KR20010050060A - A novel process for preparing 1-substituted-5-hydroxymethyl imidazole - Google Patents

Abstract

PURPOSE: A process for preparing 1-substituted 5-hydroxymethylimidazole(formula 1) by replacement of 1-substituted 5-hydroxymethylimidazole-2-thiol in position 2 with hydrogen is provided. Thereby, the desired compound can be prepared more safely, rapidly and purely in higher yield than the conventional process. CONSTITUTION: The formula compound is prepared by the reaction of 1-substituted 5-hydroxymethylimidazole-2-thiol of formula 2 in a solvent in the presence of an oxidant selected from the group consisting of hydrogen peroxide, alkyl hydrogen peroxide and alkali hypochlorite and a transition metal catalyst. In the formula, R is alkyl, hydroxy alkyl, aryl or substituted or nonsubstituted arylmethyl or diarylmethyl.

Description

A novel process for preparing 1-substituted-5-hydroxymethyl imidazole}

The present invention relates to a process for preparing 1-substituted-5-hydroxymethyl imidazole of formula (1), more specifically 1-substituted-5-hydroxymethylimidazole-2- of formula (2) To a method of preparing a compound of Formula 1 by substituting hydrogen for position 2 of thiol:

[Formula 1]

[Formula 2]

Wherein R is alkyl, hydroxyalkyl, allyl, or substituted or unsubstituted arylmethyl or diarylmethyl, respectively, preferably C _1-4 alkyl, hydroxyC _1-4 alkyl, allyl, benzyl, Substituted benzyl, in particular benzyl substituted by halogen, 3,4-dioxymethylenebenzyl or 2-arylmethyl.

The 1-substituted-5-hydroxymethyl imidazole of Formula 1 is a key intermediate known to be useful in the preparation of various anticancer agents, especially in the anti-cancer agents of the panesyl transferase inhibitor system (see Ko, JS et al. , PCT International Application Publication WO 9905117 A1 19990204, p129).

In the method for preparing the compound of Chemical Formula 1 from the compound of Chemical Formula 2, a conventionally used method removes thiol groups substituted at position 2 by heating with concentrated nitric acid or concentrated nitric acid and a catalytic amount of nitrite. (RG Jones, J. Amer. Chem. Soc., 1949, 71, 383), which has the advantage of being economically and laboratoryly simple to operate. However, this manufacturing method uses excessive concentrated nitric acid, which causes severe heat generation during the neutralization after the completion of the reaction, a large amount of gas is generated, and occurs rapidly at a moment while the reaction is warmed. It is not possible to secure safety in industrial production. In addition, the most important problem is that the electrophilic nitration reaction to the aromatic ring in the warm state is accompanied by the disadvantages of the side reaction has been developed a new manufacturing method that improves this problem.

In order to develop a new production method that can solve the above problems in the preparation of 5-hydroxymethyl imidazole, the inventors conducted extensive research.

In the oxidation of thiol groups to sulfonic acids, reports using either concentrated nitric acid or concentrated hydrochloric acid and hydrogen peroxide (see Cech, J., Collect. Czech.Chem. Commun., 1949, 14, 558) and sulfides Reactions to sulfoxides or sulfones (Vernier, CG, et al., J. Org. Chem., 1982, 47, 3773; Edwards, D., J. Chem. Soc., 1954, 3272; Paquette, LA, Org. Synth., 1985, 64, 157; Watanabe, Y., Synthesis, 1981, 204; Ho, TL, Synthesis, 1972, 561; Djerassi, C, J. Amer. Chem. Soc., 1953 , 75, 3838, etc.) have been reported in many literatures and there are many examples commonly used in the art. However, in spite of many documents as described above, the oxidative cleavage of thiol groups, which is useful in the present invention, is difficult to find an example of, and while studying a method for producing using an industrially preferred catalyst, hydrogen peroxide as a transition metal catalyst and oxidant When used, etc., it was confirmed that the desired imidazole derivative can be easily obtained with high purity under mild reaction conditions, and the present invention was completed.

The present invention reacts 1-substituted-5-hydroxymethylimidazole-2-thiol of formula (2) in the presence of an oxidizing agent such as a transition metal catalyst and hydrogen peroxide in a solvent to 1-substituted-5 of formula (1) To a process for preparing hydroxymethyl imidazole:

[Formula 1]

[Formula 2]

Wherein R is alkyl, hydroxyalkyl, allyl, or substituted or unsubstituted arylmethyl or diarylmethyl, and the like, preferably C _1-4 alkyl, hydroxyC _1-4 alkyl, allyl, benzyl Substituted benzyl, in particular benzyl substituted by halogen, 3,4-dioxymethylenebenzyl or 2-arylmethyl and the like.

However, conventional substituents other than the aforementioned substituents may also be applied without further mention.

Alkyl in the above definition is straight or branched alkyl.

The present invention is explained in more detail as follows.

The 5-substituted 5-hydroxymethylimidazole-2-thiol substituted at 1-position is reacted at room temperature to elevated temperature by adding an equivalent oxidizing agent in the presence of a catalytic amount of transition metal in water or a water-soluble solvent system or a mixture thereof. In this way, the 1-substituted-5-hydroxymethylimidazole-2-thiol can be very easily converted to 1-substituted-5-hydroxymethyl imidazole.

As a catalyst used in the preparation method of the present invention, various transition metals having oxidizing ability, for example, vanadium, chromium, molybdenum, manganese, tungsten, rhenium, ruthenium, osmium, and the like can be used, among which rhenium, ruthenium, osmium Etc. are expensive, and vanadium, chromium, manganese, tungsten, etc. are relatively inexpensive, and these transition metals are preferable in consideration of industrial aspects. More preferred transition metal catalysts are tungstic acid (H ₂ WO ₄ ), vanadium oxide (V ₂ O ₅ ) or vanadium sulfate (VOSO ₄ ). Starting materials 1-substituted-5-hydroxymethylimidazole-2-thiol of Formula 2 vs. transition metals used as catalysts, for example tungstic acid (H ₂ WO ₄ ), vanadium oxide (V ₂ O ₅ ) or vanadium sulfate (VOSO ₄ ) is usually 5: 1 to 1000: 1 and preferably 50: 1 to 1000: 1.

As the equivalent oxidizing agent useful in the present invention, hydrogen peroxide, alkyl hydrogen peroxide (t-butylhydrogen peroxide, etc.) or alkali hypochlorite (sodium or calcium) is suitable, among which 10% to 30% of hydrogen peroxide is more preferable. Do. 3-10 molar equivalents are used with respect to the compound of formula 1.

As the reaction solvent, water or a water-soluble solvent system, preferably lower alcohols or a mixture thereof is used, most preferably water, methanol, ethanol or a mixture thereof.

The reaction temperature can be reacted at 30 to 100 ° C, preferably at 50 to 70 ° C, more preferably at 40 to 70 ° C. In addition, the reaction is generally substantially terminated by the conversion of the 1-substituted-5-hydroxymethylimidazole-2-thiol of formula (2) to 1-substituted-5-hydroxymethyl imidazole of formula (1). Progress until, preferably 2 to 6 hours.

After completion of the reaction, the reaction mixture is simply basified to give a solid or the resulting solid is filtered off or basified and then extracted with a suitable solvent, for example dichloromethane or chloroform and, if necessary, a suitable solvent commonly used, for example n By further purification by treatment with -hexane or isopropyl ether, the desired product, i.e., 1-substituted-5-hydroxymethyl imidazole, can be easily recovered from the reaction mixture in high purity.

The invention is illustrated in more detail by the following examples, although the scope of the invention is not limited in any way by these.

Preparation Example 1 Preparation of 1-benzyl-5-hydroxymethylimidazole-2-thiol

Benzylamine hydrochloride (14.36 g, 0.1 mol) and 1,3-dihydroxyacetone dimer (18 g, 0.1 mol) are well suspended in 100 ml isopropanol and then thiocyanate potassium salt (14.6 g, 0.15 mol) is added. It was. Acetic acid (19.22 g, 0.32 mol) was added dropwise to the suspension, followed by stirring at room temperature for 24 hours. 50 ml of distilled water was added to the reaction solution, followed by further stirring for about 0.5 hours, filtered, washed twice with 50 ml of distilled water, and then twice with 50 ml of isopropyl ether to obtain the white solid powder, which was dried for about 3 hours. A certain weight of product was obtained. By this method 20.4 g (yield 92.6%) of pure 1-benzyl-5-hydroxymethylimidazole-2-thiol was finally obtained.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.15 (1H.s), 7.32 (2H, t, J = 7.3 Hz), 7.26 (1H, d, J = 7.3 Hz), 7.24 (2H, t, J = 7.3 Hz), 6.85 (1H, s), 5.32 (2H, s), 5.25 (1H, s), 4.14 (2H, d, J = 5 Hz)

Preparation Example 2 Preparation of Various Imidazole-2-Thiol Derivatives

Various imidazole-2-thiol derivatives were prepared in a similar manner to Preparation Example 1 and the results are shown in the table below.

Imidazole 2-thiol derivative R time yield ¹ H NMR 15 91% 12.18 (1H, s) 7.51 (2H, d, J = 8.7 Hz) 7.20 (2H, d, J = 8.7 Hz) 6.86 (1H, s) 5.28 (2H, s and 1H; -OH) 5.16 (2H, d , J = 3.7 Hz) 15 88% 12.20 (1H, s) 7.45 (1H, d, J = 7.8 Hz) 7.44 (1H, s) 7.29 (1H, t, J = 7.8 Hz) 7.22 (1H, d, J = 7.8 Hz) 6.88 (1H, s ) 5.81 (2H, s and 1H, s, -OH) 4.17 (2H, s) 22 96% 12.16 (1H, s) 6.89 (1H, d, J = 1.8 Hz) 6.85 (1H, d, J = 7.8 Hz) 6.83 (1H, s) 6.75 (1H, dd, J1 = 7.8 Hz, J2 = 1.8 Hz) 5.98 (2H, s) 5.31 (1H, s, -OH) 5.21 (2H, s) 4.17 (2H, s) Et 21 82% 11.94 (1H, s) 6.78 (1H, s) 5.20 (1H, s, -OH) 4.33 (2H, s) 4.00 (2H, q, J = 7.2 Hz) 1.21 (3H, t, J = 7.2 Hz)

Preparation Example 3 Preparation of 1-allyl-5-hydroxymethylimidazole-2-thiol

0.1 mol of allylamine hydrochloride was reacted for 23 hours in the same manner as in Preparation Example 1, and 40 ml of distilled water was added thereto, and the reaction mixture was distilled under reduced pressure to about 1/3 volume. The precipitate was filtered, washed twice with 30 ml of distilled water, twice with 30 ml of isopropyl ether and dried to give 12.5 g (yield 72.6%) of white powder.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.03 (1H, s), 6.81 (1H, s), 5.89 (1H, m), 5.21 (1H, -OH), 5.12 (1H, dd, J ₁ = _{10.5Hz, J 2 = 1.4Hz),} 4.97 (1H, dd, J 1 = 14.4Hz, J 2 = 1.4Hz), 4.67 (2H, s), 4.28 (2H, s)

Preparation Example 4 Preparation of 1- (3-hydroxypropyl) -5-hydroxymethylimidazole-2-thiol

In a similar manner to Preparation Example 1, 1- (3-hydroxypropyl) -5-hydroxymethylimidazole-2-thiol was obtained in 69% yield and its structure was confirmed by ¹ H NMR.

¹ H NMR (500MHz, DMSO-d ₆ ) δ 11.96 (1H, s), 6.80 (1H, s), 5.19 (1H, -OH), 4.56 (1H, -OH), 4.35 (2H, s), 4.02 (2H, t, 7.3 Hz), 3.40 (2H, m), 1.85 (2H, t, J = 7.3 Hz)

Example 1 Preparation of 1-benzyl-5-hydroxymethyl imidazole

1-benzyl-5-hydroxymethylimidazole-2-thiol (2.2 g, 9.99 mmol) and tungstic acid (H ₂ WO ₄ , 25 mg, 1 mol%) were mixed in 11 ml of methanol and then heated to 40 ° C. in a water bath. 30% hydrogen peroxide (3.75 g, 3.2 molar equivalents) was added dropwise for 5 minutes while warming and stirring. At this time, the temperature of the reaction mixture was increased to 65 ℃ to reflux and stirred at that temperature for 2.5 hours. When the starting material was exhausted, the mixture was cooled with an ice bath and the pH was adjusted to 10 with 1N aqueous sodium hydroxide solution (18 ml). The resulting solid was further stirred for about 15 minutes, filtered, washed twice with 15 ml of distilled water, twice with 15 ml of isopropyl ether and dried to give 1.3 g of the title compound as a white powder (yield 69%, HPLC purity 96.7%). Obtained.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.67 (1H, s), 7.35 (2H, t, J = 7.3 Hz), 7.28 (1H, t, J = 7.3 Hz), 7.17 (2H, d, J = 7.3 Hz), 6.82 (1H, s), 5.23 (2H, s), 5.11 (1H, t, -OH), 4.32 (2H, d, J = 5.5 Hz)

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 163.15, 137.68, 130.91, 128.97, 127.78, 127.40, 113.39, 53.88, 46.97

Example 2 Preparation of 1- (4-bromobenzyl) -5-hydroxymethyl imidazole

1- (4-bromobenzyl) -5-hydroxymethylimidazole-2-thiol (1.5 g, 5 mmol) and 12.5 mg (1 mol%) of tungstic acid were suspended in 7 ml of methanol and warmed up to about 40 ° C. 30% hydrogen peroxide solution was slowly added dropwise. After about 2 hours, the mixture was cooled, neutralized with 1N caustic soda solution, and the precipitate was filtered. The obtained solid was washed twice with 5 ml of distilled water and twice with isopropyl ether to obtain 1.1 g (yield 82%) of white powder.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.68 (1H, s), 7.54 (2H, dd, J ₁ = 6.4 Hz, J ₂ = 1.8 Hz), 7.12 (2H, dd, J ₁ = 6.4 Hz, J ₂ = 1.8 Hz), 6.83 (1H, s), 5.21 (2H, s), 5.12 (1H, s, -OH), 4.32 (2H, d, J _gem = 3.25 Hz)

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 139.04, 137.66, 132.07, 129.83, 128.08, 121.22, 113.75, 53.33, 47.45

Example 3: Preparation of 1- (3-bromobenzyl) -5-hydroxymethyl imidazole

1- (3-bromobenzyl) -5-hydroxymethylimidazole-2-thiol was reacted in the same manner as in Example 2 to obtain the target compound in 75% yield.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.71 (1H, s), 7.49 (1H, d, J = 7.8 Hz), 7.37 (1H, s), 7.31 (1H, t, J = 7.8 Hz), 7.16 (1H, d, J = 7.8 Hz), 6.84 (1H, s), 5.24 (sH, s), 5.13 (1H, s, -OH), 4.32 (2H, d, J _gem = 4.6 Hz)

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 141.02, 139.11, 132.14, 131.34, 130.96, 130.31, 128.08, 126.67, 124.42, 53.28, 47.35

Example 4 Preparation of 1- (3,4-Dioxymethylenebenzyl) -5-hydroxymethyl imidazole

10 ml of 1- (3,4-dioxymethylenebenzyl) -5-hydroxymethylimidazole-2-thiol (2.64 g, 10 mmol) and vanadium oxide (V ₂ O ₅ , 18 mg, 1 mol%) with ethanol Suspended in 10 ml of distilled water and then slowly added dropwise 30% hydrogen peroxide solution while warming 50 ℃. After cooling for 1 hour, the pH was adjusted to 10 with 1N caustic soda, filtered, washed twice with 15 ml of distilled water, twice with isopropyl ether, and dried to obtain 2.05 g (yield 88%) of white powder.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.64 (1H, s), 6.87 (1H, d, J = 7.5 Hz), 6.79 (2x1H, s), 6.70 (1H, d, J = 7.5 Hz), 5.99 (2H, s), 5.10 (2H, s and 1H, s, -OH), 4.34 (2H, s)

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 148.06, 147.23, 138.82, 132.09, 131.84, 127.93, 121.28, 108.80, 108.40, 101.62, 53.34, 47.87

Example 5 Preparation of 1-ethyl-5-hydroxymethyl imidazole

1-ethyl-5-hydroxymethylimidazole-2-thiol was reacted in the same manner as in Example 1, and the residue was extracted with chloroform instead of filtration to obtain the target compound in 68% yield.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.59 (1H, s), 6.76 (1H, s), 4.43 (2H, 2), 3.99 (2H, q, J = 7.3 Hz), 1.33 (3H, t , J = 7.3 Hz)

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 137.83, 131.85, 127.69, 60.92, 53.15, 16.93

Example 6 Preparation of 1-allyl-5-hydroxymethyl imidazole

1-allyl-5-hydroxymethylimidazole-2-thiol was reacted in the same manner as in Example 1, and the residue was extracted with n-butanol instead of filtration to obtain 76% of the title compound.

¹ H NMR (500MHz, DMSO-d ₆ ) δ 7.54 (1H, s), 6.79 (1H, s), 6.00 (1H, ddd, J ₁ = 20Hz, J ₂ = 10Hz, J ₃ = 5.5Hz), 6.15 _{(1H, dd, J 1 =} 10Hz, J 2 = 1.35Hz), 4.98 (1H, dd, J 1 = 16.95Hz, J 2 = 1.35Hz), 4.64 (2H, dd, J 1 = 5.5Hz, J 2 = 1.35 Hz), 4.39 (2H, s)

¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 138.47, 135.15, 132.19, 127.72, 117.37, 60.91, 47.07

Example 7 Preparation of 1- (3-hydroxypropyl) -5-hydroxymethyl imidazole

1- (3-hydroxypropyl) -5-hydroxymethylimidazole-2-thiol (5.0 g, 23.1 mmol) and tungstic acid (H ₂ WO ₄ , 58 mg, 1 mol%) were diluted with 25 mL of methanol and 25 mL of distilled water. The mixture was mixed with mL, warmed to 40 DEG C, and 3.6 g of 30% hydrogen peroxide solution was added dropwise. After stirring for about 15 minutes and cooling, the mixture was basified with 1N caustic soda, extracted twice with 25 ml of n-butanol, and the solvent was distilled under reduced pressure to obtain 3.45 g (yield 80.7%) of the title compound.

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.46 (1H, s), 6.91 (1H, s), 4.61 (2H, s), 4.15 (2H, t, J = 7 Hz), 3.52 (2H, t, J = 7 Hz), 2.01 (2H, m)

Example 8 Preparation of 1- (4-bromobenzyl) -5-hydroxymethyl imidazole

A mixed solution of 1- (4-bromobenzyl) -5-hydroxymethylimidazole-2-thiol (40 g, 0.134 mol) and 21.9 mg (0.1 mol%) of vanadium sulfate hydrate in 240 ml of ethanol and 240 ml of water Into, stirred at about 45 ° C. After a while, 30% hydrogen peroxide water (51.6 g, 3.4 mol equivalent) was slowly added dropwise while maintaining the internal temperature at about 50 ° C. When the white suspension at the beginning of the reaction turned into a pale yellow solution as the reaction proceeded, the mixture was further stirred for about 30 minutes, and the pH was adjusted to about 10 by adding 6N sodium hydroxide solution. Thereafter, ethanol was distilled under reduced pressure. At this time, the precipitated crystals were filtered, washed with distilled water, and dried until constant weight to give 28.7 g (80.4% yield, HPLC = 97%) of the title compound as a white powder.

¹ H NMR (δ, ppm, DMSO-d ₆ ) 7.68 (1H, s), 7.54 (2H, d, J = 8.3 Hz), 7.12 (2H, d, J = 8.3 Hz), 6.82 (1H, s) , 5.21 (2H, s), 5.09 (1H, t, J = 5.5 Hz), 4.31 (2H, s)

Example 9 Preparation of 1- (3,4-Dioxymethylenebenzyl) -5-hydroxymethyl imidazole

1- (3,4-dioxymethylenebenzyl) -5-hydroxymethylimidazole-2-thiol (22.15 kg, 83.8 mol) and 11 g (0.1 mol%) of vanadium sulfate hydrate were placed in a reactor and 47.1 kg of Ethanol and 55 kg of purified water were added thereto, and the reaction solution was adjusted to 44 ° C. while stirring. 32.2 kg of 30% hydrogen peroxide water was slowly added to the suspension in the range of 40 to 60 ° C., stirred at 46 ° C., and 6N sodium hydroxide solution was added to adjust the pH to about 10. Thereafter, ethanol was distilled under reduced pressure. After the distillation was completed, cooled to room temperature, filtered, washed with purified water and dried to give 11.5 kg (yield 59.9%, HPLC = 96.6%) of the title compound as an off-white powder.

¹ H NMR (δ, ppm, DMSO-d ₆ ) 7.64 (1H, s), 6.87 (1H, d, J = 7.8 Hz), 6.79 (2H, s), 6.69 (1H, d, J = 7.8 Hz) , 5.99 (2H, s), 5.10 (2H, s), 4.34 (2H, s)

As described above, the product obtained by the method of the present invention, 1-substituted-5-hydroxymethyl imidazole, is a known compound and finally is disclosed in the patent of JS Ko et al. (PCT International Application Publication No. WO 9905117 A1 19990204, p129). It is an intermediate useful for preparing anticancer agents of the specific panesyl transferase inhibitor family described.

The novel production process according to the present invention provides useful intermediates, known as 5-hydroxymethyl imidazole derivatives, in pure and high yield by a unique method of oxidative removal of thiol groups, and greatly improves upon previous techniques in the safety and reliability of the reaction. Improved. Therefore, the production method of the present invention is very suitable for industrial mass production by significantly eliminating the risk by avoiding the use of dangerous concentrated nitric acid.

Claims (9)

1-substituted-5-hydroxymethylimidazole-2-thiol of Formula 2 is reacted in the solvent in the presence of an oxidizing agent and a transition metal catalyst selected from the group consisting of hydrogen peroxide water, alkyl hydrogen peroxide water and alkali hypochlorite To prepare a 1-substituted-5-hydroxymethyl imidazole of formula (I): [Formula 1] [Formula 2] Wherein R is alkyl, hydroxyalkyl, allyl, or substituted or unsubstituted arylmethyl or diarylmethyl, respectively. The method of claim 1 wherein 10-30% hydrogen peroxide water is used as the oxidant. The method of claim 1, wherein tungstic acid (H ₂ WO ₄ ), vanadium oxide (V ₂ O ₅ ) or vanadium sulfate (VOSO ₄ ) is used as the transition metal catalyst. 2. The process of claim 1 wherein the transition metal catalyst is used in an amount of 0.001 to 0.2 molar ratio relative to the compound of formula 1 as defined in claim 1. A process according to claim 4 wherein the transition metal catalyst is used in an amount of 0.001 to 0.02 molar ratio with respect to the compound of formula 1 as defined in claim 1. The process of claim 1 wherein the reaction is carried out at a temperature of 30 to 90 ° C. The method of claim 1 wherein the solvent is at least one selected from water and lower alcohols. 8. The method of claim 7, wherein the lower alcohol is methanol or ethanol. The method of claim 1 wherein R is C _1-4 alkyl, hydroxyC _1-4 alkyl, allyl, benzyl, benzyl substituted with halogen, or 3,4-dioxymethylenebenzyl.