WO2017078097A1

WO2017078097A1 - Method for producing aminoglycoside antibiotic

Info

Publication number: WO2017078097A1
Application number: PCT/JP2016/082667
Authority: WO
Inventors: 高橋　良昭; 英二郎梅村
Original assignee: ＭｅｉｊｉＳｅｉｋａファルマ株式会社; 公益財団法人微生物化学研究会
Priority date: 2015-11-02
Filing date: 2016-11-02
Publication date: 2017-05-11
Also published as: JP2019001718A

Abstract

Provided is a method for stably producing (2S)-2-hydroxydibekacin, said method being characterized by the use of 2-hydroxykanamycin C or 2-hydroxykanamycin B as a starting material or synthetic intermediate.

Description

Method for producing aminoglycoside antibiotics

Reference to related applications

This patent application is accompanied by a priority claim based on Japanese Patent Application No. 2015-216165 (filing date: November 2, 2015) which is a previously filed patent application in Japan. The entire disclosure of this earlier patent application is hereby incorporated by reference.

The present invention relates to a novel method for producing aminoglycoside antibiotics.

In recent years, drug-resistant bacteria exhibiting resistance to antibacterial agents used for the treatment of infectious diseases have emerged, and the treatment of infectious diseases caused by the resistant bacteria has become a major problem in medical practice. In particular, MRSA is known to be one of the major drug-resistant bacteria that spread rapidly due to nosocomial infections and cause clinically serious infections, and the development of therapeutic drugs is actively being carried out.

Under such technical circumstances, aminoglycoside antibiotics have a broad antibacterial spectrum from Gram-positive bacteria to Gram-negative bacteria and have an excellent bactericidal activity, and thus are promising to overcome various resistant bacteria including MRSA. Expected to be a drug, research into its derivatives is ongoing.

Patent Document 1 discloses (2S) -2-hydroxyarbekacin as a part of the present inventors as an aminoglycoside antibiotic that exhibits a broad antibacterial spectrum and excellent antibacterial activity and can avoid severe nephrotoxicity. It is disclosed. Patent Document 1 describes that the final substance (2S) -2-hydroxyarbekacin was produced using the synthetic intermediate (2S) -2-hydroxydibekacin.

WO2007 / 142150

However, in the method described in Patent Document 1, it may be difficult to stably supply the high-purity synthetic intermediate (2S) -2-hydroxydibekacin due to contamination of unreacted substances. It has been clarified from the examination by the present inventors that the yield of the substance (2S) -2-hydroxyarbekacin is affected and the titer is lowered. From the viewpoint of industrial production of the final material, it is preferable to stably produce the synthetic intermediate (2S) -2-hydroxydibekacin. Therefore, it can be said that creation of a new method for stably producing the synthetic intermediate (2S) -2-hydroxydibekacin is desired.

Therefore, an object of the present invention is to provide a novel method for stably producing (2S) -2-hydroxydibekacin.

As a result of intensive studies, the present inventors have recently found that 2-hydroxykanamycin C (hereinafter also referred to as “compound represented by formula (1)”) or 2-hydroxykanamycin B (hereinafter referred to as “formula (16)”). When used as a raw material or a synthetic intermediate, (2S) -2-hydroxydibekacin (hereinafter, also referred to as “compound represented by formula (15)”) is stably used. It was found that it can be manufactured. The present invention is based on such knowledge.

According to this invention, the manufacturing method of the compound represented by Formula (15) characterized by using the compound represented by Formula (1) as a raw material or a synthetic intermediate is provided.

Moreover, according to this invention, use of the compound represented by Formula (1) as a raw material or a synthetic intermediate in manufacture of the compound represented by Formula (15) is provided.

Moreover, according to this invention, the manufacturing method of the compound represented by Formula (15) characterized by using the compound represented by Formula (16) as a raw material or a synthetic intermediate is provided.

Moreover, according to this invention, use of the compound represented by Formula (16) as a raw material or a synthetic intermediate in manufacture of the compound represented by Formula (15) is provided.

According to the present invention, high purity (2S) -2-hydroxydibekacin can be stably produced by using 2-hydroxykanamycin C or 2-hydroxykanamycin B as a raw material or a synthetic intermediate.

Hereinafter, a method for producing (2S) -2-hydroxydibekacin using 2-hydroxykanamycin C or 2-hydroxykanamycin B will be specifically described.

Process for producing (2S) -2-hydroxydibekacin ( compound represented by formula (15)) from 2-hydroxykanamycin C (compound represented by formula (1)) (2S) -2-hydroxydibekacin In the method for producing (the compound represented by the formula (15)), 2-hydroxykanamycin C (the compound represented by the formula (1)) which is a raw material or a synthetic intermediate is a method described in WO2009 / 069800 It can be manufactured according to.

According to the production method of the present invention, first, the amino group of the compound represented by the formula (1) is protected with a tert-butoxycarbonyl group to obtain the compound represented by the formula (2).

Next, the 6′-position and 6 ″ -position hydroxyl groups of the compound represented by the formula (2) are protected with a trityl group (triphenylmethyl group) to obtain a compound represented by the formula (3).

Next, the 3 ′ and 4 ′ hydroxyl groups of the compound represented by the formula (3) are protected with a cyclohexylidene group to obtain a compound represented by the formula (4).

Next, the 2, 2 ″ and 4 ″ -position hydroxyl groups of the compound represented by the formula (4) are protected with an acetyl group to obtain a compound represented by the formula (5).

Next, the hydroxyl groups at the 3 ′, 4 ′ and 6 ′ positions of the compound represented by the formula (5) are deprotected to obtain the compound represented by the formula (6).

Next, the hydroxyl groups at the 3 ′ and 6 ′ positions of the compound represented by the formula (6) are protected with a benzoyl group, and the hydroxyl group at the 4 ′ position of the compound represented by the formula (6) is benzylsulfonylated. The compound represented by 7) is obtained.

Next, the compound represented by the formula (7) is reacted with a base to epoxidize the 3 ′ and 4 ′ positions and deprotect the hydroxyl groups at the 2, 2 ″, 4 ″ and 6 ′ positions, A hydroxyl group at the 2 ″, 4 ″ and 6 ′ positions is protected with an acetyl group to obtain a compound represented by the formula (8).

Next, the compound represented by the formula (8) is reacted with a metal iodide salt to obtain the compound represented by the formula (9).

Next, the compound represented by the formula (9) is benzylsulfonylated at the 3 ′ position, and the compound represented by the formula (10) is eliminated by the elimination reaction of the 3′-position benzylsulfonyloxy group and the 4′-position iodine. Get.

Next, the 2, 2 ″, 4 ″ and 6′-position hydroxyl groups of the compound represented by the formula (10) are deprotected to obtain the compound represented by the formula (11).

Next, the compound represented by the formula (11) is reacted with triphenylphosphine and a metal azide to obtain the compound represented by the formula (12).

Next, the compound represented by the formula (12) is treated by the Staudinger reaction to obtain the compound represented by the formula (13).

Next, the 1,3, 2 ′, 3 ″ amino group and the 6 ″ -position hydroxyl group of the compound represented by the formula (13) are deprotected to obtain the compound represented by the formula (14). .

Next, the compound represented by the formula (14) is treated with a catalytic reduction reaction to obtain the compound represented by the formula (15).

Process for producing (2S) -2-hydroxydibekacin ( compound represented by formula (15)) from 2-hydroxykanamycin B (compound represented by formula (16)) (2S) -2-hydroxydibekacin In the method for producing (a compound represented by the formula (15)), 2-hydroxykanamycin B (a compound represented by the formula (16)) which is a raw material or a synthetic intermediate is a method described in WO2009 / 069800 It can be manufactured according to.

In the production method of the present invention, first, the amino group of the compound represented by the formula (16) is protected with a benzyloxycarbonyl group to obtain the compound represented by the formula (17).

Next, the hydroxyl group at the 3 ′ and 4 ′ positions and the hydroxyl group at the 4 ″ and 6 ″ positions of the compound represented by the formula (17) are respectively protected with a cyclohexylidene group, and the compound represented by the formula (18) is represented. To obtain a compound.

Next, the hydroxyl groups at the 2 and 2 ″ positions of the compound represented by the formula (18) are protected with an acetyl group to obtain the compound represented by the formula (19).

Next, the 3 ′ and 4 ′ positions of the compound represented by formula (19) are deprotected to obtain the compound represented by formula (20).

Next, a mesyl group is introduced into the hydroxyl groups at the 3 ′ and 4 ′ positions of the compound represented by the formula (20) to obtain the compound represented by the formula (21).

Next, the compound represented by the formula (21) is treated by the Tipson-Cohen reaction to obtain the compound represented by the formula (22) by the elimination reaction at the 3 ′ and 4 ′ positions.

Next, the compound represented by the formula (22) is subjected to base treatment and / or acid treatment to deprotect the 2, 2 ″, 4 ″ and 6-positions, and represented by the formula (23). A compound is obtained.

Next, the compound represented by the formula (23) is treated by a catalytic reduction reaction to obtain (2S) -2-hydroxydibekacin (the compound represented by the formula (15)).

Hereinafter, the present invention will be specifically described with reference to the following examples, but the present invention is not limited to these examples.

Example 1: Synthesis of (2S) -2-hydroxydibekacin from (2S) -2-hydroxykanamycin C (2-OH-KMC)
(2S) -1,3,2 ', 3 "-tetra-Nt-butoxycarbonyl-2-hydroxykanamycin C

To 40 ml of an aqueous solution containing 4.00 g (8 mmol) of 2-OH-KMC (1), 8 ml of triethylamine was added and heated to 65 ° C., and then 80 ml of 1,4-dioxane solution containing 10.5 g (48 mmol) of Boc ₂ O. And reacted at the same temperature for 16 hours. To the resulting reaction solution, 10 ml of concentrated aqueous ammonia was added and concentrated after 10 minutes. Next, water was added to the residue, and the resulting precipitate was collected by filtration and dried to obtain 4.01 g (56%) of Compound (2). Further, the filtrate was concentrated and reprecipitated with water to obtain 2.43 g (34%) of Compound (2). Compound (2) was obtained in a total of 6.44 g (90%).
MS (FAB) m / z: 901 (M ⁺ +1)
¹ H-NMR (DMSO-d6) δ1.40 (36H, s)

(2S) -1,3,2 ', 3 "-tetra-Nt-butoxycarbonyl-2-hydroxy-6', 6" -di-O-tritylkanamycin C

1.08 g (1.2 mmol) of the compound (2) was dissolved in 20 ml of pyridine, and 1.34 g (4.8 mmol) of trityl chloride was added and reacted at 60 ° C. for 16 hours. The reaction solution was added with 2 ml of MeOH, reacted at the same temperature for 10 minutes, and then concentrated. Next, ethyl acetate was added to the residue, washed with water, 10% aqueous potassium bisulfate solution, 5% aqueous potassium hydrogen carbonate solution and water, and concentrated. Next, the residue was purified by silica gel column chromatography (silica gel 30 ml, mobile phase CHCl _3- > CHCl ₃ : MeOH = 10: 1) to obtain 1.49 g (quantitative) of compound (3).
MS (FAB) m / z: 1385 (M ⁺ +1)
¹ H-NMR (CDCl ₃ ) δ7.25-7.40 (30H, m)

(2S) -1,3,2 ′, 3 ″ -Tetra-Nt-butoxycarbonyl-3 ′, 4′-O-cyclohexylidene-2-hydroxy-6 ′, 6 ″ -di-O -Trityl kanamycin C

Dissolve 2.26 g (1.63 mmol) of compound (3) in 10 ml of DMF, add 70 mg (0.41 mmol) of anhydrous p-toluenesulfonic acid and 2 ml of 1,1-dimethoxycyclohexane, and react at 30 ° C. under reduced pressure for 4 hours. It was. Next, 1 ml of triethylamine was added to the reaction solution and concentrated. Next, ethyl acetate was added to the residue, washed with 5% aqueous potassium hydrogen carbonate solution and water, and concentrated. Next, the residue was purified by silica gel column chromatography (silica gel 30 ml, mobile phase CHCl _3- > CHCl ₃ : MeOH = 30: 1) to obtain 1.96 g (82%) of compound (4).
MS (FAB) m / z: 1465 (M ⁺ +1)
¹ H-NMR (CDCl ₃ ) δ1.3-1.8 (10H, m)

(2S) -2-Acetoxy-2 ″, 4 ″ -di-O-acetyl-1,3,2 ′, 3 ″ -tetra-Nt-butoxycarbonyl-3 ′, 4′-O— Cyclohexylidene-6 ′, 6 ″ -di-O-tritylkanamycin C

2.27 g (1.55 mmol) of compound (4) was dissolved in 20 ml of pyridine, and 5 ml of acetic anhydride was added and reacted at room temperature for 16 hours. To the reaction solution, 2 ml of MeOH was added under ice-cooling, reacted at the same temperature for 10 minutes, and then concentrated. Next, ethyl acetate was added to the residue, and the mixture was washed with 10% aqueous potassium bisulfate solution, 5% aqueous potassium hydrogen carbonate solution, and water, and concentrated. Next, the residue was purified by silica gel column chromatography (silica gel 30 ml, mobile phase CHCl _3- > CHCl ₃ : MeOH = 80: 1) to obtain 2.1 g (85%) of compound (5).
MS (FAB) m / z: 1591 (M ⁺ +1)
¹ H-NMR (CDCl ₃ ) δ2.01, 2.03 and 2.04 (each 3H, s)

(2S) -2-Acetoxy-2 ″, 4 ″ -di-O-acetyl-1,3,2 ′, 3 ″ -tetra-Nt-butoxycarbonyl-6 ″ -O-tritylkanamycin C

Compound (5) (2.05 g, 1.3 mmol) was dissolved in methanol (20 ml), hydroxyamine hydrochloride (90 mg, 1.3 mmol) was added, and the mixture was reacted at room temperature for 3 hours. The reaction solution was added with 0.2 ml of triethylamine, reacted at the same temperature for 10 minutes, and then concentrated. Ethyl acetate was added to the residue, the insoluble material was removed, and the mixture was washed with 5% aqueous potassium hydrogen carbonate solution and water, and concentrated. The residue was purified by silica gel column chromatography (silica gel 30 ml, mobile phase CHCl _3- > CHCl ₃ : MeOH = 10: 1) to obtain 1.24 g (76%) of compound (6).
MS (FAB) m / z: 1269 (M ⁺ +1)
¹ H-NMR (CDCl ₃ ) δ7.25-7.40 (15H, m)

(2S) -2-Acetoxy-2 ″, 4 ″ -di-O-acetyl-4′-O-benzylsulfonyl-3 ′, 6′-di-O-benzoyl-1,3,2 ′, 3 '' -Tetra-Nt-butoxycarbonyl-6'-deoxy-6 ''-O-trityl kanamycin

1.28 g (1.01 mmol) of compound (6) was dissolved in 5 ml of pyridine, cooled to −15 to −10 ° C., 0.3 ml (2.5 eq) of benzoyl chloride was added, and the mixture was reacted at the same temperature for 1 hour. Further, 296 mg (1.5 eq) of benzylsulfonyl chloride was added to the reaction solution and reacted at the same temperature for 1 hour. Next, 0.5 ml of distilled water was added to the reaction solution, stirred at room temperature for 10 minutes, and concentrated. Ethyl acetate was added to the residue, and the mixture was washed with 10% aqueous potassium bisulfate solution, 5% aqueous potassium hydrogen carbonate solution and water, and concentrated. The residue was washed with water and concentrated to obtain 1.32 g (81%) of compound (7).
MS (FAB) m / z: 1631 (M ⁺ +1)

(2S) -2-Acetoxy-6 ′, 2 ″, 4 ″ -tri-O-acetyl-3 ′, 4′-anhydro-1,3,2 ′, 3 ″ -tetra-Nt- Butoxycarbonyl-4'-epi-6 ''-O-tritylkanamycin C

1.20 g (0.74 mmol) of the compound (7) was dissolved in 10 ml of chloroform, 1 ml of 28% sodium methoxide / methanol solution was added, and the mixture was reacted at room temperature for 1 hour. Water was added to the reaction solution and neutralized with 2N hydrochloric acid. Next, the chloroform layer was washed with water, concentrated, dissolved in 10 ml of pyridine, added with 2.5 ml of acetic anhydride, and reacted at room temperature for 16 hours. To the reaction solution, 2 ml of MeOH was added under ice cooling, reacted at the same temperature for 10 minutes, and concentrated. Ethyl acetate was added to the residue, washed with 5% aqueous potassium hydrogen carbonate solution, 10% aqueous potassium bisulfate solution and water, and concentrated to obtain 945 mg (99%) of compound (8).
MS (FAB) m / z: 1293 (M ⁺ +1)

(2S) -2-Acetoxy-6 ′, 2 ″, 4 ″ -tri-O-acetyl-1,3,2 ′, 3 ″ -tetra-Nt-butoxycarbonyl-4′-deoxy- 4'-iodo-6 "-O-trityl kanamycin C

930 mg (0.72 mmol) of compound (8) was dissolved in 12 ml of acetone, 0.8 ml of an acetic acid solution containing 1.2 g of sodium iodide and 40 mg of sodium acetate was added, heated to reflux for 6 hours, and concentrated. Ethyl acetate was added to the residue, washed twice with water and concentrated to obtain 1.03 g (quantitative) of compound (9).
MS (FAB) m / z: 1421 (M ⁺ +1).

(2S) -2-Acetoxy-6 ′, 2 ″, 4 ″ -tri-O-acetyl-1,3,2 ′, 3 ″ -tetra-Nt-butoxycarbonyl-3 ′, 4 ′ -Dideoxy-3'-eno-6 "-O-tritylkanamycin C

990 mg (0.7 mmol) of compound (9) was dissolved in 10 ml of pyridine, 230 mg (1.2 mmol) of benzylsulfonyl chloride was added at −10 to 0 ° C., and the mixture was reacted at the same temperature for 1 hour. Thereto was added 0.5 ml of water, and the mixture was reacted at 80 ° C. for 2 hours, followed by concentration. Water was added to the residue, and the resulting precipitate was collected by filtration and dried to obtain 850 mg (95%) of compound (10).
MS (FAB) m / z: 1277 (M ⁺ +1)

(2S) -1,3,2 ', 3 "-tetra-Nt-butoxycarbonyl-3', 4'-dideoxy-3'-eno-6" -O-tritylkanamycin C

850 mg (0.67 mmol) of compound (10) was dissolved in 10 ml of chloroform, 1 ml of 28% sodium methoxide / methanol solution was added, and the mixture was reacted at room temperature for 1 hour. Water was added to the reaction solution and neutralized with 2N hydrochloric acid. Next, the chloroform layer was washed with water and concentrated to obtain 732 mg (99%) of Compound (11).
MS (FAB) m / z: 1109 (M ⁺ +1)
¹ H-NMR (CDCl ₃ ) 5.81 (2H, s)

(2S) -6′-azido-1,3,2 ′, 3 ″ -tetra-Nt-butoxycarbonyl-3 ′, 4 ′, 6′-trideoxy-3′-eno-2-hydroxy-6 '' -O-trityl kanamycin C

720 mg (0.65 mmol) of the compound (11) was dissolved in 5 ml of DMF, and 0.6 ml of carbon tetrachloride, 520 mg (2 mol) of triphenylphosphine and 650 mg (10 mmol) of sodium triazide were added and reacted at 50 ° C. for 6 hours. . The reaction mixture was concentrated, ethyl acetate was added to the residue, the mixture was washed with water and concentrated. The residue was purified by silica gel column chromatography (silica gel 30 ml, mobile phase CHCl _3- > CHCl ₃ : MeOH = 10: 1) to give compound (12) 574 mg (78%) were obtained.
MS (FAB) m / z: 1134 (M ⁺ +1)

(2S) -1,3,2 ', 3 "-tetra-Nt-butoxycarbonyl-3', 4'-dideoxy-3'-eno-2-hydroxy-6" -O-tritylkanamycin B

565 g (0.5 mmol) of the compound (12) was dissolved in 20 ml of 80% THF aqueous solution, 262 mg (1 mmol) of triphenylphosphine was added, and the mixture was reacted at room temperature for 16 hours. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography (silica gel 30 ml, mobile phase CHCl _3- > CHCl ₃ : MeOH = 8: 1) to obtain 486 mg (88%) of Compound (13).
MS (FAB) m / z: 1108 (M ⁺ +1).

(2S) -3 ', 4'-dideoxy-3'-eno-2-hydroxykanamycin B

To 455 mg (0.41 mmol) of compound (13), 2.5 ml of trifluoroacetic acid was added and reacted at room temperature for 1 hour. After concentration of the reaction solution, 10 ml of water was added and neutralized with 28% aqueous ammonia, and then unnecessary substances were removed. The obtained aqueous solution was adsorbed on 30 ml of Amberlite CG-50 (NH ₄ ⁺ ), washed with water (50 ml), and eluted successively with 150 ml of 0.1N aqueous ammonia, 150 ml of 0.2N aqueous ammonia and 100 ml of 0.25N aqueous ammonia. This gave 168 mg (72%) of compound (14).
MS (FAB) m / z: 466 (M ⁺ +1).
¹ H-NMR (26% ND ₄ OD) δ5.31 (d, 1H, J = 4.5Hz), 5.60 (d, 1H, J = 5Hz), 6.06 (s, 2H)

(2S) -2-Hydroxydibekacin

125 mg (0.27 mmol) of compound (14) was dissolved in 2 ml of water, 5 mg of platinum oxide was added, and the mixture was reacted for 16 hours under pressure in a pearl reducing apparatus. After removing platinum oxide, the resulting aqueous solution was adsorbed on 25 ml of Amberlite CG-50 (NH ₄ ⁺ ), washed with water (25 ml), then 75 ml of 0.1N aqueous ammonia, 75 ml of 0.2N aqueous ammonia, 0.3N ammonia. Elution with 75 ml of water and 100 ml of 0.4N aqueous ammonia gave 98 mg (78%) of compound (15).
MS (FAB) m / z: 468 (M ⁺ +1)
¹ H-NMR (26% ND ₄ OD) δ1.37 (1H, m), 1.60 (1H, m), 1.68-1.77 (2H, m), 5.01 (d, 1H, J = 4Hz), 5.12 (d , 1H, J = 3.5Hz)

Example 2 Synthesis of (2S) -2-hydroxydibekacin from (2S) -2-hydroxykanamycin B (2-OH-KMB)
(2S) -1,3,2 ', 6', 3 "-penta-N-benzyloxycarbonyl-2-hydroxykanamycin B

50 ml of acetone was added to 100 ml of an aqueous solution containing 5.0 g (10 mmol) of 2-OH-KMB (16) and 7.50 g of potassium hydrogen carbonate, and 8.75 ml (52 mmol) of benzyloxycarbonyl chloride was added dropwise under ice cooling. The reaction was allowed to proceed for 16 hours at room temperature. The precipitate deposited from the reaction solution was collected by filtration and dried to obtain 11.2 g (95%) of compound (17).
MS (FAB) m / z: 1170 (M ⁺ +1)
¹ H-NMR (DMSO-d6) δ5.07 (10H, s), 7.35-7.5 (25H, m)

(2S) -1,3,2 ′, 6 ′, 3 ″ -penta-N-benzyloxycarbonyl-3 ′, 4 ′: 4 ″, 6 ″ -di-O-cyclohexylidene-2- Hydroxykanamycin B

16.6 g (14.1 mmol) of compound (17) was dissolved in 200 ml of DMF, 2.0 g of p-toluenesulfonic acid and 15 ml of 1,1-dimethoxycyclohexane were added, and the mixture was reacted at 45 ° C. under reduced pressure for 4 hours. Next, 10 ml of triethylamine was added to the reaction solution and concentrated. Ethyl acetate was added to the residue, washed with 5% aqueous potassium hydrogen carbonate solution and water, and concentrated to obtain 18.7 g (99%) of compound (18).
MS (FAB) m / z: 1330 (M ⁺ +1)
¹ H-NMR (DMSO-d6) δ1.3-1.8 (20H, m)

(2S) -2-Acetoxy-2 ″ -O-acetyl-1,3,2 ′, 6 ′, 3 ″ -penta-N-benzyloxycarbonyl-3 ′, 4 ′: 4 ″, 6 ′ '-Di-O-cyclohexylidenekanamycin B

18.6 g (13.1 mmol) of the compound (18) was dissolved in 120 ml of pyridine, 30 ml of acetic anhydride was added under ice cooling, and the mixture was reacted at room temperature for 16 hours. 20 ml of methanol was added to the reaction solution under ice-cooling, the mixture was reacted at the same temperature for 10 minutes, and then concentrated. Ethyl acetate was added to the residue, and the mixture was washed with 5% aqueous potassium hydrogen carbonate solution, 10% aqueous potassium bisulfate solution and water and concentrated to obtain 19.7 g (quantitative) of compound (19).
MS (FAB) m / z: 1414 (M ⁺ +1)
¹ H-NMR (DMSO-d6) δ2.11 (6H, s)

(2S) -2-Acetoxy-2 ″ -O-acetyl-1,3,2 ′, 6 ′, 3 ″ -penta-N-benzyloxycarbonyl-4 ″, 6 ″ -O-cyclohexylene Denkanamycin B

19.4 g (14.5 mmol) of the compound (19) was dissolved in 100 ml of methanol, 10 ml of a methanol solution containing 935 mg (14.5 mmol) of hydroxyamine hydrochloride was added under ice cooling, and the mixture was reacted at room temperature for 3 hours. Next, the reaction solution was concentrated (40 ml of MeOH was distilled off) and then cooled to 5 ° C. After standing at the same temperature for 16 hours, the deposited precipitate was collected by filtration and dried to obtain 15.0 g (82%) of Compound (20).
MS (FAB) m / z: 1334 (M ⁺ +1)
¹ H-NMR (DMSO-d6) δ1.3-1.65 (10H, s)

(2S) -2-Acetoxy-2 ″ -O-acetyl-1,3,2 ′, 6 ′, 3 ″ -penta-N-benzyloxycarbonyl-3 ′, 4′-di-O-mesyl- 4 ″, 6 ″ -O-cyclohexylidenekanamycin B

2.62 g (2 mmol) of the compound (20) was dissolved in 20 ml of pyridine, 0.6 ml (7.2 mmol) of methanesulfonyl chloride was added under ice cooling, and the mixture was reacted at room temperature for 6 hours. Next, 0.5 ml of water was added to the reaction solution, reacted at the same temperature for 1 hour, and concentrated. Ethyl acetate was added to the residue, and the mixture was washed with 10% aqueous potassium bisulfate solution, 5% aqueous potassium hydrogen carbonate solution and water, and concentrated to obtain 2.81 g (96%) of compound (21).
MS (FAB) m / z: 1490 (M ⁺ +1)
¹ H-NMR (DMSO-d6) δ3.17 (6H, s)

(2S) -2-Acetoxy-2 ″ -O-acetyl-1,3,2 ′, 6 ′, 3 ″ -penta-N-benzyloxycarbonyl-4 ″, 6 ″ -O-cyclohexylene Den-3 ', 4'-dideoxy-3'-enokanamycin B

4.20 g (2.8 mmol) of compound (21) was dissolved in 27 ml of DMF, 20.1 g (120 mmol) of potassium iodide and 460 mg (3.8 mmol) of potassium hydrogen carbonate were added, and the mixture was reacted at 100 ° C. for 6 hours. Ethyl acetate and water were added to the reaction solution and the phases were separated, and the organic layer was washed with 10% aqueous potassium thiosulfate solution and water, and concentrated to obtain 3.56 g (97%) of compound (22).
MS (FAB) m / z: 1300 (M ⁺ +1)
¹ H-NMR (DMSO-d6) δ5.81 (2H, s)

(2S) -1,3,2 ', 6', 3 "-penta-N-benzyloxycarbonyl-3 ', 4'-dideoxy-3'-eno-2-hydroxykanamycin B

3.56 g (2.8 mmol) of the compound (22) was dissolved in a mixed solvent of 40 ml of methanol and 10 ml of chloroform, 0.5 ml of 28% sodium methoxide methanol solution was added, and reacted at room temperature for 0.5 hours. Further, 1.5 ml of 6N hydrochloric acid was added to the reaction solution and reacted at room temperature for 1 hour. 28% ammonia water was added to the reaction solution until pH≈5-6, and after concentration, water was added. The resulting precipitate was filtered and dried to obtain 2.92 g (94%) of Compound (23).
MS (FAB) m / z: 1136 (M ⁺ +1)

(2S) -2-Hydroxydibekacin

1.10 g (0.97 mmol) of Compound (23) is dissolved in a mixed solvent of 11 ml of methanol, 3 ml of water and 0.4 ml of acetic acid, 320 mg of 10% palladium / carbon is added, and catalytic reduction is carried out at normal pressure of 40 ° C. for 24 hours. It was. After filtering the reaction solution, 28% aqueous ammonia was added until pH≈7, and the mixture was concentrated, and the solid was diluted to pH 5 with water. Adsorbed to 100 ml of Amberlite FPC-3500 (NH4 +), washed with water and eluted with 0.1 to 0.5N aqueous ammonia, and the obtained fraction was concentrated to obtain 301 mg (67%) of Compound (15).
MS (FAB) m / z: 468 (M ⁺ +1)

Reference example

The compound 15 was produced according to WO2007 / 142150 and confirmed to produce the title compound.

Claims

A method for producing a compound represented by the formula (15), wherein the compound represented by the formula (1) is used as a raw material or a synthetic intermediate.
Protecting the amino group of the compound represented by the formula (1) with a tert-butoxycarbonyl group to obtain a compound represented by the formula (2);

Protecting the 6′-position and the 6 ″ -position hydroxyl group of the compound represented by the formula (2) with a trityl group to obtain a compound represented by the formula (3),

By protecting the hydroxyl groups at the 3 ′ and 4 ′ positions of the compound represented by the formula (3) with a cyclohexylidene group, a compound represented by the formula (4) is obtained,

Protecting the hydroxyl groups at the 2, 2 ″ and 4 ″ positions of the compound represented by the formula (4) with an acetyl group to obtain a compound represented by the formula (5),

Deprotecting the hydroxyl groups at the 3 ′, 4 ′ and 6 ′ positions of the compound represented by the formula (5) to obtain a compound represented by the formula (6),

Protecting the hydroxyl groups at the 3 ′ and 6 ′ positions of the compound represented by the formula (6) with a benzoyl group and benzylsulfonylating the hydroxyl group at the 4 ′ position of the compound represented by the formula (6) Obtaining the compound represented,

The compound represented by the formula (7) is reacted with a base to epoxidize the 3 ′ and 4 ′ positions and deprotect the hydroxyl groups at the 2, 2 ″, 4 ″ and 6 ′ positions, Protecting the hydroxyl groups at the 4 ′ and 6 ′ positions with an acetyl group to obtain a compound represented by the formula (8)

The compound represented by formula (8) is reacted with a metal iodide salt to obtain a compound represented by formula (9),

By benzylsulfonylating the 4′-position of the compound represented by the formula (9), the compound represented by the formula (10) is obtained by elimination reaction of the benzylsulfonyloxy group at the 3′-position and the iodine at the 4′-position,

Deprotecting the hydroxyl groups at the 2, 2 ″, 4 ″ and 6 ′ positions of the compound represented by the formula (10) to obtain a compound represented by the formula (11);

A compound represented by the formula (11) is reacted with triphenylphosphine and a metal azide to obtain a compound represented by the formula (12),

A compound represented by the formula (12) is treated by a Staudinger reaction to obtain a compound represented by the formula (13),

Deprotecting the amino group at the 1, 3, 2 ′, 3 ″ position and the hydroxyl group at the 6 ″ position of the compound represented by the formula (13) to obtain a compound represented by the formula (14),

Treating the compound represented by formula (14) with a catalytic reduction reaction to obtain the compound represented by formula (15)

The method of claim 1 comprising:
Use of the compound represented by the formula (1) as a raw material or a synthetic intermediate in the production of the compound represented by the formula (15).
A method for producing a compound represented by the formula (15), wherein the compound represented by the formula (16) is used as a raw material or a synthetic intermediate.
Protecting the amino group of the compound represented by formula (16) with a benzyloxycarbonyl group to obtain a compound represented by formula (17),

A compound represented by the formula (18) is obtained by protecting the hydroxyl group at the 3 ′ and 4 ′ positions and the hydroxyl group at the 4 ″ and 6 ″ positions of the compound represented by the formula (17) with a cyclohexylidene group, respectively. Get

Protecting the 2 and 2 ″ hydroxyl groups of the compound represented by the formula (18) with an acetyl group to obtain a compound represented by the formula (19),

3 ′ and 4 ′ positions of the compound represented by the formula (19) are deprotected to obtain a compound represented by the formula (20),

A mesyl group was introduced into the hydroxyl groups at the 3 ′ and 4 ′ positions of the compound represented by formula (20) to obtain a compound represented by formula (21),

The compound represented by the formula (21) is treated by the Tipson-Cohen reaction to obtain a compound represented by the formula (22) by the elimination reaction at the 3 ′ and 4 ′ positions.

The compound represented by the formula (23) is obtained by deprotecting the 2, 2 ″, 4 ″ and 6 ″ positions by subjecting the compound represented by the formula (22) to base treatment and / or acid treatment. And

A compound represented by the formula (23) is treated with a catalytic reduction reaction to obtain a compound represented by the formula (15).

The method of claim 4 comprising:
Use of the compound represented by the formula (16) as a raw material or a synthetic intermediate in the production of the compound represented by the formula (15).