired temperature.

Ether cleavage according to step (iv) of the process can be carried out for example by reaction with HBr, BBr ₃ or Nasch ₃ in the presence of a solvent or inert organic diluent such as methylene chloride or dimethylformamide. The reaction is conveniently carried out at temperatures between -70 and 0 ° C (in the case of HBr or BBr ₃ ) or at 100 ° C at reflux in the case of NaSCH ₃ .

Two examples of embodiments of the invention are given below.

Example 1. Preparation of 6-methoxy-3-a-methoxy-carbonyl-1-n-propyl 7,2,3,4,4aa, 5,10,1Oafi-octahydrobenz [g] quinoline. A solution of 19.2 ml (0.14 moles) of diisopropylamine in 240 ml of tetrahydrofuran is cooled to -30 to 50 ° C. 83 ml (0.13 moles) of n-butyl lithium in hexane The mixture is stirred for 15 minutes and then for 30 minutes at a temperature of -30

A solution of 35.8 g of 6-methoxy-3-p-methoxycarbonyl-1-n-propyl-1,2,3,4,4aa, 5.1O, 1Oap is dropped to 40 ° C. -octahydrobenz (g] quinoline in 240 ml tetrahydrofuran, after which it is stirred for 45 minutes. Thereafter, a solution of 21.5 ml (0.17 moles) of trimethylsilyl chloride in 20 ml tetrahydrofuran is added to the reaction mixture and stir again for 45 minutes at a temperature of -30 to -40 ° C. Then this mixture is added to a solution of 40 ml of 30% hydrochloric acid, 40 ml of water and 200 ml of methanol, During this addition, which lasts about 30 minutes, the temperature is maintained between 1 5 and 25 ° C. Then, 100 ml of aqueous sodium chloride solution, 40 ml of concentrated ammonium hydroxide and 200 ml of toluene are added. Stirring is continued and the phases are separated, the aqueous phase is removed and the organic phase is washed with 100 ml of a 20% aqueous sodium chloride solution. After evaporation of the organic phase under reduced pressure, the residue is dissolved in 1 20 ml light oil fraction by heating to about 75 ° C, then cooled to 0 ° C to 5 ° C for 30 minutes. The solid formed is filtered and dried for 15 hours at a temperature that should not exceed 50 ° C.

Example 2. Preparation of Compound 1-n-propyl-3-a-diethylsulfamoylamam-6-hydroxy7,2,3,4,4aa, 5,10,10afl-octahydrobenz [g] quinoline (RacematJ.

2.7 ml of boron tribromide in 30 ml CH ₂ Cl ₂ at -30 ° C to a solution of 1.9 g 1 -n-propyl-3-α-diethylsulfamoylamino-6-methoxy-1,2,3,4,4a, 5,10,1Oa | 3-octahydrobenz [g] quinoline (Racemat) in 70 ml CH ₂ Cl _2. The reaction mixture is stirred for 4.5 h at -30 to -10 ° C, 100 is added ml of 1N potassium bicarbonate, the pH is raised to 12 by the addition of 1N sodium hydroxide and the mixture obtained is extracted several times with methylene chloride, the organic phases are washed until neutralized with water, dried over sulfate. sodium and concentrated to give a brown foam which is taken up in 80 ml of CH ₂ Cl ₂ / MeOH (1: 1), 9 ml of HCl 7 is added in CH ₃ OH and everything is boiled at reflux for 15 min. the product was concentrated, partitioned between CH ₂ Cl ₂ / l \ laOH 1N, extracted organic phase is washed to neutral with water, dried over sodium sulfate and evaporated. the solid residue was dissolved in boiling diethyl ether / hexane, if cool and filter, yielding the title compound as a beige powder, with melting point = 122.5 ... 1 24 ° C.

The raw material used in this synthesis is prepared as follows:

a) 7-n-Propyl-3-a-carbazoyl-6-methoxy-1,2,3,4,4act, 5,10,1 Oaft-octahydrobenz [gjquinoline (RacematJ.

Add 18.5 ml of hydrazine hydrate to a 3.5 g solution of 1-n-propyl-3-amethoxycarbonyl-6-methoxy-1,2,3,4,4aa, 5,10,1Oap-octahydrobenz [g] quinoline (Racemat) (prepared according to Example 1) in 60 ml of methanol and the reaction mixture is stirred for about 15 hours at 50 ° C. After concentration and drying under high vacuum, the residue is taken up in diethyl ether, dried over sodium sulfate and evaporated, giving the title compound as a yellow oil that crystallizes when left at rest, the solid having a melting point 84 ... 86 ° C.

b) 1-n-Propyl-3-a-amino-6-methoxy-1,2,3,4,4aa, 5,10,10afi-octahydrobenz [gjquinoline (RacematJ.

Add 8 ml of 1 N nitrosyl chloride in tetrahydrofuran solution at -30 ° C to a solution of 3.5 g of product in step a) in 80 ml of tetrahydrofuran. The reaction mixture was boiled at reflux for 1 h, 50 ml of 2N hydrochloric acid was added, the solution was further refluxed for 2 h, cooled, evaporated, the residue was brought to pH 12 by the addition of 2 N sodium hydroxide and extract with CH ₂ Cl ₂ . The organic phase is dried over potassium carbonate and concentrated, yielding the title compound as a brown oil. The product is used directly in the following reaction, as described below.

c) 1-n-Propyl-3-a-diethylsulfamoylamino-6-methoxy-1,2,3,4,4aa, 5.1O, 7Oa / 3-octahydrobenz [gjquinoline (Racemat).

1.5 g of 1-n-propyl-3-a-amino-6-methoxy-1,2,3,4,4aa, 5,10,1 OaȘ-octahydrobenz [g] quinoline (Racemat) and 3.0 ml of triethylamine is added to a solution of 1.9 g of diethylsulfammonium chloride in 50 ml of chloroform and the reaction mixture is stirred at 50 ° C for about 15 h. Add 50 ml of a 1N sodium carbonate solution. and the reaction mixture is stirred for 2 h at room temperature and extracted through

RO 112866 Partition between CH ₂ CI ₂ / water. The organic phase is dried over sodium sulfate, evaporated and purified by chromatography to give the title compound as a yellow oil that crystallizes from diethyl ether / hexane at -2 ° C, the resulting solid having a melting point.

88 ... 89 ° C.

Claims (4)

claims 1. Process for preparing octahydrobenz [g] quinoline of formula I: wherein R, and R ₂ independently represent one another hydrogen or methoxy, but both of which cannot be hydrogen, R ₃ and R ₄ independently represent one another with 1 to 4 carbon atoms, characterized in that, In a first phase, an ammonium of the compound of formula II is formed: under strongly basic conditions, after which the obtained anion passes into a cetenacetal which, in the second phase, protonates. Process according to claim 1, characterized in that the conversion to cetenacetal by direct deprotonation takes place in the same reaction medium. Process according to claim 1, characterized in that it is prepared 6-methoxy-3-a-methoxycarbonyl-1-n-propyl-1,2,3,4,4aa, 5,10,1Oap-octahidrobenz [g] quinoline.