DE2262830A1 - Oximinoaceto-ortho-toluidide prepn - from orthotoluidine hydrochloride, chloral hydrate and hydroxylammonium sulphate in presence of sodium sulphate and ethanol - Google Patents

Abstract

Title cpd. useful as precursor for 7-Meisatin which is an intermediate in prepn. of indigo dyes and pharmaceuticals, e.g. (i) virucidal and virus-inhibiting isatin thiosemicarbazones, (ii) anti-malarial quinolines, (iii) isophthalic acid-based x-ray contrast agents, (iv) local anaesthetics, is prepd. by reacting o-toluidine. HCl (II) with choral hydrate (III) and H2NOH. H2SO4 (IV) in presence of anhydrous Na2SO4 and EtOH, using water as solvent, at 20-120 (70-100) degrees C. Pref. 1 mole (II), 1-1.3 moles (III), 2-4 moles (IV), 1.5-3 moles EtOH and 0.2-0.8 moles Na2SO4 are used.

Description

Process for the preparation of Oximinoacet-o-toluidide The present Invention relates to a new, improved method for producing the known Oximinoacet-o-toluidids, which, as a precursor of 7-Methylisatins'as an intermediate can be used for the synthesis of active pharmaceutical ingredients.

It has already become known that 7-methylisatin is also obtained if o-toluidine is condensed with oxalyl chloride to give tolyl oxamidZ acid chloride, with the aid of acid-binding agents, and this is cyclized with aluminum chloride to form 7-methylisatin (see formula scheme 1 and reports 46 (1913) page 3915 and German Relchspatent 514 594).

However, this method has several disadvantages. First of all, there is a Partial step from a Friedelkrafts reaction that is technically not easy to carry out is. In addition, the starting product oxalyl chloride is technically difficult to obtain. In addition, the two reaction steps in nitrobenzene as a solution or Diluent carried out, which recovered only with great expenditure on equipment and, if not recovered, causes wastewater problems.

It has also become known that oximinoacet-o-toluidide can be prepared by reacting o-toluidine with chloral and hydroxylammonium sulfate. This can then be cyclized with sulfuric acid to 7-methylisatin (cf. Annales de Chimie 1926 (10) 323! Archiv der Pharmazie 267/39, 578 (1929) Journal fUr Praxis Chemie 9 23 (1964) 301-308).

This process could not be carried out technically until now, because the oximinoacet-o-toluldide was always oily or resinous-sticky and the Yield was unsatisfactory (cf. Journal for practical chemistry [4] 23 (1964) 304 Line 9 and your own experiments).

It has been found that the known Oxiniinoacet-o-toluidid of the formula I. obtained when o-toluidine hydrochloride of the formula II with chloral hydrate of the formula III Cl3C-CH (OH) 2 (III) and hydroxylammonium sulfate, the formula IV H2NOH .- H2S04 (IV) in the presence of anhydrous sodium sulfate and ethyl alcohol using water as a solvent, at temperatures between approx. 20 and 1200C implements.

It can be described as extremely surprising that after the Reaction according to the invention, the oximinoacet-o-toluidide in crystalline form and can be obtained in such good yield because one in view of the state of the Technology had to expect that the substance would always be preserved in an oily and resinous state will.

It was not to be expected that the addition of sodium sulfate and Ethanol the disadvantages of the already known process are canceled and the bleaching according to the invention for the first time in eo purer, more crystalline Form is technically producible.

The method according to the invention has a number of advantages. The starting materials are easily accessible from a technical point of view and very inexpensive. As a solution and thinners are only inorganic chemicals like sulfuric acid and Water used, which can be removed without difficulty.

The process is technically easy to carry out. The end product falls in good yield and high purity.

The starting materials which can be used according to the invention are already known.

The inventive reaction is preferably in the presence of Water carried out as a solvent.

The reaction is carried out at temperatures between 20 and 120 ° C., preferably between 70-1000C.

The reaction can take place at normal pressure, but also at elevated pressure, be carried out. In general, normal pressure is used.

When carrying out the process according to the invention, one sets up 1 mole of o-toluidine hydrochloride about 1 to 1.3 moles of chloral hydrate, about 2 to 4 moles Hydroxylammonium sulfate, 1.5 to 3 moles of ethanol and 0.2 to 0.8 moles of sodium sulfate a.

The reaction solution is used to isolate the o-methylisonitrosoacetanilide cooled to 40 to 500C, inoculated if necessary and continued with vigorous stirring cooled down. The resulting precipitate is filtered off and dried. He is for further reactions of sufficiently high purity.

Oximinoacet-o-toluidide can then in the usual way (cf.

Archiv der Pharmazie 267/39, 578 (1929)) with sulfuric acid and ice water be converted to 7-methylisatin.

7-methylisatin is an important intermediate in the production of indigoid dyes and medicines. It is used e.g. for the production of isatin thiosemicarbazones, which are used as virucidal and virus static agents (compare British Patent specification 1 026 401), furthermore for the production of antimalarial quinolines (J.med. Chem.

11, 1968, 2, 273 - 77), of X-ray contrast media based on isophthalic acid (Journal for practical chemistry 4 (23), 1964, p. 301) and of local anesthetics such as 2- (Diethylaminoacetylamino) -3-methyl-benzoic acid methyl ester hydrochloride (compare German Auslegeschrift 1 018 0709 Example 3).

The method according to the invention should be based on the following example can be better explained.

example 16.2 kg (110 mol) of chloral are added to 230 l of water while stirring. The temperature should not rise above 30 ° C during the entire dissolving process.

Then 40 l of water are added to a second kettle weighing 10.1 kg = 8.6 1 (100 mol) of concentrated hydrochloric acid are added and then with stirring 10.8 kg (100 mol) of o-toluidine were added. The o-toluidine hydrochloride solution thus prepared is allowed to run into the chloral solution at room temperature.

A solution of 26.8 kg (320 mol) of hydroxylammonium sulfate is used for this purpose given in 80 l of water.

Finally, 2.5 liters of 90% ethanol are added and 75 kg of anhydrous sodium sulfate stirred in.

The reaction mixture is brought to an internal temperature of 70 ° C. while stirring vigorously brought. It is heated to 90 ° C. in the next few minutes. After that, the reaction solution held in the temperature range 92 to 95 0C for a further 10 minutes.

The dark red liquid obtained is stirred up with vigorous stirring Cooled 450C, inoculated with 40 g of oximinoacet-o-toluidide and cooled further.

After crystallization, the precipitate obtained is sharply suctioned off and dried. 17.8 kg (quantitative yield) of oximinoacet-o-toluidide are obtained from melting point 98-1000C.

Usage examples: 79 kg of 96% sulfuric acid are added to 4 kg of ice.

Then 17.8 kg (100 mol) of oximinoacet-o-toluidide are vigorously Stirring entered. The mixture is heated to 70 to 75 ° C. for 15 minutes.

After cooling, the reaction solution is crushed to 150 kg Given ice, the resulting precipitate filtered off and washed with water until neutral Reaction of the filtrate washed.

After drying, 12.5 kg (78, based on theory based on o-toluidine) 7-methylisatin with a melting point of 264-266 ° C. are obtained.

(Local anesthetic) 16.5 g (0.1 mol) of 2-amino-3-methylbenzoic acid methyl ester (produced from 7-methylisatin by oxidation with H 2 O 2 according to the method described in J. Am. Soc. , 1802 (1943) described method) are dissolved in 80 ml of glacial acetic acid and 12 g (0.1 Mol) chloroacetyl chloride added. After the reaction has ended, the reaction solution is stirred in 200 ml of an aqueous solution containing 20% anhydrous sodium acetate and receives, after suction and drying, 21.8 g (91- of theory) chloroacetic acid (2-carbomethoxy-6-methylanilide), which melts at 86 to 87.50C after dissolving from an ethyl acetate-ligroin mixture.

16 g (0.07 mol) of chloroacetic acid (2-carbomethoxy-6-methylanilide) become suspended in 100 ml of dry benzene. After adding 10 g (0.14 mol) of diethylamine the suspension is refluxed for 5 hours. After it has cooled down filtered off from the precipitated diethylamine hydrochloride. The benzene solution is extracted with about 2N hydrochloric acid and the base from the hydrochloric acid solution with Potassium carbonate precipitated.

The precipitate is taken up in ether, dried over potassium carbonate, and, after the solvent has been distilled off, distilled in vacuo. You get 12 g (62, of theory) diethylaminoacetic acid (2-carbomethoxy-6-methylanilide) from Kp5 190 - 1920C. M.p. (of the hydrochloride 139-140.5; 0).

Claims (2)

Patent claims: 1) Process for the preparation of oximinoacet-o-toluidide of the formula characterized in that o-toluidine hydrochloride of the formula II with chloral hydrate of the formula III Cl3C-CH (OH) 2 (III) and hydroxylammonium sulfate of the formula IV, H2NOH * H2S04 (IV) in the presence of anhydrous sodium sulfate and ethyl alcohol using water as a solvent, at temperatures between approx. 20 and 120 ° C implements. 2) Process for the preparation of Oximinoacet-o-toluidid according to Formula I in claim 1, characterized in that the reaction is carried out at temperatures between 70 and 1000C.