KR20010077046A - New alkylation of pyrrole compound - Google Patents

Abstract

PURPOSE: A new alkylation reaction of pyrrol is provided, which is characterized by manufacturing high yield of a panethyl transfer enzyme inhibitor(formula 3), having improved safety and reliance of synthesis and doing mass production. CONSTITUTION: The panethyl transfer enzyme inhibitor(formula 3) is obtained by making a pyrrol derivative(formula 1) into an imidazole derivative(formula 2) by N-alkylation reacting in non-aqueous polar solvent under existence of an alkali metal t-alkoxide base and a polyethylene glycol monomethyl ether catalyst. In the formula 1, 2, and 3, R represents hydrogen or substituted/not substituted alkyl, aryl or aralkyl of a straight chain or a side chain having 1-8 of carbon number; R1 and R2 represent alkyl of a straight chain or a side chain having 1-4 of carbon number isolated/not isolated or substituted/not substituted by O, S, SO2 or NR4(R4 represents hydrogen or alkyl of a straight chain or a side chain having 1-4 of carbon number) respectively, or constitute 5-6 of heterocycle by reducing O, S, SO2 or NR4 with nitrogen attaching R1 and R2, and R3 represents substituted/not substituted alkyl, aryl or aralkyl of a straight chain or a side chain having 1-4 of carbon number.

Description

New alkylation of pyrrole {New alkylation of pyrrole compound}

The present invention is characterized in that in the presence of a specific base and catalyst in a non-aqueous polar solvent, the pyrrole derivative of formula (1) is N-alkylated with an imidazole derivative of formula (2), which can be usefully used as an anticancer agent. Relates to a process for preparing the compound:

[Formula 1]

[Formula 2]

[Formula 3]

In the above formula

R represents hydrogen, straight or branched chain alkyl of 1 to 8 carbon atoms, aryl or aralkyl,

R ¹ and R ² are each independently straight chains having 1 to 4 carbon atoms which are unsubstituted or interrupted or substituted by O, S, SO ₂ or NR ⁴ (R ⁴ is hydrogen or straight or branched chain alkyl having 1 to 4 carbon atoms); Represent branched alkyl or R ¹ and R ² together with the nitrogen atom to which they are attached may form a 5 to 6 membered heterocycle comprising O, S, SO ₂ or NR ⁴ as a reduction,

R ³ represents substituted or unsubstituted linear or branched alkyl, allyl or aralkyl having 1 to 4 carbon atoms, respectively.

More specifically, the present invention is accomplished by alkylating various electrophilic molecules to the nitrogen at position 1 of pyrrole-3-carboxamide in the presence of an alkali metal t-alkoxide base and a polyethyleneglycol monomethylether catalyst in a non-aqueous polar solvent. A novel method of effectively preparing anticancer agents of the lineage transferase inhibitor family (Ko, JS et al., PCT Int'l Appl. WO 9928315 A1 19990610, p226).

In general, pyrrole is a very weak acid with a pKa of about 17.5. Since the nitrogen group of pyrrole itself has low nucleophilic reactivity, anionization must be preceded in order to react with an electrophilic molecule. For this reason, N-alkylation, which is commonly used in the conventional pyrrole chemistry, was dehydrogenation with very strong bases followed by alkylation. For example, by reacting with alkali metal amide (sodium amide or potassium amide) in liquid ammonia or with alkali metal itself in an inert solvent to form its metal salt, mainly by reaction between these alkali metal salts and electrophilic molecules N-alkylation of pyrrole has been carried out (TL Gilchrist, Heterocyclic Chemistry, 2nd Ed., Longman Scientific and Technical, 1992, pp194-3). However, strong bases such as alkali metal amides or sodium hydride are reaction reagents that are largely avoided due to problems such as their handling safety in ordinary industrial mass production processes even though they are widely used in the laboratory.

In addition to the aforementioned alkali metal amides and alkali metals, sodium hydride, sodium-potassium alloy or alkyllithium may be mentioned as a strong base capable of removing hydrogen from nitrogen of pyrrole in the conventional organic chemistry field. However, alkyllithium requires extreme care in handling, and when the resulting pyrrolithium salt reacts with an electrophilic molecule, the reaction occurs mainly at adjacent carbons rather than nitrogen, and thus can be used for the intended purpose of the present inventors. Can't. In addition, although the present inventors have experimentally used sodium hydride to obtain a small amount of the target compound, in this case, the separation of the target compound was easy through silica gel column chromatography after the reaction, regardless of handling precautions.

Therefore, while trying to find a method for N-alkylation of pyrrole that can be effectively used in a mass production process while meeting the properties of pyrrole, while avoiding the above-mentioned reaction conditions, the present inventors have used potassium-t-butoxide and 18-crown. The reaction of alkylating pyrrole with -6 was found in WC Guida and DJ Mathre., J. Org. Chem., 1980, 45, 3172. In this case, however, the use of potassium-t-butoxide as a base is significantly improved and good, but since the use of the expensive 18-crown-6 is not economically feasible, intensive studies have been conducted to improve this problem. As a result, an alkali metal t-alkoxide, preferably at least one selected from sodium t-butoxide, sodium t-pentoxide and potassium t-butoxide as a base, is economically very burdensome 18- Polyethyleneglycol monomethylethers of various molecular weight ranges instead of Crown-6 (a) Hammaide, T. Synth. Comm. 1990, 20, 2913. (b) Sukata, K. Bull. Chem. Soc. Jpn., 1983, 56, 280] was found to be able to carry out the N-alkylation of pyrrole efficiently and economically using catalyst as a catalyst. N-alkylation of the pyrrole derivatives according to this method was able to prepare the target compound of Formula 3 safely and very easily without various problems derived from the aforementioned conventional methods.

Therefore, the present invention is characterized in that the anti-cancer agent is characterized in that the pyrrole derivative of Formula 1 is reacted with an imidazole derivative of Formula 2 in the presence of an alkali metal t-alkoxide base and a polyethylene glycol monomethyl ether catalyst in a non-aqueous polar solvent. It is an object of the present invention to provide a method for preparing a compound of formula 3, which can be usefully used as:

[Formula 1]

[Formula 2]

[Formula 3]

In the above formula

R represents hydrogen, or each substituted or unsubstituted straight or branched chain alkyl, aryl or aralkyl having 1 to 8 carbon atoms,

R ¹ and R ² are each independently straight chains having 1 to 4 carbon atoms which are unsubstituted or interrupted or substituted by O, S, SO ₂ or NR ⁴ (R ⁴ is hydrogen or straight or branched chain alkyl having 1 to 4 carbon atoms); Represent branched alkyl or R ¹ and R ² together with the nitrogen atom to which they are attached may form a 5 to 6 membered heterocycle comprising O, S, SO ₂ or NR ⁴ as a reduction,

R ³ represents substituted or unsubstituted linear or branched alkyl, allyl or aralkyl having 1 to 4 carbon atoms, respectively.

Representing the method according to the present invention in the scheme is shown in Scheme 1:

Wherein R, R ¹ , R ² and R ³ are as defined above. However, each substituent is not limited to those defined herein. That is, a compound of formula (3) having a substituent not defined above can be prepared by applying the method of the present invention without any problem except that it is recognized that there is a particular difficulty in applying the method according to the present invention. However, R ¹ , R ² and R ³ are functional groups which are less likely to dehydrogenate with a strong base, except for hydrogen or a hydroxyl group.

In the method according to the present invention, the imidazole derivative of the formula (2) is used in 1 to 1.5 mole times, preferably 1.1 to 1.3 mole times relative to the pyrrole derivative of the formula (1). If the compound of Formula 2 is used in less than 1 mole amount, the desired compound of Formula 3 cannot be obtained in high yield. If the compound of Formula 2 is used in excess of 1.5 mole amount, the increase in yield depending on the amount of the reactant is too small.

Preferred alkali metal t-alkoxides used as bases in the process of the present invention may refer to at least one selected from the group consisting of sodium t-butoxide, potassium t-butoxide and sodium t-pentoxide, in particular Preferably sodium t-butoxide or sodium t-pentoxide may be mentioned. The alkali metal t-alkoxide uses 2.0 to 5.0 molar equivalents, preferably 2.2 to 4.5 molar equivalents, based on the pyrrole derivative of the general formula (1) when the compound of the general formula (2) used is hydrochloride. Moreover, as polyethyleneglycol monomethyl ether used as a catalyst, the thing of the average molecular weights 500-5000, Preferably the average molecular weights 1000-2000 is used suitably. The amount of polyethylene glycol monomethyl ether added is suitably 1 to 10 mol%, preferably 5 to 10 mol%, based on the base used together.

As the non-aqueous polar solvent, at least one selected from tetrahydrofuran, dimethoxyethane, dimethylformamide and N-methylpyrrolidinone, preferably tetrahydrofuran or dimethylformamide is used. Dimethylformamide predominates in terms of reaction rate, and tetrahydrofuran is more convenient in terms of recovering the target compound.

The reaction proceeds for 8 to 24 hours at 0 to 60 ° C, preferably 10 to 40 ° C, particularly preferably 10 to 30 ° C.

After the reaction is completed, water is added to the reaction mixture and the reaction solvent is distilled appropriately, or this process is omitted, and an organic solvent which is not mixed with water is added to extract the target compound, and the layers are separated by distillation under reduced pressure. Obtaining or recrystallization of the target compound directly from the reaction extract can be further purified to easily recover the pure compound of the general formula (3) substituted with the 1-position nitrogen of the pyrrole ring from the reaction mixture.

Compounds of formula (III) prepared according to the process of the invention are disclosed in the patents of JS Ko et al. (See Ko, JS et al., PCT Int'l Appl. WO 9928315 A1 19990610, p226) as compounds known per se. It was developed as an anticancer agent of a specific panesyl transferase inhibitor family.

Hereinafter, the present invention will be described in more detail based on the following Preparation Examples and Examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention in any sense is not limited to these examples.

Comparative Example 1: [1-{[1- (1,3-benzodioxol-5-ylmethyl) -1H-imidazol-5-yl] methyl} -4- (1-naphthyl) -1H-pyrrole -3-yl] (4-methyl-1-piperazinyl) methanone preparation (sodium hydride method)

To a 250 mL round flask, (4-methyl-1-piperazinyl) [4- (1-naphthyl) -1H-pyrrole-3-yl] methanone (9.5 g, 30 mmol) was added and dimethylform was added under nitrogen atmosphere. 65 ml of amide was added. With good stirring, the reaction solution was cooled to 0 ° C. and then sodium hydride (60% oil mixture; 3.0 g, 75 mmol) was added several times while taking note that the temperature of the reaction solution did not exceed 10 ° C. and observing the generation of hydrogen. . The mixture was stirred at about 5 ° C. for 10 minutes, then 1- (1,3-benzodioxol-5-ylmethyl) -5- (chloromethyl) -1H-imidazole hydrochloride (9.4 g, 32.7 mmol) was added. The reaction solution was added several times while being careful not to exceed 15 ° C. After the addition was complete, the reaction solution was stirred at room temperature for about 2 hours, and then about 1 ml of distilled water was added to decompose the remaining sodium hydride. The reaction solution was warmed to about 50 ° C. and distilled under reduced pressure to remove most of the solvent used. The concentrated reaction mixture was extracted and separated using 150 ml of distilled water and 150 ml of ethyl acetate, and the organic layer was washed once more with 150 ml of distilled water. The organic layer was passed through a silica gel column (silica gel 150 g / ethyl acetate 500 ml → methylene chloride / methanol = 20/1, 300 ml) to recover the title compound, the organic layers were combined and concentrated under reduced pressure to give a crude solid. Purification of the solid by column chromatography gave about 7.7 g of an off-white solid (yield = 48%, HPLC purity = 95%).

¹ H-NMR (DMSO-d ₆ , ppm), δ 7.91 (1H, d, J = 8.3 Hz), 7.85 (1H, d, J = 8.7 Hz), 7.83 (1H, d, J = 8.3 Hz), 7.77 (1H, s), 7.47 (2H, m), 7.39 (1H, m), 7.20 (1H, d, J = 7.3 Hz), 7.11 (1H, s), 7.08 (1H, s), 6.87 (1H , s), 6.77 (1H, d, J = 7.8 Hz), 6.59 (1H, s), 6.52 (1H, d, J = 7.8 Hz), 5.90 (2H, s), 5.23 (2H, s), 5.17 (2H, s), 3.03 (4H, br), 2.0-1.0 (4H, br), 1.81 (3H, s)

FAB MS: [M + H] ⁺ = 534

Example 1: [1-{[1- (1,3-benzodioxol-5-ylmethyl) -1H-imidazol-5-yl] methyl} -4- (1-naphthyl) -1H-pyrrole Preparation of -3-yl] (4-methyl-1-piperazinyl) methanone

In a 250 mL volumetric flask, (4-methyl-1-piperazinyl) [4- (1-naphthyl) -1H-pyrrole-3-yl] methanone (9.5 g, 30 mmol), 1- (1,3 -Benzodioxol-5-ylmethyl) -5- (chloromethyl) -1H-imidazole hydrochloride (9.06 g, 31.5 mmol) and polyethylene glycol monomethyl ether (average molecular weight 2000, 12 g, 6 mmol) were added under nitrogen atmosphere. 95 ml of tetrahydrofuran was added. The reaction solution was cooled to 0 ° C. with good stirring, and sodium-t-butoxide (11.5 g, 120 mmol) was added in several portions while being careful not to exceed 15 ° C. in the temperature of the reaction solution. The mixture was stirred at about 25 ° C. for 18 hours and then distilled under atmospheric pressure to remove about 2/3 of the solvent used. About 70 ml of distilled water and 95 ml of n-butyl acetate were added to the reaction concentrate, and the organic layer was separated. The separated organic layer was washed with 50 ml of distilled water, washed with saturated brine and distilled under normal pressure again to completely remove the residual tetrahydrofuran. The crystals precipitated when slowly cooled from room temperature to room temperature with slow stirring. The precipitate was filtered, washed twice with 20 ml of n-butyl acetate and dried to give 10.6 g (yield = 67%, HPLC = 97%) of white crystalline powder. The target compound was identified to be the same as the compound obtained in Comparative Example 1 by analysis by NMR, MS and HPLC, and the purity was confirmed to be improved.

¹ H-NMR (DMSO-d ₆ , ppm), δ 7.91 (1H, d, J = 8.3 Hz), 7.85 (1H, d, J = 8.7 Hz), 7.83 (1H, d, J = 8.3 Hz), 7.77 (1H, s), 7.47 (2H, m), 7.39 (1H, m), 7.20 (1H, d, J = 7.3 Hz), 7.11 (1H, s), 7.08 (1H, s), 6.87 (1H , s), 6.77 (1H, d, J = 7.8 Hz), 6.59 (1H, s), 6.52 (1H, d, J = 7.8 Hz), 5.90 (2H, s), 5.23 (2H, s), 5.17 (2H, s), 3.03 (4H, br), 2.0-1.0 (4H, br), 1.81 (3H, s)

FAB MS: [M + H] ⁺ = 534

Example 2: [1- [1- {2- (2-methoxyphenyl) -ethyl} -1H-imidazol-5-ylmethyl] -4- (1-naphthyl) -1H-pyrrole-3- Production of metholone (morpholin-4-yl)

(4-morpholinyl) [4- (1-naphthyl) -1H-pyrrol-3-yl] methanone (9.19 g, 30 mmol), 1- [2- (2-methoxy Phenyl) -ethyl] -5- (chloromethyl) -1H-imidazole hydrochloride (8.67 g, 31.5 mmol) and polyethylene glycol monomethyl ether (average molecular weight 2000, 12 g, 6 mmol) were added and 90 mL of tetrahydrofuran under nitrogen atmosphere. Was added. The reaction solution was cooled to 0 ° C. with good stirring, and sodium-t-butoxide (11.5 g, 120 mmol) was added in several portions, taking care not to exceed 15 ° C .. The reaction solution was stirred at about 25 ° C. for 18 hours, and about 2/3 of the solvent was removed by atmospheric distillation. About 70 mL of distilled water and 90 mL of n-butyl acetate were added to the reaction concentrate, and the organic layer was separated. The separated organic layer was washed with 50 ml of distilled water, washed with saturated brine and distilled under normal pressure again to completely remove the residual tetrahydrofuran. The crystals precipitated when slowly cooled from room temperature to room temperature with slow stirring. The precipitate was filtered, washed twice with 20 ml of n-butyl acetate and dried to give 11.2 g of a white crystalline powder (yield = 73%, HPLC = 96%).

¹ H-NMR (CDCl ₃ , ppm), δ 8.00 (1H, d, J = 8.7 Hz), 7.84 (1H, d, J = 8.7 Hz) 7.78 (1H, d, J = 8.3 Hz), 7.61 (1H , s), 7.42 (3H, m), 7.31 (1H, d, J = Hz), 7.22 (1H, m), 7.10 (1H, d, J = 2.8 Hz), 7.09 (1H, d, J = 8.7 Hz), 6.84 (3H, m), 6.69 (1H, d, J = 2.8 Hz), 4.85 (2H, s), 4.10 (2H, t, J = 6.8 Hz), 3.79 (3H, s), 3.65 ( 1H, br, s), 3.4-2.8 (6H, br), 2.90 (2H, t, J = 6.8 Hz), 2.28 (1H. Br)

FAB MS: [M + H] ⁺ = 509

Since the farnesyl transferase inhibitor of Formula 3, which can be usefully used as an anticancer agent by the unique N-alkylation reaction of the present invention as described above, can be provided in a pure and high yield, the present invention is directed to the safety and reliability of the synthesis. The previous technology has been greatly improved. Moreover, the synthesis method of the present invention is highly suitable for industrial mass production, such as avoiding the use of dangerous alkali metals and eliminating troublesome and difficult column chromatography processes for mass production.

Claims (9)

In a non-aqueous polar solvent, a pyrrole derivative represented by the following Chemical Formula 1 in the presence of an alkali metal t-alkoxide base and a polyethyleneglycol monomethyl ether catalyst is subjected to N-alkylation with an imidazole derivative of the following Chemical Formula 2. How to manufacture: [Formula 1] [Formula 2] [Formula 3] In the above formula R represents hydrogen, or each substituted or unsubstituted straight or branched chain alkyl, aryl or aralkyl having 1 to 8 carbon atoms, R ¹ and R ² are each independently straight chains having 1 to 4 carbon atoms which are unsubstituted or interrupted or substituted by O, S, SO ₂ or NR ⁴ (R ⁴ is hydrogen or straight or branched chain alkyl having 1 to 4 carbon atoms); Represent branched alkyl or R ¹ and R ² together with the nitrogen atom to which they are attached may form a 5 to 6 membered heterocycle comprising O, S, SO ₂ or NR ⁴ as a reduction, R ³ represents substituted or unsubstituted linear or branched alkyl, allyl or aralkyl having 1 to 4 carbon atoms, respectively. The method of claim 1, wherein the alkali metal t-alkoxide is at least one selected from the group consisting of sodium t-butoxide, potassium t-butoxide and sodium t-pentoxide. The method of claim 2, wherein the alkali metal t-alkoxide is sodium t-butoxide or sodium t-pentoxide. The method of claim 1, wherein the alkali metal t-alkoxide is used in an amount of 2.0 to 5.0 molar equivalents based on the pyrrole derivative of formula (I). The method according to claim 1, wherein the polyethylene glycol monomethyl ether has an average molecular weight of 500 to 5000. The method of claim 5 wherein the polyethylene glycol monomethyl ether has an average molecular weight of 1000 to 2000. The method according to claim 5 or 6, wherein the amount of polyethylene glycol monomethyl ether added is 1 to 10 mol% based on the base used together. The method of claim 1, wherein the non-aqueous polar solvent is at least one selected from tetrahydrofuran, dimethoxyethane, dimethylformamide and N-methylpyrrolidinone. The process of claim 1 wherein the reaction is carried out at a temperature of 0 to 60 ° C.