DD244980A1 - PROCESS FOR PREPARING N-MORPHOLINOAMINOACETONITRILE AND ITS HYDROCHLORIDE - Google Patents

Abstract

Starting from simple starting materials, a synthesis of N-morpholinoaminoacetonitrile is described, which proceeds while avoiding the emergence and handling of carcinogenic intermediates. According to the invention, morpholine is reacted with 3,3-pentamethyleneoxyziridine and subsequently subjected to cyanomethylation. To obtain the intermediate product is extracted with an organic solvent, the hydrochloride is obtained after addition of a suitable hydrochloric acid solution. The compounds obtained are useful as intermediates for the preparation of PSM, dyes and pharmaceuticals.

Description

Field of the Invention _'s

The invention relates to a process for the preparation of N-morpholinoaminoacetonitrile and its hydrochloride, which are useful as intermediates for the preparation of PSM, dyes and pharmaceuticals.

Characteristic of the known technical solutions

The preparation of N-morpholinoaminoacetonitrile takes place starting from aqueous aminomorpholine solutions or hydrochloride obtained therefrom according to variants of cyanomethylation (K.Masuda et al., Chem. Pharm. Bull. 18 [1970], 128), d. H. Reaction of an amine with formaldehyde or its bisulfite adduct and cyanide, a synthetic principle that has been practiced for 80 years without significant changes (E.Knoevenagel, B. 37 [1904], 4082).

An alternative, economically competitive method for obtaining the N-aminomorpholine needed here as the nitrosation of morpholine and the subsequent reduction of N-nitrosomorpholine has not been previously known. The occurrence of N-nitrosomorpholine is thus far unavoidable. Further disadvantages resulting from the known technical solutions are:

- From morpholine to N-aminomorpholine two reaction steps are required, in the first the known carcinogenic N-nitrosomorpholine is undergone and the second is technically very complicated (isolation of the intermediates N-nitroso and N-aminomorpholine).

- The insufficient purity and the air sensitivity of the isolated intermediate N-aminomorpholine require further purification operations or entail such at the stage of N-Morpholinoaminoacetonitrils, z. B. vacuum distillation (see information in K. Masuda, supra, where no example, a distillation of the nitrile was avoided).

- The disadvantages mentioned are both in the exposure to exposure in the synthesis and in avoiding the emission in the biosphere.

The fact that the stage of development of N-aminomorpholine syntheses is unsatisfactory to this day is also clear from the fact that a further method for the reduction of N-nitrosomorpholine has recently been described (G. Lunn et al., J. Org. Chem. 49, 3470 [1984] ), which works with titanium trichloride and also has the disadvantages described above.

In addition to other possibilities that are not relevant here, there is an indication in the literature for N-amination of morpholine with 3,3-pentamethyleneoxaziridine (E. Schmitz et al., J.prakt. Chem. 319 [1977], 195). Thus, it was found that the formation of an N-N bond occurs, for which the isolation of the benzaldehyde derivative of N-aminomorpholine sufficed as proof:

CX

NH

1-I = CH-Ph 0

O,

2. 2N H ₃ SO ₄ scrap. 85 G ₃ .

89 % output

3. PhCHO / HaOAc

Object of the invention

It is an object of the invention, while avoiding technological disadvantages of the known processes to develop a new, rational one-pot process for the preparation of N-Morpholinoaminoacetonitrile or their hydrochlorides, starting from simple starting materials, in particular the formation and handling of the known high-carcinogenic intermediates N-nitrosomorpholine and N-aminomorpholine should be avoided.

Explanation of the essence of the invention

The object of the invention is achieved by a process for the preparation of N-morpholinoaminoacetonitrile and its hydrochloride, according to the invention 1 mole of morpholine in a 1 to 2 moles of 3,3-pentamethyleneoxyziridine-containing solution, preferably in toluene, at temperatures from 0 to 11O ⁰ C. is reacted and an acidic extract of this mixture, which is preferably obtained with an excess of dilute mineral acid, is subjected to the conditions of Cyanmethylierung, ie neutralization with a base, preferably with an aqueous alkali metal hydroxide solution, addition of alkali metal bisulfite, z. B. in the form of 1 to 2 moles of sodium bisulfite solution or 0.5 to 1 mol of sodium disulfite, 1 to 2 moles of formaldehyde, z. B. as a 30-40% aqueous solution, and 1 to 2 moles of a Alkalicyanide, optionally as an aqueous solution, whereupon the isolation of the N-morpholinoacetonitrile by extraction with an organic solvent and its removal takes place or subsequently to obtain the hydrochloride with a suitable hydrochloric acid solution, eg. As HCl in isopropanol, is treated. Optionally, the intermediate mineral acid extract, when recovered with hydrochloric acid, may be concentrated in vacuo prior to further processing or evaporated to dryness and the residue consisting of N-aminomorpholine hydrochloride recrystallized.

The cyanomethylation of the resulting N-aminomorpholine hydrochloride is preferably carried out with stoichiometric amounts of the reagents, based on morpholine or N-aminomorpholine hydrochloride.

The obtained by the novel N-Morpholinoaminoacetonitrile or its hydrochloride is so pure that it can be used directly for further reactions.

Embodiments ·

example 1

To a solution of 1 mol of 3,3-pentamethyloxaziridine in 2600 ml of toluene, 1 mol of morpholine are added at room temperature with stirring. The reaction temperature rises to about 20 ^c C. The mixture is stirred for 20 minutes and then to extract the formed N-Aminomorpholins 560ml 2n hydrochloric acid. After 15 minutes, stop stirring. The hydrochloric acid solution of N-aminomorpholine precipitates as the lower phase. The supernatant Toiuenphase is separated, the aqueous phase remains in the vessel.

By addition of equivalent amount of 10N NaOH, the pH of the aqueous phase is adjusted to pH 9. 95 g of Na ₂ S ₂ O ₅ and 1 mol of formaldehyde are added as a 40% strength aqueous solution with stirring.

After prolonged stirring, 1 mol of KCN is added and the batch is further stirred at 45 to 65 ° C for several hours. After cooling to room temperature precipitated inorganic substances are filtered off and the clear solution extracted 7 times with 60 ml of ethyl acetate. The extract contains the morpholinoaminoacetonitrile formed in the reaction. The mass of the residue after distilling off the ethyl acetate is 112 to 115g. The residue is dissolved in 250 ml of isopropanol and converted into the hydrochloride by addition of isopropanol / HCl.

After aspirating, washing with isopropanol and ether to obtain 83 g Morpholinoaminoacetonitrilhydrochlorid having a melting point of 17-8 to 181 ⁰ C, corresponding to a yield of 47%, calculated on the morpholine used.

Example 2

Reaction of morpholine with 3,3-pentamethyloxaziridine according to Example 1. The hydrochloric acid extract of N-aminomorpholine is concentrated in vacuo until crystallization. The crystalline residue is pasted in with 300 ml of isopropanol. After cooling, the salt is filtered off with suction, washed with isopropanol and ether and dried. This gives 93 g of N-aminomorpholine hydrochloride, corresponding to a yield of 67%, calculated on the morpholine used.

Example 3

The procedure is as in Example 1. Instead of the hydrochloric acid solution of N-aminomorpholine, the hydrochloride isolated in Example 2, dissolved in 80.5 ml of water used. With 10N sodium hydroxide solution, a pH of 9 is set. By adding Na ₂ S ₂ O ₅ , formaldehyde and KCN, the N-aminoacetonitrile hydrochloride is obtained in the form described in Example 1. Yield 70% = 83 g with a melting point of 178 to 181 "C.

Claims (6)

Invention claim: A process for the preparation of N-morpholinoaminoacetonitrile and its hydrochloride, characterized in that 1 mole of morpholine is reacted in a solution containing 1 to 2 moles of 3,3-pentamethylene oxaziridine, preferably in toluene, at temperatures of 0 to 110 ° C and an acidic one Extract of this mixture, preferably obtained with an excess of dilute mineral acid, subjected to cyanomethylation conditions, ie neutralization with a base, Preferably with an aqueous alkali hydroxide solution, addition of alkali bisulfite, eg. B. in the form of 1 to 2 moles of sodium bisulfite solution or 0.5 to 1 mol of sodium disulfite, 1 to 2 moles of formaldehyde, z. B. as 30-40% aqueous solution, and 1 to 2 moles of an alkali metal cyanides, optionally as an aqueous solution, whereupon the isolation of N-morpholino acetonitrile by extraction with an organic solvent and its removal takes place or subsequently to obtain the hydrochloride with a suitable hydrochloric acid solution, eg. As HCl in isopropanol, is treated. 2. The method according to item 1, characterized in that the reaction of morpholine with 3,3-Pentamethylenoxaziridin in toluene in the temperature range of 10 to 6O ⁰ C is performed. 3. The method according to item 1 and 2, characterized in that the toluene solution is extracted with dilute hydrochloric acid. 4. The method according to item 1 to 3, characterized in that before the cyanomethylation from the hydrochloric acid extract, the solvent is removed, wherein the residue consists of N-aminomorpholine hydrochloride. 5. The method according to item 1 to 4, characterized in that are used for Cyanmethylierung sodium bisulfite, formaldehyde and potassium cyanide. 6. The method according to item 1 to 5, characterized in that per mole of N-aminomorpholine hydrochloride 0.5 mole of sodium bisulfite, 1 mole of aqueous formaldehyde solution and 1 mole of potassium cyanide are used.