SU797575A3 - Method of preparing quinazolinone oxides - Google Patents

Abstract

Process for the preparation of quinazolinone-oxides of formula <CHEM> where: X = Cl, Br, NO2, CF3 Y = H, Br, Cl, F R1 = H, CH3 Such compounds are useful as intermediates in the preparation of 3-fluorobenzodiazepines, which are useful as tranquilizers, muscle relaxants and sedatives.

Description

(54) METHOD FOR OBTAINING A QUINAZOLINO OXIDE

I

The inventive relation to the improved method is obtained by quinazolinone oxides, which can be used in the synthesis of drugs.

A known method for the preparation of 6-chloro-4-phenyl-2 (1H) -hnnazolinone-3-oxide is obtained by taking 2-amnno-5-chloro-phenophenone-a-oxnma with phosgene; benzene with a yield of 37% 1.

A disadvantage of the known process is the low yield of quinazolinone oxides.

The goal of an inzhenernya I - increase output and more clearly. assortment of derivatives of hnnazolinone.

This goal is achieved by the method of the compounds of formula I obtained.

where X is a chlorine or bromine atom;

Y is an atom of hydrogen and fluorine;

R is a hydrogen atom or methyl, consisting in the fact that the compound of the general formula Pa and / or P b

R About I II

N - С -yJHR

ten

IS

L 6

where R is alkyl n; w phenyl; R is a hydrogen atom or zln; is subjected to interaction with the acid salt of hydroxylamine in the environment of a lower aliphatic sprint at the temperature of Kipein of the reaction mass. 3 Yield 51-85%. The yield of the known 6-chloro-4-phenyl-2 (III) nazolinon-3-oxide is 85%. The alcohols applicable to this reaction include (but not limited to) ethanol, methanol, propanol, isopropanol, butanol, 2-labels, ethylethiol, ethylene glycol, and propylene glycol. Hydroxylamine salts suitable for this reaction include salts with organic or inorganic acids with a pH of less than 2, such as hydroxyl amine hydrochloride, hydroxylamine hydrobromide, and jyDroxylamine sulfate. The starting compounds of general formula (T1 and (116) are obtained by reacting 2-amino benzophenones with organic isocyanates and, depending on the conditions, prepare compounds (Pa) and (Pb) or their mixture. Example 1. Part A. 6-Chlor-3 , 4-dihydro-4. Oxy-3-methyl-4-phenyl-2 (1H) -quinazoline A solution of 100 g (0.43 mol) of 2-amino-5-chlorobenzophenone and 40 g (0.7 mol) of methyl isocyanate in 300 ml of methylene chloride are boiled under reflux for 2 days, then the solution is cooled. The precipitate is filtered off and washed with methylene chloride. Yield 119.8 (96%) of the title compound as a white crystal. powdered powder, mp 296-298 ° С (with decomposition) Found:%: C 62.10; H 4.67; N 9.53 C. Calculated,%: C 62.39; H 4, 54; N 9.70. Part B. 6-Chloro-4-phenyl-2 (1-H) -quinazoline-3-oxide. A mixture of 86.6 g (0.3 mol) of 6-chloro-3,4- -4-hydroxy-3-methyl-4-phenyl-2 (1H) -quinazolinone dihydr and 62.5 g (0.9 mol) hydroxylamine hydrochloride and in 1500 ml of ethanol are heated under reflux for 187 h, cooled, and the precipitate filtered off, washed with ethanol and air dried. Yield 67.9 g (83%), t. Sh1. 267-269 ° C (in the form of yellow crystals). Example 2. Part A. b-Chloro-3-ethyl-3, 4-dihydro-4-hydroxy-4-phenyl-2 (1H) -quinazolino A solution of 28.4 g (31.7 ml; 0.4 mol) ethyl cyanate and 46.3 g (0.2 mol) of 2-amino-5-chlorobenzophenone in 100 ml of methylene chloride are heated under reflux for 20 h. The reaction mixture is cooled, the solid is collected on a filter and washed with methylene chloride to obtain 50.72 g (84%) of the title. compounds in the form of colorless crystals, t. Sh1. 182-184 ° C. Found,%: C 63.29; H 4.83; N 9.46. C (, H, .. Calculated,%: C, 63.57; H, 4.99; N, 9.25. Part B. 6-Chloro-4-phenyl-2 (1H) -quinazolino-3-oxide. Mixed mixture 12.11 g (0.04 mol) of 6-chloro-3-ethyl-3,4-dihydro-4-hydroxy-4-fench-1-2 (1H) -quinazolinone and 8.34 g (0.12 mol) of hydroxylamine hydrochloride in 200 ml of ethanol was boiled under reflux for 3 days, then cooled. The precipitate was collected on a filter, washed with ethanol and dried. Yield 9.27 g (85%) of the title compound as yellow crystals, mp 267-269 ° C. Example 3. Part A. 6-Chloro-3,4-dihydro-4-oxy-1,3-dimethyl-4-f-e1shl-2 (1H) -quinazolinone. A solution of 12.3 g (0, 05 mol) 5-chloro-2-metsh1 "minobenzophenone and 6 ml ( 0.1 ml) of methyl isocyanate in 50 ml of methylene chloride is heated under reflux for 3 days, then cooled. The precipitate is filtered and washed with methane to obtain 7.05 g (47%) of the title compound as yellow crystals, mp 174- 175 ° C. Found: C 63.44; H 4.96; N 8.84. C.feHisClNaOr Calculated,%: C 63.47; H 4.99; N 9.25, Part B. 6- Chlorine-1-methyl-4-phenyl-2 (1H-hiazolinon-3-oxide “Stir-blend 3.03 g (0.01 mol) 6-chloro-3,4-dihydro-4-hydroxy-1,3 -dimethyl-4-phenyl-2 (1H) -quinazolinone and 2.09 g (0.03 mol) of hydroxylamine hydrochloride in 50 ml of ethanol are boiled under reflux for 5 days. The reaction mixture is cooled, the precipitate is filtered, washed with ethanol and air dried to give 1.75 g (61%) of the title compound as yellow crystals, m.p. 289-291 ° C. Example 4. Part A. 1- (2-Benzosh1 4-chlorophenyl) -3-isopropylurea. A mixture of 14 g (0.06 mol) of 2-amino-5-chlorobenzophenone and 40 ml of isopropyl isocyanate was boiled under reflux for 3 hours. The resulting solid was taken up in 25 ml of hexane, filtered and recrystallized from ethanol to give 12.0 g (63%) of the title compound as colorless needles, m.p. 190-. 192 ° C. Found,%: C 64.21; H 5.40; N 8.78. .. Calculating,%: C 64.21; H 5.41; N 8,85. Part B. 6-Chloro-4-phenyl-2 (III) -quinazolinone-3 oxide. A stirred mixture of 6.34 g (0.02 mol) of 1- (2-benzoyl-4-chlorophenyl) -3-isoprs of shlurea and 4.17 g (0.06 mol) of gfxdiacylamine hydrochloride in 100 ml of ethanol is boiled for 48 hours under reflux, then cooled. The crystals are filtered, washed with alcohol and air dried. Yield 4.60 g (84%) of the title compound as yellow crystals, m.p. 267-269 C (with decomposition). Example 5. Part A. 1- (2-Benzoyl-4-chlorophenyl) -3-phenylurea. A solution of 13.1 g (0.11 mol) of phenylisocyanta and 23.17 g (0.1 mol) of 2-amine-5-chlorobenzo, phenol in 70 ml of methylene chloride is heated under reflux for 20 h, then evaporated to dryness under reduced pressure . The residue is recrystallized from ethanol to obtain 31.71 g (90%) of the title compound as colorless crystals. T, mp. 145-147 Navdo,%: C 68.21; H 4.50; N 8.02. CaoHfjClNiOiCalculated,%: C 68.21; H 4.50; N 8.02. . Part B. 6-Chloro-4-phenyl-2 (1H) -quinazolino-3-oxide .... A stirred mixture of 7.02 g (0.02 mol) of 1- (2-benzoyl-4-chlorophenyl) -3-phenylureas and 4.17 g (0.06 mol) of hydroxylamine hydrochloride in 100 ml of ethanol is boiled for 22 h. refrigerate, then cool. The suspended solids were collected on a filter, washed with ethanol, and air dried to give 3.82 g (70%) of the title compound as yellow crystals, m.p. 267-269 ° C. Example 6. Part A. 1- (2-Benzoyl-4-chlorophenyl) 1-methyl-3-phenylurea. A solution of 12.3 g (0.05 mol) of 5-chloro-2-methyl aminobenzophenone and 11.9 g (0.1 mol) of phenyl isocyanate in 50 ml of methylene chloride is boiled for 3 days under reflux and the solvent is distilled off to dryness with reduced pressure. The resulting oil is mixed with ether before crystallization. The crystals were collected on a filter and washed with ether, giving 12.06 (66%) of the title product as light yellow crystals. A sample of the product is recrystallized from ethanol to give colorless crystals, mp. 158-160С. Naya,%: C 68.82; H 4.73; N 7.48; ). Calculated,%: C 69.13; H 4.70; N 7.68. Part B. 6-Chloro-1-metsht-4-phenyl-2 (1H) -quinazolinone-3 - oxide. A mixture of 3.65 g (0.01 mol) of 1- (2-benzoyl-4 chlorophenyl) -1-metsh-3-phenylureas and 2.09 g (0.03 mol) of hydroxylamine hydrochloride in 50 ml of ethanol is stirred and boiled with reflux 5 days. The reaction mixture is cooled, suspended: a solid product is collected on a filter, washed with alcohol, and air dried to obtain 1.80 g (63%) of the title compound as yellow crystals, m.p. 289. Example 7. Part A. 6-Chloro-4-ztoxy-3,4-dihydro-3,4-diphenyl-2 (1H) -quinazolinone. A solution of 10.0 g (0.285 mol) of 1- (2-benzoyl4-chlorophenyl) -3-phenylurea in 50 ml of ethiol for 18 hours is refluxed and then cooled. The resulting solid was collected on a filter and washed with ethanol. receiving 9.46 g (88%) of the title compound in mp. 209-211 ° С in the form of colorless crystals, Found,%: C 70; H 5.05; N 7.35. .. Calculated,%: C 69.74; H 5.05; N 7.40. Part B. 6-Chloro-4-phenyl-2 (1H) -hnnazolinone-3-oxnd. A mixture of 3.51 g (0.0093 mol) of 6-chloro-4-ethoxy-3, 4-dihydro-3,4. 2-1 (1H) -quinazolinone and 2.09 g (0.03 mol) of hydroxylamine hydrochloride in 50 ml of alcohol for 4 days are boiled under reflux, then cooled. The resulting solid was collected on a filter, washed with ethanol, and air dried to give 1.82 g (72%) of the title compound, mp 26769 ° C. Example 8. 6-X11Lp-4-fench1-2 (1H) - cnnazolinone-3-oxide. A mixture of 12.6 g (0.05 mol) of 2-amino-5-chlorobenzophenone and 6.55 g (0.55 mol) of phenyl isocyanate is heated in a water bath for 30 minutes, then 250 ml of ethanol and 10.43 g (30 g) are added. 0.15 mol) hydroxylamine hydrochloride, after which the mixture is boiled for 2 days under reflux and cooled. The solid was collected on a filter, washed with ethanol, and air dried to give 9.42 g (69%) of the title compound as yellow crystals, m.p. 267-269 ° C. Example 9. 6-Chloro-4-phenyl-2 (1H) -quinazolinone-3-oxide. A stirred mixture of 2.89 g (0.01 mol) of 6-chloro-3,4-dihydro-4-hydroxy-3 - methyl 4-phenyl-2 (1H) -quinazolinone and 2.09 g (0.03 mole) hydroxylamine hydrochloride in 50 ml of 2-methoxynethanol (ethylene glycol methyl ether) is boiled for 2 hours under reflux, then cooled to 0 ° C. The resulting solid was collected on a filter, washed with ethanol, and air dried to obtain 1.40 g (51%) of the title product as yellow crystals, m.p. 267-269 ° C. Example 10. Part A. 6-Bromo-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2 (1H) -quinazolinone. A solution of 14.70 g (0.053 mol) of 2-amino-5-bromobenzophenone and 6.0 g (0.21 mol) of methyl isocyanate in 75 ml of methylene chloride is boiled under reflux for 2 days, then cooled. The solid reaction mixture was collected on a filter and washed with methylene chloride to give 16.18 g (90%) of the title product as a white crystalline powder, mp. 293-294С (with decomposition). Found,%; C 54.24; H 3.89; N 8.12. C jH i BrNiO / i. Calculated,%: C 54.07; H 3.93; N 8.41. Part B. 6-Bromo-4-phenyl-2- (1H) -quinazolinone-3-oxide. A stirred mixture of 28.28 g (0.085 mol) of 6-bromo-3,4-dihydro-4-hydroxy-3-methyl-4-phenyl-2PN) quinazolinone and 17.6 g (0.25 mol) of hydroxylamine hydrochloride in 425 ml of ethanol is boiled under reflux for 192 hours, then cooled. A solid portion of the reaction mixture is collected on a filter, washed with ethanol, and air dried to obtain 20.92 g (0.066 mol, 78%) of the title product as light yellow crystals, mp. 275-276 ° C.

Example 11 Part A of 6-Chloro-3-ethyl-4- (2-fluorophenyl) -3,4-dihydro-4-hydroxy-2 (1H) -quinazolinone.

A mixture of 25 g (0.1 mol) of 2-amino-5-chloro-2fluorobenzophenone and 35.5 g (0.5 mol) of ethyl isocyanate is heated under a condenser for 20 hours, then cooled. A solid portion of the reaction mixture is collected on a filter and washed with methylene chloride to obtain 19.6 g (61%) of the title compound as a white crystalline powder, t, plO 176-178 ° C (with decomposition).

Found,%: C 60.11; N / 4.44, N 8.83.

C HClFNlOaCalculated,%: C 59.92; H 4.40; N 8.73.

Part B. 6-Chloro-4- (2-fluorophenyl) -2 (1H) -quinazolinone-3-oxide.

A stirred mixture of 18.0 g (0.056 mol) of 6-chloro-3-ethyl-4- (2-fluorophenyl) -3,4-dihydro-4oxy-2 (1H) -quinazolinone, 11.8 g (0.17 mol ) hydroxylamine hydrochloride and 280 ml of ethanol are boiled under reflux for 3 days. The reaction mixture is then cooled, and the precipitate is collected on a filter and washed with ethanol to obtain 6.67 g (47%) of the title compound as an yellow crystalline powder, v. III. 268-270 ° С (with decomposition).

Found,%: C 58.01; H 2.83, N 9.59.

CdN0S1RM, 02.

Calculated: C 57.85; H 2.77; N 9.64.

The proposed method allows to obtain known quinazolinone oxides with higher yields and to expand their range.

7975758

Claims (1)

Invention Formula The method of producing quinazolinone oxides (of formula G where X is a chlorine or bromine atom; Y is a hydrogen or fluorine atom; R is a hydrogen or methyl atom, characterized in that, in order to increase the yield and expand the range of target products, the compound of the general formula Pa and / or Pb where R is - alkyl or phenyl; R is a hydrogen atom or ethyl; is reacted with an acid salt of hydroxylamine in a medium of lower aliphatic alcohol at the boiling point of the reaction mass, and the target product is isolated. Sources of information taken into account in the examination 1. Sulkowski T.S., Childress SIJ. The Formation and Subsequent Rearrangement of ...- J. Org. Chem., 27,4426, 1969 (prototype).