Process for the production of N,N-carbonyl diimidazole

Details Process for the production of N,N-carbonyl diimidazole Process for the production of N,N-carbonyl diimidazole

2001-10-24

2002-09-24

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06455702

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is concerned with the production of N,N-Carbonyl diimidazole by a simple, safe and economically viable method utilizing commercially available and less toxic chemicals. The N,N-Carbonyl diimidazole is required in synthesis of activated esters of carboxylic acids to manufacture their amide
i
and ester
ii
derivatives by the reaction of active ester with an amine or a hydroxy function-bearing compound. Active esters are the intermediates in the synthesis of various pharmaceuticals such as Viagra™ (Sildenafil)
iii
etc., and other important chemicals, intermediates and products such as biologically active peptides or biopharmaceuticals. It is also used in the conversion of amines into corresponding isocyanate
iv
and acids into hydrazides
v
. Recently N,N-Carbonyl diimidazole has also been found useful in synthesis of anticancer
vi
and antifungal
vii
compounds and in the development of a novel artificial matrix with cell adhesion peptides for cell culture and artificial and hybrid organs
viii
.
DESCRIPTION OF RELATED ART
A current method for the preparation of N,N-Carbonyl diimidazole is by the reaction of Imidazole dissolved in anhydrous tetrahydrofuran and dangerously lethal gas PHOSGENE to obtain crude Carbonyl-diimidazole in 88% yield
ix
as summarized below:
One of the serious drawbacks of this method is the gaseous and lethal nature of Phosgene, which is required in several folds excess to affect the completion of reaction. It is dangerous and uneconomical to store and handle phosgene.
It is the objective of the present invention to provide a safe and economic process for producing N,N-carbonyl diimidazole.
SUMMARY OF THE INVENTION
In accordance with the present invention, N,N-carbonyl diimidazole is produced by the reaction of imidazole with bis (trichloromethyl) carbonate with the exclusion of moisture. The reaction is summarized as follows:
1. This invention provides an economical and safer method for the production of N,N-carbonyl diimidazole.
2. This invention provides methods for reacting imidazole with bis (trichloromethyl) carbonate in the presence or absence of a solvent.
3. It provides methods for the removal of byproduct imidazole hydrochloride and isolation of N,N-Carbonyl diimidazole.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Reaction of imidazole with bis (trichloromethyl) carbonate produces carbonyl diimidazole and crystalline imidazole hydrochloride. Insoluble imidazole hydrochloride is removed from the reaction mixture quantitatively by filtration and the carbonyl diimidazole is recovered by removing the solvent or crystallization under cooling or a combination thereof.
The solvents used in the procedure of this patent can be an aromatic solvent i.e., benzene, toluene, xylene or their derivatives, a chlorinated solvent i.e., chloroform, dichloromethane, carbon tetrachloride or tetrahydrofuran (THF), dimethyl tetrahydrofuran or their derivatives or other solvents such as dimethylsulfoxide (DMSO), acetonitrile, dioxane or diphenyl ether or any aprotic solvent or a combination thereof.
The ratio of imidazole to bis (trichloromethyl) carbonate may vary from 0.05 to 2.0 moles of bis (trichloromethyl) carbonate for every mole of imidazole, however 0.83 moles of bis (trichloromethyl) carbonate for every mole of imidazole is preferred. The reaction temp. may vary from −10 to 70° C. but the preferred temp is between 20 and 40° C. The time for the reaction varies with solvents and the temperature used and, however a reaction time of 0.5-60 minutes is preferred.
The method of reacting imidazole with bis (trichloromethyl) carbonate can be varied. For example:
a) Imidazole and bis (trichloromethyl) carbonate are added simultaneously into an appropriate solvent and allowed to react and after the reaction is over byproduct imidazole hydrochloride is removed by filtration and N,N-Carbonyl diimidazole is recovered from the solvent following procedure described below.
b) A solution of imidazole is added to a solution of bis (trichloromethyl) carbonate or vice versa and allowed to react and after the reaction is over byproduct imidazole hydrochloride is removed by filtration and N,N-Carbonyl diimidazole is recovered from the solvent following procedure described below.
c) Imidazole and bis (trichloromethyl) carbonate in their solid forms are mixed mechanically in the absence of a solvent and allowed to react and after the reaction is completed, an anhydrous aprotic solvent as defined above is added to the molten reaction mixture. The separated solid imidazole hydrochloride is removed filtration and N,N-Carbonyl diimidazole is recovered from the solvent following procedure described below.
d) continuous and simultaneous addition and reaction of a solution of bis (trichloromethyl) carbonate and a solution of imidazole, comprising. removing by-product imidazole hydrochloride from the reaction stream continuously and recovering N,N-carbonyl diimidazole from the reaction stream;
Recovery of the N,N-Carbonyl Diimidazole from the Filtrate
The N,N-Carbonyl diimidazole can be isolated from the filtrate obtained from the processes described above in the following ways:
a) The solvent is removed by distillation under reduced pressure and temperatures lower then 55° C. and the crystallized N,N-Carbonyl diimidazole is collected by filtration and further drying under high vacuum and temperatures below 55° C. The overall yield of N,N-Carbonyl diimidazole is 75 to 99%.
b) Alternatively N,N-Carbonyl diimidazole can be removed from the reaction mixture by chilling the filtrate obtained above, the crystallized product was obtained by filtration and further drying of the solid under high vacuum and temperatures below 55° C. The overall yield of N,N-Carbonyl diimidazole obtained following above method is 75 to 99%.
c) N,N-Carbonyl diimidazole can also be recovered from the filtrate obtained above by a combination of evaporation of solvent and chilling to crystallize the product.
d) Total evaporation of the solvent under carefully controlled condition also provides N,N-Carbonyl diimidazole in quantitative yield.
e) N,N-Carbonyl diimidazole can also be isolated from the filtrate obtained at the end of reaction by diluting it with a solvent such as hexane or any other aprotic solvent, presence of which causes the precipitation of N,N-Carbonyl diimidazole from he reaction mixture followed by filtration and drying following the conditions described above.
This newly developed method is safer, efficient and environmentally friendly method due to the following facts:
Since bis(trichloromethyl) carbonate is a solid and is stable at, normal temperatures, it is safe to use under standard laboratory or manufacturing conditions. It can be weighed exactly and does not require to be used in more than required quantities, unlike phosgene, which due to its gaseous nature must be used in large excess. Bis(trichloromethyl) carbonate does not require any additional safety measures as required for phosgene and the training of the involved personnel. It easily decomposes in presence of water into harmless carbon dioxide and water-soluble hydrochloric acid. The hydrochloric acid solution can easily be converted into harmless brine solution.
The invention is exemplified by the following:


REFERENCES:
patent: 3868458 (1975-02-01), Baker et al.
patent: 3991071 (1976-11-01), Brookes et al.
patent: WO98/31672 (1998-07-01), None
patent: WO00/06551 (2000-10-01), None

Affiliated with

Also associated with

Rating

Process for the production of N,N-carbonyl diimidazole does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the production of N,N-carbonyl diimidazole, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the production of N,N-carbonyl diimidazole will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2816280