Process for preparing carbamoyl pyridinium compounds

Details Process for preparing carbamoyl pyridinium compounds Process for preparing carbamoyl pyridinium compounds

1999-12-20

2001-05-29

Aulakh, Charanjit S. (Department: 1612)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S314000

Reexamination Certificate

active

06239281

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to an improved process for preparing carbamoyl pyridinium compounds using novel solvent/fatty amine reaction system.
BACKGROUND OF THE INVENTION
The use of carbamoyl pyridinium compounds as cross-linking agents in photographic applications is known. See, for example, U.S. Pat. No. 4,063,952, which discloses carbamoyl pyridinium compounds having pyridine rings which carry a sulfo or sulfoalkyl group. According to the '952 method, the alkali metal salt of a starting pyridine compound is reacted with a carbamoyl halide in the presence of a solvent mixture comprising dimethylformamide and methanol, and the reaction product is actively precipitated by the addition of ethyl ether. The alkali metal halide by-product of this reaction precipitates with the desired carbamoyl pyridinium compound.
The carbamoyl pyridinium compounds of the '952 patent are described by the formula:
wherein:
R
1
and R
2
each represents an alkyl group, an aryl group, or an aralkyl group, or R
1
and R
2
together represent the groups required to complete a piperidine or a morpholine ring;
R
3
represents hydrogen, methyl or ethyl;
R
4
represents methylene, ethylene, propylene or a single chemical bond;
Me
+
represents an alkali metal cation such as Li
+
, Na
+
or K
+
; and
X
−
represents an anion such as Cl
−
or Br
−
.
J01-066,162 also describes the synthesis of carbamoyl pyridinium compounds having a pyridine ring which carries a sulfo or sulfoalkyl group. This process comprises forming the inner salt of a pyridine sulfonic acid in the presence of a tertiary amine and reacting the inner salt with a carbamoyl chloride. By this synthesis, carbamoyl pyridinium compounds free of inorganic salts, e.g., NaCl and KCl, are obtained.
DD 290,879 further describes the synthesis of carbamoyl pyridinium compounds having pyridine rings which carry a sulfo or sulfoalkyl group. This process, which involves reacting a pyridine sulfonic acid with a carbamoyl halide using a nitrile solvent and a tertiary amine, produces a tert-amine hydrochloride by-product. Acetonitrile, propionitrile, butyronitrile and benzonitrile are mentioned as suitable solvents. The object of this process is to provide a nitrile solvent in which the reactants and the tertiary amine hydrochloride by-product are soluble, and the carbamoyl pyridinium compounds are insoluble. It has been found, however, that carbamoyl pyridinium compounds prepared via this process still contain, after the reaction, significant amounts of by-product, which must be eliminated via subsequent washing steps with the nitrile solvent. The yield of the desired carbamoyl pyridinium compound is consequently lowered.
U.S. Pat. No. 5,559,239 discloses a process for preparing carbamoyl pyridinium compounds which involves reacting a pyridine sulfonic acid with a carbamoyl halide in the presence of triethylamine and a ketone (e.g. acetone) solvent. A mixture of the desired carbamoyl pyridinium compound and the tert-amine hydrochloride by-product is recovered from the reaction mixture and the carbamoyl pyridinium compound must then be separated from the by-product using a selective solvent, such as methanol. This second separation step increases the overall process cost and tends to lower yields. It is also believed that methanol washing may be detrimental to product quality.
SUMMARY OF THE INVENTION
The present invention is directed to an improved process for the preparation of carbamoyl pyridinium compounds which comprises reacting a pyridine sulfonic acid with a carbamoyl halide in a by-product solubilizing solvent, such as tetrahydrofuran, methyl t-butyl ether, 1-methyl-2-pyrrolidinone, dimethyl carbonate, dioxane, anisole, dichloroethane, dichloromethane, ethyl acetate, chlorbenzene, toluene or heptane, using a tertiary-amine (e.g. tributylamine) acid scavenger. The tertiary amine hydrohalide by-product formed by this process is solubilized by the chosen solvent, thereby substantially eliminating the need to separate the desired carbamoyl pyridinium from the amine hydrohalide by-product, as described in various prior art processes. Prior art carbamoyl pyridinium/amine hydrohalide separation steps generally remove product, thereby lowering yields.
Thus, the solvent/amine system of the instant process is more efficient in that it generally obviates the dual isolation sequence represented by the process of the '239 patent while providing high yields and purity.
DETAILED DESCRIPTION OF THE INVENTION
Other than in the Examples, or where otherwise indicated, all numbers quantifying ingredients, amounts, dimensions, reaction conditions, etc., used herein are to be understood as modified in all instances by the term ‘about’.
The process of the instant invention comprises the steps of:
a) reacting a pyridine sulfonic acid compound with a carbamoyl halide in the presence of an effective amount of a by-product solubilizing solvent and an effective amount of a tertiary amine acid scavenger, thereby forming a reaction product comprising a carbamoyl pyridinium compound, a tertiary amine hydrohalide by-product and said by-product solubilizing solvent, wherein said amine hydrohalide by-product is substantially soluble in said by-product solubilizing solvent and said carbamoyl pyridinium compound is substantially insoluble in said by-product solubilizing solvent; and
b) separating said carbamoyl pyridinium compound from said reaction product.
As used herein, the term “by-product solubilizing solvent” means any solvent or solvent composition that is a suitable medium for carrying out the reaction of step a), which has substantial solvating activity towards the tertiary-amine hydrohalide by-product thereby produced, and in which the desired carbamoyl pyridinium compound is substantially insoluble. Solvents believed to be suitable for use in the instant process are selected from the group consisting of: tetrahydrofuran, methyl t-butyl ether, 1-methyl-2-pyrrolidinone, dimethylcarbonate, dioxane, anisole, dichloroethane, dichloromethane, ethyl acetate, chlorobenzene, toluene and heptane. Dichloroethane is a preferred solvent. Due to the solvating characteristics of the instant solvents, separation of the insoluble carbamoyl pyridinium compound from the reaction product can be accomplished in one (1) step via any suitable separation technique, such as filtration or centrifugation.
Optionally, a washing step can be utilized after separation of the carbamoyl pyridinium compound from the reaction product. In this optional step, a washing solvent can be used to prepare a purified final product. This step preferably comprises filter washing the desired carbamoyl pyridinium compound with a washing solvent having solvating activity towards residual reaction impurities, such as unreacted pyridine sulfonic acid and/or tert-amine hydrohalide by-product, but which does not substantially solubilize the desired carbamoyl pyridinium compound. Suitable washing solvents include, but are not limited to, toluene, acetone, isopropyl alcohol, and dichloroethane, with toluene being preferred. An effective amount of washing solvent is used, i.e. that amount necessary to remove impurities from a given carbamoyl pyridinium compound to the desired extent. An effective amount of washing solvent for a given system can be readily determined by a skilled artisan.
Carbamoyl halides useful in the instant process correspond to the following formula:
in which:
R
1
and R
2
(which may be the same or different) each represents an alkyl group having: from 1 to 10 carbon atoms (e.g., methyl, ethyl, 2-ethylhexyl), an aryl group having from 6 to 15 carbon atoms (e.g., phenyl, naphthyl), aralkyl group having from 7 to 15 carbon atoms (e.g., benzyl, phenethyl), or R1 and R2 together form the atoms required to complete a heterocyclic ring (e.g., pyrrolidine, morpholine, piperidine, piperazine, 1,2,3,4-tetrahydroquinoline ring, etc.). X represents an halogen atom (e.g., Cl, Br).
When the term “group” or “ring” is used relative to the

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