DE976747C - Process for the preparation of substituted morpholines - Google Patents

Description

Process for the preparation of substituted morpholines The present The invention relates to a process for the preparation of substituted morpholines.

In the processes known for this purpose, substituted diethanolamines were used z. B. treated with 700 / above sulfuric acid; it had to go to temperatures of 160 can be heated to 1800 C in order to achieve the desired ring closure. In the preparation of of substituted morpholines, however, it is necessary to use particularly mild reaction conditions to find for the ring closure. Namely, there is a risk of undesirable occurrence Side reactions caused by the influence of temperature or that used for ring closure Acids can be caused.

In the German patent specification 843 4I2 a case is described, wherein when a solution of a salt of I- (3,4-dioxyphenyl) -I-oxy-2-ethanolamino-ethane is left to stand ring closure already occurs.

Such a slight ring closure is only possible in very specific individual cases limited, while otherwise more energetic conditions are generally necessary. Therefore, tests were carried out with those in the cold, but instead concentrated acids were used. However, these attempts failed because that undesirable side reactions occurred. So z. B. Diethanolamines, the substituted phenyl radicals (tolyl, anisyl, etc.) or the benzyl radical contained by concentrated acids converted into other undesirable by-products or into dark resins.

Oxyalkyl-substituted morpholines are also not in this way manufacturable.

It has now surprisingly been found that a group of substituted diethanolamines of the general formula where R1 is a phenyl radical, R2 and R3 is a hydrogen atom or a phenyl or alkyl radical and R4 is a hydrogen atom or a phenyl radical, can be subjected to the morpholine ring closure under particularly mild conditions and without troublesome side reactions.

According to the invention, substituted morpholines of the general formula are accordingly obtained by adding substituted diethanolamines of the general formula enters concentrated (96%) sulfuric acid and carries out the reaction without additional heating. In the last two formulas mentioned, 1 to R4 have the meanings given above.

If the free base is used as the starting material, it works because of the heat of neutralization under good cooling. But you can also from one Run out of the base salt, which can be converted into concentrated sulfuric acid without special cooling enters. After a few hours of standing, the desired morpholine derivative has been obtained formed, and you can work up in the usual way, for. B. by pouring on ice, Makes alkaline and ethers out, and morpholine by crystallization or distillation cleans.

The morpholines produced according to the invention are valuable pharmaceuticals, d. H. Weight-loss drugs and antidepressants or intermediates for manufacture of pharmaceuticals.

The following examples are intended to explain the invention in more detail.

Example I 2-phenylmorpholine 10 g of B-phenyl -, B, / - dioxy diethylamine hydrochloride are dissolved in 15 ccm concentrated sulfuric acid and overnight left to stand at room temperature. Then it is poured onto ice with sodium hydroxide solution made alkaline and the base taken up in ether. After drying, the Ether residue fractionally distilled. The 2-phenylmorpholine goes at 1450 C and 14mm across. Yield: 83O / o The chlorohydrate is with alcoholic hydrochloric acid and Acetone obtained, m.p. = 15I ° C.

Example 2 2-Phenyl-3-methylmorpholine According to the procedure of the Example I is obtained, starting from ß-phenyl-a-methyl-ß, ß'-dioxydiethylamine hydrochloride, 2-phenyl-3-methylmorpholine in 2% yield. The base is a liquid Kr.12 = 1380 C. The chlorine hydrate crystallizes from alcoholic hydrochloric acid and acetone, F. = I820C.

Example 3 2,3-Diphenyl-morpholine 10 g of α, β-diphenyl-β, β'-dioxy-diethylamine hydrochloride are dissolved in 15 cc of concentrated sulfuric acid and overnight at room temperature ditched. The viscous solution is poured onto ice and concentrated with Ammonia made alkaline, with the 2,3-diphenylmorpholine separating out in crystalline form, F. = 910 C. The further purification takes place via the chlorohydrate, which is produced during the addition crystallized with alcoholic hydrochloric acid and acetone. M.p. = 2650 C, yield: 67 e / o.

Example 4 2,6-Diphenyl-morpholine 10 g of ß, ß'-Diphenyl-ß, ß'-dioxy-diethylamine hydrochloride it is left dissolved in 15 cc of concentrated sulfuric acid overnight at room temperature stand. After pouring on ice, it is made alkaline with ammonia. The base falls as a tough, sticky mass that is absorbed in chloroform. The chloroform residue gives, rubbed with ether, the crystalline base of F. = Io80 C. The hydrochloride is obtained with alcoholic hydrochloric acid and acetone. F. = about 2000 C (dec.). Yield: 65o.

Claims (2)

PATENT CLAIMS: I. Process for the preparation of substituted morpholines of the general formula where R1 is a phenyl radical, R2 and R3 are a hydrogen atom or a phenyl radical or alkyl radical and R4 is a hydrogen atom or a phenyl radical, characterized in that substituted diethanolamines of the general formula in which R 1 to R 4 have the meaning given above, or salts of these diethanolamines in concentrated sulfuric acid are introduced, the reaction is carried out without additional heating and, when the free diethanolamine base is used, works with cooling. 2. The method according to claim I, characterized in that at Use of a salt of substituted diethanolamine as a starting material Room temperature works. Documents considered: German Patent No. 843 4I2; Theilheimer, Synthetic Methods of organic chemistry, Vol. 6, Section 345, 5. I28 / I29; Journal of the American Chemical Society, Vol. 73 (195I), pp. 4030 / 403I; Chemisches Zentralblatt, I952, I, p. 37I / 372.