CS217196B1 - Method of making the substituted omega-aminoacetophenons and the salts thereof - Google Patents

Description

The invention relates to a process for the preparation of substituted ω-aminoacetophenones and their salts of the general formula I

COCH ₂ NH ₂ Ac (I) wherein the substituent X at any position on the aromatic ring denotes hydrogen, bromine or nitro; and Ac is a strong inorganic acid such as hydrochloric, hydrobromic, sulfuric or phosphoric. These compounds are important intermediates in the manufacture of various drugs, particularly the antibiotic chloramphenicol and analogues thereof.

Substituted ω-aminoacetophenones of formula I can be obtained by various routes. One possible process for the preparation of these aminoketones is to form a correspondingly substituted aeetofenone of formula II

XVcoch ₃ (II) (X denotes the same as in formula I) acts with a bromine or chlorine equivalent to give the ω-haloacetophenone of formula III

XVcOCHgHal (III) (X is the same as in Formula I and Hal is a chlorine or bromine atom). This crystallized ω-haloacetophenone is reacted in an inert inert solvent with hexamethylenetetramine equivalent to give the corresponding salt of formula IV

B — Λ © ©

X-4-yCOCH ₂ / (CH ₂ ) ₆ N ₄ / Hal (IV) (X and Hal denote the same as in formula III), which is insoluble in the medium used and isolated by filtration. The hexamethylenetetramine salt is then decomposed with a strong inorganic acid such as hydrochloric acid in admixture with a lower alkanol to form the ω-eminoacetophenone of formula (I), respectively. a salt thereof with an inorganic acid used.

In all of the processes described and used so far (Uannich se sp .: Bar.

44, 1542 (1911) and Jacobs et al., J. Biol. Chem. 21, 455, 1915, Long et al., J. Am. Ctaem.

Soo. Ji, 2,473, 1949; Olinda et al., Ann. fac. farm. 561 (1954) Chem. abstr. 51, 3,496,

1957; US Pat. No. 2,515,241, 2,546,762, 2,798,871; French Pat. file number, 013 275; Nagawe sp .: Tak. Ken. Nempo 8, 22, 1956, Chem. Abstr. 52, 308 (1958) is generally carried out by isolating the haloketone of formula III in a crystalline state and the hexamethylene salt of formula IV prepared therefrom. Only this salt is converted into the desired substituted ω-aminoacetophenone of the formula I in a separate reaction step.

This process has a number of disadvantages in terms of large-scale production, especially these! two laborious filtration of crystalline intermediates, use of a new solvent in the preparation of the hexamethylenetetramine salt of formula IV, unpleasant handling of the haloketone of formula III (highly irritating and tear-forming agents), complex manufacturing equipment and considerable labor and time requirements.

These disadvantages are overcome by the process for the preparation of substituted ω-aminoacetophenones and their salts of the general formula I

Wherein the substituent at any position on the aromatic ring represents hydrogen, bromo or nitro and Ac is a strong inorganic acid such as hydrochloric, hydrobromic, sulfuric or phosphoric by reaction of an appropriately substituted acetophenone of formula II

X-COCH 3 (II) wherein X denotes the same as in formula I, with bromine or chlorine, in an inert organic solvent medium, by converting the resulting halooetophenone of general formula III

X -? - COCH ₂ Hal (III) wherein X is the same as in Formula I and Hal is a chlorine or bromine atom, by reaction with hexamethylenetetramine to the corresponding salt of formula IV © Θ

C0CH ₂ / (CH _{2) 4} GN / Hal (IV), and decomposition of the salt of a strong mineral acid, especially hydrochloric acid, in a mixture with a lower alkanol in the ω-aminoecetofenon of formula I resp. a salt thereof, according to the present invention.

The essence of this process is to carry out all the reaction steps in one sequence, in a single reaction vessel and in a single solvent environment, without isolating the individual intermediates.

In the process of the invention, the appropriately substituted acetophenone of formula (II) is chlorinated or brominated using urea as the initiator of the reaction in an inert water-immiscible organic solvent such as chloroform, gasoline, benzene, carbon tetrachloride, cyclohexane, dichloroethane and the like. From the solution of the resulting haloacetophenone of formula III, excess hydrogen halide is removed by a stream of air, stripping off under reduced pressure, brief heating or washing with water. If desired, the reaction medium is dried with an inert drying agent, e.g., anhydrous sodium sulfate or calcium chloride. Without removing the desiccant, a 10% excess of equivalent amount of hexamethylenetetramine is added to the helogenacetophenone III solution and the reaction is allowed to proceed at 20 to 40 ° C for 1 to 3 hours with stirring. The hexamethylenetetramine salt of the formula IV is eliminated and is not isolated at all, but is immediately converted into the substituted ω-aminoacetophenone of the formula I and II, respectively. a salt thereof, by adding to the slurry a continuous aqueous solution of a strong inorganic acid, preferably hydrochloric acid, in admixture with a water-miscible lower alkanol, in particular methanol or ethanol, while stirring continuously. The reaction mixture is stirred for 2-4 hours, cooled to 0 ° C and the precipitated ω-aminoacetophenone salt of formula I is collected by filtration.

The technical advantages of the method according to the invention are considerable, not only in terms of saving equipment and material, but also labor and labor. Two laborious filtration (helogenacetophenone of formula III and its hexamethylenetetramine salts of formula IV) is eliminated, which saves equipment, labor, time and material (washing solvents), there is no manipulation with these intermediates, especially haloacetophenone of formula III is highly irritating even in its crystalline state it contaminates its surroundings and against which the protection of workers is very difficult.

The whole process described can be carried out continuously in a single sequence, in a single reaction vessel (apparatus), which allows easy inspection in individual steps and simple execution. As two insulations are eliminated, the possibility of losses is reduced and the yields are considerably higher.

On the whole, the process according to the invention represents a significant technological improvement, characterized by a higher technical effect compared to the prior art.

Examples

1. Dissolve 31 g of o-chloroacetophenone in 200 ml of dichloroethane-gasoline (1: 1) and bromine is brominated at 20 ° C over 1 hour. The reaction mixture is stirred for an additional 1 hour and then shaken 3 times with 300 ml of cold water. The aqueous layer was separated, 5 g of anhydrous sodium sulfate was added to the organic layer, and after 10 minutes 30 g of hexamethylenetetramine. The reaction mixture was stirred at 30 ° C for 2 hours. After this time, a mixture of 150 ml of ethanol and 75 ml of 35% hydrobromic acid was added at the same temperature, stirred for 4 hours, cooled to 0 ° C and the precipitated o-chloroaminoacetophenone hydrobromide was filtered off with suction and washed with ice water. Yield 28 g, i.e. 70%.

2. 6.3 kg of p-nitroacetophenone are dissolved in 25 l of benzene and 6.0 kg of bromine are brominated at 30 ° C over 1 hour. After completion of the bromination, stirring was continued for 1 hour. 60 L of benzene was added to the reaction mixture and the solution was stirred three times with 25 L of water each. After complete separation of water, 1 kg of anhydrous sodium sulfate was added to the benzene solution, stirred for 5 minutes, and then 4.75 kg of hexamethylenetetramine was added at 25 ° C. Allow to react at the same temperature for 3 hours. A mixture of 13 L hydrochloric acid and 27 L methanol was then poured into the thick reaction mixture at 25 ° C with stirring. Stirring is continued for 3 hours, cooled to 0 ° C and the precipitated p-nitro-ω-eminoacetophenone hydrochloride is filtered off with suction. Yield 6.1 kg, i.e. 75%.

3. Dissolve 165 g of p-nitroacetophenone in 1.2 l of benzene and dissolve 71 g of dry chlorine gas at 25 ° C. The benzene solution was washed twice with 400 ml of water, then 20 g of anhydrous calcium chloride was added and after 10 minutes with stirring.

150 g of hexamethylenetetramine. Stir at 40 ° C for 4 hours. To the dense reaction mixture was added all at once, 50 mL of 30% sulfuric acid and 500 mL of isopropanol, then stirred for 3 hours, cooled to 0 ° C and the precipitated p-nitro-m-aminoacetophenone sulfate was filtered off with suction, washed with ice water and dried. Yield 150-170 g, i.e. 75-80%.

4. 180 g of p-bromoacetophenone are dissolved in 1.3 l of chloroformcyclohexane (2: 1) and 160 g of bromine are added with stirring at 20 ° C over 1 hour. Stir for 1 hour at the same temperature. After heating to 30-40 ° C, excess hydrogen bromide was blown off with a stream of air under slightly reduced pressure and 150 g of hexemethylenetetramine were added at 30 ° C, stirred for 2.5 hours, then a mixture of 500 ml of ethanol and 250 ml was added all at once. 35% phosphoric acid. It is stirred for 4 hours at 20-30 ° C, cooled to 0-4 ° C and the precipitated p-bromo-m-aminoacetophenone phosphate is filtered off with suction and washed with ice water. The yield of dry product is 250 to 270 g, i.e. about 80%.

Claims (1)

A process for the preparation of substituted N-aminoacetophenones and their salts of the general formula I X - (-) - COCH ₂ NH ₂ Ac (I). wherein X at any position on the aromatic ring denotes hydrogen, bromo or nitro and Ac is a strong inorganic acid such as hydrochloric, hydrobromic, sulfuric or phosphoric by reaction of an appropriately substituted acetophenone of formula II X - (-) - COCH ·, (II) wherein X denotes the same as in formula I, with bromine or chlorine in an inert organic solvent, by converting the resulting haloacetophenone of formula III X - (γ-COCH ₂ Hal (III)) wherein X denotes the same as in formula (I) and Hal is a chlorine or bromine atom, by reaction with hexamethylenetetramine to the corresponding salt of formula (IV) X - ^ - ^ - C0CH ₂ / (CH _{p) g} N ^ / Hal (IV), and decomposition of the salt of a strong mineral acid, especially hydrochloric acid, in a mixture with a lower alkanol having 1 to 4 carbon atoms, especially methanol or ethanol; in the ω-aminoacetophenone of the general formula I; a salt thereof, characterized in that all the reaction steps are carried out in a single sequence, in a single reaction vessel and in a single solvent medium, without isolation of the individual intermediates.