IE57991B1 - Process for the preparation of iminodibenzyl - Google Patents

Abstract

1. Process for the preparation of iminodibenzyl of the formula (I) see diagramm : EP0158115,P5,F2 by heating 2,2'-diaminodibenzyl of the formula (II) see diagramm : EP0158115,P5,F3 with phosphoric acids in the molten state, characterized in that reaction is carried out continuously in several stages, wherein a) molten 2,2'-diaminodibenzyl and a phosphoric acid, each of which has a temperature of between 160 and 200 degrees C, are fed separately in a molar ratio of diaminodibenzyl : P2 O5 of 1 : 1 to 1 : 2.5 into the first stage, the neutralization takes place there, with evolution of heat, and the condensation is carried out in the subsequent reaction stages at a temperature of 260 degrees C to 320 degrees C, after which b) the uncooled reaction mixture from the last stage is transferred continuously into a heated separator and is separated at 160 degrees C to 300 degrees C into a product stream containing the upper phase of molten iminodibenzyl and a discharge stream containing, as the lower phase, phosphoric acid and ammonium phosphates.

Description

The invention relates to a process for the preparation of imi nodibenzyI by reaction of molten 2,2'diami nodibenzy I and phosphoric acids in a continuous p rocedu re .

Iminodibenzyl and its derivatives are important starting substances for the synthesis of medicaments with a aide field of pharmaceutical use,, In practicez iminodibenzyl was usually prepared by heating diphosphates of 2,2 1 =d i ami nodi benzy I to about 280°--320°C in the molten state (Swiss Patent Specification 331,207) over a reaction time of 40 minutes, a yield of 92% being obtained.

The ira1nodibenzy I is then isolated from the reaction mixture by boiling with benzene and evaporating off the solvent, after washing the benzene phase.

It is furthermore mentioned in general terms in Austrian Patent Specification 200,579 that imi nodibenzy I can also be obtained from free 2,21-diaminodibenzyI by heating with po lyphosphoric acid, but more detailed process conditions and yields are not given.

All of these known processes are batchwise and therefore time-consuming, the complicated working up additionally representing an economic disadvantage. If the diphosphate of di aminodibenzyI is used as the starting substance, the fusion of the diphosphate of melting point 266 - 268°C, which precedes the reaction, represents a particularly energy-intensive measure.

It has now been possible to discover that iminodibenzyl can be prepared continuously from 2,2'-di ami nodi benzyl in an advantageous and energy-saving manner and pure imi nodibenzy I can be obtained directly in a simple working up stage if di ami nodibenzyI which has been prewarmed to not more than 200°C and phosphoric acid or polyphosphoric acid at approximately the same temperature are fed separately into the first stage of a multi-stage reaction, the neat of neutralization being used to achieve the reaction temperature and working uo being effected by simple phase separation of the hot reaction product.

The present invention accordingly relates to a process for the preparation of imi nodibenzyI of the f ormu La by heating 2,2 *-di ami nodibenzyI of the formula with phosphoric acids in the molten state, wherein the reaction is carried out continuously in several stages, wherein a) molten 2,2'-d i ami nodi benzy I and a phosphoric acid, each of which has a temperature of between 160 and 200°C, are fed separately in a molar ratio of diaminodibenzy l: P2O5 of 1 : i to 1:2.5 into the first stage, the neutralization takes place there, with evolution of heat, and the condensation is carried out in the subsequent rea c15 tion stages at a temperature of 260°C to 3 20°C, after which b) tne uncooled reaction mixture from the last stage is transferred continuously into a heated separator and is separated at 1 60°C to 300°C into a product stream con20 taining the upper phase of molten iminodibenzyl and a discharge stream containing, as the lower phase, phosphoric acid and ammonium phosphates.

One of the essential advantages of the process according to the invention is that the heat of neutrali25 zation liberated during the reaction of 2,2'-diaminod1benzyl with the phosphoric acid in the first stage is utilized for further warming to the required reaction temperature. It is thereby sufficient to prewarm the two reaction components to a substantially lower temperature, and in particular only to 160-200°C, than 1s the case with the diphosphate of 2,2’-diami nodibenzyI, which must be warmed to at Least its melting point of 266-268°C.

In additionz if the diphosphate is used as the starting substance, the heat of neutralization cannot be utilized, since this is lost when the diphosphate is isolated.

This results in a particularly advantageous energy oalance for the present process, the saving in energy being about 5 OX of the total energy required for the reaction, so that the process is also distinguished by an exceptionally good profitability.

Optimum utilization of the heat of neutralization liberated for the entire reaction is ensured in the process according to the invention by metering the reaction partners separately and continuously into the reaction space. In contrast to the batchwise processes, in which uniform external supply of heat is possible only with great difficulty, local overheating with simultaneous increased formation of by-products is thereby to be avoided, which means significantly better yields of up to 98.9X are achieved, and in addition the reaction product is already so pure that further purification of the iminodibenzyl is no longer necessary after removal of the phosphoric acid phase. This fact is another decisive advantage of the process, since by eliminating the complicated working up of the reaction mixture by cooling of the mass, extraction of the iminodipenzyl with a solvent, washing with acid and water, drying of the solution and evaporation of the solvent, as described for the batchwise processes, the method of working up is very simple and economical, which means a significant shortening of the total time required is achieved.

An additional shortening of the total time required to prepare the imi nodibenzyI furthermore results from the fact that warming and melting of the reaction components, which, in the case of the batchwise processes, requires a multiple of the time necessary for the actual reaction to give the imi nodibenzy I, takes place in a time sequence parallel to the reaction in the present continuous process and hence requires no additional expenditure on time.

On the basis of the resulting relatively short operating time and on the basis of the possibility described above of optimum control of the temperature program during the reaction by continuously feeding the preheated feed substances separately, it is possible in the present continuous process to achieve far higher space/ time yields, by appropriate dimensioning of the apparatus, than is possible in the discontinuous processes, in which there is always the danger of local overheating.

The 2,2*-di ami nodibenayl employed as the starting substance has been prepared py a method analogous to that in Swiss Patent Specification 331,20? by reduction of 2,2'-dinitrodibenzyl with Raney nickel in organic solution.

Anhydrous phosphoric acid or polyphosphoric acid with a content of 72.4-84X of phosphorus pentoxide is used for the reaction.

When carrying out the process according to the invention, it should be remembered that although heat is formed in the first stage by the neutralisation, the condensation which takes place in the subseouent stages is endothermic, so that there it must be ensured, by corresponding supply of heat, that the required reaction temperature of more than 260e£ is maintained, it i§ particularly advantageous for the reaction components to be introduced into the first stage to be prewarmed over the range of 160-200®g according to the invention to the extent that, by utilising the heat of neutralization, a temperature above the envisaged reaction temperature is established. This excess heat is then available for the endothermic reaction which starts, it is particularly preferable to establish a temperature of 29S=300eG in the first stage and to select a reaction temperature of 28Θ290^c for the subseouent stages.

The process is advantageously carried out in 8-1 S stages, it being advantageous to use, for example, a multi-chasper reactor, the chambers of which are heated, in this reactor, each chamber can be heated separately.

As a result of the measure according to the invention of compensating the increased heat requirement in the suosequent stage or stages By a higher temperature in the first stage, it is advantageously also possiole to subdivide the heating only into zones, for example into two § 20heS a in the course of passage through the reaction Chambers arranged in succession, almost complete reaction v takes place, which means that extremely high yields of imi nodibenzyI are obtained» In a particularly preferred 10 arrangement, the individual reaction chambers are arranged one όή tpp of the other, the 2,2'-di ami nodibenzyI and the phosphoric acid being fed into the reactor from the bottom and, on further passage through the stirred reaction chambers in upward flow, reacting with one another» Preferably 1 to 2 moles, particularly preferably to 1i5 moles, Of phosphoric acid (calculated as PgOg) are added per mole of 2,2'-di ami nodibenzy I in the reaction, since the yield of imi nodibenzyI drops at a molar ratio of less than 1:1. The excess of up to a molar ratio of 1:7 Used in some Of the batchwise processes produces no improvement in yields and in these cases serves, above all, as the solvent for the 2,2'-diami nodibenzyldiphosphate and to achieve a better heat transfer during melting» Separation of the phases, after the reaction has taken place, into an upper phase of molten imi nodibenzy I and a lower phase of phosphoric acid and ammonium phosphates is advantageously carried out at 160-29O°C. Particularly problem-free separation is possible at tempera30 tures from 230 to 250°G.

The process according to the invention is illustrated in more detail by the following examples: Ex amp le 1: .03 nil/minute of 2,2'-d i ami nodi Benzy I prewarmed tb 200°^ and 3.24 ml/minute of anhydrous phosphoric acid prewarmed to 2000c, With a content Of 72.6X of PgOj, corresponding to a molar ratio of diaminodibenzyl to phosphoric acid (based bn the PgOj) of 1:1.25, are introduced continuously into the lower reaction chamber Of a mu Iti-chamber reactor which has a volume of 420 ml and 1s separated into 8 reaction chambers by Daffies. The reaction takes place 1n upward flow, with stirring, with passage through all the reaction chambers. The temperature in the lower reaction chamber is 292°C, and that in the upper chambers is 286°C. The average residence time on passage through the apparatus is 46 minutes. The reaction mixture flows continuously from the top chamber into a heated separation vessel in which it is separated into two phases at temperatures of 230 to 250°C. After the separation, both the upper 1 ml nodibenzyI phase and the lower phosphoric acid phase are removed continuously.

After a reaction time of 592 minutes, 2820 g of iminodibenzyl, corresponding to a yield of 98.9%, are obtained.

The data of Examples 2 to 6, in which 2,2'-di ami ηo dibenzyl was reacted with phosphoric acid analogously to Example 1, are given in the following table.

The purity of the imi nodibenzyI was 1n each case measured by gas chromatography and was between 98.9 and 99.7%, and the melting point was 105 to 1 07°C .

Di aminodibenzyI Molar ratio of Residence Temperature Total Iminodibenzyl phosphoric acid diaminodibenzyI: time feed sub- top separa- time g % yiel (ml/minute)P2°5 (minutes) stances bottom tor (minutes) (°C) Example 2 13.1 8.6 1:1.25 18 180 283 291 230-250 657 8040 97.4 Example 3 8.72 1:1.31 26 160 263 160-190 655 4865 95.5 ——— 5.43* 290 Example 4 9.21 1:1.05 26 190 283 210-240 649 4370 90.7 10 5.06 296 Example 5 8.98 1:2.14 26 170 271 230-250 594 4615 96.9 7.77** 290 Example 6*** 12.98 1:0.75 18 200 286 250-290 660 6623 81.0 4.38 292 15 * Phosphoric acid containing 76% of P2O5 ** Phosphoric acid containing- 84% of P^O^ *** Example 6 is not given as being representative and does not illustrate the invention; OD it merely shows clearly that a ratio of at least 1:1 is essential.

Claims (8)

CLAIMS:

1. Process for the preparation of imi nodibenzy l of the formula J by heating 2,2'-di aminobenzyI of the formula H ? N with phosphoric acids in the molten state, wherein the reaction is carried out continuously in several stages, wherei n a) molten 2,2'-d i ami nodi benzy I and a phosphoric acid, each of which has a temperature of between 160 and 200°C, are fed separately in a molar ratio of di ami nodibenzy I: PjOj of 1:1 to 1:2.5 into the first stage, the neutrali zation takes place there, with evolution of heat, and the condensation is carried out in the subsequent reaction stages at a temperature of 260°C to 3 20°C, after which b) the uncooled reaction mixture from the last stage is transferred continuously into a heated separator and is separated at 160°C to 300°C into a product stream containing the upper phase of molten imi nodibenzyI and a discharge stream containing, as the lower phase, phosphoric acid and ammonium phosphates.

2. Process according to claim 1, wherein a temperature of 2 90 to 3 00°C can be established in the first reaction stage and a temperature of 280-290°C is maintained in the subsequent reaction stages.

3. Precess according to claims 1 and 2, wherein the reaction is carried out in 8 to 15 stages.

4. Process according to claims 1 to 3, wherein the 2,2’ -diami nodibenzyI and the phosphoric acid (calculated as P2O5) are employed in a molar ratio of 1:1 to 1:2.

5. Process according to claim 4, wherein the 2,2'diaminodibenzyl and the phosphoric acid (calculated as PjOj) are employed 1n a molar ratio of 1:1 to 1:1.5.

6. Process according to claims 1 to 5, wherein the 5 separation Into the product stream and discharge stream 1s carried out at a temperature of 250 to 250°C.

7. A process according to claim 1 for the preparation of iminodibenzyl, substantially as hereinbefore described and exemplified.

8. Iminodibenzyl whenever prepared by a process claimed 10 in a preceding claim.