JPS5943475B2 - Oxazolo- and thiazolopyridines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to oxazolopyridines and derivatives thereof.

More particularly, the present invention relates to oxazolopyridines and derivatives that are anti-inflammatory, antipyretic and analgesic agents. The active compounds of the invention include the following isomers: These isomers are represented by the general formula and quaternary pyridinium salts and N-oxides.

In the formula, the 6-membered ring is pyridine with nitrogen in one of the unsubstituted positions of the ring.

Y is O. R is [n is an integer from 1 to 5.

X is (ha hydrogen (2) halogen such as chlorine, fluorine or bromine (3)
Lower alkoxy of 1 to 3 carbon atoms (4) Lower alkyl of 1 to 5 carbon atoms (5) Nitro (6) Phenyl (7) Lower alkyl sulfur in which the lower alkyl group has 1 to 3 carbon atoms Fonyl (8) lower alkyl group is 1-3
trihalo-lower alkyl having 1 to 3 carbon atoms, especially trifluoromethyl (9) cyanoQω Lower alkylthio 1υ in which the lower alkyl group has 1 to 3 carbon atoms Carbamyl Q" The lower alkyl groups are the same or different and 1 to 3
Di(lower alkyl)amino having 1 to 3 carbon atoms Lower alkylamino having 1 to 3 carbon atoms Lower alkyl sulfinyl Qω having lower alkyl groups having 1 to 3 carbon atoms Mercapto positive trifluoromethoxy Qn 2 to 5 lower alkanoyl groups a-hydroxy 1g) lower alkanoyl group having 2 to 5 carbons lower alkanoylamino (21 amino (2D unsubstituted or halogen, especially chlorine or bromine, lower alkyl having 1 to 3 carbons or 1 to 3 carbons;
Benzoylamino (2 -C}-(CH2)w-N (R2 substitution in the formula\
The parts are the same or different and represent hydrogen or lower alkyl of 1 to 3 carbons.

w is an integer from 1 to 3.

)C2 conflict -(CH2)wN, (R2 and w are as described above.

)(24) -NH-(CH2)w-N (R2 and w\ are as described above.

)(2ω −SO2N( R2 is as described above.

)(26) -COOR2 (R2 is as described above.

)C9'r)-(CH2)WCOOR2(R2 and W
is as described above.

) (to) - (C2) WCN (w is as described above.

)129) It is a methylenedioxy group formed by bonding together two X groups on adjacent carbons.

] [X and n are as described above.

A represents lower alkyl (2) of 1 to 3 carbon atoms, preferably 1 carbon, and lower alkenyl (3) carbonyl of 2 to 5 carbon atoms, preferably 2 carbons.

(c) Lower alkynoles (d
) 3-7 such as cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl and especially cyclohexyl
lower cycloalkyl (e) pyridyl of carbon atoms,
2-pyridone = 3,4,5 or 6-yl, frill,
imidazol-2-yl, thiazolyl or pyrazinyl (unsubstituted or substituted with lower alkyl of 1 to 5 carbons, etc.);

) is a 5-6 membered heterocyclic group containing up to 2 heteroatoms selected from 0, N and S, such as (f) naphthyl or (g) adamantanyl.

R1 is (a) hydrogen (b) fluorine (c) lower alkyl of 1 to 5 carbon atoms such as methyl, ethyl, propyl, butyl or pentyl (d)
nitro (e) lower alkyl group having 1 to 3 carbon atoms trihalo lower alkyl especially trifluoromethyl (f) amino (g) benzoylamino (h) lower alkoxy having 1 to 3 carbon atoms (i) lower alkyl di(lower alkyl)amino(
J) lower alkylamino in which the lower alkyl group has 1 to 3 carbon atoms (k) phenyl (l) lower alkoxycarbonylamino in which the lower alkoxy group has 1 to 5 carbon atoms; be.

m is 1 or 2.

The novel compounds of the present invention are as described above.

provided that when Y is O and R1 is hydrogen or halogen, R is not unsubstituted phenyl or lower alkyl. Among the compounds of the invention, oxazolopyridines are of particular interest as anti-inflammatory analgesics and antipyretics.

A more preferred oxazolopyridine is oxazolo[4,5
-b]pyridine and oxazolo[5,41b]pyridine.

Even more preferred are those isomers of oxazolopyridine in which R is phenyl or substituted phenyl and R1 is hydrogen. Even more preferred are oxazolo[4,5-b]pyridine and oxazolo[5, 4-b] Pyridine.

Specific examples included in the most preferred group of compounds are as follows. 2-Phenyloxazolo[4,5-
b] Pyridine 2-(2-fluorophenyl)oxazolo[4,5-b]pyridine 2-(2,5-difluorophenyl)oxazolo[4,5-b]pyridine 2-
(2,6-difluorophenyl)oxazolo[4,5-
b] Pyridine 2-phenyloxazolo[5,4-b]
Pyridine 2-(2-fluorophenyl)oxazolo[5
,4-b]pyridine 2-(2-nitrophenyl)oxazolo[5,4-b]pyridine 2-(2-cyanophenyl)oxazolo[5,4b]pyridine The present invention also provides an anti-inflammatory agent containing oxazolopyridine. Methods of treating inflammation utilizing the compositions are included.

Furthermore, these compositions exhibit potent analgesic and antipyretic activity, and the invention therefore also relates to analgesic and antipyretic methods and compositions. Furthermore, the present invention
Concerning analgesic and antipyretic methods for the relief and treatment of pain and fever symptomatically not related to inflammatory diseases. After the known anti-inflammatory properties of steroids and the equally known undesirable side effects of steroid treatment, intensive research into non-steroidal anti-inflammatory agents was conducted.

Although this research has resulted in the discovery of a few highly effective nonsteroidal agents, these have their own undesirable side effects and contraindications. According to the present invention, a new series of compounds are available which are highly effective as anti-inflammatory, antipyretic and analgesic agents.

Like other known potent anti-inflammatory agents, the compounds of the present invention are inhibitors of prostaglandin E synthesis. The oxazolopyridine of the present invention has anti-inflammatory, analgesic and antipyretic activity.

These compounds have value in the treatment of arthritic diseases and skin diseases or similar diseases that respond to anti-inflammatory drugs. In general, the compounds of the invention can reduce symptoms of inflammation, fever and pain.
Used for a wide variety of diseases with proven evidence of or more. This category includes rheumatoid arthritis, osteoarthritis,
Included are diseases such as gout, infectious arthritis, acute rheumatoid arthritis and inflammatory diseases of the visual tissues. As noted above, the compounds utilized in the practice of this invention also possess useful degrees of analgesic and antipyretic activity. For these purposes, the compounds of this invention can be administered orally, topically, or parenterally in unit dosage formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. , by inhalation spray, or rectally.
) can be administered.

As used herein, the term parenteral1 refers to subcutaneous injection,
Including intravenous, intramuscular, intrasternal or infusion techniques. In addition to treating warm-blooded animals such as rats, horses, dogs, and cats, the compounds of the present invention are useful for treating humans. Pharmaceutical compositions containing the active ingredient can be in forms suitable for oral use, such as tablets, troches, sugar tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups. Or it can be an elixir.

Compositions intended for oral use may be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may be of pharmaceutical quality. And in order to provide a coherent formulation, it may contain one or more additives selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservatives. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granules and disintegrants such as corn starch or alginic acid;
Binders such as starch, gelatin or acacia and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or the tablets may be coated to delay disintegration and absorption in the gastrointestinal tract;
It can then be coated by known techniques in order to thereby provide a sustained action over a long period of time. For example, glyceryl monostearate or glycerylziz,
Time-extending agents such as alates may be used. Formulations for oral use may also be made as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, and the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil. It can be given as soft gelatin capsules.

Aqueous suspensions contain the active substances in admixture with adjuvants suitable for the manufacture of aqueous suspensions.

Such auxiliaries are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic. Dispersing or wetting agents can be naturally occurring phosphatides, such as lecithin, or condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain fatty alcohols, such as heptadecaethyleneoxycetanol or Condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydride; For example, it may be polyoxyethylene sorbitan monooleate. The aqueous suspension may also contain one or more preservatives,
For example, it may contain ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or apricot oil, or in a mineral oil such as liquid paraffin.

The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents, such as those mentioned above, can be added to provide a pleasant oral preparation. These compositions may be preserved by the addition of antioxidants such as ascorbic acid. Dispersible powders and granules suitable for preparing aqueous suspensions by the addition of water consist of the active ingredient in admixture with dispersing or wetting agents, suspending agents and one or more preservatives.

Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additionally, other excipients may be present, such as sweetening agents, flavoring agents and coloring agents. Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.

The oil phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or mixtures thereof. Suitable emulsifiers are naturally occurring gums such as gum arabic or gum tragacanth, naturally occurring phosphatides such as soybean lecithin and esters or partial esters derived from fatty acids and hexitol anhydride, such as sorbitan monooleate, and partial esters thereof. The emulsion may also contain sweetening and flavoring agents, such as condensation products of ethylene oxide and polyoxyethylene sorbitan monooleate. Syrups and elixirs may be formulated using sweetening agents such as glycerol, sorbitol or sucrose. Such prescriptions also contain emollients,
It may also contain preservatives and flavoring and coloring agents.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the pharmaceutically acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils may be advantageously employed as a solvent or suspending medium.
For this purpose, any plant fixed oil (Blandfix) containing synthetic mono- or diglycerides may be used.
edOil) may also be used. Additionally, fatty acids such as oleic acid can also be used in injectable formulations. The compounds of the invention may also be administered in the form of suppositories for rectal administration of the drug.

These compositions may be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ambient temperature but liquid at rectal temperature. This dissolves in the rectum and releases the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc. containing anti-inflammatory agents may be used.

Doses ranging from 0.5 to 140 mg/kg body weight per day are useful in the treatment of the aforementioned diseases (25 to 7 g/patient per day).

For example, inflammatory, antipyretic and analgesic activity is approximately Q.
l~501V! / weight 1k9 (5η~3.59 per day
/patient). Advantageously, about 17T19-15 tons per day/1k9 body weight (1
The amount of active ingredient that can be combined with the carrier material to give a single use form will vary depending on the host treated and the particular administration. It can vary depending on the method.

For example, a formulation intended for oral administration to humans may contain 5η to 59 active agents combined with a suitable amount of carrier material which can vary from about 5 to 95% of the total composition. Usage unit forms generally contain from about 25 to about 500 eta of active ingredient. However, the specific use for a particular patient will depend on the activity of the particular compound used, age, weight, general health, gender, food, time of administration, method of administration, rate of excretion, drug combination, and A variety of factors will vary, including the severity of the particular disease being treated.

Compounds of the present invention generally comprise amino-hydroxyminor pyridines of the formula R-8-z, where Z is -0H,
R-9-0- or halide.

) with a carboxylic acid, acid anhydride or acid halide. Depending on the condensing agent used and to some extent the specific amino-hydroxy-pyridine used, the reaction can be carried out either as a one-step ring closure or as a first step i.e. formation of the amide, then isolation of the amide forming the oxazolo ring, and a second It has been found to be advantageous to carry out the ring closure in a separate step.

In general, oxazolopyridines can be prepared by condensing aminohydroxypyridines with acid anhydrides, with or without the influence of condensing agents such as polyphosphoric acids or polyphosphoric esters.

In either case, the aminohydroxypyridine is mixed with about 1 to 3 molar equivalents of acid or ester;
Heat to reflux temperature for 0 min. After some cooling, the excess polyphosphoric acid and anhydride are destroyed and the product is isolated by standard techniques. Isomeric oxazolopyridines can also be prepared by condensing the appropriate aminohydroxypyridine with a carboxylic acid under the influence of a polyphosphoric acid or a polyphosphoric ester. A mixture of pyridine and a slight excess of carboxylic acid in the presence of a polyphosphoric acid or ester is heated to a temperature of about 1000C to about 3000C, preferably about 130C.
The polyphosphoric acid or ester is decomposed with water by heating at a temperature of C to 230 DEG C. for about 5 minutes to about 1 hour, and the desired product is then obtained by making the solution alkaline. All oxazolopyridine isomers may be prepared via the intermediate amide by reacting the acid halide with the appropriate aminohydroxypyridine, preferably in approximately equimolar amounts, in the presence of an acid acceptor.

Although any common acid acceptor commonly used for N-acylation may be used, it has been found advantageous to use an organic base such as pyridine, triethylamine or a corresponding base. A sufficient amount of organic base may be used to act as a solvent, or other inert organic solvents such as dimethyl formamide, benzene, dioxane, glyme or diglyme, etc. may be used as a medium for the reaction. Next, the amide obtained by the above reaction is
a mixture of it and a condensing agent such as phosphorous oxychloride for about 1 to 2 hours.
by refluxing for 0 hours or the amide with polyphosphoric acid at about 100°C to 300°C preferably about 130 to 230°C.
C. for about 5 to 60 minutes to cause ring closure to form the oxazolopyridine. Other condensing agents that can be used in place of phosphorus oxychloride are phosphorus pentoxide, phosphorus oxybromide, thionyl chloride, and phosphorus tribromide. The N-oxide of oxazolopyridine is prepared by heating a solution of oxazolopyridine in acetic acid with hydrogen peroxide to about 50-100°C. N-lower alkylpyridinium iodide is prepared by refluxing a solution of oxazolopyridine in acetone with lower alkyl iodide.

The N-oxide of oxazolopyridine and the N-lower alkylpyridinium iodide are each represented by the following formula: The following examples illustrate the preparation of specific compounds of the invention and are given by way of illustration only. , is not intended to limit the scope of the invention.

Example 1 2-Phenyloxazolo[4,5-b]pyridine A mixture of 2-amino-3-hydroxypyridine 219 and benzoic anhydride 1309 is heated to obtain a melt, and then the mixture is further refluxed. Heat until.

After 10 minutes, the heating is stopped and, after a few minutes of cooling, the melt is poured into benzene 21.

This solution is extracted with 4 x 200 TfL1 of 2.5N hydrochloric acid. This acidic solution is then made basic with sodium hydroxide solution. The precipitate is collected and then recrystallized from 90 ml of absolute ethanol to give 12.59 ml of 2-phenyloxazolo[4,5-b]pyridine, melting point 125-127°C. Formula (RCO)2 instead of benzoic anhydride used in Example 1
Using substantially the procedure of Example 1, but using an equivalent amount of anhydride of 0, the 2-R-oxazolo[4,5-b]pyridine shown in the table is obtained according to the following formula.

Example 6 2-(2-fluorophenyl)oxazolo[4,5-b
]Pyridine 2-amino-3-hydroxypyridine 3.3
g (0.03 mol), 2-fluorobenzoic acid 5.69 (
0.04 mol) and a mixture of polyphosphoric acid 129 and 175
Heat to °C and hold for 10 minutes.

After cooling slightly, pour the melt into a mixture of ice and water. After stirring to decompose the polyphosphoric acid, the mixture is made alkaline with ammonium hydroxide solution. The resulting precipitate is collected and then recrystallized from benzene and petroleum ether to give 4.0 g of 2-(2-fluorophenyl)oxazolo[4,5-b]pyridine having a melting point of 126-12 rC. In place of the 2-fluorobenzoic acid used in Example 6,
Using the method of Example 6 except using the equivalent amount of COOH benzoic acid, the 2-R-oxazolo[4,5-b]pyridine shown in Table 1 is obtained according to the following formula.

Example 56 2-(4-Tolyl)oxazolo[4,5 Pyridine Step A: 150 ml of 3-hydroxy-2-(4-tolylapyridine dimethylformamide and 1 ml of thylamine
2-amino-3-hydroxypyridine 5.5 in 1 ml
9 (0.05 mol) with slight cooling.
9.39 (0.06 mol) of tolyl chloride are added in portions and the mixture is then stirred at ambient temperature overnight.

The precipitate obtained is removed by filtration. The liquid was evaporated to dryness and the resulting oil was crystallized from ether and then recrystallized from aqueous ethanol Z5 to give a melting point of 134-13.
3.19 of 3-hydroxy-2-(4-tolylamino)pyridine at 5° C. is obtained.

Step B: A solution of 500 η of 3-hydroxy-2-(4-tolylamino)pyridine in 4 ml of 2-(4-tolyl)oxazolo[4,5-b]pyridineoxyphosphorus chloride is heated to
Heat for 8 hours.

The excess phosphorus oxychloride is evaporated and the residue is then treated with ice and water. The mixture is cleaned by filtration and then neutralized with concentrated ammonium hydroxide. The resulting precipitate was collected, washed with water, dried and then recrystallized from benzene-petroleum ether to give 2-(4-tolyl) having a melting point of 135-136°C.
200η of oxazolo[4,5-b]pyridine is obtained. Example 57 2-(2-fluorophenyl)oxazolo[4,5-b
] 2-(2 in pyridine-4-oxide acetic acid 10W11)
-fluorophenyl)oxazolo[4,5-b]pyridine (from Example 6) A solution of 19 is treated with 2 ml of 30% hydrogen peroxide and then heated on a steam bath for 16 hours.

After cooling, dilute the mixture with ice and water. The precipitate was collected and recrystallized from dioxane-ether, melting point 214.
~216-C2-fluorophenyl)oxazolo[4
, 5-b] to obtain pyridine-4-oxide. Example 58N-
Methyl 2-(2-fluoropheninolioxazolo[4,
5-b] Pyridinium iodide acetone 75TfL
2-(2-fluoropheninolioxazolo[4,
5-b] A solution of pyridine 600 and methyl iodide 10d is refluxed for 3 hours.

The solution is concentrated to dryness and the residue is then extracted with ether.
The ether-insoluble material is recrystallized from methanol-ethyl acetate to give N-methyl 2-(2-fluorophenyl)oxazolo[4,5-b]pyridinium iodide 500°C, melting point 229°C. Example 59 2-Ethyloxazolo[4,5-b]pyridine A mixture of 4.49 2-amino-3-hydroxypyridine, 10.49 propionic anhydride and 159 polyphosphoric acid
Heat at ℃ for 15 minutes.

The reaction mixture Z4 was slightly cooled, then poured into ice water,
Next, stir until the polyphosphoric acid is decomposed.

The solution is made alkaline with solid sodium bicarbonate and then extracted with 150 ml of methylene chloride. The dry methylene chloride solution is concentrated to dryness, then the residue is dissolved in ether and then passed through aluminum oxide. From the ether solution, 2-ethyloxazolo [melting point 52-53°C] was obtained.
4,5-b]pyridine 1.29 is obtained. Example 602-[3
-di(methyl)aminophenyl]oxazolo[4,5-
b] Pyridine 2-(3-nitrophenyl)oxazolo[
4,5-b] Pyridine 2.49, 37% formaldehyde solution 6 ml 11 acetic acid 50 ml and Raney Nickel 0
．． Hydrogenate the mixture of 259.

The catalyst is removed by filtration and the furnace liquor is then concentrated to dryness.
The residue is partitioned between aqueous sodium bicarbonate and benzene. The benzene phase is separated, dried over anhydrous sodium sulfate, and then concentrated to give an oil. This oil is taken up in methylene chloride and treated with dry ether saturated with hydrogen chloride. The resulting precipitate was collected and washed with ether to give 2-(3-dimethylaminophenyno(ha)oxazolo[4,5-b]pyridine.2) having a melting point of 208-209°C.
Obtain HC1. Example 61 2-(3-aminophenyl)oxazolo[4,5b]pyridinenitanol 2 in 50ml
A mixture of 700 mg of -(3-nitrophenyl)oxazolo[4,5-b]pyridine was added with -4 (substance) over a carbon catalyst with 5% palladium at 150°C.

The catalyst is removed by filtration and the bath is then concentrated to dryness.
The miscellaneous residue is recrystallized from chloroform-petroleum ether to give 2-(3-aminophenyl)oxazolo[4,5-b]pyridine having a melting point of 179-180.5. Example 62 2-benzoyloxazolo[4,5-b]pyridine 2-
Benzyloxazolo[4,5-b]pyridine 800,
Potassium permanganate 2.59, water 35ml and 2.
A mixture of 6 drops of 5N sodium hydroxide solution was heated to 50-55°C.
Heat for 3 hours.

After cooling, sulfuric acid is added to bring the pH to about 6, and then a sufficient amount of sodium acid sulfite is added to remove the manganese dioxide. The remaining crystalline precipitate is collected and then recrystallized from ethyl acetate to yield 2-benzoyloxazolo[4,5-b]pyridine with a melting point of 151-153°C. Example 635-methyl-
2-Phenyloxazolo[4,5-b]pyridine Step A
: Preparation of 3-hydroxy-6-methyl-2-nitropyridine 10.99 g of 3-hydroxy-6-methylpyridine is added to 40 ml of ice-cold concentrated sulfuric acid.

While maintaining the temperature at 6° C., 4.7 ml of fuming nitric acid are added dropwise with stirring. The mixture is allowed to warm to room temperature overnight. ice(
2009) under stirring. After the ice melts, the precipitate is collected, washed with water and then dried to yield 3-hydroxy-6-methyl-2-nitropyridine with a melting point of 103-105°C. Step B: Production of 2-amino-3-hydroxy-6-methylpyridine 3-hydroxy-6-methyl-2-nitropyridine (3.59) in 75 ml of methanol is reduced over carbon catalyst 19 with 5% palladium. .

The catalyst was removed by filtration, and the liquid was then concentrated to dryness.
-amino-3-hydroxy-6-methylpyridine,
This is used directly in the next step. Step C: Preparation of 5-methyl-2-phenyloxazolo[4,51b]pyridine 2-amino-3-hydroxy-6-methylpyridine 1.259, polyphosphoric acid 69 and benzoic acid 2.
Heat the mixture of 09 at 190-200°C for 10 minutes.

The cooled mixture is diluted with water and then made basic with solid sodium bicarbonate. The resulting precipitate is collected and then recrystallized from ether to yield 5-methyl-2-phenyloxazolo[4,5-b]pyridine having a melting point of 148 DEG-149 DEG C. Example 64 2-(3-acetamidophenyl)oxazolo[4,5
-b] Pyridine 0.63 2-(3-aminophenyl)oxazolo[4,5-b]pyridine in 10 ml of pyridine
The solution of 9 is treated with 0.35 ml of acetic anhydride while stirring.

After stirring over the weekend, the mixture is diluted to 50 ml with water. After brief stirring and cooling, the precipitate is collected, washed with water and then dried. Recrystallization from ethyl acetate gives 2(3-acetamidophenyl)oxazolo[4,51b]pyridine with a melting point of 201.5-202.5°C. Example 65 2-(2-methylsulfinylphenyl)oxazolo[
4,5-b]2-(2-
A solution of 0.59 methylthiophenyl)oxazolo[4,5-b]pyridine was added to sodium metaperiodate 3
Process with 9.

After stirring at room temperature over the weekend, the mixture was dissolved in 30 ml of water.
Dilute it. The acetone was distilled off, and the resulting precipitate was recrystallized to give 2-(2
-methylsulfinylphenyl)oxazolo[4,5-
b] Obtain pyridine. 2-(3-Methylsulfinylphinyl) was prepared by using the method described in Example 6 except using 2-(3-methylthiopheninolyoxazolo[4,5-b]pyridine as the starting material. Example 66 2-(2-fluorophenyl)oxazolo[5,4-b] is obtained.
Pyridine Step A: Preparation of 3-(2-fluorobenzoylamino)-2-pyridone In a solution of 3.39 (0.03 mono(c)) of 3-amino-2-pyridone in 75 ml of pyridine cooled in ice , 2-fluorobenzoyl chloride 6.39 (0.0
4 mol) in small portions over 5 minutes.

After stirring for 15 hours at ambient temperature, the mixture is poured into ice and water. The resulting precipitate was collected by filtration, washed with water, and then recrystallized from ethanol.
(2-fluorobenzoylamino)-2-pyridone is obtained. Step B: 2-(2-fluorophenyl)oxazolo[5,4-b
] Production of pyridine 3-(2-
Fluorobenzoylamino)-2-pyridone 5.

Reflux the solution of 49 for 5 hours.

The excess phosphorous oxychloride is evaporated and the residue is then treated with ice. The resulting precipitate was collected and recrystallized from benzene-petroleum ether to give 2-(2-
3.19 fluorophenyl)oxazolo[5,4-b]pyridine is obtained. In place of the 2-fluorobenzoyl chloride used in step A, a corresponding amount of formula R-COCI
Steps A and B of Example 66 except using the acid chloride of
By using the method of
3-(R-carbonylamino)-2-pyridone and 2-R-oxazolo[5,4-b]pyridine shown in Table 1 are obtained.

n Example 107 5-chloro-2-phenyloxazolo[5,4-b]pyridine Step A: Preparation of 5-chloro-3-nitro-2-pyridone 2-amino-5-chloropyridine (12,89, 0.1 mol) to 50 ml of concentrated sulfuric acid.

25 ml of concentrated nitric acid is gradually added to this while stirring. After the exothermic reaction has subsided, the mixture is cooled and poured onto ice. The precipitate is collected and added to a mixture of 12 ml of concentrated sulfuric acid and 150 ml of water. Sodium nitrite 79 is added portionwise to this solution cooled to 0.degree. C. and the resulting mixture is then warmed to room temperature. After cooling, the precipitate was collected and then recrystallized from dimethylformamide ethanol to give 5-chloro-3-nitro-2-, melting point 225-227°C.
Get Pyridone. Step B: 9) was mixed with 225 ml of ethanol and 6 ml of acetic acid in the presence of 0.69 ml of 5% palladium on carbon.
Hydrogenate in m1.

The catalyst is removed by filtration and the bottom liquor is then concentrated to dryness.
The residue is dissolved in 75 ml of pyridine, cooled in ice and then treated with 4.89 g of benzoyl chloride for 15 minutes.

The ice bath and reaction mixture are allowed to spontaneously warm to room temperature. Pour the mixture onto ice 2009. Dilute with 500 ml of water to separate the oil, wash with water and solidify (49).
The crude 3-benzoylamino-5-chloro-2-pyridone is used directly in the next step. Step C: Production of 5-chloro-2-phenyloxazolo[5,41b]pyridine Crude 3-benzoylamino-5-chloro-2
- 14 mixtures of 2.19 pyridones and 79 polyphosphoric acids
Heat at 0-150°C for 10 minutes.

Add ice and water, collect the precipitate by filtration, and then extract the solid with hot benzene. The benzene was evaporated, then the residue was taken up in ether, filtered through Al2O3 and then concentrated to dryness to give 300 ml of 5-chloro2-phenyloxazolo[5,4-b]pyridine, mp 150-151°C. get.
Example 108 4-Methyl-2-phenyloxazolo[5,4b]pyridine Step A: Preparation of 3-benzoylamino-4-methyl-2-pyridone 4-Methyl-3-nitro-2-pyridone (7.79 )
methanol 50m under carbon 0.259 with 5% palladium
Hydrogenate in 1.

The catalyst is removed by filtration and the solvent is then evaporated. Pyridine 60T! solid residue! 11, cooled to 200C and treated with 6.5 ml of benzoyl chloride.

After standing overnight, the mixture is poured into 200 ml of water and ice. The precipitate (59) is collected and then recrystallized from methanol to give 3-benzoylamino-4-methyl-2-pyridone, melting point 264-265°C. Step B: Preparation of 4-methyl-2-phenyloxazolo[5,4b]pyridine A solution of 31 ml of 3-benzoylamino 4-methyl-2-pyridone in 30 ml of phosphorous oxychloride is heated on a steam bath for 66 hours. .

The mixture is poured onto ice and then neutralized with ammonium hydroxide. The precipitate is collected and then recrystallized from methanol to give 1.49 ml of 4-methyl-2-phenyloxazolo[5,4-b]pyridine, melting point 91-92°C. Example 109 5-Nitro72-phenyloxazolo[5,4b]pyridine Step A: Preparation of 3-amino-5-nitro-2-pyridone 3,5-dinitro-2pyridone 5.5 in 200 ml methanol
The pH of the solution in step 9 was adjusted to 8 with ammonium hydroxide.

At 60-65 water C, gradually add a solution of 10.89 ml of sodium sulfide nonahydrate in 30 ml of water.

After 1 hour at 60-65°C the solvent is evaporated and the residue is then extracted with hot benzene and acetic acid to neutralize the sodium salts.

Decant off the benzene and then cool to obtain a precipitate. Recrystallized from methanol to give 3-amino-5-nitro-2
Get Pyridone. Melting point: 200-201°C. Step B: Preparation of 3-benzoylamino-5-nitro-2-pyridone 3-amino-5-nitro-2 in 1.5 ml of pyridone
- A solution of 100 η of pyridone is cooled and treated with 200 η of benzoyl chloride.

Add water after 2 hours.

The precipitated oil is washed with water and then triturated with ether. The resulting solid is recrystallized from ethyl acetate to give 3-benzoylamino-5-nitro-2-pyridone having a melting point of 267-268°C. Step C: Production of 5-nitro-2-phenyloxazolo[5,4b]pyridine A mixture of 300 η of 3-benzoylamino-5-nitro-2-pyridone and 1.59 η of polyphosphorus was heated at 180°C for 15 minutes. do.

The mixture is cooled, treated with ice, and the precipitate is collected. The precipitate is dissolved in ether, passed through Al2O3 and then evaporated to give 5-nitro-2-phenyloxazolo[5,4-b]pyridine, melting point 219-220C. Example 1
106-Methyl-2-phenyloxazolo[5,4b]
Pyridine step A: Production of 6-methyl-3-nitro-2-pyridone Concentrated sulfuric acid 2
A solution of 249 2-amino-6-methyl-3-nitropyridine in 5 ml and 380 ml water is cooled to 0° C. and then treated with 119 sodium nitrite in 25 ml water.

The temperature rises spontaneously to 45°C. After cooling, the precipitate of 6-methyl-3-nitro-2-pyridone was collected (melting point 22
2-223°C) and then directly used in the next step. Step B: Production of 3-benzoylamino-6-methyl-2-pyridone 6-methyl-3-nitro-2-pyridone (7.79)
in the presence of 5% palladium on carbon 0.259,
Hydrogenate in 50 ml of methanol.

The catalyst is removed by filtration and the liquid is then evaporated to dryness.
The residue is taken up in 60 ml of pyridine, cooled to 20° C. and then treated with 6.5 ml of benzoyl chloride.

After 2 hours at 20°C the mixture is poured onto ice.

The precipitate is collected and then dried to give 3-
Benzoylamino-6-methyl-2-pyridone 99 is obtained. Step C: A solution of 59 3-benzoylamino 6-methyl-2-pyridone in 50 ml of 6-methyl-2-phenyloxazolo[5,4-b]pyridineoxyphosphorous chloride was heated on a steam bath for 20 min.
Warm for an hour.

The solution is slowly poured onto ice under stirring. The precipitate was collected by filtration and then recrystallized from aqueous ethanol to give 6-methyl-2-phenyloxazolo, melting point 71-73°C.
5,41b] Obtain pyridine. Example 111 5-trifluoromethyl-2-phenyloxazolo[5
, 4-b] Pyridine Step A: Crushed 6-chloronicotinic acid 839 phosphorus pentachloride is added little by little to a stirred suspension of 289 6-hydroxynicotinic acid in 193 ml phosphorus oxychloride.

After stirring for 1 hour at room temperature, the mixture is heated on a steam bath overnight. The excess phosphorus oxychloride is removed in vacuo, the warm residue is then added to approximately 1.2 kg of broken ice, and the mixture is then allowed to warm to room temperature overnight with stirring. The precipitate was collected by filtration, washed with water and then dried to a melting point of 187.5-189°C.
(Decomposition) of 6-talolonicotinic acid 299 (92%) is obtained. Step B: Production of 2-chloro-5-trifluoromethylpyridine 6
- A mixture of 299 ml of chloronicotinic acid, 1309 ml of sulfur tetrafluoride and 18 ml of hydrofluoric acid was heated at 150° C.
Cook for 6 hours.

After cooling and discharging, the reaction mixture is treated with 2.5N sodium hydroxide to pH 9 while cooling to about 40°C. The mixture is extracted with chloroform, then the extract is filtered, dried, and concentrated to give a yellow oil (17 g). This is used directly in the next step. Step C: Production of 5-trifluoromethyl-2-pyridone Acetic acid 10
A solution of 5.59 ml of 2-chloro-5-trifluoromethylpyridine in 0 ml is treated with 5.59 ml of silver acetate under nitrogen.

Heat the mixture at 140° C. for about 45 hours. After the hot mixture has passed, the filter cake is washed with acetic acid. The combined door solution and washing solution are concentrated and dried. The residue is partitioned between chloroform and water, then the mixture is made basic with solid sodium bicarbonate. The mixture is filtered, the layers are separated and the aqueous phase is re-extracted with chloroform. The combined chloroform layers are dried and then concentrated to dryness. The residue is recrystallized from acetone to give 2.59 ml of 5-trifluoromethyl 2-pyridone, melting point 145-147.8°C. Process D
: Preparation of 3-nitro-5-trifluoromethyl-2-pyridone To 0.951 l of stirred fuming nitric acid is added 299 g of 5-trifluoromethyl-2-pyridone over 1 hour, then stirring is continued for 75 hours.

Evaporate the fuming nitric acid and then triturate the residue with acetone. The acetone was evaporated to about 60 ml, then the precipitate was collected by filtration and diluted with methylene chloride lyacetone 5:1.
Wash with the mixture, dry and then use directly in the next step. Step E: 3-benzoylamino-5-trifluoromethyl-2-
Production of pyridone 3-nitro-5-trifluoromethyl-
2-Pyridone (3.129) is reduced in 50 ml of ethanol in the presence of Raney nickel.

The catalyst is removed by filtration and the filtrate is then concentrated to dryness.
The residue is taken up in 10 WLI of pyridine, cooled to 5° C. and then treated gradually with 2.0 ml of benzoyl chloride. After standing overnight, the mixture is treated with ice and water to obtain an oil. The aqueous phase is decanted and the oil triturated with ether. The solid is collected and recrystallized from methanol to give 3-benzoylamino-5-trifluoromethyl-2-pyridone, melting point 207-210°C. Step F: 5-trifluoromethyl-2-phenyloxazolo[5
,4-b] Production of pyridine 3-benzoylamino-5-trifluoromethyl-2- in 4.5 ml of phosphorus oxychloride
A solution of ~300 pyridone is refluxed for 16 hours.

The excess phosphorus oxychloride is evaporated and the residue is then treated with ether and dilute sodium hydroxide solution. The ether phase is separated, dried and evaporated. The residue is recrystallized from ethyl acetate to give 5-trifluoromethyl-2-phenyloxazolo[5,4-b]pyridine having a melting point of 127-129°C. Example 112 5-Amino-2-phenyloxazolo[5,4-b]pyridine A solution of 361 η of 5-nitro-2-phenyloxazolo[5,4-b]pyridine in 30 ml of methanol with 5% palladium Hydrogenation is carried out over 0.2f1 of carbon catalyst.

The catalyst is removed by filtration and the filtrate is then concentrated to dryness.
The residue is recrystallized from methanol to give 5-amino-2-phenyloxazolo[5,4-b]pyridine having a melting point of 210°C. Example 1135-Benzoylamino-2-phenyloxazolo[5,4-b]pyridinepyridine 1d
5-Amino-2-phenyloxazolo[5,4-b
]Pyridine 80T! 19 solution with benzoyl chloride 0.0
Process with 7ml.

After standing for 1 hour, dilute the mixture with ice water.

The precipitate was collected and recrystallized from methanol to a melting point of 19
5-benzoylamino-2-phenyloxazolo[5,4-b]pyridine at a temperature of 1 to 192°C is obtained. Example 1142,
5-Diphenyloxazolo[5,4-b]pyridine 5-
Amino-2-phenyloxazolo[5,4b]pyridine 180η, benzene 10ml and isoamyl nitrite 0
．． 2 ml of the mixture are refluxed for 1% time.

After the hot solution is removed, the solution is concentrated to dryness. The residue is extracted with ether, the extract is filtered through aluminum oxide and then concentrated to dryness. The crystalline residue is recrystallized from ethyl acetate to give 2,5-diphenyloxazolo[5,4-b]pyridine having a melting point of 151-152°C. Example 115 5-isopropoxycarbonylamino-2-phenyloxazolo[5,4-b]pyridine A mixture of 300 mg of 5-amino-2-phenyloxazolo[5,4-b]pyridine and 3d of pyridine was added in ice. and then add 0.2 ml of isopropyl chloroformate to it.

The mixture is left in the refrigerator for 5 days and then diluted with ice water. The precipitate was collected and then recrystallized from isopropanol to a melting point of 2.
5-isopropoxycarbonylamino-2-phenyloxazolo[5,4-b]pyridine of 10 to 211 pC is obtained. Example 116 2-(4-carbamylpheno(ha)oxazolo[5,
4-b] Pyridine A solution of ~600 2-(4-cyanophenyl)oxazolo[5,4-b]pyridine in 8 ml of concentrated sulfuric acid is allowed to stand at room temperature for 16 hours.

The solution is poured onto ice and the white precipitate is then collected by filtration to yield 2-(4-carbamylphenyl)oxazolo[5,4-b)pyridine with a melting point of 315 DEG C. (decomposed). Example 1
17 2-(4-dimethylaminophenyl)oxazolo[5,
4-b] Pyridine 2-(4-nitrophenyl)oxazolo[5,4-b] A mixture of 2.49 pyridine, 7 ml 11 37% formaldehyde solution, 5 ml acetic acid and 0.259 Raney nickel and 125 Tf methanol is hydrogenated.

The catalyst is removed by filtration and the sap is concentrated to dryness.
The residue was extracted with water and the water-insoluble residue was then recrystallized from chloroform-petroleum ether, melting point 168-1.
2-. at 70°C. j/(4-dimethylaminophenino(ha)oxazolo[5,4-b]pyridine) is obtained.

Example 118 2-(2-aminophenyl)oxazolo[5,4-b]
Pyridine A mixture of ~700 2-(2-nitrophenyl)oxazolo[5,4-b]pyridine in 50 ml of ethanol is hydrogenated over a carbon catalyst 1507F9 with 5% palladium.

The catalyst is removed by filtration and the solvent is then concentrated to dryness.
The residue is recrystallized from chloroform-petroleum ether to give 2-(2-aminophenyl)oxazolo[5,4-b]pyridine having a melting point of 142 DEG-144 DEG C. Example 119 2-(2-benzoylaminophenyl)oxazolo[5
,4-b]Pyridine 2-(2
An ice-cold solution of -aminophenyl)oxazolo[5,4-b]pyridine 19 is slowly treated with benzoyl chloride 19.

The reaction mixture was diluted with ice water, then stirred for 10 minutes, and the resulting solid was collected by filtration and then recrystallized from benzene to give 2-(2-benzoylaminophenol) having a melting point of 197-198°C. (c) Oxazolo[5,4-b]pyridine is obtained. Example 120 5-chloro-2-(2-fluorophenyl)oxazolo[5,4-b]pyridine Step A: 5-chloro-3-(2 -fluorobenzoylamino)-
Production of 2-pyridoneEthanol 75TL1 and acetic acid 2
5-chloro-3-nitro-2-pyridone 1,7 in m1
A solution of 9 is hydrogenated over a 0.29% carbon catalyst with 570 palladium.

The catalyst is removed by filtration and the solvent is then evaporated to dryness.
The dried residue is dissolved in 30 d of pyridine, cooled in ice, and then treated with 1.69 g of 2-fluorobenzoyl chloride for 5 minutes.

The mixture is stirred at ambient temperature for about 16 hours and then poured into ice water. The obtained precipitate was collected by filtration (1.5 g).
It is then used directly in the next step without purification. Step B: Production of 5-chloro-2-(2-fluoropheninolioσdxazolo[5,4-b]pyridine) A mixture of 1.59 ml of the above amide and 5 ml of polyphosphoric acid was
Heat at 60°C for 10 minutes.

After cooling, add the mixture to ice water. The precipitate is collected and extracted with 75 ml of hot benzene, then the extract is decolorized with activated carbon and evaporated to dryness. Dissolve the residue in methylene chloride and
It is then filtered through aluminum oxide and the filtered liquid is washed with ether. The product 5-chloro-2-(2-fluorophenyl)oxazolo[5,4-b]pyridine is precipitated from the bottom liquor. The product has a melting point of 140-141°C. Example 121 5-dimethylamino-2-phenyloxazolo[5,4
-b] Pyridine methanol 75ml 11 Benzene 75ml
1 5 ml of acetic acid and 8 d of 37% formaldehyde solution
5-nitro-2-phenyloxazolo [5,4-b]
Pyridine (1,29) is hydrogenated over 1.5 tablespoons of Raney nickel.

The catalyst is removed by filtration and the bottom liquor is then diluted with 10 ml of water and made basic with solid sodium bicarbonate.
The mixture is concentrated to dryness. The residue was crystallized from ethyl acetate to give 5-dimethylamino-
2-phenyloxazolo[5,4-b]pyridine is obtained. Example 122 5-Methoxy-6-methyl-2-phenyloxazolo[5,4-b]pyridine Step A: Preparation of 3-methoxy-2-methyl-6-nitropyridine Ice cooling of 3 ml of concentrated sulfuric acid and 37 n1 of fuming nitric acid to the mixture,
0.3-methoxy-2-methylpyridine over 5 minutes.
Add 59.

After spontaneously warming to room temperature, the mixture is heated at 55-6°C for 6 hours. The mixture is cooled and then 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 with a melting point of 99-100.5°C.
- Obtain nitropyridine.

Step B: Preparation of 6-amino-3-methoxy-2-methylpyridine 3-methoxy-2-methyl- in methanol 20WLI
6-Nitropyridine (0.3179) is hydrogenated over 5% palladium on carbon catalyst 0.19.

Touch. The J9 medium was removed by filtration, and the aqueous solution was then concentrated to dryness to give 6-amino-3-methoxy-2-methylpyridine, which was used directly in the next step.

Step C: Production of 5-methoxy-6-methyl-2-pyridone To an ice-cooled mixture of 0.2 ml of concentrated sulfuric acid, 2.0 ml of water and 138 ~ of 6-amino-3-methoxy-2-methylpyridine, 1 ml of water + A solution of 75η of sodium nitrate is added.

Warm the cold solution to room temperature overnight. The mixture is diluted with a little water and then made basic with solid sodium bicarbonate. The mixture was extracted with methylene chloride, and the extract was then concentrated to dryness to give 5-methoxy6-methyl-2-pyridone 120111!
is obtained and used directly in the next step. Step D: Preparation of 5-methoxy-6-methyl-3-nitro-2-pyridone A mixture of 4.2 fl of 5-methoxy-6-methyl-2-pyridone in 50 ml of ice-cold concentrated sulfuric acid was heated at about 5° C. for 60 minutes. Add 2.5 mj of concentrated nitric acid dropwise.

Continue cold stirring overnight. About 70 ml of ice while stirring the mixture
Add to 09. After about 30 minutes, the precipitate was collected, washed with water, and then dried to give 5-methoxy-6-methyl 3-nitro-2-
3.79 g of pyridone is obtained, which is used directly in the next step. Step E: 3-benzoylamino-5-methoxy-6-methyl-2
- Preparation of pyridone 5-methoxy-6-methyl-3-nitro-2-pyridone (1.84
9) is hydrogenated over a carbon catalyst with 5% palladium.

The catalyst is removed by P filtration and the bottom liquid is then concentrated to dryness.
The residue is dissolved in 15 ml of pyridine and then treated cold with 1.2 ml of benzoyl chloride. After standing overnight at ice temperature, dilute the mixture with water. The resulting precipitate is collected and then recrystallized from ethanol. This material is extracted several times with ether and the insoluble rostrum is then recrystallized from ethanol to yield 3-benzoylamino-15-methoxy-16-methyl-2-pyridone, melting point 247-248°C. Process F:
5-Methoxy-6-methyl-2-phenyloxazolo [
5,4-b] Production of pyridine 3-benzoylamino-5
A mixture of 200 mL of methoxy-6-methyl-2-pyridone and 3 ml of phosphorus oxychloride is heated on a steam bath for 20 hours.

The mixture is concentrated to dryness, then the residue is taken up in ether, made basic with ammonium hydroxide, and then diluted with water.
The ether is separated off and the aqueous phase is extracted three times with ether.

The combined ether phases were dried and then concentrated to dryness to a melting point of 16
5-methoxy-6methyl-2-phenyloxazolo[5,4-b]pyridine having a temperature of 7-168°C is obtained. Example 123 2-(2-fluorophenyl)-5-methyloxazolo[5,4-b]pyridine Step A: 3-(2-fluorobenzoylamino)-5methyl-2
-Preparation of pyridone 3-amino-5 in 25 ml of pyridine
-Methyl-2-pyridone 3.1! The solution of 1 is cooled in ice and then treated dropwise with 4.59 g of 2-fluorobenzoyl chloride.

After stirring for about 3 hours at room temperature, the mixture is diluted with 200 ml of ice water. After 0.5 hours, the precipitate was collected, washed with water, dried, and then recrystallized from ethanol, with a melting point of 230-232
3-(2-fluorobenzoylamino)-5-methyl-2-pyridone of C is obtained.

Step B: Production of 2-(2-fluorophenyl)-5-methoxyoxazolo[5,4-b]pyridine 3-(2-fluorobenzoylamino)-5-methyl-2-pyridone 1.89
and phosphorus oxychloride 25'1rL1 is refluxed for 1.5 hours.

Evaporate the excess phosphorus oxychloride and then triturate the remaining oil with cold water. The precipitate was collected and then recrystallized from benzene/petroleum ether to give 2-(2-
Fluorophenyl)-5-methyloxazolo[5,4-
b] Obtain pyridine. Example 124 below is taken as a reference example.

Example 124 2-phenyl-sazolo[4,5-c]pyridine Step A
: Preparation of 3-nitro-4-pyridone A solution of 4-hydroxypyridine 509 in 500 ml water and 90 ml concentrated nitric acid is concentrated to about 3507 n1 in an evaporating dish on a steam bath.

The mixture is cooled and the precipitate is then collected by filtration to yield 4-hydroxypyridine nitrate 551. To a cooled solution of 35 ml of fuming sulfuric acid and 45 ml of fuming nitric acid is added 359 ml of 4-hydroxypyridine nitrate.

After warming the mixture to room temperature overnight, it was heated on a steam bath for 2 hours.
Heat for % time. Cool it and pour it onto ice 5009. The resulting precipitate was collected by deep filtration, washed with a small amount of water, and then recrystallized from water to give a melting point of 282-28.
Obtain 3nitro-4-pyridone at 4°C. Step B: Preparation of 3-amino-4-pyridone 3-nitro-4-pyridone (
7.09) is hydrogenated over 5% palladium on carbon catalyst 0.59.

The catalyst is removed by filtration and the solution is then concentrated to dryness to yield crude 3-amino-4-pyridone. Step C: Preparation of 2-phenyloxazolo[4,5-c]pyridine 3-amino-4-pyridone 69 and benzoic anhydride 4
Heat 0g of the mixture to 245°C for 20 minutes.

After cooling to about 100°C, the mixture was diluted with benzene 200Tn
1 and then the mixture is extracted six times with 2.5N hydrochloric acid. The combined acid extracts are filtered and the sap is made basic with ammonium hydroxide. The resulting precipitate was collected and then recrystallized from ethyl acetate to give 2-
Phenyloxazolo[4,5-c]pyridine is obtained. Example 125 below is taken as a reference example.

Example 125 2-(2-fluorophenyl)oxazolo[4,5-c
]Pyridine 3-(2-fluorobenzoylamino)-4
- Preparation of pyridone A solution of 5.39 ml of 3-nitro-4-pyridone in 100 mi of ethanol is hydrogenated over 0.59 ml of 570 palladium on carbon catalyst.

The catalyst is removed by filtration and the filtrate is then evaporated to dryness.
The oily residue was taken up in 75 ml of dry pyridine and cooled in ice, then 6.39 ml of 2-fluorobenzoyl chloride was added to 1 ml of dry pyridine.
Stir while adding over 0 minutes. Furthermore, at ice bath temperature 2
0 minutes, then continue stirring at room temperature for about 16 hours. The mixture was poured into ice water, and the resulting precipitate was collected by filtration.
It is then recrystallized from a dimethyl formamide ether mixture to obtain 3-(2-fluorobenzoylamino)-4-pyridone having a melting point of 298 DEG C. Step B: 2-(2-fluorophenyl)oxazolo[4,5-c
[Production of pyridine] A mixture of 3-(2-fluorobenzoylamino)-4 pyridone 19 and polyphosphoric acid 49 was
Heat at 0°C for 10 minutes.

The mixture is added to ice water to destroy excess polyphosphoric acid, filtered and neutralized with solid sodium bicarbonate. The resulting precipitate is collected by filtration and then recrystallized from benzene-petroleum ether to obtain 2-(2fluorophenino(ha)oxazolo[4,5-c]pyridine) with a melting point of 110-111°C. By using the method of Steps A and B of Example 125 except substituting a corresponding amount of acid chloride of formula R-COCI for the 2-fluorobenzoyl chloride used in Step A, 3-(R
-carbonylamino)4-hydroxypyridine and 2
-R-oxazolo[4,5-c]pyridine is obtained.

Example 166 2-(2-fluorophenino(c)thiazolo[5,4-
b] Pyridine 3-(2-fluorobenzoylamino)-
Heat 2-pyridone (29), 60 ml of xylene and 15 ml of pyridine until complete dissolution.

To this solution was added 6.59 phosphorus pentasulfide, and then the mixture was
Heat to reflux for an hour. The reaction mixture is separated from the gummy residue by hot decanting and the solvent is then concentrated to dryness. The crystalline residue was recrystallized from ethanol to give 2-.(2-fluorophenyl)thiazolo[5,4-b
] Obtain pyridine. except that instead of 3-(2-fluorobenzoylamino)-2-pyridone used in Example 166, a corresponding amount of 3-(R-carbonylamino)-2-pyridone as described in Examples 67 to 106, respectively. Example 1
By using the method of No. 66, the 2-R-thiazolo[5,4-b]pyridine shown in the table according to the following formula is obtained.

Example 207 2-(2-fluorophenyl)thiazolo[4,5-c]
3-nitro-4-pyridone (2.89) in 50 ml of pyridine methanol with 5% palladium on carbon catalyst 0.29
Hydrogenate above.

The catalyst is removed by filtration and the resulting solution is concentrated to dryness. Pyridine 25W by heating the residue to about 80°C.
Dissolves in L1.

After cooling to 10-15°C, 3 ml of 2-fluorobenzoyl chloride are added gradually, keeping the temperature below 20°C.

After standing overnight, ice was added and the resulting mixture was filtered, the filter cake was then washed with water and recrystallized from methanol to give 3-(2-fluorobenzoyl )-4-pyridone is obtained. Dissolving the amide in 100 ml of xylene and 30 ml of pyridine,
It is then heated to 130.degree. C. and treated gradually with 10.59 g of phosphorous pentasulfide.

After heating under reflux for 13 hours, the hot solution is decanted and the solvent is then concentrated to dryness.

The crystalline residue is extracted with ether. The ether extracts are combined and concentrated to dryness, and the residue is then crystallized from ethanol to give 2-(2-fluorophenyl)thiazolo[4,5-c]pyridine, melting point 116-117°C. Example 2
3-(2-fluorobenzoylamino) used in 07
By using the method of Example 207 except using 3-(R-carbonylamino)-4-pyridone as described in Examples 126 to 165, respectively, in place of -4-pyridone.
2-R-thiazolo[4,5-c] shown in the table according to the following formula
] Obtain pyridine.

Example 248 2-Phenyloxazolo[5,4-c]pyridine Step A
: Preparation of 4-amino-3-hydroxypyridine 15 4-amino-3-methoxypyridine in 200 ml of ether
Add dry hydrogen chloride to 9 until the salt precipitates.

This was removed by deep filtration, and 200ml of toluene
Aluminum chloride 509 in four equal portions to the well-stirred refluxing mixture. After refluxing for 2 hours, the mixture is poured into water and shaken with excess hydrochloric acid.

The toluene is separated off, then the aqueous acidic solution is made basic with sodium bicarbonate and extracted with ether. The ether solution was dried and then evaporated to dryness of 4-amino-
3-Hydroxypyridine is obtained. This is used directly in the next step. Step B: Preparation of 2-phenyloxazolo[5,4-c]pyridine A mixture of 3 g of 4-amino-3-hydroxypyridine, 3.5 l of benzoic acid and polyphosphorus 209 was heated in an oil bath for 15 g of 2-phenyloxazolo[5,4-c]pyridine. Heat to 2000C for minutes.

After cooling to 100° C., the mixture is poured into water, then made basic with sodium bicarbonate and extracted with ether.

The ether solution is dried, passed through a short aluminum oxide column and then evaporated to dryness. The residue is crystallized from ethyl acetate to give 2-phenyloxazolo[5,4-c]pyridine. By using a process substantially as described in Example 248 except substituting a corresponding amount of a carboxylic acid of the formula for the benzoic acid used in Step B, the compounds shown in the table are prepared according to the following formula: 2-R-oxazolo[5,4-c]pyridine is obtained.

Example 298 2-phenyl-5-benzoylaminothiazo 1[4,5
-b] Pyridine Examples 289-307 below are used as reference examples.

Example 289 2-Phenylthiazolo[5,4-c]pyridine A mixture of 4-amino-3-mercaptopyridine 29 and 10f1 of benzoic anhydride was heated to reflux for 10 minutes, then upon cooling slightly the entire mixture was Add benzene 9 to 400a.

This solution is extracted with 4×20 ml of 2.5N hydrochloric acid. The acidic solution is then made basic with sodium hydroxide and then extracted with ether. Evaporate the ether to obtain crude thiazolepyridine. Crystallization from ethyl acetate gives 2-phenylthia τ zolo[5,4-c]pyridine. Example 28
The formula (
R-CO) 20f) By using the method of Example 289 except using an acid anhydride, 2-R-thia9zolo[5,4-c]pyridine as shown in Table 1 according to the following reaction scheme get.

A mixture of 2.09 g of 2,6-diamino-3-mercaptopyridine and 159 g. of benzoic anhydride is heated at reflux temperature for 10 minutes.

After cooling slightly, the liquid mixture is poured into 300 ml of benzene. The benzene solution is extracted with 4×10 ml of 6N hydrochloric acid. The combined acid solutions were then made basic with sodium hydroxide to give 2-phenyl-5-benzoylaminothiazolo [
4,5b] Pyridine is precipitated and this is recrystallized from ethanol. 2,6-diamino-3 used in Example 298
- by using the method of Example 298 except that instead of mercaptopyridine and benzoic anhydride, corresponding amounts of 2-amino-3-mercaptopyridine and anhydride of formula (R-CO) 20 are used. 2-R-thiazolo[4,5-b]pyridine shown in the table is obtained according to the following formula.

Example 308 2-(2-cyanophenyl)oxazolo[4,51b]
Pyridine 2-(2-promophenyl)oxazolo[4,
51b] A mixture of 2.89 ml of pyridine, 1.69 ml of cuprous cyanide and 15 ml of N-methylpyrrolidinone is deaerated by passing nitrogen through for 5 minutes.

It is then heated to 175° C. in an oil bath and held at that temperature for 5 hours under a nitrogen atmosphere and then cooled to room temperature. The reaction mixture was mixed with 10% ammonium hydroxide 75T! 11 and then collect the resulting precipitate. The precipitate is extracted with 100 ml of boiling methylene chloride and the methylene chloride is then evaporated. The residue was recrystallized from methylene chloride to a melting point of 166-1.
2-(2-cyanophenyl)oxazolo[4,
5-b] Obtain pyridine. Example 3095-cyano-2-phenyloxazolo[5,4-b]pyridine 5-chloro-
2-phenyloxazolo[5,4b]pyridine 2.39
A mixture of 1.69 ml of cuprous cyanide and 15 ml of N-methylpyrrolidinone was stirred under nitrogen and then diluted with 1.69 ml of cuprous cyanide in an oil bath.
Heat to 75°C (bath temperature).

It is held at that temperature for 5 hours. The cooled dark mixture is diluted with 75 ml of 1070 ammonium hydroxide and the dark precipitate is removed by filtration. The solids are extracted with methylene dichloride. The methylene dichloride is evaporated and the residue is then crystallized from ethyl acetate. Example 310 2-(4-carboxyphenyl)oxazolo[5,4-
b] Pyridine In 10 ml of concentrated sulfuric acid at room temperature, while stirring,
2-(4-cyanophenyl)oxazolo[5,4-b]
Add 2.29 liters of pyridine.

After 2.5 hours, finely divided sodium nitrite 0.75
Gradually add 9 and then stir overnight.

After warming on a steam bath for 30 minutes, it is poured onto ice.
The precipitated product was recrystallized from methanol to give 2-
(4-carboxyphenyl)oxazolo[5,4-b]
Get pyridine. Example 311 2-(4-cyanomethylphenyl)oxazolo[5,4
-b] Pyridine 4-(cyanomethyl)benzoic acid 109 is refluxed in 70 ml of thionyl chloride for 4 hours.

Removal of the solvent yields a residue of 4-cyanomethylbenzoyl chloride. To a solution of 5.59 of 3-amino-2-hydroxypyridine in cold pyridine is slowly added, with cooling, 89 of 4-cyanomethylbenzoyl chloride. The mixture is brought to room temperature and stirred overnight. The mixture is added to 300 ml of ice and the solid amide is separated off by filtration and then recrystallized from methanol. A mixture of the above amide 39 in 50 mi of phosphorous oxychloride is heated to reflux for 5 hours. The solvent is removed in vacuo and the residue is then recrystallized from ethyl acetate to yield 2-(4-cyanomethylphenyl)oxazolo[5,4-b]pyridine. Example 312
2-(4-carboxymethylphenyl)oxazolo[5
,4-b]PyridineTo 4 ml of concentrated sulfuric acid at room temperature, 2-(4-b)
Add cyanomethylphenyl)oxazolo[5,4-b]pyridine 19.

After stirring for 2 hours, powdered sodium nitrite 0.49
Add.

After stirring overnight, the mixture is warmed in a steam bath for 30 minutes and then poured onto ice. The precipitated product is crystallized from methanol to yield 2-(4-carboxymethylphenyl)oxazo[5,4-b]pyridine. Example 313 2-[3-(aminomethino(ha)phenyl)oxazolo[4,5-b]pyridine 2-(3-cyanophenyl)oxazolo[4,5-b]pyridine (2.29,0.01
200 ml of glacial acetic acid and 1.09 mol of PtO2 catalyst
A mixture of 40 p. S. The reaction is carried out in a hydrogen atmosphere at room temperature until the theoretical amount of hydrogen is absorbed.

The mixture was filtered and the acetic acid was removed under vacuum to give 2-[3-(
Aminomethinotriphenyl]oxazolo[4,5-b]pyridine is obtained. Example 314 2-[3-(dimethylaminomethino(c)) oxazolo[4,5-b]pyridine 2-
Example 60 was substantially the same except that instead of (3-nitrophenyl)oxazolo[4,5-b]pyridine, an equivalent amount of 2-[3-(aminomethyl)phenyl]oxazolo[4,5-b]pyridine was used. Using the method described, 2−[3(
dimethylaminomethyl)phenyl]oxazolo[4,5
-b] Obtain pyridine.

Example 315 2-[3-(methylamino)phenyl]oxazolo[4
,5-b]2-(3-b) in 15 ml of pyridine ethanol
aminophenyl)oxazolo[4,5-b]pyridine 1
．． 2 g (0.006 mol) of phthalimide in suspension.
99 (0,006 mol) and then 0.6 ml of a 37% formaldehyde solution are added.

The suspension is then heated on a steam cone. During this time dissolution occurs and then new solids precipitate. After heating for 3 hours, the mixture was cooled, filtered, and the product was washed once with ethanol, then dried and after recrystallization from ethyl acetate gave 2- [3(phthalimidomethylamino)phenyl]oxazolo[4,5
-b] 1.69 pyridine is obtained.

Next, the phthalimide compound was treated with a Raney-nickel catalyst (0.
39) at 800C in 50ml of ethanol using
Reduce with hydrogen (1100 p.s.i.) for an hour. Strain the cooled mixture and wash the cake thoroughly with ethanol.
The ethanol is removed and the residue is then treated with dilute hydrochloric acid.
The acid mixture is filtered and made alkaline with sodium bicarbonate, then the precipitate is collected. The crude product is taken up in methylene chloride and treated with ethereal hydrogen chloride. 2-[3-(
Collect the precipitated hydrochloride of methylamino)phenyloxazolo[4,5-b]pynodine.

Example 316 2-(3-mercaptophenyl)oxazolo[4,5-
b] Pyridine In 11 flasks equipped with a mechanical stirrer and a thermometer to read the low temperature and immersed in an ice bath, 150 ml of concentrated hydrochloric acid and 150 ml of crushed ice are charged.

Start the stirrer and then add 15.89 (0.07
5 mol) gradually. The mixture was cooled to 0 °C and then 5.59 (0.0
Gradually add the cold solution of mono(c). The temperature is kept below 4°C. Into a flask equipped with a thermometer, addition funnel and stirrer is placed a solution of 14.09 g of potassium ethyl xanthate in 18.0 ml of water.

The mixture is warmed to 40-45°C and maintained in this temperature range during the gradual addition of cold diazonium solution. After a further 30 minutes at this temperature, the ethyl xanthate intermediate is separated and the aqueous layer is extracted twice with 10.0 ml portions of ether. The combined ethyl xanthate intermediate and extract were added to 10.0 ml of 10% sodium hydroxide solution.
Wash once with water and then several times with water until the washings are neutral to litmus. The ether solution is dried over anhydrous calcium chloride and the ether is then removed by distillation. The crude residual ethyl xanthate intermediate was dissolved in 95% ethanol 50%
．． Boil the solution and then remove the heat source. 17.59 g of potassium hydroxide are added gradually so that the hot solution remains boiling, and the mixture is then refluxed for 8 hours. Approximately 40.0 ml of ethanol are removed by distillation on a steam bath and the residue is then taken up in a small amount of water. Extract the aqueous solution three times with 10.0 ml of ether and discard the extract. The aqueous solution is adjusted to near neutrality using 6N sulfuric acid. The precipitate is collected and then recrystallized from ethyl acetate to yield 2-(3-mercaptophenyl)oxazolo[4,5-b]pyridine. Example 3172-[3-(2-Dimethylaminoethoxy)phenyl]oxazolo[4,5-b]pyridine 2-(3-
To a solution of 1.1θ (0.005 mol) of hydroxyphenyl)oxazolo[4,5b]pyridine is added 0.69 (0.011 mono(c)) of sodium methoxide little by little over about 10 minutes.

The reddish-orange solution cooled in an ice bath was heated with N
, N-dimethyl-2-chloroethylamine hydrochloride 0.7
29 (0.005 mol) in small portions over 15 minutes. The resulting mixture is then stirred for 10 minutes, placed in a 75°C oil bath and kept at 75-90°C (up to) for 20 hours. After cooling to room temperature, 15 ml of dry ether are added, with stirring, and the resulting mixture is then filtered.
The solvent is then removed from the tear fluid and the residue is then partitioned between methylene chloride and water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 2-[3-(2-dimethylaminoethoxy)phenyl]oxazolo[4,5b
] Obtain pyridine. Example 318 2-[3-(2-dimethylaminoethyl)aminophenyl]oxazolo[4,5-b]pyridine 2-(3-aminophenyl)oxazolo[4,5-b]pyridine 1.1
A mixture of 9 (0.005 mono(c)) and 50 ml of ethanol is reacted with dimethylaminoacetaldehyde [from 0.969 (0.006 mol) of dimethylaminoacetaldehyde diethyl acetal] by gentle heating to form the intermediate Schiff base. complete.

Next, the mixture was cooled and sodium borohydride 60
η (0.0015 mol) is added and the mixture is then stirred at room temperature overnight.

Water is added, the solvent is removed in vacuo, and the residue is then partitioned between water and methylene chloride. The organic layer was dried and then concentrated in vacuo to yield crude 2-[3-(2-dimethylaminoethyl)aminophenyl]oxazolo[4,5-b]pyridine,
Purification is by column chromatography using an alumina column with an ethyl acetate-ether mixture (0-60% ethyl acetate) as eluent. The compound is
It is also obtained by direct alkylation of the starting amine using 2-dimethylaminoethyl chloride hydrochloride and a base in a conventional manner. Example 319 2-(2-fluorophenyl)oxazolo[4,5-b
A mixture of 250 parts of pyridine and 25 parts of lactose is granulated with an appropriate amount of water, and then 100 parts of corn starch are added thereto.

This material is passed through a 16 mesh screen and then mixed with 3.8 parts of magnesium stearate. These are then compressed into tablets suitable for oral administration. The particular oxazolopyridine used in the above examples is similar to other oxazolopyridines or thiazolopyridines of the invention 25,100,250
By replacing Mayo with 500 parts, tablets suitable for oral administration as an anti-inflammatory, antipyretic and/or analgesic can be produced by the method of the invention.

Example 3 20 A mixture of 50 parts of 2-(2,6-difluorophenyl)oxazolo[5,4-b]pyridine, 3 parts of calcium salt of ligninsulfonic acid, and 237 parts of water was prepared so that substantially all the particles had a size of 10 Ball mill until it is smaller than a micron.

The suspension is diluted with a solution containing 3 parts of sodium carboxymethyl cellulose and 0.9 parts of butyl ester of p-hydroxybenzoic acid in 300 parts of water. In this way, an aqueous suspension suitable for oral administration for therapeutic purposes is obtained. Example 321 2-(2-fluorophenyl)oxazolo[5,4-b
A mixture of 250 parts of pyridine, 200 parts of onion starch and 30 parts of alginic acid is mixed with a sufficient amount of a 10% aqueous paste of onion starch and granulated.

The granules are dried in a warm air stream, then the dry granules are passed through a 16 mesh screen, mixed with 6 parts of magnesium stearate, and then compressed into tablets to obtain tablets suitable for oral administration. Example 3222 -Phenyloxazolo [5
, 4-b] A mixture of 500 parts of pyridine, 60 parts of corn starch and 20 parts of gum arabic is granulated with a sufficient amount of water.

The mass is passed through a 12-mesh screen and the granules are then dried in a warm air stream. The dry granules are passed through a 16-mesh screen, mixed with 5 parts of magnesium stearate, and then compressed into tablets suitable for oral administration. Example 323 (1) 10,000 tablets suitable for oral use, each containing from 500 to 500 of the active ingredient, are prepared from the following ingredients:

The powdered oxazolopyridine is granulated with a 4% aqueous solution of methylcellulose Usp (1500 c.p.S.).

Add the remaining ingredient mixture to the dry granules and compress the final mixture into tablets of appropriate weight. (2) 10,000 two-piece hard gelatin capsules suitable for oral administration, each capsule containing 250 η of oxazolopyridine, are manufactured from the following ingredients:

Powdered oxazolopyridine is mixed with starch-lactose,
Next mix with talc and calcium stearate.
The final mixture is then placed into capsules in the usual manner. In the above formulation, 100,250,5 instead of 25009
By using 00 and 10009, capsules containing oxazolopyridines 10, 25, 50 and 100 can also be prepared. (3) Soft elastic capsules Each capsule contains 200 η of oxazolopyridine in the conventional manner by first dispersing the powdered active substance in a sufficient amount of corn oil to provide an encapsulatable material. One-piece soft elastic capsules suitable for oral administration can be manufactured.

(4) Aqueous suspensions Aqueous suspensions for oral use containing 1 g of oxazolopyridine in each 5 ml can be prepared from the following ingredients:

Example 324 2-(2-methyl-3-chlorophenyl)oxazolo
-Methyl-3-b] Pyridine A mixture of 3.49 g of 2-methyl-3-chlorobenzoic acid and 1.0 g of 2-amino-3-hydroxypyridine was crushed in a mortar, and 179 g of polyphosphoric acid was crushed.
and then slowly heated the gummy mixture under nitrogen to 178°C with stirring for 75 minutes.

The resulting solution was slowly poured into 300 ml of ice water while stirring. After 1 hour, the precipitate was collected and added to a dilute sodium hydroxide solution with stirring.

After 15 minutes, the precipitate was collected, washed with water, and dried to obtain the crude product 2.
I got 19.

This was dissolved in cyclohexane 75d and recrystallized,
Pass through the mouth and concentrate to about 50 ml, and when cooled, 2-(2-methyl-3-chlorophenyl)oxazolo[4,5-b]
- 1.76 g of pyridine, melting point 118.5-120°C, was obtained.

Using the method of Example 324 but using an equimolar amount of the substituted benzoic acid identified in Table X in place of the 2-methyl-3-chlorobenzoic acid used in Example 324, the following equation The 2-(substituted phenyl)oxazolo[4,5]pyridine similarly identified in Table 1 is prepared by:

The following compounds can be obtained by the method of the present invention.

It is described as an example.

Next, embodiments of the present invention will be listed.

(1) A compound of the formula (2) according to claim 1 is combined with a compound of the formula (in the formula, Z is -0H or halogen or 'f>-δ 0-), and Z is R3 -C-0- by heating, adding in the presence of polyphosphoric acid if Z is -0H, or reacting in the presence of an acid acceptor if Z is halogen, and then adding the condensing agent. A formula characterized by heating with: δ (where N is in the α or δ position, n is 13,
2. The process according to item 1, wherein X is lower alkyl, halogen, lower alkoxy, nitro or cyano.

(3) A compound of the formula: -i\, -NH and a compound of the formula: n (wherein, Z is k=》≧d-0- or 0H), and when Z is -0H, a polyphosphoric acid Formula characterized by heating in the presence: (wherein n is 1-3).

The X substituents may be the same or different. and X is lower alkyl, halogen, lower alkoxy, nitro or cyano. 4) Round making according to paragraph 1 of the compound of formula: (5) characterized by heating the compound of formula: in the presence of the compound of formula: and polyphosphoric acid as described in paragraph 1 of the compound of formula: 2. A process according to claim 1 for the preparation of a compound of formula: wherein the compound of formula: 8u is heated in the presence of a compound of formula: and polyphosphoric acid.

(6) A method for producing a compound of formula: according to item 1, characterized in that the compound of formula: '11T is heated in the presence of a compound of formula: and polyphosphoric acid.

(7) A method for producing a compound of formula according to item 1, characterized in that the compound of formula: is heated in the presence of a compound of formula: and polyphosphoric acid.

B) A compound of formula: is reacted with a compound of formula: in the presence of an acid acceptor and then heated with a condensing agent, wherein n is 1-3 and the X substituents are the same Or different.

and X is lower alkyl, halogen, lower alkoxy,
9) A compound of the formula: which is nitro or cyano) is reacted with a compound of the formula: in the presence of an acid acceptor, and then heated with a condensing agent. The method for producing the compound according to item 1.

2. The method for producing a compound of the condensed formula: according to item 1, characterized in that the compound of the formula: is reacted with the compound of the formula: in the presence of an acid acceptor and heated with the agent.

2. The method for producing a compound of the formula: then condensation according to item 1, characterized in that the compound of the formula: is reacted with the compound of the formula: in the presence of an acid acceptor and heated with the agent.

Claims (1)

[Claims] 1 Structural formula I having N at the α or δ position ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ A compound of I with structural formula II ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ II (In the formula, Z is -OH) halogen, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼. ) and Z is ▲There are mathematical formulas, chemical formulas, tables, etc.▼
If Z is -OH, then heat reaction in the presence of polyphosphoric acid or if Z is a halogen, reaction in the presence of an acid acceptor, followed by heating with a condensing agent to form the formula : ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_3 is (a) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (n is an integer from 0 to 5. X substituents are the same or different .And X is (1)
Halogen (2) Lower alkoxy (3) Lower alkyl (4) Nitro (5) Phenyl (6) Lower alkylsulfonyl (7) Trihalo-lower alkyl (8) Cyano (9) Lower alkylthio (10) Di(lower alkyl)amino (11) Trifluoromethoxy (12) Hydroxy (13) Methylenedioxy (14) Carbamyl (15) Amino (16) Benzoylamino (17) Phthalimidomethylamino (18) Acetamide (19) Lower alkylsulfinyl (20) -NHSO_2CH_3 Or (21) ▲There are mathematical formulas, chemical formulas, tables, etc.▼. ) (b) benzyl or halobenzyl (c) lower cycloalkyl (d) naphthyl (e) adamantanyl (f) pyridyl (g) lower alkyl (h) lower alkyl substituted pyrid-2-one-3-yl (
i) styryl (j) furyl (k) thiazolyl (l) imidazolyl, or (m) benzoyl. R_4 is (a) halogen (b) lower alkyl (c) nitro (d) trihalo-lower alkyl (e) lower alkoxy (f) amino (g) benzoylamino (h) phenyl (i) isopropoxycarbonylamino, or ( j)
It is dimethylamino. m is 0-2. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ which are characterized by producing a compound of [6-membered ring is pyridine with N at the α or δ position. R^1 and R are the same as R^4 and R_3, respectively. m is 0-2. However, when m is 0,
n is not 0 and R is not 4-lower alkylphenyl. 2 Structural formula I with N at α or δ position ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Compounds of I are represented by structural formula II ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ II (In the formula, Z is -OH, halogen , or ▲There are mathematical formulas, chemical formulas, tables, etc.▼. ) and Z is ▲There are mathematical formulas, chemical formulas, tables, etc.▼
If Z is -OH, then heat reaction in the presence of polyphosphoric acid or if Z is a halogen, reaction in the presence of an acid acceptor, followed by heating with a condensing agent to form the formula : ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_3 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼(
n is an integer from 1 to 5. The X substituent is lower alkylthio. ) and R^4
is (a) halogen (b) lower alkyl (c) nitro (d) trihalo-lower alkyl (e) lower alkoxy (f) amino (g) benzoylamine (h) phenyl (i) isopropoxycarbonylamino, or (j )
It is dimethylamino. m is 0-2. ], and then the lower alkylthio group of R_3 is treated with hydrogen peroxide to convert it to lower alkylsulfinyl or lower alkylsulfonyl ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [6 The -membered ring is pyridine with N in the α or δ position. R is a ▲ mathematical formula, chemical formula, table, etc. ▼ (n is an integer from 1 to 5. The X substituent is lower alkylsulfinyl or lower alkylsulfonyl.) R^1 is the same as R^4 above. . m is 0-2. ] method for producing the compound. 3 Structural formula I with N at α or δ position ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Compounds of I are represented by structural formula II ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ II (In the formula, Z is -OH, halogen , or ▲There are mathematical formulas, chemical formulas, tables, etc.▼. ) and Z is ▲There are mathematical formulas, chemical formulas, tables, etc.▼
If Z is -OH, then heat reaction in the presence of polyphosphoric acid or if Z is a halogen, reaction in the presence of an acid acceptor, followed by heating with a condensing agent to form the formula : ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_3 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (n is an integer from 1 to 5. The X substituent is a halogen.)] Compound generate,
A method for producing an iodide of the compound having the following formula by treatment with a lower alkyl iodide: