KR100242857B1 - Process for preparing bicyclic amine - Google Patents

Abstract

Described herein is a novel process for preparing dicyclic amines represented by formula (I) which are substituents of quinolones and naphthyridine carboxylic acid derivatives having good antimicrobial activity:

(I)

(I)

Wherein R 1, R 2 and R 5 are each independently hydrogen or a lower alkyl group, R 3 and R 4 are each independently hydrogen or a lower alkyl group and one of R 3 and R 4 is hydrogen and P is an amine protecting group.

Description

[Name of invention]

Process for preparing bicyclic amine

Detailed description of the invention

[Objective of the invention]

The present invention is an antimicrobial substance having excellent antimicrobial activity, and among the intermediates which are passed through the process of synthesizing amine, which is the most important substituent of quinolone and naphthyridine carboxylic acid derivative which can be used as medicine, animal medicine, and medicinal disease The present invention relates to a new process for producing intermediates.

[Technical Field to which the Invention belongs and Conventional Technology in the Field]

Synthetic methods known to date (Ref .: Korean Patent Publication No. 96-882 and U.S. Patent 5,527,910) are complex processes involving several steps and are not effective because of their low selectivity to diastereomers. In addition, the debenzylation process carried out in such synthesis involves a high cost burden and a high cost burden.

[Technical Challenges to Invent]

Therefore, in synthesizing the amine substituents of the quinolone and naphthyridine carboxylic acid derivatives, there is a need to develop a new method that not only reduces the steps of the process and increases the selectivity for the diastereomer but also solves the problem of the debenzylation process. After much effort, the inventors have invented a new manufacturing method having a simple, safe process, low raw material costs, and excellent selectivity.

Composition and Action of the Invention

The final target compound to be synthesized in the present invention is represented by the following formula (I):

(I)

(I)

In the above formula,

R1, R2 and R5 are each independently hydrogen or lower alkyl group,

R3 and R4 are each independently hydrogen or a lower alkyl group and one of R3 and R4 must be hydrogen,

P is an amine protecting group.

Lower alkyl groups herein include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl and the like.

As used herein, the amine protecting group may be removed without disrupting the structure of the compound by reaction or proceeding with side reactions, for example, a hydrolyzable group such as acetyl, trifluoroacetyl, ethoxycarbonyl group or a benzyl or tosyl group, It includes mesyl groups.

The preparation method of the compound of formula (I) according to the present invention uses a compound represented by the following formula (II) as a starting material:

(Ⅱ)

(Ⅱ)

In the above formula,

R1, R2, R3, R4, R5 and P are as defined above.

The present invention produces the desired compound of formula (I) by sequentially performing imidization, reduction and debenzylation with respect to the compound of formula (II). This can be represented by the following scheme.

[Scheme]

(Wherein R1, R2, R3, R4, R5 and P are as defined above).

According to the above scheme, a compound of formula (II) is obtained by imidation reaction to obtain a compound of formula (III), and a reduction reaction and a debenzylation reaction of the target compound (I) and diastereomeric (ID) thereof. The mixture is obtained in a ratio of 96: 4.

In the process of the present invention, the immunization reaction during the reaction uses an acid in an organic solvent and benzyl amine represented by the following general formula (VI):

(VI)

(VI)

Organic solvents used in the imidation reaction of the present invention include chloroform, acetone, acetonitrile, diethyl ether, benzene, xylene, carbon tetrachloride, toluene, dichloromethane, dichloroethane and the like.

The reaction temperature and reaction time of the imidization reaction according to the present invention are not important variables, but the preferred range is 30 minutes to 10 hours at -20 ° C to 100 ° C.

Acids used in the imidation reaction of the present invention include silica gel, aluminum chloride, titanium chloride, tin chloride and the like.

The reduction reaction in the process of the present invention is carried out in a conventional manner in the field of organic synthesis. However, solvents that can be suitably used in the reduction reaction according to the present invention include water, methanol, ethanol, isopropanol, n-butanol, isobutanol, t-butanol and the like, and examples of the reducing agent are sodium borohydride, sodium Cyanoborohydride, lithium aluminum hydride, etc. are mentioned.

The process of the present invention is characterized as using a hydrogen source of ammonium formate under catalysis of debenzylation as a final step process. Here, examples of the catalyst that can be used include palladium carbon, palladium hydroxide, palladium barium sulfate, platinum oxide or rhodium carbon. The debenzylation reaction according to the invention can be carried out in a solvent such as water, ethanol, isopropanol, n-butanol, isobutanol or t-butanol.

Therefore, according to the present invention, the compound of formula (II) is aminated by acid and benzylamine in an organic solvent to produce a compound of formula (III), and then reduced, and then ammonium as a hydrogen source in the presence of a catalyst. Debenzylation using formate provides a process for preparing the compound of formula (I).

The following examples illustrate the invention. However, these examples should not be understood as limiting the invention.

Reference Example 1

Preparation of N-p-toluenesulfonyl-1-methyl-6-oxo-3-azabicyclo [3.2.0] heptane

100 g of 3- [N-4-toluenesulfonyl-N'-2-methyl-2-propenyl] aminopropinic acid as a known compound was suspended in 100 ml of toluene, and 27 ml of thionyl chloride was added. Heated to 85-90 ° C. The mixture was stirred for 2 hours while maintaining the same temperature, followed by distillation under reduced pressure to remove toluene and sulfur dioxide gas. 300 ml of toluene was added thereto, and the internal temperature was further heated to 85 to 90 ° C, and a solution of triethylamine diluted in 200 ml of toluene was added dropwise at the same temperature over 5 hours. When the addition was completed, the mixture was stirred for 2 to 3 hours at the same temperature. After cooling to room temperature, 80 ml of concentrated hydrochloric acid was washed with a solution dissolved in 200 ml of water. The organic layer was washed with water, and then toluene was removed to obtain 75 g of a yellowish brown solid compound (yield 80%).

1 H-NMR (CDCI3): δ: 7.7 (2H, d, 8.2 Hz), 7.3 (2H, d, 9.6 Hz), 3.84 (1H, d, 10.1 Hz),

3.67 (1H, 9.5 Hz), 3.2-2.6 (5H, m), 2.4 (3H, s), 1.3 (3H, s)

Example 1

Preparation of N-p-toluenesulfonyl-1-methyl-6-amino-3-azabicyclo [3.2.0] heptane

100 g of the compound of Reference Example 1 was dissolved in 1 L of dichloroethane, 20 g of silica gel was added, and 46.1 g of benzylamine was added with stirring, followed by reaction for 2 hours under a Dean-Stark apparatus. After cooling to room temperature, 16.3 g of sodium borohydride was added, and 500 ml of anhydrous ethanol was added thereto, followed by stirring for 1 hour. 500 ml of water were added, stirred for 1 hour and filtered to remove silica gel. The filtrate was depressurized to completely remove ethanol. 100 ml of water was added and stirred for 30 minutes. 300 ml of ethyl acetate was added, and then 2N hydrochloric acid solution was added dropwise to adjust the pH to 1.0 or less, followed by stirring for 1 hour. Filtration under reduced pressure, washing with 200 ml of ethyl acetate, and drying with air at 60 ° C. yielded 131 g of a white solid. This solid was dissolved in 1.3 L of methanol, 26.2 g of 20% palladium carbon was added, 67.8 g of ammonium formate was added, and the mixture was heated to reflux for 2 to 3 hours. The reaction solution was filtered under reduced pressure to remove palladium carbon, the filtrate was taken, and then the pH was adjusted to 1.0 or less by dropwise addition of 2N hydrochloric acid solution, and the methanol was removed under reduced pressure. Extracted with. The ethyl acetate layer was separated under reduced pressure to remove the solvent, to obtain 77.8 g of the target compound as a white solid (yield 77.4%). The selectivity to diastereomer of this compound was 96: 4, and a small amount of peak of diastereomer was observed on 1 H-NMR.

1H-NMR (CDCI3) δ: 7.7 to 7.1 (4H, m), 3.4 to 2.0 (10H, m), 2.3 (3H, s), 1.3 (3H, s)

IR: 3321cm_1 (N-H)

Example 2

Preparation of N-p-toluenesulfonyl-1-methyl-6-amino-3-azabicyclo [3.2.0] heptane

100 g of the compound of Reference Example 1 was dissolved in 1 L of chloroform, 40 g of aluminum chloride was added thereto, and 46.1 g of benzylamine was added while stirring, followed by reaction for 2 hours under a Dean-Stark apparatus. After cooling to room temperature, 16.3 g of sodium borohydride was added, and 500 ml of anhydrous ethanol was added thereto, followed by stirring for 1 hour. 500 ml of water were added, stirred for 1 hour and filtered to remove silica gel. The filtrate was depressurized to completely remove ethanol. 100 ml of water was added and stirred for 30 minutes. 300 ml of ethyl acetate was added, and then 2N hydrochloric acid solution was added dropwise to adjust the pH to 1.0 or less, followed by stirring for 1 hour. Filtration under reduced pressure, washing with 200 ml of ethyl acetate, and drying with air at 60 ° C. yielded 131 g of a white solid. This solid was dissolved in 1.3 L of methanol, 26.2 g of 20% palladium carbon was added, 67.8 g of ammonium formate was added, and the mixture was heated to reflux for 2 to 3 hours. The reaction solution was filtered under reduced pressure, the filtrate was collected, 2N hydrochloric acid solution was added dropwise to adjust the pH to 1.0 or less, methanol was removed under reduced pressure, ammonia water was gradually added to adjust the pH to between 8 and 10, and extracted with ethyl acetate. The ethyl acetate layer was separated under reduced pressure to remove the solvent, to obtain 73.4 g of the target compound as a white solid (yield 73.0%). The selectivity to diastereomer of this compound was 96: 4, and a small amount of peak of diastereomer was observed on 1 H-NMR.

1H-NMR (CDCI3) δ: 7.7 to 7.1 (4H, m), 3.4 to 2.0 (10H, m), 2.3 (3H, s), 1.3 (3H, s)

IR: 3321cm_1 (N-H)

Example 3

Preparation of N-p-toluenesulfonyl-1-methyl-6-amino-3-azabicyclo [3.2.0] heptane

100 g of the compound of Reference Example 1 was dissolved in 1 L of acetone, 40 g of titanium chloride was added, and 46.1 g of benzylamine was added while stirring, followed by reacting for 2 hours under a Dean-Stark apparatus. After cooling to room temperature, 16.3 g of sodium borohydride was added, and 500 ml of anhydrous ethanol was added thereto, followed by stirring for 1 hour. 500 ml of water were added, stirred for 1 hour and filtered to remove silica gel. The filtrate was depressurized to completely remove ethanol. 100 ml of water was added and stirred for 30 minutes. 300 ml of ethyl acetate was added, and then 2N hydrochloric acid solution was added dropwise to adjust the pH to 1.0 or less, followed by stirring for 1 hour. After filtration under reduced pressure and washing with 200 ml of ethyl acetate, the mixture was air dried at 60 deg. C to obtain 131 g of a white solid. This solid was dissolved in 1.3 L of methanol, 26.2 g of 20% palladium carbon was added, 67.8 g of ammonium formate was added, and the mixture was heated to reflux for 2 to 3 hours. The reaction solution was filtered under reduced pressure, the filtrate was collected, 2N hydrochloric acid solution was added dropwise to adjust the pH to 1.0 or less, methanol was removed under reduced pressure, ammonia water was gradually added to adjust the pH to between 8 and 10, and extracted with ethyl acetate. The ethyl acetate layer was separated under reduced pressure to remove the solvent, to obtain 69.8 g of the target compound as a white solid (yield 69.4%). The selectivity to diastereomer of this compound was 96: 4, and a small amount of peak of diastereomer was observed on 1 H-NMR.

1H-NMR (CDCI3) δ: 7.7 to 7.1 (4H, m), 3.4 to 2.0 (10H, m), 2.3 (3H, s), 1.3 (3H, s)

IR: 3321cm_1 (N-H)

Example 4

Preparation of N-p-toluenesulfonyl-1-methyl-6-amino-3-azabicyclo [3.2.0] heptane

100 g of the compound of Reference Example 1 was dissolved in 1 L of acetonitrile, 20 g of silica gel was added thereto, 46.1 g of benzylamine was added with stirring, and reacted for 2 hours under a Dean-Stark apparatus. After cooling to room temperature, 16.3 g of sodium borohydride was added, and 500 ml of anhydrous ethanol was added thereto, followed by stirring for 1 hour. 500 ml of water were added, stirred for 1 hour and filtered to remove silica gel. The filtrate was depressurized to completely remove ethanol. 100 ml of water was added and stirred for 30 minutes. 300 ml of ethyl acetate was added, and then 2N hydrochloric acid solution was added dropwise to adjust the pH to 1.0 or less, followed by stirring for 1 hour. Filtration under reduced pressure, washing with 200 ml of ethyl acetate, and drying with air at 60 ° C. yielded 131 g of a white solid. This solid was dissolved in 1.3 L of methanol, 26.2 g of 20% palladium carbon was added, 67.8 g of ammonium formate was added, and the mixture was heated to reflux for 2 to 3 hours. The reaction solution was filtered under reduced pressure, the filtrate was collected, 2N hydrochloric acid solution was added dropwise to adjust the pH to 1.0 or less, methanol was removed under reduced pressure, ammonia water was gradually added to adjust the pH to between 8 and 10, and extracted with ethyl acetate. The ethyl acetate layer was separated under reduced pressure to remove the solvent, to obtain 75.6 g of the target compound as a white solid (yield 75.2%). The selectivity to diastereomer of this compound was 96: 4, and a small amount of peak of diastereomer was observed on 1 H-NMR.

1H-NMR (CDCI3) δ: 7.7 to 7.1 (4H, m), 3.4 to 2.0 (10H, m), 2.3 (3H, s), 1.3 (3H, s)

IR: 3321cm_1 (N-H)

Example 5

Preparation of N-p-toluenesulfonyl-1-methyl-6-amino-3-azabicyclo [3.2.0] heptane

100 g of the compound of Reference Example 1 was dissolved in 1 L of benzene, 20 g of tin chloride was added thereto, and 85.2 g of dibenzylamine was added while stirring, followed by reaction for 3 hours under a Dean-Stark apparatus. After cooling to room temperature, 16.3 g of sodium borohydride was added, and 500 ml of anhydrous ethanol was added thereto, followed by stirring for 1 hour. 500 ml of water were added, stirred for 1 hour and filtered to remove silica gel. The filtrate was depressurized to completely remove ethanol. 100 ml of water was added and stirred for 30 minutes. 300 ml of ethyl acetate was added, and then 2N hydrochloric acid solution was added dropwise to adjust the pH to 1.0 or less, followed by stirring for 1 hour. After filtration under reduced pressure and washing with 200 ml of ethyl acetate, the mixture was air dried at 60 deg. C to obtain 131 g of a white solid. This solid was dissolved in 1.3 L of methanol, 26.2 g of 20% palladium carbon was added, 67.8 g of ammonium formate was added, and the mixture was heated to reflux for 2 to 3 hours. The reaction solution was filtered under reduced pressure, the filtrate was collected, 2N hydrochloric acid solution was added dropwise to adjust the pH to 1.0 or less, methanol was removed under reduced pressure, ammonia water was gradually added to adjust the pH to between 8 and 10, and extracted with ethyl acetate. The ethyl acetate layer was separated under reduced pressure to remove the solvent, to obtain 74.8 g of the target compound as a white solid (yield 74.4%). The selectivity to diastereomer of this compound was 96: 4, and a small amount of peak of diastereomer was observed on 1 H-NMR.

1H-NMR (CDCI3) δ: 7.7 ~ 7.1 (4H, m), 3.4 ~ 2.0 (10H, m), 2.3 (3H, s), 1.3 (3H, s)

IR: 3321cm (N-H)

Example 6

Preparation of N-p-toluenesulfonyl-1-methyl-6-amino-3-azabicyclo [3.2.0] heptane

100 g of the compound of Reference Example 1 was dissolved in 1 L of toluene, 20 g of tin chloride was added thereto, and 52.1 g of α-methylbenzylamine was added with stirring, followed by reaction for 3 hours under a Dean-Stark apparatus. After cooling to room temperature, 16.3 g of Sonyumborohydride was added, and 500 ml of anhydrous ethanol was added thereto, followed by stirring for 1 hour. 500 ml of water were added, stirred for 1 hour and filtered to remove silica gel. The filtrate was depressurized to completely remove ethanol. 100 ml of water was added and stirred for 30 minutes. 300 ml of ethyl acetate was added, and then 2N hydrochloric acid solution was added dropwise to adjust the pH to 1.0 or less, followed by stirring for 1 hour. Filtration under reduced pressure, washing with 200 ml of ethyl acetate, and drying with air at 60 ° C. yielded 131 g of a white solid. This solid was dissolved in 1.3 L of methanol, 26.2 g of 20% palladium carbon was added, 67.8 g of ammonium formate was added, and the mixture was heated to reflux for 2 to 3 hours. The reaction solution was filtered under reduced pressure, the filtrate was collected, 2N hydrochloric acid solution was added dropwise to adjust the pH to 1.0 or less, methanol was removed under reduced pressure, ammonia water was gradually added to adjust the pH to between 8 and 10, and extracted with ethyl acetate. The ethyl acetate layer was separated under reduced pressure to remove the solvent, yielding 68.2 g of the target compound as a white solid (yield 67.8%). The selectivity to diastereomer of this compound was 96: 4, and a small amount of peak of diastereomer was observed on 1 H-NMR.

1H-NMR (CDCI3) δ: 7.7 to 7.1 (4H, m), 3.4 to 2.0 (10H, m), 2.3 (3H, s), 1.3 (3H, s)

IR: 3321cm1 (N-H)

[Effects of the Invention]

The method for preparing bicyclic amines according to the present invention is expected to significantly increase the synthesis yield and purity of the antibacterial quinolone and carboxylic acid derivatives because the process is simple and the selectivity to diastereomer is quite high.

Claims (5)

Amination of a compound of formula (II) with an acid and benzylamine in an organic solvent to produce a compound of formula (III), followed by reduction, followed by debenzylation to produce a compound of formula (I) Process according to claim 1, characterized in that the debenzylation reaction is carried out using ammonium formate as a hydrogen source in the presence of a catalyst:

(I) In the above formula, R1, R2 and R5 are each independently hydrogen or lower alkyl group, R 3 and R 4 are each independently hydrogen or a lower alkyl group and one of R 3 and R 4 must be hydrogen. P is an amine protecting group. The temperature of -20 ° C to 100 ° C according to claim 1, wherein the amination reaction is carried out in an organic solvent selected from the group consisting of chloroform, acetone, acetonitrile, diethyl ether, benzene, xylene, carbon tetrachloride, toluene, dichloromethane and dichloroethane. Process for 30 minutes to 10 hours under conditions. The process according to claim 1 or 2, wherein the acid in the amination reaction is selected from the group consisting of silica gel, aluminum chloride, titanium chloride and tin chloride. The method of claim 1, wherein the reduction reaction is carried out in a solvent selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, isobutanol and t-butanol as sodium borohydride, sodium cyanoborohydride and And using a material selected from the group consisting of lithium aluminum hydride. The method of claim 1, wherein the catalyst used in the debenzylation reaction is selected from the group consisting of palladium carbon, palladium hydroxide, palladium barium sulfate, platinum oxide and rhodium carbon, and water, ethanol, isopropanol, n-butanol, iso Characterized in that it is carried out in a solvent selected from the group consisting of butanol and t-butanol.