JPS6287573A - Production of quaternary ammonium salt - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for producing a remedy for ulcer having histamine H2-receptor antagonistic effect, in high yield and purity, by alkylating an imidazole derivative in a polar solvent using inexpensive dimethyl sulfate as the alkylation agent. CONSTITUTION:The objective 5-methyl-imidazolylmethyl quaternary ammonium salt of formula II [e.g. diethylmethyl-(5-methylimidazol-4-yl)-methyl ammonium methylsulfate] can be produced by reacting an imidazole derivative of formula I (R<1> and R<2> are lower alkyl; R<1> and R<2> may together from an alkylene which may contain oxygen atom in the carbon chain) (e.g. 4-diethylaminomethyl-5- methyl-imidazole) with dimethyl sulfate in a polar solvent such as water, methanol, their mixture, etc., preferably at room temperature. USE:Intermediate for producing cimetidine, etintidine, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new production wave of intermediates for the production of ulcer therapeutic agents having histamine H2-receptor antagonistic activity, such as cimetidine or etchintidine, in the pharmaceutical field. It is.

BACKGROUND ART Known methods for producing 5-methylimidazole ammonium salt include those disclosed in JP-A-58-162576 and JP-A-58-162576;
No. 9-7172 is known. Namely.

% (in which +X0 represents a lower alkyl group, a lower alkenyl group, or an aralkyl group). and Q represents an acid residue) is reacted with an alkylating agent represented by the general formula (wherein,
and ×3 having the above meaning).

Problems to be Solved by the Invention From 5-methyl-imidazolylmethylamine derivatives to 5-
In a known production method for methyl-imidazolylmethyl quaternary ammonium salt, the target compound is obtained by reacting a 5-methyl-imidazolylmethylamine derivative, which is a raw material, with a sophisticated methyl iodide as an alkylating agent. . This method is unsuitable for industrial production due to the handling of the alkylating agent and the cost of its raw materials.

Means for Solving the Problems As a result of intensive research into a method for producing 5-methyl-imidazolylmethyl quaternary ammonium salt suitable for industrialization, the present inventors used inexpensive sulfurized dimethyl as an alkylating agent, and in addition It has been discovered that when the alkylation reaction is carried out in a polar solvent as the reaction solvent, 5-methylnomidazolylmethyl 4-treated ammonium salt can be obtained in high yield and high purity,
Completed non-invention.

Function The present invention is directed to -9 di-formula (wherein R1r3 and CR2 represent a lower alkyl group).

Note that R1 and R2 may be linked to each other to form an alkylene group that may contain three atoms in the carbon chain). The present invention relates to a novel method for producing a quaternary ammonium salt represented by the general formula (wherein R and R have the above-mentioned meanings).

Next, the low-plate alkyl groups mentioned in J1 for each of the three listed in the Unknown Fence Layer are, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc. It is an alkyl group consisting of 1 to 6 carbon atoms. Further, the alkylene group which may contain an oxygen atom in the carbon chain is, for example, a tetramethylene group, a pentamethylene group, or a ni group.

Next, the manufacturing method of the present invention will be explained.

The target compound of the present invention is usually 1 to 3 mol of 9 per 1 mol of the imidazole derivative represented by the general formula 7.
It is preferably prepared by reacting 1 to 1.5 moles of 6ffl f4 dimethyl in a polar solvent. The polar solvent used at this time is:

Water, methanol or a mixed solvent thereof is preferred.

The reaction temperature is at least below room temperature, preferably -20°C.
to 10°C. The reaction time is 10 minutes to 24 hours, preferably 0.5 hours to 8 hours.

The target compound of the present invention can be isolated from the reaction solution obtained as described above, for example, by extraction and concentration, and further, by column chroma 1 graphography or crystallization using a common solvent. Further, the product can be used as a single reaction solution for Ha of cimetidine or edintidine without isolation or purification.

Next, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

Example 1 4-diethylamine methyl-5-methylimidazole 1
．． 0g (6.0mmal) in water 6. Dissolved in Od e, C, while stirring under water cooling, sulfurized dimethyl 0.75, d
(6.0 mmof) was added dropwise over about 10 minutes.

After completion of the dropwise addition, the two reaction solutions were stirred for 20 minutes under water cooling and for 1 hour at room temperature, and then adsorbed with resin Diaion HP-20100r.
rd column. The target product was eluted with 200 ml of water, the fractions containing the target product were collected, and the solvent was distilled off under reduced pressure. Diethylmethyl-(5-methylimidazole-4
-yl〉methylammonium to methylsulfuric acid 1,
Colorless and transparent oil (q. Yield 1.629 (yield 92%)'H-IJMR(DO,)DSS)
δ: 1.40 (6H, t, J=7Hz), 2.32 (3
H.

S), 2.90 (3H, S), 3.35 (4H, Q
, J=7H2), 3.72(3H,S), 4.3
2(2H,S)7,75(IH,S) Br IRv Cm-1: 3700-2700(
dr), 1650, 1470゜jnaX 125
a, 1070.1020.760 Actual example 2 4-piperidinomethyl-5-methylimidazole i, 0
8 y (6.0 m mol) was dissolved in a mixed solvent of 3 Iri of methanol and 3 mol of water, and 0.75 m (6.0 m mof) of dimethyl sulfur was dissolved in a mixture of about 10
Drip over a minute. After completion of the dropwise addition, the mixture was stirred for 1 hour under water cooling and for 3 hours at both temperatures, and then the solvent was distilled off under reduced pressure.

Dissolve the residue in 25 m2 of water and add adsorption resin Diamond Ion H.
P-20 (100 mJ column) to elute the 5 target compounds that contain the target compound, collect the fraction containing the target compound, and distill off the solvent under reduced pressure. )
Methyl-\-methylpiperidium methylsulfate is obtained as a clear colorless oil. Yield 1.65a (
Yield=90918)'HNHR(D20.'DSS>δ 1,5~2.2(6)f,m), 2.33(3H3
), 2.98 (3H, S), 3.18-3.35 (
4H, m), 3.70 (3H, S), 3.18~3
．． 55(4)1. m), 3.70 (3H, s).

4, 40 (2H, s), 7.80 (IH, 5) KBr
-1 IRv am: 3700~270
0,1460,1260゜"ax1230.'l06
0.1010.760 Test Example 4-Diethylamine methyl-5-methylimidazole 1
0h + y (0,60m mol) in the table below - 1xe
After dissolving in 0.6 d of various R-treated solvents and maintaining at respective temperatures, dimethyl sulfate 57 μm (0.60 m mo
l) or 62μI methyl iodide (0,606m m
ol) was added dropwise.

Test Examples K to 5 and Comparative Example 1 were reacted for each time period.
Reaction solutions 6 to 6 were obtained.

Methanol was added to each reaction solution obtained as above to dilute it to 50%. Internal standard substance solution (4-methylimidazole 1.0Rg,
Using high-performance liquid chromatography, two 10-μm aliquots of each solution obtained by adding 200 μm of 200 μm of the internal standard substance of each sample and the reaction product diethylmethyl-(5-methylimidazole-4 -yl)ammonium methyl sulfate or diethylmethyl-
(5-methylimidazol-4-yl)ammonium
Measure the peak area ratio with iodide. Each yield was determined using a calibration curve obtained in the same manner from the standard sample. The results are shown in Table-■.

(Left below) Measurement conditions for high performance liquid chromatography Column: De
velosil■0PS5 (46mm<id) x 2
50mm> Mobile phase: 0.1) 1-acetic acid (containing 0.01-1 sodium hexane sulfonate)/acetonitrile = 85. /15 Flow rate: 1. O/'nf! /min Detection: UV230nm (blank below) As is clear from the surface treatment, if the reaction is carried out at a temperature below room temperature using dimethyl sulfate as the alkylating agent or water or a mixture thereof as the polar solvent, The desired quaternary ammonium salt can be obtained in extremely high yield.

Effects of the Invention The present invention provides 5-methyl-imidazolylamine derivatives with
By acting with dimethyl sulfate as an alkylating agent in a polar solvent, 5-
Methyl-imidazolylmethyl quaternary ammonium salt can be produced easily, in high yield, and furthermore at low cost.

Claims (3)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [II] (In the formula, R^1 and R^2 represent a lower alkyl group. In addition, R^1 and R^2 are connected to each other to form a carbon may form an alkylene group that may contain an oxygen atom in the chain)
There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [ I ] (where R^1 and R^2 are the above-mentioned A method for producing a quaternary ammonium salt represented by (2) The production method according to claim 1, characterized in that water, methanol, or a mixture thereof is used as the polar solvent. (3) The production method according to claim 1, characterized in that the reaction is carried out at a temperature of at least room temperature or lower.