GB2223492A - Preparation of carboxylic acid morpholides - Google Patents

Description

4.

1 1, - - ' 2 2,233) 4 2 T 927 FF PREPARATION OF CARBOXYLIC ACID AMIDES The present invention relates to a process for the preparation of carboxylic acid amides, in particular acyl morpholides.

The synthesis of carboxylic acid morpholides is well known. In general, one equivalent of an acyl halide is reacted with two equivalents of a morpholine whereby the excess morpholine functions as a scavenger for the hydrogen halide formed. The second equivalent of morpholine may be replaced by another base but both methods are quite expensive due to the excess of amine or the auxiliary base which have to be either discarded or recovered.

It has also been observed that morpholinium halides, like most other amine hydrohalides, degrade at elevated temperature forming the respective morpholine and hydrogen halide. The morpholine can then react with further acyl halide giving the desired acyl morpholide. Thus, the reactants can be employed in about equimolar amounts. However, the general disadvantage of this method is that the boiling points of the acyl halide and the morpholin I e have to be higher than the degradation temperature of the respective morpholinium halide. lk j PS14016 k Surprisingly, it has-.-,nowbeen-found that the preparation of acyl morpholides can also be carried out with low-boiling acyl halides or morpholines. Accordingly, the present invention provides a process 5 for the synthesis of an acyl morpholide of formula I R 2 1 - /-X R CO-N 0 \--y R 3 wherein R 1 is either methyl or ethyl; R 2 is hydrogen, C 1-4 -alkyl, or C 1-4 -alkoxy; and R 3 is hydrogen or C 1-4 -alkyl; which comprises reacting an acyl halide of formula li R 1 - CO - X (ii) wherein R 1 has the above meaning and X is chlorine or bromine with a morpholine of formula III 2 HN 0 R (III) wherein R 2 and R 3 have the above meaning in the presence of an inert solvent, characterised in that the acyl halide reactant is pre-heated in the inert solvent before reaction takes place.

PS14016 k The process according to the invention is preferably carried out in an inert solvent which does not interfere with the reaction and the boiling point of which is equal to or higher than the degradation temperature of incidentally formed morpholinium halide IV.

e e,7 NH 2 0 R 2 R 3 (IV) The solvent may be a hydrocarbon solvent e.g. toluene, xylene, mesitylene, a high boiling point ether e.g. dioxan or solvents such as dimethyl sulphoxide.

The pre-heating of the acyl halide reactant preferably takes place at a temperature in the range of 500 to 100'C, e.g. 70C.

The amount of the inert solvent employed is preferably 3- to 6-fold compared to the amount of the lower boiling component. The process is especially useful in the case where R 1 is methyl, X is chlorine, and R 2 and R 3 are both hydrogen. 20 The molar ratio of the reaction components may be 1:1 but an excess of the lower boiling component is preferred so that the molar ratio is preferably in the range from 1:1.25 to 1.25:1. According to the reactivity of the components the reaction temperature is maintained in the range from the boiling point of the lower boiling component to 20C above the degradation temperature of the respective morpholinium halide IV. Preferably, it is PS14016 k -- 4 higher than the degradation temperature of.the morpholinium halide.

The process provides a markedly improved route for the simple and inexpensive preparation of lower acyl morpholides in high yields (80%90%) in that now only a small excess, e.g. a 1.1 fold excess, of the lower boiling component is appropriate and the products are almost 100% pure whereas the prior art routes disclosed in Komori et al. J. Chem. Soc. Japan

Ind. Chem. Sect. 62, 220 (1959), Medard, Bull. Soc.

Chin. France 3, 1343 (1936), and De Benneville et al. J. Org. Chem. 21, 1072 (1956) are more complicated and/or more expensive. Moreover the reaction time of the process according to the invention is dramatically reduced over processes which do not employ the pre-heating step.

The process according to the invention is further illustrated by the following examples. Example 1 Preparation of N-acetyl morpholine A solution of acetyl chloride (103.6g, 1.32mol) in toluene (400ml) was first heated to 700C and then morpholine (104.6g, 1.20mol) was added over a period of 45 minutes. The temperature of the reaction mixture increased to 90-95C and a large amount of morpholine hydrochloride precipitated. The resulting slurry was stirred under reflux and the hydrogen chloride developed was absorbed in 10% aqueous sodium hydroxide. When the boiling point of the reaction mixture had increased to 110-115C, no re acetyl chloride (10.4g, 0.132mol) was added dropwise. The resulting mixture was stirred for another two hours under reflux. When the reaction was finished the mixture was cooled to room temperature and filtered.

Toluene and small amounts of morpholine were PS14016 1 k evaporated and the remaining red-brown oil purified by fractional distillation. The prerun comprised about 75% N-acetyl morpholine and 25% of morpholine whereas the main fraction (bp 12 115-117C) contained the desired product. Yield: 89% Examples 2 to 6 The process of Example 1 was repeated using different concentrations of acetyl chloride in toluene. The results are given below.

n D - 1.4825 (ref. 1.4827) concentration of acetyl chloride in toluene Reaction (mol acetyl chloride Time Yield Example per mol of toluene) (h) (%) 2 1.77 3.5 80 3 2.20 3.5 85 4 3.30 4.5 89 4.40 6.0 87 6 5.74 7.0 81 Comparative Example Preparation of N-acetyl morpholine without the pre-heating step Acetyl chloride (0.266nol) and morpholine (0.266mol) were mixed at room temperature in toluene (100m1). The mixture was then heated to reflux and the reaction carried out according to the procedure of Example 1.

The reaction was relatively slow and took 13 hours to complete. The yield was 75% or, when more PS14016 1 acetyl chloride (0.1mol) was added, 83% of the. theoretical.

It can be seen that the pre-heating step produces considerable advantage in that the reaction time is dramatically reduced whilst the yield is maintained at a high level or even increased.

PS14016 t 1 k

Claims (6)

1. A process for the preparation of an acyl morpholide of formula I 1 - R CO-N 0 T 927 FP R

2 R 3 (I) wherein R 1 is either methyl or ethyl; 2 is hydrogen, C 1-4 -alkyl or C 1- 4 -alkoxy; and 3 is hydrogen or C 1-4 -alkyl, which comprises reacting an acyl halide of formula II R 1 - CO - X wherein 1 has the above meaning and is chlorine or bromine with a morpholine of formula III PS14016 (II) 11 HN 0 2.

R 2 R 3 (III) wherein R 2 and R 3 have the above meaning in the presence of an inert solvent, characterised in that the acyl halide reactant is pre-heated in the inert solvent before reaction takes place. A process according to claim 1 characterised in that the reaction is carried out in an inert solvent whose boiling point is equal to or higher than the degradation temperature of incidentally formed morpholinium halide of formula IV 2 R 9 a / -- X NH 0 (IV) R 3 wherein R 2, R 3, and X have the above meaning.

3. A process according to claim 1 or 2 characterised in that the acyl halide reactant is pre-heated to a temperature in the range of 50 to 1006C.

4. A process according to any one of the preceding claims characterised in that R 2 and R 3 are both hydrogen.

5. A process according to any one of the preceding claims characterised in that the molar ratio of PS14016 1 the acyl halide (II) to the morpholine (III) is in the range from 1:1.25 to 1.25:1.

6. A process according to any one of claims 2 to 5 characterised in that the reaction temperature is in the range from the boiling point of the lower boiling component to 20C above the degradation temperature of the morpholinium halide IV.

PS14016 PubhshedI990atThePazent Office. State House. 66 71 High Holborn, London WClR4TP. Further copies maybe obtained from The Patent Office Sales Branch. St Mary Cray. Orpington, Kent BRS 3RD. Printed by Multiplex techniques ltd. St Mary Cray. Kent. Con 1'87