# Patent

## Title
Process for preparing a catalyst for conversion of cyanopyridines to nicotinamides

## Abstract

Nicotinamides and isonicotinamides, used in the preparation of anti-TB drugs i.e. isoniazid and as an intermediate of vitamin B12 are prepared from cyanopyridines and nicotinamides. Catalysts useful for the preparation of nicotinamide and isonicotinamide.

## Background
RELATED APPLICATION
This is a division of parent application Ser. No. 11/124,142 filed May 9, 2005, now U.S. Pat. No. 7,345,176, which is a continuation application of Ser. No. 10/392,388 filed Mar. 20, 2003, now abandoned, the priority of which is hereby claimed under 35 U.S.C. §120.


FIELD OF THE INVENTION
The present invention relates to an improved process for conversion of cyanopyridines to nicotinamides. More particularly the present invention relates to the preparation of nicotinamides and isonicotinamides which are used to prepare an anti-TB drug i.e. isoniazid and as an intermediate of vitamin B12. The present invention also relates to a process for preparing a catalyst useful for the preparation of nicotinamide and isonicotinamide.
BACKGROUND OF THE INVENTION
Reference is made to Bull. Chem. Soc., Japan, Vol.-40, P-1660 (1967) wherein nickel oxide has been used as a catalyst for the hydration of 3-cyanopyridine to nicotinamide. The drawbacks are that the catalytic activity was reported to be low and the yield of nicotinamide was also low. Reference is also made to U.S. Pat. No. 4,008,241 to Gelbein et al for the production of nicotinamide from 3-cyanopyridine by an aqueous ammonia solution. The reaction temperature was 90-150° C., the reaction time was 4-8 hours and the ammonia concentration was 3-8 molar. The maximum conversion of 3-cyanopyridine was about 70%. The hydrolysis was also effected in the presence of ammonium nicotinate in an amount sufficient to essentially eliminate production thereof to produce a hydrolysis effluent containing nicotinamide, ammonia, unconverted 3-cyanopyridine and ammonium nicotinate, at a nicotinamide selectivity of essentially 100%. Further, in this process unconverted 3-cyanopyridine and ammonia were separated from the product nicotinamide by a multi-step separation process which is not cost effective and is a very difficult procedure to obtain the pure product. These are the main drawbacks of the above process.
Prior art also discusses the hydration of nitrites to amides. The conversion of nitrites to amides has been achieved by both chemical and biological means. Japanese Patent 93-206579, August, 1993, H. Hirayama (To Showa Denko K.K., Japan), European Patent 85-306670, Sep., 19, 1985, S. Asano and J. Kitagawa (to Mitsui Toatsu Chemicals Inc.) describe the use of a modified Raney Nickel Catalyst for this reaction. WO 90/09988 A1, Sep., 17, 1990, of A. McKillop and D. Kemp. (to Interlex Chemicals, Ltd.) describes the use of alkali metal borates for this reaction. U.S. Pat. No. 2,471,518, May 31, 1949 (to Pyridium Company); U.S. Pat. No. 4,721,709, Dec. 6, 1988 (to Standard Oil Company); German Patent Application 2,517,054, Apr. 17, 1975, (to Degussa Company), discuss the hydrolysis of 3-cyanopyridine in presence of sodium hydroxide. The use of a magnesium oxide catalyst for this hydration reaction are discussed in Chemical Engineering Science, 35, 330, 1975, by C. B. Rossa and G. B. Smith. Alkaline hydrolysis of 3-cyanopyridine to nicotinamide of the Degussa process is one of the most important commercial processes adopted by some firms in India. However, this process has some disadvantages i.e., the yield of nicotinamide is not very high and the conversion of 3-cyanopyridine is about 99%. The reaction has been conducted at a higher reaction temperature with an appreciable alkali concentration. Nicotinic acid is also produced with nicotinamide in the above process.
British Patent 1,133,013; 1968, describes the catalytic hydration of nitriles by manganese dioxide. Manganese dioxide has been prepared by the Redox method using potassium permanganate and manganese sulphate in an alkaline medium. The hydration of 3-cyanopyridine has been conducted using a catalyst to 3-cyanopyridine mole ratio of 2.16:1, and the yield is only 79.28 mole %. The process i.e., conversion of 3-cyanopyridine to nicotinamide, is similar to the conversion of 4-cyanopyridine to isonicotinamide. Manganese dioxide has been prepared by the Redox method using potassium permanganate and manganese sulphate in an alkaline medium. The main drawbacks of the process are that (a) the yield of isonicotinamide is less (b) it is not eco-friendly and (c) the amount of catalyst per mole of the feed for conversion is quite high.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide an improved process for conversion of cyanopyridines to nicotinamides.
Another object of the present invention is to provide a process for synthesis of nicotinamide from 3-cyanopyridine and isonicotinamide from 4-cyanopyridin using specially prepared Manganese Dioxide as the catalyst which obviates the drawbacks as detailed above.
Yet another object of the present invention is to use a specially prepared manganese dioxide catalyst of specific characteristics for the hydration of 3- and 4-cyanopyridines to nicotinamide and isonicotinamide respectively with high conversion and selectivity.
SUMMARY OF THE INVENTION
Accordingly, the invention provides a process for conversion of cyanopyridines to nicotinamides comprising dissolving the cyanopyridine in water; adding a transition metal catalyst prepared in neutral medium, refluxing the reaction mixture, cooling, filtering and washing the resultant mixture and evaporating the filtrate to dryness to obtain the product.
In another embodiment of the invention, the refluxing temperature is in the range of 100 to 115° C. and the refluxing time is in the range of 6 to 15 hours.
In one embodiment of the invention, the amount of cyanopyridine dissolved in water is in the range of 0.8 to 2.0 moles for every 1.5 to 8.0 moles of water and a transition metal oxide catalyst is added to in an amount in the range of 0.01 to 0.03 moles.
In another embodiment of the invention, the catalyst used is manganese dioxide.
In another embodiment of the invention, the manganese dioxide catalyst is prepared by a Redox method using a potassium permanganate and manganese chloride solution in neutral medium.
In another embodiment of the invention, the produced nicotinamide is more than 99% pure as confirmed by melting point determination and by FTIR Spectroscopy.
The present invention also relates to a process for preparation of a catalyst useful for the preparation of nicotinamide and isonicotinamide which comprises reacting a potassium permanganate and manganous salt solution in a neutral medium by drop-wise addition of the aqueous solution of manganous salt to the aqueous solution of potassium permanganate with constant stirring, allowing the reaction mixture to stand, filtering the precipitate of MnO2 and washing with distilled water, drying the precipitate to obtain the catalyst.
In one embodiment of the invention, the drop-wise addition of the aqueous solution of manganous salt to the aqueous solution of potassium permanganate is carried out at a temperature in the range of 30 to 80° C. and for a time period in a range of 30 minutes to 1 hour.
In another embodiment of the invention, the reaction mixture is allowed to stand for a time period in the range of 10 to 15 hours.
In yet another embodiment of the invention, the precipitate of manganese dioxide is dried in an air oven at 110° C. for 3-4 hours.
In another embodiment of the invention, the manganous salt is selected from manganese chloride and manganese sulphate.


DETAILED DESCRIPTION OF THE INVENTION
It is known to prepare solid oxide catalyst generally by, for example, by calcining the hydroxide, to convert it to the corresponding oxide. The hydroxide can be formed in the simplest embodiment, by means of normally referred to as precipitation. Such a precipitation method comprises adding to an aqueous solution containing dissolved therein water soluble inorganic or organic salts of manganese, for examples halide, nitrate, sulphate, formate, acetate, oxalate, a water soluble basic substance preferably an alkali metal hydroxide, carbonate or bicarbonate such as NaOH, KOH, Na2 CO3, NaHCO3 and ammonium carbonate or bicarbonate to cause the precipitation of the hydroxide, filtering the resulting hydroxide, washing the remaining solid with water and drying the product.
The process steps for the preparation of the catalyst employs a Redox method using an oxidising agent like KMnO4 and a reducing agent like manganous salt, i.e. manganese chloride in a neutral medium. While the catalyst used in this invention can be prepared by any of the above-described methods, a catalyst prepared by the Redox method in a neutral medium is preferred.
Manganese dioxide catalyst has also been prepared by other methods i.e. heating Mn(NO3)2×H2O, by reacting manganese acetate, sulphuric acid and potassium persulphate. Manganese dioxide catalyst prepared by the Redox method using potassium permanganate and manganese chloride in a neutral medium showed the highest activity and selectivity in the hydration of 3- and 4-cyanopyridines to isonicotinamide. The purity of isonicotinamide is confirmed by determining its melting point and by FTIR Spectroscopy. The maximum yield of isonicotinamide achieved so far is 110-112% (wt. %)(90.2-91.8 mole %).
The present invention also provides a process for preparation of a catalyst useful for the conversion of 3- and 4-cyanopyridines to nicotinamide and isonicotinamide respectively which consists of employing a Redox Method using a potassium permanganate and manganese chloride solution in a neutral medium. The process consists of the drop-wise addition of an aqueous solution of manganese sulphate to an aqueous solution of potassium permanganate at a temperature in the range of 70 to 80° C. with constant stirring for a time period in the range of 30 minutes to one hour, it is left standing for a time period in the range of 10 to 15 hours, filtering the precipitate of MnO2 and washing it with distilled water until the filtrate becomes sulphate free, drying the precipitate in an air oven at 110° C. for three hours; dissolving the cyanopyridines (in the range of 0.8 to 2.0 moles) in water in the range of 1.5 to 8.0 moles; the addition of a specially prepared manganese dioxide in the range of 0.01 to 0.03 moles; refluxing the reaction mixture at a temperature in the range of 100 to 115° C. for a time period in the range of 6 to 15 hours; cooling, filtering and washing (with water) the resultant mixture and evaporating the filtrate to dryness to obtain the product.
The manganese dioxide is preferably prepared by the Redox method using a potassium permanganate and manganese chloride solution in a neutral medium. The catalyst so developed for the above conversions is an inexpensive, water insoluble transition metal oxide, particularly a manganese dioxide catalyst of specific characteristics due to its generation of more hydroxyl groups characterized by a broad I.R. band in the region 3100-3600 cm−1. The separation of the catalyst from the hydration effluent is very much easier.
The nicotinamide produced using this catalyst is more than 99% pure; this purity has been confirmed by melting point determination and also by FTIR Spectroscopy analysis.
The mechanism of hydration using the manganese dioxide catalyst is explained as follows:
The role of manganese in the reaction has not yet been elucidated. It may be postulated that since the reaction is bi-phasic, adsorption of the substrate is followed by hydrolysis and subsequent desorption of the product. More easily hydrolysable compounds are, however, those that would be expected to form the most stable carbonium ion, which may perhaps play an important role in the reaction mechanism. The peculiar effectiveness of the manganese dioxide may in part be related to the fact that as ordinarily prepared by precipitation and it is a ‘non-stoichiometric’ compound, has oxygen content slightly less than that corresponding to the dioxide and also contains water (3-4%) which cannot be removed thermally without further loss of Oxygen (J. T. Grey, J. Amer. Chem. Sec., 1946,68,605). The water is present probably as an hydroxyl group linked to manganese. To confirm this statement, I.R of different samples of MnO2 prepared by different methods were recorded and in some cases broad bands in the region 3100-3600 cm−1 were observed indicative of the presence of hydroxyl groups. The formation of hydroxylated intermediates may be assisted, if not caused, by these hydroxyl groups in manganese dioxide resulting in the formation of amides.
The novelty of the present invention resides in preparing the catalyst manganese dioxide in a neutral medium, having 100% selectivity, which is useful for the conversion of 3- and 4-cyanopyridines to nicotinamide and isonicotinamide respectively without use of an alkali or an acid in comparison to prior art catalysts, which necessitates an extremely complicated and cumbersome separation procedure for the conversion. This catalyst eliminates the formation of nicotinic acid in comparison to prior art catalysts.
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLE 1
125 ml of 0.471 molar aqueous solution of manganese sulphate was added drop-wise to 150 ml of 0.395 molar aqueous solution of potassium permanganate at 80° C. with constant stirring for an hour and left standing for 15 hours. The precipitate of MnO2 was filtered and washed with distilled water until the filtrate became sulphate free. The precipitate was dried in an air oven at 110° C. for three hours. The weight of manganese dioxide was observed to be 0.1497 mole.
0.096 mole of 3-cyanopyridine was dissolved in 5.556 mole of water and 0.0115 mole of MnO2, prepared by above method, was added to this. The mixture was refluxed at 105° C. for 8 hrs. The reaction mixture was cooled and filtered. The filtrate was evaporated in dryness to get solid nicotinamide 0.095 mole. Yield of isonicotinamide was 98.9 mole %.
EXAMPLE 2
115 ml of 0.649 molar aqueous solution of potassium permanganate was added drop-wise to 225 ml of 0.5 molar aqueous solution of manganese chloride at 70° C. temperature with vigorous stirring. The addition was continued for 1 hour and kept standing for 15 hours. The precipitate of manganese dioxide was filtered, washed with distilled water to make it chloride ion free. The precipitate was put in an air oven at 110° C. for 3 hours and the weight of MnO2 was 0.189 mole.
0.096 mole 3-cyanopyridine was dissolved in 4.55 mole of water and 0.0115 mole of MnO2 which was prepared by above method was added to this. The mixture was refluxed at 100° C. for 13.5 hrs. The reaction mixture as cooled and filtered. The filtrate was evaporated to dryness to get solid nicotinamide 0.0879 mole. Yield of nicotinamide was 91.56 mole %.
EXAMPLE 3
225 ml of 0.332 molar aqueous solution of potassium permanganate was added to 100 ml of 1.125 mole aqueous solution of manganese chloride with continuous stirring at 30° C. The produced manganese dioxide was filtered, then washed with distilled water till free from chloride ions. The precipitated manganese dioxide was dried in an air oven at 110° C. for 4 hours. The weight of manganese dioxide was 0.23 mole.
0.096 mole of 3-cyanopyridine was dissolved in 5.556 mole water and 0.0115 mole of manganese dioxide, which was prepared by above method, was added to this solution. The reaction mixture was stirred and refluxed at 100° C. for 8 hours. The reaction mixture was cooled, filtered and washed with distilled water thoroughly. The filtrate was evaporated on a steam bath to dryness. After drying the weight of nicotinamide was 0.0957 mole, equivalent to a yield of 99.6 mole %.
COMPARATIVE EXAMPLES FOR PREPARATION OF MnO2 USING POTASSIUM PERMANGANATE AND MANGANOUS SALT IN PRESENCE OF SODIUM HYDROXIDE
EXAMPLE 4
300 ml of 0.303 molar aqueous solution of manganese chloride and 60 ml 9.75 molar solution of sodium hydroxide were added simultaneously drop-wise to an aqueous solution of 300 ml of 1.013 molar potassium permanganate at 70° C. for an hour with constant stirring and kept standing for 12 hrs. The precipitate of manganese dioxide was filtered and washed with distilled water till free from chloride ions. The precipitate was dried at 110° C. for 8 hrs. The yield of manganese dioxide was 0.198 mole.
0.096 mole 4-cyanopyridine was dissolved in 5.556 mole water and 0.0115 mole of manganese dioxide, which was prepared by above method, was added to this. The reaction mixture was refluxed at 100° C. for 8 hrs. in a glycerine bath. The reaction mixture was cooled, filtered and washed thoroughly with distilled water. The filtrate was evaporated on a steam bath to dryness. Weight of isonicotinamide was 0.089 mole. Yield was 92.71 mole %.
EXAMPLE 5
0.112 mole of Mn(NO3). 6H2O. was heated by 430° C. for 4 hrs in the muffle furnace 0.107 mole of MnO2 was obtained. The yield of MnO2 was 95.5 mole %.
0.096 mole of 4-cyanopyridine was dissolved in 1.94 mole of water and 0.0115 mole MnO2, which was obtained by above method, was added to this and the reaction mixture was refluxed for 8 hours at 115° C. in an oil bath. The reaction mixture was extracted with organic solvent (CCl4). The aqueous layer was evaporated to dryness and the yield of isonicotinamide was 0.0082 mole. The yield of unreacted 4-cyanopyridine was 0.048 mole. The yield of isonicotinamide was 8.5 mole %.
EXAMPLE 6
270 ml of 0.332 molar aqueous solution of MnSO4.4H2O and 117 ml 10.0 molar aqueous solution of sodium hydroxide were added drop-wise simultaneously with constant stirring to a hot (at 70° C.) 600 ml of 1.0123 molar aqueous solution of KMnO4. After addition of the MnSO4.4H2O and sodium hydroxide solution, the whole mass was stirred and heated again at 70° C. for 90 minutes. It was kept for settling for 12 hrs. It was filtered and the precipitate was washed several times with distilled water until the precipitate was free from SO4−2 and OH ions. The precipitate was dried in an air oven at 110° C. till it reaches a constant weight. The yield of MnO2 was 0.314 mole.
0.1923 mole 3-cyanopyridine was dissolved in 7.778 mole of water and 0.023 mole manganese dioxide, which was prepared by above method, was added to this solution. The mixture was refluxed at 100° C. for 8 hrs in a glycerine bath. The reaction mixture was cooled, filtered and washed with distilled water. The filtrate was evaporated on a steam bath to dryness. The weight of nicotinamide was 0.165 mole and the yield was 85.0 mole %.
The main advantages of the present invention are:

    1. Nicotinamide can be produced by a catalytic hydration of 3-cyanopyridine without the use of an alkali or an acid as used in the prior art catalyst, which necessitates an extremely complicated and cumbersome separation procedure for the nicotinamide product.
    2. The catalyst hydrated manganese dioxide is prepared by a Redox method using potassium permanganate and manganese chloride solution in a neutral medium.
    3. The catalyst used in the present invention eliminates the formation of nicotinic acid which is produced in substantial amount using the prior art catalysts (acid or alkali).
    4. The yield of nicotinamide is 91.8 mole % and the selectivity is 100% which is much higher than the catalyst report so far.
    5. The process also provides for easy and economic recovery of nicotinamide from the resulting hydrolysis effluents.

## Claims

1. A process for the preparation of a MnO2-based catalyst useful for the preparation of nicotinamide and isonicotinamide, the process comprising:
a) reacting a potassium permanganate and manganous salt solution in a neutral medium by adding an aqueous solution of a manganous salt drop-wise to the potassium permanganate solution to obtain a reaction mixture;
b) continuously stirring the reaction mixture obtained in step (a);
(c) allowing the reaction mixture to stand;
(d) filtering a precipitate of MnO2 formed after step (c) and washing the precipitate with distilled water; and
e) drying the precipitate to obtain the catalyst.

2. The process as claimed in claim 1, wherein the drop-wise addition of the aqueous solution of the manganous salt to the aqueous solution of the potassium permanganate is carried out at a temperature in a range of 30 to 80° C. and for a time period in a range of 30 minutes to 1 hour.

3. The process as claimed in claim 1, wherein the reaction mixture is allowed to stand for a time period in a range of 10 to 15 hours.

4. The process as claimed in claim 1, wherein the precipitate of MnO2 is dried in an air oven at 110° C. for 3 to 4 hours.

5. The process as claimed in claim 1, wherein the manganous salt is selected from the group consisting of manganese chloride and manganese sulphate.