JPS6045192B2 - Method for producing 4-amino-morpholine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION 4-Aminomorpholine is used as a raw material for the production of organic compounds, especially pharmaceuticals.

The process for the preparation of 4-aminomorpholine known in the literature has significant drawbacks for various reasons, so that the conversion of this known process to the production scale is expensive and requires high industrial outlays. It's inappropriate.

There Knorr and Brownsdon” (Br.
ownsdon) is Chemische Berich
te3ゝ4474 has published a method for producing 4-aminomorpholine by reducing 4-nitrosomorpholine using zinc dust and acetic acid.

Since it has been demonstrated in animal experiments that 4-nitrosomorpholine is one of the carcinogens (carcinogens) that acts extremely rapidly on the liver, 4-aminomorpholine can be produced with a yield of B%. There are problems with the industrial implementation of this process to produce olins [Zeitschrift fj
ir Krebsforschun (company) Fox 103-
201 (1967)].

Another method for producing 4-aminomorpholine is to react chloramine and morpholine in the form of an aqueous solution.

Due to the easy decomposition nature of calchloramine, the yields in this process can only be reproduced if the targeted reaction conditions are strictly adhered to. Journal of Organ
ic Chemistry 24, 1785, (1959
) of R. H. Wiley. sH. K. White and G
．． The conditions described as optimal by Irick, i.e., reaction of a freshly prepared chloramine solution from ammonia and hypochlorite with morpholine of equal molecular weight within 5 minutes, require significant equipment costs. Therefore, it cannot be used on an industrial scale. According to a further known method (DE 1172679), β.
The reaction of β''-dichlorodiethyl ether with hydrazine gives 4-aminomorpholin in a yield of 60-70%.

Strong mucosal irritation effect of β●β5-dichlorodiethyl ether (K.B. Lehmann and F. FlurylTO
xikOlOgieundHygienedertec
hnischenL6sungsmittel/Ber
linl938/P. This process, apart from hydrazine, also has the disadvantage that it can only be carried out in the presence of an excess of hydrazine. Complete separation of excess hydrazine from the reaction product can only be achieved by additional time-consuming and costly purification operations. The object of the present invention is an economical, safe, and industrially easy to implement method for producing 4-aminomorpholine, and its gist is that morpholine-4-carbonamide is mixed with alkali hypochlorite in the form of an aqueous solution, The purpose is to react in the presence of an alkali hydroxide according to the following reaction formula: The reaction between a 6-membered heterocyclic compound and an alkali hypochlorite occurs in a few cases (however, in this case, the carbonamide group is is well known in the pyridine- and quinoline series (bonded to the nuclear carbon atom of
．． ■, P. 279).

In this case, insofar as yields are generally stated, they are generally only low or, in the case of reasonable yields, due to specific substitutions. The well-known reports regarding heterocyclic acid amides do not permit any inference regarding the reaction course and yield in the reaction of the present invention.

The same can be said of the known method of reacting monosubstituted urea with alkali hypochlorite (see US Pat. No. 2,917,545). The stated yield for the final product which can be isolated in this case is only 33%. Therefore, morpholine-4-carbonamide can be reacted with 4-carbonamide in an industrially easily carried out reaction with excellent yield and high purity.
It is amazing what can be done with aminomorpholine. To carry out the reaction according to the invention, an aqueous solution of morpholine-4-carbonamide is cooled to 0 to 10°C and then 2 to 4 mol, in particular 3
After adding mol of alkali hydroxide, it is advantageous to add 1 to 1.5 mol, in particular 1.3 mol, of an alkali hypochlorite solution cooled to 0 to 10 DEG C.

After adding the alkaline hypochlorite solution, the reaction temperature rises to 20-50°C, depending on external cooling.

Considering the yield and purity of 4-aminomorpholine, 2
A reaction temperature of 0 to 25°C has been found to be particularly advantageous.

If appropriate, this temperature should be regulated by heat supply or heat rejection. Generally, it must be cooled. Potassium hypochlorite is commonly used as the alkali hypochlorite, but especially from a cost perspective, sodium hypochlorite is used, which is a commercially available hypochlorite containing 11-15% available chlorine. It can be used directly in the form of an aqueous sodium chlorate bleach solution.

Potassium hydroxide, but especially sodium hydroxide, is usually used as alkali hydroxide. The ratio of alkali hydroxide to morpholine-4-carboxylic amide is 2:1 to 4.
:1, preferably 3:1. The molar ratio of alkali hypochlorite to morpholine-4-carbonamide should also be between 1.5:1 and 1:1, especially 1.3:1. The reaction is generally complete after 30-4 C@. The produced 4-aminomorpholine can be extracted directly from the alkaline aqueous reaction solution using a water-immiscible solvent, such as ethyl acetate or ethyl or toluene, in a well-known manner, or
Alternatively, benzaldehyde is added to the reaction solution to precipitate a crystalline benzylidene compound, from which 4-aminomorpholine can be isolated by a well-known method. Morpholine-4-carbonamide required as a raw material is
It can be produced in a quantitative yield by reacting morpholine hydrochloride and alkali cyanate in an aqueous solution at room temperature using a well-known method.

The aqueous solution of morpholine-4-carbonamide that can be easily produced by this method can be directly reacted with alkali hypochlorite according to the present invention to form 4-aminomorpholine without being subjected to any purification or isolation treatment. be able to. The two reaction steps mentioned above can advantageously be carried out successively in one reaction vessel. Starting from morpholine, 4-aminomorpholine is thus obtained in a yield of over 84%. Example 1 Morpholine-4-carbonamide 130y (1 mol)
After dissolving in 400mt of water and cooling to 0-5℃, add 400mt of water.
Mix with a solution cooled to 0-5° C. containing 160 g (4 mol) of sodium hydroxide in 0.00 ml.

Subsequently, 880 ml (1.3 mol) of a cooled sodium hypochlorite solution containing 11y of available chlorine per 100 ml is rapidly added dropwise. At this time, the reaction solution is cooled so that the reaction temperature does not exceed 25°C. After thoroughly stirring the mixture, glacial acetic acid is added to adjust the reaction solution to pH 6.

Subsequently, benzaldehyde 106y (1 mol) was added,
Stir well for about 9 minutes until crystals of the benzylidene compound precipitate. The crystalline precipitated benzylidene compound was suctioned off, washed with water and then treated with 150 ml of concentrated hydrochloric acid and 15 ml of concentrated hydrochloric acid.
Dissolve in a mixture with 0 mt water. This solution is subjected to steam distillation until no more benzaldehyde distills out. The reaction solution is then evaporated to dryness under vacuum. 4-Aminomorpholine hydrochloride 115y (83.1% of theory) having a melting point of 169 DEG -170 DEG C. is thus obtained. Example 2 Morpholine 78y (1 mol) is dissolved in 150 ml of water, to which 100 ml of 10N monohydrochloric acid is added.

89y (1.1 mol) in 180 ml of water after cooling to 15
of potassium cyanate is added.

The reaction temperature rises to 30-40°C. After stirring well for u hours at room temperature (approximately 20°C) without cooling, the mixture was cooled to 0°C. A solution containing 120y (3 mol) of sodium hydroxide in 300 ml of water, cooled to 0-5°C, is then added.
Subsequently, 880 ml (1.3 mol) of a sodium hypochlorite solution cooled to 0° C. containing 11 f of active chlorine per 100 ml is added dropwise. At this time, the reaction solution is cooled so that the reaction temperature does not exceed 25°C. Stir well at room temperature for about 4 minutes. It is then worked up as described in Example 1 after addition of glacial acetic acid until pH 6 is reached. Yield: melting point 169-1700
4-Aminomorpholine-hydrochloride of C 113V (71.7% of theory).

Claims (1)

[Scope of Claims] 1. A method for producing 4-amino-morpholin, which comprises reacting morpholin-4-carbonamide and alkali hypochlorite in an aqueous solution in the presence of alkali hydroxide. 2. Mix the aqueous solutions of the reaction components cooled to 0-10°C. A method according to claim 1. 3. The method according to claim 1 or 2, which is carried out at a temperature of 20 to 25°C after the reaction after mixing the reaction components. 4. The method according to any one of claims 1 to 3, wherein the molar ratio of alkali hydroxide to morpholine-4-carbonamide is 2:1 to 4:1. 5. The method according to any one of claims 1 to 4, wherein the molar ratio of alkali hydroxide to morpholine-4-carbonamide is 3:1. 6. The method according to any one of claims 1 to 5, wherein the molar ratio of alkali hypochlorite to morpholine-4-carbonamide is 1.5:1 to 1:1. 7. The method according to any one of claims 1 to 6, wherein the molar ratio of alkali hypochlorite to morpholine-4-carbonamide is 1.3:1.