DE1445402A1 - Process for the manufacture of quinazolinone derivatives - Google Patents

Description

Process for the preparation of quinazolinone derivatives The compound relates to the preparation of new organic compounds, in particular new 7-chloro-1, 2, 3,4-tetrahydro-4-oxoquinazolines which are substituted in the 2-position by lower alkyl groups, which are represented by the following general formula reproduced hydrogen, where IL is a lower alkyl group and R2 -C - a lower-alkyl, -Q-aryl and-C-0-lower a-alkyl- mean residues.

Appropriate lower alkyl radicals which are in question according to the invention come are solahe with up to four carbon atoms, with methyl and ethyl groups to be favoured. An example . for aryl groups is the phenyl group.

The process according to the invention for the preparation of 4-oxa-6-sulfamy 2, 3,4-tetrahydroquinazolinone derivatives of the general formula: where R and R3 are hydrogen or alkyl radicals with up to 6 carbon atoms, R and R are hydrogen or alkyl radicals with up to 6 carbon atoms or aralkyl groups and I is halogen or an alkyl group or a trihalomethyl group, consists in that (a) a quinazolinone of the formula: wherein R, R1, R2 and R3 have the meaning given above with chlorosulfonic acid to introduce the chlorosulfonic acid group in the 6-position to form a compound of the formula (b) the 6-chlorosulfonquinazolinone of the formula III is then reacted with ammonia to form the compound of the formula I.

The invention also provides a process for the preparation of compounds of the general formula R '-rY "# # R2 IV N - R3 # C n 0, in which X is a halogen atom, an alkyl group or a trihalomethyl group, R is a hydrogen atom, an alkyl group or a -C-lower-alkyl- C-aryl- or -C-0-lower-alkyl- 0 0 0 group and 21t R and R3 are hydrogen atoms or alkyl radicals with up to 6 carbon atoms, which consists in that an anthranilamide substituted in the 4-position of the general formula with an aldehyde or ketone of the formula or an acetal or eetal of these aldehydes or eetones is reacted. The new compounds obtainable according to the invention are as. Muscle relaxants and useful as diuretics and can be administered orally or parenterally. They show pronounced diuretic activity at 5-10 mg / kg and depression activity on the central nervous system at 500-750 mg / kg.

Furthermore, the newly available compounds are important as intermediates for the production of 7-halogen-6-sulfamyl-1,2,3,4-tetrahydro-4-oxoquinazolines, which valuable diuretics and saluretics are of considerable potency.

These compounds are described in U.S. Patent (Serial No.

823,806, dated June 30, 1959, by Cohen and Vaughan. They have the following formula: where R H "H'lower Alkyl is oxo, R is hydrogen or lower alkyl, R2 is hydrogen or lower alkyl and d X is halogen or trifluoromethyl.

The use of the new compounds obtainable according to the invention for the preparation of the diuretics described in the Cohen and Vaughan application listed above is described in detail below.

According to the invention, the connections are very easy and easy to prepare from 4-haloanthranilamides.

It is only necessary to use the same with a lower alkyl aldehyde or lower alkylacetal vmzusetzene This reaction is carried out in the presence of acids, e.g. B. sulfuric acid carried out and preferably in an organic reaction medium, e.g. an alkanol, glycol ethers and the like. Furthermore, it is an advantage that the reaction conditions are not critical and the reaction; runs pretty quickly. The temperatures are moderate, for example between about 30 ° to about 130 ° C, with optimal results at about 80 ° to 100 ° C can be achieved. This allows a very simple. no temperature control. The only thing necessary is the use of an organic solvent, z. B. an alcohol which boils at the temperature at which it is desired will perform the reaction. The reaction can then be refluxed with a automatic temperature control and carried out under very simple working conditions will.

The 4-haloanthranilamide can easily be obtained by a Sandmeyer reaction obtained from a halogen-2-hitroaniline with copper-I-cyanide, with as an intermediate product a 4-halo-2-nitrobenzonitrile is formed, which leads to the 4-haloanthranilamide is reduced and hydrolyzed.

As stated above, the compounds according to the invention can be prepared by reactions using aldehydes or acetals. Although either type of compound can be used, the yields are better when acetals are used and, in fact, nearly twice as high. This is particularly the case when the ethyl group is to be introduced, as Benn regards the compounds obtainable according to the invention as intermediates for the preparation of the 7-halogen-6-sulfamyl-1, 2, 3, 4-tetrahydro-4-oxoquinazolines and their usefulness it is of interest to compare the number of stages required and their type, and especially the number of stages, when starting from technically available raw materials. The process by Cohen and Vaughanv described in the US application cited above, which is also described in the patent specification ........... (432768IVb / 12 @), starts from 5-chloro-o-toluidine as explained schematically below, whereby seven levels are required: In the new process made possible according to the invention, only five steps are required in order to obtain the final connection, assuming industrially available materials, as set out below. C1 cil NO; -Diazotization: 'Fe + acid -IIH2 Cu2 (CN) 2-CN Athai3ol 2 2 2 DMF H , zOC2H5 H I-OC HH Cl <2 5 ° 2E5 v \ / N \ H l> 1 E '-CONH? Acid-ethanol. C. O 0 With the intermediates according to the invention, only two steps are then required and these are shown in the following reaction scheme: It emerges quite clearly that this route of technically available materials and using the new intermediate products according to the invention eliminates two stages of the known process, which results in great savings.

The first stage of the two-stage process, starting from the new ones Intermediates, contains a new step process improvement itself. It has been found that the chloro sulfonation does not produce useful yields there, aubiers when there is a fairly large amount of a halide salt, which may consist of an alkali halide, alkaline earth halide or the like. Because of its cheapness and excellent properties, sodium chloride is used predominantly preferred The presence of sodium chloride in the chlorosulfonation step is not based on its effect as a catalyst. In other words, very sincere small amounts of the salt do not give good results. The salt has been in pretty substantial amounts To be present in amounts which reach those of the other reactants.

Although the working conditions ultimately differ from the respective Given ratios, useful yields of the desired compounds can be obtained can be obtained by adding 3-10 parts by weight of chlorosulfonic acid for one part of quinazoline, 0.5-4 parts of salt and 0.1-1 part of sodium metabisulphite were used. If desired can the sulfonyl chloride by crystallization from a solvent, e.g. B. methylene chloride cleaned and then treated with ammonia to obtain the final product. The amidation step can either be with aqueous ammonia or with anhydrous ammonia can be carried out at temperatures from -80 ° C to 30 ° C.

The temperature at which the chlorosulfonation is carried out, is not critical and can range between about room temperature or slightly above vary up to 70 or 80 ° C.

Although the temperature is not critical, it does have some influence and best yields are generally achieved between 10 and 50 ° C, which consequently may be considered to be a preferred range, although the invention will hereinafter be considered Scope is not limited by this .....

Regarding the type of use in the chlorosulfonation step The following specific examples describe the use of the coming salt of sodium chloride, however, it goes without saying that this choice is due to economical Considerations are made and that good results also with other halide salts, such as z. B. potassium chloride9 calcium chloride and similar are achievable.

The following examples serve to further illustrate the invention. Parts are by weight unless otherwise specified.

Example 1 Preparation of 7-chloro-2-ethyl-1. 2, 3,4-tetrahydro-4-oxoquinazoline A mixture of 200 parts by volume of methanol, 4.7 parts of propionaldehyde, 9.8 parts of 4-chloroanthranilamide and 0.1 part of sulfuric acid was prepared. The mixture was refluxed for a few hours until the reaction had ended and then it was cooled and neutralized with 0.3 part sodium bicarbonate and decolorized with one part activated charcoal. The filtrate was concentrated to a syrup and diluted with a very small volume of ethyl acetate. After complete cooling, a crystalline product precipitated, which was removed by filtration and washed with a cold mixture of alcohol, ethyl acetate and petroleum ether. 3. g of material was obtained. The yield was well over 30%. The material was then purified by recrystallization from ethyl acetate to give a product which melted at 130-132 ° C.

Example 2 The connection according to Example 1 was made by Formation of a mixture of 500 parts of anhydrous ethanol, 29 parts of 4-chloroanthranilamide, 33 parts of propionaldehyde diethyl acetal and 0.15 part of concentrated sulfuric acid. The reaction mixture was then refluxed, 80-81 C, for six Heated for hours. The main amount of anhydrous alcohol and converted acetal was then removed by vacuum distillation. After cooling, 76% of a product became obtained with a slightly better ranking than that of Example 1. It can be seen that the use of the acetal instead of the aldehyde increases the yield more than doubled and that the use of the acetal is therefore preferred.

Example 3 Preparation of 7-chloro-2-methyl-1,2,3 4-tetrahydro-4-oxoquinazoline 9.44 parts of diethyl acetal, 8.6 parts of 4-chloroanthranilamide and 0.09 part of concentrated sulfuric acid were added to 130 parts by volume of alcohol with stirring. The mixture was heated to reflux for four hours, concentrated under reduced pressure to about 30 volumes, and cooled to induce crystallization. The product was separated by filtration, washed with 20 parts by volume of cold alcohol and dried in air at 50 ° C. The first crop was 3 g. An additional 3.2 g of product was isolated from the Llutter liquor. The overall yield was 6.2 g (63.10% of theory), mp 140-143 °.

The crude product was ester by recrystallization from acetic acid purified, m. 143-147 ° C.

Example 4 Chlorosulfonation of the product according to Example 1 to give quinazalinesulfonyl chloride With stirring, 17.1 g of sodium chloride were added to a mixture of 46.5 parts of chlorosulphonic acid and 12 g of product according to Example 1 in portions over the course of 35 minutes, while the temperature of 34 to 41 ° C. was maintained. The mixture was then heated to a temperature of 41 to 44 ° C for an additional period of 1-1 / 2 hours. It was then poured into 400 parts of an ice-water mixture maintained at a temperature of Q to 4 ° C. The granular product that formed was separated off by filtration, washed thoroughly with water and pressed into a moist cake. A 15 g portion of the moist product was dried by removing the water by azeotropic distillation using methylene chloride, giving 1.5 g (25.5%) of the product with an mp = 180 ° C. Treatment of this product with ammonia as described in Example 6 gave the desired sulfonamide.

Bine from 11.6 parts of chlorosulfonic acid and 4.0 parts of 7-chloro-2-ethyl-1, 2, 3, 4-tetrahydro-4-oxoquinazoline existing mixture, but which does not contain sodium chloride Contained, was over a period of 2 hours to a temperature of 40 heated to 65 ° C. The melt was divided into 75 parts of an ice-water mixture at a Poured temperature from 2 to 5 ° C, The product was collected by filtration, Washed with three 100 ml portions of water and exercise in a desiccator, the Containing sulfuric acid, dried under vacuum. The crude product was 2.5 g (42, 7%) 'It was obtained by successive triturations with small volumes of chloroform and ethyl acetate purified, the yield being 2.0 g (34.3%) when a sample of the Sulfonylchlorides produced in this way Was treated with ammonia, no 7-chloro-2-ethyl-1, 2, 3, 4-tetrahydro-4-oxo-6-quinazoline sulfonamide was obtain.

Example 5 46.5 parts of chlorosulfonic acid were cooled and 1 Partly treated sodium metabisulphite. 6.7 parts of 7-chloro-2-ethyl-1, 2, 3, 4-tetrahydro-4-oxoquinazoline were slowly stirred into the mixture obtained, while a temperature of 15-25 ° C was maintained. The mixture was heated to 40 ° C for a period. heated by 1/3 hour and a mixture containing 17, 1 part of sodium chloride and 1 part Sodium metabisulphite was added in small portions over the course of 3/4 hours added at a temperature of 40-46 ° C. The mixture was then left for an additional 3 hours heated at this temperature and in 25Q parts an ice-water mixture at a Poured at a temperature of about Q ° C. The product was then collected on a filter, with three 250 ml portions of cold water. washed and the water through azeotropic Distillation with methylene chloride and subsequent air drying at 45 ° C removed, the yield was 4.7.7 g (47.8%, mp 179 ° C (dec.)).

The product was made by dissolving in methylene chloride, clarifying the Solution to remove the insoluble components, concentration close to dryness, purified before the product was allowed to crystallize.

Example 6 Preparation of 7-chloro-2ethyl-1,2,3,4-tetrahydro-4-oxo-6-quinazoline sulfonamide 1.4 parts of purified 7-chloro-2-ethyl-1, 2, 3, 4-tetrahydro-4-oxo-6-quinazoline sulfonyl chloride was added to 40 parts by volume of liquid ammonia and over an hour touched.

The remaining ammonia was removed in vacuo and the reaction mixture added to enough cold acetic acid to obtain a pH of 5.92, while maintaining a temperature of 0 ° C. The product was on a Filters collected, washed with water and dried in air at 100 ° C. the Yield of material was 1.0 g (76.4%), mp = 222-228 ° C. Purification from aqueous Acetone gave a material with a mp = 232-235 ° C. The melting point of an authentic one Sample made from 2-amino-4-chloro-5-sulfamylbenzamide was 234-238 ° C. The melting point of a mixture of the two samples was 233-238 ° C. That Infrared spectrum of the purified product corresponded to that of the authentic Sample.

Example 7 Preparation of 7-chloro-2-ethyl-1. 2,3 4-tetrahydro-4-oxo-6-quinazoline sulfonamide 4 parts of 7-chloro-2 ~ ethyl-1, 2, 3, 4-tetrahydro-4-oxo-6-chiriazoline sulfonyl chloride were liquid in a mixture of 8 parts by volume of water and 125 parts by volume Stir in ammonia at a temperature of -38 ° C to -45 ° C. The reaction became 2 Allowed to drain for hours at this temperature and the excess Ammonia removed under vacuum to a volume of about 40 ml. This mixture was added to cold, dilute mineral acid solution and the final mixture brought to a pH of 5.4 4. The product obtained was on a filter collected, washed with water and air-dried at 50 ° C., 2 g of crude product (53k4%). This material was further purified from aqueous acetone and the result was a product with a temperature of 230-232 ° C., melting point of an authentic sample 230-232 ° C, mixed melting point 230-233 ° C.

The infrared spectrum of the purified product was with that identical to an authentic sample.

Example 8 Preparation of 1-acetyl-7-chloro-2-ethyl-1,2,3,4-tetrahydro-4-oxoquinazoline A mixture consisting of 5 g of 7-chloro-2-ethyl-1, 2, 3, 4-tetrahydro-4-oxoquinazoline, 10 g of acetic anhydride and 0.1 g of hydrochloric acid was heated to a temperature of about 98 ° C. over a period of heated for an hour. It was then cooled to 90 ° C. and diluted with 75 g of water. The product was collected on a filter, washed with water and air-dried at 60 ° C., yielding 5.6 g (87.5%) of crude product, mp 188-198 ° C. It was purified by recrystallization from a mixture of three parts of dimethylformamide and 10 parts of water, a product having a melting point of 200-217 ° C. resulted.

Claims (4)

Claim 1.) Process for the preparation of 4-oxo-6-sulfamyl-1,2,3,4-tetrahydroquinazolinone derivatives of the general formula wherein R and R3 are hydrogen or alkyl radicals with up to 6 carbon atoms, R1 and R2 are hydrogen or alkyl radicals with up to 6 carbon atoms or aralkyl groups and X H is a log or an alkyl group or a trihalomethyl group, characterized in that (a) a quinazolinone of the formula where Es; E, Rp and R sit as indicated above, with chlorosulfonic acid to introduce the chlorosulfonic acid group into the e 6-position to form one of the formula and d (b) the 6-chlorosulfonquinazolinone of the formula III is then treated with ammonia to form the compound of the formula I. 2.) The method according to claim 1, characterized in that compounds can be used in which X is a halogen atom, preferably chlorine. ... ~~ .-. 3.) The method according to claim 1 or 2, characterized in that sulfonation in the presence of a halide salt of an alkali-forming metal, preferably sodium chloride, and that the halide salt is preferably carried out in an amount of 0.5 to 4 parts by weight per part by weight of the compound of the formula II is present. 4.) Process for the preparation of compounds of the general formula wherein X is a halogen atom, an alkyl group or a trihalomethyl group, R is a hydrogen atom, an Alkl group or a 000 «" -C-lower-alkyl -, - C-aryl or -CQ-lower-alkyl group, and R1, R2 and R3 denote hydrogen atoms or alkyl radicals with up to 6 carbon atoms, characterized in that an anthranilamide substituted in the 4-position of the general formula with an aldehyde or ketone of the formula or an acetal or ketal of the aldehyde or ketone is reacted.