PL166914B1 - Method of obtaining octahydrobenzo(g)quinolines - Google Patents

Abstract

Method for the preparation of octahydrobenz / g / quinolines of formula I, in which R 1 and R 2 independently of each other represent hydrogen or methoxy groups, both of which cannot simultaneously represent hydrogen, R3 and R4 independently - both represent alkyl radicals with 1-4 carbon atoms, characterized in that in the first step an anion of the compound of formula II is produced, in which R1, R2, R3 and R4 are as defined above, under strongly basic conditions, then the obtained anion is converted into the ketene acetal and in the second step the ketene acetal is profaned. PATTERN 1 PL

Description

The invention relates in particular to a new process for the preparation of 1,2,3,4,4a, 5,10, 10α-octahydrobenzo / g / quinolines.

EP 77 754 discloses a process for producing octahydrobenzo (g) quinolines in which the product is a racemate, which is then separated by chromatography. It is also possible to carry out epimerization in an alkaline environment. However, this method requires a 3x2 day reaction time in 1N NaOH in MeO H / H 2 O (9: 1) (Example 5 of the cited description).

A new method for the preparation of compounds of formula 1 has been developed, in which R1 and R2 independently of each other represent hydrogen atoms or methoxy groups, where both of these substituents cannot be hydrogen simultaneously, and R3 and R4 independently of each other represent alkyl radicals of 1-4 atoms of C.

According to the invention, the compounds of formula 1 are obtained by producing in a first step the anion of the compound of formula 2 in which R 1, R 2, R 3 and R are as defined above, under strongly basic conditions, the resulting anion is converted then into the ketene acetal and in a second step the ketene acetal is protonated.

A compound of formula II can be converted to the corresponding anion in a manner known per se under highly basic conditions, e.g. by treating a strong, non-nucleophilic base under reaction conditions. The base used is, for example, lithium dicyclohexylamide, lithium tetramethylpiperidide, lithium isopropylcyclohexylamide or preferably lithium diisopropylamide, which can be generated in situ. Preferably at least one equivalent of base is used per proton removed.

The anion can be produced in an aprotic polar solvent, for example an ether such as tetrahydrofuran. The reaction temperature is preferably -110 ° C to + 50 ° C, especially -50 ° C to -10 ° C.

The conversion to the ketene acetal can be carried out in a manner known per se, e.g. by reaction with a trialkylsilyl halide, preferably trimethylsilyl chloride. Preferably, the conversion to the ketene acetal is carried out immediately after deprotonation in the same reaction medium. Preferably at least one equivalent of the trialkylsilyl halide is used per equivalent of the compound of Formula 2. The reaction is preferably carried out in the same temperature range as stated above.

Fixing the anion in the form of ketene acetal means that in kinetic protonation, the proton can attack only from the desired side, i.e. from above, and in this way only the axial relationship is formed.

Subsequent kinetic protonation can be accomplished either by rapidly adding the proton source at low temperature, for example at -110 ° C to -20 ° C, or conversely by slowly adding ketene acetal to the proton source at a temperature of for example -20 ° C

166 914 to + 30 ° C, preferably -20 ° C to + 25 ° C. For example, water and / or methanol are used as the proton source. It is also possible to use an acid such as, for example, acetic acid, hydrochloric acid or tartaric acid, preferably in an aqueous medium or else in an organic solvent, for example in an ether such as tetrahydrofuran, or in an alcohol such as, for example, methanol, or a mixture of these unions.

The process of the invention is an epimerization which allows the compounds of formula 2 to be practically quantitatively converted into an epimeric compound of formula 1.

The starting compounds of formula 2 can be prepared, for example, according to Scheme 1 shown in the figure, via compounds of formula 4,5,6,7,8,9,10 wherein R 1, R 2, R 3 and R 4 are as defined above, and represents an alkyl radical of 1-4 carbon atoms.

All these reactions can be carried out in known manner. Thus, the compounds of formula IV can be prepared from compounds of formula III (variant a), e.g. with ammonium acetate (prepared in situ from ammonia and acetic acid) in the presence of a dehydrating agent, especially molecular sieve.

The process according to variant b / is a classic enamine reduction reaction and can be carried out e.g. catalytically or with the aid of borohydrides such as NaBH. 4

The connection according to variant c / can be carried out at room temperature.

The ring closure process (variant d) is known as the Dieckmann reaction and may be carried out, for example, by heating at about 80 ° C in the presence of a base such as sodium methoxide. Practically exclusively compounds of formula VII in which rings A and B are trans-linked are formed here.

In the process of reducing the 4-oxo compounds of formula 7 to 4-OH-compounds of formula 8 (variant e), the NH group is first protected with a nitrogen protecting group such as benzyloxycarbonyl (BOC) and then the oxo group is reduced to an OH group. with a known reducing agent such as NaBH4. The protecting group, e.g. BOC, is then removed in a known manner, e.g. hydrogenolytically using palladium on carbon as a catalyst.

Variant f) is a classical N-alkylation process and can be carried out e.g. with an alkyl halide in the presence of a base such as K2CO3.

The compounds of formula 9 are dehydrated in known manner to the compounds of formula 10 (variant g), preferably with thionyl chloride as dehydrating agent.

Finally, the compounds of formula 10 are hydrogenated with a double bond, e.g. with Raney nickel as a catalyst to give the racemate 3α-alkoxycarbonyl-1,2,3,4,4a, 5,10, 10a a- and 3β-alkoxycarbonyl -1,2,3,4,4a, 5,10,10a β-octahydrobenzo / g / quinoline.

Compounds of formula III are known or can be prepared in a known manner.

The compounds of the formula I exhibit, as described, for example, in European Patent Specification No. 77,754, interesting pharmacological properties, e.g. reduction of the PRL, and dopaminergic properties. In addition, they can be used as a starting product for the production of other octahydrobenzo / g / quinolines, also mentioned in the above patent. Such compounds can be obtained by transforming the -COOR4 group as described in the above European patent specification, or otherwise, e.g. by reducing the -COOR4 group to a CH2OH group, or by reaction to an amide or nitrile group. For example, compounds of formula 1 can be used to prepare compounds of formula la wherein R 3 is as defined above R '1 and R'2 are each independently hydrogen, hydroxy or methoxy, provided that both R' 1 and R '2 cannot be simultaneously hydrogen, and R9 and Rw independently from each other are hydrogen atoms or C1-3alkyl radicals or together form a - / CH2 / 4- or - / CH2 / 5- group.

The preparation of compounds of formula 1a is shown in Scheme 2 in the figure, in which R 3 and R 4 are as defined above, R 1 and R 2 independently of each other represent hydrogen atoms or methoxy groups, but R 1 and R 2 cannot be at the same time. hydrogen, R "1 and R" 2 are independently of each other hydrogen or hydroxyl, with the proviso that R "1 and R2 cannot both be hydrogen.

The process according to variant i / can be carried out by known methods.

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The process according to variant ii / can be carried out, for example, by reaction with nitrosyl chloride. Preferably a solvent is used, for example tetrahydrofuran. The reaction temperature is preferably -40 ° C to 0 ° C.

The process according to variant iii) is carried out by acylation with a suitable aminosulfonic acid, e.g. the compound HO-SO2-N / R9 / R10 or a reactive derivative thereof. Suitable reactive derivatives are the corresponding acid chlorides and bromides. The reaction is preferably carried out in the presence of an organic base such as triethylamine and an inert organic solvent or an organic diluent such as chloroform at normal or slightly elevated temperatures.

The ether cleavage according to variant iv) can be carried out, for example, by reaction with HBr, BBr or NaSCH3, in the presence of an inert organic solvent or diluent such as methylene chloride or dimethylformamide. The reaction is preferably carried out at a temperature of e.g. -70 ° C to 0 ° C (HBr or BBr3), or at a temperature of 100 ° C to reflux (NaSCH3).

The following examples explain the process according to the invention in more detail.

Example 1 6-methoxy-3a-methoxycarbonyl-1-n-propyl-1,2,3,4,4aa, 5,10,10a, β-octahydro-benzo (g) quinoline.

A solution of 19.2 mL (0.14 mol) of diisopropylamine in 240 mL of tetrahydrofuran was cooled to -30 ° C to -40 ° C. 83 ml / 0.13 mol / n-butyllithium in hexane are added over 15-30 minutes. The mixture is stirred for 15 minutes, then a solution of 35.8 g of 6-methoxy-3-methoxycarbonyl-1-n-propyl-1,2 is added dropwise over 30 minutes while cooling to -30 ° C to -40 ° C. 3,4,4aa, 5, 10, 10a, β-octahydrobenzo / g / quinoline in 240 ml of tetrahydrofuran. After stirring for 45 minutes, a solution of 21.5 ml (0.17 mol) of trimethylsilyl chloride in 20 ml of tetrahydrofuran is added to the reaction medium and stirring is continued for 45 minutes at -30 ° C to -40 ° C.

The mixture is then added to a solution of 40 ml of 30% hydrochloric acid, 40 ml of water and 200 ml of methanol, the temperature being kept at 15-25 ° C during this addition (about 30 minutes). Then 100 ml of 20% aqueous NaCl solution, 40 ml of concentrated NH4OH and 200 ml of toluene are added to the mixture. The mixture is stirred further and the phases are separated. The aqueous phase is removed and the organic phase is washed with 100 ml of 20% aqueous NaCl solution. After evaporation of the organic phase under reduced pressure, the residue was dissolved in 120 ml of light petroleum under heating to a temperature of about 75 ° C. It is then cooled to 0-5 ° C in about 30 minutes. The resulting solid is filtered off and dried at a temperature not exceeding 50 ° C for 15 hours.

Example II. 1-n-propyl-3α-diethylsulfamoylamino-6-hydroxy-1,2,3,4,4aa, 5,10,10a -octahydro-benzo (g (quinoline) racemate).

2.7 ml of boron tribromide in 30 ml of CH2Cl2 are added dropwise at -30 ° C to a solution of 1.9 g of 1-n-propyl-3α-diethylsulfamoylamino-6-methoxy-1,2,3,4,4a, 5, 10, ^^ a (3-octahydro-benzo (g (quinoline) racemate) in 70 ml of CH 2 Cl 2 The mixture is stirred for 4.5 hours at -30 ° C to -10 ° C, 100 ml of 1 N are added. KHCO3, the pH value is adjusted to 12 by adding 1N NaOH and the resulting mixture is extracted several times with methylene chloride The organic phases are washed neutral with water, dried over sodium sulphate and concentrated to a brown foam. This foam is taken up to 80 ml CH2Cl2 / MeOH (1: 1), 9 ml of 7N HCl in CH3OH are added and the mixture is boiled under reflux for 15 minutes, the product is concentrated, extracted by partitioning between CH2G2 (1N NaOH), the organic phase is washed with water until neutral , dried over sodium sulfate and evaporated. The solid residue is dissolved by boiling in diethyl ether / hexane, cooled and filtered to give the title compound aches of a beige powder, m.p. 122.5-124 ° C.

The starting materials are obtained as follows:

a / 1-n-propyl-3a-carbazoyl-6-methoxy-1,2,3,4,4a α, 5, 10, 1Oa β-octahydro-benzo / g / quinoline / racemate /

18.5 ml of hydrazine hydrate is added to the solution of 3.5 g of 1-n-propyl-3a-methoxycarbonyl-6-methoxy-1,2,3,4,4aa, 5,10,10a β-octahydro-benzo / g / of quinoline (racemate) / prepared according to Example 1 / in 60 ml of methanol and the mixture is stirred for about 15 hours at a temperature of

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50 ° C. After concentration and drying under high vacuum, the residue is taken up in diethyl ether, dried over sodium sulfate and evaporated to give the title compound as a yellow oil which crystallizes on standing, mp 84-86 ° C.

b / 1-n-propyl-3a-amino-6-methoxy-1,2,3,4,4aa, 5,10,10a β-octahydro-benzo / g / quinoline / racemate / ml of 1N solution of nitrosyl chloride in tetrahydrofuran 2.5 g of the product of step a / are added to a solution of 80 ml of tetrahydrofuran at -30 ° C. After 5 minutes the reaction is complete. The resulting reaction mixture is boiled under reflux for 1 hour, 50 ml of 2N HCl are added, the solution is boiled under reflux for a further 2 hours, cooled, concentrated, the residue is adjusted to pH 12 by adding 2N NaOH solution and extracted. methylene chloride. The organic phase is dried over potassium carbonate and concentrated to afford the title compound as a brown oil. The product is used directly in the next reaction.

c / 1-n-propyl-3a-diethylsulfamoylamino-6-methoxy-1,2,3,4,4aa, 5,10,10a, 10a β-octahydro-benzo / g / quinoline / racemate /

1.5 g of 1-n-propyl-3a-amino-6-methoxy-1,2,3,4,4aa, 5,10,10a β-octahydro-benzo / g (quinoline / racemate) and 3.0 ml of triethylamine 1.9 g of diethylsulfamoyl chloride in 50 ml of chloroform are introduced into a solution and the reaction mixture is stirred for about 15 hours at 50 ° C. Then 50 ml of 1N sodium carbonate solution are added to the mixture, the mixture is stirred for 2 hours at room temperature and extracted by partitioning between CH2Cl2 / water. The organic phase is dried over sodium sulfate, evaporated and purified by chromatography to afford the title compound as a yellow oil which crystallizes from diethyl ether / hexane at -20 ° C to give a product, mp 88-89 ° C.

166 914 un.

R.

H.

COOR4

MODEL 1

MODEL 1a

PATTERN 2

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MODEL 3

b

MODEL 4

c + CH ₂ = CH-C00R4 ^{FORMULA 5}

NH-CH2-CH2 -COOR2

COOR ’

MODEL 6

SCHEME (i)

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MODEL 7

R

coor ₄

PATTERN 2 SCHEME 1 (2)

MODEL 8

COOR ₄

PATTERN 9 coor ₄

PATTERN W

SCHEME 2

Publishing Department of the UP RP. Circulation of 90 copies

Price PLN 1.00.

Claims (1)

Patent claim The method for the preparation of octahydrobenzo (g) quinolines of the formula I, in which Ri and R2 independently represent hydrogen atoms or methoxy groups, both of which cannot be simultaneously hydrogen, R3 and R4 independently of each other represent alkyl radicals with 1-4 atoms carbon, characterized in that in the first step an anion of the compound of formula II is prepared in which R1, R2, R3 and R4 are as defined above, under strongly basic conditions, and then the obtained anion is converted into the ketene acetal and in the second step the ketene acetal undergoes protonation. The subject of the invention is a process for the preparation of octahydrobenzo (g) quinolines with pharmacological properties.