JPS6130574A - Preparation of imidazole - Google Patents

Abstract

PURPOSE:To obtain easily the titled substance useful as a raw material for drugs, a dyeing auxiliary for acrylic fibers, etc. in high yield, by reacting an alpha- hydroxycarbonyl compound with a formamide as raw materials while keeping pH of the reaction solution in a specific range. CONSTITUTION:An alpha-hydroxycarbonyl compound shown by the formula I (R<1> and R<2> are H, saturated alkyl, saturated cycloalkyl, aryl, etc.) is reacted with a formamide while keeping pH of the reaction solution at 4-10, preferably at 7-10, to give a compound shown by the formula II. A molar ratio of formamide to alpha-hydroxycarbonyl compound of the former/the latter = usually 1/1- 10/1, preferably 2/1-4/1. When the compound shown by the formula I is added to the formamide little by little, usually 0.01-1mol/hr., preferably 0.03-0.5 mol/hr. based on the latter is selected.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a method for producing imidazoles unsubstituted at the 2-position, and more particularly, to a method for producing an unsubstituted imidazole at the 2-position, which comprises reacting an α-hydroxycarbonyl compound (I) with a formamide. This relates to a method of manufacturing a class of products.

Imidazoles are not only used as raw materials for medicines and agricultural chemicals, but also as dyeing aids for acrylic #Jli#, various dye intermediates, etc.
It is also a very useful compound as a curing agent and curing accelerator for epoxy resins, or as an industrial disinfectant, rust preventive, antistatic agent, etc.

Conventional Technology There have been many studies on the production of imidazoles for a long time, but all of them have drawbacks such as using expensive raw materials and complicated manufacturing processes, so they are not suitable for mass production.

For example, the method of obtaining imidazole by reacting an aldehyde and ammonia with a 1,2-dicarbonyl compound has the drawback that the 1,2-dicarbonyl compound cannot be mass-produced. The method of obtaining imidazole by reacting cupric acid has the disadvantages that imidazole cannot be produced in high yield, that it involves complicated steps, and that it consumes a large amount of expensive cupric acetate. In addition, a method to obtain imidazole by dehydrogenating imidacillin, an intermediate produced by the reaction of l,2-diamine and hydrogen cyanide, in the presence of a nickel formate catalyst has already been industrialized, but It has the disadvantage that it cannot be synthesized.

Problems to be Solved by the Invention The inventors of the present invention provide a production method that is simpler than conventional methods and does not have the drawbacks of the conventional methods described above and can produce imidazoles unsubstituted at the 2-position in high yield. The purpose is to

Means and Action for Solving the Problems As a result of various searches to achieve the above object, the present inventors have found that the 2-position non-functional compound can be easily obtained in high yield from α-hydroxycarbonyl compound (I) and formamides. The present invention was completed by discovering that substituted imidazoles can be produced.

Imidazoles unsubstituted at the 2-position are useful as raw materials for pharmaceuticals, but imidazoles substituted at the 2-position are useless as raw materials for pharmaceuticals. For example, 4-methylimidazole, which is a raw material for a specific drug against nervous gastric ulcers, can be obtained in high yield by the reaction of α-hydroxyacetone and formamide.

In the method of the present invention, no matter which method is used to react the α-hydroxycarbonyl compound and formamide, 2
Position-unsubstituted imidazoles are produced, but the yields are not necessarily the same.

The most preferred method is to add the α-hydroxycarbonyl compound little by little into excess formamide, and in the case of dimethylimidazole, a high yield of over 70% can be achieved.

[11 Below, each raw material used in the method of the present invention will be explained in detail.

(1) α-Hydroxycarbonyl compound is the following -
It is represented by general formula (I).

OH (wherein R1 and R2 are hydrogen or a group selected from the group consisting of a saturated alkyl group, a saturated cycloalkyl group, and an aryl group, and may be the same or different).

Examples of such compounds include the following.

■ Aliphatic carbonyl: acetoin, 1so-butyroyl-1so-propylcarbinol, tert-valeroyl-tert-butylcarbinol, n-butyroyl-n-propylcarbinol, acetylethylcarbinol, acetylphenylcarbinol■ Aromatic Carbonyl: benzoin, P-)ruyl-p-tolylcarbinol,
benzoylmethylcarbinol, m-toluyl-ter
t-Butylcarbinol, α-naphthoylmethylcarbinol, p-anthranoyl-ethylcarbinol.

・]) Aryl alkyl carbonyl system: (phenylacetyl)-benzyl carbinol, (p-ayudyl-n
-propionyl)-methylcarbinol.

・4 Alicyclic carbonyl system: (cyclohexylacetyl)-methylcarbinol, (
p-methylcyclohexylformyl)-ethylcarbinol, (cyclohexanoyl)-cyclohexylcarbinol.

(2) Formamides include formamide, its oligomers, polymers, and those forming adducts or complexes with other compounds.

``The one commonly used is formamide monomer.

Examples of formamide adducts include sodium hydrogen sulfite adducts and hydrogen cyanide adducts.

[21] Next, the amount of raw materials used, reaction conditions, etc. for carrying out the method of the present invention will be explained.

(1) The ratio of each raw material used in the method of the present invention is as follows.

The molar ratio of formamide and α-hydroxycarbonyl compound is selected to be former/latter = usually 1/1 to 10/1, preferably 2/1 to 4/1. This ratio is the value for the total amount used, and does not necessarily match the ratio during the progress of the reaction in each addition method.

When adding the α-hydroxycarboxol compound little by little into formamide, the latter is usually added at a rate of 0.01 to 1 + iol/hr, preferably 0.03 to 0.5 mol per 1 mol of the former. /hr is a good choice. In this case, the rate at which the latter is added may be changed,
It can also be added intermittently in portions. For example, by adding the remaining amount required at an appropriate time during the reaction period,
The molar ratio is adjusted to -10/l, preferably 2/1 to 4/1.

(2) The reaction conditions are as follows.

■ The reaction temperature is usually 100 to 250°C, preferably 15°C.
The temperature is selected from 0 to 200°C, but when using oligomers, polymers, adducts, complexes, etc. of formamide, it is necessary to select a temperature at which formamide is regenerated from them.

(Reaction pressure is 500mmHg ~ 20kgf/cm
' However, the volatility and decomposition of raw materials and main products,
Appropriate pressure should be selected taking into account solubility and similar properties of by-products.

(2) Although the reaction time varies depending on the addition rate, it is desirable to provide an additional post-reaction time after the completion of the addition. The post-reaction time is usually 1 to 10 hr, preferably 1 to 5 hr.

(2) It is useful to neutralize the formic acid produced by the reaction and then distill it off. As the neutralizing agent, for example, gaseous ammonia is used, but the neutralizing agent is not limited thereto.

(2) Maintain the pH of the reaction solution at 4-10, preferably 7-10. This pH is defined as the pi of an aqueous solution obtained by adding the same volume of pure water to the reaction solution.

This will be explained in more detail below with reference to Examples.

Example 1 243.2 g of formamide was charged under normal pressure into a four-hole flask equipped with a stirrer, thermometer, dropping funnel, and ester tube, and heated to 180°C. While stirring, 100.0 g of hydroxyacetone was added. Water and formic acid produced as by-products are distilled out of the system, and the reaction solution is added dropwise over 4 hours while maintaining the pH of the solution at 4 to 10. After completion of the dropwise addition, continue stirring at 180°C for 2 hours. Distilling the reacted compound directly under reduced pressure yields 78.8g of 4-methylimidazole (813.3% of Fl! theory) with a boiling point of 122-124°C/4mm). is obtained. The structure was determined by NNR, IR, MS, and elemental analysis.

Elemental analysis: Cs H6N2 82.1048
Calculated values: C5B, 52% H7, 37%N 34
．． 12% Actual value: C58, 48% H7, 34%N 34
．． 18% Example 2 A flask equipped with a stirrer, a thermometer, and a dropping funnel was charged with formamide 38; Drip the mixture over 2 hours. After completion of the dropwise addition, continue stirring at 150°C for 2 hours. The reaction mixture was directly distilled under reduced pressure to obtain 10.7 g (65.2% of theory) of 4-methylimidazole.

Example 3 Formamide 3e and Og were charged under normal pressure into a four-loop flask equipped with a stirrer, a thermometer, and two dropping funnels, and 18
While heating to 0°C and stirring Wl, add hydroxyacetone 1
4.8 g and 16.8 g of sodium bicarbonate powder were added dropwise over 1 hour. After completion of the dropwise addition, the reaction mixture was continued to be stirred at 185° C. for 2 hours and distilled under reduced pressure to obtain 10.2 g (62.1% of the theoretical amount) of 4-methylimidazole.

Example 4 72.1 g of formamide was charged into an autoclave,
Heating to 180°C, adding hydroxyacetone at a rate of 8.8+aQ/hr using two feed pumps, 48
%-'=i+1 Sorter aqueous solution at 4,4 d/h
r (7) and feed for 4 hours. The pressure is 5-1
L rises to 0 kg/cm', but continues as it is for 2 hours, 1
Continue stirring at 80°C. The reaction mixture was directly distilled under reduced pressure to obtain 19.1 g (58.2% of the theoretical amount) of 4-methylimidazole.

Example 5 In the same manner as in Example 1, 36.0 g of formamide and 17.6 g of acetoin were reacted and distilled under reduced pressure to produce 13.7 g of 4.5-dimethylimidazole at 165-170°C/10 m+aHg (theoretical). 71.3% of the amount)
was gotten. HHR, Il'1. The structure was determined by MS and elemental analysis.

Elemental analysis: C3H8N296.131El calculated value
: C62,47% H8,39%N 29.14% Actual value: C[f2.47% H8,33%N
28.20% Example 6 Using the same apparatus as in Example 1, 36.0 g of formamide was heated to 180°C under normal pressure, and while stirring, a solution of 84.9 g of pentuin and 38.0 g of formamide was added in the middle. By-product water and formic acid are distilled out of the system, and the pH of the reaction solution is adjusted to 4.
While maintaining the temperature at ~10, drop the mixture over 2 hours. After completion of the dropwise addition, continue stirring at 180°C for 2 hours. Add ether to the reaction mixture and wash with the same amount of water five times. After washing with water, drying with anhydrous sodium sulfate, distilling off the ether, and recrystallizing with ethanol, 6.8 g of 4.5-diphenylimidazole a having a melting point of 228-230°C (53.1% of the theoretical amount)
)was gotten.

The structure was determined by NMR, IR, MS, and elemental analysis.

Elemental analysis: Cs5Ht2N2 220.273
4 Calculated values: C81,79% H5,49%N 1
2.72% Actual value: C81,78% H5,51%N 12
．． 71% Effects of the Invention As detailed above, by the production method of the present invention, 2-position unsubstituted imidazoles, which have conventionally been difficult to produce industrially, can be produced easily and in high yield.

For example, the effects of the present invention are extremely significant, as 4-methylimidazole, which is a raw material for a specific medicine against nervous gastric ulcers, can be obtained with a high yield of about 70% by the production method of the present invention.

Claims (1)

[Claims] (1) The α-hydroxycarbonyl compound represented by the general formula (I) and formamides were mixed at a pH of 4 to 4.
A method for producing imidazoles that are unsubstituted at the 2-position, the method comprising producing imidazoles represented by general formula (II) by carrying out the reaction while maintaining the temperature at the 2-position. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In formulas I and II, R^1 and R^2 are hydrogen, saturated alkyl groups, saturated cyclo (a group selected from the group consisting of an alkyl group and an aryl group, which may be the same or different).