IE871488L - Synthesis of n-amino-3-azabicyclo £3,3,0| octane. - Google Patents

Abstract

1. A process for continuous synthesis of N-amino-3-aza-bicyclo[3,3,0]octane characterized by reacting a solution of ammonium hydroxide and ammonium chloride with an aqueous solution of sodium hypochlorite at a temperature between -15 degrees C and -7 degrees C in an alkaline medium, - then reacting the thus formed monochloroamine with 3-aza-bicyclo[3,3,0]octane in a two-phase medium in a suitable reaction vessel equipped with a blade agitator at a temperature between 30 degrees C and 90 degrees C in an alkaline medium, - then separating by destillation the ammonia and subsequent the non-reacted 3-aza-bicyclo[3,3,0]octane from the reaction medium for recycling, - then isolating under demixing a concentrated solution of N-amino-3-aza-bicyclo[3,3,0]octane by addition of sodium hydroxide to the reaction medium and, if desired, purifying the thus formed hydrazine by destillation. [EP0277267A1]

Description

b 6 6 1 - l - /if-S'g/g'T' I R E L A M D PATEMTS ACT, 1954 COMPLETE SPECIFICATION "Mew process for the synthesis of N-amino-3-asabicyclo[3.3.0]octane" Patent Application by ORIL S.A., a Societe Anoxiyme organised and existing tinder the Lews of Prance of 13 Ewe Augusta Desgenetais 76210 Boibee France„ 5 9 6 81 - 2 - The present invention relates to a novel process for the synthesis of N-amino-3-azabicyclo[3.3.0]octane.

N-amino-3-a2abicyclo[3.3.0 Joctane or N-amino-octahydrocyclopent[c]pyrrole is a compound very often used as an intermediate in the synthesis of medicaments (GB Patent No. 1,153,982).

At present, the only method described in the literature for the preparation of that compound is the process of Wright J.B. and Willette R.E. (J.Med, and Pharm. Chem. 1962, 5, 819) which consists in a nitrosation of 3~azabicyclo[3.3.0Joctane and then a reduction of the N~nitrosated derivative obtained. That synthesis results in fairly good yields but it requires two separate stages and the product resulting from the first stage has to be handled with great care owing to its potential toxicity, and that presents operational problems from the industrial standpoint.

Moreover, it is recognised that, for the preparation of the various hydrazines, recourse is often had to the reaction known as the "Raschig" reaction which consists in synthesising monochloroamine by the reaction of ammonia with a sodium hypochlorite solution and then reacting the monochloroamine formed with an amine to obtain the corresponding hydrazine. That process is quite difficult to put into practice because it requires two separate stages, the first carried out at reduced temperature for the synthesis of the monochloroamine and the second carried out at elevated temperature, during which the actual synthesis of the hydrazine is effected. In addition, the monochloroamine has to be in the presence of a 3 sufficient excess of amine in the intermediate solutions in order to avoid secondary degradation reactions, and consequently the process always requires very large quantities of solutions to be treated. 5 French Patent Application Wo. 76.34692 describes a process for the synthesis of N,M~dimethylhydrazine which is carried out continuously starting from ammonia, sodium hypochlorite and dimethylamine in an aqueous medium.

That process, however, cannot be used for the preparation of 10 all alkylhydrazines and especially not for the preparation of M-amino-3-azabicyclo[3.3.0]octane, taking into account the fact that the starting material necessary for its synthesis, 3-azabicyclo[3.3.0]octane, has special physico~chemical properties which are very different from those of 15 dimethylamine. On the one hand this bicyclic amine is soluble in aqueous alkaline solutions at average concentrations and especially at reduced temperature. On the other hand, it can react with the monochloroamine only at elevated temperatures at which mixtures of water and 3-a2abicyclo[3.3.0]octane 20 undergo demixing.

The applicants have now discovered a novel process for the synthesis of N-a:mino~3-azabicyclo[ 3.3.0 joctane. That process, which is operated continuously, resides partly in a modification of the Raschig process, which consists in 25 preparing chloroamine by the action of sodium hypochlorite on ammonia at low temperature, and then, and herein lies its great originality, causing the resulting chloroamine to act on 3-azabicyclo[3.3.0]octane in a biphasic medium, then extracting the hydrazine formed and recovering and recycling 30 the starting amine in the form of an aqueous solution directly without any additional stage. - 4 - The present invention relates more especially to a process for the continuous synthesis of N-amino~3~azabicyclo[3.3.0joctane, characterised in that a solution of ammonium hydroxide and ammonium chloride is reacted with an aqueous solution of 5 sodium hypochlorite at a temperature of between -15°C and -7°C in an alkaline medium, and then the resulting monochloroamine is reacted with 3-azabicyclof3.3.0joctane in a biphasic medium in a suitable reactor equipped with a coaxial paddle stirrer at a 10 temperature of between 30°C and 90°C and in an alkaline medium, the ammonia is then separated from the reaction medium and afterwards the 3~azabicyclo[3.3.0joctane that has not reacted is separated from the reaction medium by distillation in order to be recycled, 15 - then a concentrated solution of N-amino-3-azabicyclo-[3.3.0joctane is isolated by demixing by the addition of sodium hydroxide to the reaction medium, and the resulting hydrazine is purified, if desired, by distillation.

In order to form the monochloroamine, an aqueous solution of 20 sodium hypochlorite is mixed, with stirring, with a solution of ammonium hydroxide and ammonium chloride. The reaction is effected in an alkaline medium having a pH of from 9=2 to 10 in the presence of an excess of ammonium hydroxide and ammonium chloride. 25 The ratio of the molar concentrations of ammonium hydroxide and ammonium chloride to sodium hypochlorite is approximately from 2.5 to 3 and the ratio of the molar concentrations of ammonium chloride to ammonium hydroxide is approximately from 0.50 to 0.80. - 5 - The reaction of the monochloroamine with 3-azabicyclo-[3.3 . 0Joctane is effected in the presence of an aqueous sodium hydroxide solution at elevated temperature. The ratio of the molar concentrations of 3-azabicyclo[3•3.0Joctane to 5 monochloroamine is to be greater than 4 and less than 8. The reaction time is variable and depends on the temperature at which the reaction is carried out and on the ratio of the concentrations of the reagents and is of the order of from 20 to 40 seconds. 10 After the formation of M-amino=3»azabicyclo[3.3.0Joctane and cooling, the reaction solution undergoes degassing in order to eliminate the ammonia, and the 3-azabicyclo[3.3.0Joctane that has not reacted is separated from the reaction medium by simple distillation under atmospheric pressure and at a 15 temperature of approximately from 90° to 100°C. Under those conditions, the amine is obtained in the form of an aqueous solution having a 30 % concentration of 3-azabicyclo~ [3.3.0Joctane. That solution is recycled immediately.

The reaction solution containing the hydrazine is then treated 20 with sodium hydroxide. That operation, which is carried out in two stages, permits the separation of the N-amino-3-azabicyclo[3.3.0Joctane in an organic phase having a 92 % concentration of hydrazine. The resulting concentrated solution can be used directly or distilled under reduced 25 pressure.

The process of the present invention accordingly permits not only the continuous synthesis of N-amino~3-azabicyclo-[3.3.0Joctane, without the formation of toxic intermediates, but also the inexpensive obtainment of hydrazine. 30 The conventional Raschig synthesis generally requires a large excess of amine, which is a considerable disadvantage when the amines used as starting material for the preparation of the ~ 6 - corresponding hydrazines are very expensive. That is the case for 3-azabicyclo[3.3.0]octane.

The process of the present invention (reaction in a biphasic medium, geometry of the reactors) enables that excess of 3-azabicyclo[3.3.0]octane to be limited to less than 5-fold relative to the quantity of monochloroamine. Furthermore, owing to the recovery and recycling of 3-azabicyclo~ [3.3.0joctane that has not reacted, it enables N~amino~3~ azabicyclo[3.3.0Joctane to be obtained very inexpensively compared with the other known processes. The isolation of 3-azabicyclo[3.3.0Joctane in the form of an aqueous solution at a relatively low temperature is also another very original feature as well as a considerable economic advantage of the process of the invention. It is known that 3-azabicyclo-[3.3.0Joctane is a thermodegradable product which boils at atmospheric pressure at only 184°C. The process of the present invention permits the isolation of 3-azabicyclo[3.3.0Joctane in the form of a heteroazeotrope at a lower temperature.

Another advantage of the process results from the easy demixing of N-amino-3-azabicyclo[3.3.0Joctane in the form of a concentrated solution (92 % N-amino~3-azabicyclo-[3.3.0Joctane) simply by adding sodium hydroxide to the reaction medium, from which ammonia and 3-azabicyclots . 3 . 0 Joctane have previously been removed.

A detailed, non-limiting description of the implementation of the process of the invention is given hereinafter, the basis scheme of which process is shown in Figure 1. - 7 - EXAMPLE 1: Preparation of N-amino~3-azabicyclo[3.3.0Joctane All the quantities indicated correspond to one operating unit and are relative to one litre of injected hypochlorite. 5 One litre of sodium hypochlorite solution assaying at 48°C by chlorometry and one litre of a solution having an ammonia concentration of 3.60 mole l"1 and an ammonium chloride concentration of 2.37 mole l"1 are introduced in continuous fashion into a stirred reactor (R,) at the rate of 3.1 ml L0 min"1.

The temperature inside the reactor is maintained at between -8° and ~10°C, and the pH of the reaction is approximately 10. At the outlet of R,, a solution of monochloroamine is obtained having a titre greater than 1 mol.l"1, which corresponds to a L5 yield of approximately 100 % relative to the sodium hypochlorite.

The synthesis of M-amino~3-azabicyclo[3.3.0Joctane is effected in a biphasic medium in a cylindrical reactor (Ra) which is stirred vigorously by means of a coaxial paddle stirrer in 20 such a manner as to keep the mixture emulsified. The height of the reactor is approximately 25 cm and its volume is 31.6 ml.

The chloroamine solution obtained above (2 litres), the aqueous solution of 3-azabicyclo[3.3.0Joctane (3.8 litres, 30 25 %) and the sodium hydroxide (0.5 litre at 6 mol.l"1) are introduced simultaneously and continuously into the reactor R2 at a rate suitable for obtaining a molar ratio of 3-a2abicyclo[3.3.0Joctane to monochloroamine of approximately 5.2 and a pH fixed at 13.4. The reaction temperature is - 8 - maintained at approximately 50°C. After 30 seconds' reaction, the reaction mixture is cooled again in an exchanger to 16°C and becomes monophasic again. A mixture is obtained having a concentration of approximately 0.26 mol.l'1 of hydrazine. The reaction mixture then undergoes a degassing operation to eliminate the ammonia contained in the solution. The reaction solution, from which the ammonia has been removed, is distilled at 98.4°C under atmospheric pressure (distillation column DC,) in order to eliminate the 3-azabicyclo[3.3.Ojoctane that has not reacted. The amine is obtained after distillation in the form of an aqueous solution having a composition of approximately 30 % amine. That solution is then recycled and used immediately.

After separating 3-azabicyclo[3.3.0Joctane, the reaction solution containing the hydrazine is treated by the addition of solid sodium hydroxide in order to separate the M-amino-3~ azabicyclo[3.3.0Joctane in an organic phase having a titre of approximately 92 % hydrazine. Depending on the specifications for use, the concentrated hydrazine solution can then be used directly or distilled under reduced pressure (distillation column DC2) .

The yield of hydrazine relative to the 3-azabicyclo~ [3.3.0Joctane consumed is between 88 and 92 %.

Claims (1)

1. Process for the continuous synthesis of N-amino-3-azabicyclo[3.3.0Joctane, characterised in that a solution of ammonium hydroxide and ammonium chloride is reacted with an aqueous solution of sodium hypochlorite at a temperature of between -15°C and ~7°C in an alkaline medium, and then the resulting monochloroamine is reacted with 3-azabicyclo[3.3.0Joctane in a biphasic medium in a suitable reactor equipped with a coaxial paddle stirrer at a temperature of between 30°C and 90°C and in an alkaline medium, the ammonia is then separated from the reaction medium and afterwards the 3-azabicyclo[3.3.0Joctane that has not reacted is separated from the reaction medium by distillation in order to be recycled, then a concentrated solution of W-amino-3-azabicyclo[3.3.0Joctane is isolated by demixing by the addition of sodium hydroxide to the reaction medium, and the resulting hydrazine is purified, if desired, by distillation. Process according to claim 1, characterised in that the molar ratio of 3~azabicyclo[3.3.0Joctane/monochloroamine is greater than 4 and less than 8. Process according to claim 1, characterised in that the reaction of the monochloroamine with the 3-azabicyclo-[3.3.0Joctane is effected at a pH of between 13 and 14. Process according to claim 1, characterised in that the excess of 3~azabicyclo[3.3.Ojoctane which has not reacted _ 10 - with the monochloroamine is distilled at a temperature of between 90°C and 100°C under atmospheric pressure, before being recycled. A process substantially as hereinbefore described with reference to the example and drawings. N-amino-3-a2abicyclo[3.3.0Joctane whenever prepared by a process as claimed in any preceding claim. Dated this 5th day of June, 1987. CRUICKSHANK & CO., Agents for the Applicants 1, Holies Street, Dublin 2.