FR2540110A1 - New process for the industrial manufacture of N-nitrosoazabicycloalkanes - Google Patents

Abstract

New process for the manufacture of N-nitrosoazabicycloalkanes by catalytic reduction of 1,2-cycloalkanedicarboximides to the corresponding amines which are then nitrosated in situ. The process is particularly advantageous when the reduction is carried out in the presence of a catalyst such as poisoned copper chromite under hydrogen pressures of between 60 and 120 bars and at temperatures situated between 200 and 800 DEG C.

Description

The subject of the present invention is an industrial process for the preparation of nitroso azabicycloalkanes, intermediates useful for the synthesis of drugs, of general formula I:

 where n is an integer from 2 to 5.

The derivatives of general formula I are usually prepared by chemical reduction of the 1,2-cycloalkanedicarboximides of general formula II

in which n takes the previously defined meaning, in corresponding secondary amines of general formula III

 in which n has the value stated above.

which are then, n :: dews in N-nitroso bicycloalkane derivatives of general formula I.

 In the Laboratory, it is known that the reduction of the compounds of general formula II, described in the literature, into corresponding amines III, is possible by the use of a chemical reducing agent chosen from the group of metal hydrides and in particular double lithium hydride and aluminum.

 However, these chemical reductions have numerous drawbacks for their industrial implementation since chemical reducers are very expensive products and very dangerous to handle. Indeed, the double hydride of lithium and aluminum ignites spontaneously as soon as it is in the presence of a trace of water or even when it is exposed to the humidity of atmospheric air. This particular chemical property therefore requires on the one hand the use of industrial equipment which is particularly airtight and on the other hand the need to conduct the reactions in an inert atmosphere, that is to say in the presence of '' a rare gas or dry nitrogen.

 This property also requires working in anhydrous solvents such as diethyl ether, but this has the effect of considerably increasing the cost price of the operation as well as the risks of ignition of the reaction mixture.

 Finally, it should be noted that, during the hydrogenation, the lithium aluminum hydride breaks down into alumina and lithine, colloidal substances, which have the disadvantage of retaining the solvents and the reduction products: it is then necessary to carry out pressure filtration which is particularly difficult to implement.

 Furthermore, the catalysts generally used for catalytic hydrogenations cannot be used on 1,2-cycloalkanedicarboximides because they cause the opening of the eyclic amines formed and release of ammonia instead of only achieving the reduction of the imide functions.

 The aim of the present invention is to provide an industrial process for the catalytic reduction of cycloalkanedicarboximides using a catalyst such as copper chromite poisoned by a metallic impurity preferably chosen from barium, calcium or even alumina (Al203 ) which avoids side-opening reactions. This reduction is carried out at a fairly high temperature between 200 and 3000C, preferably between 250 and 3000C, as well as under a pressure between 60 and 120 bars, preferably between 80 and 100 bars. These conditions obviously require having a stable solvent. For example, methyl or ethyl alcohols cannot be used because they are the cause of a secondary alkylation reaction on the nitrogen atom and the opening of rings. On the other hand, dioxane and tetrahydrofuran are solvents stable under these reaction conditions. This new process for catalytic reduction of cycloalkanedicarboximides eliminates the various drawbacks of chemical reduction using metal hydrides and in particular a simplified and less expensive and above all less dangerous industrial implementation while providing the expected product with the exclusion of degraded products.

 The following examples, given without limitation, illustrate the invention.

Example 1:
In the process according to the invention, the cycloalkanedicarboximide is dissolved in a reactor in a solvent, such as for example dioxane, and the necessary quantity of poisoned copper chromite is added.

The container is then purged a first time using a stream of nitrogen and then a second time with hydrogen.

The reaction mixture is then started to heat while stirring until a temperature of between 200 and 300 tu is obtained.

The hydrogen is then introduced into the reactor at a pressure of between 60 and 120 bars and the mixture is thus stirred for 5 to 6 hours. The reaction is complete when the absorption of hydrogen becomes zero.

The temperature is then lowered to between 20 and 500C and the reactor is carefully decompressed. The reaction mixture is then filtered in order to separate the catalyst from it, which can subsequently be used again for other catalytic hydrogenations. The catalytic reduction of the cycloalkanedicarboxymides proper to the amine is complete. The solution obtained after filtration is directly usable for carrying out the nitrosation reaction.

To this end, the filtrate obtained previously is treated with 36N sulfuric acid to give the sulfate of the amine which separates from the dioxane by decantation in the form of a very viscous liquid which is diluted by the addition of water. After separation of the two phases, the solvent is washed with water and the aqueous phases containing the azabicycloalkane sulfate are combined. This solution is further diluted with water, cooled and added with stirring to a dilute aqueous solution of sodium nitrite.

The reaction medium is then heated to a temperature between 50 and 900C for a period of between 45 and 75 minutes without stopping the stirring. After cooling, the nitrosed derivative is allowed to settle at the bottom of the container and it is separated from the aqueous phase.

The latter is then extracted several times with dichloroethane and the combined organic phases are joined to the oily nitrose derivative decanted previously.

The nitrosed compound is finally recovered by azeotropic distillation of the solvent first under ordinary pressure at 900C and then under reduced pressure.

Example 2
Weighted example of catalytic reduction according to the invention described in the previous example.

- Cycloalcanedicarboximide-1,2: 600 moles - Dioxane: 308 liters - Copper chromium stocked with barium: 24 kg - Sulfuric acid 36N: 600 moles; 29.4 Kg - Water: 340 liters - Sodium Nitrite: 660 moles; 4.55 Kg - Sodium nitrite dilution water: 160 liters - Dichlorethane: 600 liters - Aqueous sodium hydrogen carbonate: 100 liters - Hydrogenation temperature: 250 to 3000C - Hydrogenation pressure: 90 bars - Yield 67%.

Example 3 to 7
The following derivatives were prepared according to the process described in examples 1 and 2 Li - Aza-3 nitroso-3 bicyclo (3,2,6) heptane from cyclobutanedicarboximide-1, 2 5 - Aza-3 nitroso-3 bicyclo (3,3,0) octane from -cyclopentanedicarboximide-i, 2 6 - Aza-8 nitroso-8 bicyclo (4,3,0) nonane from cyclohexanedicarboximide-i, 2 7 - Aza-9 nitroso-9 bicyclo (5,3,0) decane from cycloheptanedicarboximide-i, 2

Claims (3)

 CLAIMS 1. Process for the preparation of nitrosoazabicycloalkanes of general formula I

 in which n is an integer from 2 to 5, by reduction of 1,2-cycloalkanedicarboximides of general formula II

III  in which n has the same meaning as before, in corresponding secondary amines of general formula  in which has the meaning given above, then nitrosation into a compound of formula I, process characterized in that the reduction is carried out by catalytic hydrogenation at a pressure between 60 and 120 bars, at a temperature between 200 and 3000C and in the presence of copper chromite poisoned by a metal such as barium, calcium or aluminum. 2. Method according to claim 1 characterized in that the reduction is carried out at a temperature between 250 and 3000C. 3. Method according to claim 1 characterized in that the hydrogen pressure is between 80 and 100 bars.  11. Method according to claim 1 characterized in that the catalyst used is copper chromite poisoned with barium.