BE635084A

BE635084A -

Info

Publication number: BE635084A
Authority: BE
Priority date: 1963-07-17
Also published as: FR1531323A; NL295387A

Description

       

   <EMI ID=1.1>  La présente invention est relative à un nouveau procédé de préparation de dérivés de dibenzocycloheptène et, plus particulièrement, la présente invention concerne un procédé de

  
 <EMI ID=2.1> 

  
tués sur l'atome de carbone en position 5 par un radical aminopropyle secondaire, La présente invention concerne également la synthèse d'intermédiaires utilisés pour obtenir ces produits.

  
Les composés finals selon la présente invention sont intéressants dans le traitement de maladies mentales, en ce sens

  
 <EMI ID=3.1> 

  
tranquillisants ou excitateurs psychiques. Les composés sont, de préférence, administrés sous la forme de leurs sels d'addition avec des acides et ces sels entrent également dans le cadre de. la présente invention.

  
Les composés finals obtenus par le procédé selon la présente invention peuvent être représentés par la formule générale suivante:

  

 <EMI ID=4.1> 
 

  
 <EMI ID=5.1> 

  
tent de l'hydrogène, un groupe alcoyle contenant jusqu'à 6 atomes de carbone, un groupe alcényle contenant jusqu'à 6 atomes de carbone, un groupe perfluoroalcoyle contenant jusqu'à 4 atomes de

  
.

  
carbone, un radical phényle ou un radical phényle substitué, un groupe acyle contenant jusqu'à 4 atomes de carbone, un groupe perfluoroacyle contenant jusqu'à 4 atomes de carbone, un groupe amino, un groupe alcoylamino contenant jusqu'à 4 atomes de carbone, un groupe dialcoylamino contenant jusqu'à 8 atomes de carbone, un groupe acylamino contenant jusqu'à 4 atomes de carbone, un groupe perfluoroacylamino contenant jusqu'à 4 atomes de carbone, un groupe alcoylsulfonylamino contenant jusqu'à 4 atomes de carbone, des halogènes (fluor, chlore, brome ou iode), un groupe hydroxyle, un groupe alcoxyle contenant jusqu'à 4 atomes de carbone, un groupe perfluoroalcoxyle contenant jusqu'à 4 atomes de carbone, un groupe cyano, un groupe carboxy, un groupe carbamyle, un groupe alcoylcarbamyle contenant jusqu'à 5 atome:

  . de carbone, un groupe dialcoylcarbamyle contenant jusqu'à 9 atomes de carbone, un groupe carbalcoxy contenant jusqu'à; 6 atomes de carbone, un groupe mercapto, un groupe alcoylmercapto contenant jusqu'à 4 atomes de carbone, un groupe perfluoroalcoylmercapto contenant jusqu'à 4 atomes de carbone, un groupe alcoylsul-

  
 <EMI ID=6.1> 

  
vant se trouver sur chaque noyau benzénique.

  
Le procédé selon la présente invention peut Atre 

  
 <EMI ID=7.1>  
 <EMI ID=8.1> 
 dans les formules qui précèdent, R qui est éliminé au coure du procédé, représente un radical alcoyle, aryle, aralcoyle,

  
 <EMI ID=9.1> 

  
dessus.

  
Le procédé selon la présente invention part du composé

  
 <EMI ID=10.1>  Les composés diméthylamino propylidéniques sont bien connus et sont décrits à plusieurs endroits dans la littérature.

  
Ces composés sont préparés, par exemple, à partir des 5H-dibenzo-

  
 <EMI ID=11.1> 

  
cycloheptène-5-ones. Les composés de départ pour les cétones et, particulièrement, ceux possédant des substituants sur les noyaux berzéniques, peuvent également être préparés par les procédés suivants décrits dans la littérature.

  
Comme montré par le schéma de réaction ci-dessus, le premier stade du procédé selon la présente invention comporte une conversion du composé uréthane propylidénique en le composé uréthane propylique correspondant. Dans un essai typique, du

  
 <EMI ID=12.1> 

  
drogénation est, de préférence, effectuée en dissolvant le composé uréthane propylidénique dans un solvant et en appliquant une hydrogénation sous pression, en utilisant un catalyseur d'hydrogénation, qui peut être, de manière appropriée, du charbon de bois sur palladium, bien que d'autres catalyseurs puissent également être utilisés. L'intermédiaire propylique désiré est ensuite isolé en filtrant la solution, à la fin de la réaction, en concentrant le filtrat sous vide et en opérant une extraction à l'aide d'un solvant approprié.

  
Les étapes d'opération décrites ci-dessus sont préférées pour les composés dans lesquels R représente un groupe

  
 <EMI ID=13.1> 

  
par exemple, un groupe aralcoxy, il est souhaitable de former le composé uréthane propylique en hydrogénant d'abord le précurseur de diméthylamino propylidène, de manière à former le dérivé diméthylamino propylique correspondant et en formant ensuite l'uréthane par réaction avec un haloformiate, comme montré dans le schéma de réaction suivant : 

  

 <EMI ID=14.1> 


  
Pour préparer les composée amino propyliques acylés dans lesquels R est un radical alcoyle, aryle ou aralcoyle, le composé uréthane propylique correspondant, dans lequel R est un groupe alcoxy, aroxy ou aralcoxy, est d'abord préparé comme décrit ci-dessus. Le groupe uréthane est ensuite séparé par hydrolyse, selon un stade opératoire qui sera décrit en détails dans la suite du présent mémoire, de manière à former le composé monométhylamino propylique. Cet intermédiaire est ensuite acylé à l'aide d'un agent d'acylation approprié, comme par exemple, l'anhydride acétique, lorsque R est un groupe alcoyle et le chlorure de benzoyle, lorsque R est un groupe aryle et le chlorure de phénylacétyle, lorsque R est un groupe aralcoyle, comme montré par les réactions schématiques suivantes : 

  

 <EMI ID=15.1> 


  
Les intermédiaires ainsi obtenus par les divers procédés décrits ci-dessus, sont ensuite soumis à un stade de déshydrogénation en position 10,11, stade dans lequel une molécule d'hydrogène est enlevée, afin d'obtenir le composé correspondant qui est insaturé aux positions 10,11. Selon la présente invention, on effectue le stade de déshydrogénation, de préférence, avec un agent de déshydrogénation contenant de l'halogène.

  
Comme agents de déshydrogénation contenant de l'halogène, on peut citer la N-bromosuccinimide, la N-chlorosuccinimide, le brome, le chlore et le chlorure de sulfuryle, bien que l'on puisse utiliser également d'autres agents d'halogénation.

  
Comme montré dans le schéma de réaction, le composé insaturé désiré est formé directement à partir du composé 10,11-  dihydro. Cependant, dans une autre méthode, on peut également former l'intermédiaire contenant de l'halogène en position 10 ou 
11, cet intermédiaire pouvant être déshydrohalogéné, de manière 

  
à former le composé insaturé. Généralement, on obtient un mélange du composé insaturé en position 10,11 et l'intermédiaire 10-halo par traitement du composé uréthane propylique par l'agent

  
de déshydrogénation contenant de l'halogène. Le mélange est ensuite complètement converti en le composé insaturé par déshy-

  
 <EMI ID=16.1> 

  
 <EMI ID=17.1> 

  
génation par élimination d'un halogénure d'hydrogène avec une aminé tertiaire, par exemple, la triéthylamine, bien que d'autres procédés de déshydrohalogénation puissent également être utilisé

  
Comme illustration du second stade du procédé selon

  
 <EMI ID=18.1> 

  
Les conditions réactionnelles préférées pour la mise en oeuvre du stade de déshydrogénation désiré avec de la N-bromosuccinimide, comprennent la dissolution du composé uréthane propylique dans un solvant inerte tel que le tétrachlorure de carbone, le benzène, l'heptane, le chloroforme, le tétrahydrofurane et analogues, cette dissolution étant suivie par une  réaction sous reflux avec une quantité appropriée de N-bromosuc...

  
 <EMI ID=19.1> 

  
eaux libres, en présence d'un accepteur d'hydrogène halogène, tel que la pyridine, la collidine,. le chlorure d'allyle ou un époxyde, A la fin de la réaction, le mélange réactionnel est filtré, le filtrat est concentré sous vide et le résidu est purifié, de manière à donner le mélange désiré* Le mélange obtenu ci-dessus est ensuite chauffé au reflux en présence d'une base tertiaire en solution, puis 'il est acidifié, extrait par un solvant approprié et concentré,

  
de manière à obtenir le composé uréthane ou acyle insaturé désiré, La recristallisation dans un solvant approprié, par exemple du méthanol, donne le composé sous la forme purifiée. 

  
Finalement, le composé uréthane ou acyle propylique
10,11 insaturé est hydrolysé afin de convertir le groupe carbamyle substitué en un atome d'hydrogène. L'hydrolyse peut être effectuée dans des condition.-: basiques ou acide , bien que l'on préfère utiliser l'hydrolyse basique. Dans un essai typique, le composé est chauffé au reflux sous atmosphère d'azote dais une solution d'hydroxyde de potassium dans du n-butanol, A la fin de l'hydrolyse, le solvant est évaporé sous vide et le r ésidu est extrait à l'aide de solvants appropriés en vue d'isoler le produit hydrolyse. Le produit d'hydrolyse est constitué par le

  
 <EMI ID=20.1> 

  
cycloheptène. Une purification ultérieure par cristallisation dans une solution d'acide, donne le produit sous une forme plus pure.

  
pure, Les exemples suivants illustrent la présente invention, sans pour autant la limiter.

Exemple 1

  
 <EMI ID=21.1> 

  
mole) dans 100 ml de benzène est ajoutée , en l'espace d'une heure, à une solution de 32,4 g de chloroform iate d'éthyle 

  
(0,3 mole) dans 100 ml de benzène, tout en agitant. La solution réactionnelle est chauffée au reflux pendant 2 heures, puis elle

  
 <EMI ID=22.1>  

  
on obtient 29,5 g d'une huile épaisse qui est constituée sen-

  
 <EMI ID=23.1> 

  
En suivant le mode opératoire décrit ci-dessus et en utilisant des quantités équivalentes de bromoformiate de propy. le et de chloroformiate de phényle au lieu de chloroformiate d'éthyle, on obtient le composé N-carbophénoxy uréthane correspondant,

  
Exemple 

  
 <EMI ID=24.1> 

  
d'environ 0,02 mole d'hydrogène. Le catalyseur est séparé par filtration et le méthanol est évaporé, de manière à donner 6,5 g d'un résidu huileux qui est le produit sous sa forme sensible-

  
 <EMI ID=25.1> 

  
en utilisant le composé N-carbophénoxy uréthane, au lieu du composé N-carboéthoxyamino, on obtient le composé N-carbophénoxy correspondant.

Exemple 3

  
 <EMI ID=26.1> 

  
dans 400 ml de méthanol on introduit 4 ml d'acide chlorhydrique concentré; après l'addition de 10 g de palladium sur charbon de 

  
 <EMI ID=27.1> 

  
sion initiale de 70 kg/cm<2>  <EMI ID=28.1> 

  
vide jusqu'à obtenir une huile épaisse. L'huile est ensuite dissoute dans 200 ml d'eau, et on ajoute une solution de 32 g d'hydroxyde de sodium dans 140 ml d'eau. La base est extraite par du benzène (3 x 100 ml), séchée sur MgS04 et concentrée sous vide jusqu'à poids constant. On obtient ainsi 55,9 g du dérivé
10,11-dihydro de la matière de départ, sous forme d'une huile

  
à peu près incolore.

  
Une solution de 52,4 g du composé dihydro obtenu cidessus (0,188 mole) dans 216 ml de benzène est ajoutée, en l'espace d'une heure, tout en agitant, à une solution de 65 g

  
de chloroformiate de benzyle dans 580 ml de benzène et la solution est chauffée au reflux pendant 2 heures. Dès que la réac.

  
 <EMI ID=29.1> 

  
de benzène, à la température ambiante. La solution est chauffée du reflux, tout en agitant, pendant 20 heures, puis elle est rofroidie jusqu'à la température ambiante et extraite par 3 x 

  
 <EMI ID=30.1>  cachée sur du sulfate de magnésium et évaporée jusqu'à siccité,

  
 <EMI ID=31.1> 

  
d'hydroxyde de potassium dans 255 ml de n-butanol. Après refroidissement jusqu'à la température ambiante, le solvant est évaporé sous vide, le résidu est agité avec 200 ml d'eau, 300 ml de n-hexane, les couches sont séparées, la couche aqueuse est extraite à nouveau par 100 ml de n-hexane, les couches combinées sont lavées par de l'eau (2 x 100 ml) et ensuite par de l'acide

  
 <EMI ID=32.1> 

  
ml de pyridine, on ajoute 15 g d'anhydride acétique et le mélange est ensuite chauffé au reflux pendant 1 heure. On chasse par distillation sous vide l'excès de pyridine et d'anhydride
(2 - 5 mm). Le résidu est dissous dans 100 ml de .benzène, lavé

  
 <EMI ID=33.1>  

Exemple 5

  
 <EMI ID=34.1> 

  
20 ml de pyridine, on ajoute 7 g de chlorure de benzoyle et le mélange est maintenu à la température ambiante pendant environ
12 heures. Le mélange est versé sur 200 g d'eau glacée, extrait par 3 x 100 ml d'éther, l'extrait est lavé à l'aide de HCl dilué

  
 <EMI ID=35.1> 

  
dans 500 ml de tétrachlorure de carbone et sont mélangés à 43 g
(0,21+_mole) de N-bromosuccinimide; on ajoute 0,6 g d'azo-bisbutyronitrile et 24,2 g (0,2 mole) de collidine symétrique et le mélange est chauffé au reflux, tout en agitant, pendant 15 minutes. Lorsque le mélange atteint le point d'ébullition, une réaction vigoureuse s'amorce. Après repos à la température de glacière

  
 <EMI ID=36.1>   <EMI ID=37.1> 

  
En suivant le mode opératoire décrit ci-dessus et en utilisant les composes N-carbométhoxy, N-carbophénoxy, N-carbo-

  
 <EMI ID=38.1> 

  
lieu du composé N-carboéthoxyamino, on obtient les composée N-carbométhoxy, N-carbophénoxy, N-carbobenzoxy, N-acétyle, Nbenzoyle et N-phénylacétyle correspondants.

  
' Exemple 7

  
 <EMI ID=39.1> 

  
cycloheptane. , 

  
36,1 g du mélange obtenu à l'exemple 6 sont chauffés au reflux dans un mélange de 77 ml de diméthylformamide et de

  
 <EMI ID=40.1> 

  
zote) pendant 2 heures. Le mélange réactionnel est ensuite refroidi brusquement en le versant sur un mélange de 300 g de

  
 <EMI ID=41.1> 

  
mélange réactionnel par du benzène ( 1 x 500 ml; 3 x 200 ml), la solution benzénique est ensuite lavée avec 3 x 100 ml de HC1 dilué, puis elle est lavée jusqu'à neutralité par de l'eau,

  
 <EMI ID=42.1> 

  
lieu du composé N-carboéthoxyamino, on obtient les dérivés N-  carbométhoxy, N-carbophénoxy, N-acétyle, N-benzoyle, N-phényl-  acétyle et N-carbobenzoxy correspondants. 

  
 <EMI ID=43.1> 

  
 <EMI ID=44.1> 



   <EMI ID = 1.1> The present invention relates to a novel process for preparing dibenzocycloheptene derivatives and, more particularly, the present invention relates to a process for

  
 <EMI ID = 2.1>

  
killed on the carbon atom in position 5 by a secondary aminopropyl radical. The present invention also relates to the synthesis of intermediates used to obtain these products.

  
The final compounds according to the present invention are useful in the treatment of mental illnesses, in that sense.

  
 <EMI ID = 3.1>

  
tranquilizers or psychic stimulants. The compounds are preferably administered in the form of their addition salts with acids and these salts are also within the scope of. the present invention.

  
The final compounds obtained by the process according to the present invention can be represented by the following general formula:

  

 <EMI ID = 4.1>
 

  
 <EMI ID = 5.1>

  
tent hydrogen, an alkyl group containing up to 6 carbon atoms, an alkenyl group containing up to 6 carbon atoms, a perfluoroalkyl group containing up to 4 carbon atoms

  
.

  
carbon, a phenyl radical or a substituted phenyl radical, an acyl group containing up to 4 carbon atoms, a perfluoroacyl group containing up to 4 carbon atoms, an amino group, an alkylamino group containing up to 4 carbon atoms , a dialkylamino group containing up to 8 carbon atoms, an acylamino group containing up to 4 carbon atoms, a perfluoroacylamino group containing up to 4 carbon atoms, an alkylsulfonylamino group containing up to 4 carbon atoms, halogens (fluorine, chlorine, bromine or iodine), a hydroxyl group, an alkoxyl group containing up to 4 carbon atoms, a perfluoroalkoxyl group containing up to 4 carbon atoms, a cyano group, a carboxy group, a carbamyl group , an alkylcarbamyl group containing up to 5 atoms:

  . carbon, a dialkylcarbamyl group containing up to 9 carbon atoms, a carbalkoxy group containing up to; 6 carbon atoms, a mercapto group, an alkylmercapto group containing up to 4 carbon atoms, a perfluoroalkylmercapto group containing up to 4 carbon atoms, an alkylsul group

  
 <EMI ID = 6.1>

  
vant to be on each benzene ring.

  
The method according to the present invention can be

  
 <EMI ID = 7.1>
 <EMI ID = 8.1>
 in the above formulas, R which is eliminated during the process, represents an alkyl, aryl or aralkyl radical,

  
 <EMI ID = 9.1>

  
above.

  
The process according to the present invention starts from the compound

  
 <EMI ID = 10.1> Dimethylamino propylidene compounds are well known and are described in several places in the literature.

  
These compounds are prepared, for example, from 5H-dibenzo-

  
 <EMI ID = 11.1>

  
cycloheptene-5-ones. The starting compounds for the ketones and, particularly, those having substituents on the berzen rings, can also be prepared by the following methods described in the literature.

  
As shown by the reaction scheme above, the first stage of the process according to the present invention comprises a conversion of the urethane propylidene compound into the corresponding urethane propyl compound. In a typical test,

  
 <EMI ID = 12.1>

  
Drogenation is preferably carried out by dissolving the propylidene urethane compound in a solvent and applying hydrogenation under pressure, using a hydrogenation catalyst, which may suitably be charcoal on palladium, although other catalysts can also be used. The desired propyl intermediate is then isolated by filtering the solution, at the end of the reaction, by concentrating the filtrate in vacuo and by extracting using an appropriate solvent.

  
The operating steps described above are preferred for compounds in which R represents a group

  
 <EMI ID = 13.1>

  
for example, an aralkoxy group, it is desirable to form the urethane propyl compound by first hydrogenating the precursor of dimethylamino propylidene, so as to form the corresponding dimethylamino propyl derivative and then forming the urethane by reaction with a haloformate, such as shown in the following reaction scheme:

  

 <EMI ID = 14.1>


  
To prepare the acylated propyl amino compounds in which R is an alkyl, aryl or aralkyl radical, the corresponding urethane propyl compound, in which R is an alkoxy, aroxy or aralkoxy group, is first prepared as described above. The urethane group is then separated by hydrolysis, according to an operating stage which will be described in detail later in this specification, so as to form the monomethylamino propyl compound. This intermediate is then acylated using an appropriate acylating agent, such as, for example, acetic anhydride, when R is an alkyl group and benzoyl chloride, when R is an aryl group and phenylacetyl chloride , when R is an aralkyl group, as shown by the following schematic reactions:

  

 <EMI ID = 15.1>


  
The intermediates thus obtained by the various processes described above are then subjected to a dehydrogenation stage at position 10,11, a stage in which a hydrogen molecule is removed, in order to obtain the corresponding compound which is unsaturated at the positions 10.11. According to the present invention, the dehydrogenation step is preferably carried out with a dehydrogenating agent containing halogen.

  
As the halogen-containing dehydrogenating agents, there may be mentioned N-bromosuccinimide, N-chlorosuccinimide, bromine, chlorine and sulfuryl chloride, although other halogenating agents can also be used.

  
As shown in the reaction scheme, the desired unsaturated compound is formed directly from the 10,11-dihydro compound. However, in another method, the intermediate containing halogen at position 10 or
11, it being possible for this intermediate to be dehydrohalogenated, so

  
forming the unsaturated compound. Generally, a mixture of the unsaturated compound in position 10,11 and the intermediate 10-halo is obtained by treatment of the urethane propyl compound with the agent.

  
dehydrogenation system containing halogen. The mixture is then completely converted to the unsaturated compound by dehydration.

  
 <EMI ID = 16.1>

  
 <EMI ID = 17.1>

  
generation by removal of a hydrogen halide with a tertiary amine, e.g. triethylamine, although other dehydrohalogenation methods can also be used

  
As an illustration of the second stage of the process according to

  
 <EMI ID = 18.1>

  
The preferred reaction conditions for carrying out the desired dehydrogenation stage with N-bromosuccinimide comprise dissolving the urethane propyl compound in an inert solvent such as carbon tetrachloride, benzene, heptane, chloroform, tetrahydrofuran and the like, this dissolution being followed by reaction under reflux with an appropriate amount of N-bromosuc ...

  
 <EMI ID = 19.1>

  
free water, in the presence of a halogenated hydrogen acceptor, such as pyridine, collidine ,. allyl chloride or an epoxide, At the end of the reaction, the reaction mixture is filtered, the filtrate is concentrated in vacuo and the residue is purified, so as to give the desired mixture * The mixture obtained above is then heated to reflux in the presence of a tertiary base in solution, then 'it is acidified, extracted with an appropriate solvent and concentrated,

  
in order to obtain the desired unsaturated urethane or acyl compound, Recrystallization from a suitable solvent, for example methanol, gives the compound in the purified form.

  
Finally, the urethane or propyl acyl compound
10,11 unsaturated is hydrolyzed to convert the substituted carbamyl group to a hydrogen atom. The hydrolysis can be carried out under basic or acidic conditions, although it is preferred to use basic hydrolysis. In a typical test, the compound is heated to reflux under a nitrogen atmosphere in a solution of potassium hydroxide in n-butanol, At the end of the hydrolysis, the solvent is evaporated in vacuo and the residue is extracted. using appropriate solvents to isolate the hydrolyzed product. The hydrolysis product consists of

  
 <EMI ID = 20.1>

  
cycloheptene. Further purification by crystallization from an acid solution gives the product in a purer form.

  
pure, The following examples illustrate the present invention without, however, limiting it.

Example 1

  
 <EMI ID = 21.1>

  
mole) in 100 ml of benzene is added, over the course of one hour, to a solution of 32.4 g of ethyl chloroform iate

  
(0.3 mol) in 100 ml of benzene, while stirring. The reaction solution is heated under reflux for 2 hours, then it

  
 <EMI ID = 22.1>

  
29.5 g of a thick oil are obtained which is made up of

  
 <EMI ID = 23.1>

  
By following the procedure described above and using equivalent amounts of propy bromoformate. the and phenyl chloroformate instead of ethyl chloroformate, the corresponding N-carbophenoxy urethane compound is obtained,

  
Example

  
 <EMI ID = 24.1>

  
about 0.02 moles of hydrogen. The catalyst is separated by filtration and the methanol is evaporated, so as to give 6.5 g of an oily residue which is the product in its substantial form.

  
 <EMI ID = 25.1>

  
by using the N-carbophenoxy urethane compound, instead of the N-carboethoxyamino compound, the corresponding N-carbophenoxy compound is obtained.

Example 3

  
 <EMI ID = 26.1>

  
4 ml of concentrated hydrochloric acid are introduced into 400 ml of methanol; after the addition of 10 g of palladium on charcoal

  
 <EMI ID = 27.1>

  
initial pressure of 70 kg / cm <2> <EMI ID = 28.1>

  
empty until a thick oil is obtained. The oil is then dissolved in 200 ml of water, and a solution of 32 g of sodium hydroxide in 140 ml of water is added. The base is extracted with benzene (3 x 100 mL), dried over MgSO4 and concentrated in vacuo to constant weight. This gives 55.9 g of the derivative
10,11-dihydro starting material, as an oil

  
almost colorless.

  
A solution of 52.4 g of the dihydro compound obtained above (0.188 mol) in 216 ml of benzene is added, over the course of one hour, while stirring, to a solution of 65 g

  
of benzyl chloroformate in 580 ml of benzene and the solution is heated under reflux for 2 hours. As soon as the react.

  
 <EMI ID = 29.1>

  
of benzene at room temperature. The solution is heated under reflux, while stirring, for 20 hours, then it is cooled to room temperature and extracted with 3 x

  
 <EMI ID = 30.1> hidden over magnesium sulfate and evaporated to dryness,

  
 <EMI ID = 31.1>

  
of potassium hydroxide in 255 ml of n-butanol. After cooling to room temperature, the solvent is evaporated off in vacuo, the residue is stirred with 200 ml of water, 300 ml of n-hexane, the layers are separated, the aqueous layer is extracted again with 100 ml of n-hexane, the combined layers are washed with water (2 x 100 ml) and then with acid

  
 <EMI ID = 32.1>

  
ml of pyridine, 15 g of acetic anhydride are added and the mixture is then heated under reflux for 1 hour. Excess pyridine and anhydride are removed by vacuum distillation.
(2 - 5 mm). The residue is dissolved in 100 ml of .benzene, washed.

  
 <EMI ID = 33.1>

Example 5

  
 <EMI ID = 34.1>

  
20 ml of pyridine, 7 g of benzoyl chloride are added and the mixture is kept at room temperature for about
12 hours. The mixture is poured into 200 g of ice-cold water, extracted with 3 x 100 ml of ether, the extract is washed with dilute HCl

  
 <EMI ID = 35.1>

  
in 500 ml of carbon tetrachloride and are mixed with 43 g
(0.21 + _mole) of N-bromosuccinimide; 0.6 g of azo-bisbutyronitrile and 24.2 g (0.2 mol) of symmetrical collidine are added and the mixture is heated to reflux, while stirring, for 15 minutes. When the mixture reaches the boiling point, a vigorous reaction begins. After standing at cooler temperature

  
 <EMI ID = 36.1> <EMI ID = 37.1>

  
By following the procedure described above and using the compounds N-carbomethoxy, N-carbophenoxy, N-carbo-

  
 <EMI ID = 38.1>

  
Instead of the N-carboethoxyamino compound, the corresponding N-carbomethoxy, N-carbophenoxy, N-carbobenzoxy, N-acetyl, Nbenzoyl and N-phenylacetyl compounds are obtained.

  
'Example 7

  
 <EMI ID = 39.1>

  
cycloheptane. ,

  
36.1 g of the mixture obtained in Example 6 are heated to reflux in a mixture of 77 ml of dimethylformamide and

  
 <EMI ID = 40.1>

  
zote) for 2 hours. The reaction mixture is then suddenly cooled by pouring it onto a mixture of 300 g of

  
 <EMI ID = 41.1>

  
reaction mixture with benzene (1 x 500 ml; 3 x 200 ml), the benzene solution is then washed with 3 x 100 ml of dilute HCl, then it is washed until neutral with water,

  
 <EMI ID = 42.1>

  
Instead of the N-carboethoxyamino compound, the corresponding N-carbomethoxy, N-carbophenoxy, N-acetyl, N-benzoyl, N-phenyl-acetyl and N-carbobenzoxy derivatives are obtained.

  
 <EMI ID = 43.1>

  
 <EMI ID = 44.1>

Claims

at reflux, while stirring under a nitrogen atmosphere, for 17 hours. The solvent is removed by vacuum distillation,

then heated for a short time to 70 [deg.] C, extracted with hexane (2 x 100 ml); the acidic layer is alkalized by adding 12N sodium hydroxide solution (phenolphthalein indicator) the separated base is extracted

with ether, washed with water, dried and evaporated, so as to give 9 g of an oily product which is identified as

By following the procedure described above and using the N-carbomethoxy, N-carbophenoxy, N-carbobenzoxy, N-acetyl, N-benzoyl and N-phenylacetylurethane derivatives, at

Instead of the N-carboethoxyamino compound, the same methylamino propyl compound is obtained as above.

Example 9

By following the procedure described in the examples above and using N-chlorosuccinimide, chlorine,

midway, the corresponding final compounds are obtained,

Example 10

above and by using starting compounds substituted by substituents X and X 'as described above, one obtains them.

corresponding desired end products substituted by

not substituted on the carbon atom in position 5 by a secondary aminopropyl radical, of formula <EMI ID = 51.1> <EMI ID = 52.1>

have hydrogen, an alkyl group containing up to 6 carbon atoms, an alkenyl group containing up to 6 carbon atoms, a perfluoroalkyl group containing up to 4 carbon atoms, a phenyl radical or a substituted phenyl radical , an acyl group containing up to

up to 4 carbon atoms, an amino group, an alkylamino group containing up to 4 carbon atoms, a dialkoylamino group containing up to 8 carbon atoms, an acylamino group containing up to 4 carbon atoms, a group perfluoroacylamino containing up to 4 carbon atoms, an alkylsulfonylamino group containing up to 4 carbon atoms, halogens (fluorine, chlorine, bromine or iodine), a hydroxyl group, an alkoxyl group containing

containing up to 4 carbon atoms, a cyano group, a

. carboxy group, a carbamyl group, an alkylcarbamyl group containing up to 5 carbon atoms, an <EMI ID = 55.1> group

a group . carbalkoxy containing up to 6 carbon atoms, a mercapto group, an alkylmercapto group containing up to

containing up to 4 carbon atoms, an alkylsulfonyl group containing up to 4 carbon atoms, a parfluoroalkylsulfonyl group containing up to 4 carbon atoms, a sulfamyl group, an alkylsulfamyl group containing up to 4 carbon atoms or a dialkylsulfamyl group containing up to 8 carbon atoms; more than one of these sub-

characterized in that a compound of formula is reacted;

with hydrogen so as to obtain a compound of formula:

in that said compound is dehydrogenated so as to obtain a compound of formula:

obtain the desired product. 2.- Process for the preparation of intermediates for

the carbon atom in position 5 with a secondary aminopropyl radical, said intermediates having the following formula:

have hydrogen, an alkyl group containing up to 6 carbon atoms, an alkenyl group containing up to 6 carbon atoms, a perfluoroalkyl group containing up to 4 carbon atoms, a phenyl radical or a substituted phenyl radical , an acyl group containing up to 4 carbon atoms, a perfluoroacyl group containing up to 4 carbon atoms, an amino group, an alkylamino group containing up to 4 carbon atoms, a dialkoylamino group containing up to 8 atoms carbon, an acylamino group containing up to 4 carbon atoms, a perfluoroacylamino group containing up to 4

up to 4 carbon atoms, halogens (fluorine, chlorine, bromine or iodine), a hydroxyl group, an alkoxyl group containing up to 4 carbon atoms, a perfluoroalkoxyl group containing up to 4 carbon atoms, a group cyano, a carboxy group, a carbamyl group, an alkylcarbamyl group containing up to 5 carbon atoms, a

<EMI ID = 67.1> of carbon, a carbalkoxy group containing up to 6 carbon atoms, a mercapto group, an alkylmercapto group containing up to 4 carbon atoms, a perfluoroalkylmercapto group containing up to 4 carbon atoms, a alkylsulfonyl group containing up to 4 carbon atoms, perfluoroalkylsulfonyl group containing up to 4

more than one of these substituents possibly being on each benzene ring and R represents an alkyl, aryl, aralkyl, alkoxy or aroxy radical, characterized in that a compound of formula is brought into contact

the carbon atom in position 5 with a secondary aminopropyl radical, said intermediates having the following formula;

<EMI ID = 71.1> wherein X and X 'are the same or different and represent hydrogen, an alkyl group containing up to 6 carbon atoms, an alkenyl group containing up to 6 carbon atoms, a perfluoroalkyl group containing up to 4 carbon atoms carbon, a phenyl radical or a substituted phenyl radical, an acyl group containing up to 4 carbon atoms, a perfluoroacyl group containing up to 4 carbon atoms, an amino group, an alkylamino group containing up to 4 carbon atoms carbon, a dialkoylamino group containing up to 8 carbon atoms, an acylamino group containing up to 4 carbon atoms, a perfluoroacylamino group containing up to 4 carbon atoms,

an alkylsulfonylamino group containing up to 4 atoms

carbon, halogens (fluorine, chlorine, bromine or iodine), a hydroxyl group, an alkoxyl group containing up to 4 carbon atoms, a perfluoroalkoxyl group containing up to 4 carbon atoms, a cyano group, a carboxy group , a carbamyl group, an alkylcarbamyl group containing up to 5 carbon atoms, a dialkylcarbamyl group containing up to 9 carbon atoms, a group

holding up to 4 carbon atoms, an alkylsulfonyl group containing up to 4 carbon atoms, a perfluoroalkylsulfonyl group containing up to 4 carbon atoms, a sulfamyl group, an alkylsulfamyl group containing

famyl containing up to 8 carbon atoms; more than one of these substituents possibly being on each benzene nucleus, and R represents an alkyl, aryl, aralkyl, alkoxy, aroxy or aralkoxy radical, characterized in that a compound of formula is dehydrogenated: <EMI ID = 74.1>

in which X and X 'are the same or different and represent hydrogen, an alkyl group containing up to

than 6 carbon atoms, a perfluoroalkyl group containing up to 4 carbon atoms, a phenyl radical or a substituted phenyl radical, an acyl group containing up to 4 carbon atoms, a perfluoroacyl group containing up to 4 atoms of carbon, an amino group, an alkylamino group containing up to 4 carbon atoms, a dialkoymamino group containing up to 8 carbon atoms, an acylamino group containing up to 4 carbon atoms, a perfluoroacylamino group containing up to 4 carbon atoms, an alkylsulfonylamino group containing up to 4 carbon atoms, halogens (fluorine, chlorine, bromine or iodine), a hydroxyl group, an alkoxyl group containing

bamyl containing up to 5 carbon atoms, a dialkoylcarbamyl group containing up to 9 carbon atoms, a carbalkoxy group containing up to 6 carbon atoms, a mercapto group, an alkylmercapto group containing up to 4 carbon atoms, a perfluoroalkylmercapto group containing up to 4 carbon atoms, an alkylsulfonyl group containing up to 4 carbon atoms, a

carbon, a sulfamyl group, an alkylsulfamyl group containing up to 4 carbon atoms or a dialkylsulfamyl group containing up to 8 carbon atoms; more than one of these substituents possibly being on each benzene ring, characterized in that a compound of formula is reacted

in which R is an alkyl, aryl, aralkyl, alkoxy or aroxy radical and 1 and X 'are as defined above, with hydrogen, so as to obtain a compound of formula: <EMI ID = 81.1>

and in that said compound is dehydrogenated so as to form said intermediates.

drolysis of said compound to form said desired product.

6.- Process for the preparation of 5- (3-methylamino-pro,

hydrolyzes said compound to form said desired product. <EMI ID = 84.1>

then drolysis of said compound to form said desired product.

8.- Process for the preparation of 5- (3-methylamino-

that said compound is hydrolyzed in basic solution, so as to form said desired product.

cyclohept not substituted on the carbon atom in position 5 by a secondary aminopropyl radical, of formula;

<EMI ID = 87.1> where X and X 'are the same or different and represent hydrogen, an alkyl group containing up to

6 carbon atoms, an alkenyl group containing up to 6 carbon atoms, a perfluoroalkyl group containing up to 4 carbon atoms, a phenyl radical or a substituted phenyl radical, an acyl group containing up to 4 carbon atoms, a perfluoroacyl group containing up to 4 carbon atoms, an amino group, an alkylamino group containing up to 4 carbon atoms

up to 4 carbon atoms, halogens (fluorine, chlorine, bromine or iodine), a hydroxyl group, an alkoxyl group containing up to 4 carbon atoms, a perfluoroalkoxyl group containing

carboxy, a carbamyl group, an alkylcarbamyl group containing up to 5 carbon atoms, a dialkylcarbamyl group containing up to 9 carbon atoms, a carbalkoxy group containing up to 6 carbon atoms, a mercapto group, an alkyl mercapto group containing up to 4 carbon atoms, a perfluoroalkylmercapto group containing up to 4 carbon atoms, an alkylsulfonyl group containing up to 4 carbon atoms,

containing up to 8 carbon atoms; more than one of these substituents possibly being on each benzene ring, characterized in that a compound of formula is reacted: <EMI ID = 92.1>

in which R is an alkyl, aryl, aralkyl, alkoxy radical

hydrogen so as to produce a compound of the formula;

generation, so as to form a mixture of compounds of formula;

wherein Y is halogen; in that said mixture is reacted with a tertiary amine in order to convert said mixture substantially into said non-halogen compound by then hydrolyzing said compound so as to obtain the desired product.

carbon in position 5 by a secondary aminopropyl radical, said intermediates comprising a mixture of compounds, having the formulas <EMI ID = 98.1> <EMI ID = 99.1>

identical or different and represent hydrogen, an alkyl group containing up to 6 carbon atoms, a group

fluoroalkyl containing up to 4 carbon atoms, a phenyl radical or a substituted phenyl radical, an acyl group containing

perfluoroalkoxyl group containing up to 4 carbon atoms, cyano group, carboxy group, carbamyl group, alkylcarbamyl group containing up to 5 carbon atoms, dialkylcarbamyl group containing up to 9 carbon atoms, carbalkoxy group containing up to 6 atoms of

up to 4 carbon atoms, a perfluoroalkylmorcapto group containing up to 4 carbon atoms, an alkylsulfonyl group containing up to 4 carbon atoms, a perfluoroalkylsulfonyl group containing up to 4 carbon atoms, a sulfamyl group, an alkylsulfamyl group containing up to 4 <EMI ID = 103.1>

up to 8 carbon atoms; more than one of these substituents possibly being on each benzene ring and R is an alkyl, qryl, aralkyl, alkoxy, aroxy or aralkoxy radical, characterized in that a compound of formula is reacted:

-mixture of intermediates.

11, - Process for the preparation of intermediates for

carbon atom in position 5 with a secondary aminopropyl radical, said intermediates having the following formula:

tent hydrogen, an alkyl group containing up to 6 carbon atoms, an alkenyl group containing up to 6 carbon atoms

carbon, a phenyl radical or a substituted phenyl radical, a

bone, a dialkylamino group containing up to 8 carbon atoms, an acylamino group containing up to 4 carbon atoms, a perfluoroacylamino group containing up to 4 carbon atoms, an alkylsulfonylamino group containing up to 4 carbon atoms carbon, halogens (fluorine, chlorine, bromine or iodine), a hydroxyl group, an alkoxyl group containing up to 4 carbon atoms, a perfluoroalkoxyl group containing up to 4 carbon atoms, a cyano group, a carboxy group , a carbamyl group, an alkylcarbamyl group containing up to 5 atoms

carbon mes, a carbalkoxy group containing up to 6 carbon atoms, a morcapto group, an alkylmercapto group containing up to 4 carbon atoms, a perfluoroalkylmercapto group containing up to 4 carbon atoms, an alkylfonyl group containing up to 4 carbon atoms with 4 carbon atoms, a perfluoroalkylsulfonyl group containing up to 4 carbon atoms, a sulfamyl group, an alkylsulfamyl group containing up to

up to 8 carbon atoms; more than one of these substituents possibly being on each benzene ring and R represents an alkyl, aryl, aralkyl, alkoxy or aroxy or aralkoxy radical, characterized in that a mixture of compounds of formulas is reacted:

in which X, X 'and R are as defined above and

Y is halogen with a tertiary amine so as to produce said desired intermediate.

12, - Process for the preparation of 5- (3-methylaminopropyl) -5H-

bromocycloheptene, in that said mixture is reacted with

triethylamine to convert said mixture substantially

in said non-brominated compound and in that said compound is hydrolyzed so as to form said desired product.

13.- Process for preparing a mixture of intermediates

tent hydrogen, an alkyl group containing up to 6 carbon atoms, an alkenyl group containing up to 6 carbon atoms, a perfluoroalkyl group containing up to 4 carbon atoms, a phenyl radical or a substituted phenyl radical, a acyl group containing up to 4 carbon atoms, perfluoroacyl group containing up to 4 carbon atoms, amino group, alkylamino group containing up to 4 carbon atoms, dialkoylamino group containing up to 8 carbon atoms , an acylamino group containing up to 4 carbon atoms, a perfluoroacylamino group containing up to 4 carbon atoms, an alkylsulfonylamino group containing up to 4 carbon atoms, halogens (fluorine, chlorine, bromine or iodine), a hydroxyl group, an alkoxyl group containing up to 4 carbon atoms,

a perfluoroalkoxyl group containing up to 4 carbon atoms, a cyano group, a carboxy group, a group

carbon, a dialkylcarbamyl group containing up to 9 carbon atoms, a carbalkoxy group containing up to 6 carbon atoms, a mercapto group, an alkylmercapto group

capto containing up to 4 carbon atoms, an alkylsulfonyl group containing up to 4 carbon atoms, a per-

sulfamyl group, an alkylsulfamyl group containing up to 4 carbon atoms or a dialkylaulfamyl group containing up to 8 carbon atoms; more than one of these substituents possibly being on each benzene ring, characterized in that a compound of formula is reacted:

<EMI ID = 122.1> with hydrogen, so as to produce a compound of the formula:

and in that said hydrogenated compound is reacted with a

R is an aralkoxy radical, so as to produce a compound of formula:

in that said compound is dehydrogenated, so as to form a compound having the formula:

and in that said compound is hydrolyzed, so as to form the desired product.

secondary propyl of formula <EMI ID = 128.1> <EMI ID = 129.1>

tent hydrogen, an alkyl group containing up to 6 carbon atoms, an alkenyl group containing up to 6 carbon atoms, a perfluoroalkyl group containing up to 4 carbon atoms, a phenyl radical or a radical substituted phenyl, an acyl group containing up to 4 carbon atoms, a perfluoroacyl group containing up to 4 carbon atoms,

my carbon, a dialkoylamino group containing up to 8 atoms: carbon, an acylamino group containing up to 4 carbon atoms, a perfluoroacylamino group containing up to 4 carbon atoms, an alkylsulfonylamino group containing up to 4 carbon atoms, halogens (fluorine, chlorine, bromine or iodine) , a hydroxyl group, an alkoxyl group containing up to 4 carbon atoms, a perfluoroalkoxyl group containing up to 4 carbon atoms, a cyano group, a carboxy group, a carbamyl group, an alkylcarbamyl group containing up to 5 atoms carbon, a dialkylcarbamyl group containing up to 9 carbon atoms, a carbalkoxy group containing up to 6 carbon atoms, a mercapto group, an alkylmercapto group containing up to 4 carbon atoms, a perfluoroalkylmercapto group containing up to ' with 4 carbon atoms,

an alkylsulfonyl group containing up to 4 carbon atoms, a perfluoroalkylsulfonyl group containing up to 4 atoms

carbon, a sulfamyl group, an alkylsulfamyl group containing

containing up to 8 carbon atoms; more than one of these substituents possibly being on each benzene ring, characterized in that a compound of formula is hydrolyzed:

<EMI ID = 132.1> in which R is an alkoxy, aroxy or aralkoxy group, so as to force a compound of formula:

and in that said compound is acylated so as to form a compound of formula:

in which R is an alkyl, aralkyl or aryl group,

in this pu'on dehydrogenates said compound, so as to form a compound of formula:

and in that said compound is hydrolyzed, so as to form said desired product.

17.- Chemical organic intermediates for synthesis

carbon in position 5 with a secondary aminopropyl radical, said intermediates having the following formula: <EMI ID = 137.1>

carbon monoxide, an alkenyl group containing up to 6 carbon atoms, a perfluoroalkyl group containing up to 4 carbon atoms, a phenyl radical or a substituted phenyl radical, an acyl group containing up to 4 carbon atoms, a perfluoroacyl group containing up to 4 carbon atoms, an amino group, an alkylamino group containing up to 4 carbon atoms

carbon atoms, an acylamino group containing up to 4 carbon atoms, a perfluoroacylamino group containing up to 4 carbon atoms, an alkylsulfonylamino group containing

or iodine), a hydroxyl group, an alkoxyl group containing up to 4 carbon atoms, a perfluoroalkoxyl group containing

carboxy, a carbamyl group, an alkylcarbamyl group containing up to 5 carbon atoms, a dialkoylcarbamyl group containing

up to 6 carbon atoms, a mercapto group, an alkyl mercapto group containing up to 4 carbon atoms, a perfluoroalkylmarcapto group containing up to 4 carbon atoms, an alkylsulfonyl group containing up to 4 carbon atoms,

myle containing up to 8 carbon atoms; more than one of these substituents may be on each benzene ring; y is a halogen and R is an alkyl, aryl, aralkyl, alkoxy, aroxy or aralkoxy radical,

18.- Chemical intermediates for the synthesis of 5H-

in position 5 by a secondary aminopropyl radical, said intermediates having the following formula:

have hydrogen, an alkyl group containing up to 6 carbon atoms, an alkenyl group containing up to 6 carbon atoms, a perfluoroalkyl group containing up to 4 carbon atoms, a phenyl radical or a substituted phenyl radical , an acyl group containing up to 4 atoms

carbon, an amino group, an alkyl group containing

up to 8 carbon atoms, an acylamino group containing up to 4 carbon atoms, a perfluoroacylamino group containing

holding up to 4 carbon atoms, halogens (fluorine, chlorine, bromine and iodine), a hydroxyl group, an alkoxyl group containing

eg carboxy, a carbomyl group, an alkyl carbamyl group containing up to 5 carbon atoms, a dialkylcarbamyl group containing up to 9 carbon atoms, a carbaleoxy group containing up to 6 carbon atoms, a mercapto group, a group

<EMI ID = 152.1> perfluoroalkylmercapto containing up to 4 carbon atoms, an alkyleulfonyl group containing up to 4 carbon atoms,

can be found on each benzene ring; and R is an alkyl, aryl, alkoxy, aroxy, aralkyl or aralkoxy radical.