DD278473A3 - PROCESS FOR THE PREPARATION OF 2-AMINO-5-CHLORO-BENZOPHENONES - Google Patents

Abstract

The invention includes a process for the preparation of amino compounds, in particular substituted benzophenones, from substituted 3-phenyl-benzo-isoxazole. The process uses the Bechamp reduction by carrying out the reduction and subsequent work-up in the presence of a surfactant. Suitable surfactants are anionogenic, cationogenic or nonionic compounds. The inventive Bechamp reduction results in amino compounds as valuable intermediates for pharmaceuticals.

Description

Characteristic of the known state of the art

From BIOS Final Report 116,959.9861 and II, 1143,1144,1146,114,115,12,1153 and 1355 technically realized Bechamp Brimmeyr reductions are known and described, (fine extensive review of Bechamp reductions is in Houben-Weyl , Methods of Organic Chemistry, 4th Edition, Volume XI / 1, page 394 ff and Volume IV, Part 1 c, page 742 ff .. Furthermore, the technical-economic advantage of these reductions in Ulimann's Encyclopedia of technical chemistry , 4th Edition, Volume 7, page 397 ff., Or page 567 for the preparation of amino compounds from nitro compounds., Further, from Houben-Weyl, Methods of Organic Chemistry, Volume XI / 1, page 394 ff., HEFierz- David and L.BIangey, Basic Operations of Color Chemistry, 8th edition, Springer-Verlag Vienna 1952, page 76 ff and H. Krauch -W Kunz, reactions of organic chemistry, 4th edition, 1969, Hüthig-Verlag Heidelberg, page 57, known that the preparation of amino compounds according to the Bechamp Reduk tion always takes place from the corresponding nitro compounds. However, the production of amines according to Bochamp, not starting from nitro compounds, is unknown. The possibilities of converting compounds with functional N groups without amine properties into amines by reduction or reducing media are sufficiently known from Houben-Weyl, Methods of Organic Chemistry, Volume XI / 1, page 341 et seq. These groups are divided into three classes (Table 43), with the 2nd and 3rd class being particularly sensitive to acid. The reduction, especially in the presence of acids, according to Houben-Weyl leads to non-uniform reaction products, sometimes even to secondary and tertiary amines, which are less desirable in such cases.

From Houben-Weyl, Volume XI / 1, page 398 ff. Furthermore, the relationships and conditions are known, which must be complied with in order to achieve optimal results in this technically so simple variant. Thus, the good mixing of the individual reactants and the etching of iron for a quantitative course is given great importance. It should be noted that the etching of iron can only be done separately; in a procedure in which all reactants are presented, at least the nitro compound, iron and the solvent or diluent and the acid is then added, an etching is practically impossible.

Furthermore, it is noted in the same work page 403 et seq., That in nitro compounds which have saponifiable groups, as small amounts of acid are added or even worked in the neutral range to exclude by-products. The reaction times are relatively short for simply built nitro compounds and the yields are almost quantitative. For more complex compounds, the time shifts to longer reaction times, the quality decreases due to prolonged exposure and the yields are lower.

Furthermore, the separation of the iron sludge from the reactant mixture often causes great difficulties. In the case of working in a higher aliphatic alcohol, but especially in isopropanol, it is possible to work according to the variant DD-PS 149858 (C 07 C 85/11). In this case, the addition of caustic soda, a large part of the iron or iron hydroxide is bound, but all the sludge is not separated. These iron components cause especially in the subsequent reaction steps adverse subsequent reactions. In particular, the formation of colored impurities often does not give quality-appropriate intermediates.

Object of the invention

The object of the invention is to find a technically simple variant in which isoxazole of the formula II according to Bochamp be converted into corresponding amino-benzophenones.

Explanation of the essence of the invention

The object of the invention is to convert 5-chloro-3-phenylbenz [c] isoxazole of the formula II into the 2-amino-5-chloro-benzophenones of the formula I by the Bechamp process. Above all, to prevent the formation of by-products and secondary products by the inventive method in a targeted reaction and a quantitative and qualitative improvement can be achieved.

According to the invention, the object is achieved by reacting a mixture consisting of 5-chloro-3-phenylbenz [c] isoxazole of the formula II, solvent or diluent, iron and an acid, a surfactant or a mixture of surfactants added.

Thus, the addition of surfactants to Bechamp reduction causes activation of the iron. This activation of the surface of the iron has a particularly advantageous effect on the etching process. An increase in yield, reaction time reduction and a more uniform reaction process are the consequences.

The formed iron sludge is then separated in a known manner by addition of sodium hydroxide solution at reductions in inert organic solvents or diluents, according to the invention in the presence of a surfactant or

several surfactants of the iron sludge is completely separated.

As surfactants are anionic <3 surfactants such as alkyl sulfonates, arylsulfonates, alkyl sulfates, aryl sulfates, arylalkyl sulfates, arylalkyl sulfonates, but also cationic surfactants such as quaternary ammonium salts having at least 12 carbon atoms and in the form of their chlorides or sulfates, but also nonionic surfactants, suitable as anionic surfactants are also soaps and alkylcarbonylamides.

According to the invention, the procedure is such that the reaction mixture, consisting of the compound to be reduced, water and / or an inert organic solvent, iron and an acid, a surfactant or a mixture of surfactants in amounts of 0.1 to 10 parts by mass in% added. The addition may be carried out before or after the acid addition. The acids used are advantageously inorganic acids, such as hydrochloric acid, sulfuric acid, methylsulfuric acid, phosphoric acid, or organic acids, such as acetic acid, formic acid, oxalic acid.

The acids are used in amounts of 5 to 50%, based on the stoichiometrically necessary amount of iron neutralization.

The reaction mixture is at the boiling point dr: s solvent or diluent for 1 to 15 hours, preferably 1 to 3 hours, boiled and then worked up. In the case of organic solvents or mixtures with water, the separation of iron or iron hydroxides by the addition of sodium hydroxide, the presence of the surfactant or more surfactants in unexpected manner allows complete separation of iron sludge.

Suitable inert organic solvents or diluents are particularly lower aliphatic alcohols having 1 to 8C atoms, lower aliphatic ketones having 3 to 10C atoms, aliphatic and aromatic hydrocarbons, chlorinated aliphatic and aromatic hydrocarbons or mixtures thereof.

The reductions thus made are faster and more uniform compared to the reductions without surfactant addition.

The formation of secondary and secondary products is avoided, oxidation reactions are largely suppressed.

The following embodiments serve to explain the present invention.

embodiments example 1

230 kg of 5-chloro-3-phenyl-beriz [c] isoxazole are introduced into 1,200 l of isopropanol. Thereto is added water and Rl 300I an ethoxylated nonylphenol with ethylene oxide 9MoI and stirred for 0.5 hours at 20 to 25 ⁰ C. To this end, then added 112kg of iron powder and at a temperature of 20 to 3O ⁰ C 115lkonz. Added hydrochloric acid. The feed should take place within 0.5 hour. Now the mixture is heated to the boiling point and the mixture is stirred under reflux for 3 hours.

Thereafter, to the reaction mixture 1801 conc. Sodium hydroxide solution at a temperature of 50 to 60 ⁰ C, wherein all iron sludge adhered and a clear organic phase formed.

It is decanted, again extracted with 5001 isopropanol. The combined organic phases are concentrated to 1200 l, admixed with 5 kg of activated charcoal and filtered at 50 to 60 ° C. The filtrate is cooled to 20 to 25 ° C., stirred for 1 hour and filtered with suction.

Yield: 208kg 2-amino-5-chloro-benzophenone £ 9O ⁰ C theory.

Analytical control:

TLC: eluent: CHCl ₃ , methanol, NH ₄ OH.

100% 2-amino-5-chloro-benzophenone, no by-products.

Mp .: 96-98 ⁰ C.

Example 2

The procedure is analogous to Example 1, but without the addition of 5I of a 9MoI ethylene oxide ethoxylated nonylphenol.

Yield: 191kg2-amino-5-chloro-benzophenone A 82.5% of theory.

Analytical control:

UV spectroscopy: 0.3% 2-hydroxylamino-5-chlorobenzophenone.

Fp.:9&-98°C.

Example 3

The procedure is analogous to Example 1, but with the addition of 3 kg of nonylbenzenesulfonate and 1 kg of hexadecylsulfonate.

Yield: 204kg ^ -Amino-5-chloro-benzophenone = 88% of theory.

Analytical control:

UV spectroscopy: 0.2% 2-hydroxylamino-5-chloro-benzophenoπ.

Mp .: 95-98 ⁰ C.

Example 4

The procedure is as in Example 1, but with BkgTetradecylammoniumchlorid.

Yield: 196kg 2-Amino-5-chloro-benzophenone A 84.5% of theory.

Analytical control:

UV spectroscopy: 0.1% 2-hydroxylamino-5-chloro-benzophenone.

Mp .: 95-98 ⁰ C.

Example 5

To 242 kg of 5-chloro-3-phenyl-benz | c) isoxazole 7801 dimethyl sulfate are added and slowly heated to 70 ⁰ C. Stirred at 7O ⁰ C for 3 hours, with all Aiisgangsprodukt goes into solution.

Then add 16801 methanol and stir well. Now one destroyed by the addition of 1001 water the unreacted dimethyl sulfate and cooled to 3O ⁰ C. 51 is added to a 9MoI ethylene oxide ethoxylated nonylphenol and 25kg of iron powder. It occurs immediately violent foaming and it is stirred for 1.5 hours at 50 ⁰ C. It is again cooled to 3O ⁰ C, added 175 kg of iron powder and boiled for 1 hour at reflux. Thereafter, about 500 liters of methanol are added, the mixture is stirred and the reaction mixture is allowed to sit for 0.5 hours. The iron sludge sinks to the bottom, the upper organic phase is separated.

The residual amount is filtered. The organic phase is mixed with about 3000 ^{1 of} water and stirred well, filtered off with suction and centrifuged.

Yield: 226 kg of 2-methylamino-5-chloro-benzophenone & 95% of theory.

Analytical control:

TLC: eluent: CHCl ₃ , methanol, NH ₄ OH. 100% 2-methylamino-5-chloro-benzophenone, not 2-amino-5-chloro-benzophenone.

Mp .: 93-96 ⁰ C.

Example 6

The procedure is analogous to Example 5, but without the addition of 5I of 9MoI ethylene oxide ethoxylated nonylphenol.

Yield: 192kg 2-Meihylamino-5-chloro-benzophenone ^ 80% of theory.

Analytical control:

TLC: 0.5% 2-amino-5-chloro-benzophenone.

M.p .: 93-97 ⁰ C.

Example 7

The procedure is analogous to Example 5, untar addition of 1 kg of tridodecylbenzylammonium sulfate and 3kg tridecylethylammonium chloride.

Yield: 207kg 2-methylamino-5-chloro-benzophenone = 86% of theory.

Analytical control:

UV spectroscopy: 0.2% 2-amino-5-chloro-benzophenone.

TLC: 0.2% 2-amino-5-chloro-benzophenone.

Mp: 93-97 ° C.

Example 8

The procedure is analogous to Example 5, but with the addition of 4 kg of octadecylsulfonate.

Yield: 202 kg 2-methylamino-5-chloro-benzophenone = 84.5% of theory.

Analytical control:

UV spectroscopy and TLC: 0.2% 2-amino-5-chloro-benzophenone.

M.p .: 93-97 ⁰ C.

KHR

II

Claims (6)

1. A process for the preparation of i-amino-B-chloro-benzophenone of the general formula!, Wherein R is hydrogen or a methyl radical, by reduction of 5-chloro-3-phenyl-benz [c] isoxazole of the formula II according to Bechamp by means of iron, acid and solvent or diluent and subsequent separation of the iron sludge by addition of sodium hydroxide, characterized in that one carries out the reduction and the work-up in the presence of one or more surfactants. 2. The method according to claim 1, characterized in that one adds the surfactants before or after the addition of acid. 3. Process according to claims 1 and 2, characterized in that one brings the surfactants in amounts of 0.1 to 10%, based on the solvent or diluent used. 4. Process according to claims 1 to 3, characterized in that one uses anionic surfactants, such as alkyl sulfates, aryl sulfates, arylalkyl sulfates, alkylsulfonates, arylsulfonates, arylalkylsulfonates, soaps or Alkylcarbonylamide. 5. Process according to claims 1 to 3, characterized in that cationic surfactants, for example quaternary ammonium compounds, with at least 12 C-Atc nen in the form of their chlorides or sulfates used. 6. Process according to claims 1 to 3, characterized in that nonionic Te.iside, such as ethoxylated alkylphenols, Fettalkohola, fatty amines or polyether alcohols, dinsetzt. For this 1 page formulas Field of application of the invention The invention relates to a process for the preparation of 2-amino-5-chloro-benzophenones of the general formula I in which R is hydrogen or a methyl radical by reduction of 5-chloro-3-phenylbenz [c] isoxazole of the formula II according to the Bochamp method. The compounds of the formula I are valuable intermediates for pharmaceuticals.