A method for synthesizing aminoglycoside antibiotic arbekacin

Abstract

The invention discloses a method for synthesizing aminoglycoside antibiotic arbekacin, which belongs to the field of arbekacin preparation. The preparation process is as follows: the method has high yield.

Description

Technical Field

[0001] The invention discloses an organic synthesis method, in particular to a new synthesis method of aminoglycoside antibiotic arbekacin. Background Art

[0002] Arbekacin was discovered in 1973 and was listed as an extremely important antibiotic in the 21st century by the World Health Organization in 2005. English name: Arbekacin, chemical name: (S)-O-3-amino-3-deoxy-Α-D-glucopyranosyl-(1→6)-O-[2,6-diamino-2,3,4,6-tetradeoxy-Α-D-azido-hexapyranosyl-(1→4)-]-N-(L-amino-2-hydroxy-L-oxobutyl)-2-deoxy-D-streptamine. It belongs to the aminoglycoside antibiotics, which mainly acts on the ribosomes in bacteria and inhibits protein synthesis. It has a very good inhibitory effect on Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa, and some Gram-positive bacteria. Even with the presence of ototoxicity, nephrotoxicity and bacterial resistance, these problems still do not limit the clinical application of Arbekacin.

[0003] The current organic synthesis uses kanamycin B as raw material. Kanamycin B is a byproduct of fermentation to produce kanamycin A, accounting for about 5% of the fermentation product. Kanamycin B is highly toxic and is not suitable for long-term antibacterial treatment of human body. It is currently only used for veterinary medicine. In addition, some enterprises discharge it into the wastewater treatment system as the mother liquor of producing kanamycin A, causing water pollution and other problems. Therefore, kanamycin B has not been effectively utilized. Foreign countries use kanamycin B as raw material, chemically modify it to obtain semi-synthetic aminoglycoside antibiotics dibekacin and arbekacin, which not only solves the problem of environmental pollution, but also brings economic benefits. The synthesis process of dibekacin and arbekacin is mainly mastered by two companies, Meiji Pharmaceutical of Japan and Riken Pharmaceutical of South Korea. Due to the long synthesis route, complex process technology, high process parameter requirements and other difficulties, it has not been listed and industrialized in China.

[0004] At present, the existing arbekacin synthesis methods at home and abroad often divide the synthesis route into two parts, one part is the synthesis of kanamycin B intermediate dibekacin, and the other part is the synthesis of arbekacin from the intermediate dibekacin. There are several methods for synthesizing intermediate dibekacin and arbekacin in the prior art:

[0005] US Patent No. 4,156,078 (published on May 22, 1979) and US Patent No. 4,169,939 (published on October 2, 1979) disclose a method for synthesizing the intermediate dibekacin.

[0006] Its synthetic route is:

[0007]

[0008]

[0009] Among them, R1 represents an amino-protecting group of lower alkylsulfonyl, arylsulfonyl and aralkylsulfonyl, and R2 represents a hydroxy-protecting group of lower alkylsulfonyl, arylsulfonyl and aralkylsulfonyl.

[0010] The synthesis method disclosed in the above US patent has the following problems:

[0011] The use of sulfonyl protection in both the first and third steps of the reaction will affect the selectivity and reduce the yield. The lower alkylsulfonyl reagent is usually methylsulfonyl chloride, which is highly toxic and can cause harm to the health of the experimenters and pollute the environment.

[0012] The catalyst used for double bond hydrogenation reduction in the reaction is platinum oxide, which is expensive and will increase production costs. In addition, the method used to remove the sulfonyl protection is the alkali metal reduction method of liquid ammonia / metal sodium. The reaction temperature of this method is -65°C, the reaction conditions are harsh, and a large amount of metal sodium is required, which poses certain safety hazards in mass production.

[0013] In general, the steps of this synthetic route are lengthy, the total yield is only 10%, the economic benefits are not high enough, and there are certain obstacles to large-scale production.

[0014] British patent GB1537905 (publication date: January 10, 1979) and US patent US4357465 (publication date: November 2, 1982) disclose a method for synthesizing the intermediate dibekacin.

[0015] Its synthetic route is:

[0016]

[0017] Method 1:

[0018]

[0019] Method 2:

[0020]

[0021] Among them, R1 represents an H atom, an alkyl group or an aryl group, R2 represents a benzoyl group or an acetyl group, R3 represents a methanesulfonyl group, a toluenesulfonyl group or a benzylsulfonyl group, and Z represents an alkylene group, an arylene group, a cyclohexylene group or a tetrahydropyranyl group.

[0022] Although this patent overcomes the disadvantage of low sulfonyl protection selectivity in US Pat. No. 4,156,078 and US Pat. No. 4,169,939 and also avoids the use of liquid ammonia / metallic sodium, it still has the following shortcomings:

[0023] When protecting the amino group in the first step of the reaction, ethyl chloroformate is used, which is highly toxic and can cause physical harm to the experimenters and serious pollution to the environment. At the same time, the use of methanesulfonyl chloride in the subsequent reaction will also cause the same problem. In this route, different protective reagents are needed to achieve separate protection of the ortho-hydroxyl groups, which is difficult and easily leads to low selectivity, and ultimately reduces the yield. At the same time, by-products are easily generated in the reaction, and the conversion of by-products to the target product requires multiple steps of reaction; and the xanthate catalyst used in the reaction is usually expensive, both of which will increase the overall reaction cost.

[0024] If method 2 is used to synthesize dibekacin, the steps of the synthesis route are generally too long and the total yield is less than 10%. If method 1 is used to synthesize dibekacin, the total yield is increased to 15% compared with method 2, which has great disadvantages in mass production.

[0025] Chinese patent CN101575354A (publication date: November 11, 2009) discloses a method for synthesizing the intermediate dibekacin.

[0026] Its synthetic route is as follows:

[0027]

[0028] Wherein, Bs represents a benzylsulfonyl group.

[0029] Although the synthesis method disclosed in the patent overcomes the problem of the influence of the sulfonylating agent on the hydroxyl group in protecting the amino group in US Pat. No. 4,156,078 and the difficulty in achieving selective acylation in US Pat. No. 4,357,465, and the yield is increased to 25%, the use of liquid ammonia / metallic sodium is still not avoided when removing the protecting group. Moreover, when benzylsulfonyl chloride is used to protect the amino group and the hydroxyl group in the reaction, the selectivity does not achieve satisfactory results. At the same time, the use of platinum oxide as a catalyst for reduction hydrogenation will cause cost increases.

[0030] U.S. Patent No. 4,297,485 (published on October 27, 1981) discloses a method for synthesizing arbekacin.

[0031] Its synthetic route is as follows:

[0032]

[0033] Wherein R represents benzyl formate, R1 represents trifluoroacetyl, and Cbz-L-HABA represents 4-benzyloxycarbonylamino-2-hydroxybutyric acid.

[0034] The synthesis method disclosed in the above US patent has the following problems:

[0035] The solvent used in the first step of the reaction is dimethyl sulfoxide, which makes post-processing difficult. In addition, two different amino protecting groups are used in the reaction, which increases the number of reaction steps and easily produces a variety of impurities, affecting the efficiency of subsequent separation and purification. Another disadvantage is that the yield is reduced.

[0036] Chinese patent CN101575354A (publication date: November 11, 2009) discloses a method for synthesizing arbekacin.

[0037] Its synthetic route is as follows:

[0038]

[0039] Wherein Boc represents tert-butyloxycarbonyl.

[0040] This patent overcomes the problem caused by zinc ion complexation in the synthesis route of US Pat. No. 4,297,485. However, when protecting the amino group in this patent route, it is necessary to control the feeding amount of di-tert-butyl dicarbonate to achieve the purpose of selective protection, which easily leads to a decrease in the yield of product 7 and increases the difficulty of separation and purification. The catalyst used in the hydrogenation reduction is still platinum oxide, which increases the production cost.

[0041] The several synthetic routes reported in the above patents have their own advantages and disadvantages, but the final yields of the reactions are all low, and multiple isomers are easily generated during the reaction process, which creates difficulties for purification and separation operations. Summary of the invention

[0042] The present invention provides an arbekacin synthesis method with simple process operation, high final product yield, low production cost and environmental friendliness. The method improves the selectivity of the reaction, increases the final product yield to more than 16%, and reduces the number and difficulty of separation and purification by optimizing and adjusting the process route.

[0043] The synthesis method of arbekacin provided by the present invention comprises the following steps:

[0044] (1) Synthesis of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-kanamycin B, product 1

[0045] Dissolve kanamycin B in water, dissolve di-tert-butyl dicarbonate in isopropanol and pour into the system, add sodium carbonate, react at 10-50°C for 10-20 hours, wash with water and filter to obtain penta-nitrogen-tert-butyloxycarbonyl-kanamycin B, i.e., product 1.

[0046] (2) Synthesis of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-4",6"-oxy-cyclohexylidene-kanamycin B, i.e., product 2

[0047] The product 1 obtained in step (1) is dissolved in N,N-dimethylformamide, anhydrous p-toluenesulfonic acid and cyclohexanone dimethyl acetal are added, and the mixture is reacted at 10 to 50° C. for 10 to 20 hours, and the mixture is added into water for crystallization, and filtered to obtain penta-nitrogen-tert-butyloxycarbonyl-4”,6”-oxy-cyclohexylidene-kanamycin B, i.e., product 2.

[0048] (3) Synthesis of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylidene-kanamycin B, i.e., product 3

[0049] The product 2 obtained in step (2) is dissolved in pyridine, 4-dimethylaminopyridine is added, p-nitrobenzenesulfonyl chloride is dissolved in dichloromethane and added dropwise to the system, reacted at 10-50° C. for 2-10 hours, and dichloromethane is added for extraction to obtain penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylidene-kanamycin B, i.e., product 3.

[0050] (4) Synthesis of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylidene-kanamycin B, i.e., product 4

[0051] The product 3 obtained in step (3) is dissolved in N,N-dimethylformamide, zinc powder and sodium iodide are added, and the mixture is reacted at 90-150° C. for 0.5-3 hours. Dichloromethane is added for extraction to obtain 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylidene-kanamycin B, i.e., product 4.

[0052] (5) Synthesis of 3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-kanamycin B, product 5

[0053] The product 4 obtained in step (4) is dissolved in a mixed solution of methanol and hydrochloric acid, and reacted at 10 to 50° C. for 1 to 7 hours to obtain 3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-kanamycin B, i.e., product 5.

[0054] (6) Synthesis of 3',4'-didehydro-3',4'-dideoxy-kanamycin B (Product 6)

[0055] The product 5 obtained in step (5) is dissolved in a mixed solution of water and methanol, and metallic magnesium is added. The mixture is reacted under ultrasonic stirring at 10 to 50° C. for 0.5 to 3 hours to obtain 3',4'-didehydro-3',4'-dideoxy-kanamycin B, i.e., product 6.

[0056] (7) Synthesis of 1,3,2',6',3"-penta-nitrogen-trimethylsilyl-2",4",6"-tri-oxygen-trimethylsilyl-3',4'-didehydro-3',4'-dideoxy-kanamycin B (Product 7)

[0057] The product 6 obtained in step (6) is dissolved in acetonitrile, hexamethyldisilazane and trimethylchlorosilane are added, and the reaction is refluxed for 12 to 20 hours to obtain 1,3,2',6',3"-penta-nitrogen-trimethylsilyl-2",4",6"-tri-oxygen-trimethylsilyl-3',4'-didehydro-3',4'-dideoxy-kanamycin B, i.e., product 7.

[0058] (8) Synthesis of 1-nitrogen-(L-γ-benzyloxycarbonylamino-α-hydroxybutyryl)-3',4'-didehydro-3',4'-dideoxy-kanamycin B, product 9

[0059] ① L-γ-amino-α-hydroxybutyric acid and sodium carbonate are added to a mixed solution of water and acetone in sequence, benzyl chloroformate is added at -10 to 0°C to react for 10 to 24 hours, and ether is added for extraction to obtain L-γ-benzyloxycarbonylamino-α-hydroxybutyric acid, i.e., intermediate product 10.

[0060] ② The intermediate product 10 synthesized in ①, N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added to acetone in sequence, and reacted at 10-50° C. for 1-4 hours to obtain a suspension containing 2,5-dioxo-1-pyrrolidinyl (2S)-α-hydroxy-γ-[[(phenylmethoxy)carbonyl]amino]butyrate, i.e., the intermediate product 11.

[0061] ③ The product 7 obtained in step (7) is dissolved in acetone, water is added and stirred for 0.5 to 2 hours, and then the suspension containing the intermediate product 11 obtained in step ② is added, and the reaction is carried out at 0 to 30° C. for 0.5 to 4 hours to obtain the compound of product 8, and then 3 to 9M hydrochloric acid is added to continue the reaction for 0.5 to 3 hours, and the reaction temperature is 10 to 50° C. to obtain 1-nitrogen-(L-γ-benzyloxycarbonylamino-α-hydroxybutyryl)-3',4'-didehydro-3',4'-dideoxy-kanamycin B, i.e., product 9.

[0062] (9) Synthesis of 1-nitro-(L-4-amino-2-hydroxybutyryl)-3',4'-dideoxy-kanamycin B

[0063] The product 9 obtained in step (8) is dissolved in water, a Pd / C catalyst is added, the pH value of the system is adjusted to 1-4 with hydrochloric acid, and the reaction is carried out at a temperature of 10-50° C. and a hydrogen pressure of 0.1-0.5 MPa for 12-72 hours to obtain 1-nitrogen-(L-4-amino-2-hydroxybutyryl)-3',4'-dideoxy-kanamycin B, i.e., arbekacin (I).

[0064]

[0065] In the above step (1), the molar ratio of di-tert-butyl dicarbonate, sodium carbonate and kanamycin B is 4-10:2-7:1, preferably 6-9:4-6:1, the reaction temperature is preferably 20-30° C., and the reaction time is preferably 10-14 hours.

[0066] In the above step (1), the volume ratio of water to isopropanol is 1 to 3:1.

[0067] In the above step (2), the molar ratio of cyclohexanone dimethyl acetal, anhydrous p-toluenesulfonic acid and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-kanamycin B is 6-12:1-5:1, preferably 8-10:2-4:1, the reaction temperature is preferably 20-30°C, and the reaction time is preferably 10-14 hours.

[0068] In the above step (3), the molar ratio of p-nitrobenzenesulfonyl chloride, 4-dimethylaminopyridine and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-4",6"-oxy-cyclohexylidene-kanamycin B is 5-11:5-11:1, preferably 6-10:6-10:1, the reaction temperature is preferably 20-40°C, and the reaction time is preferably 5-8 hours.

[0069] In the above step (4), the mass ratio of sodium iodide, zinc powder and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxygen-p-nitrobenzenesulfonyl-4",6"-oxygen-cyclohexylidene-kanamycin B is 3-8:0.03-0.09:1, preferably 5-6:0.04-0.06:1, the reaction temperature is preferably 110-130°C, and the reaction time is preferably 0.5-1.5 hours.

[0070] In the above step (5), the volume ratio of methanol to hydrochloric acid is 1 to 3:1, the concentration of hydrochloric acid is 6 M, the reaction temperature is preferably 20 to 40° C., and the reaction time is preferably 3 to 4 hours.

[0071] In the above step (6), the molar ratio of magnesium metal to 3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-kanamycin B is 7-15:1, preferably 9-12:1, the reaction temperature is preferably 20-30°C, the reaction time is preferably 0.5-1.5 hours, and the ultrasonic frequency is 40KHz.

[0072] In the above step (6), the volume ratio of water to methanol is 1 to 3:1.

[0073] In the above step (7), the molar ratio of hexamethyldisilazane, trimethylchlorosilane and 3',4'-didehydro-3',4'-dideoxy-kanamycin B is 5-11:0.1-0.8:1, preferably 7-9:0.3-0.5:1, and the reaction time is preferably 15-17 hours.

[0074] In step (8) ① above, the volume ratio of acetone to water is 3 to 5:1, the molar ratio of sodium carbonate, benzyl chloroformate and L-γ-amino-2-hydroxybutyric acid is 0.5 to 4:0.5 to 3:1, preferably 1 to 2:0.7 to 1.5:1, the reaction temperature is preferably -5 to -2°C, and the reaction time is preferably 18 to 22 hours.

[0075] In step (8) ② above, the molar ratio of N-hydroxysuccinimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and L-γ-benzyloxycarbonylamino-α-hydroxybutyric acid is 0.5-3:0.5-3:1, preferably 0.7-1.5:0.7-1.5:1, the reaction temperature is preferably 20-30° C., and the reaction time is preferably 2-3 hours.

[0076] In the above step (8) ③, the molar ratio of water, 2,5-dioxo-1-pyrrolidinyl (2S)-α-hydroxy-γ-[[(phenylmethoxy)carbonyl]amino]butyrate and 1,3,2',6',3"-penta-nitrogen-trimethylsilyl-2",4",6"-tri-oxo-trimethylsilyl-3',4'-didehydro-3',4'-dideoxy-kanamycin B is 20-70:0.5-2:1, preferably 40-60:1-1.5:1.

[0077] In step (8) ③, the reaction temperature is preferably 20 to 30°C, the reaction time after adding water is preferably 0.5 to 1 hour, the reaction time after adding 2,5-dioxo-1-pyrrolidinyl (2S)-α-hydroxy-γ-[[(phenylmethoxy)carbonyl]amino]butyrate is preferably 1 to 3 hours, and the reaction time after adding hydrochloric acid is preferably 0.5 to 1 hour.

[0078] In step (8) ③ above, the concentration of hydrochloric acid is preferably 5 to 7 M, and the volume ratio of hydrochloric acid to acetone is preferably 0.7 to 1:1.

[0079] In the above step (9), the mass ratio of Pd / C catalyst to 1-nitrogen-(L-γ-benzyloxycarbonylamino-α-hydroxybutyryl)-3',4'-didehydro-3',4'-dideoxy-kanamycin B is 0.1-0.4:1, the hydrochloric acid is 6M, the pH value is preferably 3-4, the reaction temperature is preferably 20-30°C, the pressure is preferably 0.3-0.4 MPa, and the reaction time is preferably 24-36 hours.

[0080] The synthetic route of the present invention is as follows:

[0081]

[0082]

[0083] Among them, Boc represents tert-butyloxycarbonyl, Ns represents p-nitrobenzenesulfonyl, and R represents trimethylsilyl.

[0084] The synthesis route of 2,5-dioxo-1-pyrrolidinyl (2S)-α-hydroxy-γ-[[(phenylmethoxy)carbonyl]amino]butyrate in step (8) is as follows:

[0085]

[0086] Compared with the prior art, the method of the present invention has the following beneficial effects:

[0087] (1) High yield. The separation yield of arbekacin prepared by the method of the present invention reaches about 18%, which is higher than the 10% yield of U.S. Patent No. 4297485 and the 12% yield of Chinese Patent No. CN101575354A compared with the existing patent technology.

[0088] (2) In the elimination of the 3' and 4' hydroxyl groups, the method of the present invention adopts the Tipson-Cohen method, i.e., using zinc powder and sodium iodide to convert two adjacent sulfonyloxy sugars into unsaturated sugars. This avoids the problem of using different protecting group reagents to selectively protect the ortho-hydroxyl groups in U.S. Pat. No. 4,357,465 and U.S. Pat. No. 4,156,078, and also avoids the use of toxic reagents such as ethyl chloroformate and methanesulfonyl chloride when forming epoxy groups, thus demonstrating that the reaction route and process are environmentally friendly.

[0089] (3) Compared with U.S. Pat. No. 4,156,078, U.S. Pat. No. 4,169,939 and Chinese Patent No. CN101575354A, the amino group protecting agent uses a cheaper di-tert-butyl dicarbonate, which reduces the reaction cost and avoids the process of removing the sulfonyl group by using liquid ammonia / metal sodium, making it more suitable for industrial production.

[0090] (4) The amount of sodium iodide added in the present invention is 5 to 6 times that of the raw material, and the amount of zinc powder added is 0.04 to 0.06 times that of the raw material. Compared with U.S. Pat. No. 4,156,078 and U.S. Pat. No. 4,169,939, the amount of zinc powder and sodium iodide used is reduced, thereby reducing environmental pollution.

[0091] (5) Compared with other methods, the method of the present invention reduces the number of resin purification times, reduces the cycle production time, and improves production efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0092] Figure 1 1H NMR of the final product arbekacin of the present invention.

[0093] Figure 2 This is the 13C NMR of the final product arbekacin of the present invention. DETAILED DESCRIPTION

[0094] The present invention will be further described below in conjunction with examples, but the present invention is not limited to the following examples.

[0095] Example 1

[0096] (1) 4.84 g of kanamycin B (10.0 mmol) and 5.50 g (52.0 mmol) of sodium carbonate were weighed and dissolved in 60 mL of water, and 16.4 g (75.0 mmol) of di-tert-butyl dicarbonate was dissolved in 30 mL of isopropanol. The mixture was reacted at 25° C. for 12 hours. After the reaction was completed, the system was filtered by suction, and the filter cake was washed three times with water, filtered by suction, and dried to obtain 9.15 g of white solid penta-nitrogen-tert-butyloxycarbonyl-kanamycin B, with a yield of 93%.

[0097] (2) Weigh 9.84 g (10.0 mmol) of penta-nitrogen-tert-butyloxycarbonyl-kanamycin B and 5.17 g (30.0 mmol) of anhydrous p-toluenesulfonic acid and dissolve them in 120 mL of N,N-dimethylformamide, add 15.2 mL (100.0 mmol) of cyclohexanone dimethyl acetal, and continue to react at 25° C. under vacuum for 12 hours. After the reaction is completed as monitored by TLC, the system is added to 0.5 L of water for water dispersion, filtered, and the filter cake is washed with water three times, filtered, and dried to obtain 10.11 g of white solid penta-nitrogen-tert-butyloxycarbonyl-4",6"-oxy-cyclohexylidene-kanamycin B, with a yield of 95%. 1 H NMR (600MHz, DMSO-d6) δ5.98(d,J=7.1Hz,1H),5.71(d,J=8.1Hz,1H),5.44–5.37(m,1H),5.23(t,J=7.1Hz,1H),5.08(d,J=5.7Hz,1H),5.02(dd,J=7.0 ,3.8Hz,2H),4.94–4.86(m,2H),4.39(d,J=6.0Hz,1H),4.37–4.30(m,1H), 4.18–4.07(m,2H),4.06–3.98(m,1H),4.02–3.91(m,2H),3.91–3.86(m,1H) ,3.89–3.83(m,1H),3.86–3.79(m,2H),3.77(d,J=2.7Hz,2H),3.71(m,J=8 .2,7.3,5.9,3.9Hz,2H),3.65–3.53(m,2H),2.06(ddd,J=13.0,7.4,6.3Hz, 2H),1.85(ddd,J=13.0,6.4,4.8Hz,2H),1.84–1.77(m,2H),1.80–1.75(m,1 H),1.77–1.72(m,2H),1.74–1.68(m,2H),1.68–1.52(m,4H),1.42(s,45H).

[0098] (3) Weigh 2.13 g (2.0 mmol) of penta-nitrogen-tert-butyloxycarbonyl-4", 6"-oxy-cyclohexylidene-kanamycin B and 1.95 g (16.0 mmol) of 4-dimethylaminopyridine and dissolve them in 30 mL of pyridine. Weigh 3.55 g (16.0 mmol) of p-nitrobenzenesulfonyl chloride and dissolve it in 70 mL of dichloromethane. Add it dropwise to the system at a uniform rate and react at 30° C. for 8 hours. After the reaction is completed, remove the pyridine, add dichloromethane to dissolve, wash three times with water, wash three times with saturated sodium bicarbonate, and wash three times with saturated saline. The organic phase is retained and dried by rotation to obtain 2.60 g of light yellow solid 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxy-p-nitrobenzenesulfonyl-4", 6"-oxy-cyclohexylidene-kanamycin B with a yield of 80%.

[0099] (4) Weigh 1.62 g (1.0 mmol) of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylidene-kanamycin B and dissolve it in 25 mL of N,N-dimethylformamide. Weigh 9.72 g (65.0 mmol) of sodium iodide and 0.10 g (15.0 mmol) of zinc powder again and add them to the system. The reaction is carried out at a constant temperature of 130°C for 1.5 hours. After the reaction was completed and the system was cooled, dichloromethane was added, and the mixture was washed three times with water, three times with a saturated sodium thiosulfate aqueous solution, and three times with a saturated saline solution. The organic phase was retained and spin-dried to obtain 1.02 g of dark yellow solid 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylidene-kanamycin B with a yield of 84%.

[0100] (5) Weigh 1.22 g (1.0 mmol) of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylene-kanamycin B and dissolve it in a mixed solvent of 10 mL of methanol and 10 mL of 6M hydrochloric acid, and react at 40°C for 4 hours. After the reaction is completed, the pH value of the system is adjusted to 7-8 with aqueous ammonia, and purified and separated with a macroporous weakly acidic cationic adsorption resin. The collected product is spin-dried to obtain 0.70 g of light brown solid 3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-kanamycin B with a yield of 91%.

[0101] (6) 1.27 g (2.0 mmol) of 3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-kanamycin B was weighed and dissolved in a mixed solvent of 10 mL of water and 10 mL of methanol, and 0.50 g (20.0 mmol) of magnesium was added. The mixture was reacted at 30°C and an ultrasonic frequency of 40 kHz for 1 hour. After the reaction was completed, the filtrate was filtered, and the pH value of the system was adjusted to 7-8 with ammonia water. The filtrate was purified and separated with a macroporous weakly acidic cationic adsorption resin, and the mixture was collected and spin-dried to obtain 0.74 g of khaki solid 3',4'-didehydro-3',4'-dideoxy-kanamycin B with a yield of 82%. 1 H NMR(600MHz,Deuterium Oxide)δ5.80–5.66(m,2H),5.29(d,J=3.9Hz,1H),4.99(d,J=3.9Hz,1H),4.35(ddt,J=6.7 ,4.8,2.4Hz,1H),3.87(ddd,J=10.1,4.4,2.6Hz,1H),3.75–3.66(m,2H),3.54–3.47(m,2H ),3.45(dd,J=10.4,3.8Hz,1H),3.33(t,J=9.4Hz,1H),3.28(t,J=9.8Hz,1H),3.21(t,J=9 .5Hz,1H),2.95(s,1H),2.82(s,4H),1.92(dh,J=12.7,4.2Hz,1H),1.19(q,J=12.4Hz,1H).

[0102] (7) 0.90 g (2.0 mmol) of 3',4'-didehydro-3',4'-dideoxy-kanamycin B was weighed and dissolved in 12 mL of acetonitrile, followed by the addition of 3.1 mL (15.0 mmol) of hexamethyldisilazane and 150 μL (0.8 mmol) of trimethylchlorosilane, and the system was refluxed for 16 hours. After the reaction was completed, the mixture was spin-dried to obtain 1.85 g of a light yellow solid 1,3,2',6',3"-penta-nitrogen-trimethylsilyl-2",4",6"-tri-oxygen-trimethylsilyl-3',4'-didehydro-3',4'-dideoxy-kanamycin B, with a yield of 90%.

[0103] (8) Synthesis of 1-nitrogen-(L-γ-benzyloxycarbonylamino-α-hydroxybutyryl)-3',4'-didehydro-3',4'-dideoxy-kanamycin B

[0104] ① Weigh 1.19g (10.0mmol) of L-γ-amino-α-hydroxybutyric acid and 1.87g (17.6mmol) of sodium carbonate and dissolve them in a mixed solution of 10mL water and 40mL acetone. When the system is at -2°C, add 1.6mL (11.0mmol) of benzyl chloroformate dropwise, and react at constant temperature for 20 hours after addition. After the reaction is completed, add ether to extract several times until the aqueous phase is clear and then combine the organic phases, wash three times with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate for 4 hours, filter with suction, and the filtrate is spin-dried to obtain 2.41g of white solid L-4-benzyloxycarbonylamino-2-hydroxybutyric acid, with a yield of 95%.

[0105] ② Weigh 0.35g (1.4mmol) of L-γ-benzyloxycarbonylamino-α-hydroxybutyric acid, 0.18g (1.5mmol) of N-hydroxysuccinimide and 0.30g (1.5mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and dissolve them in 20mL of acetone, and react at 25°C for 12 hours. After the reaction is completed, the suspension obtained is 2,5-dioxo-1-pyrrolidinyl (2S)-2-hydroxy-4-[[(phenylmethoxy)carbonyl]amino]butyrate.

[0106] ③ Weigh 1.10g (1.0mmol) of 1,3,2',6',3"-penta-nitrogen-trimethylsilyl-2",4",6"-tri-oxygen-trimethylsilyl-3',4'-didehydro-3',4'-dideoxy-kanamycin B and dissolve it in 20mL of acetone. Add 1mL of water to the system and stir at 30℃ for 30 minutes. Then slowly drop the suspension prepared in ②. After the addition, react at 30℃ for 2.5 hours. Then add 17mL of 6M hydrochloric acid and react at 30℃ for 1 hour. After the reaction is completed, spin dry the system to obtain a brown solid 1-nitrogen-(L-γ-benzyloxycarbonylamino-α-hydroxybutyryl)-3',4'-didehydro-3',4'-dideoxy-kanamycin B crude product.

[0107] (9) The crude 1-nitrogen-(L-γ-benzyloxycarbonylamino-α-hydroxybutyryl)-3',4'-didehydro-3',4'-dideoxy-kanamycin B obtained in step (8) was dissolved in 30 mL of water, the pH value of the system was adjusted to 3.5 with 6 M hydrochloric acid, 0.2 g of Pd / C catalyst was added, and the reaction was carried out at 30° C. and a pressure of 0.4 MPa for 36 hours at constant temperature and pressure. After the reaction was completed, the Pd / C catalyst was removed by suction filtration, the filtrate was diluted with deionized water, purified and separated with a macroporous weakly acidic cationic adsorption resin, and the mixture was collected and spin-dried to obtain 0.27 g of milky white solid arbekacin, with a yield of 45%. 1H NMR(600MHz,DeuteriumOxide)δ5.75(d,J=3.6Hz,1H),5.10(d,J=3.8Hz,1H),4.21(dd,J=9.3,3.8Hz,1H) ,4.16–3.93(m,3H),3.89–3.65(m,6H),3.58(t,J=10.1Hz,1H),3.46(ddd,J=10.8,5.9,3.6Hz,1H),3.39– 3.25(m,2H),3.17(dd,J=13.4,3.2Hz,1H),3.10(t,J=7.3Hz,2H),3.00(dd,J=13.4,8.3Hz,1H),2.10(pd, J=7.1,6.6,2.8Hz,2H),2.04–1.93(m,1H),1.96–1.81(m,3H),1.76(q,J=12.7Hz,1H),1.58–1.43(m,1H).

[0108] Example 2

[0109] In step (1), the molar ratio of di-tert-butyl dicarbonate, sodium carbonate and kanamycin is 6:4:1, and the other conditions and steps are the same as those in Example 1, to obtain 8.36 g of penta-nitrogen-tert-butyloxycarbonyl-kanamycin B with a yield of 85%.

[0110] Example 3

[0111] In step (1), the molar ratio of di-tert-butyl dicarbonate, sodium carbonate and kanamycin is 5:5:1, and the other conditions and steps are the same as those in Example 1, to obtain 6.88 g of penta-nitrogen-tert-butyloxycarbonyl-kanamycin B with a yield of 70%.

[0112] Example 4

[0113] In step (1), the molar ratio of di-tert-butyl dicarbonate, sodium carbonate and kanamycin is 7:5:1, and the other conditions and steps are the same as those in Example 1, to obtain 8.85 g of penta-nitrogen-tert-butyloxycarbonyl-kanamycin B with a yield of 90%.

[0114] Example 5

[0115] In step (1), the molar ratio of di-tert-butyl dicarbonate, sodium carbonate and kanamycin is 10:6:1, and the other conditions and steps are the same as those in Example 1, to obtain 8.75 g of penta-nitrogen-tert-butyloxycarbonyl-kanamycin B with a yield of 89%.

[0116] Example 6

[0117] In step (1), when the amount of isopropanol added is 60 mL, the other steps are the same as in Example 1, and 8.46 g of penta-nitrogen-tert-butyloxycarbonyl-kanamycin B is obtained with a yield of 86%.

[0118] Example 7

[0119] In step (1), when the amount of isopropanol added is 20 mL, the other steps are the same as in Example 1, and 8.06 g of penta-nitrogen-tert-butyloxycarbonyl-kanamycin B is obtained with a yield of 82%.

[0120] Example 8

[0121] In step (2), the molar ratio of p-toluenesulfonic acid, cyclohexanone dimethyl acetal and penta-nitrogen-tert-butoxycarbonyl-kanamycin B is 2:8:1, and the other conditions and steps are the same as those in Example 1, to obtain 7.45 g of penta-nitrogen-tert-butoxycarbonyl-4", 6"-oxy-cyclohexylidene-kanamycin B with a yield of 70%.

[0122] Example 9

[0123] In step (2), the molar ratio of p-toluenesulfonic acid, cyclohexanone dimethyl acetal and penta-nitrogen-tert-butoxycarbonyl-kanamycin B is 3:9:1, and the other conditions and steps are the same as those in Example 1, to obtain 9.37 g of penta-nitrogen-tert-butoxycarbonyl-4", 6"-oxy-cyclohexylidene-kanamycin B with a yield of 88%.

[0124] Example 10

[0125] In step (2), the molar ratio of p-toluenesulfonic acid, cyclohexanone dimethyl acetal and penta-nitrogen-tert-butoxycarbonyl-kanamycin B is 4:10:1, and the other conditions and steps are the same as those in Example 1, to obtain 9.58 g of penta-nitrogen-tert-butoxycarbonyl-4", 6"-oxy-cyclohexylidene-kanamycin B with a yield of 90%.

[0126] Embodiment 11

[0127] In step (3), the molar ratio of p-nitrobenzenesulfonyl chloride, 4-dimethylaminopyridine and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-4",6"-oxygen-cyclohexylidene-kanamycin B is 3:4:1, and the other conditions and steps are the same as those in Example 1, to obtain 0.83 g of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxygen-p-nitrobenzenesulfonyl-4",6"-oxygen-cyclohexylidene-kanamycin B, with a yield of 26%.

[0128] Example 12

[0129] In step (3), the molar ratio of p-nitrobenzenesulfonyl chloride, 4-dimethylaminopyridine and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-4",6"-oxygen-cyclohexylidene-kanamycin B is 6:4:1, and the other conditions and steps are the same as those in Example 1, to obtain 1.91 g of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxygen-p-nitrobenzenesulfonyl-4",6"-oxygen-cyclohexylidene-kanamycin B, with a yield of 59%.

[0130] Embodiment 13

[0131] In step (3), the molar ratio of p-nitrobenzenesulfonyl chloride, 4-dimethylaminopyridine and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-4",6"-oxygen-cyclohexylidene-kanamycin B is 6:6:1, and the other conditions and steps are the same as those in Example 1, to obtain 2.04 g of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxygen-p-nitrobenzenesulfonyl-4",6"-oxygen-cyclohexylidene-kanamycin B, with a yield of 63%.

[0132] Embodiment 14

[0133] In step (3), the molar ratio of p-nitrobenzenesulfonyl chloride, 4-dimethylaminopyridine and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-4",6"-oxygen-cyclohexylidene-kanamycin B is 7:10:1, and the other conditions and steps are the same as those in Example 1, to obtain 2.43 g of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxygen-p-nitrobenzenesulfonyl-4",6"-oxygen-cyclohexylidene-kanamycin B, with a yield of 75%.

[0134] Embodiment 15

[0135] In step (3), the reaction temperature is 0°C, and the other steps are the same as in Example 1, to obtain 1.55 g of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylidene-kanamycin B with a yield of 48%.

[0136] Example 16

[0137] In step (3), the reaction temperature is 10° C., and the other steps are the same as those in Example 1, to obtain 2.01 g of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxygen-p-nitrobenzenesulfonyl-4",6"-oxygen-cyclohexylidene-kanamycin B with a yield of 62%.

[0138] Embodiment 17

[0139] In step (3), the reaction temperature is 50° C., and the other steps are the same as in Example 1, to obtain 1.94 g of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxygen-p-nitrobenzenesulfonyl-4",6"-oxygen-cyclohexylidene-kanamycin B with a yield of 60%.

[0140] Embodiment 18

[0141] In step (4), the mass ratio of sodium iodide, zinc powder and 1,3,2',6',3''-penta-nitrogen-tert-butyloxycarbonyl-3',4',2''-tri-oxygen-p-nitrobenzenesulfonyl-4',6''-oxygen-cyclohexylidene-kanamycin B is 3:0.02:1, and the other steps are the same as those in Example 1 to obtain 0.49 g of 1,3,2',6',3''-penta-nitrogen-tert-butyloxycarbonyl-3',4'-didehydro-3',4'-dideoxy-2''-oxygen-p-nitrobenzenesulfonyl-4',6''-oxygen-cyclohexylidene-kanamycin B with a yield of 40%.

[0142] Embodiment 19

[0143] In step (4), the mass ratio of sodium iodide, zinc powder and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxygen-p-nitrobenzenesulfonyl-4",6"-oxygen-cyclohexylidene-kanamycin B is 3:0.04:1, and the other steps are the same as those in Example 1 to obtain 0.57 g of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4'-didehydro-3',4'-dideoxy-2"-oxygen-p-nitrobenzenesulfonyl-4",6"-oxygen-cyclohexylidene-kanamycin B with a yield of 47%.

[0144] Embodiment 20

[0145] In step (4), the mass ratio of sodium iodide, zinc powder and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxygen-p-nitrobenzenesulfonyl-4",6"-oxygen-cyclohexylidene-kanamycin B is 5:0.06:1, and the other steps are the same as those in Example 1 to obtain 0.95 g of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4'-didehydro-3',4'-dideoxy-2"-oxygen-p-nitrobenzenesulfonyl-4",6"-oxygen-cyclohexylidene-kanamycin B with a yield of 78%.

[0146] Embodiment 21

[0147] In step (4), the mass ratio of sodium iodide, zinc powder and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxygen-p-nitrobenzenesulfonyl-4",6"-oxygen-cyclohexylidene-kanamycin B is 8:0.06:1, and the other steps are the same as those in Example 1 to obtain 0.97 g of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4'-didehydro-3',4'-dideoxy-2"-oxygen-p-nitrobenzenesulfonyl-4",6"-oxygen-cyclohexylidene-kanamycin B with a yield of 80%.

[0148] Embodiment 22

[0149] In step (4), the reaction temperature is 90° C., and the other steps are the same as in Example 1, to obtain 0.79 g of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylidene-kanamycin B with a yield of 65%.

[0150] Embodiment 23

[0151] In step (4), the reaction temperature is 120° C., and the other steps are the same as in Example 1, to obtain 0.97 g of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylidene-kanamycin B with a yield of 80%.

[0152] Embodiment 24

[0153] In step (4), the reaction temperature is 150° C., and the other steps are the same as those in Example 1, to obtain 0.85 g of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylidene-kanamycin B with a yield of 70%.

[0154] Embodiment 25

[0155] In step (5), the amount of hydrochloric acid added was 3 mL, and the other steps were the same as in Example 1, to obtain 0.50 g of 3',4'-didehydro-3',4'-dideoxy-2'-oxy-p-nitrobenzenesulfonyl-kanamycin B with a yield of 78%.

[0156] Embodiment 26

[0157] In step (5), the amount of hydrochloric acid added was 20 mL, and the other steps were the same as in Example 1, to obtain 0.54 g of 3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-kanamycin B with a yield of 85%.

[0158] Embodiment 27

[0159] In step (6), the molar ratio of magnesium metal to 3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-kanamycin B is 8:1, and the other steps are the same as those in Example 1, to obtain 0.61 g of 3',4'-didehydro-3',4'-dideoxy-kanamycin B with a yield of 68%.

[0160] Embodiment 28

[0161] In step (6), the molar ratio of magnesium metal to 3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-kanamycin B is 11:1, and the other steps are the same as those in Example 1, to obtain 0.73 g of 3',4'-didehydro-3',4'-dideoxy-kanamycin B with a yield of 81%.

[0162] Embodiment 29

[0163] In step (7), the molar ratio of hexamethyldisilazane, trimethylchlorosilane and 3',4'-didehydro-3',4'-dideoxy-kanamycin B is 5:0.2:1, and the other steps are the same as in Example 1, to obtain 1.11 g of 1,3,2',6',3"-penta-nitrogen-trimethylsilyl-2",4",6"-tri-oxygen-trimethylsilyl-3',4'-didehydro-3',4'-dideoxy-kanamycin B, with a yield of 54%.

[0164] Embodiment 30

[0165] In step (7), the molar ratio of hexamethyldisilazane, trimethylchlorosilane and 3',4'-didehydro-3',4'-dideoxy-kanamycin B is 6:0.4:1, and the other steps are the same as those in Example 1, to obtain 1.70 g of 1,3,2',6',3"-penta-nitrogen-trimethylsilyl-2",4",6"-tri-oxygen-trimethylsilyl-3',4'-didehydro-3',4'-dideoxy-kanamycin B, with a yield of 83%.

[0166] Embodiment 29

[0167] In step (7), the molar ratio of hexamethyldisilazane, trimethylchlorosilane and 3',4'-didehydro-3',4'-dideoxy-kanamycin B is 10:0.4:1, and the other steps are the same as those in Example 1, to obtain 1.80 g of 1,3,2',6',3"-penta-nitrogen-trimethylsilyl-2",4",6"-tri-oxygen-trimethylsilyl-3',4'-didehydro-3',4'-dideoxy-kanamycin B, with a yield of 88%.

[0168] Embodiment 30

[0169] In step (7), the reaction temperature is 60° C., and the other steps are the same as in Example 1, to obtain 1.03 g of 1,3,2',6',3"-penta-nitrogen-trimethylsilyl-2",4",6"-tri-oxygen-trimethylsilyl-3',4'-didehydro-3',4'-dideoxy-kanamycin B with a yield of 50%.

[0170] Embodiment 31

[0171] In step (7), the reaction temperature is 80° C., and the other steps are the same as in Example 1, to obtain 1.62 g of 1,3,2',6',3"-penta-nitrogen-trimethylsilyl-2",4",6"-tri-oxygen-trimethylsilyl-3',4'-didehydro-3',4'-dideoxy-kanamycin B with a yield of 79%.

[0172] Embodiment 32

[0173] In step (8) ①, the molar ratio of sodium carbonate, benzyl chloroformate and L-γ-amino-2-hydroxybutyric acid is 1:1.1:1, and the other steps are the same as in Example 1 to obtain 2.08 g of L-4-benzyloxycarbonylamino-2-hydroxybutyric acid with a yield of 82%.

[0174] Embodiment 33

[0175] In step (9), the pH value of the system was adjusted to 1 with 6M hydrochloric acid, and the other steps were the same as in Example 1 to obtain 0.06 g of arbekacin with a yield of 10%.

[0176] Embodiment 34

[0177] In step (9), the pH value of the system was adjusted to 2 with 6M hydrochloric acid, and the other steps were the same as in Example 1 to obtain 0.18 g of arbekacin with a yield of 30%.

[0178] Embodiment 34

[0179] In step (9), 0.1 g of Pd / C catalyst was added, and the other steps were the same as in Example 1 to obtain 0.16 g of arbekacin with a yield of 27%.

[0180] Embodiment 34

[0181] In step (9), the pressure is 0.3 MPa, and the other steps are the same as in Example 1, to obtain 0.23 g of arbekacin with a yield of 39%.

[0182] The specific embodiments described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing arbekacin, characterized in that: The following steps are involved: (1) Synthesis of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-kanamycin B, product 1 Dissolve kanamycin B in water, dissolve di-tert-butyl dicarbonate ((Boc)2O) in isopropanol (i-PrOH) and pour into the system, add sodium carbonate (Na2CO3), react at 10-50°C for 10-20 hours, wash with water and filter to obtain penta-nitrogen-tert-butyloxycarbonyl-kanamycin B, i.e., product 1; (2) Synthesis of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-4",6"-oxy-cyclohexylidene-kanamycin B, i.e., product 2 The product 1 obtained in step (1) is dissolved in N,N-dimethylformamide (DMF), anhydrous p-toluenesulfonic acid (TsOH) and cyclohexanone dimethyl acetal are added, and the mixture is reacted at 10 to 50° C. for 10 to 20 hours, and the mixture is added into water for crystallization, and filtered to obtain penta-nitrogen-tert-butyloxycarbonyl-4”,6”-oxy-cyclohexylidene-kanamycin B, i.e., product 2; (3) Synthesis of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylidene-kanamycin B, i.e., product 3 The product 2 obtained in step (2) is dissolved in pyridine, 4-dimethylaminopyridine (DMAP) is added, p-nitrobenzenesulfonyl chloride (NsCl) is dissolved in dichloromethane and added dropwise to the system, reacted at 10-50° C. for 2-10 hours, and dichloromethane is added for extraction to obtain penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylidene-kanamycin B, i.e., product 3; (4) Synthesis of 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylidene-kanamycin B, i.e., product 4 The product 3 obtained in step (3) is dissolved in N,N-dimethylformamide, zinc powder (Zn) and sodium iodide (NaI) are added, and the mixture is reacted at 90-150° C. for 0.5-3 hours, and dichloromethane is added for extraction to obtain 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylidene-kanamycin B, i.e., product 4; (5) Synthesis of 3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-kanamycin B, product 5 The product 4 obtained in step (4) is dissolved in a mixed solution of methanol (MeOH) and hydrochloric acid (HCl), and reacted at 10 to 50° C. for 1 to 7 hours to obtain 3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-kanamycin B, i.e., product 5; (6) Synthesis of 3',4'-didehydro-3',4'-dideoxy-kanamycin B (Product 6) The product 5 obtained in step (5) is dissolved in a mixed solution of water and methanol, and magnesium (Mg) is added, and the mixture is reacted under ultrasonic stirring at 10 to 50° C. for 0.5 to 3 hours to obtain 3',4'-didehydro-3',4'-dideoxy-kanamycin B, i.e., product 6; (7) Synthesis of 1,3,2',6',3"-penta-nitrogen-trimethylsilyl-2",4",6"-tri-oxygen-trimethylsilyl-3',4'-didehydro-3',4'-dideoxy-kanamycin B (Product 7) The product 6 obtained in step (6) is dissolved in acetonitrile (ACN), hexamethyldisilazane (HMDS) and trimethylsilyl chloride (TMSCl) are added, and the mixture is refluxed for 12 to 20 hours to obtain 1,3,2',6',3"-penta-nitrogen-trimethylsilyl-2",4",6"-tri-oxygen-trimethylsilyl-3',4'-didehydro-3',4'-dideoxy-kanamycin B, i.e., product 7; (8) Synthesis of 1-nitrogen-(L-γ-benzyloxycarbonylamino-α-hydroxybutyryl)-3',4'-didehydro-3',4'-dideoxy-kanamycin B, product 9 ① L-γ-amino-α-hydroxybutyric acid and sodium carbonate are sequentially added to a mixed solution of water and acetone, benzyl chloroformate is added at -10 to 0°C to react for 10 to 24 hours, and ether is added for extraction to obtain L-γ-benzyloxycarbonylamino-α-hydroxybutyric acid, i.e., intermediate 10; ② The intermediate product 10 synthesized in ①, N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) are sequentially added to acetone, and reacted at 10 to 50° C. for 1 to 4 hours to obtain a suspension containing 2,5-dioxo-1-pyrrolidinyl (2S)-α-hydroxy-γ-[[(phenylmethoxy)carbonyl]amino]butyrate, i.e., the intermediate product 11; ③ The product 7 obtained in step (7) is dissolved in acetone, water is added and stirred for 0.5 to 2 hours, and then the suspension containing the intermediate product 11 obtained in step ② is added, and the reaction is carried out at 0 to 30° C. for 0.5 to 4 hours to obtain the compound of product 8, and then 3 to 9 M hydrochloric acid is added to continue the reaction for 0.5 to 3 hours, and the reaction temperature is 10 to 50° C. to obtain 1-nitrogen-(L-γ-benzyloxycarbonylamino-α-hydroxybutyryl)-3',4'-didehydro-3',4'-dideoxy-kanamycin B, i.e., product 9; (9) Synthesis of 1-nitro-(L-4-amino-2-hydroxybutyryl)-3',4'-dideoxy-kanamycin B The product 9 obtained in step (8) is dissolved in water, a Pd / C catalyst is added, the pH value of the system is adjusted to 1-4 with hydrochloric acid, and the reaction is carried out at a temperature of 10-50° C. and a hydrogen pressure of 0.1-0.5 MPa for 12-72 hours to obtain 1-nitrogen-(L-4-amino-2-hydroxybutyryl)-3',4'-dideoxy-kanamycin B, i.e., arbekacin (I); Wherein, Boc represents tert-butyloxycarbonyl, Ns represents p-nitrobenzenesulfonyl, and R represents trimethylsilyl; The synthesis route of 2,5-dioxo-1-pyrrolidinyl (2S)-α-hydroxy-γ-[[(phenylmethoxy)carbonyl]amino]butyrate in step (8) is as follows:

2. The method according to claim 1, characterized in that In the step (1), the molar ratio of di-tert-butyl dicarbonate, sodium carbonate and kanamycin B is 4-10:2-7:1, the reaction temperature is 20-30° C., the reaction time is 10-14 hours, and the volume ratio of water to isopropanol is 1-3:

1.

3. The method according to claim 2, characterized in that The molar ratio of di-tert-butyl dicarbonate, sodium carbonate and kanamycin B is 6-9:4-6:

1.

4. The method according to claim 1, characterized in that In the step (2), the molar ratio of cyclohexanone dimethyl acetal, anhydrous p-toluenesulfonic acid and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-kanamycin B is 6-12:1-5:1, the reaction temperature is 20-30°C, and the reaction time is 10-14 hours.

5. The method according to claim 4, characterized in that The molar ratio of hexanone dimethyl acetal, anhydrous p-toluenesulfonic acid and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-kanamycin B is 8-10:2-4:

1.

6. The method according to claim 1, characterized in that In the step (3), the molar ratio of p-nitrobenzenesulfonyl chloride, 4-dimethylaminopyridine and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-4",6"-oxy-cyclohexylidene-kanamycin B is 5-11:5-11:1, the reaction temperature is 20-40°C, and the reaction time is 5-8 hours.

7. The method according to claim 6, characterized in that The molar ratio of p-nitrobenzenesulfonyl chloride, 4-dimethylaminopyridine and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-4",6"-oxy-cyclohexylidene-kanamycin B is 6-10:6-10:

1.

8. The method according to claim 1, characterized in that In the step (4), the mass ratio of sodium iodide, zinc powder and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxygen-p-nitrobenzenesulfonyl-4",6"-oxygen-cyclohexylidene-kanamycin B is 3-8:0.03-0.09:1, the reaction temperature is 110-130° C., and the reaction time is 0.5-1.5 hours.

9. The method according to claim 8, characterized in that The mass ratio of sodium iodide, zinc powder and 1,3,2',6',3"-penta-nitrogen-tert-butyloxycarbonyl-3',4',2"-tri-oxy-p-nitrobenzenesulfonyl-4",6"-oxy-cyclohexylidene-kanamycin B is 5-6:0.04-0.06:

1.

10. The method according to claim 1, characterized in that In the step (5), the volume ratio of methanol to hydrochloric acid is 1-3:1, the concentration of hydrochloric acid is 6M, the reaction temperature is 20-40°C, and the reaction time is 3-4 hours.

11. The method according to claim 1, characterized in that In the step (6), the molar ratio of magnesium metal to 3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-kanamycin B is 7-15:1, the reaction temperature is 20-30°C, the reaction time is 0.5-1.5 hours, the ultrasonic frequency is 40KHz, and the volume ratio of water to methanol is 1-3:

1.

12. The method according to claim 11, characterized in that The molar ratio of metal magnesium to 3',4'-didehydro-3',4'-dideoxy-2"-oxy-p-nitrobenzenesulfonyl-kanamycin B is 9-12:

1.

13. The method according to claim 1, characterized in that In the step (7), the molar ratio of hexamethyldisilazane, trimethylchlorosilane and 3',4'-didehydro-3',4'-dideoxy-kanamycin B is 5-11:0.1-0.8:1, and the reaction time is 15-17 hours.

14. The method according to claim 13, characterized in that The molar ratio of hexamethyldisilazane, trimethylchlorosilane and 3',4'-didehydro-3',4'-dideoxy-kanamycin B is 7-9:0.3-0.5:

1.

15. The method according to claim 1, characterized in that In step (8) ①, the volume ratio of acetone to water is 3 to 5:1, the molar ratio of sodium carbonate, benzyl chloroformate and L-γ-amino-α-hydroxybutyric acid is 0.5 to 4:0.5 to 3:1, the reaction temperature is -5 to -2°C, and the reaction time is 18 to 22 hours; In step (8) ②, the molar ratio of N-hydroxysuccinimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and L-γ-benzyloxycarbonylamino-α-hydroxybutyric acid is 0.5-3:0.5-3:1, the reaction temperature is 20-30° C., and the reaction time is 2-3 hours; In step (8) (3), the molar ratio of water, 2,5-dioxy-1-pyrrolidinyl (2S)-α-hydroxy-γ-[[(phenylmethoxy)carbonyl]amino]butyrate and 1,3,2',6',3"-penta-nitrogen-trimethylsilyl-2",4",6"-tri-oxygen-trimethylsilyl-3',4'-didehydro-3',4'-dideoxy-kanamycin B is 20-70:0.5-2:1, the reaction temperature is 20-30°C, the reaction time after adding water is 0.5-1 hour, the reaction time after adding 2,5-dioxy-1-pyrrolidinyl (2S)-α-hydroxy-γ-[[(phenylmethoxy)carbonyl]amino]butyrate is 1-3 hours, the reaction time after adding hydrochloric acid is 0.5-1 hour, the concentration of hydrochloric acid is 5-7M, and the volume ratio of hydrochloric acid to acetone is 0.7-1:

1.

16. The method according to claim 15, characterized in that The molar ratio of sodium carbonate, benzyl chloroformate and L-γ-amino-α-hydroxybutyric acid is 1-2:0.7-1.5:1; The molar ratio of N-hydroxysuccinimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and L-γ-benzyloxycarbonylamino-α-hydroxybutyric acid is 0.7-1.5:0.7-1.5:1; The molar ratio of water, 2,5-dioxo-1-pyrrolidinyl (2S)-α-hydroxy-γ-[[(phenylmethoxy)carbonyl]amino]butyrate and 1,3,2',6',3"-penta-nitrogen-trimethylsilyl-2",4",6"-tri-oxo-trimethylsilyl-3',4'-didehydro-3',4'-dideoxy-kanamycin B is 40-60:1-1.5:

1.

17. The method according to claim 1, characterized in that In the step (9), the mass ratio of Pd / C catalyst to 1-nitrogen-(L-γ-benzyloxycarbonylamino-α-hydroxybutyryl)-3',4'-didehydro-3',4'-dideoxy-kanamycin B is 0.1-0.4:1, the hydrochloric acid is 6M, the pH value is 3-4, the reaction temperature is 20-30°C, the pressure is 0.3-0.4MPa, and the reaction time is 24-36 hours.

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