Preparation of 1-alkyl-1,4-dihydro-7-substituted-4-oxo-1,8-naphthyridine-3-carboxylic acids via the 3-acetyl analogs
United States Patent [19 Lesher et al.  
 &#39;[11] 3,875,172 ir/1%, Apr. 1,1975  
 [ PREPARATION OF I-ALKYL-1,4-DIHYDRO-7-SUBSTITUTED-4- OXO-l,8-NAPI-ITHYRIDINE-3-CARBOXYLIC ACIDS VIA THE 3-ACETYL ANALOGS [75] Inventors: George Y. Lesher; R. Pauline Brundage, both of Schodack, NY.  
 [73] Assignee: Sterling Drug Inc., New York, NY.  
 [22] Filed: Feb. 20, 1973 [21] Appl. No.: 333,541  
 [52] US. Cl... 260/2955 B, 260/295 R, 260/295 N,  
  260/296 N, 424/266 [5 l] Int. Cl C07d 31/36 [58] Field of Search 260/296 N, 295 N, 295.5 B  
 [56] References Cited UNITED STATES PATENTS 3,225,055 l2/l965 Lcshcr 260/2955 B FOREIGN PATENTS OR APPLICATIONS l.022,2l4 3/1966 United Kingdom 260/2955 B OTHER PUBLICATIONS Lappin et al.. Journal of Organic Chemistry, Vol. 15, pp. 377-380 Williams and Wikins Publishers, (1950). Klingsberg, Pyridine and Its Derivatives, Part Two, pp. 125-127 lnterscience Publishers, (1961). Klingsberg, Pyridine and Its Derivatives Part Three,  
 pp. 190-193 Interscience Publishers (1962).  
 Primary Examiner-Alan L. Rotman Attorney, Agent, or FirmRobert K. Bair; B. Woodrow Wyatt [57] ABSTRACT Process of reacting 2-amino-6-Q&#39;-pyridine (I) with lower-alkyl (lower-alkoxy)methyleneacetoacetate (II) to produce lower-alkyl a-(6-Q-2-pyridylaminomethylene)acetoacetate (III&#39;), heating lower-alkyl a-(6- Q-Z-pyridylaminomethylene)acetoacetate (III), to produce 3-acetyll ,4-dihydro-7-Q-4-oxol ,8- naphthyridine (IV) which is tautomeric with 3-acetyl- 4-hydroxy-7-Q-l,S-naphthyridine (IVA), reacting IV (or IVA) with a lower-alkylating agent to produce 3- acetyl- 1 lower-alkyl)- I ,4-dihydro-7-Q-4-oxol ,8- napthyridine (V) and converting V to l-(lower-alkyl)- l,4-dihydro-7-Q-4-oxol ,8-naphthyridine-3-carboxylic acid (VI), where Q is lower-alkyl, hydroxymethyl, lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)- pyridyl having one or two lower-alkyl substituents, and Q is like Q but excluding lower alkanoyloxyniethyl. The compounds of formula VI are known antibacterial agents. Also given are alternative routes of preparing III and IV where Q is lower-alkanoyloxymethyl by &#39;reacting the N-oxides of III and IV, respectively, where Q is methyl with a lower-alkanoic acid anhydride.-  
 18 Claims, No Drawings PREPARATION OF l-ALKYL-l,4-DIHYDRO-7-SUBSTITUTED-4-OXO- 1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACIDS VIA THE 3-ACETYL ANALOGS PROCESS AND INTERMEDIATES having one or two lower-alkyl substituents, and Q is like Q but excluding lower-alkanoyloxy-methyl. The compounds of formula VI are known antibacterial agents. In addition to said combination of the four steps, other process aspects of the invention are each individual step and the consecutive combinations of two or three steps.  
  The invention in its composition aspects resides in the compounds: lower-alkyl a-(6-Q-2-pyridylaminomethylene)-acetoacetate of the formula III I II COCH coon NIICH=C where R is lower-alkyl; 3-acetyl-l,4-dihydro-7-Q-4- oxo-l,8-naphthyridine and its tautomeric 3-acetyl-4- hydroxy-7-Q-l,8-naphthyridine of the respective formulas IV and IVA IVA and 3-acetyl-l-(lower-alkyl)-1,4-dihydro-7-Q-4-oxol,8-naphthyridine of the formula V where R, is lower-alkyl and Q in each of the formulas III, IV, IVA and V is defined as hereinabove.  
  The compounds of formulas III, IV, IVA and V are disclosed and claimed in copending application Ser. No. 453,928, filed Mar. 22, 1974.  
  Preferred process and composition embodiments, because of high antibacterial activity of final products and ready availability of intermediates are those where Q is methyl, hydroxymethyl, acetoxymethyl, 4-pyridyl, 3- pyridyl, 2-methyl-4-pyridyl and 2,6-dimethyl-4-pyridyl, and Q? is like Q but excluding acetoxymethyl.  
  Other process aspects of the invention comprise the steps of converting the compound of formula III or IV (or IVA) where Q is methyl, that is, lower-alkyl oz-(6- methyl-2-pyridylaminomethylene)acetoacetate or 3- acetyll ,4-dihydro-7-methyl-4 -oxo-l ,8-naphthyridine (or 3-acetyl-4-hydroxy-7-methyl-1,8-naphthyridine) to its 6-methyl-l-oxo-2-pyridyl derivative or 8-0xide, respectively, by reacting it with an agent capable of forming N-oxides and then reacting said 1-oxo-2-pyridyl compound or 8-oxide with a lower-alkanoic anhydride to produce the compound of formula III or Iv (or IVA), respectively, where Q is lower-alkanoyloxymethyl.  
  The term lower-alkyl, as used herein, e.g., as represented by R in formula III, Q in formulas III, IV, IVA and V, or R, in formula V, means alkyl radicals having from one to six carbon atoms which can be arranged as straight or branched chains, illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl, isobutyl, namyl, n-hexyl, and the like.  
  The term lower-alkoxy, as used herein, e.g., in the intermediate lower-alkyl (lower-alkoxy)methyleneacetoacetate (II), means alkoxy radicals having from one to six carbon atoms which can be arranged as straight or branched chains, illustrated by methoxy, ethoxy, n-propoxy, isopropoxy n-butoxy, 2-butoxy, isobutoxy, n-amoxy, n-hexoxy, and the like.  
  The term lower-alkanoyl, as used herein, e.g., in the definition of the Q substituent as loweralkanoyloxymethyl in formulas III, IV, IVA and V, means alkanoyl radicals having from one to six carbon atoms, including the straightand branched-chained radicals, illustrated by formyl, acetyl, propionyl (propanoyl), butyryl (butanoyl), isobutyryl (2- OCH methylpropanoyl) and caproyl (hexanoyl).  
  Illustrative of the Q substituent in I or the Q substituent in formulas III, IV, IVA and V where Q or Q is 4(or 3)-pyridyl having one or two lower-alkyl substituents are the following: 2-methyl-4-pyridyl, 2,6-dimethyl-4- pyridyl, 3-methyl-4-pyridyl, 2methyl-3-pyridyl, 6-methyl-3-pyridyl (preferably named 2methyl-5-pyridyl), 2,3-dimethyl-4-pyridyl, 2,5-dimethyl-4-pyridyl, 2- ethyl-4-pyridyl, 2-isopropyl-4-pyridyl, 2-n-butyl 4- pyridyl, 2-n-hexyl-4-pyridyl, 2,6-diethyl-4-pyridyl, 2,6-diethyl-3-pyridyl, 2,6-diisopropyl-4-pyridyl, 2,6-di n-hexyl-4-pyridyl, and the like. Because of ready availability, ease of preparation and/or high antibacterial activity of the final products, i.e., the l(lower- 3 alkyl)-l,4-dihydro-7-[mono(or di)-(lower-alkyl)-4(or 3 )-pyridyl]-4-oxol ,8-naphthyridine-3-carboxylic acids, preferred embodiments of this group are those where 4(or 3)-pyridyl is substituted by one or two methyl, especially the 2-methyl-4-pyridyl and 2,6-dimethyl-4-pyridyl compounds. Other preferred embodiments are those having unsubstituted-4(or 3)- pyridyl as Q.  
  As shown above, 3-acetyl- 1,4-dihydro-7-Q-4-oxo- I ,8-naphthyridine of formula IV is tautomeric with 3-acetyl-4-hydroxy-7-Q-l ,8- naphthyridine of formula IVA. As with all tautomeric systems, the rate of the transformation IV 2 IVA and the ratio IV/IVA are dependent on the thermodynamic enivronment, including the state of aggregation; so that measurements by any particular techniques do not necessarily have validity except under the conditions of the measurement, thereby, among other consequences, giving rise to problems for any simple designation of the physical embodiments. Thus, measurements of the infrared spectra, in potassium bromide admixture, or in chloroform or mineral oil, indicate existence predominantly as W and the names of the compounds herein therefore are preferably based on structure IV, although it is understood that either or both structures are comprehended.  
  The intermediate 2-amino-6-Q-pyridines (I) are either known or, where novel, are prepared from known compounds by conventional means as illustrated hereinbelow.  
  The molecular structures of the composition aspects (III, IV, IVA and V) of our invention were assigned on the basis of evidence provided by infrared, ultraviolet and nuclear magnetic resonance spectra, by chromatographic mobilities, and, by the correspondence of calculated and found values for the elementary analyses for representative examples.  
  The manner of making and using the instant invention will now be generally described so as to enable a person skilled in the art of chemistry to make and use the same, as follows:  
  The reaction of 2-amino-6-Q-pyridine (I) with lower-alkyl (lower-alkoxy)methyleneacetoacetate (II) to produce lower-alkyl a-(6-Q&#39;-2-pyridylaminomethylene)acetoacetate (III) is carried out by mixing the reactants (I and II), preferably in a molar ratio of 1:1 and preferably with stirring, either in the absence or presence of a suitable inert solvent, at about room temperature (20-25C.) to about 100C. Higher temperatures can be used but to no particular advantage. In some instances the reaction takes place exothermally. The reaction is conveniently run by mixing the reactants, preferably using ethyl ethoxymethyleneacetoacetate because of its ready availability and low cost, with stirring in a lower-alkanol, preferably ethanol, at room temperature and then warming the reaction mixture on a steam bath for a short period to ensure completion of the reaction. Other suitable solvents inert under the reaction conditions include acetonitrile, dimethylformamide, benzene, and the like.  
  The reaction of lower-alkyl a-(6-Q-2- pyridylaminomethylene)acetoacetate (III) to produce 3-acetyll ,4-dihydro-7-Q-4-oxo-I ,S-naphthyridine (IV) is carried out by heating III in an inert solvent at about 200325C., preferably at about 250300C. Such solvents include mineral oil, diethyl phthalate, dibenzyl ether, nitrobenzene, the eutectic mixture or diphenyl and diphenyl ether (Dowtherm A), and the like.  
 Alternatively, the above two steps can be run consec- 4 utively without isolation of compound III.  
  The reaction of 3-acetyl-l,4-dihydro-7-Q-4-oxo-l,8- naphthyridine (IV) or its tautomeric 3-acetyl-4- hydroxy-7-Q-l,8-naphthyridine (IVA) with a loweralkylating agent to produce 3-acetyl-l-(lower-alkyl)- 1,4-dihydro-7-Q-4-oxol ,S-naphthyridine (V) is generally carried out by reacting said compound of formula IV or IVA with a lower-alkyl ester of a strong inorganic acid or an organic sulfonic acid, said ester having the formula R An, where An is an anion of a strong inorganic acid or an organic sulfonic acid, e.g., chloride, bromide, iodide, sulfate, methanesulfonate, benzenesulfonate, and para-toluenesulfonate, and R, is loweralkyl. This alkylation is preferably run using a slight excess of the alkylating agent. The chloride, bromide or iodide is preferred because of the ready availability of the requisite lower-alkyl halides; and the reaction is carried out preferably in the presence of an acidacceptor. The acid-acceptor is a basic substance which preferably forms freely water-soluble by-products easily separable from the product of the reaction, including for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium alkoxides, potassium alkoxides, sodium amide, and the like. The acid-acceptor takes up the hydrogen halide (or I-IAn) which is split out during the course of the re-&#39; action and also takes up the proton from the l-position of IV or from the 4OH of IVA to generate the resulting anion of IV or IVA. The reaction can be carried out in either the presence of absense of a suitable solvent, but preferably in a solvent such as lower-alkanol, acetone, dioxane, dimethylformamide, dimethyl sulfoxide, hexamethyl phosphoramide, or a mixture of solvents, e.g., a mixture of water and a loweralkanol. The reaction is generally carried out at a temperature between about room temperature (about 20-25C.) and C, preferably heating on a steam bath in a stirred mixture of dimethylformamide and anhydrous potassium carbonate.  
  The conversion of 3-acetyl-l-(lower-alkyl)-l ,4- dihydro-7-Q-4-oxo-l,8-naphthyridine (V) to l-(loweralkyl)-1,4-dihydro-7-Q-4-oxo-l,8-naphthyridine-3- carboxylic acid (VI) is carried out by treating V with an agent capable of converting -COCI-l to COOH. This is conveniently done by reacting V with chlorine or bromine and an alkali metal hydroxide, preferably sodium or potassium hydroxide, or the corresponding alkali hypohalite. This conversion of V to VI also can be carried out by reacting V with iodine and pyridine followed by reacting the resulting -COCI-I NC H l with alkali, e.g., aqueous sodium or potassium hydroxide solution; the reaction with the iodine and pyridine is conveniently carried out by heating the reaction mixture on a steam bath and the reaction of the resulting pyridinium iodide compound is conveniently hydrolyzed in refluxing aqueous sodium or potassium hydroxide solution. Alternatively, the conversion of V to VI is carried out by reacting V with a mixture of potassium or sodium hydroxide and carbon tetrachloride, preferably at about 2580C. with stirring in a suitable aqueous solvent, e.g., water and a lower-alkanol, e.g., t-butanol. Also, the conversion ofV to V] is carried out by heating V with dilute aqueous nitric acid, preferably refluxing 20% nitric acid.  
 The reaction of lower-alkyl a-(6-methyl-2- pyridylaminomethylene)acetoacetate (III) or 3acetylpyridylaminomethylene )acetoacetate or 3-acetyl-1,4- dihydro-7-methyl-4-oxol ,8-naphthyridine-8-oxide or its tautomeric -8-oxide is carried out by reacting Ill or 1V(or IVA) with an oxidizing agent capable of forming N-oxides, preferably with a per acid, e.g., peracetic acid, perbenzoic acid, 3-chloroperbenzoic acid, and the like, or with other oxidizing agents, e.g., hydrogen peroxide, in&#39;thepresence of a suitable inert solvent, e.g., acetic acid, chloroform, and the like. The reaction is conveniently run by mixing the reactants carefully at room temperature (about 25C.) up to about 40-50C., preferably with stirring, and then heating the reaction mixture on a steam bath to ensure completion of the reaction.  
  The conversion of lower-alkyl a-(6-methyl-l-oxo-2- pyridylaminomethylene)acetoacetate or 3-acetyl-l,4- dihydro-7-methyl-4-oxo- 1 ,8-naphthyridine-8-oxide (or tautomer) to the corresponding lower-alkyl a-[6- (lower-alkanoyloxymethyl )-2-pyridylaminomethylene]acetoacetate or 3-acetyl- -dihydro-7-(lower-alkanoyloxymethyl)-4-oxo-1,8- naphthyridine (or tautomer), respectively, is carried out by reacting the 6-methyl-1-oxo-2-pyridyl compound or -8-oxide with a lower-alkanoic acid anhydride. The reaction is conveniently run using as solvent an excess of the anhydride or the corresponding alkanoic acid, e.g., acetic acid with acetic anhydride, or any suitable solvent unreactive to said anhydrides, e.g., acetonitrile, benzene, toluene, dimethylformamide, and the like. This reaction is generally carried out in the range of about 70-15&#39;0C., preferably on a steam bath.  
  The best mode contemplated for carrying out the invention is now set forth as follows:  
 EXAMPLE 1 Ethyl a( 6-methyl-2-pyridy1aminomethylene )acetoacetate To a solution containing 21.6 g. of 2-amino-6- methylpyridine in 100 ml. of ethanol was added with stirring 38 g. of ethyl ethoxymethyleneacetoacetate whereupon an exothermic reaction ensued causing the solution to warm up to about 67C. After being allowed to stand for about fifteen minutes, the reaction mixture was heated on a steam bath for 20 minutes, diluted to a volume of about 200 ml. with ethanol, allowed to cool and chilled. The resulting crystalline precipitate was collected, washed with cold ethanol, and dried in vacuo at 50C. to yield 6.5 g. of white crystalline ethyl a-(6- methyl-Z-pyridylaminomethylene)acetoacetate, 99-10lC.  
  Following the procedure described above in Example 1 but using in place of ethyl ethoxymethyleneacetoacetate a molar equivalent quantity of the appropriate lower-alkyl (lower-alkoxy)methyleneacetoacetate, there are obtained: methyl a-(6-methyl-Z-pyridylaminomethylene)acetoacetate using methyl methoxymethyleneacetoacetate; n-propyl pyridylaminomethylene)acetoacetate using n-propyl n-propoxymethyleneacetoacetate; isobutyl a-( 6- methyl-2-pyridy1aminomethylene)acetoacetate using isobutyl ethoxymethyleneacetoacetate; n-hexyl a-(6- methyl-2-pyridylaminomethylene)acetoacetate using n-hexyl n-hexoxymethyleneacetoacetate; and isopropyl a-( 6-methyl-2-pyridylaminomethylene )acetoacetate using isopropyl isopropoxymethyleneacetoacetate.  
 EXAMPLE 2 3-Acetyl-l,4-dihydro-7-methyl-4-oxo-1,8- naphthyridine A mixture containing 34.5 g. of ethyl a-(6-methyl-2- pyridylaminomethylene)acetoacetate and 700 ml. of mineral oil was heated with stirring to a temperature of 300C, kept at 300C. for about 30 seconds and allowed to cool with stirring to about C. The precipitate was collected, triturated with hot n-hexane and crystallized from dimethylformamide to yield 9.0 g. of 3-acetyl-1 ,4-dihydro-7-methyl-4-oxo-1,8- naphthyridine, m.p. 326329C. A sample was puritied for analysis by dissolving it in 10% aqueous potassium hydroxide solution, boiling the solution for about two minutes, neutralizing it with hydrochloric acid, and collecting the product, m.p. 338340C. A mixed melting point with the original material melting at 326329C. showed no depression.  
  The above cyclization of ethyl a-(6-methyl-2- pyridylaminomethylene)acetoacetate to produce 3- acetyl-l,4-dihydro-7-methy1-4-oxo-1,S-naphthyridine also was carried out in refluxing Dowtherm A (eutectic mixture of diphenyl and diphenyl ether) for 1 hour and by heating it in diethyl phthalate at 290C. for about 5 to 10 minutes.  
  3-Acetyl-1,4- dihydro-7-methyl-4-oxo-1,8-naphthyridine also is produced by following the above-described procedure but using in place of ethyl a-(6-methyl-2-pyridylaminomethylene)acetoacetate a molar equivalent quantity of other lower-alkyl a-(6-methyl-2-pyridylaminome thylene)acetoacetates, e.g., methyl, n-propyl, isopropyl, isobutyl or n-hexyl a-(6-methyl-2- pyridylaminomethylene)acetoacetate.  
 EXAMPLE 3 3Acetyl-l-ethyl-1,4-dihydro-7-methyl-4-oxo-l,8- naphthyridine To a heated (on steam bath) suspension containing 16.2 g. of 3-acetyl-l,4-dihydro-7-methyl-4-oxo-1,8- naphthyridine in ml. of dimethylformamide was added with stirring 16.5 g. of anhydrous potassium carbonate and the mixture stirred for about 15 minutes, during which period some dissolution had occurred. To the hot stirred mixture was added 16.2 ml. of ethyl iodide and the resulting mixture was heated with stirring for 90 minutes. The hot reaction mixture was filtered and the filtrate, from which crystals started to separate,  
 was chilled. The crystalline product was collected, triturated with warm water, washed sparingly with acetone and dried at 60C. in vacuo to yield 13.2 g. of 3-acetyll-ethyl-l ,4-dihydro-7-methyl-4-oxo-1,S-naphthyridine, m.p. 179-18 1C.  
 EXAMPLE 4 l-Ethyl- 1 ,4-dihydro-7-methyl-4-oxo-1 ,8- naphthyridine-3-carboxylic acid To a stirred solution kept at 010C. and containing 33 g. of sodium hydroxide (98%) in 280 m1. of water is added over a period of 15 minutes 48 g. of bromine. To this solution is added 23 g. of 3-acetyl-l-ethyl-1,4- dihydro-7-methyl-4-oxo-1,8-naphthyridine and the resulting reaction mixture is stirred for 1 hour at 010C., for 6 hours at room temperature (about 20-25C.) and for 30 minutes on a steam bath. The  
 hot reaction mixture is filtered and the filtrate is acidified with aqueous hydrochloric acid to precipitate the product. The precipitate is collected and recrystallized from acetonitrile to yield l-ethyl-l,4-dihydro-7- methyl-4-oxol ,8-naphthyridine-3-carboxylic acid, m.p. 228230C.  
  The conversion of 3-acetyl-l-ethyl-l,4-dihydro-7- methyl-4-oxol ,8-naphthyridine to l-ethyl-l ,4- dihydro-7-methyl-4-oxol ,8-naphthyridine-3- carboxylic acid also is carried out alternatively as follows: by warming on a steam bath for ninety minutes a mixture containing 2.42 g. of 3-acetyl-l-ethyl-l,4- dihydro-7-methyl-4-oxo-l,S-naphthyridine, 4.8 ml. of pyridine and 1.72 g. of iodine, allowing the reaction mixture to stand overnight at room temperature, removing the excess pyridine in vacuo, drying the residue in vacuo at 130C, heating the residue under reflux for 1 hour in 70 ml. of 1N potassium hydroxide solution in diethylene glycol which contained 2ml. of water, diluting the solution with water, acidifying the solution with hydrochloric acid, extracting the mixture with ether, extracting the product from the ether with dilute sodium bicarbonate, decolorizing the resulting aqueous solution with decolorizing charcoal, acidifying the resulting solution and collecting the crystalline l-ethyll.4-dihydro-7-methyl-4-oxol ,8-naphthyridine-3- carboxylic acid.  
  Another conversion of said 3-acetyl compound to the 3-carboxy compound is carried out by heating a mixture containing 1 g. of the 3-acetyl compound, 4 g. of powdered potassium hydroxide, 5 ml. of t-butanol, 3 ml. of water and ml. of carbon tetrachloride at 6070C. for 45 minutes, and then working up the reaction mixture as in the preparation given in the immediately preceding paragraph.  
  In another conversion of the 3-acetyl compound to l-ethyl-l ,4-dihydro-7-methyl-4-oxo-l ,8- naphthyridine-3-carboxylic acid, a 2.32 g. portion of said 3-acetyl compound is refluxed for 5 hours with 70 ml. of 20% nitric acid, the reaction mixture is evaporated to dryness in vacuo, the residue is boiled for minutes with acetic acid, the the separated 3- carboxylic acid is collected and recrystallized from acetonitrile.  
  Following the procedures described in Example 1 but using in place of 2-amino-6-methylpyridine a molar equivalent quantity of the appropriate 2-amino-6-Q- pyridine. the compounds of Examples 5-9 and 14-21 are obtained:  
 EXAMPLE 5 Ethyl oz-( 6-ethyl-2-pyridylaminomethylene acetoacetate using 2-amino-6-ethylpyridine.  
 EXAMPLE 6 Ethyl a-(6-n-propyl-2-pyridylaminomethylene)acetoacetate using 2-amino-6-n-propylpyridine.  
 EXAMPLE 7 Ethyl oz-(6-isobutyl-2-pyridylaminomethylene)acetoacetate using 2-amino-6-isobutylpyridine, the latter prepared by reacting 2-isobutylpyridine with sodamide.  
 EXAMPLE 8 Ethyl a-(6-n-hexyl-2-pyridylaminomethylene)acetoacetate using 2-amino-o-n-hexylpyridine, the latter prepared by reacting Z-n-hexylpyridine with sodamide.  
 EXAMPLE 9 Ethyl a-(6-hydroxymethyl-Z-pyridylaminomethylene)acetoacetate using 2-amino-6-hydroxymethylpyridine, which is prepared by reacting 2-acetylamino- 6-methylpyridine-l-oxide with acetic anhydride and hydrolyzing with aqueous potassium hydroxide solution the resulting 6-acetoxymethyl-2-acetylaminopyridine to remove both the O-acetyl and N-acetyl groups.  
 EXAMPLE 10 Ethyl a-(6-acetoxymethyl-Z-pyridylaminomethylene)acetoacetate is prepared by reacting the 6- hydroxymethyl compound of Example 9 with acetic anhydride or in two steps by first oxidizing ethyl a-(6- methyl-Z-pyridylaminomethylene )-acetoacetate to form the corresponding 6-methyl-l-oxo-2-pyridyl compound and reacting the latter compound with acetic anhydride.  
 EXAMPLE 1 l Ethyl a-(6-propionoxymethyl-2-pyridylaminomethylene)acetoacetate is prepared as in Example 10 but using propionic anhydride instead of acetic anhydride in each instance.  
 EXAMPLE l2 Ethyl a-(6-isobutyroxymethyI-Z-pyridylaminomethylene)acetoacetate is prepared as in Example 10 but using isobutyric anhydride instead of acetic anhydride in each instance.  
 EXAMPLE l3 Ethyl a-(6-hexanoyloxymethyl-Z-pyridylaminomethylene)acetoacetate is prepared as in Example 10 but using hexanoic acid anhydride instead of acetic anhydride in each instance.  
 a-[6-( 2-ethyl-4-pyridyl )-2-pyridylaminom eusing 2-amino-6-(2-ethyl-4- Ethyl thylene Iacetoacetate pyridyl )pyridine.  
 EXAMPLE 19 a-[ 6-( 3-ethyl-4-pyridyl )-2-pyridylaminomeusing 2-amino-6-(3-ethyl-4- Ethyl thylene]acetoacetate pyridyl )pyridine.  
 EXAMPLE Ethyl a-[ 6-( 2,6-dimethyl )4-pyridyl)-2- pyridylaminomethylene]acetoacetate using 2-amino-6- (2,6-dimethyl-4-pyridyl )pyridine.  
 EXAMPLE 21 Ethyl a-[6-( 3,5-dimethyl-4-pyridyl )-2- pyridylaminomethylene]acetoacetate using 2-amino-6- (3,5-dimethyl-4-pyridyl)pyridine.  
  Following the procedure described in Example 2 but using in place of ethyl a-(6-methyl-2-pyridylaminomethylene)acetoacetate a molar equivalent quantity of the appropriate ethyl a-(6-Q-2-pyridylaminomethylene)acetoacetate, the compounds of Examples 22-38 are obtained:  
 EXAMPLE 22 3-Acetyl-7-ethyll ,4-dihydro-4-oxol ,8- naphthyridine using ethyl pyridylaminomethylene)acetoacetate.  
 EXAMPLE 23 3-Acetyl-l ,4-dihydro-4-oxo-7-n-propyll ,8- naphthyridine using ethyl a-( 6-n&#39;propyl-2- pyridylaminomethylene)acetoacetate.  
 EXAMPLE 24 3-Acetyl-l ,4-dihydro-7-isobutyl-4-oxo-l ,8- naphthyridine using ethyl a-( 6-isobutyl-2- pyridylaminomethylene )acetoacetate.  
 EXAMPLE 25 3-Acetyl-7-n-hexyl-l ,4-dihydro-4-oxol ,8- naphthyridine using ethyl a-( 6-n-hexyl-2- pyridylaminomethylene )acetoacetate.  
 EXAMPLE 26 3-Acetyl- 1 ,4-dihyro-7-hydroxymethyl-4-oxo-1 ,8- naphthyridine using ethyl a-(6-hydroxymethyl-2- pyridylaminomethylene)acetoacetate.  
 EXAMPLE 27 7-Acetoxymethyl-3-acetyl-l ,4-dihydro-4-oxo- 1,8- naphthyridine using ethyl a-(6-acetoxymethyl-2- pyridylaminomethylene)acetoacetate. Alternatively, 7-acetoxymethyl-3-acetyll ,4-dihydro-4-oxol ,8- naphthyridine is prepared by reacting 3-acetyl-l,4- dihydro-7-methyl-4-oxo-l,S-naphthyridine with peracetic acid to form its 8-oxide and reacting the 8-oxide with acetic anhydride.  
 EXAMPLE 28 3-Acetyl-l ,4-dihydr0-4-oxo-7-propionoxymethyl- 1,8-naphthyridine using ethyl a-(6-propionoxymethyl- Z-pyridylaminomethylene)acetoacetate. Alternatively, 3-acetyll ,4-dihydro-4-oxo-7-propionoxymethyl-l ,8- naphthyridine is prepared by reacting 3-acetyl-l,4- dihydro-7-methyl-4-oxo-l,8-naphthyridine with pera-( 6-ethyl-2- acetic acid to produce its 8-oxide and reacting the 8- oxide with propionic anhydride.  
 EXAMPLE 29 3-Acetyl-l ,4dihydro-7-isobutyroxymethyl-4-oxo- 1,8-naphthyridine using ethyl a-(6-isobutyroxymethyl- Z-pyridylaminomethylene)acetoacetate. Alternatively, 3-acetyll ,4-dihydro-7-isobutyroxymethyl-4-oxo-l ,8-  
  10 naphthyridine is prepared by reacting 3-acetyl-1,4- dihydro-7-methyl-4-oxo-1,8-naphthyridine with peracetic acid to produce its 8-oxide and reacting the 8- oxide with isobutyric anhydride.  
 EXAMPLE 30 EXAMPLE 32 3-Acetyl-l,4-dihydro-4-oxo-7-(3-pyridy])-1,8  
 naphthyridine using ethyl a-[6-( 3-pyridyl)-2- pyridylaminomethylene]acetoacetate.  
 EXAMPLE 33 3-Acetyll ,4-dihydro-7-( 2-methyl-4-pyridyl)-4-oxol,8-naphthyridine using ethyl a-[6-(2-methyl-4- pyridyl)-2-pyridylaminomethylene]acetoacetate.  
 EXAMPLE 34 3-Acetyll ,4-dihydro-7-( 3-methyl-4-pyridyl)-4-oxo- 1,8-naphthyridine using ethyl a-[6-(3-methyl-4- pyridyl)-2-pyridylaminomethylenelacetoacetate.  
 EXAMPLE 35 3-Acetyl-7-(2-ethyl-4-pyridyl)-1,4-dihydro-4-oxol,8-naphthyridine using ethyl a-[6-(2-ethyl-4-pyridyl)- 2-pyridylaminomethylene]acetoacetate.  
 EXAMPLE 36 3-Acetyl-7-( 3-ethyl-4pyridyl 1 ,4-dihydro-4-oxo- 1,8-naphthyridine using ethyl a-[6-(3-ethyl-4-pyridyl)- 2-pyridylaminomethylene]acetoacetate.  
 EXAMPLE 37 3-Acetyl-1,4-dihydro-7-(2,6-dimethyl-4-pyridyl)-4- oxo-l,8-naphthyridine using ethyl a-[6-(2,6-dimethyl- 4-pyridyl)-2-pyridylaminomethylene]acetoacetate.  
 EXAMPLE 38 3-Acetyl-1,4-dihydro-7-(3,5- dimethyl-4-pyridyl)-4-oxo-l ,8-naphthyridine using ethyl a-[6-(3,5-dimethyl-4-pyridyl)-2- pyridylaminomethylene]acetoacetate.  
  Following the procedure described in Example 3 but using in place of 3-acetyl-l,4-dihydro-7-methyl-4-oxo- 1,8-naphthyr&#39;idine a molar equivalent quantity of the appropriate 3-acetyll ,4-dihydro-4-oxo-7-Q-l ,8- naphthyridine, the compounds of Examples 39-55 are obtained:  
 EXAMPLE 39 3-Acetyl-l,7-diethyl-l,4-dihydro-4-oxo-1,8- naphthyridine using 3-acetyl-7-ethyl-l,4-dihydro-4- oxo-1,8-naphthyridine. Similarly, using said 7-ethyl iphthyridine-3-carboxylic acid using 3-acetyl-l- 1,4-dihydro-7-(2-methyl-4-pyridyl)-4-oxo-1,8- hyridine.  
 EXAMPLE 8O thyl-l,4-dihydro-7-(3-methyl-4-pyridyl)-1,8- hyridine-3-carboxylic acid using 3-acetyl-l-ethyl- .hydro-7-( 3-methyl-4-pyridyl l ,S-naphthyridine.  
 EXAMPLE 81 thyl-7-( 2-ethyl-4-pyridyl l ,4-dihydro- -l,8-naphthyridine-3-carboxylic acid using 3- l -l-ethyl-7-(2-ethyl-4-pyridyl)-1,4-dihydro-4- ,S-naphthyridine.  
 EXAMPLE 82 thyl-7-(3-ethyl-4-pyridyl)-l,4-dihydro-4-oxo-1,8- .hyridine-3-carboxylic acid using 3-acetyl-l-ethyl- :thyl-4-pyridyl )-l ,4-dihydro-4-oxo- 1,8-  
 :hyridine.  
 EXAMPLE 83 thyll ,4-dihydro-7-( 2,6-dimethyl-4-pyridyl)-4- ,8-naphthyridine-3-carboxylic acid using 3- H -ethyll ,4-dihydro-7-( 2,6-dimethyl-4-pyridyl -l ,8-naphthyridine.  
 EXAMPLE 84 thyl-l ,4-dihydro-7-( 3 ,5-dimethyl-4-pyridyl)-4- ,8-naphthyridine-3-carboxylic acid using 3- ll -ethyll ,4-dihydro-7-( 3,5-dimethyl-4-pyridyl -l ,S-naphthyridine.  
  claim: l&#39;he process which comprises reacting 2-amino-6- &#39;ridine with lower-alkyl (lower-alkoxy)meneacetoacetate to produce lower-alkyl a-( 6-Q&#39;-2- ylaminomethylene)acetoacetate, heating lowera-(6-Q-2-pyridylaminomethylene)acetoacetate in ert solvent at about 200-335C. to produce 3- l-l,4-dihydro-7-Q-4-oxo-1,8-naphthyridine, reg said 4-oxo-l,8-naphthyridine with a lowerlting agent to produce 3-acetyl-l-(lower-alkyl)- ihydro-7-Q-4-oxo- 1 ,S-naphthyridine and converthe latter to l-(lower-alkyl)-l,4-dihydro-7-Q-4- ,8-naphthyridine-3-carboxylic acid by reaction an agent capable of converting COCH to lOH, where Q is lower-alkyl, hydroxymethyl, low- :anoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)- yl having one or two lower-alkyl substituents, and like Q but excluding lower-alkanoyloxymethyl. The process which comprises reacting 2-amino-6- Iridine with lower-alkyl (lower-alkoxy)meneacetoacetate to produce lower-alkyl a-(6-Q&#39;-2- ylaminomethylene)acetoacetate, where Q is lowtyl, hydorxymethyl, 4(or 3)-pyridyl or 4(or 3)- yl having one or two lower-alkyl substituents. The process which comprises heating lower-alkyl Q-2-pyridylaminomethylene)acetoacetate in an solvent at about 200-335C. to produce :tyll ,4-dihydro-7-Q-4-oxol ,8-naphthyridine,  
  Q is lower-alkyl, hydroxymethyl, lowerloyloxymethyl, 4(or 3)pyridyl or 4(or 3)-pyridyl lg one or two lower-alkyl substituents.  
 The process which comprises converting 3-acetylwer-alkyl )-l ,4-dihydro-7-Q-4-oxo-l ,8-  
 thyridine to 1-(lower-alkyl)-1,4-dihydro-7-Q-4- l,8-naphthyridine-3-carboxylic acid by reaction with an agent capable of converting COCH to COOH, said agent selected from: a) chlorine or bromine and an alkali metal hydroxide; b) iodine and pyridine followed by reacting the resulting 3-carbonylmethylpyridinium iodide with alkali; c) potassium or sodium hydroxide and carbon tetrachloride in water and a lower-alkanol; or, d) aqueous nitric acid; where Q is lower-alkyl, hydroxymethyl, lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)-pyridyl having one or two lower-alkyl substituents.  
  5. The process which comprises reacting 2-amino-6- Q-pyridine with lower-alkyl (lower-alkoxy)methyleneacetoacetate to produce lower-alkyl a-(6Q-2- pyridylaminomethylene)acetoacetate, heating loweralkyl a-(6-Q-Z-pyridylaminomethylene)acetoacetate in an inert solvent at about 200335C. to produce 3- acetyl-l ,4-dihydro-7-Q-4-oxo-1,8-naphthyridine and reacting 3-acetyll ,4-dihydro-7-Q-4-oxo-l ,8- naphthyridine with an alkylating agent to produce 3- acetyll lower-alkyl l ,4-dihydro-7-Q-4-oxol ,8- naphthyridine, where Q is lower-alkyl, hydroxymethyl, lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)- pyridyl having one or two lower-alkyl substituents and Q is like Q but excluding lower-alkanoyloxymethyl.  
 6. The process which comprises heating lower-alkyl a-(6-0-2-pyridylaminomethylene)acetoacetate in an inert solvent at about 200335C. to produce 3-acetyl- 1,4-dihydro-7-Q-4-oxol ,8-naphthyridine, reacting said 4-oxo-1,8-naphthyridine with a lower-alkylating agent to produce 3-acetyl-l-(lower-alkyl)-1,4-dihydro- 7-Q-4-oxo-1,8-naphthyridine and converting the latter to 1-( lower-alkyl )-1 ,4-dihydro-7-Q-4-oxo-l ,8- naphthyridine-3-carboxylic acid by reaction with an agent capable of converting --COCH to COOH, where Q is lower-alkyl, hydroxymethyl, loweralkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)-pyridyl having one or two lower-alkyl substituents.  
  7. The process which comprises reacting 2-amino-6- Q&#39;-pyridine with lower-alkyl (lower-alkoxy)methyleneacetoacetate to produce lower-alkyl a-(6-Q-2- pyridylaminomethylene)acetoacetate and heating lower-alkyl a-(6-Q-2-pyridylaminomethylene)acetoacetate in an inert solvent at about 200335C. to produce 3-acetyll ,4-dihydro-7-Q-4-oxo-l ,8- naphthyridine, where Q is lower-alkyl, hydroxymethyl, lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)- pyridyl having one or two lower-alkyl substituents, and Q is like Q but excluding lower-alkanoyloxymethyl.  
  8. The process which comprises heating lower-alkyl a-(6-0-2-pyridylaminomethylene)acetoacetate in an inert solvent at about 200-335C. to produce 3-acetyli ,4-dihydro-7-Q-4-oxol ,8-naphthyridine and reacting 3-acetyl-l ,4-dihydro-7 -Q-4-oxol ,S-naphthyridine with an alkylating agent to produce 3-acetyl-1-(loweralkyl)-l,4-dihydro-7-Q-4-oxo-1,8-naphthyridine, where Q is lower-alkyl, hydroxymethyl, loweralkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)-pyridyl having one or two lower-alkyl substituents.  
  9. The process which comprises reacting 3-acetyll,4-dihydro-7-Q-4-oxo-1,8-naphthyridine with a loweralkylating agent to produce 3-acctyl-1-(lower-alkyl)- 1,4-dihydro-7-Q-4-oxol ,8-naphthyridine and converting the latter to l-(lower-alkyl)-l,4-dihydro-7-Q-4- oxo-l,8-naphthyridine-3-carboxylic acid by reaction with an agent capable of converting COCl-l to -COOH, said agent selected from: a) chlorine or bromine and an alkali metal hydroxide; b) iodine and pyridine followed by reacting the resulting 3-carbonylmethyl-pyridinium idoide with alkali; c) potassium or sodium hydroxide and carbon tetrachloride in water and a lower-alkanol; or, (1) aqueous nitric acid; where Q is lower-alkyl, hydroxyethyl, loweralkanoyloxymethyl, 4(or 3)-pyridyl or 4(or 3)-pyridyl having one or two lower-alkyl substituents.  
  10. The process according to claim 1 where Q and Q are each methyl and the lower-alkylating agent is an ethylating agent to produce 1-ethyl-l,4-dihydro-7- methyl-4-oxo-l,8-naphthyridine-3-carboxylic acid.  
  11. The process according to claim 2 where Q is methyl and lower-alkyl is ethyl.  
  12. The process according to claim 3 where Q is methyl and lower-alkyl is ethyl.  
  13. The process according to claim 4 where Q and Q are each methyl and lower-alkyl is ethyl.  
  14. The process according to claim 5 where Q and Q are each methyl, lower-alkyl in each instance is ethyl and an ethylating agent is used in the last step.  
  15. The process according to claim 6 where Q is methyl, lower-alkyl in both instances is ethyl and an ethylating agent is used in the second step.  
  16. The process according to claim 7 where Q and Q areeach methyl, lower-alkyl is ethyl and loweralkoxy is ethoxy.  
  l7.-The process according to claim 8 where Q is methyl, lower-alkyl in both instances is ethyl and an ethylating agent is used in the second step.  
  18. The process according to claim 9 where Q is methyl, lower-alkyl is ethyl and an ethylating agent is UNITED STATES PATENT OFFICE CERTIFICATE OF CORECTION PATENT NO. 5 172 Page 1 DATED April 1, 1975 INVENTOR(S) 1 George Y. Lesher and Ruth Pauline Brundage H is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:  
 Column line 6, Omit &#34;PROCESS AND INTERMEDIATES&#34;.  
 line 23, &#34;Iv&#34; should read IV line 62 line 68, &#34;or&#34; should read of Column Column 2 Column 3 Column line 30, &#34;of&#34;, first occurrence, should read or Column 5 line 20, &#34;3-acetyl-&#34; should read &#34;Zmethyl&#34; should read 2-;nethyl 3-acetyl-l,4- and line 21, omit the before &#34;dihydro&#34;.  
 Column 11, line 55, insert &#34;3&#34; before &#34;-acetyl. Column ll, line 59, &#34;sio&#34; should read iso Column 12, line 52, change &#34;dihyto read dihydroand line 55, omit &#34;0-&#34;.  
 Column 14, line 62, insert &#34;1&#34; before &#34;-methyl&#34;. Column 15, one to five letters have been omitted from the left-hand margin of each printed line of text. The corrections are listed below line by line, plus any errors that occur elsewhere in the line.  
 line 1, add na line 11, add l-E line 2, add ethylline 12, add 4=-oxo line 3, add napht line 13, add acetyl line 6 add l-E line 14, add oxo-l -F; line 7, add napht line 17, add l-E line 8, add 1,4-di line 18, add napht ----7 UNITED STATES PATENT OFFICE CERTIFICATE OF CQRRECTIQN PATENT NO. 3,875,172 Page 2 DATED April 1, 1975 INVENTOR( 1 George Y. Lesher and Ruth Pauline Brundage It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:  
 line 19, add 7-(3-e line 45, add oxo l =3 line 20, add napht line 46, add with --g line 23, add 1-2: line 47, add co -f line 24, add oxo-l line 48, add er-alk line 25, add acety line 49, add pyrid --7 line 26, add 4-oxo- ----7 line 50, add Q is -7 line 29, add 1-52 ---7 line 52, add Q&#39;-py line 30, add oxo-l line 53, add thyle line 31, add acety line 54, add pyrid -f;  
 line 32, add 4-oxo line 55, add er-a.lk and &#34;hydorxymethyl&#34; should reafi line 33, add We hydroxymethyl line 34, add l. &#39;1  
  line 35, add Q&#39;-py iine 56, add pyri ---1 line 36, add thylen line 58, add cx-(6- 7 5 line 37, add pyrid line 59, add inert line 38, add alkyl line 60, add 3-ace line 39, add an in line 61, add where line 40, add acety line 62, add alkan --7 line 41, add acting line 63, add havin =3 line 42, add alkyla line 65, add 1-10 line 43, add 1,4-d line 66, add naph and,  
 line 44, add ing t line 67, add oxo-l UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,875, 172 Page 3 DATED 1 April 1, 1975 INVENTOWS) i George Y. Lesher and Ruth Pauline Brundage it is certrfied that error appears in the above-identified patent and that saro&#39; Letters Patent are hereby corrected as shown below:  
 Column 16, line 13, &#34;(6Q&#39;&#34; should read (6-Q Column l7 line 5, &#34;hydroxyethyl&#34; should read hydroxymethyl Signed and geaied this twenty-second Day Of July 1975 [SEAL] AIIESI. RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner of Parenrs and Trademarks