FI57417B - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ANALYZED 2-SUBSTITUTES-OXAZOLO- (4,5-B) -PYRIDINER - Google Patents

Description

ΓβΙ / «v NOTICE r7419 SgfiÄ IBJ (11) UTLAGGNINGSSKRIFT O / i% [SC (45) 11 ^ ° ^ v (51) Ky.ik.3 / int.a.3 C 07 D 498/04 FINLAND —FINLAND (21 ) Pmnttlhtkmu »- Puu ntmiakmng 1657/73 22.05.73 * '(23) ALkupUvI — GlMghutadig 22.05> 73 (41) Tullut slikuu - BIMt offtntllg 15.12.73

National Board of Patents and Registration / 44) Nlhtlvlktlpunon | t KuLFultaltun date— »D

Patent · och registerstyrelsen Ansakin utltgd och utUkrtftun publkursd 30.04.oO

(32) (33) (31) Requested curiosity Begird prlorltut lU. 06.72 USA 262898 (71) Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey, USA (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 (US) (7M 0y Kolster Ab (5I +) Process for the preparation of therapeutically useful 2-substituted-oxazolo-β, 5-b7-pyridines - For the preparation of therapeutically useful 2-substituted-oxazolo-β, 5-b7-pyridines [h, 5- This invention relates to a process for the preparation of therapeutically useful 2-substituted-oxazolo [4,5-b] pyridines.

The compounds according to the invention can be represented by the general structural formula: <~ CX r 2 5741 7 in which the formula / Γ \ ^ Χη R is C "j, where n is a number from 0 to 3 and X is (1) halogen, (2) lower alkoxy, having 1 to 3 carbon atoms (3) lower alkyl having 1 to 5 carbon atoms, (4) nitro, (5) trifluoromethyl or (6) cyano: R 1 is (a) chlorine (b) lower alkyl having 1 to 5 carbon atoms 5 carbon atoms (c) nitro or (d) trifluoromethyl, and wherein m is 0-2, 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

OH

r1 — μ if i • m nh2

is reacted with a compound of formula II

^^ C-R

z- "" '11 p

e II

wherein Z is -OH, halogen or R-C-O-, by heating when Z is n; by heating in the presence of polyphosphoric acid when R-C-0 3,57417 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:

T> —R

where R is as defined above.

In particular, the invention provides compounds of the structural formula: -οο-σ'1 wherein n is 1-2, R 'is hydrogen or C 1-4 lower alkyl and X is (a) lower alkyl (b) lower alkyd (c) chlorine ( d) fluorine (e) trifluoromethyl Of these compounds, special mention should be made of: 2- (3-t-butylphenyl) oxazolo [1,5-b] pyridine, 2- (3,5-di-t-butylphervyl) oxazolo [5- b) pyridine, 2- (2-methyl-3-chlorophenyl) oxazolo [1,4-b] pyridine »2- (2-methyl-3-methoxyphenyl) oxazolo [4,5-b] pyridine, 2- (3- methyl-5-t-butylphenyl) oxazolo [4,5-b] pyridine, 2- (3,5-di-t-butylphenyl) -5-methyloxazolo [1,5-b] pyridine, and 2- (3- chloro-2-methylphenyl) -5-methyloxazolo [1,5-b] pyridine.

4,541,7 2- (2,5-difluorophenyl) oxazolo [4,5-b] pyridine, and 2- (2,6-difluorophenyl) oxazolo [5,5] b] pyridine.

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 indicated above, when used in practice, the compounds of the invention have also been found to have a useful amount of analgesic and antipyretic activity.

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.

s 5741 7

The following table shows the inhibitory effect of oxazolo [1,5-b] pyridines in both carrageenan-induced inflammation of the rat paw (edema) and the prostaglandin synthetase inhibition assay.

00 ^ '

Inhibition of prostaglandin syn-Edema tetase _R_ 30 mg / kg 10 / ml 1 / ml 0.5 0.2 2-fluorophenyl 6 h 90 33 3-chlorophenyl 32 87 23 2-chlorophenyl 38 86 36 3-methoxyphenyl IU 90 76 2-methoxyphenyl 9 73 32 2-methylphenyl 0 89 20 U-chloro-2-fluorophenyl 19 72 3k

2,5-difluorophenyl 18 80 IU

2,6-difluorophenyl 66 0 3-ethoxyphenyl lk 97 lii 3-methylphenyl 19 28 3,5-dimethoxyphenyl 7 68 35 7 2,3-dimethylphenyl 0 28 2-chloro-3-methylphenyl 97 3,5-dimethylphenyl 15 U6 3 - t-butyl-5-methylphenyl 95 3,5-di (t-butyl) phenyl 96 2-methyl-3-methoxyphenyl 95 6-methyl-2-methyl-3-chloro-

phenyl 9U

3-iodophenyl 8U

2-chloro-3-methoxyphenyl 88 3-fluoro-2-methylphenyl 1-O-3-chloro-5-methylphenyl 86 3-t-butylphenyl 98 95 2-ethyl-3-chloro phenyl .0-92 83 3 3-chloro-2 .5-dimethyl phenyl 95 83 75 2-chloro-5-t-butyl phenyl 99 3 "t-butyl-5 * methoxyphenyl 95 6 57417

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

N I ^ H2 Q | OF

Depending on the condensing agent used and the amount of amino-hydroxypyridine used, the reaction can 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, oxazolopyridines can be prepared by condensing amino-hydroxypyridine with an anhydride with or without the use of a condensing agent such as polyphosphoric acid or polyphosphoric acid ester. In either case, the amino-hydroxypyridine is mixed with 1 to 3 molar equivalents of acid anhydride 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 amino-hydroxypyridine with a carboxylic acid under the influence of polyphosphoric acid or polyphosphoric acid poester. 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 the amide intermediate by reacting the acid halide with the 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 oxazolo = pyridine 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, 5- 60 minutes. Instead of phosphorus = oxychloride, other condensing agents can be used, such as phosphorus pentoxide, phosphorus oxybromide, thionyl chloride and phosphorus tribromide.

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

Example 1 2- (2-fluorophenyl) oc8at8oloA t5-b / pyridine

A mixture of 3.3 g (0.03 mol) of 2-amino-3-hydroxypyridine, 5.6 g (0.04 mol) of 2-fluorobenzoic acid and 12 g of polyphosphoric acid was heated to 175 ° C. and held there for 10 minutes.

After cooling slightly, the melt was poured into a mixture of ice and water. After stirring to decompose the polyphosphoric acid, the mixture was made alkaline with ammonium hydroxide solution. The resulting precipitate was collected and crystallized from benzene / petroleum ether to give 4.0 g of 2- (2-fluorophenyl) oxazolo [5-1] pyridine, m.p. 126-127 ° C.

Using the procedure described in Example 1, but substituting an equivalent amount of benzoic acid of formula R-COOH for the 2-fluorobenzoic acid used therein, the 2-R-oxazolo [4,5-b] pyridines shown in Table I were obtained according to the following reaction equation: 8 57417

Rm K jl R-COOH-> R * -i ~] f / R

n u / N. in JL / ^ NH2

Table I

R1 R Sp. (° C) H 2,4-difluorophenyl 140-142 H 2-ethylphenyl 150 H 2,6-dichlorophenyl 139-140 H 2-chloro-6-fluorophenyl 86-88 H 3-chlorophenyl 142-143 H 2-chlorophenyl 92 -93 H 3,4-dimethoxyphenyl 193-195 H 3-nitrophenyl 199-201 H 3-methoxyphenyl 111-113 H 2-methoxyphenyl 108-109 H 2-methylphenyl 64-66 H 4-chloro-2-fluorophenyl 154-156 H 2,5-difluorophenyl 130-132 H 2,5-dichlorophenyl 119-120 H 2-bromophenyl 60-61 H 2,6-difluorophenyl 113-114 H 2-trifluoromethylphenyl 63-64 H 3-ethoxyphenyl 102-104 H 3 -methylphenyl 106-107.5 H 3,5-dimethoxyphenyl 151-152.5 H 2,3-dimethylphenyl 72-73 H 2-chloro-3-methylphenyl 75-77 H 3,5-dimethylphenyl 155-157 H 3- isopropoxyphenyl 68.5-70.5 H 3-t-butyl-5-methylphenyl 131-132 H 2-methyl-3-methoxyphenyl 138-141 6-CH 6 -2-methyl-3-chlorophenyl 139-143 H 3-iodophenyl 172-176 H 2-chloro-3-methoxyphenyl 165.5-167 9 57417

Table I (continued) R1 R Sp. (° C) H 3-Fluoro-2-methylphenyl 98-100 H 3-chloro-5-methylphenyl 121-123 H 3-t-butylphenyl 12U-126 6-CH 3 -3,5-di (t-butyl) phenyl 161-163 H 2-nitrophenyl 123-125 H 2-cyanophenyl 166-167 H H-nitrophenyl 2H2-2H3 H H-cyanophenyl 220-221 H 3-trifluoromethylphenyl 1H7-1H9 5-NO2-phenyl 219-220 5-CF3- phenyl 127-129 5-C1-2-fluorophenyl 1H0-1H1

Example 2 5-Methyl-2-phenyloxazolo [1,5-b] pyridine Step A: Preparation of 3-hydroxy-6-methyl-2-nitropyridine To HO ml of ice-cold concentrated sulfuric acid was added 10.9 g of 3-hydroxy-6- metyylipyridiiniM. While maintaining the temperature at 6 ° C, H, 7 mL of fuming nitric acid was added dropwise with stirring. The mixture was allowed to warm to room temperature overnight. 200 g of ice were added with stirring. After the ice had melted, the precipitate was collected, washed with water and dried to give 3-hydroxy-6-methyl-2-nitropyridine, m.p. 103-105 ° C.

Step B: Preparation of 2-amino-3-hydroxy-6-methylpyridine 3.5 g of 3-hydroxy-6-methyl-2-nitropyridine in 75 ml of methanol were reduced using 1 g of 5% palladium on carbon. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give 2-amino-3-hydroxy-6-methylpyridine, which was used directly in the next step.

Step C 5-Methyl-2-phenyl-oxazolo [5 "b) Preparation of pyridine A mixture of 1.25 g of 2-amino-3-hydroxy-6-methylpyridine, 6 g of polyphosphoric acid and 2.0 g of benzoic acid was heated to 190 At -200 ° C for 10 minutes The cooled mixture was diluted with water and basified with solid sodium bicarbonate, and the resulting precipitate was collected and crystallized from ether to give 5-methyl-2-phenyloxazolo [1H, 5-b] pyridine, mp 148-1H9 ° C. .

10 5741 7

Example 3 2- (2-Ethyl-3-chlorophenyl) oxazolo [4,5-b] pyridine A mixture of 3.1 g of 2-methyl-3-chlorobenzoic acid and 1.0 g of 2-amino-3-hydroxypyridine was triturated. and mixed well with 17 g of polyphosphoric acid. The gummy mixture was slowly heated to 17d ° C under nitrogen for 75 minutes with stirring. The resulting solution was slowly poured into 300 ml of ice water with stirring. After 1 hour, the precipitate was collected and added to dilute sodium hydroxide solution with stirring. After 15 minutes, the precipitate was collected, washed with water and dried to give 2.1 g of crude product. This was recrystallized by dissolving in 75 ml of cyclohexane, filtering, concentrating to a volume of about 50 ml and cooling to give 1.76 g of 2- (2-methyl-3-chlorophenyl) oxazolo [1,5-b] pyridine, m.p. 118.5-120 ° C.

Example ** 2- (3-Chloro-2,5-dimethylphenyl) Ioxazolo-1H-5'-pyridine Step A: Preparation of 3-amino-2,5-dimethylbenzoic acid 2,5-dimethyl-3-nitrobenzoic acid (10.0 g) hydrogenated in 200 ml of methanol in the presence of 0.5 g of 5 E of palladium on carbon, the catalyst was removed as a filter and the filtrate was concentrated to dryness to give 8.3 g of 3-amino-2,5 "dimethylbenzoic acid, m.p. 5.5-1.5 ° C.

Step B: Preparation of 3-chloro-2,5 “dimethylbenzoic acid

A slurry of U, 95 g of the amino compound from Step A in 25 mL of 6N hydrochloric acid was cooled in an ice-acetone bath (-3-0 ° C) and a solution of 2.3 g of sodium nitrite in 6 mL of water was added. In 0.5 ml portions over about 20 minutes. After holding at 0-5 ° C for about 1 hour, the mixture was poured into a solution of U g of cuprous chloride in 25 ml of concentrated hydrochloric acid at 1 ° C. After 0.5 h at 1-2 ° C, after 2 h at room temperature, after 1 h at 60 ° C and after 15 h at room temperature, the precipitate was collected, washed with water and dried to give U, 5 g of 3-chloro- 2,5-dimethylbenzoic acid, m.p. 167.5-170 ° C.

Step C: Preparation of 2- (3-chloro-2,5-dimethylphenyl) -oxazolo [5-b] pyridine

Substantially following the procedure described in Example 3 but substituting the molar equivalent of 2-methyl-3-chlorobenzoic acid for 3 "chloro-2,5" dimethylbenzoic acid gave 2- (3-chloro-2,5-dimethylphenyl) oxazolo [5-] b7pyridine, m.p. 99.5-101 ° C.

11 5741 7

Example 5 2- (2-Chloro-5-t-butylphenyl) oxazolo [5-b] pyridine

Step A: Preparation of 5-t-butyl-2-nitrobenzoic acid 3-t-butylbenzoic acid (7.0 g) was added portionwise over about 50 minutes to 50 ml of fuming red nitric acid at -5 ° C with stirring. After 15 minutes at 0 ° C, the mixture was poured into ice water and after stirring for 15 minutes the precipitate was collected and washed with water (m.p. 128-131 ° C). It (12 g) was dissolved in 65 ml of ethanol, filtered, heated to 70 ° C and water was added to a volume of about 100 ml. After cooling, the precipitate was collected, washed with water and dried (9 * 55 g) · It was extracted with 200 ml of warm cyclohexane and the insoluble matter was collected to give 6.1 g of 5-t-butyl-2-nitrobenzoic acid. , mp 137-139 ° C.

Step B: Preparation of 2-amino-5-t-butylbenzoic acid

The nitro compound from Step A (6.2 g) was hydrogenated in 100 mL of methanol in the presence of 0.5 g of 5 P palladium on carbon. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give 5 * 0 g of 2-amino-5-t-butylbenzoic acid, m.p. IU2-1l * 5 ° C, which re-solidified and remelted at 151 ° C.

Step C: Preparation of 2-chloro-5-t-butylbenzoic acid

The amino compound from Step B (3.86 g) was stirred in 25 ml of 6N hydrochloric acid and a solution of 1.6 g of sodium nitrite in 3 ml of water was added over 0.5 hours at -2 ° C. After 0.5 hours at 0 ° C, the mixture was poured into 2.7 g of cuprous chloride in 20 ml of concentrated hydrochloric acid at 0 ° C. After 0.5 h at 0 ° C and 0.5 h at room temperature, the precipitate was collected, washed with water and dried to give Yield A (0.17 g, mp 88-9 ° C). The filtrate and some copper powder were heated at 100 ° C for 0.5 hours and cooled. The precipitate was collected, dissolved in sodium hydroxide and remixed by the addition of hydrochloric acid. This material was collected, washed with water and dried to give Yield B (3.15 g, mp 99-103 ° C). Yields A and B were combined and recrystallized from 20 ml of n-hexane to give 1.6 g of 2-chloro-5-t-butylbenzoic acid, m.p. 106-108.5 ° C.

Step D: 2- (2-Chloro-5-t-butyl-phenyl) -oxazolo [1,5-b] pyridine

Following the procedure described in Example 3 but substituting the molar equivalent of 2-methyl-3-chlorobenzoic acid for 2-chloro-5-t-12,541 7 butylbenzoic acid gave 2- (2-chloro-5-t-butyl phenyl) oceazolo [5 'b β-pyridine, m.p. 111-112 ° C.

Example 6 2- (3-t-Butyl-5-methoxyphenyl) oxazolo [5-b] pyridine

Step A: Preparation of 3-t-butyl-5-methoxybenzoic acid

A mixture of 2.8 g of potassium hydroxide in 9 ml of water, 17 · 1 g of pyridine and 5.0 g of 3-t-butyl-5-methoxytoluene was heated in an oil bath at 95 ° C. 11.1 g of potassium permanganate were then added over 2 hours with rapid stirring and heating was continued at 95 ° C for 1.5 hours. After cooling to room temperature, 5 ml of alcohol was added. The mixture was filtered and the filtrate was shaken with 100 mL of ether to give 3 layers. The bottom layer (50 mL) and the middle layer (25 mL) were collected separately and each was concentrated to a volume of about 1/2 and acidified to pH 2 using Un sulfuric acid. The precipitates were collected, washed with water and air-dried to give 0.6 g and 1.1 g of crude product, respectively, m.p. 75-85 ° C, from which, after combining and recrystallization from 10 ml of acetic acid and 5 ml of water, 0.85 g of 3-t-butyl-5-methoxybenzoic acid were obtained, m.p. 8U-87 ° C.

Step B: Preparation of 2- (3-t-butyl-5-methoxyphenyl) oxo azolo [5'-b] pyridine

A mixture of 6.0 g of polyphosphoric acid, 0.8 g of 3-t-butyl-5-methoxybenzoic acid and 0.1 x 6 g of 2-amino-3-hydroxypyridine under a nitrogen atmosphere was placed in a preheated oil bath at 150 ° C. After stirring for about 12 minutes, the melt was poured into 100 ml of ice slurry. The precipitated gum was taken up in methylene chloride, washed once with 20 ml of 2.5 N sodium hydroxide and once with 25 ml of water, dried over magnesium sulfate, filtered and concentrated to an oil which crystallized to give 0.8 g of product, which was recrystallized from n-hexane. 0.5 g of 2- (3-t-butyl-5-methoxyphenyl) oxazolo [5,5-b] pyridine was obtained, m.p. 119-121 ° C.

Example 7 2- / 3,5 "di (t-butyl) phenyl '/ oxazolo [1,5-b] pyridine

A mixture of 30 g of polyphosphoric acid, 5.0 g of 3,5-di (t-butyl) benzoic acid and 2.1 g of 2-amino-3-hydroxypyridine under a nitrogen atmosphere was heated with rapid stirring at 180 ° C for 10 minutes. The mixture was poured into 500 ml of ice water. The mixture was adjusted to pH 8.0 with concentrated ammonium hydroxide and stirred until the precipitate was fine. The precipitate was taken up by filtration, washed twice with 100 ml of water and dried. The crude product was dissolved in 200 mL of n-hexane, treated with decolorizing charcoal, filtered and concentrated to a volume of about 75 mL. On cooling, the product crystallized to give 3.5 g of 2- [3,5-di (t-butyl) phenyl] oxazolo [5,5-b] pyridine, m.p. 15U-156 ° C.

Example 8Γ 2- [3,5-di (isobutyl) phenyl] oxy A, 5-bipyridinium

Step A: Preparation of 2- [3,5-di (bromomethyl) phenyl] oxazolo [5,5-b] pyridine

A mixture of 10 millimoles of 2- (3,5-dimethylphenyl) oxazolo? 5'-pyridine and 21 millimoles of N-bromosuccinimide in 50 ml of carbon tetrachloride was stirred and irradiated with sunscreen for 1 * 5 minutes. The insoluble matter was removed by filtration, and the filtrate was concentrated to dryness under nitrogen while the residue was stirred with 25 ml of methanol. The crude 2- [3,5-di (bromomethyl) phenyl] oxatholo [1,5-b] pyridine was recovered.

Step B; 2- / 3 »5“ di (2-methylallyl) phenyl] oxazoloA * 5 ”b7pyridine

A mixture of 5 mmol of the product from step A and 11.0 mmol of triphenylphosphine in 15 ml of dimethylformamide was stirred and refluxed under nitrogen for 3 hours. The mixture was cooled and the phosphonium salt was collected by filtration.

A mixture of 1 * millimoles of phosphonium salt, 100 ml of ethanol, 1 ml of acetone and 10 ml of 0.3N ethanolic lithium ethoxide was stirred at room temperature under a nitrogen atmosphere for 2 hours. Water (100 ml) was added and the mixture was cooled in an ice bath. The precipitate was collected and purified by chromatography on silica gel using 2% methanol in chloroform as eluent to give 2- [3,5-di (2-methylethyl) phenyl] -oxazolo [1,5-b] pyridine.

Step C: Preparation of 2- [3,5-di (isobutyl) phenyl] oxazolo-A, 5-b] pyridine

The product from step B (3 mmol) was hydrogenated in 25 mL of methanol in the presence of 500 mg of 5 P palladium on carbon under 3 atmospheres of hydrogen. The catalyst was removed by filtration and the filtrate was concentrated to dryness. The residue was crystallized from n-hexane to give 2- / 3,5 "di (isobutyl) phenyl] oxazolo / 5.5" b7pyridine.

Example 9 2- (3-t-Butyl-2-methoxyphenyl) oxazolo [5b] pyridine

Step A: Preparation of 3-t-butyl-2-methoxytoluene

A mixture of 0.12 mol of 2-t-butyl-5-methylphenol and 12.0 ml of 10.0 N sodium hydroxide solution was stirred and heated on a k 57417 steam bath for 1 hour. The water was evaporated in vacuo. The residue was added portionwise with stirring to 0.2 mol of dimethyl sulfate, and the mixture was stirred at 95 ° C for 6 hours and at room temperature for 15 hours. Sodium carbonate (0.25 mol) in 100 ml of water was added and stirring was continued for 5 hours. The mixture was extracted three times with 100 ml of ether and the extract was dried and concentrated to dryness to give 3-t-butyl-2-methoxytoluene.

Step B: Preparation of 3-t-butyl-2-methoxybenzoic acid

A mixture of 0.01 mol of 3-t-butyl-2-methoxytoluene, 0.01 mol of potassium permanganate and 100 ml of 1N sodium hydroxide solution was heated under reflux and a further 0.01 mol of potassium permanganate was added every hour until a total of 0.05 mol / l was added. moles (U hours). After the unreacted starting material was heated to reflux for an additional 2 hours, it was steam distilled. Ethanol was added to the residue to decompose excess permanganate, and the mixture was filtered hot. After the filtrate was acidified with sulfuric acid, the product precipitated and was collected, washed with water and dried to give 3-t-butyl-2-methoxybenzoic acid.

Step C: Preparation of 2- (3-t-butyl-2-methoxyphenyl) oxazolo [5-b] pyridine

Following the procedure of Example 3 but substituting an equivalent amount of 3-t-butyl-2-methoxybenzoic acid for 2-methyl-3'-chlorobenzoic acid gave 2- (3-t-butyl-2-methoxyphenyl) oxa-Solo [5-b] pyridine.

Claims (1)

A process for the preparation of therapeutically useful 2-substituted-oxazolo [1,5-b] pyridines having the structural formula: wherein R is _ / AN, wherein n is 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, (^) nitro, (5) trifluoromethyl or ( 6) cyano; R 1 is (a) chlorine, (b) lower alkyl of 1 to 5 carbon atoms, (c) nitro or (d) trifluoromethyl, and wherein m is 0 to 2; provided that when m is zero then n is not zero and R is not k-lower alkylphenyl, characterized in that the compound of formula I is reacted with a compound of formula II Wherein Z is -OH, halogen or RC-O-, by heating when Z is 2 »by heating in the presence of polyphosphoric acid then RC-O ie by 5 741 7 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: wherein R is as defined above. 17 5741 7 For the preparation of a therapeutically active 2-substituent oxazolo ^ *, 5-b ^ -pyridine with a structural form «Η ^ ΊΓ color R ar _ ^, color n är ett or 0-3 och X är (1) halogen , (2) alkoxy of 1-3 colaters, (3) alkyl of 1-5 colaters, (H) nitro, (5) trifluoromethyl or (6) cyano; R 1 is (a) chlorine, (b> middle alkyl of 1-5 cholatomers, (c) nitro or (d) trifluoromethyl, and the color is m or et or 0-2; is R inte H-alkyl-alkylphenyl, which is treated with the form of I 0H 4-ft 1 ss ^ \ NH2 is reacted with the formulation of formula II ^^ CR II "0 0>" Il color Z is -OH, halogen or RC-0-, genomic upstream of Z is RC-0; genomic upstream of nervar in polyphosphoric acid and Z-OH;