DD276285A1 - PROCESS FOR PREPARING 5- (4-NITRO-PHENYL) -OXAZOLIDINO- [3,4-C] -OXAZOLIDINE - Google Patents

Abstract

The invention relates to a process for the synthesis of 5- (4-nitrophenyl) oxazolidino- & 3,4-c! -Oxazolidine (I) by reacting 1- (4-nitrophenyl) -2-amino-propane 1,3-diol (II) with formaldehyde. Compared with the known processes in which the resulting water must be azeotropically driven off with entraining agents and which lead to an impure product, in the process according to the invention, after partial conversion of II to the hydrochloride in the weakly alkaline medium under the influence of a weak base as catalyst in aqueous suspension at a maximum temperature of 30C, a very pure product recovered in high yield. II is obtained as a by-product of the chloramphenicol synthesis and, after its conversion to I z. B. Use to cleave the DL base of chloramphenicol in the enantiomers.

Description

Field of application of the invention

The invention relates to a process for preparing the bicyclic oxazolidines of 1- (4-nitro-pl.enyl) -2-amino-propane-1,3 · diol (II), a by-product obtained in the chloramphenicol synthesis.

The 6- (4-nitro-phenyl) -oxazolidino- (3,4-c) -oxazolidine (I) can be used as starting material, organic syntheses, inactivating peroxy compounds and cleaving the D, L base of chloramphenicol into the enantiomers be used.

(D

- CH ₁ OH

Characteristic of the known state of the art

The oxazolidine and its derivatives have been known for decades. Monocyclic oxazolidines are obtained by reacting equimolar amounts of aminoalcohols and aldehydes; e.g .:

Good yields are obtained when this reaction is carried out in a solvent which forms an azeotope with water.

which is continuously separated during the heat-going reaction.

Prototype of the simple oxazolidines is the 4 / dimethyl-1,3-oxazolidine, also called oxazolidine A, an intermediate for the Synthesis of N-substituted oxazolidines. Bicyclic oxazolidines are accessible in the same way, if one per mole of a 2-amino-1,3-diol with two moles

an aldehyde reacts:

C I

t 2

C ⁺ I

Implementations of this type have been described by several authors wot den, z. By M. Senkus, J. Amer. Chem. Soc. 67.1515

(1945), A.Pedrozzoli and S.Tricarri, HeIv. Chim. Acta 39,965 (1956), W.B. Johnston, US 2448890, J.A. Frump, US 3738992 and US Pat

T.A. Crabb u. Co-workers, Tetrahedron 293, 3389 (1973). Dio workup of the reaction mixture obtained in the boiling heat is carried out by fractional distillation or separation

of the solvent in vacuo.

Compound I was first obtained by W.H., Edgarton and coworkers (J.Amer.Chem. Soc., 79, 6487 (19571), and indeed

also according to the method specified by Senkus; by refluxing a benzene solution of Ilmit wfltßnp'ir formaldehyde solution and azeotropic dehydration of the reaction mixture for 15 hours.

The product obtained is a sticky product which tends to harden when hardened and caked with formaldehyde inclusions

the processing of which causes considerable difficulties.

This method has disadvantages that preclude a technical use. These are the long implementation times, the

higher energy and additional solvent requirement, and finally the unsatisfactory yield and purity of the product thus obtained.

Object of the invention

The aim of the invention is to develop an effective and Abproduktarmos process for the preparation of I, which meets the requirements of tech'ischen scale and creates a new way to economically advantageous utilization of the by-product of chloramphenicol synthase, the L-base (II) ,

Explanation of the essence of the invention The invention is based on the technical problem of providing a process for preparing the bicyclic oxazolidines I of the 1- (4-nitro-

phenyl) -2-amino-propane-1,3-diols II to develop, which requires less equipment and energy expenditure compared to the prior art, requires no organic solvents and beierheblich shortened reaction time gives well-crystallized products in high yield and nbproduktarm is.

It has been found that the reaction of II with aqueous formaldehyde surprisingly with water splitting beroits

in the aqueous suspension and boi room temperature and runs very quickly and almost completely when passing through

Conversion of a portion of the aminodiol Il in its hydrochloride and subsequent use of a mild alkaline Catalyst initiated and carried out in a weakly alkaline medium. According to the invention Il is suspended in an excess of aqueous formaldehyde, preferably in an operating ratio

vpn 4 to 6 moles of formaldehyde per 1 mole of II. Then, a small amount of II, preferably 4 to 6Ma .-% of the use of II, converted by the addition of hydrochloric acid in its hydrochloride. Subsequently, using a weak base like

Ammonia water and / or a water-soluble amine a weakly alkaline medium of pH 8.0 to 8.5 set. Under these conditions, the formation of I starts spontaneously even at room temperature and is weakly exothermic History finished in less than an hour. A crystalline product is obtained in almost quantitative yield.

It has proved els conducive to the complete Ablaif the implementation, after reaching the maximum temperature in the reaction mixture of the uncooled schwac'i exothermic reaction to dilute the suspension with water from 28 ° C to 30 ° C to one and a half times to double their volume.

The attempt to carry out the reaction without the action of the Baiischen catalyst, the extension of the reaction time to 7 to 9 hours result. The reaction without the initiation according to the invention via the hydrochloride requires a higher starting temperature (50.degree. C. to 60.degree. C.) and leads to products containing formaldehydeinschlüasen, which must be nirirvigt in an additional process stage. In both cases, a shortfall is the result.

embodiments

example 1

100 g of dried II (0.42 mol) in 200 ml of 30% aqueous Formaldhydlösung (2.1 mol) are added with stirring in a 500 ml round bottom flask with stirrer and thermometer. With continued stirring, this suspension is mixed with 2.5 ml of 35% strength hydrochloric acid and five minutes of completion of addition of hydrochloric acid with as much 25% strength aqueous ammonia solution until the suspension has reached a weak alkalinity of from pH 0.6 to 8.5.

Due to the onset of slightly exotheous reaction, the suspension is heated from 28 ° C to 30 ° C. The reaction almost ended after 15 minutes. Now you are 200ml of water from 28 ⁰ C to 30 ⁰ C added and stirred to complete the reaction for two hours. An indication of the implementation is the whitening of the color of the suspension from krempellich to white. The liquid is sharply Chase suction filtered, the solid was covered three times with 50 ml of water, suction filtered and dried at 5O ⁰ C.

Yield: 107gö97% of theory

Melt / range: 74.5 ⁰ Cbis78 ⁰ C

Example 2

On a production scale, by-product II of the chloramphenicol synthesis is obtained as a water-moist product with (50 ± 5% by mass) water moisture. The reaction of this product to the bicyclic oxazolidine is carried out as described in Example 1, but with the following changes:

200 ml of the aqueous 30% Fcrmaldehyds 200g of the water-moist base are used, the initiation of the reaction is carried out by adding 3.5 ml of concentrated hydrochloric acid and the suspension 120 ml of water are added after reaching the maximum temperature.

Yield: 105g Δ 95% of theory

Melting range. 74 ° C-78 ° C

Claims (4)

1. Process for the preparation of 5- (4-nitrophenyl) -oxazolidino- (3,4-c) -oxazolidine (I) (O by reacting 1- (4-nitrophenyl) -2-amino-propane-1,3-diol (II) with formaldehyde, characterized in that II is suspended in an excess of aqueous formaldehyde and by addition of hydrochloric acid to a small proportion is reacted in the hydrochloride, whereupon a pH of 8.0 to 8.5 adjusted by means of a weak base and the reaction is carried out at a reaction temperature of a maximum of 3O ⁰ C. 2. The method according to claim 1, characterized in that formaldehyde in a ratio of 4 to 6 moles per i mol! I is used. 3. The method according to claim 1 and 2, characterized in that a proportion of 4 to 6 Ma, -% of the Il used is converted into the hydrochloride. 4. The method according to claim 1 to 3, characterized in that is used as a weak base ammonia water and / or a water-soluble amine.