FI58921B - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ANALYZED 2-SUBSTITUTES-OXAZOLO- (5,4-B) -PYRIDINER - Google Patents

Description

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JMTa LJ UTLÄGGNINGSSKRIFT

C, .e, Patc-nlfcl «ySr.no tty 11 05 1931 • (45)

Patent Meddelat (51) Kv.tk.Vct · 3 C 07 D 4-98 / 04 FINLAND —FINLAND (21) PM * nttlt «k.mu« -Pt «> a ™ ökivlnf 800611 (22) HukumlipiM - Amökntnpd ** 28.02.80 ^ ^ (23) AlkupUvt — Glttighcudag 22.05-73 (41) Tulkit lulklMksI - Bllvtc offuncllg 28.02.80 hlMII. |> MIWIMta ηηΜ ¥. | ΙΜ) Μ.η. "...,

Patent- och r * gi «t * r» tyr * l «* n '' Ansekan uttagd och utl. * Krtft # n pubtlcurtd iU. 01. ol (32) (33) (31) Requested «arrives — 8« glrd priority lU.06.72 USA (US) 262898 (71) Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey, USA (US) (72) Tsung-Ying Shen, Westfield, New Jersey, Robert Long Clark, Woodbridge,

New Jersey, Arsenio Alessandro Pessolano, Colonia, New Jersey, Bruce Edward Witzel, Westfield, New Jersey, Thomas Joseph Lanza, Jr., Edison, New Jersey, USA (74) Oy Roister Ab (5U) Method of Therapeutically Applicable 2 for the preparation of -substituted-oxazolo- [5, U-b] pyridines - Förfarande för framställning av therapeutiskt användbara 2-substituerade-oxazolo- [5, U-b7-pyridine (62) Separated from application 1657/73 (patent 57 ^ 17 This invention relates to a process for the preparation of therapeutically useful 2-substituted-oxazolo-η 5,4-β-pyridines.

The compounds of the invention can be described by the general structural formula:

. OF

2,58921 wherein X is R wherein · is n is 0-3 and X is (1) halogen, (2) lower alkoxy of 1-3 carbon atoms, (3) lower alkyl of 1-5 carbon atoms, (4) nitro, (5) trifluoromethyl or (6) cyano; R is (a) chlorine, (b) lower alkyl of 1 to 5 carbon atoms, (c) nitro, (d) trifluoromethyl or (e) lower alkoxy of 1 to 3 carbon atoms and wherein m is 0 to 2 ; provided that when m is zero then n is not zero and R is not 4-lower alkylphenyl.

The process according to the invention for the preparation of these compounds is mainly characterized in that the compound of the formula I

<~ ΖΎ

OH

is reacted with a compound of formula II

° \

^^ C-R II

Z "

O

f ·

wherein Z is -OH, halogen or R-C-O-, by heating when O

Z is £ _ £ _q? heating in the presence of polyphosphoric acid when Z is -OH; or in the presence of an acid scavenger and then heating with a condensing agent when Z is halogen to form a compound of formula: 3,58921

OF

r ^ W

R1--> - R

where R is as defined above.

In particular, the invention provides compounds of the structural formula:; - in which n is 1-2, R 'is hydrogen or C 1-4 lower alkyl and X is (a) lower alkyl (b) lower alkoxy (c) chlorine (d) fluorine (e) trifluoromethyl.

Since the anti-inflammatory properties of steroids as well as the undesirable side effects of steroid therapy have become well known, non-steroidal anti-inflammatory agents have been widely sought. In this study, a few highly effective, useful, and non-steroidal agents have been found that, however, have their own unwanted side effects and contraindications.

The present invention has now provided novel compounds which are highly effective as anti-inflammatory, antipyretic and analgesic agents. Like other known potent anti-inflammatory agents, they are inhibitors of prostaglandin E synthesis. The new compounds are valuable in the treatment of joint and skin diseases and conditions that may be affected by anti-inflammatory drugs. In general, they can be used to treat a wide variety of conditions with one or more symptoms of inflammation, fever, and pain. These include diseases such as rheumatoid arthritis, osteoarthritis, gout, infectious inflammation, rheumatic fever, and inflammatory conditions of the ocular system. As described above 4,58921, the compounds of the invention have also been found to have a useful amount of analgesic and antipyretic activity in practice.

For said purposes, the compounds may be administered orally, topically, parenterally, by inhalation spray, or rectally in dosage units containing conventional non-toxic pharmaceutically acceptable carriers, excipients, and media. The term parenteral as used herein means subcutaneous, intravenous, intramuscular or intrasternal injection or fluid injection technique. In addition to treating warm-blooded animals such as mice, rats, horses, dogs, cats, etc., the compounds of the invention may also be used to treat humans.

The following table shows the anti-inflammatory effect of oxazolo-5,4-b-pyridines. It was determined as follows: A group of 6 male rats (Sprague Dawley) is formed and each rat is orally administered the test compound one hour before injecting 0.1 ml of a 1% suspension of carrageenan into the right hind paw. Immediately after this and 3 hours later, the volume of the foot is measured. The difference between the initial volume and the final volume indicates the magnitude of the inflammation (edema) that has occurred. The values given in the table are inhibition percentages.

Table I

* 3 6 '5' -OCM? X R1 Esto-% 2'-CN H 61 2 '-Cl H 50 21-Br H 31 2', 6'-diF H 50 4'-FH 27 4'-Cl H 14 4 * -OCH3 H 29 31- FH 35 4'-CN H 17 5 58921 X R1 Esto-% 3'-CF3 H 7 2'-FH 61 3'-CH3 H 14 2'-NO2 H 57 H 5 -NO2 27 21-F 5-CH3, 6-C2H5- 22 21-F5-NO2 12 2'-CN 5-CH3-6-C2H5 11 2'-Br 5-CH3,6-C2H5 3 2'-F 5_CH3 19 2'-NH2-4'- FH 13 2'-Br-5'-OCH3 H 23 2'-CN-5'-OCH3 H 10

The novel 2-substituted-oxazolo [5,4-b] pyridines of the invention are prepared by condensate cyclization of an amino-hydroxypyridine with a carboxylic acid, acid anhydride or acid halide according to the following reaction scheme: o | n.

r1 - ^ \> R -> R1_ (fiV] | ^ \ - I <m ^ // 'm U. JJ ___ / ^ o | h_z

Depending on the condensing agent used and, to some extent, the aminohydroxypyridine used, the reaction may take place either in one step at the ring closure or in two steps, the first step forming an amide and the second step forming an oxazolo ring at the ring closure. In many cases, it is preferred and appropriate to isolate the intermediate amide and perform the ring closure in a second separate step.

For example, osazolopyridines can be prepared by condensing aminohydroxypyridine with an acid anhydride with or without the use of a condensing agent such as polyphosphoric acid or polyphosphoric acid ester. In either case, the aminohydroxy-pyridine is mixed with 1 to 3 molar equivalents of the acid an-6,58921 hydride and heated to reflux for about 5 to 30 minutes. After cooling, the excess polyphosphoric acid and anhydride are decomposed and the product is separated in a known manner.

However, oxazolopyridines are usually prepared by condensing an amino-hydroxypyridine with a carboxylic acid under the influence of a polyphosphoric acid or a polyphosphoric acid ester. The mixture of pyridine and a small excess of carboxylic acid is heated in the presence of polyphosphoric acid or an ester thereof for 5 minutes to about 1 hour at a temperature of about 100-300 ° C, preferably about 130-230 ° C. The polyphosphoric acid or its ester is decomposed with water and the desired product is obtained by making the solution alkaline.

Oxazolopyridines can also be prepared via an amide intermediate by reacting an acid halide with an amino-hydroxypyridine, preferably in approximately equimolar amounts, in the presence of an acid scavenger. Any of the acid scavengers conventionally used in N-acylation may be used, but it has been found suitable to use an organic base such as pyridine, triethylamine or an equivalent base. Sufficient organic base may be used to also act as a solvent, or another inert organic solvent such as dimethylformamide, benzene, dioxane, glyme or diglyme or the like may be used as the reaction medium. The amide obtained in the above reaction is then cyclized to form oxazolopyridine by heating a mixture of it and a condensing agent such as phosphorus oxychloride at reflux for about 1-20 hours, or by heating the amide with polyphosphoric acid at about 100-300 ° C, preferably about 130-230 ° C. -60 minutes. Instead of phosphorus oxychloride, other condensing agents such as phosphorus pentoxide, phosphorus oxybromide, thionyl chloride and phosphorus tribromide can be used.

The following examples illustrate embodiments of the method of the invention.

Example 1 2- (2-fluorophenyl) oxazolo [5,4-b] pyridine Step A; Preparation of 3- (2-fluorobenzoylamino) -2-pyridone To a solution of 3.3 g (0.03 mol) of 3-amino-2-pyridone in 75 ml of pyridine cooled in an ice bath was added portionwise 6.3 g (0, 04 moles) of 2-fluorobenzoyl chloride over 5 minutes. After stirring for 15 hours at ambient temperature, the mixture was poured into ice water. The resulting precipitate was collected by filtration, washed with water and crystallized from ethanol to give 3- (2-fluorobenzoylamino) -2-pyridone, m.p. 223 ° C.

7,58921

Step B: Preparation of 2- (2-fluorophenyl) oxazolo [5,144-b] pyridine

A solution of 5.4 g of 3- (2-fluorobenzoylamino) -2-pyridone in 55 ml of phosphorus oxychloride was heated under reflux for 5 hours. Excess phosphorus oxychloride was evaporated off and the residue was treated with ice. The resulting precipitate was collected and crystallized from benzene / petroleum ether to give 3.1 g of 2- (2-fluorophenyl) oxazolo [5,4-t] pyridine, m.p. 119-120 ° C.

Using steps A and B of the procedure of Example 1, but replacing the 2-fluorobenzoyl chloride used in step A with an equivalent amount of the acid chloride of formula R-COCl, 3- (R-carbonylamino) -2-pyridones and 2-R-oxazolo [4,4-b] were obtained. the pyridines shown in Table II according to the following reactions:

Step A R * -L + ^ C-R -— V R1 '- \ ~ H 0 H 0 0

1 r ^ V-NH '"" R

Step B R1_1 p 1__ | R

mit pocun / * -r / ^ N ^ 'Q / H °

Table II

R ^ R Melting point of the product (° C)

Step A Step B

H 2-nitrophenyl 233-235 123-125 H 2-cyanophenyl 282 221 H 4-nitrophenyl 307 (dec.) 242-243 H 3-fluorophenyl 214-215 90-91 H 4-methylphenyl 210-211 115-116 8 58921

Talukko II (continued) r "* R Melting point of the product (° C)

Step A Step B

H 4-cyanophenyl 258-260 220-221 H 3-trifluoromethylphenyl 205-207 147-149 H 3-methylphenyl 199-200 101-102 H 4-fluorophenyl 200-202 117-118 H 4-methoxyphenyl 249-251 146-148 H 4-chlorophenyl 215-217 153-154 H 3-methoxyphenyl 198-200 107-109 H 2-chlorophenyl 192-194 87-89 H 2,4-dichlorophenyl 253-254 135-137 H 3-chlorophenyl 206-207 156 -158

Example 2 5-Chloro-2-phenyloxazolo [5,4-b] pyridine

Step A; Preparation of 5-chloro-3-nitro-2-pyridone 12.8 g (0.1 mol) of 2-amino-5-chloropyridine were added to 50 ml of concentrated sulfuric acid. To this was slowly added 25 ml of concentrated nitric acid with stirring. After the exothermic reaction was attenuated, the mixture was cooled and poured onto ice. The precipitate was collected and added to a mixture of 12 ml of concentrated sulfuric acid and 150 ml of water. To this solution, cooled to 0 ° C, 7 g of sodium nitrite was added portionwise and the resulting mixture was allowed to self-warm to room temperature. After cooling, the precipitate was collected and recrystallized from dimethylformamide / ethanol to give 5-chloro-3-nitro-2-pyridone, m.p. 225-227 ° C.

Step B: Preparation of 3-benzoylamino-5-chloro-2-pyridone 5.3 g of 5-chloro-3-nitro-2-pyridone were hydrogenated in 225 ml of ethanol and 6 ml of acetic acid in the presence of 0.6 g of 5 % palladium on carbon. The catalyst was removed by filtration and the filtrate was concentrated to dryness. The residue was dissolved in 75 ml of pyridine, cooled with ice and treated with 4.8 g of benzoyl chloride over 15 minutes. The ice bath and reaction mixture were allowed to warm to room temperature. The mixture was poured into 200 g of ice. Upon dilution with 500 ml of water, an oil separated which, on washing with water, solidified (4 g). Crude 3-benzoylamino-5-chloro-2-pyridone was used directly in the next step.

Step C: Preparation of 5-chloro-2-phenyloxazolo [S, 4-b] pyridine

A mixture of 2.1 g of crude 3-benzoylamino-5-chloro-2-pyridone and 7 g of polyphosphoric acid was heated at 140-150 ° C for 10 minutes. Ice water was added, the precipitate was collected as a filter and the solids were extracted with hot benzene. The benzene was evaporated and the residue was taken up in ether, filtered through alumina and concentrated to dryness to give 300 mg of 5-chloro-2-phenyloxazolo [4-b] pyridine, m.p. 150-161 ° C.

Example 3 4-Methyl-2-phenyloxazolo [5,4-b] pyridine

Step A: Preparation of 3-benzoylamino-4-methyl-2-pyridone 7.7 g of 4-methyl-3-nitro-2-pyridone was hydrogenated in 50 ml of methanol using 0.25 g of 5% palladium on carbon. The catalyst was removed by filtration and the solvent was evaporated.

The solid residue was dissolved in 60 ml of pyridine, cooled to 20 ° C and treated with 6.5 ml of benzoyl chloride. After allowing to stand overnight, the mixture was poured into 200 ml of ice water. The precipitate (5 g) was collected and crystallized from methanol to give 3-benzoylamino-4-methyl-2-pyridone, m.p. 264-265 ° C.

Step B: Preparation of 4-methyl-2-phenyloxazolo [4,4-b] pyridine

A solution of 3 g of 3-benzoylamino-4-methyl-2-pyridone in 30 ml of phosphorus oxychloride was heated on a steam bath for 66 hours. The mixture was poured onto ice and neutralized with ammonium hydroxide. The precipitate was collected and crystallized from methanol to give 1.4 g of 4-methyl-2-phenyloxazolo [5,4-b] pyridine, m.p. 91-92 ° C.

Example 4 5-Nitro-2-phenyloxazolo [5,4-b] pyridine

Step A: Preparation of 3-amino-5-nitro-2-pyridone

A solution of 5.5 g of 3,5-dinitro-2-pyridone in 200 ml of methanol was adjusted to pH 8 with ammonium hydroxide. A solution of 10.8 g of sodium sulfide nonahydrate in 30 ml of water was added at 60-65 ° C. After 1 hour at 60-65 ° C, the solvent was evaporated and the residue was extracted with hot benzene and acetic acid to neutralize the sodium salt. The benzene was decanted and cooled to give a precipitate. Recrystallization from methanol gave 3-amino-5-nitro-2-pyridone, m.p. 200-201 ° C.

Step B: Preparation of 3-benzoylamino-5-nitro-2-pyridone

A solution of 100 mg of 3-amino-5-nitro-2-pyridone in 1.5 ml of pyridine was cooled and treated with 200 mg of benzoyl chloride. After 2 hours, water was added. The separated oil was washed with water and mixed with ether. The resulting solid was recrystallized from ethyl acetate to give 3-benzoylamino-5-nitro-2-pyridone, m.p. 267-268 ° C.

Step C: Preparation of 5-nitro-2-phenyloxazolo [5,4-b] pyridine

A mixture of 300 mg of 3-benzoylamino-5-nitro-2-pyridone and 1.5 g of polyphosphoric acid was heated at 180 ° C for 15 minutes.

The mixture was cooled, treated with ice and the precipitate was collected. The precipitate was dissolved in ether, filtered through N 2 O 3 and evaporated to give 5-nitro-2-phenyloxazolo [5,4-b] pyridine, m.p. 219-220 ° C.

Example 5 6-Methyl-2-phenyl-oxazolo [5,4-b] pyridine

Step A: Preparation of 6-methyl-3-nitro-2-pyridone

A solution of 24 g of 2-amino-6-methyl-3-nitropyridine in 25 ml of concentrated sulfuric acid and 380 ml of water was cooled to 0 ° C and treated with 11 g of sodium nitrite in 25 ml of water. The temperature rose rapidly to 45 ° C. After cooling, a precipitate of 6-methyl-3-nitro-2-pyridone (m.p. 222-223 ° C) was collected and used directly in the next step.

Step B: Preparation of 3-benzoylamino-5-methyl-2-pyridone 7.7 g of 6-methyl-3-nitro-2-pyridone was hydrogenated in 50 ml of methanol in the presence of 0.25 g of 5% palladium carbon. The catalyst was removed by filtration and the filtrate was evaporated to dryness.

The residue was taken up in 60 ml of pyridine, cooled to 20 ° C and treated with 6.5 ml of benzoyl chloride. After 2 hours at 20 ° C, the mixture was poured onto ice. The precipitate was collected and dried to give 9 g of 3-benzoylamino-6-methyl-2-pyridone, m.p. 241-242 ° C.

Step C: Preparation of 6-methyl-2-phenyloxazolo [5,4-b] pyridine

A solution of 5 g of 3-benzoylamino-6-methyl-2-pyridone in 50 ml of phosphorus oxychloride was heated on a steam bath for 20 hours. The solution was slowly poured onto ice while stirring well. The precipitate was collected as a filter and crystallized from aqueous ethanol to give 6-methyl-2-phenyloxazolo [5,4-b] pyridine, 11,58921 m.p. 71-73 ° C.

Example 6 5-Trifluoromethyl-2-phenyloxazolo [5,4-b] pyridine

Step A; Preparation of 6-chloronicotinic acid

To a stirred suspension of 28 g of 6-hydroxynicotinic acid in 193 ml of phosphorus oxychloride was added 83 g of phosphorus pentachloride portionwise. After stirring for 1 hour at room temperature, the mixture was heated on a steam bath overnight. Excess phosphorus oxychloride was removed in vacuo and the warm residue was added to about 1.2 liters of crushed ice and the mixture was allowed to warm to room temperature with stirring overnight. The precipitate was collected by filtration, washed with water and dried to give 29 g (92%) of 6-chloronicotinic acid, m.p. 187.5-189 ° C (dec.).

Step B: Preparation of 2-chloro-5-trifluoromethylpyridine

A mixture of 29 g of 6-chloronicotinic acid, 130 g of sulfur tetrafluoride and 18 ml of hydrofluoric acid was heated in a tube at 150 ° C for 16 hours. After cooling and opening the tube, the reaction mixture was treated while cooling to about 40 ° C with 2.5 N sodium hydroxide solution to pH 9. The mixture was extracted with chloroform, and the extract was filtered, dried and concentrated to a yellow oil (17 g), which was used directly in the next step.

Step C: Preparation of 5-trifluoromethyl-2-pyridone

A solution of 5.5 g of 2-chloro-5-trifluoromethylpyridine in 100 ml of acetic acid was treated with 5.5 g of silver acetate under nitrogen. The mixture was heated at 140 ° C for about 45 hours. The hot mixture was filtered and the cake was washed with acetic acid. The combined filtrate and washings were concentrated to dryness. The residue was partitioned between chloroform and water, and the mixture was basified with solid sodium bicarbonate. The mixture was filtered, the layers separated and the aqueous phase re-extracted with chloroform. The combined chloroform layers were dried and concentrated to dryness. The residue was crystallized from acetone to give 2.5 g of 5-trifluoromethyl-2-pyridone, m.p. 145-147 ° C.

Step D: Preparation of 3-nitro-5-trifluoromethyl-2-pyridone To 0.95 liters of stirred fuming nitric acid was added 29 g of 5-trifluoromethyl-2-pyridone over 1 hour and stirring was continued for 75 hours. The fuming nitric acid was evaporated and the residue was treated with acetone. The acetone was evaporated to a volume of about 2,58921 60 ml and the precipitate was collected as a filter and washed with a 5: 1 mixture of methylene chloride and acetone and dried and used directly in the next step.

Step E: Preparation of 3-benzoylamino-5-trifluoromethyl-2-pyridone 3.12 g of 3-nitro-5-trifluoromethyl-2-pyridone were reduced in 50 ml of ethanol in the presence of Raney nickel. The catalyst was removed by filtration and the filtrate was concentrated to dryness.

The residue was taken up in 10 ml of pyridine, cooled to 5 ° C and slowly treated with 2.0 ml of benzoyl chloride. After allowing to stand overnight, the mixture was treated with ice water to give an oil. The aqueous phase was decanted and the oil was mixed with ether. The solid was collected and recrystallized from methanol to give 3-benzoylamino-5-trifluoromethyl-2-pyridone, m.p. 207-210 ° C.

Step F: Preparation of 5-trifluoromethyl-2-phenyloxazolo [5,4-b] pyridine

A solution of 300 mg of 3-benzoylamino-5-trifluoromethyl-2-pyridone in 4.5 ml of phosphorus oxychloride was heated under reflux for 16 hours. The excess phosphorus oxychloride was evaporated and the residue was treated with ether and dilute sodium hydroxide solution. The ether phase was separated, dried and evaporated. The residue was crystallized from ethyl acetate to give 5-trifluoromethyl-2-phenyl-oxazolo [5,4-b] pyridine, m.p. 127-129 ° C.

Example 7 5-Chloro-2- (2-fluorophenyl) oxazolo [5,4-b] pyridine

Step A: Preparation of 5-chloro-3- (2-fluorobenzoylamino) -2-pyridone

A solution of 1.7 g of 5-chloro-3-nitro-2-pyridone in 75 ml of ethanol and 2 ml of acetic acid was hydrogenated using 0.2 g of 5% palladium on carbon. The catalyst was removed by filtration and the solvent was evaporated to dryness.

The dried residue was dissolved in 30 ml of pyridine, cooled with ice and treated with 1.6 g of 2-fluorobenzoyl chloride over 5 minutes. The mixture was stirred at ambient temperature for about 16 hours and poured into ice water. The resulting precipitate was collected as a filter (1.5 g) and used directly in the next step without purification.

13, - 58921

Step B: Preparation of 5-chloro-2- (2-fluorophenyl) oxazolo [5,4-b] pyridine

A mixture of 1.5 g of the above amide and 5 ml of polyphosphoric acid was heated at 160 ° C for 10 minutes. After cooling, the mixture was added to ice water. The precipitate was collected and extracted with 75 ml of hot benzene and the extract was decolorized with activated carbon and evaporated to dryness. The residue was dissolved in methylene chloride and filtered through alumina and the filtrate was washed with ether. The product 5-chloro-2- (2-fluorophenyl) oxazolo [4,5-b] pyridine crystallized from the filtrate and had a melting point of 140-141 ° C.

Example 8 5-Methoxy-6-methyl-2-phenyloxazolo [5,4-b] pyridine

Step A: Preparation of 3-methoxy-2-methyl-6-nitropyridine To an ice-cold mixture of 3 ml of concentrated sulfuric acid and 3 ml of fuming nitric acid was added 0.5 g of 3-methoxy-2-methylpyridine over 5 minutes. After the mixture itself warmed to room temperature, it was heated at 55-60 ° C for 6 hours.

The mixture was cooled and added to 35 ml of ice water. After stirring for 2 hours, the precipitate was collected and dried

To give 3-methoxy-2-methyl-6-nitropyridine, m.p. 99 to 100.5 ° C

Step B; Preparation of 6-amino-3-methoxy-2-methylpyridine 0.317 g of 3-methoxy-2-methyl-6-nitropyridine in 20 ml of methanol was hydrogenated using 0.1 g of 5% palladium on carbon. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give 6-amino-3-methoxy-2-methylpyridine, which was used directly in the next step.

Step C: Preparation of 5-methoxy-6-methyl-2-pyridone To an ice-cold mixture of 0.2 ml of concentrated sulfuric acid, 2.0 ml of water and 138 mg of 6-amino-3-methoxy-2-methylpyridine was added a solution containing 75 mg of sodium nitrite in 1 ml of water.

The cold solution was allowed to warm to room temperature overnight.

The mixture was diluted with a small amount of water and basified with solid sodium bicarbonate. The mixture was extracted with methylene chloride, and the extract was concentrated to dryness to give 120 mg of 5-methoxy-6-methyl-2-pyridone, which was used directly in the next step.

Step D: Preparation of 5-methoxy-6-methyl-3-nitro-2-pyridone

To a mixture of 4.2 g of 5-methoxy-6-methyl-2-pyridone in 50 ml of ice-cold concentrated sulfuric acid was added 2.5 ml of concentrated nitric acid dropwise at 5 ° C over 60 minutes. Stirring at 14,58921 was continued in the cold overnight. The mixture was added to about 700 g of ice with stirring. After about 30 minutes, the precipitate was collected, washed with water and dried to give 3.7 g of 5-methoxy-6-methyl-3-nitro-2-pyridone, which was used directly in the next step.

Step E: Preparation of 3-benzoylamino-5-methoxy-6-methyl-2-pyridone 1.84 g of 5-methoxy-6-methyl-3-nitro-2-pyridone in 100 ml of methanol was hydrogenated using 0.5 g of 5%: palladium on carbon. The catalyst was removed by filtration and the filtrate was concentrated to dryness. The residue was dissolved in 15 ml of pyridine and treated with 1.2 ml of benzoyl chloride in the cold. After standing overnight at ice temperature, the mixture was diluted with water. The resulting precipitate was collected and crystallized from ethanol. This material was extracted several times with ether and the insoluble material was recrystallized from ethanol to give 3-benzoylamino-5-methoxy-6-methyl-2-pyridone, m.p. 247-248 ° C.

Step F: Preparation of 5-methoxy-6-methyl-2-phenyloxazolo [4,4-b] pyridine

A mixture of 200 mg of 3-benzoylamino-5-methoxy-6-methyl-2-pyridone and 3 ml of phosphorus oxychloride was heated on a steam bath for 20 hours. The mixture was concentrated to dryness and the residue was taken up in ether, basified with ammonium hydroxide and diluted with water. The ether was separated and the aqueous phase was extracted three times with ether. The combined ether phases were dried and concentrated to dryness to give 5-methoxy-6-methyl-2-phenyloxazolo [5,4-b] pyridine, m.p. 167-168 ° C.

Example 9 2- (2-Fluoro-phenyl) -5-methyloxazolo [5,4-b] pyridine

Step A; Preparation of 3- (2-fluorobenzoylamino) -5-methyl-2-pyridone

A solution of 3.1 g of 3-amino-5-methyl-2-pyridone in 25 ml of pyridine was cooled with ice and treated dropwise with 4.5 g of 2-fluorobenzoyl chloride. After stirring for about 3 hours at room temperature, the mixture was diluted with 200 ml of ice water and after 0.5 hours the precipitate was collected, washed with water, dried and crystallized from ethanol to give 3- (2-fluorobenzoylamino) -5-methyl-2- pyridone, m.p. 230-232 ° C.

Step B: Preparation of 2- (2-fluorophenyl) -5-methyloxazolo [5,4-b] pyridine 15,58921

A mixture of 1.8 g of 3- (2-fluorobenzoylamino) -5-methyl-2-pyridone and 25 ml of phosphorus oxychloride was heated under reflux for 1.5 hours. The excess phosphorus oxychloride was evaporated and the remaining oil was mixed with cold water. The precipitate was collected and crystallized from benzene / petroleum ether to give 2- (2-fluorophenyl) -5-methyloxazolo [5,4-b] pyridine, m.p. 136-137 ° C.

Claims (2)

Claim: A process for the preparation of therapeutically useful 2-substituted-oxazolo [5,4-b,] pyridines having the structural formula: k1 -% - R OS _ xn wherein R is - · where n is a number from 0 to 3 and X is (1) halogen (2) lower alkoxy of 1 to 3 carbon atoms, (3) lower alkyl of 1 to 5 carbon atoms, (4) nitro, (5) trifluoromethyl or (6) cyano; R is (a) chlorine, (b) lower alkyl of 1 to 5 carbon atoms, (c) nitro, (d) trifluoromethyl or (e) lower alkoxy of 1 to 3 carbon atoms, and wherein m is 0 to 2: provided that when m is zero then n is not zero and R is not 4-lower alkylphenyl, characterized in that the compound of formula I is reacted with a compound of formula I II SSSS5: ^% a ^^ CR II Z "17 58921 O • f wherein Z is -OH, halogen or RCO-, by heating when OZ is r_ £ _; by heating in the presence of polyphosphoric acid when Z is -OH; or by an acid-binding in the presence of a substance and then heating with a condensing agent when Z is halogen to form a compound of formula: N "i-IC AX" "wherein R is as defined above. 18 58921 For the preparation of therapeutically active 2-substituted-oxazolo-5,4-b-pyridines with structural formulations. N -r color R är-u, color n är ett or 0-3 och X är (1) halogen, (2) alkoxy with 1-3 cholaters, (3) alkyl with 1-5 cholaters, (4) nitro, (5) trifluoromethyl or (6) cyano; R is (a) chlorine, (b) a alkyl having 1-5 cholaters, (c) nitro, (d) trifluoromethyl or (e) a alkoxy having 1-3 cholera, and a color m or 0-2? under the invention of the same zero and the same zero and R inte 4-alkyl-alkylphenyl, the parent compound being treated with the form of I nh2 r1 — rv m. I x OH reagents with a formulation of Form II II Z " 0 O II II color Z is -OH, halogen or R-C-O-, genomic upstream of Z is R-C-0; genomic uppermosting in a polyphosphoric moiety of Z is -OH; eller i