KR820000099B1 - Process for preparing pyrido (2,1-b)quinazoline derivatives - Google Patents

Abstract

Title compds. (I; R1, R2, R3 = H, lower alkyl, lower allzoxy lower alkylthio, halogen, cyclopropyl, cyclobutyl, hydroxy; R4 = III; A = pyvaloyloxymethoxy; Y = H, methyl; n = 0-1), useful as anti-allergics were prepd. by the reaction of II and halomethylpyvalate. Thus, 28.7 g 5-methylanthranyl, 25.0 g 6-chloronicotinic acid and 1.32 g potassium iodide were heated in 50 ml triethylene glycol dimethylether at 150≰C in Ar gas overnight to give 15.3 g 2-methyl-11-oxo-11H-pyrido[2,1-b quinazoline-carboxylic acid.

Description

Method for preparing pyrido [2,1-b] quinazoline derivatives

The present invention relates to a pyrido [2, 1-b] quinazoline derivative of the general formula (I), useful as an anti-allergic agent, and a method for preparing a pharmaceutically toxic acid addition salt thereof.

의 기(여기서 A는 피바로일옥시메톡시이고 Y는 수소 또는 메틸이고 n은 0 또는 1이다)이며, 단 R₁,R₂및 R₃중 적어도 하나는 수소가 아니다.Wherein R ₁ , R ₂ and R ₃ are each hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, cyclopropyl, cyclobutyl, hydroxy and R ₄ is a general formula

Is a group wherein A is pivaloyloxymethoxy and Y is hydrogen or methyl and n is 0 or 1, provided that at least one of R ₁ , R ₂ and R ₃ is not hydrogen.

"Lower alkyl" as used herein refers to methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, neopentyl, pentyl, heptyl as straight or branched chain hydrocarbon groups of 1 to 7 carbon atoms. "Lower alkoxy" refers to an alkoxy group where the lower alkyl group is such as, for example, methoxy, ethoxy, propoxy, phenoxy.

"Halogen" means bromine, chlorine, fluorine and iodine.

Particularly preferred compounds of the present invention are compounds of general formula (I)

In the general formula, R ₁ ′, R ₂ ′, R ₃ ′ are hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen or hydroxy and R ₄ is as described above.

(여기서 Y와 A는 전술한 바와 같다)인 일반식(I')의 화합물도 포함한다. 더욱이, 바람직한 화합물에는 R₄가 일반식

의 기(여기서 A는 전술한 바와 같다)인 일반식(I')의 화합물도 포함된다.More preferred compound is a compound of formula (I ') wherein at least one of R ₁ ′, R ₂ ′ and R ₃ ′ is lower alkylthio, and in certain aspects the invention provides that R ₄ is a general formula

Also included are compounds of formula (I ') wherein Y and A are as defined above. Furthermore, preferred compounds include R ₄ in general formula

Also included are compounds of formula (I ') wherein a group wherein A is as defined above.

In addition, preferred compounds of the present invention also include compounds of formula (I) wherein at least one of R ₁ , R ₂ and R ₃ is cyclopropyl or cyclobutyl.

In a more preferred aspect, the compound of the present invention is a compound of formula (I) in which at least one of R ₁ , R ₂ and R ₃ is lower alkyl, lower alkoxy or lower alkylthio and R ₂ is in position 8 and R ₂ is hydrogen Is preferred, wherein R ₁ / and or R ₃ are not hydrogen and R ₄ is at the 8 position.

The compound of formula (I) of the present invention and its pharmaceutically toxic acid addition salts are reacted with a tertiary organic base and chloro-bromo or iodomethyl pivalate, and the compounds obtained if necessary Is prepared by converting to a pharmaceutically harmless salt.

In the above general formula

R ₁ , R ₂ , R, Y and n are as described above.

In the reaction, the compound of general formula (I) is inert such as a compound of general formula (II) such as a tertiary organic base such as tri-lower alkylamine, chloro-bromo-, iodomethylpivalate and dimethylformamide. It can be prepared by reacting at room temperature to about 120 ° C. in the presence of a solvent, and the reaction product can be recovered by a known method such as crystallization.

The compound of formula (II) used as a starting material may be prepared by reacting a compound of formula (III) with a halopyridine derivative of formula (III).

의 기(여기서 A는 하이드록시이고 Y 및 n은 전술한 바와 같다)이고 X는 할로겐이다.Wherein R is hydrogen or lower alkyl, R ₁ , R ₂ and R ₃ are as described above and R ₄ ′ is general formula

Where A is hydroxy and Y and n are as described above and X is halogen.

In the reaction, anthranilic acid or ester of formula (III), which is a known compound or can be prepared by a known method, is used with a halopyridine of formula (IV), which is also a known compound or can be prepared by a known method. The reaction is carried out in the presence or absence of a solvent at 100 ° to 200 ° C, and the reaction is carried out in the presence of a catalytic amount of alkali metal iodide (eg, sodium iodide, potassium iodide, cesium iodide, etc.). As a solvent, high boiling point solvents such as acetic acid, niglyme, triglyme, and the like are used. The reaction is usually carried out at atmospheric pressure, and the reaction product can be recovered by conventional methods (eg, crystallization).

Compounds of formula (I) react with acids to produce pharmaceutically toxic salts, and organic acids such as methanesulfonic acid, P-toluenesulfonic acid, hydrochloric acid, bromic acid, sulfuric acid, and the like are used.

Compounds of formula (I) and their pharmaceutically harmless salts have inhibitory effects on skin hypersensitivity in rats and are therefore useful for the prevention of allergic reactions, for example for the treatment of bronchial asthma. Anti-hypersensitivity effects can be achieved through a passive skin hypersensitivity test (PcA test) in rats. The experiment also included a passive local sensitivity test in mice by antiserum intradermal injection. After 24 hours of incubation, the test compound, pyri (2,1-b) quinazoline, is injected intraperitoneally and 5 minutes later, antigen and Evans Blue dye are injected intravenously. Local antigen-antibody reactions are measured by the size of the lesion formed on the skin. The activity of the test compound is determined by comparing the size of the lesion with the control.

In addition, the anti-allergic activity of the compound of general formula (I) was demonstrated in the actively sensitized morphot (IgC). In this experiment, morphotes are sensitized with horse serum for one day and intravenous administration of antigen (horse serum) for 11 to 14 days induces hypersensitivity reactions (bronchoconstriction, IHR bronchospes m). Intravenous injection of an anti-allergic compound prior to administration of the antigen inhibited IHR and inhibited bronchial contraction.

Anti-allergic activity has also been demonstrated in passively sensitized rats (IgE). In this experiment, antiserum was injected intravenously 18 hours prior to intravenous administration of antigen (egg albumin) in rats. Administering the antigen induces IHR. Intravenous injection of an anti-allergic compound prior to administration of the antigen inhibited IHR and prevented bronchial contraction.

Compounds of formula (I) and their pharmaceutically harmless salts can be administered orally or parenterally as anti-allergic agents, for example, for the treatment of bronchial asthma (with varying doses from individual to individual). These can be administered orally or parenterally, using a suitable dosage such as tablets, capsules, elixirs, suspensions, solvents, and the like.

These may be administered in admixture with suitable pharmaceutical carriers or excipients such as corn starch, calcium stearate magnesium carbonate calcium silicate, dicalcium phosphate, talc, lactose and the like. They may also be added with buffers or isotonic agents, sterilized if necessary and may also contain other therapeutically valuable substances.

The amount of active agent may vary, but in the case of capsules or tablets, it is preferable to contain 10 to 20 mg of the base of the general formula, or pharmacologically nontoxic salts thereof.

The frequency of administration of the agent depends on the amount of active agent, the needs and requirements of the patient. Typically, however, about 20 mg / kg of the compound is administered several times a day. However, this is merely an example and does not limit the scope and implementation of the present invention.

The following examples illustrate the invention in detail and all temperatures are in degrees Celsius.

Example 1

2-substituted-pyrido [2,1-b] quinazoline-8-carboxylic acid

[Method A]

Condensation of anthranilic acid and 6-chloronicotinic acid to synthesize 2-substituted-pyrido [2,1-b] quinazolin-8-carboxylic acid is carried out using 2-methyl-11-oxo-11H-pyrido [2, 1-b] can be explained by the synthesis method of quinazoline-8-carboxylic acid. 28.7 g of 5-methylanthranyl 25.0 g of 6-chloronicotinic acid and 1.32 g of 3, potassium iodide are dissolved in 50 ml of triglyme and heated to 150 ° in an argon stream overnight. After cooling, the mixture was treated with ethanol and filtered to give 31.8 g of a yellow solid (melting point: 295 to 310), which was recrystallized from dimethyl formamide acetic acid to give 15.3 g (38%) of 2-methyl-11-oxo-11H-pyridine. [2,1-b] quinazoline-carboxylic acid (melting point [<: 350)) is obtained.

[Method B]

The method of reacting anthranilic acid hydrochloride with 6-chloronicotinic acid can be explained by the production of 2-ethoxy-11-oxo-11H-pyrido [2,1-b quinazoline-8-carboxylic acid. 7.5 g of 5-ethoxyanthranilic acid hydrochloride, 6.3 g of 6-chloronicotinic acid and 1.2 g of potassium iodide are suspended in 12 ml of triglyme and overnight heated to 145-150 °).

After cooling, the mixture was treated with ethanol and filtered to yield 7.7 g of product (melting point: 260 to 265) which was recrystallized from dimethylformamide to 4.14 g (42%) of 2-ethoxy-oxo-11H-pyrido. [2,1-b] quinazoline-8-carboxylic acid (melting point: 285 to 287 °) is obtained.

[Method C]

The reaction of substituted methyl anthranilate hydrochloride with 6-chloronicotinic acid can be explained by the synthesis of 2-methoxy-11-oxo-11H-pyrido [2,1-b] quinazolin-8-carboxylic acid. have.

134 methyl-5-methoxy-anthranilate hydrochloride, 106.7 g of 6-chloronicotinic acid and 9.0 g of potassium iodide were dissolved in 300 ml of triglyme and heated at 150 ° overnight, and the resulting suspension was heated to 200 ml of ethanol. Dilution with filtration gave 177.9 g of a compound (melting point: 278 to 290 °), which was recrystallized from 2.5 L of dimethylformamide and 500 ml of glacial acetic acid to 93.3 g (56%) of 2-methoxy-11-oxo-. 11H-pyrido [2,1-b] quinazoline-8-carboxylic acid (melting point> 310 °) is obtained.

a) DMF = dimethylformamide HOA _C acetic acid Pr = isopropyl alcohol

DMEA = N, N-dimethylethanol amine

b) Melting point determination with Dupont Instruments Model 900 thermal analyzer

c) The compound recrystallized with this solvent is precipitated with water with acetic acid to obtain a free acid.

Example 2

2-nitro-5-methylthio benzoic acid

To a solution of 50 ml of methyl mercaptanol and 200 ml of dimethylformamide, 48 g of sodium hydride was added little by little at 40 °. Then, 100.0 g of 5-chloro-2-nitrobenzoic acid was added and the reaction temperature was raised to -10 ° and then -40 °. Get off. Excess reactant is removed with 1N hydrochloric acid and stirred at room temperature for 2 hours to yield 102.3 g (97%) of product having a melting point of 165-169 °. Recrystallization with methanol-ethyl acetate yields 52.14 g of a material having a melting point of 173 to 174 ° and an analytical sample is obtained from ethyl acetate. Melting Point: 174-175 °

Example 3

Methyl 2-amino-5-methylthio benzoate

To an aqueous solution of 52.1 g of 2-nitro-5-methylthio-benzoic acid dissolved in 250 ml of methanol and cooled was added an ethereal solution of diazomentane until the reaction was confirmed by thinning chromatography. The resulting solution is evaporated to dryness and used as is. In some cases the crude product is crystallized with methanol to give a yellow needle of methyl 2-ni-5-5-methylthiobenzoate (melting point: 53-54 °).

The crude product obtained above was suspended in 280 ml of glacial acetic acid solution with 55.5 g of iron powder, the bath temperature was raised to 125 ° or more for 30 minutes and the gray suspension obtained was filtered through cooled celite.

Evaporation gave a dark oily residue which was treated with methanolic hydrochloric acid to give a white solid which was then crystallized with methanol-ether to give 33.32 g (58%) of methyl 2-amino-5-methylthio benzoate hydrochloride ( Melting point: 193 to 194 °).

7.35 g (13%) of a secondary product having a melting point of 191 to 192 ° are obtained from the filtrate, and an analytical sample having a melting point of 196 to 197 ° is obtained from methanol-ether.

Example 4

Crude 2-methoxy-11-oxo-11H-pyrido [2,1-b] quinazolin-8-carboxylic acid hydrochloride

A 1 L three-necked flask is equipped with an agitator, argon injector, short condenser and collector, oil bath, heating plate, thermowatch thermostat and bath thermometer. Argon is passed through the flask, and 135 g of 5-methoxy anthranilic acid, 135 g of 6-chloronicotinic acid, 2.0 g of potassium iodide and 400 ml of triethylene glycol dimethyl ether (triglyme) are placed in the flask. The reaction mixture is stirred and heated in an argon stream. When the bath reaches 140 °, the solids are almost completely dissolved. If heating is continued, yellow solid slowly precipitates. Stir in the argon stream while maintaining the temperature of the bath at 150 °. The resulting dense mixture was cooled to 50 ° or less, treated with 200 ml of ethanol and the resulting slurry was filtered under vacuum, washed with 100 ml of anhydrous ethanol and dried under vacuum at 60 ° to give 326 g of crude 2-methoxy-. 11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid hydrochloride is obtained.

Example 5

Purification of 2-methoxy-11-oxo-11H-pyrido [2,1-b] quinazolin-8-carboxylic acid hydrochloride through ethylenediamine salt

326 g of crude hydrochloride of Example 4 is dissolved in 6.2 L of pyridine (25 ml / g) and heated to reflux in a 12 L three-necked flask. To this stirred reflux solution is added 81.1 ml of distilled ethylene diamine for 5 minutes and the resulting slurry is refluxed for 10 minutes. After removing the heating mantle and stirring the reaction to room temperature (for about 4 hours), the crystals were collected by vacuum filtration, washed twice with 250 ml of pyridine and dried overnight under vacuum at 60 ° until a constant volume yielded 189.9 g of ethylene. Diamine salt is obtained as a yellow solid. This material is dissolved in 500 ml of hot water and recrystallized. The hot solution is poured into a three-necked flask containing 500 ml of reflux pyridine and slowly added 5.2 liter of pyridine to atmospheric distillation of the pyridine-water azeotrope. During distillation, 1.0 L of pyridine is slowly added to the stirred mixture (about 1 hour) and the product begins to separate. Continue distillation until the head tomp reaches 110 ° and stop distillation when about 2.7 L of distillate is collected and allow the mixture to cool below reflux. 27 ml of distilled ethylenediamine are added with stirring and cooled to room temperature for 3 hours. The resulting crystals are collected, washed with a small amount of pyridine and rapidly dried under pressure. The reaction product (about 200 g) is used immediately or stored in vacuo.

Example 6

Regeneration of purified 2-methoxy-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid

200 g of ethylene diamine salt of recrystallized quinazoline is dissolved in 1.0 L of water, and 1.5 L of water dissolved in 300 ml of glacial acetic acid is added dropwise for 2 hours, followed by stirring at room temperature. The final pH of the mixture is about 4 on Accucutt paper. The resulting crystals are collected, washed twice with 1.0 L of water and dried overnight in 100 ° in vacuo to yield 95 g of a yellow solid (melting point: 322 °). This material is dissolved in 1.25 L reflux pyridine to crystallize. Quickly vacuum filter the hot solution through a booter panel while passing through the steam and wash the filter and flask with 300 ml of boiled pyridine. The filtrate is placed in a 2 L bulb Erlenmeyer flask and heated to redissolve all solids. The resulting solution is slowly cooled to room temperature and again cooled to 0 ° for 2 hours. The crystals are filtered off, washed with 200 ml of cold pyridine, pressurized and dried overnight under vacuum at 115 ° while passing through an air stream to yield 87.6 g of product having a melting point of 325 °.

Example 7

2-methoxy-11-oxo-11H-pyrido [2,1-b] quinazolin-8-sodium carboxylate salt monohydrate

27.023 g of 2-methoxy-11-oxo-11H-pyrido [2,1-b] quinazolin-8-carboxylic acid is stirred in 50 ml of water at room temperature and 100 ml of 1.0N sodium hydroxide solution are added. The resulting compound is stirred for about 30 minutes until almost all of the solids are dissolved. The solution is vacuum filtered to remove insoluble matter and the filtrate is placed in a 5 L three-necked flask with 1.0 L of pyridine. The resulting slurry is heated to reflux at a temperature at which almost all solids solidify.

The solvent is distilled at atmospheric pressure while slowly adding 1.0 L of pyridine. Even if the quinazoline product begins to separate, distillation continues until the spinneret temperature reaches 100 ° (about 1 liter of distillate). The slurry was cooled to room temperature for about 3 hours, filtered and washed twice with 100 ml of pyridine and dried in vacuo at 95 ° through a stream of nitrogen to convert 30.2 g (97.0%) of monohydrate sodium salt into a pale yellow solid. To obtain.

Example 8

2-methoxy-11-oxo-11H-pyrido [2,1-b] quinazolin-7-carboxylic acid

2.80 g of 5-methoxyanthranilic acid, 2.65 g of 2-chloronicotinic acid and 0.135 g of potassium iodide are suspended in triglyme, stirred and heated at 150 ° for 21 hours while passing argon medium. After cooling, 40 ml of methanol is added and the yellow solid is filtered off. The crude product is recrystallized from ethylenediamine salt with pyridine, treated with acetic acid to reverse conversion to free acid, and then recrystallized with acetic acid to store 0.42 g (9%) of pure 2-methoxy-11-oxo-11H-pyrido. [2,1-b] quinazolin-7-carboxylic acid (melting point: 323 to 327 °) is obtained.

Example 9

2-methoxy-11-oxo-11H-pyrido [2,1-b] quinazolin-6-carboxylic acid

1.05 g of 5-methoxyanthranilic acid, 0.99 g of 2-chloronicotinic acid and 0.050 g of potassium iododide are suspended in 5 ml of triglyme, stirred and heated at 150 ° for 17 hours by passing steam. After cooling, 15 ml of methanol is added and the yellow solid is filtered off. The crude product was purified by recrystallization with N, N-dimethylformamide / acetic acid to purify 0.67 g (40%) of pure 2-methoxy-11-oxo-11H-pyrido [2,1-b] quinazolin-6-. A carboxylic acid (melting point: 272 to 273.5 °) is obtained.

Example 10

Pivaloyloxymethyl-2-methoxy-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylate

0.40 g of 2-methoxy-11-oxo-11H-pyrido [2,1-b] quinazolin-8-carboxylic acid is suspended in 30 ml of dimethylformamide and 0.4 ml of triethylamine are added. 0.4 ml of chloromethylpivalate was added to the solution, stirred, and heated at 100 ° for 19 hours. Further 0.3 ml of chloromethylpivalate are added and heating is continued at 100 ° for 4.5 hours. The solvent is removed on an oil pump, water is added, and the crude product is filtered off. Purify by chromatography on 15 g silicagen using 60% ethyl acetate-benzene as effluent and recrystallize from methanol-water to 0.37 g (65%) pure pivaloyloxymethyl-2-methoxy-11-oxo -Pyrido [2,1-b] -quinazolin-8-carboxylate (melting point: 129 to 131 °) is obtained.

Example 11

2-methoxy-11-oxo-11H-pyrido [2,1-b] quinazolin-8-acetic acid

The mixture of 0.836 g of 5-methoxyanthranilic acid, 0.858 g of 2-chloropyridine-5-acetic acid and 15 potassium iodide was heated to 150 ° for a quarter hour in medium argon and cooled, followed by solid Treat with propyl alcohol and filter out the yellow solid. The crude product was purified by recrystallization of ethylene diamine salt from pyridine and inverted into free acid by treatment with acetic acid to purify 0.054 g (3.8%) of pure 2-methoxy-11-oxo-11H-pyrido [2,1 -B] quinazoline-8-acetic acid (melting point: 281 ° to 282 °) is obtained.

Example 12

2-n-butyl-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid

11.6 g of 5-n-butylanthranilic acid, 9.4 g of 6-chloronicotinic acid and 0.1 g of potassium iodide are suspended in 20 ml of triglyme and heated at 150 ° C. through argon vapor. After cooling, the mixture was treated with ethanol and water and filtered to obtain 7.6 g of a dark yellow solid (melting point: 265 to 292 °). Formation of ethylene diamine salt in hot pyridine yields a water soluble salt. This salt was dissolved in water, pure acid was precipitated with dilute acetic acid, and then recrystallized from dimethylformamide-acetic acid-water to give 1.8 g (10.1%) of pure 2-n-butyl-11-oxo-11H-pyrido [2, 1-b] quinazoline-8-carboxylic acid (melting point: 252 to 253 °) is obtained.

Example 13

2-Ethyl-11 oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid

The title compound is prepared by the method in Example 12.

Yield: 26.4%, Melting point: 313 to 315 °

Example 14

2-bromo-4-isopropyl acetanilide

50 g of 4-isopropylaniline is dissolved in 160 ml of glacial acetic acid, stirred and refluxed for 2 hours. Cool the solution to 45 ° and add 60 g bromine dropwise. Now dropwise at constant speed to keep the reaction temperature below 55 °. The reaction is stirred for 1 hour and the resulting dark liquid is added to 2 liters of ice with stirring. The resulting suspension is added with 5.0 g of sodium bisulfite while stirring for 10 minutes and then stirred until the color of bromine disappears. The solid is filtered off, washed with water and air dried overnight.

The wet solid (115 g) was recrystallized from 1 L of 50% aqueous ethanol to afford 64.4 g (68.2%) of 4-isopropyl-2-bromo acetanilide (melting point: 122-126).

Example 15

2-cyano-4-isopropylacet anilide

1.0075 g of 2-bromo-4-isopropylacet anilide and 0.7308 g of cyanide are dissolved in 10 ml of N-methylpyrrolidinone and heated and stirred at 180 ° for 7 hours. The reaction mixture was poured into 50 ml of water containing 1 ml of ethylene diamine, stirred vigorously for 5 minutes, extracted with chloroform, the extract was washed with 10% sodium cyanide solution, washed again with water, dried over magnesium sulfate and dried in vacuo. Concentrate in to obtain oil. The remaining N-methylpyrrolidinone is distilled off (boiling point 33 to 37 DEG C / 0.1 mm) and cooled to crystallize the viscous residue. This was recrystallized from ether-hexane to give 2-cyano-4-isopropyl anilide (0.5920 melting point: 98-100 °).

Example 16

5-isopropylanthranilic acid

0.4870 g of 2-cyano-4-isopropylacet anilide is dissolved in 5 ml of acetic acid and 10 ml of 50% sulfuric acid and refluxed for 2.5 hours. The solution is concentrated on an oil pump to make a small volume, add water (5 ml) and adjust the pH to 4 with 6N sodium hydroxide. After cooling, the precipitate was filtered and dried to afford 0.3426 g of material which was recrystallized from ligroin to give 5-isopropyl anthranilic acid (0.3010 g, melting point: 75 to 80 °).

Example 17

2-bromo-4-cyclopropyl acetanilide

15.20 g of 4-cyclopropylacet anilide and 10.45 g of acetamide are dissolved in 1 L of chloroform, cooled to 25 °, and 300 ml of chloroform containing 13.8 g of bromine are added dropwise with stirring for 2 hours. The reaction mixture is stirred at −25 ° C. for 70 hours and then warmed to 5 °. Filtration removes precipitate and the filtrate is concentrated in vacuo. The crude product is dissolved in ethyl acetate, dehydrated on anhydrous sodium sulfate and concentrated in vacuo to give an orange solid which is chromatographed on 1.2 kg silica gel with 40% ethyl acetate-toluene as eluent. The combined pure fractions are concentrated in vacuo to afford 11.2 g of pure 2-bromo-4-cyclopropyl-acet anilide (melting points: 108.5 to 110).

Example 18

2-cyano-4-cyclopropylacet anilide

500 ml of anhydrous dimethylformamide solution containing 11.22 g of 2-bromo-4-cyclopropyl acetanilide and 8.96 g of cyanide are stirred and refluxed for 3 hours. After cooling to 25 ° the dimethylformamide is removed in vacuo. The residue is stirred with 500 ml of water containing 15 ml of ethyleneamine for 30 minutes and extracted with ethyl acetate. The extract was dehydrated over sodium sulfate and concentrated in vacuo to afford a solid which was then crystallized with ethyl acetate-hexane to afford 6.45 g of pure 2-cyano-4-cyclopropylacet anilide (melting point: 140-142 °).

Example 19

5-cyclopropylanthranilic acid

6.30 g of 2-cyano-4-cyclopropyl acetanilide is dissolved in 60 ml of ethylene glycol and 60 ml of water, and 8.86 g of potassium hydroxide is added. The reaction mixture is refluxed for 19 h with stirring, cooled and 1 l of water is added. The precipitate is filtered off and the filtrate is extracted several times with ethyl acetate. The basic aqueous layer is adjusted to pH 3 with acetic acid and then extracted with ethyl acetate. The extract is dried and concentrated in vacuo to give a solid which is crystallized from ether-hexane to give 2.31 g of pure 5-cyclopropylanthranilic acid. (Melting point: 157.5 to 158.5 °)

Example 20

2-isopropyl-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid

6.0 g of 5-isopropylanthranilic acid, 5.4 g of 6-chloronicotinic acid and 0.05 g of potassium iodide are suspended in 10 ml of triglyme and heated overnight to 150 ° in medium argon.

After cooling, the mixture was treated with ethanol and water and filtered to obtain 5.89 g of crude product (melting point: 280 to 287 °). This material is dissolved in hot pyridine and treated with ethylene diamine to form the corresponding salt, which is collected by filtration. This salt is dissolved in water, pure acid is precipitated with rare acid, and then recrystallized with dimethylformamide-acetic acid-water to give 2.5 g (26.6%) of 2-isopropyl-11-oxo-11H-pyrido [2,1 -B] quinazoline-8-carboxylic acid (melting point: 314 to 316 °) is obtained.

Example 21

5-hydroxy-2-nitrobenzoic acid

A mixture of 5 L water, 800 g sodium hydroxide and 504 g 5-chloro-2-nitrobenzoic acid is refluxed for 24 hours. The solution is cooled and acidified with 1.75 L of concentrated hydrochloric acid. The acidic mixture was extracted three times with 1.5 L of ether and the combined ether extracts were dehydrated over anhydrous magnesium sulfate, filtered through celite and evaporated to give a pale yellow solid (473 g) which was recrystallized from ether-petroleum ether. 298 g (65.2%) of 5-hydroxy-2-nitrobenzoic acid (melting point: 167-169 °) are obtained.

Example 22

5-isopropoxy-2-nitrobenzoic acid isopropyl ester

A mixture of 55.3 g of 5-hydroxy-2-nitrobenzoic acid, 450 ml of dimethylformamide and 93.9 g of anhydrous potassium carbonate was stirred for 10 minutes at room temperature, and 100 ml of isopropyl bromide was mixed and the mixture was brought to 100 °. Heat stirring for hours. The reaction mixture is cooled, diluted with ice water and the pH adjusted to 8 with 4N-sodium hydroxide solution. The reaction mixture was extracted three times with 500 ml of ether and the combined ether extracts were washed with 500 ml of saturated brine, dried over anhydrous potassium carbonate, filtered through celite and evaporated to give a yellow oil which crystallized while cooling 74.0 g (91.7%) of 5-isopropoxy-2-nitrobenzoic acid isopropyl ester (melting point: 45-50) is obtained. This material is distilled under vacuum to obtain pure water. (Melting point: 51 to 52 °)

Example 23

5-isopropoxy-anthranilic acid

74.0 g of 5-isopropoxy-2-nitrobenzoic acid isopropyl ester are dissolved in 650 ml of ethanol and 145 ml of 4N sodium hydroxide solution and the solution is stirred at room temperature for 16 hours. The reaction mixture is washed with 2.0 L of water and three times with 1 L of dichloroethane. The aqueous layer is adjusted to pH (2 with concentrated hydrochloric acid and extracted three times with 1.0 L of ether). The combined ether extracts are washed with 1.0 L of saturated brine, dehydrated over anhydrous sodium sulfate, filtered through celite and evaporated. Orange oil (65.9 g) is obtained, which solidifies upon cooling (melting point: 127 to 131 °).

This solid was dissolved in 1.0 L of ethyl acetate and 3.1 g of 10% Pd / c was used as a catalyst when the catalyst was stopped. The catalyst was filtered off and the filtrate was evaporated to a yellow solid with a melting point of 120 ° to 122 °. 49.5 g are obtained.

Example 24

2-isopropoxy-11-oxo-11H-pyramid [2,1-b] quinazoline-8-carboxylic acid

A mixture of 23.2 g of 5-isopropoxy anthranilic acid, 15.7 g of 6-chloronicotinic acid, 0.1 g of potassium iodide and 50 ml of triglyme is heated to 150 ° for 16 hours while passing argon vapor. The reaction mixture is cooled, diluted with 50 ml of ethanol and filtered to give 18.9 g of crude product (melting point: 256-267 °). This material is dissolved in 50 ml of hot pyridine, 4.8 ml of ethylene diamine is added, the mixture is cooled and the precipitated crystals are filtered off, washed with pyridine, pressure dried and dissolved in 50 ml of water. The aqueous solution was carefully acidified with acetic acid with stirring, and the precipitated crystals were collected, washed with water, ethanol and ether, and dried. 9.8 g of 2-isopropoxy-11-oxo-11H-pyrido [2,1- b] quinazoline-8-carboxylic acid (melting point: 278-280) is obtained.

Example 25

2-methylthio-1-oxo-11H-pyrido [2,1-b] quinazolin-8-carboxylic acid

A mixture of 50 g of methyl-5-methyl-mercapto anthranilate hydrochloride, 34.7 g of 6-chloronicotinic acid and 0.1 g of potassium iodide is immersed in an oil bath preheated to 150 ° and carefully watched for 40 ml of triglim Apply wisely. The reaction mixture is heated to 175 ° under argon vapor for 16 hours, cooled, and the resulting solid residue is dissolved in hot dimethylformamide and glacial acetic acid, filtered and cooled. The resulting precipitate was collected, washed with ethanol and dried to give 31.3 g (51%) of 2-methylthio-11-oxo-11 pyrido [2,1-b] quinazoline-8-carboxylic acid (melting point: 303 to 320 °). ).

Crude (10 g) is dissolved in 150 ml of hot pyridine and 1.25 ml of ethylene diamine is added to this solution. The resulting mixture is cooled with stirring. The resulting crystals are combined, dried under pressure, dissolved in water, and the resulting aqueous solution is carefully acidified with dilute acetic acid and the resulting precipitate is filtered and dried to yield 1.7 g of pure material. (Melting point: 337 °)

Example 26

2-cyclopropyl-11-oxo-11H-pyrido [2,1-b] quinazolin-8-carboxylic acid

2.12 g of 5-cyclopropylanthranic acid and 1.89 g of 6-chloronicotinic acid are dissolved in 20 ml of toluene and boiled to remove toluene. The resulting solid mixture is heated at 150 to 25 minutes, then cooled and the solid residue is treated with ether and then filtered. The resulting solid was crystallized with acetic acid and then ethanol to yield 0.275 g of pure 2-cyclopropyl-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid (melting point: 316 to 318 °). To obtain.

Example 27

4-isopropyl-isonitrosoacet anilide

1480 g of sodium sulfate and decahydrate are dissolved in 1.8 L of water and the following solution is added to the stirred solution. 440 ml water with 100 g p-isopropylaniline, 66 ml concentrated hydrochloric acid, 2.6 l 90% aqueous ethanol solution with 244 g chloryl hydrate and 700 ml water with 162 g hydroxyl amine hydrochloride . The reaction mixture was refluxed for 12 hours, then cooled to room temperature and extracted with 1.8 L of dichloromethane. The organic layer is separated and evaporated to partition the dark oil into 1.0 L of 10% sodium hydroxide and 500 ml of ether. The aqueous layer is separated and washed twice with 500 ml of ether. The aqueous layer is acidified with concentrated hydrochloric acid and extracted three times with 500 ml of ether. The combined ether extracts were dehydrated over anhydrous sodium sulfate, filtered through Celite, evaporated and dried to yield 160 g of 4-isopropyl-isonitroso acetanilide, and the crude product was recrystallized from 250 ml of benzene to 46.6 g. The product (melting point: 126 to 130 °) is obtained.

Example 28

5-isopropyl anthranilic acid

460 ml of concentrated sulfuric acid is stirred and heated to 70 ° and then 46.6 g of 4-isopropylisonitrosodiacet annilide is added while maintaining the reaction temperature between 70 ° and 80 °. Cool with water if necessary. Hold at 80 ° for 30 minutes and allow the reaction mixture to cool to room temperature and pour into 4 liters of ice. The resulting suspension is stirred for 15 minutes and the precipitated 5-isopropylisatin is filtered off. This solid is washed with water and dissolved in 460 ml of 1N sodium hydroxide solution. The mixture is filtered to remove insoluble matters and the filtrate is treated with 30% peroxide until the iodine starch test is positive.

The reaction mixture was cooled in an ice bath, acidified with 6N hydrochloric acid to adjust the pH to 4, and the precipitated product was collected and dried to yield 28.0 g of 5-isopropylanthraphylic acid (melting point: 90 to 96 °). This product is very pure.

Example 29

[Capsule Formulation]

[Way]

The active ingredients of formula (I), lactose and corn starch are mixed in a suitable mixer and ground by milling, then mixed with magnesium stearate and talc and filled into capsules.

Example 30

[Tablet preparation]

[Way]

The active ingredient of formula (I), lactose, microcrystalline cellulose, modified starch and corn starch are mixed for 1 to 15 minutes in a suitable mixer, magnesium, stearate is added and mixed for 5 minutes and tableted.

Example 31

[Wet Granule Tablets]

[Way]

The active ingredient of formula (I), lactose, and gelatinized starch are mixed in a suitable mixer, ground in a grinder, mixed with modified starch and magnesium stearate and tableted.

Claims (1)

A process for preparing the compound of formula (I) and acid addition salts thereof, characterized by reacting a compound of formula (II) with a tertiary organic base and chloro-, bromo, or iodomethyl pivalate.

Wherein R ₁ , R ₂ and R ₃ are each hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, cyclopropyl, cyclobutyl or hydroxy, and R ₄ is a general formula

Courage Wherein A is pivaloyloxymethoxy and Y is hydrogen or methyl and n is 0 or 1, provided that at least one of R ₁ , R ₂ and R ₃ is not hydrogen.