Manufacture of macrocyclic polyethers

This invention deals with a process for the preparation of macrocyclic polyethers of the general formula: ##STR1## wherein x is 1-9; k is 0 or 1 and each R, which may be the same or different, represents a hydrogen atom or a lower alkyl or aryl group, or two R bonded to two adjacent carbon atoms form together with these carbon atoms a cyclic hydrocarbyl configuration, by reacting a compound of the general formula: ##STR2## with a sulphonyl halide in the presence of a base and a halogen-containing solvent, preferably chlorobenzene. The process is of special interest for the manufacture of 18-crown-6.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to a process for the preparation of 
macrocyclic polyethers, commonly referred to as "crown ethers". The 
invention relates in particular to the preparation of 
1,4,7,10,13,16-hexaoxacyclooctadecane, also known as 18-crown-6. 
2. Description of the Prior Art 
Synthetic macrocyclic polyethers are of great interest in that they contain 
intra-molecular cavities which are fit to accomodate alkali metal or 
alkaline-earth metal ions depending on the particular shape of the 
macrocyclic polyether applied. Therefore, salts of alkali metals and 
alkaline-earth metal ions, which are substantially insoluble, become 
solubilized in the presence of certain macrocyclic polyethers. It is also 
possible to dissolve such salts in organic solvents such as benzene or 
toluene in the presence of certain macrocyclic polyethers. Macrocyclic 
polyethers, and especially 18-crown-6, have found recognition as solvents 
for chemical reactions as well as phase-transfer catalysts for chemical 
reactions. 
A number of synthetic techniques has been proposed for preparing 
macrocyclic polyethers. Among those, reference may be made to the 
catalytic oligomerization of ethylene oxide as described in U.S. Pat. No. 
3,928,386 leading to mixtures of various macrocyclic polyethers. The 
reaction of tetraethyleneglycol with bis(2-chloroethyl) ether in the 
presence of potassium hydroxide and tetrahydrofuran without addition of 
water is described in "Synthesis" (1976) pages 515-516. However, even 
after reaction time of at least 18 hours, moderate yields are obtained and 
the working-up procedure includes a distillation or distillative 
decomposition of the macrocyclic polyether (complex) produced. It is 
further known from J. Chem. Soc. Chem. Comm., 1978, pages 504-505 that 
macrocyclic polyethers may be prepared by reacting (un)substituted 
polyethylene glycols having suitable ethylenoxy units with a sulphoxyl 
chloride in the presence of an alkali metal hydroxide in an aprotic 
solvent such as dioxane or dimethoxyethane, followed by pyrolysis of the 
salt complex obtained in order to liberate the macrocyclic polyether. 
It is remarkable, however, that despite a fast growing interest in 
macrocyclic polyethers large scale preparations have not yet been 
reported. 
SUMMARY OF THE INVENTION 
It has now been found that macrocyclic polyethers can be prepared on a 
large scale without the serious disadvantage of either having to decompose 
a solid complex or to purify the product by distillation by carrying out 
the process in the presence of a halogen-containing solvent. The present 
invention therefore relates to a process for the preparation of 
macrocyclic polyethers according to the general formula: 
##STR3## 
wherein x is an integer of from 1 to 9; k is 0 or 1, and each R, which may 
be the same or different, represents a hydrogen atom or a lower alkyl or 
aryl group, or two R bonded to two adjacent carbon toms form together with 
these carbon atoms a cyclic hydrocarbyl configuration. The process 
comprises reacting a compound according to the general formula: 
##STR4## 
wherein x and R have the meaning as defined hereinbefore, with a sulphonyl 
halide in the presence of a base and a halogen-containing solvent. 
The process according to the present invention is of special interest for 
the preparation of macrocyclic polyethers according to the general formula 
I wherein x is an integer of from 2 to 4 inclusive; k is 0 or 1 and each 
R, which may be the same or different, represents a hydrogen atom or a 
lower alkyl group, by reacting a compound according to the general formula 
II with a sulphonyl chloride in the presence of a base and a 
halogen-containing solvent. The process according to the present invention 
relates in particular to the preparation of 18-crown-6 by reacting 
triethylene glycol (formula II, x=3, and formula I, K=1) with a sulphonyl 
chloride in the presence of a base and a halogen-containing solvent. 
It should be noted that the handleability of the reaction mixture is a key 
issue in the manufacture of large quantities of macrocyclic polyethers and 
that the use of oxygenated solvents such as tetrahydrofuran and dioxane 
gives rise to serious working-up problems, which do not occur or occur 
only to a minor degree in small-scale operations. They also require a 
solvent switch during the working-up procedure which is very unattractive 
and cause severe filtration problems. It is surprising that the use of a 
halogenated solvent enables the large scale preparation of macrocyclic 
polyethers to be carried out in an economically attractive manner. 
DETAILED DESCRIPTION OF THE INVENTION 
It will be appreciated that the process according to the present invention 
may occur via cyclization of a polyethylene glycol derivative originating 
from the appropriate polyethylene glycol as well as via cyclization of 
polyethylene glycol derivatives obtained from smaller polyethylene units 
which may have been subject to a condensation reaction. For instance, 
18-crown-6 can be prepared starting from hexaethylene glycol but also 
starting from triethylene glycol or from mixtures containing triethylene 
glycol. It has been found in general that a polyethylene glycol having one 
oxygen atom more in the molecule than the macrocyclic polyether to be 
produced is to be preferred as a starting material over a lower 
polyethylene glycol unit having one oxygen atom more than half the amount 
of oxygen atoms present in the macrocyclic polyether to be produced. 
Sulphonyl halides which can be used suitably in the process according to 
the present invention comprise alkyl, aryl, alkaryl and aralkyl sulphonyl 
chlorides and bromides containing up to 12 carbon atoms in the molecule. 
Preference is given to the use of alkyl sulphonyl halides, and especially 
of alkyl sulphonyl chlorides, having up to 6 carbon atoms in the molecule 
such as methane sulphonyl chloride and ethane sulphonyl chloride, as well 
as to aryl and alkaryl sulphonyl halides having up to 12 carbon atoms in 
the molecule such as benzene-sulphonyl chloride and toulene-p-sulphonyl 
chloride. Normally, the sulphonyl halide will be applied in the 
stiochiometrically required amount. A moderate excess of the sulphonyl 
halide, e.g. up to 50% on polyethylene glycol intake can be used 
advantageously. 
Suitable bases which can be used in the process according to the present 
invention comprise inorganic bases such as lithium hydroxide, sodium 
hydroxide, potassium hydroxide, calcium hydroxide and barium hydroxide as 
well as mixtures of such bases. Also metal alkoxides, such as potassium 
t-butoxide or isopropoxide can be used. They can be applied as solids, 
e.g. in the form of pellets, powders or flakes. Preference is given to the 
use of powdered potassium hydroxide or potassium hydroxide/sodium 
hydroxide mixtures. Normally an excess of base is used in order to 
facilitate the reaction. Up to 5 times the molar amount of base can be 
used conveniently, amounts up to 3 times being preferred. Very large 
amounts of base should be avoided as this may lead to a thick, unstirrable 
reaction mixture. 
Suitable halogen-containing solvents comprise polyhalogenated aliphatic 
hydrocarbons and halogenated aromatic hydrocarbons. Examples of 
halogenated aliphatic hydrocarbons include dichloromethane, 
dichloroethane, trichloroethane, tetrachloroethane, dibromoethane and 
tetrachloroethylene, preference being given to dichloromethane, Examples 
of halogenated aromatic hydrocarbons include chlorobenzene, bromobenzene, 
.alpha.-dichlorobenzene and m-dichlorobenzene. Preference is given to the 
use of halogenated aromatic compounds, and especially to the use of 
chlorobenzene since the use of this solvent has also considerable 
advantages in the working-up procedure of the crude macrocyclic polyether 
as will be explained hereinafter. 
The amount of solvent to be used should be sufficient to ensure at least a 
workable reaction mixture. Amounts of solvent in the range of from 2 to 30 
times the weight of the reactants can be suitably applied. Higher ratios 
can also be applied but they are not advantageous in that this would 
require the handling of very large quantities of solvent during the 
working-up procedure. Preference is given to a solvent:reactants weight 
ratio in the range of from 2 to 10. 
The temperature at which the process according to the present invention is 
carried out is not critical. Normally, the reactions are slightly 
exothermic and can be conveniently carried out at room temperature or 
under gentle heating. Higher temperatures can also be applied when 
desired. The process is normally carried out under atmospheric or 
autogeneous pressure. Higher pressures can be applied but do not 
contribute substantially to the process. 
The process according to the present invention can be operated batch wise 
or semi-continuously. It has been found convenient to add a mixture of the 
appropriate polyethylene glycol and the sulphonyl halide (if desired in 
the presence of small amount of the halogen-containing solvent) to a 
slurry containing the base in a finely divided form and the bulk of the 
halogen-containing solvent. If required, the reactants may also be added 
in stages and it is also possible to add a further quantity of the 
sulphonylhalide, if necessary in the halogen-containing solvent, after the 
exothermic reaction has subsided. It is also highly recommended to equip 
the reactor with an adequate stirring device and, if necessary, to add 
additional solvent so as to ensure the operability of the reaction 
mixture. 
The reaction mixture obtained may be worked up in various manners. It is 
possible, for instance to isolate the macrocyclic polyethers produced in 
the form of suitable complexes by the addition of suitable complexing 
agents, which can then be separated from the reaction mixture by 
filtration. A number of solids will be entrained with the separated mass, 
however, so that an appropriate wash with a complexing agent such as 
nitromethane or acetonitrile will be necessary to obtain the macrocyclic 
polyether complex. But it is an implied disadvantage of this method that 
the complex formed to isolate the product has to be decomposed in order to 
liberate the macrocyclic polyether. This last step normally involves a 
distillation/re-complexation of the macrocyclic polyether produced and 
this is preferably to be avoided. 
It has been found that a very convenient and attractive working-up 
procedure can be applied which comprises removal of at least part of the 
halogen-containing solvent, and especially of chlorobenzene, by 
distillation. The use of chlorobenzene has a further advantage in that 
water--produced during the reaction--is removed simultaneously in the form 
of the low-boiling chlorobenzene-water azeotrope which precedes the 
removal of chlorobenzene. Since the amount of halogenated solvent to be 
removed is much larger than the amount of water produced, the 
chlorobenzene-water removal also provides an almost quantitative removal 
of water from the reaction mixture. As the chlorobenzene-water azetrope is 
a heterogeneous azeotrope, any chlorobenzene obtained after the azeotropic 
drying can be easily separated from the water and can be recycled partly 
or totally to the reactor or the appropriate make-up stream. Normally, the 
azeotropic drying is carried out at atmospheric pressure at a temperature 
of about 135.degree. C. The subjection of the reaction mixture to an 
advanced temperature during the azeotropic distillation has also the 
advantage that macrocyclic polyether complexes are decomposed in a very 
dilute system to give the free macrocyclic polyether without it being 
distilled as such. If desired, a filtration step can be incorporated after 
the azeotropic drying step to remove any solid materials. Finally, the 
remaining reaction mixture comprising predominantly the macrocyclic 
polyethers in the remainder of the halogen-containing solvent, is 
subjected to a distillation which can be carried out at reduced pressure 
in order to remove the solvent while leaving the macrocyclic polyether as 
the bottom product. The product may be used as such in many applications 
since any salts and/or solvent have been removed already. 
In order to obtain the macrocyclic polyether in a very pure state, the 
product obtained may be subjected to a final purification procedure. Use 
can be made of purification methods known in the art, e.g., by 
complexation with acetronitrile or nitromethane, followed by isolation and 
decomposition of the complex obtained. Very good results can be obtained, 
depending to some extent on the macrocyclic polyether produced by using 
dimethyl oxalate or dimethylcarbonate, especially dimethyl oxalate.

The invention will now be illustrated by means of the following Examples, 
which are not meant to limit the invention: 
EXAMPLE 1 
A one-liter reactor equipped with a stirrer, a reflux condensor, a dropping 
funnel and a gas outlet tube was charged with chlorobenzene (650 grams 
(g)) and powdered potassium hydroxide (412.6 g). During two hours a 
mixture of triethlene glycol (39 g), methane sulphonyl chloride (31 g) and 
chlorobenzene (50 g) was added through the dropping funnel to the 
suspension obtained. The temperature of the reaction mixture rose to 
45.degree. C. Finally, a further mixture of methane sulphonyl chloride 
(6.3 g) and chlorobenzene (7 g) was added and the reaction mixture was 
kept under stirring for another hour. 
Thereafter, the contents of the reaction was heated to reflux while 
azeotropically removing water produced during the reaction. During this 
azeotropic drying the temperature rose to 135.degree. C. When no more 
water distilled the reaction mixture was allowed to cool to 40.degree. C. 
The reaction mixture was then filtered in order to remove potassium 
chloride and potassium methane sulphaonate salts. The removed salts were 
washed with chlorobenzene (50 g). The filtrate was then subjected to a 
flash distillation under reduced pressure (0.2 kPa) in order to remove the 
solvent chlorobenzene. During the distillation the temperature rose to 
110.degree. C. A residue was obtained (35 g), containing uncoverted 
triethyleneglycol (8 g), and 18-crown-6 (13 g selectivity 45%) the 
remainder being heavy ends. 
In order to obtain 18-crown-6 in a very pure state, the residue obtained 
hereinabove was dissolved in a mixture of methyl tertiary butyl ether (40 
g) and isopropanol (8 g). After filtration, molten dimethyl oxalate (7 g) 
was added and the mixture kept for two hours at 5.degree. C. During this 
time the 18-crown-6/dimethyl oxalate complex precipitated. It was filtered 
off and washed with a mixture of methyl tertiary butyl ether (85 g) and 
isopropanol (1 g). The complex thus obtained was subjected to pyrolysis to 
distill off the dimethyl oxalate at elevated temperature (110.degree. 
C.-145.degree. C.) and reduced pressure (0.3 kPa). As bottom product 
18-crown-6 was obtained as a pure product (&gt;99% w) in a yield of 11.2 g 
(76% calculated on crude product). 
EXAMPLE 2 
The experiment described in the previous Example was repeated using 
dichloromethane as the solvent (750 ml), twice the amount of potassium 
hydroxide and 1.6 times the amount of triethylene glycol and methane 
sulphonyl chloride, but in the absence of a further addition of the last 
two reactants. 18-crown-6 was obtained in a very pure state (&gt;99% in a 
reasonable yield). 
EXAMPLE 3 
The experiment described in Example 1 was repeated on a larger scale. To a 
suspension of powdered potassium hydroxide (208 g) in chlorobenzene (3250 
g) in a five-liter reactor was added at room temperature during two hours 
a mixture of triethyleneglycol (195 g) and methane sulphonylchloride (155 
g) in chlorobenzene (250 g). During the addition the temperature gradually 
rose to 45.degree. C. Thereafter a mixture of methane sulphonylchloride 
(31.5 g) in chlorobenzene (35 g) was added at once and the reaction 
mixture kept under stirring for another hour. After the azeotropic removal 
of water (about 85 g) the reaction product was worked up in the manner as 
described in Example 1, giving after the final pyrolysis of the 
18-crown-6/dimethyloxalate complex at elevated temperature and reduced 
pressure, a residue of very pure 18-crown-6 (&gt;99%) in a yield almost 
identical to that obtained in the experiment described in Example 1. 
EXAMPLE 4 
The experiment described in Example 3 was repeated on a kmol scale while 
recycling chlorobenzene obtained from the heterogeneous 
chlorobenzene/water azeotrope to the reactor. Due to the use of a 
halogenated solvent no problems with respect to handleability were 
encountered during the reaction procedure. The reaction mixture could be 
stirred efficiently during the reaction. During the various stages of this 
production run, samples were taken and analyzed which were in full 
agreement with the product compositions as detected in the earliest 
experiments described hereinbefore. 
EXAMPLE 5 
The experiment described in Example 1 was repeated using a commercially 
available polyethylene glycol (PEG 300) as the reactant together with a 
mixture of powdered sodium hydroxide and powdered potassium hydroxide in 
chlorobenzene. After the removal of water by azeotropical drying and the 
removal of the excess chlorobenzene by flash distillation, a mixture of 
crown-ethers ranging from 15-crown-5 to 27-crown-9 was obtained, the main 
product being 18-crown-6. This compound could be recovered almost 
quantitatively from the reaction products using dimethyloxalate as the 
complexing agent in the manner as described in Example 1.