Chichibabin reaction

by: McGill, Charles K.; Sutor, James J.;

In a Chichibabin amination of a nitrogen-containing heterocyclic base by sodamide in an organic solvent, the improvement comprising conducting the reaction under pressure of at least about 50 psi in the gas phase above the reaction mixture and adding ammonia to the mixture sufficient to produce a partial pressure of ammonia of at least about 5 psi in the gas phase. Preferred temperature and pressure ranges are disclosed, as are catalysts and other preferred steps for practicing the reaction. Significant results are obtained including improved and changed yields from those classically expected in Chichibabin aminations, including new compositions of matter in at least three cases.

BACKGROUND OF THE INVENTION

This invention relates generally to amination of nitrogen-containing heterocycles by alkali metal amides, and in particular to a significant discovery with respect to the time-honored Chichibabin amination reaction.

In 1914, Chichibabin and Seide first reported that a-picoline, or more commonly 2-methypyridine, underwent direct amination in the free a-position on the ring when treated with sodium amide in toluene at elevated temperatures. Chichibabin and Seide, J. Russ. Phys. Chem. Soc., 46, 1216 (1914). This reaction was later extended by Chichibabin and his contemporaries to amination of many pyridine, quinoline and isoquinoline bases. It has since been recognized as one of the more important and influential developments in pyridine chemistry, so much so that the reaction itself has become synonymous with the name of its discoverer. Its commercial importance should also not be discounted as, for example, the 2-amino amination product of pyridine itself has become an enormously important and useful starting material for further synthesis in many areas.

The Chichibabin reaction has been the subject of much study and comment through the years, both as to scope and as to the mechanism of the amination. For example, although first carried out in toluene, the reaction has since been carried out in other aprotic solvents of which dialkylanilines, liquid paraffin and other hydrocarbons such as benzene, xylene, cumene, mesitylene and petroleum fractions are most common. Similarly, although first accomplished using sodium amide, or more commonly sodamide, the reaction has since been carried out with other metal amides such as potassium amide, barium amide, etc., particularly when using low temperatures and long reaction times in attempting to slow the reaction to study the mechanism of its amination process. The Chichibabin mechanism remains one of the least understood nucleophilic substitution reactions in heterocyclic chemistry owing to the difficulty in handling the alkali metal amides and in studying kinetics of a process which takes Place under heterogeneous conditions at high temperatures. Classicly, those conditions have included heating the mixture at atmospheric pressure and at temperatures between about 100.degree.-200.degree. C. Another characteristic feature has been the evolution of hydrogen gas and ammonia gas which signals the start of the reaction and identifies its progress toward completion. Novikov, Pozharskii & Doron'kin, Translated from Khim. Geterotsikl. Soedin., No. 2, 244 (1976); Levitt & Levitt. Chem. & Ind., 1621 (1963).

The base compound which undergoes amination has also received much study. Reports document the amination of mono and diazines such as pyridines, quinolines, isoquinolines, benzoquinolines, phenanthridines, acridines, benzimidazoles, quinazolines, naphthyridines, pyramidines, pyrazines and other heterocyclic systems. Reactions related to the Chichibabin amination have also been studied which are not heterocycles, but have a N=CH group such as Schiff bases. Pozharskii, Simonov and Doron'kin, Russ. Chem. Rev., 47, 1042 (1978), Translated from Uspekhi Khim., 47, 1933 (1978). The result of these efforts is that the predictability of Chichibabin aminations is thought to be high for a given base compound, as are the expected product or products of the reaction. Although such certainty is helpful, situations arise where a partial or complete change in the Chichibabin result is desirable. For example, expected products may not be desired, or new products may be wanted, or isomer ratios may be preferably reversed.

An important example of this last category is the case of 3-substituted pyridine bases, and particularly 3-alkyl derivatives, which are known to undergo Chichibabin amination to produce predominantly 2-amino-3-alkylpyridine ("2,3-isomer") and to a much lesser extent 2-amino-5-alkylpyridine ("2,5-isomer"). The amination of 3-methylpyridine, also known as 3- or .beta.-picoline, is an excellent example, which reportedly yields the 2,3- and 2,5-isomers in a ratio of about 10.5:1. Abramovitch, Advan. Heterocycl. Chem.. 6, 294 (1966); Abramovitch Helmer and Saha, Chem. & Ind., 659 (1964); Abramovitch, Helmer and Saha, Can. J. Chem., 43, 727 (1965). This is highly unfortunate as the 2,5-isomers are much preferred because of their usefulness as starting materials and intermediates for the preparation of herbicides, insecticides and pharmaceuticals. Chemical manufactures are hard-pressed to meet the demand for 2,5-products since they are left with very large quantities of largely unusable 2,3-isomer at this time. Understandably, there is thus a substantial need to change the classic Chichibabin amination in this case in a way that improves the yield of these 2,5-products, of which 2-amino-5-methylpyridine is most preferred, at least at this time.

Notwithstanding the many years of study of the Chichibabin reaction, no significant breakthrough has been reported which teaches or suggests a methodology to change the reaction's classic mechanism or its anticipated results given a particular heterocyclic base compound. That is, not until now.

SUMMARY OF THE INVENTION

Applicants' invention does just that, and in so doing, addresses much more than the sPecific need for improving preparation of these 2,5-isomer products. APPlicants have discovered a major improvement to the classic Chichibabin amination involving conducting the reaction under pressure in the gas phase above the solid liquid heterogeneous reaction mixture and having a partial pressure of ammonia in the gas phase at least equal to the autogenous pressure of ammonia generated in situ by the reaction.

In its preferred forms, applicants' work thus far improves the classic Chichibabin amination of a nitrogen-containing heterocyclic base by sodamide in an organic solvent, by pressurizing the reaction vessel to an initial pressure of at least about 50 pounds per square inch (psi) coupled with adding ammonia to the vessel sufficient to produce an initial partial pressure of ammonia of at least about 5 psi in the gas phase. Characteristics of other alternate forms include conducting the reaction in a substantially inert atmosphere at temperatures betWeen about 100.degree.-250.degree. C. and without refluxing the mixture as is common in the classic Chichibabin reaction. The added ammonia may be injected in gaseous form, or left as liquid ammonia in the reaction mixture as when sodamide is prepared in situ by reacting sodium in excess liquid ammonia prior to conducting the amination. The temperature and pressure in the vessel are preferably maintained for a period sufficient to cause substantial amination to occur as measured by the production of hydrogen gas by the reaction, although both may vary from their initial settings. For example, temperature is preferably maintained between about 130.degree.-200.degree. C. whereas reaction pressures of at least about 300 psi are preferred with at least about 15-50 psi of ammonia being initially present. The autogenous pressure of gases evolved during amination can be used to pressurize the reaction vessel, and excess gases can be vented off to prevent too much build up.

Applicants have also discovered that a beneficial effect is achieved by adding a catalyst to the reaction, preferably an amino-heterocycle and more preferably one or more of the desired products of the reaction. And in yet another alternate method of characterizing applicants' preferred invention, it is the improvement of increasing pressure and adding ammonia to the gas phase above the reaction mixture sufficient to increase yield by at least about one third of a product expected in the Chichibabin amination or to produce a yield of at least about 10% of a product not expected in the Chichibabin amination, each yield being as a percent of total amination products obtained.

The specific products of applicants' work have varied with the base used and the conditions observed. Applicants have discovered, however, that results at least as good as those classically expected have been achieved and that for most bases tested to date, a significant change was observed in the product or products expected to result from a Chichibabin amination. As to whether anticipated products increase or decrease in yield or new ones appear, or isomer ratios vary, reference should be made to the specific examples which follow. In the case of at least one base, new compositions of matter were obtained.

Further objects and advantages of the present invention will become apparent from the description of the preferred embodiments which follows.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

For the purposes of promoting an understanding of the principles of the invention, reference will now be made to the several embodiments of applicants' work and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, such alterations and further modifications, and such further applications of the principles of the invention therein being contemplated as would normally occur to one skilled in the art to which the invention relates.

In its broadened form, one embodiment of applicants' invention was the discovery that significant and in most cases surprising results were achieved by conducting a Chichibabin amination of a nitrogen-containing heterocyclic base by sodamide in an organic solvent under pressure with some addition of ammonia to produce a partial pressure of ammonia in the gas phase above the solid liquid heterogeneous reaction mixture. Specific results varied with the base used, as shown in the examples which follow. It can be said, however, that the results were at least as good as classically expected in all cases and that with all but a few bases tested thus far, the results differed significantly from anticipated products and percentages of classic Chichibabin aminations.

In a preferred form, after the reactants were combined in a pressure vessel the gas phase above the mixture was initially pressurized to at least about 50 psi and ammonia was added to the vessel sufficient to produce an initial partial pressure of ammonia of at least about 5 psi in this gas phase. The mixture was brought to a temperature sufficient to cause amination to occur, and pressure was maintained at or above this initial 50 psi level during the course of the reaction until hydrogen evolution had substantially ceased. Although the autogenous pressure of gases evolved in situ during amination was used to assist in maintaining pressure during the reaction, it was preferred to initially purge the vessel of air and pressurize it using an inert gas such as nitrogen and then to conduct the amination in the substantially inert nitrogen atmosphere. In this regard, the term "substantially" is meant to define the condition that develops during amination in which evolved hydrogen and possible other gases enter the gas phase resulting in a predominent, but not totally inert nitrogen atmosphere.

It was more preferred in this embodiment to have an initial ammonia pressure of at least about 15-50 psi in the gas phase. Most preferred at this time was about 45 psi. As the amination proceeded, it was found that some ammonia was lost in venting off excess pressure due to hydrogen and other gases being evolved without detracting from the results of the reaction. This depends, of course, upon the size and efficiency of the pressure vessel and condenser used.

In another method of characterizing an alternate preferred form of applicants' invention, it was the improvement of a classic Chichibabin amination comprising increasing pressure and adding ammonia to the gas phase above the reaction mixture sufficient to increase yield by at least about one third of a product expected in the Chichibabin amination or to produce a yield of at least about 10% of a product not expected in the Chichibabin amination, each yield being as a percent of total amination products obtained. The specific products of applicants' work have varied with the base used and the conditions observed. In the case of at least three bases, namely 3-(3-phenylpropyl)pyridine, 4-(4'-methylpiperidino)pyridine, and 2-(3-pentyl)pyridine, new compositions of matter were obtained. For more detail as to the specific products obtained thus far, reference should be made to the specific examples which follow.

Several sources of ammonia were used. For example, in one embodiment sodamide was prepared in situ by reacting sodium in excess liquid ammonia. After the sodamide was prepared, some of the liquid ammonia was removed and an organic solvent was added to the same vessel. The base was combined in the vessel. Enough liquid ammonia remained so that when the mixture was brought to a temperature sufficiently high to cause amination to begin, the partial pressure of the remaining ammonia in the gas phase was sufficient to achieve the beneficial effect of the invention. In similar fashion, quantities of liquid ammonia or compounds which disassociate into free ammonia are usable to provide the ammonia source. Most preferred in most cases tested thus far, however, was direct injection of gaseous ammonia into the vessel during pressurizing of the gas phase.

As to other conditions of the reaction, after bringing the mixture to a temperature sufficiently high to cause hydrogen evolution (and thus amination) to begin, the reaction mixture was maintained at a temperature sufficiently high to cause, or to permit, substantial amination to take Place. A temperature range of between about 100.degree.-250.degree. C. was preferred, while most preferred was a range of about 130.degree.-200.degree. C. based on experiments to date. The length of time required for amination depended, of course, upon many variables and has no importance or distinction with regard to the invention. Experimental times varied between about 5-20 hours to arrive at commercially practical yields. As to the solvent used, toluene and xylene were preferred although other organic solvents work equally well. Many such solvents are common to Chichibabin aminations.

Applicants' work to date has included the amination of pyridine, quinoline, and pyrimidine bases using their improved Chichibabin procedure. In this regard, the term "base" is understood to include both the parent compound itself and all its substituted derivatives. By way of example only, of the pyridine bases tested thus far, the yields from pyridine and 2-aminopyridine were comparable to or slightly better than would be expected in classic Chichibabin aminations of these bases. Tests of 3- and 4-aminopyridine have not given significant yields of diaminopyridines either under classic conditions or under applicants' invention. Other bases tested have shown surprising and unexpected results, differing greatly from their classic reactions as Pointed out in detail in the specific examples which follow. Those tested include pyridine; aminopyridines including 2-aminopyridine, 3-aminopyridine and 4-aminopyridine; 3-picoline; nicotinic acid; nicotinamide; 3-hydroxypyridine; 4-dimethylaminopyridine; 4-(5-nonyl)pyridine; 3- lower alkylpyridines including 3-ethylpyridine, 3-propylpryidine, 3-isopropylpyridine and 3-butylpyridine; 3-(3-phenylpropyl)pyridine; 3-phenylpyridine; 3,4-lutidine., 3-propanolpyridine; 5-methylpyrimidine; quinoline; 2-picoline; 4-(4'-methylpiperidino)pyridine; 2-benzylpyridine; 3-methypyridine; 2-chloro-3-aminopyridine; 2-(3-pentyl)pyridine; and 2,2'-dipyridylamine.

The most preferred embodiment to date in applicants' work has comprised the step of adding an amount of base to a pressure vessel such as an autoclave in which sodamide has been preformed in at least a slight stoichiometric excess. This adding step took place at room temperature and with the prior addition of an organic solvent such as toluene or xylene and Possibly a dispersing agent such as oleic acid. The vessel was then sealed, purged of air with nitrogen, and pressurized to about 45 psi with gaseous ammonia and to about 200 psi with nitrogen in the gas phase above the solid liquid heterogenous reaction mixture. The vessel and its contents were heated rapidly with stirring to between about 130.degree.-200.degree. C. at which time evolution of hydrogen gas began, thereby signaling the start of amination. The pressure in the vessel increased because of this temperature rise and because of gas evolution even without further pressurizing with nitrogen gas. The temperature was maintained at or somewhat below this 130.degree.-200.degree. C. range and the pressure was maintained between about 300-1000 psi as a commercially practicable range, with about 350 psi being most preferred, for a period of about 5 hours or until hydrogen evolution had substantially ceased. Excess pressure was vented off during the reaction through a pressure relief valve or other means. At the end of the amination, the vessel was allowed to cool to room temperature and was vented to atmospheric pressure. The reaction mixture was hydrolyzed and removed, and the products of the reaction were isolated using standard procedures.

In an alternate embodiment of this most preferred procedure, a catalyst was also added to the mixture prior to pressurizing the vessel to help initiate the reaction and encourage formation of the desired product or products. Applicants have found amino-heterocyclic compounds to be preferred catalysts for this purpose, although most preferred has been the use of one or more of the desired products of the particular reaction. In the amination of 3-picoline, for example, the catalyst of choice was a mixture of various ratios of the 2.5- and 2,3-isomer products.

In an effort to further describe and define in detail the nature and scope of the invention, the following specific examples are now given of improved Chichibabin aminations which have been performed using applicants' discovery. In these examples as in the entire specification and the claims which follow, temperatures are given in degrees centigrade (.degree. C.) and pressures are given in Pounds per square inch absolute (psi) unless otherwise stated.

EXAMPLE 1

Amination of 3-picoline

In a liter, 3 neck flask, equipped with a mechanical stirrer, was prepared 1.3 moles of sodamide by slowly adding 29.9 g of sodium to about 700 cc of liquid ammonia containing a catalytic amount of ferric nitrate hexahydrate. The ammonia was substantially evaporated and replaced with 300 cc of xylene containing 0.1 cc of oleic acid. At room temperature, 93 g (1.0 mole) of 3-picoline was added. The mixture was transferred from the flask to a liter Magne Drive autoclave, using 100 cc of xylene to rinse the flask.

The autoclave was purged of air with nitrogen. pressurized to 30 pounds per square inch gauge (psig) with ammonia and to 600 psig with nitrogen. It was then heated rapidly with stirring to 145.degree. C. and maintained at 145.degree.-152.degree. C. for 12 hours. The pressure reached 1040 psig during the heating period. At the end of the heating, the autoclave was cooled to room temperature and vented to atmospheric pressure. The reaction mixture was carefully hydrolyzed with 150 cc of water. The xylene layer was separated and the aqueous phase was extracted again with 25 cc of xylene. Both xylene extracts were combined and distilled to give 72.4 g of distillate with a freezing point of 60.6.degree. C. . A GLC analysis showed a ratio of 3.92:1 of 2-amino-5-methylpyridine to 2-amino-3-methylpyridine in the isomer products. This ratio differed substantially from the corresponding about 1:10.5 ratio of these isomers reported by Abramovitch and other literature references. The recovered 2-amino-5-methylpyridine was useful in the synthesis of various herbicides. It also has uses in pharmaceutical and insecticidal applications, and is reported in Gadekar, U.S. Pat. No. 3,974,281 (1976) to be used in the synthesis of pirfenidone which is an analgesic, antipyretic, antiinflammatory compound and which is effective in treating a number of respiratory ailments.

EXAMPLE 2

Amination of 3-picoline

A liter Magne Drive was equipped with a water cooled reflux condenser. Non-condensable gas was led from the reflux condenser through a pressure relief valve (set at 350 psig) to a vent. A mixture of 58.5 g (1.5 moles) of sodamide, 400 cc of xylene, 0.1 cc of oleic acid, 93 g (1.0 mole) of 3-picoline and 5.4 g (0.05 mole) of a mixture of 2-amino-5-methylpyridine and 2 amino-3-methylpyridine in a ratio of 2.9:1 was placed in the Magne Drive. The autoclave was purged of air with nitrogen and pressurized to 30 psig with ammonia and to 220 psig with nitrogen. Cooling water was turned on the reflux condenser. The autoclave was slowly heated to 152.degree. C. at which time hydrogen evolution began. During this time the total pressure of the system reached 350 psig causing the pressure relief valve to activate. The reaction continued for about 5 hours, during which time the reaction temperature was gradually lowered to 140.degree. C. without any noticeable drop in the reaction rate. When hydrogen evolution became very slow the autoclave was cooled to room temperature and vented to atmospheric pressure. The reaction mixture was carefully hydrolyzed with 150 cc of water. The xylene phase was separated and the aqueous phase was extracted again with 25 cc of xylene. Both xylene extracts were combined and distilled to give 84.7 g of distillate with a freezing point of 60.8.degree. C. A GLC analysis showed a ratio of 2-amino-5-methylpyridine to 2-amino-3-methylpyridine of 3.69:1. This once again significantly improved upon prior reported ratios, and uses for the 2,5-isomer product were the same as in Example 1.

EXAMPLE 3

Amination of Nicotinic Acid

Into a liter Magne Drive, equipped as described in Example 2, was placed a slurry of 50.7 g (1.3 moles) of sodamide in 500 cc of xylene containing 0.1 cc of oleic acid. To the slurry was slowly added 73.9 g (0.6 mole) of nicotinic acid. The acid formed the sodium salt with evolution of ammonia. The autoclave was closed and purged with nitrogen and pressurized to 30 psig with gaseous ammonia and then to 200 psig with nitrogen. The pressure relief valve was set at 355 psig. The Magne Drive was heated with stirring to 150.degree. and kept within 150.degree.-155.degree. for 3.5 hours while hydrogen was released through the pressure relief valve. At the end of this heating period, hydrogen evolution ceased. The autoclave was continually heated for an additional 4 hours gradually increasing the temperature to a maximum of 200.degree. C. There was very little gas evolved during this time. The autoclave was cooled to room temperature and vented to atmospheric pressure. The reaction mixture was carefully hydrolyzed with 150 cc of water. The aqueous layer was separated and the pH was adjusted to 6.0 with concentrated hydrochloric acid. At this pH a precipitate was obtained. It was filtered, washed with water and dried to give 21.3 g of 6-aminonicotinic acid, m.p. 315.degree. C. with decomposition. The yield was 25.7%. The structure was verified by NMR and IR spectra. A mixed melting point with an authentic sample of 6-aminonicotinic acid gave no depression. This result differed substantially from literature reports such as Bojarska-Dahlig and Nantka-Namirski, Roczniki Chem., 30, 621 (1956) which reports that the result of the Chichibabin amination of nicotinic acid was the di-substituted 2,6-diaminopyridine. Applicants' 6-aminonicotinic acid product was useful in the preparation of pharmceuticals for antacids and ulcer inhibitors, such as those disclosed in Regnier et al., Ger Offen. 2,419,535 (1974).

EXAMPLE 4

Amination of Nicotinamide

A mixture of 50.7 g (1.3 moles) of sodamide preformed in situ as in Example 1, 400 cc of xylene containing 0.1 cc of oleic acid and 73.3 g (0.6 mole) of nicotinamide was placed in an autoclave such as the one described in Example 2. The autoclave was closed and purged of air with ammonia. It was pressurized to 60 psig with ammonia and 200 psig with nitrogen. The pressure relief valve was set at 360 psiq. The autoclave was heated to 122.degree.-145.degree. C. and maintained within this temperature range for 3 hours during which time hydrogen was evolved. The reaction mixture was cooled to room temperature and carefully hydrolyzed with 150 cc of water. Maximum temperature during hydrolysis was 18.degree. C. The hydrolyzed mixture was filtered. The filter cake was washed with water and dried to give 14.3 g of 6-aminonicotinamide, m. p. 240.degree.-247.degree. C. The aqueous phase of the filtrate was separated and adjusted to pH 6.0 with concentrated hydrochloric acid. A precipitate formed which was filtered, washed with water and dried to give 5.4 g of 6-aminonicotinic acid, m.p. 314.degree. C. with decomposition. The yield of 6-aminonicotinamide was 17.4% and the yield of 6-aminonicotinic acid was 6.5%. Both structures were confirmed by IR and NMR spectra. This result significantly differed from prior art references which report the classic Chichibabin amination product of nicotinamide to be exclusively 2-aminonicotinamide. Caldwell, Tyson and Lauer, J. Am. Chem. Soc., 66, 1479 (1944). Uses for the 6-aminonicotinic acid product of applicants' reaction were the same as stated in Example 4, whereas the recovered 6-aminonicotinamide was found effective as a rodenticide as reported in Johnson, Can. Patent 1,089,763, and for its inhibitory effect against Lactobacillus arabinosus as reported in Kitamura, et al., Yakuqaku Zasshi, 95, 547 (1975).

EXAMPLE 5

Amination of 3-Hydroxypyridine

A mixture of 89.7 g (2.3 moles) of sodamide, 500 cc of xylene containing 0.1 cc of oleic acid and 95 g (1 mole) of 3-hydroxypyridine was placed in a Magne Drive as described in Example 2. The autoclave was closed and purged of air with ammonia, pressurized with ammonia to 40 psig and to 200 psig with nitrogen. The pressure relief valve was set at 350 psig. The mixture was heated (158.degree.-186.degree. ) for almost 5 hours, during which time hydrogen was evolved. The autoclave was cooled to room temperature, vented to atmospheric pressure and hydrolyzed with 250 cc of water. The temperature during the hydrolysis was 60.degree. C. The aqueous phase was separated and neutralized to pH 7.0 with concentrated hydrochloric acid. It was extracted 3 times with 4-picoline. The picoline extracts were combined and distilled to give 39.3 g of recovered 3-hydroxypyridine and 40.6 g of 2-amino-3 -hydroxypyridine boiling 223.degree.-228.degree. C. at 29 mm. The melting point of the 2-amino-3-hydroxypyridine. recrystallized from methanol-xylene, was 162.degree.-163.degree. C. The structure was confirmed by NMR and the IR spectrum was identical to the spectrum of 2-amino-3-hydroxypyridine found in Aldrich Library of Infrared Spectra. 2nd ed., p. 1157E. The yield of 2-amino-3-hydroXypyridine, based on 3-hydroxypyridine recovered, was 62.9%. This result significantly differed from the literature report by Levitt and Levitt, Chemistry and Industry, 1621 (1963) which reports the amination of 3-hydroxypyridine gave 2.6-diaminopyridine in good yield while also pointing out that 2-amino-3-hydroxypyridine should, in fact, not be obtained. This is not true of applicants' discovery. The recovered 2-amino-3-hydroxypyridine was found useful, for example, in preparing prostaglandin synthetase inhibitors as reported in Belg. Patent 830,786 (1975), in preparing anti-inflammatory agents, analgesics and antipyretics as reported in Shen, et al., Ger. Offen. 2,330,109 (1974), and in preparing antibacterials as reported in Meszaros et al., Hung Telies, 10,957 (1975). The 2-amino-3-hydroxypyridine was also found useful in the preparation of metallized azo dyes for dyeing wool, polyamide, and acrylic fibers as reported in Back and Buehler, Ger. Offen. 2,236,299 (1973) and Ger. Offen. 2,236,269 (1973).

EXAMPLE 6

Amination of 4-Dimethylaminopyridine

A mixture of 54.6 g (1.4 moles) of sodamide preformed in situ as in Example 1, 400 cc of xylene containing 0.1 cc of oleic acid, 9.4 g (0.1 mole) of 2-aminopyridine and 122 g (1 mole) of 4-dimethylaminopyridine was placed in a Magne Drive such as the one described in Example 2. The autoclave was closed and purged of air with ammonia, pressurized to 50 psig with ammonia and to 200 psig with nitrogen. The pressure relief valve was set at 360 psig. The mixture was heated at 145.degree.-160.degree. C. for 6.5 hours. Hydrogen was evolved during this time. The autoclave was cooled to room temperature, vented to atmospheric pressure and hydrolyzed with 150 cc of water. A mass of crystals was observed in the autoclave. The mixture was heated to about 75.degree. C. and 100 cc of 4-picoline was added to dissolve the solids. The addition of the Picoline caused 3 phases to form, a top xylene phase, a middle picoline phase which contained some xylene and most of the reaction product, and a bottom aqueous caustic phase. The phases were separated at about 70.degree. C. The aqueous phase was extracted again with 4-picoline. The picoline extracts were combined and treated with dry ice to neutralize any caustic. The extracts were distilled until dry and the residue was filtered hot (to remove inorganic salts). To the filtrate was added toluene and the solution was allowed to cool. Crystals formed on cooling. They were filtered at room temperature, washed with toluene and dried to give 64.9 g of 4-aminopyridine, m.p. 156.degree.-162.degree. C. The yield was 69%. The filtrate could have been distilled to yield more 4-aminopyridine. This result differed significantly from a prior report by pozharskii, et al., Khim. Geterotsikl. Soedin., 1232 (1973) that a standard Chichibabin amination of 4-(dimethylamino)pyridine gave a yield of 30% of 2-amino-4-(dimethylamino)-pyridine. Applicants' recovered 4-aminopyridine product was found to have many uses as reported in the literature, including use in the protection of corn fields from blackbirds as reported in DeGrazio, et al., J. Wildl. Manage., 36, 1316 (1972) and Stickley, et al., J. Wildl. Manage., 40, 126 (1976). and as hardening accelerators for epoxy resins as reported by Nishimura, Japan, Kokai, 74 48,800.

EXAMPLE 7

Amination of 4-(5-Nonyl)pyridine









A mixture of 50.7 g (1.3 moles) of sodamide preformed in situ as in Example 1, 350 cc of xylene containing 0.1 cc of oleic acid, and 205 g (1 mole) of 4-(5-nonyl)pyridine was placed in a Magne Drive such as the one described in Example 2. The autoclave was closed and purged of air with nitrogen, pressurized to 10 psig with ammonia and 200 psig with nitrogen. The pressure relief valve was set at 350 psig. The mixture was heated to 173.degree. C. at which temperature amination began. The temperature was reduced and the reaction was run at 158.degree.-163 .degree. C. for 8.7 hours. Hydrogen was evolved during this time. The autoclave was cooled to room temperature, vented to atmospheric pressure and hydrolyzed with 150 cc of water. The xylene phase was separated and the bottom aqueous caustic phase was re-extracted with 25 cc of xylene. Both xylene extracts were combined and distilled to give 2-amino-4-(5-nonyl)pyridine boiling at 197.degree.-225 .degree. C. at 22 mm Hg. The yield was 67.3%. This result substantially increases the yield of 2-amino-4-(5-nonyl)pyridine over that reported previously by one of the applicants, McGill, U.S. Pat. No. 4,177,349 (1979) and McGill, U.S. Pat. No. 4,267,335 (1981). In this prior work, 4-(5-nonyl)pyridine was shown to prefer to couple in the presence of sodamide, giving high yields of 4,4'-di-(5-nonyl)-2,2'-bipyridyl but only low yields of 2-amino-4-(5-nonyl)pyridine. This increased yield of 2-amino-4 (5-nonyl)pyridine is of importance because the compound has valuable biocidal properties.

EXAMPLE 8

Amination of 3,4-Lutidine

A mixture of 46.8 g (1.2 moles) of sodamide, 450 cc of toluene, 107 g (1 mole) of 3,4-lutidine and 5.0 g (0.05 mole) of 3-aminopyridine was placed in the apparatus described in Example 2. The autoclave was secured and purged of air with ammonia and pressurized to 45 psi with ammonia and then to 215 psi with nitrogen. The pressure relief valve was set at 365 psi. Cooling water was turned on the reflux condenser. The autoclave was heated with stirring to 185.degree. C. at which temperature hydrogen evolution began. The reaction continued at 185.degree.-189.degree. C. for about 4 hours until hydrogen stopped coming through the pressure relief valve. The autoclave was cooled to room temperature and vented to atmospheric pressure. The reaction mixture wa carefully hydrolyzed with 150 cc of water. The toluene phase was separated and the aqueous phase was extracted twice with 25 cc of toluene. All of the toluene extracts were combined and distilled to recover 22.9 g of 3,4-lutidine and 79.1 g of a mixture of 2-amino-3,4-dimethylpyridine and 2-amino-4,5-dimethylpyridine. The yield of both isomers based on 3,4-lutidine recovered was 81.1%. The ratio of 2-amino-3,4-dimethylpyridine to 2-amino-4,5-dimethylpyridine was 1.09:1. This ratio of almost equal isomers differed substantially from that in the literature which showed that the ratio of 2-amino-3,4-dimethylpyridine to 2-amino-4,5 dimethylpyridine of 3.5:1 was obtained from a Chichibabin reaction of 3,4-lutidine at atmospheric pressure in N,N-dimethylaniline. Siegel. J. Heterocyclic Chem., 18, 1613 (1981). The isomer 2-amino-4,5-dimethylpyridine is useful in preparing 1,3-bis(2'-pyridylimino)isoindoline chelating ligands.

EXAMPLE 9

Amination of 3-(3-phenylpropyl)pyridine

There was placed in a liter Magne Drive, equipped as described in Example 2, a mixture of 46.8 g (1.2 moles) of sodamide, 450 cc of toluene containing 0.1 cc of oleic acid, 5.0 g (.05 mole) of 4-aminopyridine, and 197 g (1.0 mole) of 3-(3-phenylpropyl)pyridine. The autoclave was closed and purged with ammonia and pressurized to 45 psi with ammonia and then to 215 psi with nitrogen. The pressure relief valve was set at 365 psi. Cooling water was turned on the reflux condenser. The autoclave was slowly heated with stirring to 168.degree. C. at which temperature moderate hydrogen evolution began. The reaction continued to evolve hydrogen for 3.5 hours to a maximum temperature of 186.degree. C. The autoclave was cooled and vented to atmospheric pressure. The reaction mixture was hydrolyzed with 150 cc of water (maximum temperature was 50.degree. C.). The toluene phase was separated and the aqueous phase was extracted twice with 50 cc of toluene. The toluene extracts were combined, treated with carbon dioxide to neutralize any caustic present, and distilled to recover 23.9 g of 3 (3-phenylpropyl)pyridine and 150.4 g of a mixture of 2-amino-5-(3-phenylpropyl)pyridine and 2-amino-3-(3-phenylpropyl)pyridine boiling at 182.degree.-198.degree. C. at 2 mm Hg. A GLC analysis of the mixture showed a ratio of 2,5-isomer:2,3-isomer of 5.9:1. The yield of both isomers, based on 3-(3-phenylpropyl)pyridine recovered, was 80.7%. This ratio differed greatly from the ratio obtained when 3-(3-phenylpropyl)pyridine was aminated with sodamide in refluxing xylene at atmospheric pressure. Under atmospheric pressure the ratio was turned around giving a 3.1:1 ratio 2,3-isomer:2,5-isomer. These two isomers, 2-amino-5-(3-phenylpropyl)pyridine and 2-amino-3-(3-phenylpropyl)pyridine are new compositions of matter. The 2,3- and 2,5-isomers are valuable for their biocidal properties.

EXAMPLE 10

Amination of 3-phenylpyridine

A mixture of 33.2 g (0.85 mole) of sodamide. 450 cc of toluene containing 0.1 cc of oleic acid, and 126.9 g (0.82 mole) of 3-phenylpyridine was placed in a liter Magne Drive, equipped as described in Example 2. The autoclave was closed and purged of air with ammonia, pressurized to 45 psi with ammonia and then to 215 psi with nitrogen. Cooling water was turned on the reflux condenser. The autoclave was heated with stirring to 150.degree. C. and maintained between 150.degree. and 160.degree. C. for about 3 hours, during which time hydrogen evolved and passed through the pressure relief valve. The autoclave was cooled to room temperature and vented to atmospheric pressure. The reaction mixture was carefully hydrolyzed with 100 cc of water. The toluene phase was separated and the aqueous phase was extracted twice with 25 cc of toluene. The toluene extracts were combined and distilled to give 46.9 g of a mixture of 2-amino-5-phenylpyridine and 2-amino-3-phenylpyridine boiling 201.degree.-227.degree. C. at 24 mm Hg. A GLC analysis showed that the ratio of 2.5-isomer:2,3-isomer was 38.1:1. The 2-amino-5-phenylpyridine, crystallized from pyridine, had a melting point of 136.degree.-137.degree. C. This ratio differed considerably from the ratio obtained when 3-phenylpyridine was aminated with sodamide in xylene at atmospheric pressure. The ratio obtained under atmospheric conditions was 11.0:1, 2,5-isomer to 2,3-isomer. The 2-amino-5-phenylpyridine isomer was found to have useful biocidal properties.

EXAMPLE 11

Amination of 2-Aminopyridine

A mixture of 85.8 g (2.2 moles) of sodamide and 500 cc of toluene containing 0.5 cc of oleic acid was placed in a liter Magne Drive, equipped as described in Example 2. To the mixture was added 94 g (1.0 mole) of 2-aminopyridine. When the 2-aminopyridine came in contact with the sodamide, the sodium salt of 2-aminopyridine was formed with the evolution of ammonia. The ammonia evolution purged the autoclave of air. The vessel was closed and pressurized to 15 psi with ammonia and to 100 psig with nitrogen. The pressure relief valve was set at 100 psig. Cooling water was turned on the reflux condenser. The autoclave was heated to 180.degree. C. with stirring. The temperature was maintained between 180.degree.-185.degree. C. for 2 hours while hydrogen was evolved and bled off through the pressure relief valve. The autoclave was cooled and carefully hydrolyzed at 50.degree. C. with 100 cc of isopropanol and 150 cc of water. The organic phase was separated at about 50.degree. C. The aqueous phase was re-extracted twice with a solution of 3 parts of toluene and 1 part of isopropanol. The extracts were combined and distilled to give 58.7 g of recovered 2-aminopyridine and 36.4 g of 2,6-diaminopyridine yield, based on 2-aminopyridine consumed, 88.8%. The 2,6-diaminopyridine is useful in the preparation of phenazopyridine, an antiseptic drug used in genitourinary tract infections.

EXAMPLE 12

Amination of 3-Ethylpyridine

A mixture of 46.8 g (1.2 moles) of sodamide. 400 cc of toluene containing 0.1 cc of oleic acid, and 107 g (1.0 mole) of 3-ethylpyridine was placed in a liter Magne Drive autoclave, equipped as described in Example 2. The vessel was purged of air with ammonia, pressurized to 30 psig with ammonia and then to 200 psig with nitrogen. The pressure relief valve was set at 350 psig. Cooling water was turned on the reflux condenser. The autoclave was slowly heated with stirring. The temperature reached 180.degree. C. before hydrogen evolution began. After the amination started, the reaction continued for 3.5 hours while the temperature was gradually lowered to 151.degree. C. The autoclave was cooled, vented to atmospheric pressure and carefully hydrolyzed with 150 cc of water. The toluene phase was separated and the aqueous phase was extracted again with 25 cc of toluene. Both toluene extracts were combined and distilled to give 90.9 g boiling 163.degree. C. at 43 mm to 195.degree. C. at 34 mm of a mixture of 2-amino-5-ethylpyridine and 2-amino-3-ethylpyridine. Yield of both isomers was 74.5%. An analysis of the mixture showed a ratio of 4.55:1 of 2-amino-5 ethylpyridine to 2-amino-3-ethylpyridine. The ratio is significantly different from the literature where it is reported 3.5:1, 2,3-isomer:2,5-isomer. Ban and Wakamatsu, Chem. Ind. 710 (1964). Uses for 2-amino-5-ethylpyridine were included in Example 1 in addition to its biocidal properties.

EXAMPLE 13

Amination of 3-n-Butylpyridine

A mixture of 46.8 g (1.2 moles) of sodamide, 400 cc of toluene containing 0.1 cc of oleic acid, and 135 g (1.0 mole) of 3-n-butylpyridine was placed in a liter Magne Drive autoclave, equipped as described in Example 2. The vessel was purged of air with ammonia, pressurized to 30 psig with ammonia and then to 200 psig with nitrogen. The pressure relief valve was set at 340 psig. Cooling water was turned on the reflux condenser. The autoclave was heated with stirring to 208.degree. C. when hydrogen evolution began. Hydrogen continued to evolve for 2 hours. During the first hour, the autoclave was slowly cooled to 165.degree. C. and then kept at 160.degree.-165.degree. C. for about another hour. The vessel was cooled, vented to atmospheric pressure and carefully hydrolyzed with 150 cc of water. The toluene phase was separated. The aqueous phase was extracted twice with 30 cc of toluene. The toluene phases were combined and distilled to recover 8.3 g of unreacted 3-n-butylpyridine and 114.7 g of a mixture of 2-amino-5-n-butylpyridine and 2-amino-3-n-butylpyridine, the mixture of two products boiling at 176.degree.-194.degree. C. at 76 mm. An analysis by GLC showed the ratio of the 2,5-isomer to the 2,3-isomer was 3.5:1. The yield of both isomers based on recovered 3-n-butylpyridine was 81.5%. The ratio obtained is greatly different from that reported in the literature where the ratio of 2,5-isomer to 2,3-isomer is stated as 1:4. Hardegger and Nikles, Helv. Chim. Acta, 39. 505 (1956). The 2-amino-5 n-butylpyridine is useful in the preparation of fusaric acid, a drug with hypotensive activity. Fusaric acid is also a dopamine beta-hydroxylase inhibitor.

EXAMPLE 14

Amination of pyridine

Into a liter Magne Drive, equipped as described in Example 2, were placed 93.6 g (2 4 moles) of sodamide, 450 cc toluene containing 0.1 cc of oleic acid, and 158 g (2 moles) of pyridine. The autoclave was purged of air with ammonia, pressurized to 15 psi with ammonia and then to 100 psig with nitrogen. The pressure relief valve was set at 100 psig. Cooling water was turned on the reflux condenser. The amination was run, with stirring, over 2.25 hours within a temperature range of 140.degree.-165.degree. C., during which time hydrogen was evolved through the pressure relief valve. The autoclave was cooled and vented to atmospheric pressure and carefully hydrolyzed with 250 cc of water. The toluene phase was separated and the aqueous phase was extracted again with 50 cc of toluene. Both toluene extracts were combined and distilled to obtain 148.3 g of 2-aminopyridine and 7.4 g of 2,6-diaminopyridine. The yield of 2-aminopyridine, was 78.9% and the yield of 2,6-diaminopyridine was 6.8%. The 2-aminopyridine is useful as a starting material for antihistamines and the 2-6 diaminopyridine has the same use as given in Example 11.

EXAMPLE 15

Amination of 3-propanolpyridine

In a liter 3-neck flask, equipped with a mechanical stirrer, was prepared 2.2 moles of sodamide by slowly adding 50.6 g of sodium to about 750 cc of liquid ammonia containing a catalytic amount of ferric nitrate hexahydrate. The ammonia was substantially evaporated and replaced with 350 cc of toluene containing 0.5 cc of oleic acid. The sodamide slurry was transferred to a liter Magne Drive, using 100 cc of toluene to rinse the 3-neck flask. To the slurry in the autoclave was cautiously added 137 g (1.0 mole) of 3-propanolpyridine. When the alcohol came in contact with sodamide, ammonia was evolved and the sodium salt of the alcohol was made. The Magne Drive was equipped with a water-cooled reflux condenser. Noncondensable gas was led from the reflux condenser through a pressure relief valve (set at 350 psig) to a vent. The autoclave was initially pressurized to 30 psig with ammonia and then to 200 psiq with nitrogen. Cooling water was turned on the reflux condenser. The autoclave was heated to 142.degree. C. over a period of 1 hour before the mixture could be stirred (due to the insoluble sodium salt of 3-propanolpyridine). Agitation and heating continued for about 3 hours within a temperature range of 142.degree.-160.degree. C. During this time, the total pressure of the system reached 350 psig causing the pressure relief valve to activate and release hydrogen. Toward the end of the 3-hour heating period, hydrogen evolution stopped. The autoclave was cooled to 50.degree. C. and slowly vented to atmospheric pressure. The reaction mixture was carefully hydrolyzed with 250 cc of water. After adding 100 cc of 4-picoline to the mixture, an aqueous phase was allowed to separate and was removed. The aqueous phase was extracted twice with 100 cc of an equal volume solution of toluene and 4-picoline. The original oil layer and extracts were combined and distilled to recover 76.0 g of 3-propanolpyridine and to obtain 46.1 g of a mixture of 2-amino 5-propanolpyridine and 2-amino-3-propanolpyridine. The yield of the mixture. based on 3-propanolpyridine recovered, was 67.8%. The ratio of 2 amino-5-propanolpyridine to 2 -amino-3-propanolpyridine, by GLC was 4.18:1. This ratio differed greatly from the ratio obtained when 3-propanolpyridine wa aminated with sodamide in refluxing pseudocumene at atmospheric pressure. Under atmospheric pressure the ratio of 2,5-isomer to 2,3-isomer was 1:8.3. These 2,3- and 2,5- isomers are valuable as catalysts for curing epoxy resins.

EXAMPLE 16

Amination of 5-Methylpyrimidine

A mixture of 46.8 g (1.2 moles) of sodamide, 500 cc of toluene containing 0.5 cc of oleic acid, and 94.1 g (1.0 mole) of 5-methylpyrimidine was placed in a liter Magne Drive, equipped as described in Example 15. The autoclave was closed and purged of air with ammonia gas, pressurized to 30 psig with ammonia and then to 200 psig with nitrogen. The pressure relief valve was set at 350 psig. Cooling water was turned on the reflux condenser. The autoclave was heated with stirring to 100.degree. C. and maintained between that temperature and 105.degree. C. for about 2 hours, during which time hydrogen evolved and passed through the pressure relief valve. The autoclave was then cooled to room temperature, vented to atmospheric pressure and hydrolyzed with 100 cc of isopropanol and 100 cc of water. The reaction mixture was allowed to separate into two phases. The aqueous phase was removed and extracted twice with 50 cc of pyridine. The original oil layer and the two extracts were combined and distilled to give 25.9 g of a mixture of 2-amino-5-methylpyrimidine and 4-amino 5-methylpyrimidine boiling at 155.degree. C. (at 51 mm Hg) to 200.degree. C. (at 63 mm Hg). A GLC analysis of the mixture showed a ratio of 4-amino-5-methylpyrimidine to 2-amino-5-methylpyrimidine of 3.2:1. This ratio differed significantly from the ratio obtained when 5-methylpyrimidine was aminated with sodamide in refluxing toluene at atmospheric pressure according to classic Chichibabin conditions. Under atmospheric pressure, the ratio of 4-amino-5-methylpyrimidine to 2-amino-5-methylpyrimidine was 8.6:1. These aminoalkylpyrimidines are useful in preparation of herbicides as reported by Suzuki et al., Japan. Kokai 79 144,383. The 2-amino-5-methylpyrimidine is also valuable in preparing pyrimidinoaminomethylergoline derivatives which possess adrenolytic, hypotensive, and analgesic activities as reported in Arcari et al., Ger. Offen. 2,459,630 (1975). Both the 2-amino-5-methyl- and 4-amino-5-methylpyrimidines are also valuable as catalysts for curing epoxy resins.

EXAMPLE 17

Amination of Quinoline

A mixture of 46.8 g (1.2 moles) of sodamide. 400 cc of toluene containing 0.5 cc of oleic acid and 129.2 g (1.0 mole) of quinoline was placed in a liter Magne Drive, equipped as described in Example 15. The autoclave was closed and purged of air with ammonia, pressurized to 30 psig with ammonia and then to 200 psig with nitrogen. The pressure relief valve was set at 350 psig. Cooling water was turned on the reflux condenser. The autoclave was heated with stirring for 2 hours within a range of 138.degree.-148.degree. C. No hydrogen evolution was observed. The autoclave was cooled and vented to atmospheric pressure. The reaction mixture was carefully hydrolyzed (external cooling) with 150 cc of water. The maximum temperature was 30.degree. C. The hydrolyzed mixture contained organic crystalline material. In order to dissolve the crystals, 200 cc of 4-picoline was added and the mixture thoroughly stirred. The aqueous phase was allowed to settle and was removed. The organic phase was placed under vacuum at 40.degree. C. to remove most of the residual ammonia. It was then treated with dry ice and filtered to remove carbonates. The filtrate was topped to a liquid temperature of 110.degree. C. at 50 mm Hg. To the residue was added about 2 parts of toluene and the solution was allowed to crystallize. The mixture was filtered to give 57.4 g of 2-amino-3,4-dihydroquinoline, m.p. of 134.9.degree.-136.3.degree. C. The dihydroquinoline was hydrolyzed in boiling water to give 3,4-dihydrocarbostyril m.p. 165.7.degree.-167.1.degree. C. It is reported in Tetsuji et al., J. Heterocycle Chem., 2, 330 (1965) that the Chichibabin amination of quinoline in toluene at atmospheric pressure gave only 2-aminoquinoline. Derivatives of 3,4-dihydrocarbostryril have anti-inflammatory and blood platelet coagulation activities as claimed by Nakagawa et al., Japan. Kokai 77 73,866.

EXAMPLE 18

Amination of 2-picoline

A mixture of 105.7 g (2.71 moles) of sodamide and 337 cc of xylene containing 1.0 cc of oleic acid was placed in a liter Magne Drive, equipped as described in Example 15. The autoclave was closed, purged of air with nitrogen and pressurized to 100 psig with nitrogen (pressure relief valve was set at 100 psig). The sodamide slurry was heated with stirring to 190.degree. C. and 191.7 g (2.06 moles) of 2-picoline was started adding from a Fisher-porter pressure bottle. The addition was completed over a period of 84 minutes within a temperature range of 188.degree.-198.degree. C. During the addition, ammonia and hydrogen were evolved and passed through the pressure relief valve. The reaction mixture was heated about 10 minutes longer, cooled to 40.degree. C. and hydrolyzed with 200 cc of water. After adding 50 cc of ispropanol, the aqueous phase was separated. It was extracted twice, each time with 60 cc of a solution of 2 volumes of xylene to 1 volume of isopropanol. The original oil layer and extracts were combined and distilled to recover 37.7 g of 2-picoline. 48.7 g of 2-amino-6-methylpyridine and 72.8 g of material boiling from 212.degree. C. at 102 mm to 220.degree. C. at 104 mm. The material was a solid at room temperature and analyzed 90% pure by GLC. An analytical sample (m.p. 63.4.degree.-64.6.degree. C.) was prepared by recrystallization from isopropanol. The NMR spectra was identical with m-phenylenediamine. Anal. Calc'd. for C.sub.6 H.sub.8 N.sub.2 : C, 66.67; H, 7.41; N, 25.92. Found: C, 66.90; H, 7.21; N, 26.08. The N,N'-diacetyl-m-phenylenediamine derivative was prepared, m.p. 190.degree.-191.degree. C. Literature m.p. is 191.degree. C. Beilstein 13, (1), 13. The yield of m-phenylenediamine, based on 2-picoline recovered, was 36.6%. The amination of 2-picoline at atmospheric pressure under standard Chichibabin conditions gives little if an m-phenylenediamine. The m-phenlenediamine is a rubber curing agent and is also valuable as a corrosion inhibitor.

EXAMPLE 19

Amination of 4-(4'-Methylpiperidino)pyridine

A mixture of 46.8 g (1.2 moles) of sodamide, 400 cc of toluene containing 0.1 cc of oleic acid, 9.4 g (0.1 mole) of 2-aminopyridine, and 141.0 g (0.8 mole) of 4-(4'-methylpiperidino)pyridine was placed in a liter Magne Drive, equipped as described in Example 15. The autoclave was closed and purged of air with ammonia, pressurized to 30 psig with ammonia and then to 300 psig with nitrogen. The pressure relief valve was set at 350 psig. Cooling water was turned on the reflux condenser. The autoclave was heated with stirring at 177.degree.-185.degree. C. for 1 hour. Hydrogen was evolved during the heating period. The autoclave was cooled, vented to atmospheric pressure, and hydrolyzed with 150 cc of water. The organic phase was separated at 50.degree. C. and the aqueous phase was extracted again at 50.degree. C. with 25 cc of toluene. The extracts were combined and distilled under vacuum to obtain 0.06 mole of 2-aminopyridine, 0.06 mole of 2,6-diaminopyridine, 0.20 mole of 4-aminopyridine, 0.34 mole of 4-(4'-methylpiperidino)pyridine, and 0.04 mole of 2-amino 4-(4'-methylpiperidino)pyridine which is a new composition of matter (m.p. 126.degree.-127.degree. C.) useful for curing epoxy resins. At atmospheric pressure this Chichibabin amination gives predominantly the 2-amino-4-(4'-methylpiperidino)pyridine. The 2-aminopyridine in this example is valuable as a starting material for antihistamines and 2,6-diaminopyridine is useful in the preparation of phenazopyridine, an antiseptic drug used in genitourinary tract infections. The 4-aminopyridine has the same uses as shown in Example 6.

EXAMPLE 20

Amination of 2-Benzylpyridine

A mixture of 85.8 g (2.2 moles) of sodamide, 400 cc of toluene containing 0.2 cc of oleic acid, and 169.1 g (1.0 mole) of 2-benzylpyridine was placed in a liter Magne Drive, equipped as described in Example 15. The autoclave was closed and purged of air with nitrogen and then pressurized to 300 psig with nitrogen. The pressure relief valve was set at 350 psig. Cooling water was turned on the reflux condenser. The autoclave was heated was stirring at 155.degree.-170.degree. C. for 1.5 hours. Hydrogen was evolved during the heating time. The autoclave was cooled, vented to atmospheric pressure, and hydrolyzed with 200 cc of water. The two phases were separated and the aqueous phase was extracted twice with 30 cc of a solution of 2 volumes of toluene to 1 volume of ispropanol. The organic phase and extracts were combined and distilled under vacuum to give 0.39 mole of 2-aminopyridine, 0.14 mole of 2,6-diaminopyridine. 0.06 mole of 2-benzylpyridine, and 0.13 mole of 2-amino-6-benzylpyridine. The Chichibabin amination of 1.0 mole of 2-benzylpyridine at 167.degree.-171.degree. C. (in boiling pseudocumene) at atmospheric pressure for 1.25 hours gave only 0.66 moles of recovered 2-benzylpyridine and 0.22 moles of 2-amino-6-benzylpyridine (freezing point 50.7.degree. C.). The 2-aminopyridine and 2,6-diaminopyridine have valuable properties as described in Example 19. The 2-amino-6-benzylpyridine is valuable as a starting material for the preparation of antimalarial and anti-inflammatory agents as described in Lesher, U.S. Pat. No. 3,907,798 (1975).

EXAMPLE 21

Amination of 3-Methoxypyridine

A mixture of 28.1 g (0.72 mole) of sodamide, 400 cc of toluene containing 0.1 cc of oleic acid, and 65.5 g (0.60 mole) of 3-methoxypyridine was placed in a liter Magne Drive, equipped as described in Example 15. The autoclave was closed and purged of air with ammonia, pressurized to 30 psig with ammonia and then to 200 psig with nitrogen. The pressure relief valve was set at 340 psig. Cooling water was turned on the reflux condenser. The mixture was heated with stirring to 120.degree. C. and kept heating (maximum temperature 136.degree. C.) for about 4.5 hours until noncondensable gases stopped passing through the pressure relief valve. The autoclave was cooled the 25.degree. C., vented to atmospheric pressure, and hydrolyzed with 150 cc of water. The oil phase was separated. The aqueous phase was extracted twice with 50 cc of an equal volume solution of 4-picoline and toluene. The oil layer and extracts were combined and distilled under vacuum to give 0.14 mole of recovered 3-methypyridine, 0.05 moles of 2-aminopyridine. 0.02 moles of 3-aminopyridine, 0.02 moles of 2-amino-3-methylpyridine, and 0.18 moles of 3-hydroxypyridine. When 3-methoxypyridine was aminated with sodamide in refluxing xylene at atmospheric pressure, a 40.3% yield of 2-amino-3-methoxypyridine (m.p. 79.degree.-80.degree. C.) was obtained. Both 2-amino-3-methylpyridine and 2-amino-3-methoxypyridine are valuable as starting materials for preparing herbicides as shown in Suzuki et al., Ger. Offen. 2,831,578 (1979). The 3-hydroxypyridine is a valuable starting material for the preparation of the drugs pirbuterol (cardiostimulant and oral brochodialator) and pyridostigmine (cholinergic).

EXAMPLE 22

Amination of 2-Chloro-3-aminopyridine

A mixture of 85.8 g (2.2 moles) of sodamide, 400 cc of toluene containing 0.1 cc of oleic acid and 128.6 g (1.0 mole) of 2-chloro 3 aminopyridine was placed in a liter Magne Drive, equipped as described in Example 15. The autoclave was closed and purged of air with ammonia, pressurized to 20 psig with ammonia and then to 350 psig with nitrogen. The pressure relief valve was set at 350 psig. Cooling water was turned on the reflux condenser. The autoclave was heated with stirring at 120.degree.-136.degree. C. for 1.5 hours. It was cooled to room temperature and vented to atmospheric pressure. The reaction mixture was hydrolyzed with 250 cc of water while being cooled with an ice bath. The maximum temperature during hydrolysis was 23.degree. C. Before separating the aqueous layer, 100 cc of 4-picoline was stirred into the reaction mixture. The aqueous phase was extracted again with a solution of 100 cc of 4-picoline and 50 cc of toluene. The extracts were combined and distilled under vacuum to recover 6.4 g of the starting 2-chloro-3-aminopyridine and 21.3 g (23.2% yield) of 1H-pyrrole-3-carbonitrile (m.p. 54.2.degree.-55.4.degree. C., crystallized from cyclohexane containing 6% toluene). This yield of 3-cyanopyrrole is considerably better than the 12.7% yield obtained at atmospheric pressure in refluxing xylene. A yield of no more than 1% was reported by H. G. den Hertog et al., Tetrahedron Lett., No. 36, 4325 (1966) by treating 2-chloro-3-aminopyridine with sodamide in liquid ammonia at room temperature. The 3-cyanopyrrole is valuable as a herbicide.

EXAMPLE 23

Amination of 2-(3-pentyl)pyridine

A mixture of 105.8 g (2.71 moles) of sodamide and 332 g of xylene containing 1.0 cc of oleic acid was placed in a liter Magne Drive, equipped as described in Example 15. The autoclave was closed and purged of air with nitrogen and pressurized to 100 psig with nitrogen. The pressure relief valve was set at 100 psig. Cooling water was turned on the reflux condenser. The mixture was heated with stirring to 190.degree. C. and 235.0 g (1.58 moles) of 2-(3-pentyl)pyridine was started adding from a Fisher-porter pressure bottle. The addition required 5.5 hours at 190.degree. C.-215.degree. C. The reaction mixture was heated an additional 5 hours within that temperature range until hydrogen almost stopped passing through the relief valve. The autoclave was cooled to 50.degree. C., vented to atmospheric pressure and hydrolyzed with 200 cc of water. The oil layer was separated and distilled under vacuum to give 258.6 g of 2 -amino-6-(3-pentyl)pyridine. b.p. 163.degree. C. at 60 mm. n.sup.25.sub.D 1.5357 (yield 68.1%). This 2-amino-6-pentyl)pyridine is a new composition of matter. It is a novel liquid aminopyridine and has valuable biocidal properties. When this amination is repeated at atmospheric pressure under classic Chichibabin conditions, the product is 6,6'-di-(3-pentyl)-2,2'-bipyridyl as shown in McGill, U.S. Pat. No. 4,177,349 (1979) and McGill, U.S. Pat. No. 4,267,335 (1981).

EXAMPLE 24

Amination of 2,2'-Dipyridylamine

A mixture of 46.8 g (1.20 moles) of sodamide, 400 cc of toluene containing 0.5 cc of oleic acid, and 85.6 g (0.50 mole) of 2,2'-dipyridylamine was placed in a liter Magne Drive, equipped as described in Example 15. The autoclave was closed, purged of air with ammonia, pressurized to 30 psig with ammonia and to 250 psig with nitrogen. The pressure relief valve was set at 350 psig. Cooling water was turned on the reflux condenser. The mixture was heated with agitation to 188.degree. C. and maintained at 188.degree.-203.degree. C. for about 7 hours. Hydrogen was evolved. The autoclave was cooled to room temperature, vented to atmospheric pressure and hydrolyzed with 200 cc of water containing 100 cc of isopropanol. The mixture was warmed to 50.degree. C. and stirred at that temperature for 1 hour. Phases were allowed to separate and the organic phase was separated at 50.degree. C. The aqueous phase was extracted at 60.degree. C. with 60 cc of a solution of 2 volumes of toluene to 1 volume of ispropanol. The organic extracts were combined and distilled under vacuum to give 0.25 mole of 2-aminopyridine, 0.36 mole of 2.6-diaminopyridine, and 9.6 g (0.05 mole) of di-(6-amino-2-pyridyl)-amine (m.p. 171.degree.-173.degree. C.) which is a catalyst for curing epoxy resins. When this experiment was repeated at atmospheric pressure in boiling pseudocumene, only 0.10 mole of 2-aminopyridine and 0.14 mole of 2,6-diaminopyridine were obtained. The 2-aminopyridine is valuable as a starting material for antihistamines and 2,6-diaminopyridine is useful in the preparation of phenazopyridine, an antiseptic drug used in genitourinary tract infections.

Insulating insert for magnetic valves

Intraocular lens

Stabilized throttle control system

Ice body delivery apparatus

Structurally efficient inflatable protective device

Fast circuit switching system

Multiple pouch bagging apparatus

Flexible chain conveyor

Multipurpose exercising apparatus

Liquid container

Seal press

Pharmaceutically active morpholinol

Polishing apparatus

Moisture-curing polyamides

Motor control system

Process for decoking catalysts

Endoscope signal level control

Aerobic exercise device

Manual floor sweeper

Developing unit for electro-photographic apparatus

1-(2-Aryl-4,5-disubstituted-1,3-dioxolan-2-ylmethyl)-1H-imidazoles and 1H-1,2,4-triazoles

Catalyzed fluorination of chlorocarbons

Wheelchair motorizing apparatus

Sliding exhaust brake system

Ion-channel forming peptides

Substitute milk fat compositions

Pulse width modulation operation circuit

Imidazodiazepine derivative

Cotton gin control

Heterocyclic-methylene-penems

Door clip

Multi-channel optical transmission system

Oscillator circuit

Workpiece feeding-ejection mechanism

Pest bait station

Multiple unit cigarette package

Golf club stand device

Clear impact-resistant syndiotactic polypropylene

Automatic trimming machine

Golf putt training apparatus

Thin layer ablation apparatus

Laterally supported flexible sign

Gypsum-cement system for construction materials

Motor vehicle wiper

Magnetic blanket for horses

Mower deck bumper

Method of preparing ferroelectric ceramics

Brake pressure control valve

Soybean cultivar 40064423

Variable delay memory system

Reversible code compander

High temperature diesel deposit tester

Outdoor enclosure with heated desiccant

Stacker bundler shuttle system

Passive lavatory cleanser dispensing system

Collapsible wheelbarrow

Polysaccharides and preparation thereof

Printer control system

Optical fiber strain relief device

Signal amplifier

Plastic orientation measurement instrument

Perfusive chromatography

Three dimensional space viewing device

Neck towel and adjustable clasp

Tissue anchoring system and method

Method of fabricating electronic circuits

Depth-resolved fluorescence instrument

Flash memory device

Photographic film and film cassette

Dual chamber water filter

Movement detector

Fuel system for multicylinder engines

Thin floss brush

Motor vehicle gearbox

Thermosensitive recording sheet

Lithography process

Non-aqueous electrochemical cell

Dual-wavelength x-ray monochromator

Splash guard

Process for coating glass

Plain bearing

Vertical storage toolbox

Thread wound golf ball

Hollow fiber separatory device

Start-up circuit for voltage regulators

Towable "V" rake agricultural machine

Automated nut-cracking apparatus and method

Asymmetric wire rope isolator

Power-generating control apparatus for vehicle

Process for concentrating fluids

Selective hydrogenation of olefins

Screw

Glass compositions

Display hook system

Triarylpropyl-azabicyclooctanes

Naso-gastric tube retainer