KR0151818B1 - Process for the preparation of pyridyl imidazole derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of pyridyl imidazole derivatives useful for inhibiting the hypertension induced by angiotensin II by inhibiting the action of angiotensin II. An amide compound is prepared by reacting with an acid anhydride, which is characterized in that a pyridyl imidazole derivative of the following general formula (I) is prepared by bromination, hydrolysis, nitration, reduction and cyclization.

Where A, B, R and X are as defined in the specification.

Description

Method for preparing pyridyl imidazole derivative

The present invention relates to a process for the preparation of pyridyl imidazole derivatives useful for inhibiting the hypertension induced by engiotensin II by inhibiting the action of engiothecin II.

Pyridyl imidazole series heterocyclic compounds are important as intermediates of various medicinal products with physiological activity. In particular, angiotensin II antagonists having imidazo [4,5-b] pyridine as a basic structure are well known. . (See N. B. Mantlo et al, J. Med. Chem. 34, 2919 (1991); D. S. Dhanoa et al., J. Med. Chem. 36, 4239 (1993)).

In the conventional method for preparing imidazo [4,5-b] pyridine, the 2-position of the 2-aminopyridine derivative is nitrated and the nitro group is reduced to prepare 2,3-diaminopyridine. The reaction was used to form an imidazole ring.

However, in the above method, when there is no substituent at the 5-position of 2-aminopyridine during the nitration reaction, there is a problem in that the 3-position nitrated compound and the 5-position nitrated compound are obtained.

EP-A-400, 974 and 513, 979 nitrate 2-amino-4, 6-dimethylpyridine to 2-amino-3-nitro-4,6-dimethylpyridine and 2-amino-5 A method for obtaining nitro-4,6-dimethylpyridine in a ratio of 55:45 is described.

As described above, in the case of the above methods, since the positional isomer is generated in the nitration reaction, the yield of the target compound is low, and it is difficult to separate and purify, and the separation of the diamino compound reduced by the nitro group is not easy to react with the carboxylic acid derivative. Therefore, there is a disadvantage in that it is cumbersome in the process of forming an imidazole ring and then separating it. In addition, when halogenated 2-aminopyridine to prepare imidazo [4,5-b] pyridine substituted with halogen at the 6-position, the halogenated compound at the 5-position as well as the halogenated compound at the 3-position 3,5-dihalogenated compounds are obtained as by-products.

Therefore, in the present invention, the above-mentioned by-products are not produced when the imidazo [4,5-b] pyridine is prepared, and thus, a new pyri can be prepared with high yield and imidazo [4,5-b] pyridine. It is an object of the present invention to provide a method for preparing a dimethyl imidazole derivative.

That is, in the method for producing a pyridyl imidazole derivative according to the present invention, (i) a 2-aminopyridine compound of the following general formula (II) is reacted with a carboxylic acid chloride or a carboxylic anhydride, and the following general formula (III) To prepare an amide compound of formula (ii) and to bromine the amide compound of formula (III) to prepare a compound of formula (IV), and (iii) to hydrolyze the compound of formula (IV). And nitration to prepare a compound of formula (V), (iv) reduction of the compound of formula (V) to produce a diamino compound of formula (VI) or (iii), followed by (v And a cyclization reaction of the diamino compound to produce a pyridyl imidazole derivative of the following general formula (I).

In the above formula,

R is straight, branched or cyclic C _1-6 alkyl, OR ₁ or NR ₂ R ₃ , wherein R ₁ is H or straight, branched or cyclic C _1-6 alkyl, and R ₂ and R ₃ are Each independently is H or straight, branched or cyclic C _1-6 alkyl),

R 'is C _1-4 alkyl,

A and B are each independently H or straight, branched or cyclic C _1-6 alkyl, or halogen,

X is H or halogen.

Looking in more detail below the manufacturing method of the present invention.

In the present invention, first, the 2-aminopyridine compound of formula (II) is reacted with carboxylic acid chloride or carboxylic anhydride in the presence of a base to prepare an amide compound of formula (III) (step (i)). .

Wherein A, B and R 'are as defined above. In preparing the amide compound of formula (III), 1 to 2 equivalents of carboxylic acid chloride or carboxylic anhydride are used, and methylene chloride, chloroform, ethyl acetate or the like as a reaction solvent in the presence of a base such as triethylamine or pyridine. The reaction is carried out at 0 to room temperature using tetrahydrofuran.

Subsequently, the obtained amide compound of formula (III) is reacted with 1 to 1.3 equivalents of bromine in an acetic acid solvent at room temperature to prepare a 5-brominated compound of formula (IV) (step (ii)). According to the process of the present invention, no by-products such as 3-brominated compounds or 3,5-dibrominated compounds are produced.

Wherein A, B and R 'are as defined above.

Next, the brominated compound of the general formula (IV) is reacted with concentrated sulfuric acid at room temperature for 4 to 10 hours to hydrolyze the amide group, and then it is reacted at 0 ° C to room temperature with 1 to 1.5 equivalents of nitric acid added. To prepare the 3-nitro compound of (V) (step (iii)).

Wherein A, B and R 'are as defined above.

2,3-Diane of the following general formula (VI) in which the nitro group is reduced by reacting the compound of Formula (V) prepared as described above with hydrochloric acid and iron, tin or zinc metal as a reducing agent in a mixed solvent of water and ethanol A mino-4-bromo compound is prepared or a 2,3-diamino compound of the following general formula (VII) wherein the nitro group and the bromine group are reduced by hydrogenation in the presence of a palladium metal catalyst (step (iv)) . In the preparation of the compound of formula (VI), 4 to 10 equivalents of iron, tin or zinc metal and 0.1 to 0.3 equivalents of hydrochloric acid are reacted at the boiling point of the mixed solvent.

Wherein A and B are as defined above.

Finally, the 2,3-diamino compound of general formula (VI) or general formula (VII) is heated with the carboxylic acid or the nitrile compound to 90 to 120 ° C in the presence of polyphosphoric acid to form an imidazole ring. To prepare pyridyl imidazole of formula (I) according to (step (v)). In this case, the polyphosphoric acid is preferably used 5 to 10 times by weight based on the 2,3-diamino compound.

Another method for preparing pyridyl imidazole derivatives from 2,3-diamino compounds of general formula (VI) or general formula (VII) compounds in accordance with the present invention is in an alcoholic solvent such as ethanol together with imidate hydrochloride Or heating in an alcoholic solvent such as ethanol in the presence of a copper compound such as copper sulfate or copper acetate together with the aldehyde compound.

Wherein A, B, X and R are as defined above.

According to the production method according to the present invention as described above it is possible to prepare a pyridyl imidazole derivative in a higher yield than the prior method.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1

Preparation of 6-bromo-5-methyl-butylimidazo [4,5-b] pyridine

[Step 1]

Preparation of 2-acetamido-6-methylpyridine

10 g (0.092 mol) of 2-amino-6-methylpyridine was dissolved in 120 ml of methylene chloride, and 15,5 ml (0.111 mol) of triethylamine was added thereto. 7.9 ml (0.111 mol) of acetyl chloride was slowly added to the solution at 0 ° C. over 20 minutes, and further reacted at 0 ° C. for 30 minutes, and then 50 ml of water was added to terminate the reaction. The organic layer was extracted with methylene chloride (100 ml × 2) and washed with 50 ml of saturated aqueous sodium hydrogen carbonate solution and 50 ml of saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed to give 13.88 g of the title compound as a white solid (yield 99.9%).

¹ H NMR (200MHz, CDCl ₃ ) δ

2.15 (s, 3H), 2.41 (s, 3H), 6.64 (d, 1H), 7.58 (dd, 1H), 8.01 (d, 1H), 9.08 (s, 1H)

[Step 2]

Preparation of 2-acetamido-5-bromo-6-methylpyridine

12 g (0.08 mol) of 2-acetamido-6-methylpyridine prepared in step 1) was slowly added thereto, followed by stirring for 4 hours. The reaction was then cooled to 0 ° C. and 6N NaOH was added slowly to adjust the pH of the solution to about 10. The resulting solid was filtered, washed with water (20ml × 3) and dried under reduced pressure to give 16 g of the title compound as a white solid (yield 87%).

¹ H NMR (200MHz, CDCl ₃ ) δ

2.18 (s, 3H), 2.51 (s, 3H), 7.73 (d, 1H), 7.90 (d, 1H), 8.05 (s, 1H)

[Step 3]

Preparation of 2-amino-3-nitro-5-bromo-6-methylpyridine

10.5 g (0.046 mol) of 2-acetamido-5-bromo-6-methylpyridine prepared in step 2) was dissolved in 30 ml of concentrated sulfuric acid, and stirred at room temperature for 4 hours. The reaction was then cooled to 0 ° C. and 4.2 ml (0.055 mol) of 60% nitric acid was slowly added over 20 minutes and then stirred at room temperature for 1 hour. The reaction was poured slowly onto crushed ice and adjusted to pH by adding 6N aqueous sodium hydroxide solution to adjust the pH to about 4. The resulting solid was filtered, washed with water (20ml × 3) and dried to give 9.4 g of the title compound as a yellow solid. Was obtained (yield 88%).

¹ H NMR (200MHz, CDCl ₃ ) δ

1.70-2.22 (br s, 2H), 2.55 (s, 3H), 8.51 (s, 1H)

[Step 4]

Preparation of 2,3-diamino-5-bromo-6-methylpyridine

10 g (0.043 mol) of 2-amino-3-nitro-5-bromo-6-methylpyridine prepared in step 3) was dissolved in a mixed solvent of 40 ml of ethanol and 10 ml of water, and 9.6 g (0.172 mol) of iron powder was dissolved. ) Was added, and 0.39 ml (0.013 mol) of concentrated hydrochloric acid was added thereto, followed by heating to reflux for 1 hour. The reaction was filtered in a filter filled with celite while the reaction was not cooled, and washed with hot ethanol until all the yellow solution came out. The filtered solution was concentrated under reduced pressure to give 7.6 g of the title compound in the yellow form (yield 87%).

¹ H NMR (200MHz, CDCl ₃ ) δ

2.39 (s, 3H), 3.00 ~ 3.50 (br s, 2H), 4.10 ~ 4.50 (br s, 2H), 7.02 (s, 1H)

[Step 5]

Preparation of 6-bromo-5-methyl-2-butylimidazo [4,5-b] pyridine

7.2 g (0.0356 mol) of 2,3-diamino-5-bromo-6-methylpyridine and 4.65 ml (0.0428 mol) of valeric acid prepared in step 4) were added to 43 g of polyphosphoric acid, followed by a mechanical stirrer at 120 ° C. The reaction was stirred for 5 hours. 30 ml of water was slowly added while the reaction mixture was not cooled, and the pH was adjusted to about 10 with 6N aqueous sodium hydroxide solution while cooling with ice water. 50 ml of ethyl acetate was added thereto, stirred for 5 minutes, and the solid formed in the aqueous layer was filtered and removed. The filtrate was extracted with acyl acetate (50 ml × 2), and then washed with 2N sodium hydroxide (50 ml) and saturated brine (50 ml). The product was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 14.2 g of the title compound (yield 85%).

¹ H NMR (200MHz, CDCl ₃ ) δ

0.95 (t, 3H), 1.45 (m, 2H), 1.85 (m, 2H), 2.80 (s, 3H), 2.95 (t, 2H), 8.15 (s, 1H)

Example 2

Preparation of 5-methyl-2-butylimidazo [4,5-b] pyridine

[Step 1]

Preparation of 2,3-diamino-6-methylpyridine

10 g (0.043 mol) of 2-amino-3-nitro-5-bromo-6-methylpyridine prepared in step 3) of Example 1 was dissolved in 150 ml of ethanol, and 1.0 g of 10% Pd / C was added, followed by hydrogenation. The apparatus was reacted for 5 hours at 50 psi hydrogen atmosphere. The reaction solution was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate solvent to give 5 g of the title compound (yield 95%).

¹ H NMR (200MHz, CDCl ₃ ) δ

2.75 (s, 3H), 3.04 (br s, 4H), 7.22 (d, 1H), 8.19 (d, 1H)

[Step 2]

Preparation of 5-methyl-2-butylimidazo [4,5-b] pyridine

Example 1 except that 5.0 g (0.0406 mol) of 2,3-diamino-6-methylpyridine prepared in Step 1) was used instead of 2,3-diamino-5-bromo-6-methylpyridine. Reaction was carried out in the same manner as in Step 5), to obtain 6.7 g of the title compound (yield 87%).

¹ H NMR (200MHz, CDCl ₃ ) δ

0.89 (t, 3H), 1.44 (m, 2H), 1.98 (m, 2H), 2.80 (s, 3H), 3.34 (t, 2H), 7.32 (d, 1H), 8.36 (d, 1H)

Example 3

Preparation of 6-bromo-5-methyl-2-butylimidazo [4,5-b] pyridine

[Step 1]

Preparation of 2-Valerylamino-6-methylpyridine

The title compound was reacted in the same manner as in Step 1), except that 6.2 g (0.057 mol) of 2-amino-6-methylpyridine was used and 7.6 g (0.063 mol) of valeryl chloride was used instead of acetyl chloride. 10.5 g was obtained (yield 96%).

¹ H NMR (200MHz, CDCl ₃ ) δ

0.92 (t, 3H), 1.38 (m, 2H), 1.68 (m, 2H), 2.36 (t, 2H), 2.45 (s, 3H), 6.88 (d, 1H), 7.58 (t, 1H), 8.05 (d, 1H), 8.10 (br s, 1H)

[Step 2]

Preparation of 2-Valerylamino-5-bromo-6-methylpyridine

In the same manner as in step 2) of Example 1, except that 10.5 g (0.055 mol) of 2-valerylamino-6-methylpyridine prepared in Step 1) was used instead of 2-acetamino-6-methylpyridine. Reaction gave 12.8 g of the title compound (yield 86%).

¹ H NMR (200MHz, CDCl ₃ ) δ

0.89 (t, 3H), 1.32 (m, 2H), 1.65 (m, 2H), 2.32 (t, 2H), 2.49 (s, 3H), 7.70 (d, 1H), 7.95 (d, 1H), 8.40 (br s, 1H)

[Step 3]

Preparation of 2-amino-3-nitro-5-bromo-6-methylpyridine

Except for using 12.8 g (0.047 mol) of 2-valerylamino-5-bromo-6-methylpyridine prepared in Step 1) instead of 2-acetamido-5-bromo-6-methylpyridine The reaction was carried out in the same manner as in Step 3 of Example 1, to obtain 9.49 g of the title compound (yield 87%).

¹ H NMR (200MHz, CDCl ₃ ) δ

1.70-2.22 (br s, 2H), 2.55 (s, 3H), 8.51 (s, 1H)

[Step 4]

Preparation of 6-bromo-5-methyl-2-butylimidazo [4,5-b] pyridine

In the same manner as in Step 4) and 5) of Example 1, 1.42 g of the title compound were obtained (yield 85%).

¹ H NMR (200MHz, CDCl ₃ ) δ

0.95 (t, 3H), 1.45 (m, 2H), 1.85 (m, 2H), 2.80 (s, 3H), 2.95 (t, 2H), 8.15 (s, 1H)

Example 4

Preparation of 6-bromo-5,7-dimethyl-2-butylimidazo [4,5-b] pyridine

[Step 1]

Preparation of 2-acetamido-4,6-dimethylpyridine

120 g of the title compound was obtained by the same method as step 1) of Example 1, except that 90 g (0.74 mole) of 2-amino-4,6-dimethylpyridine was used instead of 2-amino-6-methylpyridine (yield) 99%).

¹ H NMR (60MHz, CDCl ₃ ) δ

2.15 (s, 3H), 2.30 (s, 3H), 2.40 (s, 3H), 6.73 (s, 1H), 7.85 (s, 1H), 8.32 (s, 1H)

[Step 2]

Preparation of 2-acetamido-5-bromo-4,6-dimethylpyridine

Same as step 2) of Example 1, except that 120 g (0.73 mol) of 2-acetamido-4,6-dimethylpyridine prepared in Step 1) was used instead of 2-acetamido-6-methylpyridine. Reaction was carried out to give 151 g of the title compound (yield 84%).

¹ H NMR (200MHz, CDCl ₃ ) δ

2.13 (s, 3H), 2.38 (s, 3H), 2.52 (s, 3H), 7.90 (s, 1H), 8.00 (s, 1H)

[Step 3]

Preparation of 2-amino-3-nitro-5-bromo-4,6-dimethylpyridine

Except for using 110 g (0.45 mol) of 2-acetamido-5-bromo-4,6-dimethylpyridine prepared in Step 2) instead of 2-acetamido-5-bromo-6-methylpyridine Was reacted in the same manner as in Step 3 of Example 1, to obtain 78 g of the title compound (yield 70%).

¹ H NMR (200MHz, CDCl ₃ ) δ

2.55 (s, 3H), 2.57 (s, 3H), 5.85 (br s, 2H)

[Step 4]

Preparation of 2,3-diamino-5-bromo-4,6-dimethylpyridine

180 g (0.73 mol) of 2-amino-3-nitro-5-bromo-4,6-dimethylpyridine prepared in step 3) instead of 2-amino-3-nitro-5-bromo-6-methylpyridine Reaction was carried out in the same manner as in Step 4) of Example 1, except that the title compound was obtained 144 g (91% yield).

¹ H NMR (60MHz, CDCl ₃ ) δ

2.30 (s, 3H), 2.45 (s, 3H), 3.25 (br s, 2H), 4.20 (br s, 2H)

[Step 5]

Preparation of 6-bromo-5,7-dimethyl-2-butylimidazo [4,5-b] pyridine

Instead of 2,3-diamino-5-bromo-6-methylpyridine, 144 g (0.67 mol) of 2,3-diamino-5-bromo-4,6-dimethylpyridine prepared in step 4) was used. Except that the reaction was carried out in the same manner as in Step 5) of Example 1 to obtain 164 g of the title compound (yield 87%).

¹ H NMR (200MHz, CDCl ₃ ) δ

0.95 (t, 3H), 1.45 (m, 2H), 1.80 (m, 2H), 2.70 (s, 3H), 2.80 (s, 3H), 2.98 (t, 2H), 12.20 (br s, 1H)

Example 5

Preparation of 6-bromo-7-methyl-2-butylimidazo [4,5-b] pyridine

[Step 1]

Preparation of 2-acetamido-4-methylpyridine

Reaction was carried out in the same manner as in Step 1) of Example 1, except that 20 g (0.19 mol) of 2-amino-4-methylpyridine was used instead of 2-amino-6-methylpyridine to give 22.2 g of the title compound (yield 80). %).

¹ H NMR (60MHz, CDCl ₃ ) δ

2.16 (s, 3H), 2.32 (s, 3H)

[Step 2]

Preparation of 2-acetamido-5-bromo-4-methylpyridine

In the same manner as in Step 2) of Example 1, except that 10 g (0.067 mol) of 2-acetamido-4-methylpyridine prepared in Step 1) was used instead of 2-acetamido-6-methylpyridine. Reaction gave 6.11 g of the title compound (yield 40%).

¹ H NMR (200MHz, CDCl ₃ ) δ

2.20 (s, 3H), 2.45 (s, 3H), 8.13 (s, 1H), 8.26 (s, 1H)

[Step 3]

Preparation of 2-amino-3-nitro-5-bromo-4-methylpyridine

Except for using 6.11 g (0.027 mol) of 2-acetamido-5-bromo-4-methylpyridine prepared in Step 2) instead of 2-acetamido-5-bromo-6-methylpyridine Reaction was carried out in the same manner as in Step 3 of Example 1, to obtain 5.89 g of the title compound (yield 95%).

¹ H NMR (200MHz, CDCl ₃ ) δ

2.56 (s, 3H), 5.88 (s, 2H), 8.30 (s, 1H)

[Step 4]

Preparation of 2,3-diamino-5-bromo-4-methylpyridine

3.49 g (0.015 mol) of 2-amino-3-nitro-5-bromo-4-methylpyridine prepared in step 3) was used instead of 2-amino-3-nitro-5-bromo-6-methylpyridine. Except that, the reaction was carried out in the same manner as in Step 4 of Example 1, to obtain 2.42 g of the title compound (yield 80%).

¹ H NMR (60MHz, CDCl ₃ ) δ

2.45 (s, 3H), 3.27 (br s, 2H), 4.30 (br s, 2H), 8.30 (s, 1H)

[Step 5]

Preparation of 6-bromo-7-methyl-2-butylimidazo [4,5-b] pyridine

Except for using 1.85 g (0.0092 mol) of 2,3-diamino-5-bromo-4-methylpyridine prepared in step 4) instead of 2,3-diamino-5-bromo-6-methylpyridine Then, the reaction was carried out in the same manner as in Step 5) of Example 1 to obtain 2.22 g of the title compound (yield 90%).

¹ H NMR (200MHz, CDCl ₃ ) δ

0.92 (t, 3H), 1.42 (m, 2H), 1.85 (m, 2H), 2.68 (s, 3H), 2.95 (t, 2H), 8.28 (s, 1H)

Claims (9)

(i) reacting a 2-aminopyridine compound of the following general formula (II) with a carboxylic acid chloride or a carboxylic anhydride to prepare an amide compound of the following general formula (III), and (ii) the general formula (III) Bromine the amide compound to prepare a compound of formula (IV), and then (iii) hydrolyze and nitrate the compound of formula (IV) to prepare a compound of formula (V), (iv) reducing the compound of formula (V) to produce a diamino compound of formula (VI) or (iii), and then (v) cyclizing the diamino compound to the following general formula: Process for the preparation of pyridyl amidazole derivatives of formula (I). Wherein R is straight, branched or cyclic C _1-6 alkyl, OR ₁ or NR ₂ R ₃ , wherein R ₁ is H or straight, branched or cyclic C _1-6 alkyl, R ₂ and Each R ₃ is independently H or straight, branched or cyclic C _1-6 alkyl, R ′ is C _1-4 alkyl and A and B are each independently H or straight, branched or cyclic C _1-6 alkyl, or halogen, X is H or halogen. The method according to claim 1, wherein in step (i), the carboxylic acid chloride or carboxylic anhydride is used in an amount of 1 to 2 equivalents, and the reaction is carried out at 0 ° C to room temperature in a solvent in the presence of a base. The process of claim 1, wherein the bromination in step (ii) is carried out using 1 to 1.3 equivalents of bromine at room temperature in an acetic acid solvent. The method according to claim 1, wherein the step (iii) performs a hydrolysis reaction of the amide group with concentrated sulfuric acid at room temperature, and then performs a nitration reaction with nitric acid at 0 ° C to room temperature. The process according to claim 1, wherein the reduction of step (iv) is carried out in a water-ethanol mixed solvent using hydrochloric acid and iron, tin or zinc metal as reducing agents. The method according to claim 1, wherein the reduction of the step (iv) is carried out by hydrogenation in the presence of a palladium metal catalyst. The process according to claim 1, wherein the cyclization reaction of step (v) is carried out by heating to 90 to 120 ° C in the presence of a carboxylic acid or a nitrile compound and a polyphosphoric acid. The process according to claim 1, wherein the cyclization reaction of step (v) is carried out by heating in the presence of imidate hydrochloride and an alcohol solvent. The process according to claim 1, wherein the cyclization reaction of step (v) is carried out by heating in an alcohol solvent in the presence of an aldehyde compound and a copper compound.