JPS6154796B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing so-called crown ethers. What are crown ethers?
This is the name conventionally given to macrocyclic polyethers, which were first synthesized by CJ Pedersen and have the ability to form complexes with alkali metal and alkaline earth metal cations, as well as ammonium ions, heavy metal ions, etc. As it has become clear that it has the following properties, it has begun to be used in a wide range of fields such as organic synthesis, separation analysis, biochemistry, and pharmaceuticals, making it an interesting compound both industrially and theoretically. Note that naming crown ethers using the IUPAC method would be very complicated, so here we will follow the commonly used and simple nomenclature (CJPedersen, J.Am.Chem.Soc., 89 , 2495
(1967)). Crown ethers are produced by various methods,
Although they have already been manufactured on an industrial scale, these manufacturing methods can be roughly divided into two. One method is to utilize the template effect of polyethylene glycol or an aromatic o-dihydroxy compound, polyethylene glycol dihalide, ditosylate, etc. in the presence of an alkali metal hydroxide, etc., as shown in formula (1). This is a condensed ring. However, in this method, for example, when a dihalide is used, it is usually necessary to react at high temperature (about 100° C.) for a long time, and the yield is low. In addition, when ditosylate is used, good yields have been reported in rare cases in the cyclization condensation step, but in most cases special alkali metal alkoxides such as t-BuOK and t-BuON ₂ are required during cyclization. There is a drawback that. Furthermore, this conventional method requires a synthesis step for starting materials such as dihalides and ditosylates, and it is not always easy to obtain crown ethers in high yields, and the cost is inevitably high. I have no choice but to do so. Another method is, for example, as shown in formula (2), in which ethylene oxide is cyclopolymerized in a solvent such as dioxane in the presence of an anhydrous metal salt having a template effect. However, according to this method, a mixture of crown ethers with different ring sizes (in formula (2), m
0, 1, 2, 3, etc.), and the selectivity of the metal salt used is a problem. Furthermore, according to this method, it is difficult to produce crown ethers having substituents except in special cases. As described above, the conventional methods for producing crown ethers have many drawbacks, and furthermore, there is a cost problem, and currently only extremely limited types of crown ethers are produced. In addition, in order to further expand the uses of crown ethers, it is necessary to easily and inexpensively produce crown ethers having substituents containing active functional groups, but conventional methods do not take into account the cost. Even if there isn't,
Manufacturing itself is extremely difficult. The present invention was made in consideration of the above-mentioned points in the production of crown ethers, and generally aims to provide a new method for producing substituted and unsubstituted crown ethers. , in particular, substitution of substituted and unsubstituted polyethylene glycols in one step with good yield under mild reaction conditions,
An object of the present invention is to provide a method for producing unsubstituted crown ethers. The method for producing crown ethers according to the present invention involves reacting substituted or unsubstituted polyethylene glycol with an approximately equimolar amount of a leaving group-forming compound in a solvent in the presence of a metal compound having a template effect. Then, a leaving group is formed at one end of the polyethylene glycol chain, and then, at this one end, intramolecular condensation and cyclization is performed with the hydroxyl group at the other end of the polyethylene glycol chain, and at the same time, the leaving group is eliminated. Features. The polyethylene glycol that can be used in the present invention has the general formula () (However, R ¹ to ^{R 4} each independently represent hydrogen, an alkyl group, or an aryl group, and x and y each independently represent a number of 0 to 5.), and if desired, the general formula ( ), a mixture of different x and y can also be used as a starting material. Furthermore, the above-mentioned template effect means:
This refers to the effect of creating a suitable steric configuration for the reaction by forming a complex by utilizing the affinity between the metal cation and the oxygen atom of the polyoxyethylene chain. One type of metal compound or a mixture thereof used to exhibit a template effect is used. Examples of these metal compounds include metal hydroxides such as lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, lithium hydride, potassium hydride, sodium hydride,
Metal hydrides such as calcium hydride, potassium
Examples include metal alkoxides such as t-butoxide and sodium-t-butoxide. Next, the leaving group-forming compound used in the present invention is a compound that reacts with one hydroxyl group of the polyethylene glycol of the formula () to form a leaving group at one end of the polyoxyethylene chain as shown in the formula () below. It is a compound that forms the group L. (However, for R ¹ to R ⁴ , x and y are the same as above,
L represents a leaving group. ) The leaving group-forming compound is represented by the general formula () R ^{5 -SO} ₂ sulfonic acid halides represented by the general formula () R ⁶ -SO ₂ -O-SO ₂ -R ⁷ () (wherein R ⁶ and R ⁷ each independently represent an alkyl group or an aryl group). Acid anhydrides are particularly preferred, and examples of the sulfonic acid halide represented by the general formula () include methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, -p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, etc. be able to. Furthermore, examples of the sulfonic anhydride represented by the general formula () include methanesulfonic anhydride, benzenesulfonic anhydride, and the like. The leaving group L formed by this leaving group-forming compound at the end of the polyoxyethylene chain is formed by coordinating the oxygen atom of the polyoxyethylene molecule with an alkali metal ion, etc., as shown in formula (3) below, and forming a leaving group L at the end of the polyoxyethylene chain. It is a group that leaves when p-toluenesulfonyl chloride is used.

[Formula] is L. The reaction according to the invention is normally carried out in a solvent. Any solvent can be used as long as it does not participate in the reaction, but usually aprotic solvents are used.
solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, monoglyme,
diglyme, dimethyl sulfoxide (DMSO),
Preferred are N.N-dimethylformamide (DMF), hexamethylphosphoric acid triamide (HMPA), and the like. However, solvents such as acetonitrilebenzene and n-hexane can also be used. The reaction according to the present invention can be carried out, for example, by dissolving a substituted or unsubstituted polyethylene glycol having a polyoxyethylene chain of an appropriate chain length and the leaving group-forming compound in an appropriate solvent at a molar ratio of about 1:1. This is carried out by dropping the metal hydroxide or the like into a solvent with vigorous stirring. Furthermore, a polyethylene glycol solution and a solution of a leaving group-forming compound may be added to a dispersion of metal hydroxide, or a leaving group-forming compound solution may be added to a mixed solution of polyethylene glycol and an alkali metal hydroxide. A chemical compound solution may also be added. The reaction temperature is in the range of 0°C to 150°C, although it depends on the solvent used, and usually in the range of room temperature to 80°C. In the reaction in the present invention, polyethylene glycol is expressed in the general formula () where x+y is 1, 2,
3 or more, that is, when the polyethylene glycol is tetra, penta, hexaethylene glycol or longer chain polyethylene glycol, substituted or unsubstituted 12-crown-4, 15-crown-5, Macrocyclic crown ethers of 18-crown-6 or more are obtained, respectively. For example, acting on pentaethylene glycol with -p-toluenesulfonyl chloride in the presence of sodium hydroxide, according to formula (3), 15-
Crown-5 is obtained as a complex compound. On the other hand, when polyethylene glycol is triethylene glycol in which x+y is 0 in the above general formula (), under similar reaction conditions, the following formula
As shown in (4) and (5), 2 moles or more of triethylene glycol are cyclized and condensed to yield 18-crown-6 and macrocyclic crown ether. Furthermore, in the present invention, by using a mixture of polyethylene glycols with different chain lengths and appropriately selecting a metal compound having a template effect, two or more types of crown ethers with different ring sizes can be produced. A mixture of can be obtained. In some cases, in order to enhance the mold effect,
The reaction is carried out using two or more metal compounds, or by adding another metal compound, such as a metal salt compound such as lithium chloride or lithium perchlorate, to a hydroxide, hydride, or alkoxide. Good too. According to the method of the present invention, as described above, crown ethers are usually obtained as complex compounds, which are isolated and purified by column chromatography, thermal decomposition, continuous extraction with n-hexane, etc. can do. According to the method of the present invention, as described above, substituted or unsubstituted polyethylene glycol is reacted with a leaving group-forming compound such as a sulfonic acid halide in the presence of a metal compound having a template effect. Crown ethers can be produced in a high yield in one step under mild reaction conditions that allow the reaction to work satisfactorily. However, in the method of the present invention, there is no need to prepare the starting materials through several steps before the cyclization condensation step, and polyethylene glycol, alkali metal hydroxide, and sulfonic acid halide, which are usually easily and inexpensively available, can be used. Since crown ethers are produced all at once using these as direct starting materials, crown ethers can be obtained much more easily and at a lower cost than conventional methods. Furthermore, according to the present invention, various substituents can be added by, for example, ring-opening of substituted epoxides with polyethylene glycol, or adding ethylene oxide to glycols having appropriate functional groups using an acid catalyst. Therefore, crown ethers having various substituents, which were extremely difficult to obtain by conventional methods, can also be easily obtained. Examples are given below. Example 1 4.76 g of pentaethylene glycol and p-chloride
-4.0g of toluenesulfonyl in 20ml of monoglyme
6.0 g of powdered sodium hydroxide was gradually added dropwise to the suspended monoglyme. After the addition was completed, the mixture was stirred at about 30° C. for 1 hour, and the precipitate was filtered and washed with ether, and the washings and liquid were concentrated to obtain 5.3 g of a colorless oil. The IR spectrum indicates that this compound is a complex compound consisting of 15-crown-5, sodium p-toluenesulfonate, and sodium chloride.
DC550 or Carbowax 20M, temperature 200℃, carrier gas is nitrogen) gives almost a single peak,
As a result of quantitative analysis by GLC, the yield was 70%. The above oily compound was decomposed by heating to 150°C under reduced pressure, and 2.7g (yield 61%) of 15-crown-5 was obtained.
I got it. Example 2 Hexaethylene glycol 1.0g and chloride-p
- 0.7 g of toluenesulfonyl was dissolved in 60 ml of THF and 1.1 g of powdered potassium hydroxide was suspended.
It was added dropwise to THF at room temperature and treated in the same manner as in Example 1. The obtained product was treated by column chromatography to obtain 0.65 g (69% yield) of 18-crown-6-. Example 3 3.9 g of tetraethylene glycol and 3.6 g of benzenesulfonyl chloride were dissolved in 30 ml of t-butanol and added dropwise at room temperature to 30 ml of dioxane in which 6.4 g of lithium-t-butoxide was suspended.
After heating and stirring at a temperature of ~50°C for 1 hour, the precipitate was removed to obtain 4.25 g of an oily substance. This oily product is GLC
As a result of analysis, it was found that it contained 30% by weight of 12-crown-4-. Example 4 1.5 g of triethylene glycol and p-chloride
1.9 g of toluenesulfonyl was dissolved in 15 ml of monoglyme, and 2.8 g of potassium hydroxide powder was suspended in 20 ml of monoglyme, which was then added dropwise at 20 to 25°C, and then treated in the same manner as in Example 1 to form an oily substance. 1.6g was obtained. As a result of GLC quantitative analysis, 0.58 g (yield 43%) of this oily product was found to be 18-crown-6.
It was recognized that this includes Example 5 A mixed solution was prepared by adding 4.8 g of pentaethylene glycol and 1.6 g of powdered sodium hydroxide to 40 ml of diglyme, and a solution of 2.3 g of methanesulfonyl chloride dissolved in 20 ml of diglyme was gradually added to the above mixed solution with vigorous stirring. added to. After the addition, the same procedure as in Example 1 was carried out to obtain 4.5 g of an oily substance. As a result of GLC analysis, this oil was found to contain 58% by weight of 15-crown-5. Heating under reduced pressure yielded 1.8 g (41% yield) of 15-crown-5. Example 6 Ethylene oxide was added to propylene glycol in the presence of boron trifluoride etherate to obtain an adduct with an average number of added moles of 4.8, which was distilled under reduced pressure to obtain a 4-mole ethylene oxide adduct (bp.147~
150℃/0.02mmHg) and 5 molar adduct (bp.180~
183℃/0.02mmHg) was collected. 5.0 g of the above 4 molar adduct and 3.8 g of -p-toluenesulfonyl chloride were dissolved in 50 ml of dioxane,
After adding 2.0 g of powdered sodium hydroxide to 50 ml of dioxane in which it was suspended, the suspension was treated in the same manner as in Example 1 to obtain 5.3 g of an oily substance. This product showed almost a single peak in GLC, and the results of IR, NMR, and MS analysis of the product obtained by fractionation with GLC showed that
It was confirmed to be methyl-15-crown-5. The isolated yield was 45%. In addition, the above 5 mol ethylene oxide adduct was treated in the same manner as above to obtain methyl-18-crown-6 in a yield of 38
Obtained in %.

Claims (1)

[Scope of Claims] 1 Polyethylene glycol is produced by reacting substituted or unsubstituted polyethylene glycol with an approximately equimolar amount of a leaving group-forming compound in a solvent in the presence of a metal compound having a template effect. A crown characterized in that a leaving group is formed at one end of the chain, and then, at this one end, intramolecular condensation and cyclization is performed with a hydroxyl group at the other end of the polyethylene glycol chain, and at the same time, the leaving group is eliminated. Method for producing ethers. 2. The method for producing crown ethers according to claim 1, wherein the leaving group-forming compound is a sulfonic acid halide or a sulfonic acid anhydride. 3. The method for producing crown ethers according to claim 1, wherein the leaving group-forming compound is a sulfonic acid chloride. 4. The method for producing crown ethers according to claim 1, wherein the metal compound having a template effect is an alkali metal or alkaline earth metal hydroxide. 5. The method for producing crown ethers according to claim 1, wherein the metal compound having a template effect is an alkali metal alkoxide. 6 Substituted or unsubstituted polyethylene glycol has the general formula (However, R ¹ to ^{R 4} each independently represent hydrogen, an alkyl group, or an aryl group, and x and y each independently represent a number from 0 to 5.) A method for producing crown ethers according to item 1.