Method for the preparation of furan-2-carboxylic acid amide and the corresponding furan-2-carboxylic acid

Furan-2-carboxylic acid-amide and the corresponding furan-2-carboxylic acid are prepared by contacting carbamoyl chloride and furan at a temperature in the range of from about 10.degree. to about 30.degree. C. in a suitable reaction medium.

This invention relates to the preparation of furan-2-carboxylic acid-amide 
and the corresponding furan-2carboxylic acid. 
THE INVENTION 
This invention involves the discovery that furan-2-carboxylic acid-amide 
and the corresponding acid can be formed in good yield and high purity by 
the simple expedient of contacting carbamoyl chloride and furan at a 
temperature in the range of from about 10.degree. to about 30.degree. in a 
suitable reaction medium to form the 2-acid-amide which can then be 
hydrolyzed to the acid. This reaction is accomplished without the 
necessity of a catalyst and furthermore only 2-substituted products are 
formed. 
The process of this invention may be generally depicted by the following 
equation: 
##STR1## 
In the process furan-2-carboxylic acid-amide can be isolated from the 
reaction mixture and then hydrolyzed to the corresponding acid in a 
separate container; preferably the acid-amide is converted directly to the 
acid in the same vessel without the necessity of isolating the acid-amide. 
This can be accomplished by the addition of base to the medium in order to 
hydrolyze the amide to the acid. 
In practicing this invention, contacting the furan and carbamoyl chloride 
should be effected within a temperature range so that the carbamoyl 
chloride is not substantially degraded. Preferably the furan and carbamoyl 
chloride are contacted at temperatures in the range of from about 
10.degree. to about 30.degree. C. and most preferably between 15.degree. 
and 25.degree. C. 
Suitable reaction media are those which facilitate the contacting of the 
reactants without interfering with the desired reaction. Accordingly, in 
the process use is made of a liquid inert reaction medium or diluent. 
Among the suitable solvents which may be used are saturated, halogenated 
hydrocarbons such as carbon tetrachloride, chloroform, methylene chloride, 
1,2-dichloroethane, and the like; saturated or aromatic ethers such as 
diethyl ether, dioxane, dimethoxyethane, anisole, diphenyl ether, and the 
like; saturated hydrocarbons such as n-pentane, n-hexane, n-octane, 
n-decane, cyclopentane, cyclohexane, and the like; nitro compounds such as 
nitrobenzene, nitromethane, and the like; acetonitrile; acetic anhydride; 
and chlorinated aromatics such as chlorobenzene, and the like. Naturally, 
use should be made of compounds which exist in the liquid state at the 
reaction temperature and afford sufficient solvency for the reactants at 
the desired temperature. Compounds which contain olefinic unsaturation, or 
other functionality reactive with carbamoyl chloride are not desirable. 
Preferred solvents are those which have normal boiling points between 
about 10.degree. and about 60.degree. C., as these facilitate workup 
procedures. Methylene chloride is a particularly preferred solvent for use 
in the process because of its low cost, availability and favorable boiling 
characteristics. The amount of the liquid reaction medium used is 
generally discretionary; preferably the amount of solvent falls within the 
range of 50 to 300 mole percent based on the number of moles of the furan 
being used. If desired, amounts of solvent above or below the preferred 
amounts can be successfully employed. It will be appreciated that the 
reaction system should be essentially anhydrous. 
The ratio of carbamoyl chloride to furan used may vary widely, however, it 
is preferred that this ratio be at least stoichiometric and in a 
particularly preferred embodiment a 10 to 20 percent excess of carbamoyl 
chloride is used. 
Contacting of furan with carbamoyl chloride to form the acid-amide 
generally involves reaction periods falling within the range of from about 
6 to about 20 hours, with 10 to 14 hours being preferred. The termination 
of the amidization reaction may be determined by monitoring the amount of 
HCl given off or by other means known to the art. At termination, or at 
any point desired during the reaction, workup of the product is 
accomplished by decomposition of any unreacted carbamoyl chloride, removal 
of any unreacted furan and conversion of the acid-amide to the 
corresponding acid. Preferably this workup is carried out in the order 
recited although deviations from this workup order permit production of 
the acid. For example, it may be desirable to remove unreacted furan prior 
to decomposition of the carbamoyl chloride. 
Decomposition of the carbamoyl chloride is preferably effected by addition 
of an excess amount of water (i.e., a 0.8 to 100 mole percent excess above 
the theoretical stoichiometric amount necessary on the basis that one mole 
of water is required to decompose one mole of carbamoyl chloride) having a 
temperature of below 10.degree. C. and preferably below about 5.degree. C. 
Decomposition of the carbamoyl chloride by water yields ammonium chloride 
and carbon dioxide. Unreacted furan can be removed by means known to the 
art such as application of a vacuum to the reaction vessel or by the 
introduction of steam into the unreaction medium. The acid-amide can then 
be converted to the corresponding acid salt by the addition of an excess 
of a base, i.e., about 10 to about 15 percent excess based on the amount 
of acid-amide formed. Preferably, an inorganic base such as sodium 
hydroxide, potassium hydroxide, ammonia and the like is employed, with 
sodium hydroxide being particularly preferred. The product 
furan-2-carboxylic acid can then be isolated by addition of an acid 
(preferably an inorganic acid such as HCl, H.sub.2 SO.sub.4, SO.sub.2 and 
the like) followed by extraction and separation by means known in the art. 
For example, an extraction solvent such as diethyl ether, chloroform, and 
the like is added to the mixture containing the acid, the phase containing 
the acid is then removed, e.g., by decantation and the product 
furan-2-carboxylic acid is isolated by distillation of the extraction 
solvent. 
Another method of converting the acid-amide to the acid entails addition of 
an excess amount of water having a temperature below 10.degree. C. to 
decompose any residual carbamoyl chloride followed by saponification or 
hydrolysis of the acid-amide to the acid salt. This is effected by 
addition of an excess of base (preferably an inorganic base, and most 
preferably sodium hydroxide) at temperatures up to about 120.degree. C. 
(preferably between about 4 and 18 hours). Any unreacted furan and 
unhydrolyzed acid-amide is then extracted with an inert, liquid solvent 
(e.g., a lower aliphatic halogenated hydrocarbon such as chloroform) 
followed by acidification of the acid salt. As above, the acid salt is 
preferably converted to the corresponding acid by addition of an inorganic 
acid such as HCl, H.sub.2 SO.sub.4, SO.sub.2 and the like. The product 
furan-2-carboxylic acid is then easily re-extracted with an inert, liquid 
solvent such as chloroform, diethyl ether and the like. The 
furan-2-carboxylic acid is then isolated by means known in the art such as 
distillation. 
Furans which may be used in the process of this invention include furan, 
nitrofuran or alkyl furans having the formula 
##STR2## 
wherein R.sub.1 and R.sub.2 are, independently, hydrogen, nitro or alkyl 
each having up to about 3 carbon atoms with the proviso that at least one 
of the positions adjacent the oxygen atom carries a hydrogen substituent. 
Carbamoyl chloride (NH.sub.2 COCl) is an unstable, colorless, pungent 
smelling liquid. It reacts explosively with water to give ammonium 
chloride and carbon dioxide and it decomposes visibly on standing. It can 
be stabilized by deep freezing and for a limited time (around 24 hours) by 
moderate cooling in solution with 1,2-dichloroethane or other solvents. L. 
Gattermann prepared this chloride for the first time in 1888 in a 
batch-wise manner by passing a stream of phosgene gas over heated aluminum 
chloride. Today, carbamoyl chloride is normally prepared continuously by 
reacting ammonia with phosgene in equal molar ratio at about 500.degree. 
C. See Hopf, Ohlinger, and Angew. Chem., 61 (5), 183 (1949). 
A particular embodiment of the present invention is illustrated in the 
following example.

EXAMPLE 
Carbamoyl chloride (7.94 grams, 0.1 moles) and furan (6.8 grams, 0.1 moles) 
in 10 ml (13.3 g, 0.16 moles) of methylene chloride were reacted for a 
period of about 12 hours at about 20.degree. C. in a reaction vessel 
immersed in an ice-water bath. An excess of water having a temperature of 
about 3.degree. C. was then added to the reaction mixture in order to 
decompose the unreacted carbamoyl chloride. After cessation of the 
vigorous decomposition reaction, steam was introduced into the reaction 
milieu for a period of 60 minutes in order to remove the unreacted furan. 
A 15 percent molar excess of sodium hydroxide (based on the amount of 
acid-amide produced) was then added to the reaction medium and this 
mixture was refluxed for 4 hours. After cooling, the reddish solution was 
freed from unhydrolyzed amide by extraction with chloroform followed by 
distillation of the chloroform to yield 1.7 grams of the amide. 
Subsequently, the amide-free solution was acidified using 20 percent 
hydrochloric acid. 3.3 Grams of furan-2-carboxylic acid were isolated by 
extraction with chloroform followed by water removal and distillation of 
the chloroform. The total yield of furan-2-carboxylic acid and 
furan-2-carboxylic acid-amide was 5 grams (0.0447 moles). Based on the 
total number of moles of furan used (0.1 moles), the yield was 44.7%. 
The carboxylated furans disclosed herein are useful as intermediates for 
organic synthesis, especially in the preparation of oxygen containing 
drugs. For example, 5-nitrofuran is carboxylated to form 2-carboxylic 
acid-5-nitrofuran followed by reduction of the carboxyl group to an 
aldehyde functionality to form 5-nitrofurfural. Derivatives of this 
compound (e.g., nitrofuroxime) are known to possess both bacteriostatic 
and bacteriocidal properties. See Lednicer and Mitscher, The Organic 
Chemistry of Drug Syntheses, John Wiley and Sons, pp. 228-232 (1977).