JPH038324B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an alkylating agent that is used for the alkylation of oxygen atoms (O-alkylation) or nitrogen atoms (N-alkylation) and has hydrophilic properties. Conventionally, compounds having an alkylating functional group have used their alkylating ability as a functional group for expressing one of the main biological activities, and have been used as anticancer agents, antiviral agents,
It is known to exhibit biological activities such as antibacterial agents. The alkylating functional groups that are used or expected to be used as physiologically active compounds, including pharmaceuticals, are mainly the following atomic groups. C-Cl,

[Formula] C-Br, C-I, C-OCONR ₁ R ₂ ,

[Formula] C-OSO ₂ CH ₃ ,

【formula】

[Formula] However, R, , R ₂ are each H or a substituted or unsubstituted aralkyl group. These alkylated atomic groups are generally hydrophobic, and when these functional groups are introduced into molecules, they generally become more hydrophobic than the parent compound, which poses considerable obstacles when used as biologically active substances. ing. The present inventors have provided an alkylating agent that has strong alkylating ability, can be used stably and safely during storage and use, and has an alkylating functional group introduced that makes the entire molecule more hydrophilic. As a result of intensive research, it was discovered that the compound represented by the above general formula is suitable for this purpose, and the present invention was completed. That is, the present invention relates to a hydrophilic alkylating agent for oxygen or nitrogen atoms, which is characterized by being composed of a sulfonic acid ester represented by the following general formula. (HOCH ₂ CH ₂ SO ₂ -O-) _o・R However, n is 1
or 2, R is an alkyl group or alkylene group having 1 to 7 carbon atoms. Specific examples of R include methyl, ethyl, isopropyl, ethylene, propylene, tetramethylene, pentamethylene, and those groups in which a portion of the hydrogen atoms are substituted with halogen atoms, hydroxyl groups, etc. Specific compounds of the present invention include, for example, n
Isethionic acid methyl ester (β-hydroxyethanesulfoxymethane) with =1, R= _CH3
HOCH ₂ CH ₂ SO ₂ OCH ₃ , n=2, R=-(CH ₂ ) ₄
-1,4- _di- (β _- hydroxyethanesulfoxy) _butane HOCH2CH2SO2O-( _CH2 ) _{4-
OSO2CH2CH2OH} , n=2 _, 1,5 _- di-(β-hydroxyethanesulfoxy) _pentane with R=-( _CH2 ) _{5- , HOCH2CH2SO2O-} ( _CH2 ) ₅ −
Examples include OSO ₂ CH ₂ CH ₂ OH. The alkylating agent of the present invention can be produced, for example, by the following two methods. The corresponding silver salt of sulfonic acid containing an amount of ethylene and the corresponding hydroxyl group containing R are combined with iodine, bromine,
Alternatively, it can be produced by reacting a halogen compound substituted with chlorine in an organic solvent. Although it is preferable that the amount of reaction between the sulfonic acid and the halogen compound is equivalent, it is not necessarily limited to this, and may be a certain amount of excess or deficiency. The reactivity is with iodine, followed by bromine, and in the case of chlorine, it is necessary to either lengthen the reaction time or raise the reaction temperature. The reaction is generally carried out in an organic solvent, such as acetonitrile, and does not require a catalyst. The amount of the solvent to be used may be in accordance with the conventional method used in the desilver halide reaction between an organic silver brewing salt and an alkyl halide, and is approximately several tens of times the amount of the alkyl halide. The reaction temperature may be either room temperature or heating, but heating is preferable from the viewpoint of reaction rate. If the temperature is too high, the yield will decrease, so a temperature of 60°C or lower is suitable. The required reaction time varies somewhat depending on the type of reaction raw materials and reaction temperature, but is about 24 to 48 hours at room temperature, and about 10 hours at 45 to 60°C, for example. After the reaction, the precipitated silver halide is removed by suitable means, and the solution is subjected to distillation to remove the solvent to obtain the desired product, or alternatively, as a means of separation and purification, silica gel or the like is filled. It is also preferable to use a column that has been prepared. It may be produced by reacting a corresponding sulfochloride containing an ethylene group with a corresponding alcohol containing R in an organic solvent. The only existing example of this production method is a report on the production of butyl isethionate. However, the drawback of this method is that isethionic acid chloride, for example, is extremely unstable and is only stable at -20°C. The hydrophilic alkylating agent of the present invention is used, for example, to alkylate oxygen atoms in alcohols, phenols, etc., and to alkylate nitrogen atoms in various amines, etc., and exhibits excellent alkylating ability. Next, the present invention will be explained in more detail with reference to Examples and Comparative Examples. In each example, infrared absorption spectrum analysis was performed using a chloroform solution using a NaCl cell. Example 1 (n=1, R=CH ₃ example) and Comparative Example 1 First, isethionic acid methyl ester was produced as follows. 2.5 g of silver isethionate and 23 g of methyl iodide were dissolved in 30 ml of acetonitrile and left at room temperature for 8 hours. After filtering the precipitated silver iodide and concentrating the liquid, the remaining liquid was distilled under reduced pressure to 80~95℃~2mmHg.
Isethionic acid methyl ester was obtained as a fraction. What was obtained was a colorless liquid with a yield of 80
It was %. Nuclear magnetic resonance spectroscopy (hereinafter referred to as NMR analysis), infrared absorption spectrum analysis (hereinafter referred to as IR analysis), and elemental analysis were performed on this. NMR analysis: (See Figure 1) 3.23ppm (1H, singlet) 3.38ppm (2H, triplet, J=5H,) 3.94ppm (3H, singlet) 4.06ppm (2H, triplet, J=5H ₂ ) IR analysis: (See Figure 2) 980CM ^-1 (S-O-C stretching) 1155CM ^-1 (S(=O) ₂ symmetrical stretching) 1355CM ^-1 (S(=O) ₂ asymmetrical stretching) 3550CM ^-1 (OH stretching) Elemental analysis: (C ₃ H ₈ O ₄ S) Estimated value H5.75%, C25.71% Measured value H6.01%, C25.96% Methyl isethionate thus obtained The alkylation reaction was then carried out using the ester. Mix 20ml of 0.25M4-(P-nitrobenzyl)pyridine (hereinafter referred to as NBP)-acetone solution, 20ml of 1/15M phosphate buffer PH6.0, and 10ml of 1.36× ^10-3M isethionic acid methyl ester-acetone solution. ,
By doing this, 1.5 ml to 2 ml each is poured into 10 to 15 ampoules, and the air in the ampoules is replaced with nitrogen gas.
Seal the ampoule and react at 37. Take out the ampoule over time, measure out 1.0 ml from the reaction solution, add 4 ml of water, 0.5 ml of INNaOH aqueous solution, and 5 ml of benzene.
Add this to a test tube containing ml and shake well to extract the dye into the benzene layer. Dry the benzene layer with potassium hydroxide and measure the absorbance at 535 mm. Incidentally, for the purpose of comparative study with isethionate methyl ester, methanesulfonic acid methyl ester was also subjected to the same operation (Comparative Example 1). The results are shown in FIG. 3. As shown in Figure 3, isethionate methyl ester reached a plateau at OD* 1.578. Calculated from the theoretical value of OD1.627 when all the alkylating agents react with NBP, 97% of isethionate methyl ester is
It is thought that it reacted with NBP. Furthermore, if the time required to show an OD of 1/2 of the OD that reached the plateau is t1/2, it is thought that the reaction rate can be compared using this value, but the value t1/2 = 2.2 hr. Ta. On the other hand, for methanesulfonic acid methyl ester, the OD at which it reached a plateau was 1.497, indicating that 92% of methanesulfonic acid methyl ester reacted with NBP. In addition, t1/2 = 3.3 hr. From the above results, the alkylation ability of isethionic acid methyl ester is superior to that of methanesulfonic acid methyl ester, as shown by NBP, and the reaction rate is also very high. It was shown that it is true. *Optical Density Example 2 (n=1, R=C ₂ H ₅ example) and Comparative Example 2 First, isethionic acid ethyl ester was produced as follows. Dissolve 1.7 g of silver isethionate and 8.1 g of ethyl bromide in 20 ml of acetonitrile and heat at 37℃ for 28 hours.
Warm for an hour. After filtering the precipitated silver bromide and concentrating the liquid,
The desired product was separated and purified from the remaining liquid using a column packed with 25 g of silica gel and eluted with 5 methanol-dichloromethane to obtain isethionic acid ethyl ester. What was obtained was a colorless liquid with a yield of 85%
It was hot. NMR analysis, IR analysis and elemental analysis were performed on this. NMR analysis: (See Figure 4) 1.45ppm (3H, triplet, J=7H ₂ ) 2.92ppm (1H, triplet, J=6H ₂ ) 3.42ppm (2H, triplet, J=6H ₂ ) 4.14ppm (2H, quartet, J=6H ₂ ) 4.42ppm (2H, quartet, J=7H ₂ ) IR analysis: (See Figure 5) 910,995CM ^-1 (S-O-C expansion and contraction) 1155CM ^{- 1} (S(=O) ₂ symmetrical stretching) 1345CM ^-1 (S(=O) ₂ asymmetrical stretching) 3550CM ^-1 (O-H stretching) Elemental analysis: (C ₄ H ₁₀ O ₄ S) Estimated value H6.54 %, C31.16% Measured value H6.84%, C30.94% Using the isethionic acid ethyl ester thus obtained, an alkylation reaction was then carried out. An alkylation reaction was carried out in the same manner as in Example 1, except that an isethionate ethyl ester-acetone solution was used instead of the isethionate methyl ester-acetone solution. For comparison, methanesulfonic acid ethyl ester was used (Comparative Example 2). The results are shown in Figure 6. As shown in Figure 6, it plateaus at OD1.106.
The reaction with NBP was 68%, and the t1/2 value was 28 hours. On the other hand, methanesulfonic acid ethyl ester
It can be seen that there was a plateau at OD 0.960 and 59% reacted with NBP. Furthermore, the t1/2 value was 50 hr, indicating that isethionic acid ester was slightly superior to methanesulfonic acid ester among ethyl esters. Example 3 (an example _where n=1, R= _C3H7 ) and Comparative Example 3 First, isethionic acid i-propyl ester was produced as follows. 2.5 g of silver isethionate, 5 g of i-propyl iodide
g was dissolved in 20 ml of acetonitrile and left at room temperature for 20 hours. After filtering the precipitated silver iodide and distilling off the liquid, the desired product is extracted from the remaining liquid using 50g of silica gel.
The mixture was separated and purified using a column packed with chloroform and eluted with chloroform to obtain isethionic acid i-propyl ester as a colorless liquid. The yield was 85%. NMR, IR and elemental analysis were performed on this. NMR analysis: (See Figure 7) 1.44ppm (6H, doublet, J=7H ₂ ) 2.65ppm (1H, singlet) 3.35ppm (2H, triplet, J=5H ₂ ) 4.08ppm (2H, triplet line, J=5H ₂ ) 5.01ppm (1H, septet, J=7H ₂ ) IR analysis: (see Figure 8) 910CM ^-1 (S-O-C expansion and contraction) 1159CM ^-1 (S(=O) ₂ 1332CM ^-1 (S(=O) ₂ asymmetrical stretching) 3550M ^-1 (O-H stretching) Elemental analysis: (C ₅ HA ₂₈ O ₄ S) Estimated value H7.17%, C35.70% Measured value H7.46%, C35.26% Using the isethionic acid i-propyl ester thus obtained, an alkylation reaction was then carried out. In Example 1, the alkylation reaction was carried out in the same manner as in Example 1, except that isethionic acid i-propyl ester was used instead of the isethionic acid methyl ester-acetone solution. For comparison, methanesulfonic acid i-propyl ester was used (Comparative Example 3). The results are shown in Figure 9. As can be seen from Figure 9, isethionic acid i-propyl ester plateaus at an OD of 0.137.
The reaction with NBP was 8% and the t1/2 value was 20 hr, while for methanesulfonic acid i-propyl ester
There was a plateau at OD 0.106, 7% reacted with NBP, and t1/2 was 35 hours. Therefore, it can be seen that isethionic acid ester has a superior alkylation ability to methanesulfonic acid ester as well as the previous two i-propyl esters.

[Brief explanation of drawings]

Figure 1 is an NMR spectrum diagram of isethionic acid methyl ester used in Example 1, and Figure 2 is its NMR spectrum.
The IR spectrum diagram, FIG. 3, is a diagram showing the progress of the alkylation reaction of NBP using isethionic acid methyl ester. Figure 4 is an NMR spectrum diagram of isethionic acid ethyl ester used in Example 2, Figure 5 is its IR spectrum diagram, and Figure 6 is a diagram showing the progress of the alkylation reaction of NBP using isethionic acid ethyl ester. be. Figure 7 is an NMR spectrum diagram of isethionic acid i-propyl ester used in Example 3, Figure 8 is its IR spectrum diagram, and Figure 9 is the progress of the alkylation reaction of NBP using isethionic acid i-propyl ester. FIG.

Claims (1)

[Scope of Claims] 1. A hydrophilic alkylating agent for alkylating an oxygen atom or a nitrogen atom, characterized by comprising a sulfonic acid ester represented by the following general formula.
(HOCH ₂ CH ₂ SO ₂ -O) _o ·R However, n is 1 or 2, and R is an alkyl group or alkylene group having 1 to 7 carbon atoms.