JPH046708B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing so-called monoaza crown ethers. What are crown ethers?
This is the name conventionally given to macrocyclic polyethers, and as it became clear that they have the ability to form complexes with various cations, they were used in a wide range of fields such as organic synthesis, separation analysis, biochemistry, and pharmaceuticals. It is an industrially interesting compound that has begun to be used. Compounds in which a portion of the oxygen atoms of crown ethers are replaced with atomic groups containing nitrogen atoms are generally referred to as azacrown ethers, and like crown ethers, they have recently been synthesized. , is a unique compound that is attracting attention due to its physical properties. Aza-crown ethers have a greater ability to form complexes with so-called soft transition metal and heavy metal ions than crown ethers, and are expected to be used in various fields by utilizing this property, especially for long-chain alkyl ions. Derivatives with groups exhibit a unique cloud point phenomenon in the presence of metal ions (M.Okahara et al., JCSChcm.Comm.,
(1980, 586) There is also interest from the aspect of surfactant action. In recent years, the synthesis of crown ethers with functional groups, which are important key compounds for the synthesis of various functional crown ethers, has been attracting attention in the chemistry of crown ethers. (For example, for hydroxymethyl crown ether, see F.
Montanariet al., Tetrahedron Lett., 1979 ,
5055; B.Czech, Tetrahedron Lett., 1980 ,
4197; M.Okahara et al., J.Org.Chem., 45 ,
5355 (1980); M. Okahara et al., JCSChem.Comm., for bromomethyl crown ether.
1981, 219). These compounds utilize the difference in reactivity of their functional groups to form various substituted crown ethers,
Crown ethers (IOSutherland)
et al., JCSChem.Comm., 1979 , 307), or polymerization and immobilization on resin (J.
Smid, Ind.Eng.Chem.Prod.Res.Dev., 19 , 364
(1980)). Here, bis(crown ether) is a bicyclic crown ether connected by an appropriate linking group. X: Linking group e.g. -(CH ₂ -) _o , -(CH ₂ CH ₂ O-) _o [Formula] [Formula], etc. Because it has a completely new metal ion selectivity different from ordinary crown ethers, it is biochemically It is not only an important model compound, but also a carrier for ion-selective electrodes (GARechnitz et al.,
Anal.Chem., 44 , 370 (1972)). In addition, if it can be made insoluble in solvents and given mechanical strength by polymerization and immobilization in resin, it will be easier to recover and reuse when used as a phase transfer catalyst, metal ion extractant, etc. It also has great industrial value. N-unsubstituted monoaza crown ethers are functional crown ethers that have the above characteristics due to the presence of a secondary amino group (NH) that increases their reactivity, and are interesting compounds both theoretically and industrially. However, the only known manufacturing method is one that requires multiple steps and extremely complicated reaction operations. For example, N-substituted dialkanolamines such as N-tosyl, N-benzyl, N-trityldiethanolamine, etc. are reacted with polyethylene glycol ditosylate to form the corresponding N-substituted monoazacrown ethers, and then the compound This is done by removing the N-protecting group of {(1) MRJohnson et al; JC
S. Perkin I, 357 (1979), (2) GW Gokel et al;
Tetrahedorn Lett., 317 (1977), (3) RN Greene,
Tetrahedorn Lett., 1973 (1972)}. This method inevitably requires an increase in the number of steps because it involves a step of introducing an N-protecting group into the raw material dialkanolamine and a step of removing the protecting group from the intermediate product N-substituted monoaza crown ethers. Not only that, but the introduction and removal operations of the protecting group are extremely troublesome, the overall yield is low, and the manufacturing cost is naturally high, so it is difficult to apply it industrially. When macrocyclic polydentate ligands such as crown ethers are synthesized from acyclic precursors, chain-like polymers are generally likely to be produced. For example, if (n-C ₄ H ₉ )4N ⁺ OH ^- is used instead of the ion showing selectivity,
It is known that linear polymers are the main products and the yield of cyclic compounds is significantly reduced. (Michio Hiraoka, Crown Compounds, Kodansha, April 1, 1978) However, when the reaction is carried out in the presence of ions derived from metal compounds whose ligands exhibit selectivity,
It is also known that intramolecular reactions take precedence over intermolecular reactions, and cyclic compounds can be obtained in high yields.
This ion is called a template ion (or template ion), and its effect is called a template effect (or template effect). This is thought to be because when the precursor cyclizes, the reaction site is brought closer to the appropriate position by coordination with the ion. The present invention has been made in view of the above, and includes:
The purpose of the present invention is to provide a new production method that can industrially advantageously produce N-unsubstituted monoaza crown ethers, and according to the present invention, the desired production method can be obtained from dialkanolamine and polyethylene glycol derivatives at once. By setting appropriate conditions, it is possible to produce monoaza crown ethers, and by utilizing the difference in reactivity for nucleophilic substitution reactions between alkoxide anions and amino groups, expensive N-protecting groups can be prepared. It is distinctive in that it is not used. That is, the present invention is based on the general formula () (However, in the formula, R and R' are the same or different groups and represent a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, or a fluorocarbon group) Dialkanolamine represented by the general formula () (However, in the formula, X is [Formula] or Cl, n is an integer from 1 to 6) is reacted with a polyethylene glycol derivative represented by the following in the presence of a metal compound having a template effect. General formula () (In the formula, R, R' and n have the same meanings as above.) This is a method for producing monoaza crown ethers represented by the following formula. In the dialkanolamine () formula used in the present invention, substituents represented by R and R' include hydrogen atoms; methyl, ethyl, propyl, butyl, hexyl, octyl, lauryl, palmityl, Alkyl groups having 1 to 22 carbon atoms such as stearyl; aryl groups such as phenyl, tolyl, and xylyl; aralkyl groups such as benzyl; CnF _2o+1 (n:
Examples 1 to 8) include fluorinated carbon groups. Examples of the polyethylene glycol derivative which is one of the starting materials include ditosylate or dichloride of diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol, and hexaethylene glycol. Further, as the metal compound having a template effect that is allowed to coexist in the reaction system, alkali metals, their hydroxides, hydrides, alkoxides, and alkaline earth metal hydroxides and hydrides are preferably used. Specifically, metallic sodium, metallic potassium, metallic lithium, sodium hydroxide, potassium hydroxide,
Examples include lithium hydroxide, sodium hydride, potassium hydride, lithium hydride, calcium hydroxide, calcium hydride, sodium t-butoxide, potassium t-butoxide, and the like. The amount of these metal compounds used should be at least a chemical equivalent to the two hydroxyl groups of the dialkanolamine, and in the case of an alkali metal compound, it is at least 2 times the mole, preferably 2.5 to 4 times the mole. . The reaction according to the invention is usually carried out in an inert organic solvent. Suitable solvents include, for example, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, dimethyl sulfoxide,
Examples include N,N-dimethylformamide, t-butanol, hexamethylphosphoric triamide, and the like. In the present invention, dialkanolamine () and polyethylene glycol derivative () are reacted at a molar ratio of 1:1 in the presence of a metal compound having a template effect. Usually, a solution of polyethylene glycol derivative (2) is gradually dropped into a solution containing dialkanolamine (2) and a predetermined amount of the above-mentioned metal compound while stirring. Alternatively, separately prepared solutions of dialkanolamine () and polyethylene glycol derivative may be simultaneously dropped into the solution of the metal compound. The reaction temperature varies depending on the type of polyethylene glycol derivative to be reacted with the dialkanolamine (); in the case of polyethylene glycol ditosylate, it is room temperature to the reflux temperature of the solvent, preferably about 40 to 80°C; In the case of dichloride, a temperature of about 60°C to 120°C is suitable. After the reaction is completed, the target product can be easily isolated by liquid-liquid extraction of the reaction mixture or by thermal decomposition distillation, and if necessary, it can be separated as a complex compound and purified by thermal decomposition. It can also be made into a product. In the present invention, when a metal compound having a template effect is not used, the yield is extremely low and the main component is a linear polymer, which cannot be said to be an industrial production method for obtaining the desired monoaza crown ether. According to the method of the present invention, dialkanolamine is reacted with polyethylene glycol ditosylate or polyethylene glycol dichloride as it is in the presence of a metal compound having a template effect without protecting the dialkanolamine as in conventional methods. Since monoaza crown ethers can be easily produced, it can be said to have extremely great industrial significance. Hereinafter, this will be explained in detail using examples. Example 1 3.15 g (0.03 mol) of diethanolamine and 2.07 g (0.09 mol) of sodium metal were dissolved in 250 ml of t-butanol, and triethylene glycol ditosylate (dissolved in 150 ml of dioxane while maintaining the temperature at 40°C) was added to the solution. 13.7g, 0.03mol)
dripped over time. After stirring for an additional hour, the reaction mixture was filtered and the solvent was distilled off under reduced pressure. 25 ml of water was added to the residue, and then extracted with hexane to remove the hexane extract. Thereafter, extraction was performed three times with dichloromethane. The dichloromethane extracts were combined and the solvent was distilled off under reduced pressure. The residue was then fractionally distilled using a Kugel-Rohr distiller to obtain a white solid. (Yield 3.1g, b.p80-85
℃/0.02mmHg, mp23~26℃). This product is
GLC analysis gives almost a single peak, IR
It was identified as monoaza 15-crown-5 [wherein R, R'=H, n=2] by spectra, mass spectra, and NMR spectra. Crude yield
49%. Furthermore, a sodium thiocyanate chain was obtained by treatment with a solution of sodium thiocyanate in acetone-hexane, and this was thermally decomposed to obtain a pure product. yield
20%, mp30~32℃, literature value (MRJohnson et
al; JCS Perkin I 357 (1979)): 27-30°C. Examples of monoaza crown ethers synthesized according to similar reaction procedures are shown in the table below. [Table] Note) a) Crude isolation yield

b) Abbreviation for

c) Recrystallized from hexane, mp49-51℃, literature value (assumption): 49-51℃
d) MS: 307 (M ⁺ ); ¹ H NMR (CDCl ₃ , δ): 2
.64(s,1H),2.79(t,4H),3.56−3.80(s＋m,24H)
e) MS: 247 (M ⁺ ), ¹ H NMR (CDCl ₃ , δ): 1
.05−1.22(m,6H),2.59(s,1H),2.42−2.80(m,4H),3.40−
3.84(s＋m,14H)
f) MS: 291 (M ⁺ ); ¹ H NMR (CDCl ₃ , δ): 1
.06−1.22(m,6H),2.54(s,1H),2.38−2.83(m,4H),3.37−
3.89(s＋m,18H)
Example 2 3,14-dioctyl monoaza 15-crown-5
Manufacturing of The dialkanolamine () used in this example is described in Avetyan MG et al. Arm.Khim.Zh, 27(1),
31-34 (Russ) (1979) from the following raw materials. Sodium hydride 2.9 in a 1-volume four-necked flask
g (0.12 mol), 200 ml of dimethylformamide, and 16.5 g (0.05 mol) of the dialkanolamine prepared above [in the formula (), R = R ¹ = C ₈ H ₁₇ ] were added, and after stirring at 80 ° C. for 1 hour. , 50 ml of a dimethylformamide solution containing 22.9 g (0.05 mol) of triethylene glycol ditosylate was added dropwise over 1 hour. After further stirring for 20 hours, the reaction mixture was filtered, and dimethylformamide was distilled off from the filtrate under reduced pressure to obtain a brown semi-solid. This was dissolved in 50 ml of water and then extracted three times with methylene chloride. The solvent was distilled off from the methylene chloride extract layer under reduced pressure to obtain 24 g of a brown viscous liquid. This was purified by thin film molecular distillation and bp240℃/1×10 ^-4 mmHg
7.1g of fraction was obtained. Yield 32%. This is MS, IR,
As a result of NMR analysis, 3,14-dioctyl monoaza
It was confirmed that it was 15-crown-5. Example 3 3,14-diphenylmonoaza 15-crown-5
Manufacturing of In a four-necked flask from Step 1, 12.9 g (0.05 mol) of dialkanolamine synthesized from ammonia and styrene oxide [formula (2)], 30 ml of dioxane, and 6.0 g (0.15 mol) of powdered sodium hydroxide. A solution of 22.9 g (0.05 mol) of triethylene glycol ditosylate dissolved in 200 ml of dioxane was added dropwise at 80° C. over 2 hours. After further stirring for 12 hours, the precipitated salt was filtered off, and dioxane was distilled off from the filtrate under reduced pressure to obtain 19 g of a brown liquid. This was rectified by thin film molecular distillation to obtain 7.6 g of wax-like solid at 260° C./1×10 ⁻⁴ mmHg. Yield 41%. Example 4 Production of 3-decyl monoaza 18-crown-6 5.6 g (0.05 mol) of potassium t-butoxide and dimethyl sulfoxide in a 500 ml four-necked flask.
100 ml was added, and then dialkanolamine prepared from 1-chloro-2-dodecanolamine and ethanolamine [in the formula (), R=H, R′=
Add 4.9 g (0.02 mol) of C ₁₀ H ₂₁ and 1
After stirring for an hour, 4.6 g (0.02 mol) of tetraethylene glycol dichloride was added to dimethyl sulfoxide.
A solution dissolved in 50 ml was added dropwise at 60°C over 1 hour. After further stirring for 6 hours, the precipitated salt was filtered off,
Dimethyl sulfoxide was distilled off from the filtrate under reduced pressure to obtain a brown semi-solid. This was dissolved in 30 ml of water and then extracted three times with methylene chloride. At this time, it becomes an emulsion, making it difficult to separate the layers, but if a small amount of ethanol is added, the layers separate relatively quickly. Then, the solvent was distilled off from the methylene chloride layer under reduced pressure to obtain 9.6 g of a crude product. This is fractionated using a Kugel-Rohr distillation apparatus, bp210~215℃/
2.3 g of a 0.02 mmHg fraction was obtained. Yield 29%. This is a viscous transparent liquid, and as a result of IR, MS, NMR analysis and elemental analysis, it was confirmed to be 3-decyl monoaza 18-crown-6. Example 5 Production of 3-perfluorooctyl monoaza 12-crown-4 The dialkanolamine [in the formula (), R=H, R ¹ =C ₈ F ₁₇ ] used in this example was prepared from the following raw materials according to the method described in German Published Application No. 2357780. 300 ml of t-butanol in a 1-volume four-necked flask
Then, 1.4 g (0.15 mol) of metallic lithium was added to completely dissolve the metallic lithium. Next, the above dialkanolamine [in the formula (), R=H, R ¹ =
C ₈ F ₁₇ ) 26.2 g (0.05 mol) was added, and after stirring for 2 hours, 2.07 g of diethylene glycol ditosylate was added.
(0.05 mol) dissolved in 100 ml of dioxane was added dropwise at reflux temperature over 2 hours. After further stirring for 6 hours, the precipitated salt was filtered off, and t-butanol was distilled off from the filtrate under reduced pressure to obtain 32 g of a crude product.
This is fractionated using a thin-film molecular distillation device to produce a bp230
5.9 g of a liquid having a temperature of ^0.degree . C./1.times.10.sup.-4 mmHg was obtained. Yield 20
%.

Claims (1)

[Claims] 1 General formula () (However, in the formula, R and R' are the same or different groups and represent a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, or a fluorocarbon group) Dialkanolamine represented by the general formula () (However, in the formula, X is [Formula] or Cl, n is an integer from 1 to 6) is reacted with a polyethylene glycol derivative represented by the following in the presence of a metal compound having a template effect. General formula () (However, in the formula, R, R' and n have the same meanings as above.) A method for producing monoaza crown ethers represented by: 2. The manufacturing method according to claim 1, wherein the metal compound having a template effect is an alkali metal or alkaline earth metal hydroxide or hydride. 3. The manufacturing method according to claim 1, wherein the metal compound having a template effect is an alkali metal alkoxide. 4 At least 2 based on dialkanolamine
Claim 1: A dialkanolamine and a polyethylene glycol derivative are reacted at a molar ratio of 1 in an organic solvent in the presence of twice the molar amount of alkali metal hydroxide, hydride or alkoxide.
Manufacturing method described in section. 5. The production method according to claim 4, wherein the reaction temperature is in the range of room temperature to reflux temperature.