SU867308A3 - Method of preparing chromone derivatives or their salts - Google Patents

Abstract

PURPOSE:Reaction of a phenol derivative with a tetrazol-5-yl acetic acid to form a tetrazol-5-yl acetophenone, which is then allowed to react with a formic acid derivative, affording a chromone derivative having anti-allergic activity.

Description

(54) METHOD FOR OBTAINING CHROMON DERIVATIVES The invention relates to methods for producing chromone derivatives of the form where m is an integer equal to 0.1 or 2; R is a hydrogen atom or a halogen nitro group, a lower alkoxy group, a lower alkyl or butadienylene (), which forms a benzene ring by means of two adjacent carbon atoms in the 5,6,7 and 8, or their salts / These compounds have valuable biologically active properties. A known method for the preparation of chromone derivatives, formula I, is that the acrylonitrile aromatic benzopyran of the formula where and m have the indicated meanings, is reacted with sodium azide in the presence of anhydrous aluminum sulphide aluminum chloride in tetrahydrofuran medium at the boiling point of the reaction medium L1. The disadvantage of this method is that the use of ftat azide contributes to the release of nitrous hydrochloric acid vapor, which is explosive and toxic, which makes it difficult to apply this method. The purpose of the invention is to simplify the process. . This goal is achieved by the fact that the compound of the formula и iSCo, IR and L) have the indicated hydrogen atom, lower alkyl, or RJ or benzyl, is reacted with formic acid or its derivative in the presence of a mineral acid, base or halide compound at a temperature 20-150 ° C, and in the case R 1 is lower alkyl or benzyl, the protecting group is removed, followed by isolation of the desired product in free form or as a salt.

The reaction of Compound II with a derivative of formic acid is preferably carried out in the presence of a base, for example sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium, potassium hydrides, in an organic solvent such as alcohol, for example methanol, ethanol, propanol, butanol. - etc., hydrocarbons, such as benzene, toluene, xylene, etc., as well as ethers, such as tetrahydrofuran, dioxane, ethyl ether, dimethyl ether, ethylene glycol, etc. When using an amide derivative of its formic acid number n e is critical, although preferably 1-40 molar equivalents are used with respect to the compound of formula II.

As the inorganic halide derivative, it is preferable to use such as phosphorus oxychloride, phosphorus trichloride, tetrachloropyrophosphoric acid, thionyl chloride, phosphorus pentachloride or phosgene. An amide derivative is used as an organic solvent. Aromatic hydrocarbons, such as benzene, toluene m silol or halogenated hydrocarbons, such as chloroform, dichloromethane and tetrachloroethane can also be used.

Sulfuric, hydrobromic, hydroiodic or phosphoric acids are used as the acid. The amount of formic acid is not critical, since it can be a solvent, although it is best to use a ratio of 1-100 molar equivalents relative to the starting compound. Temperature and reaction time are not critical. Usually, the reaction is carried out at a temperature from room temperature to within 30 minutes to 3 days. The ratio of hydrobromic and formic acids, as well as the corresponding volumes, do not play a decisive role, although it is preferable that the starting compound is dissolved homogeneously upon heating.

If necessary, the protecting group Rl is removed from the compound obtained by cyclization of the compound of formula tl. Deletion of a valid group .Р. carried out in the presence of a mineral acid or a Lewis acid. As examples of the mineral acid, hydrochloric, hydrobromic acid, hydrogen bromide, hydrogen chloride or a solution of hydrogen chloride or hydrogen bromide in an organic acid (for example, acetic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid) can be used. The Lewis acid may be, for example, aluminum chloride, aluminum bromide, zinc chloride.

or boron trifluoride. When the Lewis acid is a solid, the reaction is usually carried out in an organic solvent, for example aromatic hydrocarbons such as benzene, toluene and xylene, as well as halogenated hydrocarbons such as chloroform, dichloromethane n, dichloroethane and tetrachloroethane.

The ratio of mineral acid or Lewis acid used in the reaction to remove the protecting group Rj is preferably 1-100 molar equivalents per salt of the compound obtained by cyclization of the compound of formula 1I. The reaction is usually carried out.

at 40-160C for 30 min 3 days.

The compound of formula II can be converted to the corresponding salt of an organic amine, alkali metal salt or ammonium salt, for example, by heating a compound of the formula together with an organic amine, for example ethanolamine

dl-methylephedrine, 1- (3,5-cyhydroxyphenal) -L-isopropylaminoethanol, isoproterenol, dextromethorphan, hetrasane (diethylcarbamazine), diethylamine, triztilamino, etc.-

alkali metal hydroxide (sodium hydroxide, potassium hydroxide, etc.) or

ammonia in a suitable solvent.

Example 1. A solution consisting of ethyl- (1H-tetrazol-5-yl) -acetate (1.64 g), tert-butanol (1.2 ml), trifluoroacetic acid (4.0 ml) and concentrated sulfuric acid (0.3 ml), stirred at room temperature for 24 hours, after which it is concentrated under reduced pressure. A sodium hydroxide N-solution (20 ml) was added to the obtained residue along with a concentrated aqueous solution of sodium hydroxide (5 ml), followed by stirring at room temperature for 2 hours. The reaction mixture was shaken with ethyl acetate, the aqueous layer was acidified with concentrated salt hydrochloric acid And extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate and the solvent is distilled off. The residue obtained is recrystallized from ethyl acetate-ether. According to the described procedure, (2-tert.-butyl-2H-tetrazol-5-yl) -acetic acid is obtained in the form of colorless crystals. Yield 1.01, m.p. 125-127p.

Elemental analysis:

Found: C, 45.91 H, 6.60; N, 30.56.

Calculated, ": C 45.64; H 6.57; N 30.42. ; Example 2. A mixture of 3.1 g of ethyl (1H-tetrazol-5-yl) -acetate, 20 ml of dimethylformamide, 2.8 g of ethyl bromide, 8.9 g of triethylamine are stirred at room temperature for 5 hours. The solvent is distilled off and after adding 70 ml of water, the residue is extracted with ethyl acetate. The ethyl acetate layer is washed with a 20% aqueous solution of ammonia and water, then the ethyl acetate is distilled off, resulting in a yield of 3.0 g of a pale yellow oil. Based on NMR spectrum (in deuterochloroform), this product was identified as a mixture of ethyl (2-ethyl-2H-tetrazol-5-yl) -acetate and ethyl (1-ethyl-1H-teTraeol-5-yl) -acetate in a ratio of approximately 3: 1 2.8 g of this mixture are heated under reflux with 50 ml of 5% alcoholic sodium hydroxide solution for 1.5 hours. The solvent is distilled off and the residue is shaken with this acetate. The aqueous layer is acidified with hydrochloric acid. After adding sodium chloride, the oily precipitate is extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride and chased, resulting in 1.6 g of crystalline product, which was recrystallized twice from ethyl acetate. According to the described procedure, (2-ethyl-2H-tetrazol-5-yl) acetic acid is obtained in the form of colorless needles. t, pl. 88-92 C. Elemental analysis: Found,%: C 38.62) H4.87 N 36.16. csHfl N400. C, 38.46 g; H 5.16); calculated;% N, 36.88. Example 3. A mixture of 1.56.g ethyl- (1H-tetrazol-5-yl} -acetate, 2 m of tert.-butanol, 10 ml of trifluoroacetic acid and 5 drops of concentrated sulfuric acid is stirred at room temperature for one hour. The solvent is distilled off under reduced pressure and water is added to the residue. The resulting oily liquid is extracted with ethyl acetate. The ethyl acetate layer is washed with water, diluted with an aqueous solution of ammonia, again with water, and distilled off. According to the described procedure, 1.8 g of ethyl- (2-third, -Ayl-2H-terazo-5-yl) acetata as an oily residue. This the residue is heated under reflux with a refrigerator with 10 ml of a 10% potassium hydroxide solution for 2 hours after which the solvent is distilled off. Water is then added to the residue and the mixture is poured into hydrochloric acid, and crystals are precipitated. 1.2 g of crystals are grown.Then crystals are converted from ethyl Metatyl to give (2-tert.-butylt2H-tetrazol-5-yl) -acetic acid as colorless prisms, m.p. 124125 0. Elemental analysis; Found: C 45.54 H 6.31 N 30.73. Calculated,%: C 45.64 H, 6.57 N, 30.42. . Example 4. According to the method described in examples 2 and 3, the following compounds are synthesized. (1-n-Butyl-1H-tetraeol-5-yl) acetic acid, m. 114-115 ° C. Elemental analysis. Found,% C 45.73 N 6.58 N 30.52. St. N 4M40a Calculated,%: C 45.64 N 6.57 N 30.42. (2-Beneyl-2H-tvtraz g-5-yl) acetic acid, so pl. 87-88 0. Elemental analysis Found,% t С 54.92 H 4.65 N 25.58. C H O M O O Calculated,% t C 55.04 N 4.62 N 25.68. (1-B0nzil-1H-tetrazol-5-yl) acetic acid, m.p. 150-15lc. Elemental analysis; Found,% | C, 54.74; H, 4.47; N, 26.02. С ОН о «40а Calculated,%: C 55.04 N 4.62 N 25.68. Example 5. A mixture of 5.0 g of (2-ethyl-2H-tetrazol-5-yl) -acetic acid, 4.9 g of p of phosphorus pentachloride and 20 ml of benzene is mixed at 70-75 0 for 1.5 hours. The solvent and the phosphorus side oxychloride is distilled off under reduced pressure. According to the described procedure, 5.5 g of (2-ethyl-2H-tetrazol-5-yl) -acetyl chloride are obtained in the form of an oily, pure product. Example 6 A mixture of 18.4 g (2-tert.-butyl -2H-tetrazole-5-yl) acetic acid and 150 ml of benzene are stirred and after adding a little 21.8 g of pt-chordosy phosphorus, the mixture is stirred at 70-75 ° C. for 1.5 hours. The solvent and side OXYHL01RD phosphorus are distilled off. under reduced pressure. According to the described procedure, 20.0 g of 3- (2-tert.-butyl-2H-tbTrasod-5-yl) -acetate chloride are obtained in the form of an oily liquid. IR spectrum (liquid film): 180.0 cm-. NMR spectrum: fCDCIj) ppm: 1.73 (9H, S) 4.48 (2H, S). PRI me R 7. -2.1 g of the oil obtained in Example 5 is added to

mixtures of 1.4 g of p-ethylanisole and 20 ml of 1,2-dichloroethane. After that, 2.8 g of anhydrous aluminum chloride is added. The mixture is heated under reflux with stirring for 2 hours. The reaction mixture is then poured onto ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, a dilute sodium hydroxide solution, again with water, and dried over anhydrous magnesium sulfate. The ethyl acetate is distilled off and the oily residue is purified by chromatography on silica gel (elution with benzene). According to the described procedure, 1.2 g of 2- (2-ethyl-2H-tetrazol-5-yl) -5-ethyl-2-methoxyacetate is obtained as an oily product.

A mixture of 0.7 g of this oil and 7 ml of 47% hydrobromic acid is heated under reflux for 1 h after which water is added. The resulting oily residue is extracted with benzene and the benzene layer is washed with a dilute aqueous solution of ammonia and water, then dried over anhydrous magnesium sulphate. The benzene is distilled off and n-hexane is added to the solid residue. As a result of filtration, 400 mg of crystalline substance is obtained. Recrystallization from a mixture of benzene and n-hexane gives 2- (2-ethyl-2H-tetrazol-5-yl-5-ethyl-2-oxyacetophenone as colorless flakes, mp. 6869 ° C.

Elemental analysis: Found,%: C 59.87; H 6.28; N 21.64.

with aIuChO / g.

Calculated,%: C 59.99; H 6.20; N 21.53.

Example 8. A mixture of 6.1 g of p-ethylphenol, 80 ml of 1,2-dichloroethane and 10 g of anhydrous aluminum chloride is stirred at room temperature and a mixture of the acid chloride obtained in Example 6 and 4 ml of dichloroethane is added dropwise over 20 min The mixture is then heated under reflux for 3 hours. After adding water, the dichloroethane layer is separated and the aqueous layer is extracted with ethyl acetate. Solvent solids are drained and washed with 5% sodium hydroxide solution and then with water. The solvents are distilled off to obtain 11.5 g of a brown oil.

To remove the by-product of p- (2-tert.-butyl-2H-tetrazol-5-yl) -acetoxyethylbeneol, this oil (11.5 g) and 40 ml of 10% alcoholic potassium hydroxide solution are heated under reflux for 1 , 5 h. The solvent is distilled off and, after adding water, the oily residue is extracted with ethyl acetate. The extract is washed with water and dried over anhydrous magnesium sulphate. The ethyl acetate is distilled off and the oily residue is purified by chromatography on silica gel (elution with a mixture of benzene-ethyl acetate). The crystalline product is recrystallized from a mixture of n-hexane with this acetate. According to the described method, 2- (2-tert. -Butyl-2n-tetrazol-5-yl) -5-ethyl-2-pxyacetophenone is obtained in the form of colorless flakes, m.p. 7576C.

Elemental analysis:

Found: C.62.56; H 7.00; . N 19.66.

C4S-H3oN40i

Calculated,%: C, 62.48; H 6.99; N 19.43.

According to the procedure described in examples 1 and 2, the following compounds are synthesized.

 2- (1-Ethyl-1H-tetrazol-5-yl) -5-yl-5-ethyl-2-oxyacetophenone, m.p. 107108С.

 Elemental analysis:

Found,%: C 60.11; H 6.27; N 21.53.

Calculated,%: C 59.99; H 6.20; N 21.53.

2- (1H-Tetrazol-5-yl) -5-ethyl-2-oxyacetophenone, m.p. 172-173s.

Elemental analysis:

Found: C, 56.93; H 5.06; N 23.94.

.

Calculated,%: C, 56.89; H, 5.21; N 24

2- (2-Benzyl-2H-tetrazol-5-yl) -5-ethyl-2-oxyacetophenone, m.p. 8283C.

Elemental analysis:

Found,%: C, 66.80; H 5.48 N 17.39.

Calculated,%: C 67.07; H 5.63; N 17.38 ..

 2- (1-Benzyl-1H-tetrazol-5-yl) -5 - TIl-2-oxyacetophenone, m.p. 97, 598, 5С.

Elemental analysis:

Found,%: C, 56.87; H 5.52; N 17.75;

Calculated,%: C 67.07; H 5.63; N 17.38.

2- (2H-Butyl-2H-tetrazol-5-yl) -5-e1IL-2-hydroxyacetophenone. IR spectrum (liquid film: 1643 cm

2- (2-tert.-Butyl-2H-tetrazrl-5-yl) -4-methoxy-2-hydroxyacetophenoHg m.p. 72-73c.

2- (2-tert.-Butyl-2H-tetrazol-5-yl) -5-chloro-2-oxyacetophenone, m.p. 133-135C.

1-Oxy-2-G2- (2-tert. -Butyl-2H-tetrazol-5-yl) -acetyl - naphthalene, m.p. 129-130 C.

Example 9. A mixture of 1.99 g of (2-tert.-butyl-2H-tetrazol-5-yl) -acetic acid, 2.3 g of phosphorus pentachloride and 4 ml of dichloroethane is stirred at 30 ° C for 2.5 h and after cooling by adding; 1 in 8.0 g of p-ethylene ether. A mixture of 2.9 g of anhydrous tin chloride and 3 ml of ethane dichloe is then added dropwise. The mixture was stirred at 8085 ° C for 2 hours, after which 10 ml of water and 2 ml of concentrated hydrochloric acid were added to the reaction mixture while cooling with ice. The resulting dichloroethane layer is separated and the aqueous solution is extracted with fresh dichloroethane. The dichloroethane layers are drained and washed with dilute hydrochloric acid and water, and then with a dilute aqueous solution of ammonia and water. Dichloroethane was distilled off to obtain 4.15 g of oil. The diluted aqueous ammonia layer is acidified with hydrochloric acid. The resulting crystalline residue was extracted with ethyl acetate to obtain 0.44 g of crystalline substance. Recrystallization from ethyl acetate gives 2- (1H-tetrazol-5-yl) -5-these methoxy acetophenone as colorless needles, mp. 159-160s. Elemental analysis: Found;%: C 58.54; H 5.90 N 22.74. C aBAd Calculated, C 5B, 52t And 5.73 N 22.75. 4, 15 g of the described oil are purified on silica gel (elution with a mixture of n-g of san and ethyl acetate). According to this procedure, 0.2 g of 2- (-tert-butyl-2H-tetrazol-5-yl) -5-et -2 is obtained. -oxiacetophenone and 1.45 g of 2- (2-tert-butyl-2H-tetrazol-5-yl) -5-these -2-methoxyacetophenone. The first thing is in good agreement with the authentic substance, according to thin-layer hsmatog1 data. The latter substance crystallizes on standing. Recrystallization from a mixture of n-hexane / ethyl acetate gives the colorless we, mp. 44-46 C. Elemental analysis: Found,%: C 63.56 N 7.62 N 18.43. (6 × 10 .. Calculated,%: C 63/55 H, 7.33 N 18.53. Example 10. A mixture of 4.0 g of 2- (2-tert.-butyl-2H-tetrazol-5-yl) - 5-Ethyl-2-methoxy-acetophenone, 30 ml of 99% acetic acid and 10 ml of 50% - L of sulfuric acid are heated under reflux for 16 hours and after cooling, 100 ml of water are added. The resulting crystalline precipitate is extruded ethyl acetate. The ethyl acetate acetate layer was shaken with a dilute aqueous ammonia solution and the dilute aqueous ammonia layer was acidified with hydrochloric acid, and then the crystalline residue was extracted with ethyl acetate. This layer was washed with water and distilled to give 2.85 g of crystals.Recrystallization from ethyl acetate gave 2- (1H-tetrazole-5-. -yl) -5-ethyl-2-methoxyacetophenone as colorless needles, mp. 159-160 C. Example 11. A mixture of 1.5 g of 2- (1H-tetrazol-5-yl) -5-ethyl-2-methoxyacetophenone and 8 "l of 48% hydrobromic acid is stirred at 120-130 seconds for 3 hours. After cooling, 100 ml of water are added. The resulting crystalline precipitate is extracted with ethyl acetate. The ethyl acetate layer was washed with water and the ethyl acetate was distilled off to obtain 1.42 g of crystals, which were recrystallized from ethyl acetate. According to the procedure described, 2-1H-tetrazol-5-yl) -5-yl) -5-ethyl-2-oxyacetophenone is obtained in the form of colorless needles, mp. 172173 C. Example 12 A mixture of 0.59 g of 2-D2-tert-butyl-2H-tetrazol-5-yl) -5-ethyl-2-methoxyacetophenone, 1 ml of 99% acetic acid and 5 ml of 47% hydrobromic acid is stirred at 110 -120 seconds over 6 hours and after cooling water is added. The resulting crystalline precipitate is extracted with ethyl acetate. The ethyl acetate layer was shaken with a dilute solution of a1 in a "1k. The dilute ammonia-water layer is acidified with hydrochloric; acid and extracted with ethyl acetate. The ethyl acetate is washed with water and distilled to obtain 0.35 g of crystalline substance. According to IR analysis, these crystals are 2- (1H-tetrazol-5-yl) -5-ethyl-2-oxyacetophenone. Example 13. A mixture of 1.07 g of 3- {lH-tetrazol-5-yl) -mix and 20 ml of sodium hydroxide solution I was heated with stirring for 1 hour. Then the mixture was acidified with hydrochloric acid, and the resulting precipitate was filtered and recrystallized from ethanol. According to the procedure described, 690 mg of 2- (lH-tetrael-5-yl) -2-oxyacetophenone are obtained in the form of colorless needles, which melt at 200-201 ° C. Elemental analysis: Found,%: C 52.88; H 3.66; N 27.36. Sd HB N4 O J Calculated,%: C 52.94; H 3.95 N 27.44. . In the described way receive soy-, dinene presented in table 1.

Starting compound I of formula I

2- (1H-Tetrazol-5-yl) -5-ethyl-2-oxyacetophenone

2- (1H-Tetrazol-5-yl) -3, 5-dimethyl-2-oxyacetophenone

1-OXY-2 C2- (1H-tetrazol-5-yl) -acetylD-naphthalene

2- (1n-Tetraeol-5-yl) -5-NITRO-2-oxyacetophenone

2- {1H-Tetrazol-5-yl) -5-n-pr6pyl-2-hydroxy-2-acetophenone

2- (1H-Tetrazol-5-yl) -4-methoxy-2-oxyacetophenone

2- (1n-Tetrazol-5-yl) -5-chloro-2-hydroxyschistophenone

Example 14. A mixture of 232 g of 2- (1H-tetrazol-5-yl) -5-ethyl-2-hydroxyacetophenone, 0.2 ml of tert-butane, 1 MP of trifluoroacetic acid and 2 drops of sulfuric acid is stirred at room temperature for 1h, after which it is concentrated under reduced pressure. Ox / ethyl acetate was added to the resulting residue, the ethyl acetate layer was washed with a nano aqueous solution of sodium hydrogencarbonate, then with solution I

Table 1

T, mp, C (recrystallization from solvent)

172-173 (Ethanol)

231-233 (Ethanol)

261-263 (dimethylformamide)

235-236 (Ethanol)

167-168 (Ethanol)

196-197 (Ethanol)

207-208 (Ethanol)

hydrochloric acid and dried over anhydrous sodium sulphate. The solvent is then distilled off under reduced pressure. By the described procedure, 300 mg of 2- (2-tert.-butyl-2H-tetrazol-5-yl) -5-ethyl-2-oxyacetophenone are obtained as an oily residue.

NMR spectrum (CDCIj) A: 4.62 (2H, S, CHjt); 1.73 (9H, S, CHj x 3).

In the described manner, the compounds shown in Table 2 are obtained.

table 2

2- (2-tert.-Butyl- 108-109-2H-tetrazole-5- (Ethanol) -yl) -3, З-Dimethyl-2-oxyacetophenone

1-Hydroxy-2-G2- (2- 129-130-tert.-butyl-2H- (Ethanol) -tetrazol-5-yl) -acetyl-naphthalene Example 15. In 19 ml of ethanol are dissolved 600 mg of metallic cotton and after cooling, 14 ml of ethyl formate are added with stirring. Then 1, -27 g of 2- (2-methyl-2H-tetrazol-5-yl) -5-ethyl-2-hydroxyacetophenone is added and the mixture is heated under reflux for 6.5 hours. The solvent is distilled off and after the addition the residue is acidified with hydrochloric acid. The ethyl acetate layer is washed with water and dried over the anhydrous gagni sulfate. Ethyl acetate is chased, the residue is crystallized by the addition of n-hexane to ethyl acetate. Filtration yields 1.16 g of crystalline material. Recrystallization from ethyl acetate of n-hexane gives b-ethyl- (2-ethyl-2H-tetraeol-5-yl) -chromone as colorless needles, mp. 98,100 C. Elemental analysis: Found,%: C 62.19 H 5.05; N 20.67. C 4Hi + N.Ol Calculated,% i С 62.21; H 5.22; N 20.73. .. Example 16. V12ML ethanol is dissolved 400 mg of metallic sodium. After cooling, 9 ml of ethyl Formate are added. Then, 900 ml of 2- (2-tert.-butyl-3H-tetrazol-5-yl) -B-ethyl-2-oxy-acetophenone is added and the mixture is heated under reflux. 6 h. The solvent was distilled off and the residue was diluted with ethyl acetate and water. The mixture is acidified with hydrochloric acid. The ethyl acetate layer is washed with water and dried over anhydrous magnesium sulfate. Ethyl acetate is chased and the resulting oily residue is purified by chromatography on a force gel (elution with a mixture of benzol ethyl acetate). According to the described procedure, 0.85 g of 6-ethyl-3- (2-tert. -Butyl-2H-tetrazol-5-yl) -chromone is obtained. This product crystallizes on standing, m.p. 54-56.C. Elemental analysis: Found,% from 64.40; H 6.09; N 19.05. .g Calculated,%: C 64.41; H 6-, 08; N 18.78. According to the described method, the following substances are synthesized. b-Ethyl-3- (2-benzyl-2H-tetrazol-5-yl) -chromone, m.p. 95-9bs. Elemental analysis: Found,%: C 68.46; H 4.68; N 17.17. - (b N + 0 Calculated,%; C 68.66; And 4.85; N 16.96. 6-g Ethyl-Z- (2-butyl-2H-tetrazol-5-yl), mp 96 -97® C. Elemental analysis: Found,%: C 64.54; H 6.00; N19.09. Calculated,%: C 64.41; H 6.08; N 18.78. Example 17. K 2 ml of dimethylformamide solution 210 mg of 1-hydroxy-2-f2- (2-tert.-butyl-2H-tetraz6l-5-yl) -naphthalene is added dropwise 0, 4 ml of trichloride phosphorus with ice cooling for 5 minutes The mixture is stirred for 30 minutes while cooling with ice and then for 5 hours at room temperature. The reaction mixture is poured into a mixture of ice and water and the resulting precipitate is recovered by filtration and washed with As a result of recrystallization from ethanol, 100 mg of 3- (2-tert.-butyl-2H-tetrazol-5-yl) -benzo (H) chromone are obtained in the form of pale yellow needles, mp 176- 178 pp. Example 18. To 5 ml of a benzene solution, 310 mg of l-OKCH-2-f2- (2-tert-butyl-2H-tetrazol-5-yl) -acetyl-naphthalene, 0.6 ml of triethylamine was added. Then, at 5-7C, 1 ml (about 5 mmol) of the ethereal solution, mixed formic-acetic anhydride is added dropwise over 10 minutes. This mixture was stirred at room temperature for 1 hour, while cooling with ice, and another 0.3 ml of triethylamine and 0.5 ml (about 5 mmol) of an ethereal solution mixed with formic anhydride were added, followed by stirring at room temperature for an hour . The reaction mixture is poured into a mixture of ice water, maintaining the pH at 2 with 10% HCI solution and extracted with benzene. The benzene layer is washed with water and dried over N3.504. After the solvent is distilled off, the residue is crystallized in ethanol. According to the described procedure, 270 mg of 3- (2-tert.butyl-2H-tetrazol-5-yl) -benzo- (h) -chromone are obtained in the form of colorless needles, mp. 176-1770С. Example 19. A mixture of 370 mg of 6-ethyl-3- (2-tert.-butyl-2H-tetrazol-5-yl) -chromone, 2 ml of acetic acid and 4 g of 60% hydrochloric acid is heated under reflux for 2.5 hours Heu is added to the reaction mixture, and the resulting crystalline regene {is filtered by filtration and recrystallized from ethanol. According to the written procedure, 6-ethyl3- (1H-tetrazol-5-yl) -hrmon is obtained in the form of colorless needles, so pl. 219-221 s. The JK-spectrum (KBg) of this product completely coincides with the spectrum of the artificial sample. Example 20. A mixture of 540 mg-ethyl-3- (2-ethyl-2H-tetrazol-5-yl) chromone, 5.4 ml of 57% hydroiodic acid and 1 ml of acetic acid is heated under reflux for 27 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate is shaken with a dilute aqueous ammonia solution and the aqueous layer; The mixture is concentrated, acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate is distilled off and the crystalline residue is recrystallized from ethanol. By the described method I get b-ethyl-3- (1H-tetraeol-5-yl) -chromium as colorless needles, so pl. 219221 C., Example 21. A mixture of 200 mg of 6-ethyl-3- (2-benzyl-2H-tetraeol-5-yl) -chromone. and 2 ml of 47% hydrobromic acid bromist is heated with Htw reflux for 0.5 hours. Water is added to the reaction mixture and the resulting precipitate is recovered by filtration and recrystallized from dimethylformamide-water. According to the described method, b-ethyl-3- {1H-tetrazol-5-yl) -chromone is obtained in the form of colorless needles, mp. 218-22lc. Example 22. Crude (2-ethyl-2H-tetrazol-5-yl) acetic acid crystals containing 25% (1-ethyl-1H-tetrazol-5-yl) acetic acid are processed as described in examples 5 and 1 to obtain a mixture of 2- (2-ethyl-2H-tetrazol-5-yl) -ethyl-2-oxyacetophene and 2- (l-ethyl-lfi-tetrazol-5-yl) ethyl-2-oxyacetafenone. This mixture was worked up as described in Examples 15 and 20 to give b-ethyl-3- (1H-tetrazol-5-yl} -chromone. Example 23. In 30 ml of ethanol, 1.4 mg of metallic metal was dissolved and then added 1.5 g of 2- (1H-tetrazol-5-yl) -5-ethyl-2-hydroxyacetophe nona and 20 g of ethyl formate. The mixture is heated under reflux for 2 h, then ethanol is distilled off. 120 ml of hydrochloric acid and crystalline precipitate are regenerated by filtration and recrystallized from ethanol. By the described procedure, 6-ethyl-3- (1H-tetrazol-5-yl) -chromone is obtained as colorless needles, mp 219-221 ° C. Elemental analysis: Found,%: C 59.35; H 4.10; N 23.29. CiaH oN40i C 59.50; H 4, 16; Calculated,% 23.13. 24. In 2 ml of ethanol. Example: 35 mg of sodium metal are dissolved and then 116 mg of 2- (1H-tetrazol-5-yl) -3, 5-dimethyl-2-oxy-acetophenone and 0.5 are added. ml of ethyl formate. The mixture is heated under reflux with stirring for 2 hours. To this reaction mixture is added a solution of 35 mg of metallic sodium in 2 ml of ethanol along with QfS MP ethyl formate, and the entire mixture is heated under reflux for 1.5 h. The solvent is distilled off and the residue is acidified hydrochloric acid. The poorly soluble fraction is recovered by filtration and recrystallized from dimethylformamide. According to the described procedure, 62 mg of 6,8-dimethyl-3- (1H-tetrazol-5 yl) -chromone are obtained as colorless crystals, m.p. 273-274C (decomposition). Example 25. A mixture of 3.5 g of 2- (1H-tetrazole) -5-ethyl-2-oxyacetophenone, 35 ml of 95% formic acid and 3.5 ml of concentrated sulfuric acid is stirred at 120 ° C for 13 hours and after cooling 100 ml of water are added to the precipitated crystals. The crystals are recovered by filtration and recrystallized from ethanol. According to the described procedure, 3.15 g of 6-ethyl-3- (1H-tetrazol-5-yl) -chromone are obtained in the form of colorless needles, mp. 219-221 C. Example 26. A mixture of 1.19 g of 2- (2-tert.-butyl-2H-tetrazol-5-yl) -5-ethyl-2-methoxy acetophenone, 6 ml of 85% formic acid and 6 A ml of 47% hydrobromic acid is stirred at 110-120 ° C for 7 hours and, after cooling, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was shaken with a dilute ammonia solution, separated from dilute aqueous ammonia, and concentrated to give 0.16 g of an oily residue. This residue is purified by chromatography on silica gel (elution with a mixture of n-hexane and ethyl acetate). According to the described procedure, 6-ethyl-3- (2-tert .-- butyl-2H-tetrazap-5-nl) -chromone is obtained. The IR spectrum of the obtained product coincides with the artificial sample. The diluted aqueous ammonia layer is acidified with hydrochloric acid and the resulting crystals are extracted with ethyl acetate to obtain 0.87 g of a crystalline residue. As a result of recrystallization from ethanol, 6-ethyl-Z- (1H-tetrazol-5-yl) -chromone is obtained in the form of needles, mp. 219-22lc. Using thin layer chromatography, it was confirmed that the mother liquor contains 6-ethyl-3- {1H-tetrazol-5-yl) -5-ethyl-2-oxyacetophenone. . Example 27. A mixture of O, 83 g of 2- (1H-tetrazol-5-yl-1-5-ethyl-2-methoxy-acetophenone, 4.5 ml of b5% mu | picric acid and 4.5 ml of 47% | Hydrochloric acid is stirred at 110-120 ° C for 7 hours and, after cooling, diluted with water and extracted with ethyl acetate, to give 0.8 g of crystals. Based on the thin-layer chromatography, it is established that this mixture is 6-ethyl H- (1H-tetrazol-5-yl) -chromone and 2- (1H.-tetrazol-5-yl) -5-ethylg2-oxyacetophenone. This mixture is mixed with 9 ml of 95% formic acid and | 0.7 ml of concentrated sulfuric

acid at 110-120 ° C for 9 hours and after cooling water is added. The resulting crystalline precipitate is recovered by filtration, and then recrystallized from ethanol. According to the described procedure, 0.46 g of 6-ethyl-3- (1H-tetrazol-5-ylU-x-OMONZ in the form of needles are obtained, t, pl. 219-221 s .

Claims (6)

1. A method for preparing. Chromone derivatives of general formula I F -N where m is an integer; equal to 0.1 or 2; RI is a hydrogen or halogen atom, a nitro group, a lower alkoxy group, a lower alkyl or butadienylene (-CH CH-CH CH-), which forms a benzene ring using any two adjacent carbon atoms at positions 5,6,7 and 8 ,. or their salts, characterized in that, in order to simplify the process technology, the compound of general formula II by (p pg-mG - „  coCHf T) Kg Nn where R and m have the indicated meanings; - a hydrogen atom, lower alkyl or benzyl, is reacted with formic acid or I its derivative in the presence of a mineral acid, a base or an inorganic x halogen compound at a temperature of 20-150 0, in the case of R / j lower alkyl or benzyl, the protective fi -rpynny is removed, followed by addition of the desired product in free form or in the form of a salt. 2. The method according to Clause I., of which is carried out in that the processes are carried out in an organic solvent medium. 0 g 3. The method according to Claim 1, I differ by the fact that formic acid amide is used as a derivative of formic acid, such 5 as dimethylformamide, mixed formic acid anhydride or ether. formic acid such as ethyl formate. 4. A method according to claim 1, characterized in that hydrochloric acid, hydrochloric acid or hydrobromic acid is used as the mineral acid. 5. The method according to claim 1, which is based on the fact that sodium methylate or sodium ethoxide is used as a baseline. 6. The method according to claim 1, with the t and l with the fact that, as the halide compound used 0 phosphorus trichloride. Sources of information taken into account in the examination 1. US patent 3896114, cl. 260-240E, published. 06/22/75 5 (prototype).