A method for synthesizing the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane.

Abstract

This invention relates to a method for synthesizing the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane. The method uses 1-benzylmethylpyrrolidine-2,4-dione as the starting material and proceeds through five steps: cyclization, oxime formation, chiral asymmetric reduction, salt formation, and amino protection to obtain the target product. Specifically, the cyclization reaction uses an alkylating agent and a base to construct a spirocyclic structure; the oxime reaction introduces a methoxyimino group via methoxyamine hydrochloride; the chiral asymmetric reduction uses a catalytic system composed of a chiral ligand and a boron reagent to construct the chiral center, followed by purification via maleic acid salt formation; and finally, the amino group is protected with di-tert-butyl dicarbonate to obtain the target product. This invention offers high atom economy, good process scalability, simple operation, controllable cost, and high product purity, providing a reliable intermediate synthesis scheme for the efficient preparation of sitafloxacin active pharmaceutical ingredient.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, and particularly relates to a method for synthesizing 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane, an intermediate of sitafloxacin. Background Technology

[0002] Sitafloxacin, chemically named 7-[(7S)-7-amino-5-azaspiro[2,4]hept-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-cis-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, is a broad-spectrum fluoroquinolone antibiotic developed by Daiichi Sankyo Co., Ltd. Its unique cis-fluorocyclopropylamine group in its molecular structure endows the drug with superior pharmacokinetic properties while effectively reducing the risk of adverse reactions. Compared to most similar drugs, sitafloxacin exhibits significantly enhanced in vitro antibacterial activity and is mainly used clinically to treat severe refractory infectious diseases and bacterial infections caused by drug-resistant bacteria.

[0003]

[0004] 7(S)-tert-Butoxycarbonylamino-5-azaspiro[2,4]heptane is a key intermediate in the synthesis of sitafloxacin. However, this intermediate has poor stability, posing a significant challenge for long-term storage. In contrast, its precursor compound, 5-benzyl-7(S)-tert-Butoxycarbonylamino-5-azaspiro[2,4]heptane, exhibits excellent stability and can be directly involved in subsequent reactions by immediately removing the benzyl group. Therefore, developing an efficient preparation process for this precursor compound is of great significance for the industrial production of sitafloxacin.

[0005] Currently, existing technologies for the synthesis of 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane mainly fall into the following categories: Method 1 is the racemic resolution method, which first synthesizes a racemic intermediate and then resolves it to obtain a single-configuration compound. For example, the preparation method disclosed in Chinese patent CN201310329592 has a core drawback: the resolution process wastes another chiral isomer, resulting in low atom economy. The synthetic route is as follows: .

[0006] Method 2 involves the asymmetric synthesis of chiral amines. The literature (Chem. Pharm. Bull., 1998, 46, 587) reports a method using 5-benzyl-4,7-dioxo-5-azaspiro[2,4]heptane as a starting material. A chiral center is introduced via enzymatic asymmetric reduction, followed by a Mitsunobu reaction and amino protection to yield 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane. While this route is shorter, the enzymatic catalysis requires high standards for scale-up and stability control in industrial production, posing a bottleneck for large-scale application. The synthetic route is as follows: .

[0007] Method three utilizes chiral auxiliary reagents for induction. For example, Chinese patent CN202510221293 discloses a method for preparing the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane. Starting with 5-benzyl-4,7-dioxo-5-azaspiro[2,4]heptane, it undergoes a condensation reaction with (S)-tert-butylsulfinamide to obtain an imine. Subsequently, the imine and amide are reduced, and the tert-butylsulfinamide protecting group is removed under acidic conditions. Finally, amine protection yields 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane. While this method yields products with high yield and high optical purity, inert gas protection is required throughout multiple steps, and the chiral auxiliary group cannot be recycled, resulting in high production costs.

[0008]

[0009] In summary, existing technologies generally suffer from problems such as chiral waste, difficulty in industrial scale-up, and complex or high costs. Therefore, it is necessary to develop a preparation method that is simple to operate, has a mild reaction, produces high-purity products, and is suitable for industrial production. Summary of the Invention

[0010] The present invention addresses the problems existing in the prior art. Specifically, the technical problem to be solved by the present invention is to provide a method for synthesizing the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane, which is simple to operate, has a mild reaction, produces a high-purity product, and is suitable for industrial production.

[0011] To achieve the above objectives, the technical solution adopted in this invention is: a method for synthesizing the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane, using 1-benzylmethylpyrrolidine-2,4-dione as the starting material, and through cyclization, oximeization, chiral asymmetric reduction, salt formation, and amino protection reactions, 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane is obtained; the reaction equation is as follows:

[0012] Among them, compound 2 is 1-benzylpyrrolidine-2,4-dione, compound 3 is 5-benzyl-4,7-dioxo-5-azaspiro[2,4]heptane, compound 4 is 5-benzyl-7-(methoxyimino)-5-azaspiro[2,4]hept-4-one, compound 5 is a chiral amine, compound 6 is a chiral amine maleate, and compound 1 is 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane.

[0013] Furthermore, the specific steps include: (1) Compound 2 was cyclized with an alkylating agent under the action of a base to obtain compound 3; (2) Compound 3 undergoes an oxime reaction under the action of an oxime reagent and a base to give compound 4 containing a methoxyimino group; (3) Compound 4 obtained in step (2) was asymmetrically reduced by a chiral catalytic system formed by chiral ligand and boron reagent to prepare compound 5, which was then salted to obtain compound 6; (4) After the compound 6 obtained in step (3) is freed by alkali, it reacts with ditert-butyl dicarbonate to protect the amino group and obtain compound 1.

[0014] Furthermore, the alkylating agent in step (1) is one of 1,2-dibromoethane, 1-bromo-2-chloroethane, and vinyl sulfate; the base is one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, and sodium ethoxide; and the reaction solvent is one of toluene, DMF, THF, and 2-methyltetrahydrofuran.

[0015] Furthermore, in step (1), the molar ratio of compound 2: alkylating agent: base is 1:1~3:2~3.

[0016] Furthermore, the oxime reagent in step (2) is methoxyamine hydrochloride, the base is one of pyridine, triethylamine, and diisopropylethylamine, and the reaction solvent is one of pyridine, dichloromethane, THF, and acetonitrile.

[0017] Furthermore, in step (2), the molar ratio of compound 3: oxime reagent: base is 1:1~1.5:1.5~3.

[0018] Furthermore, in step (3), the chiral ligand is one or more of R-(+)-diphenylproline, (R)-BINOL, and L-proline, the boron reagent is dimethyl sulfide borane, the chiral catalytic system also includes the activator trimethyl borate, the reaction solvent is one of toluene, THF, dichloromethane, and diethyl ether, and the molar ratio of compound 4: chiral ligand: boron reagent: activator is 1:0.1~0.2:2~3:0.1~0.2.

[0019] Furthermore, the solvent used in the salt formation reaction in step (3) is one of ethanol, methanol, isopropanol, and acetonitrile, and the molar ratio of compound 5 to maleic acid is 1:0.8~1; after salt formation, crystallization can be carried out by adding one of n-heptane, n-hexane, and petroleum ether.

[0020] Furthermore, the alkali used in step (4) is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate. The amount of alkali used is such that the pH of the reaction system is 9~11, and the molar ratio of compound 6 to ditert-butyl dicarbonate is 1:1~1.2. The reaction solvent is one of THF, dichloromethane, ethyl acetate, and acetone.

[0021] Compared with the prior art, the present invention has the following advantages: The present invention is reasonably designed, has high atom economy, good process scale-up, simple operation, controllable cost, and high product purity. It effectively overcomes the shortcomings of the prior art, such as chiral waste, difficulty in industrialization, and complex operation. It provides an efficient, stable, and economical technical solution for the industrialization of the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane, and has important industrial application value and market prospects. Detailed Implementation

[0022] The present invention will now be described in further detail with reference to specific embodiments.

[0023] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0024] It should be noted that in this invention, compounds 3 and 4 can be purified according to the needs of subsequent reactions. If the subsequent reactions are more tolerant to impurities, the crude products can be used directly in the next step to simplify the process and improve the yield.

[0025] The abbreviations for the reaction reagents mentioned in the instructions are as follows: DMF: N,N-dimethylformamide; THF: Tetrahydrofuran.

[0026] This invention discloses a method for synthesizing 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane, an intermediate of sitafloxacin, aiming to overcome the shortcomings of existing synthetic methods that are not conducive to industrial production. This synthetic method uses 1-benzylmethylpyrrolidine-2,4-dione as the starting material, and obtains 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane through cyclization, oximeization, chiral asymmetric reduction, salt formation, and amino protection reactions. The reaction equation is as follows:

[0027] Among them, compound 2 is 1-benzylpyrrolidine-2,4-dione, compound 3 is 5-benzyl-4,7-dioxo-5-azaspiro[2,4]heptane, compound 4 is 5-benzyl-7-(methoxyimino)-5-azaspiro[2,4]hept-4-one, compound 5 is a chiral amine, compound 6 is a chiral amine maleate, and compound 1 is 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane.

[0028] Specifically, the synthesis method of 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane includes the following steps: (1) 1-Benzylpyrrolidine-2,4-dione (compound 2) was cyclized with an alkylating agent under the action of a base to give 5-benzyl-4,7-dioxo-5-azaspiro[2,4]heptane (compound 3); (2) 5-Benzyl-4,7-dioxo-5-azaspiro[2.4]heptane (compound 3) underwent an oxime reaction in the presence of an oxime reagent and a base to give compound 4 containing methoxyimino; (3) The chiral amine (compound 5) was prepared by asymmetric reduction of compound 4 obtained in step (2) through a chiral catalytic system formed by chiral ligand and boron reagent, and then obtained by salt formation to obtain chiral amine maleate (compound 6). (4) The chiral amine maleate (compound 6) obtained in step (3) is freed by alkali and then reacted with ditert-butyl dicarbonate to protect the amino group to obtain compound 1.

[0029] Specifically, the alkylating agent in step (1) is one of 1,2-dibromoethane, 1-bromo-2-chloroethane, and vinyl sulfate; the base is one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, and sodium ethoxide; and the reaction solvent is one of toluene, DMF, THF, and 2-methyltetrahydrofuran. Further, the molar ratio of compound 2: alkylating agent: base in step (1) is 1:1~3:2~3.

[0030] Specifically, in step (2), the oxime reagent is methoxyamine hydrochloride, the base is one of pyridine, triethylamine, and diisopropylethylamine, and the reaction solvent is one of pyridine, dichloromethane, THF, and acetonitrile. Further, in step (2), the molar ratio of compound 3: oxime reagent: base is 1:1~1.5:1.5~3.

[0031] Specifically, in step (3), the chiral ligand is one or more of R-(+)-diphenylproline, (R)-BINOL, and L-proline; the boron reagent is dimethyl sulfide borane; the chiral catalytic system also includes the activator trimethyl borate; the reaction solvent is one of toluene, THF, dichloromethane, and diethyl ether; and the molar ratio of compound 4: chiral ligand: boron reagent: activator is 1:0.1~0.2:2~3:0.1~0.2. Further, in step (3), the solvent used for the salt formation reaction is one of ethanol, methanol, isopropanol, and acetonitrile; and the molar ratio of compound 5 to maleic acid is 1:0.8~1. After salt formation, crystallization can be performed by adding one of n-heptane, n-hexane, and petroleum ether to improve the purity of compound 6.

[0032] Specifically, the alkali used in step (4) is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate. The amount of alkali used is such that the pH of the reaction system is 9~11, and the molar ratio of compound 6 to ditert-butyl dicarbonate is 1:1~1.2. The reaction solvent is one of THF, dichloromethane, ethyl acetate, and acetone. After the reaction is completed, the product of compound 1 is obtained by concentration, pulping, and recrystallization. The recrystallization solvent is selected from one of n-heptane, n-hexane, petroleum ether, and cyclohexane.

[0033] In summary, this method uses 1-benzylpyrrolidine-2,4-dione as the starting material and proceeds through five steps: cyclization, oxime formation, chiral asymmetric reduction, salt formation, and amino protection to obtain the target product. Specifically, the cyclization reaction utilizes an alkylating agent and a base to construct a spirocyclic structure; the oxime reaction introduces a methoxyimino group via methoxyamine hydrochloride; the chiral asymmetric reduction employs a catalytic system composed of a chiral ligand and a boron reagent to construct the chiral center, followed by purification via maleic acid salt formation; and finally, the amino group is protected with di-tert-butyl dicarbonate to obtain the target product.

[0034] Example 1: Preparation of Compound 3

[0035] The specific operating steps are as follows: Compound 2 (60.55 g, 0.32 mol) was added to toluene (600 mL) in a three-necked flask and stirred until dissolved. Then, tetrabutylammonium bromide (0.52 g, 0.0016 mol) and 1,2-dibromoethane (63.12 g, 0.336 mol) were added sequentially. The temperature was raised to 40~60℃, and 40% sodium hydroxide aqueous solution (80 mL) was added dropwise while stirring. After the addition was completed, the reaction was stirred for 16 h. The reaction of the starting material was detected by TLC to be complete. The reaction system was cooled to room temperature and allowed to stand. The upper organic phase was separated, and the lower aqueous phase was extracted with toluene (300 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (180 mL × 2), dried over anhydrous sodium sulfate, and filtered through a Buchner funnel lined with silica gel (200-300 mesh, 30 g). The filter cake was washed with toluene, and the filtrate was concentrated under reduced pressure at 40-60 °C to obtain 66.12 g of crude compound 3, with a yield of 96% and an HPLC purity of 91.2%. The crude compound 3 obtained in this example was used directly in the next reaction without further purification.

[0036] Example 2: Preparation of Compound 3 The specific operating steps are as follows: Compound 2 (119.2 g, 0.63 mol) was added to DMF (800 mL) in a three-necked flask at 10–25 °C. The mixture was stirred until dissolved. Potassium carbonate (221.14 g, 1.60 mol) was then slowly added. After the addition was complete, the reaction solution was heated to 50 °C, and 1,2-dibromoethane (126.24 g, 0.672 mol) was added dropwise. The reaction system was exothermic during the dropwise addition. The temperature of the reaction solution was controlled at 60–70 °C. After 4 hours of reaction, TLC was used to confirm the completeness of the reaction. The reaction system was cooled to room temperature, filtered, and the filtrate was diluted with ethyl acetate (1200 mL). Process water (1200 mL) was added, and the mixture was stirred and allowed to stand. The upper organic phase was separated, and the lower aqueous phase was extracted with ethyl acetate (600 mL × 2). All organic phases were combined and washed with saturated sodium chloride solution (480 mL × 3). The organic phase was concentrated under reduced pressure using a water pump to remove the low-boiling solvent (ethyl acetate), and then the high-boiling solvent (DMF) was removed under reduced pressure using an oil pump. The concentration temperature was controlled to not exceed 60°C to obtain crude compound 3. Methyl tert-butyl ether (240 mL) was added to the crude product, and the mixture was heated to reflux and stirred for 2 h. The temperature was then lowered to 10–20°C and stirred for 2.5 h. After crystallization, the mixture was filtered, and the filter cake was washed with methyl tert-butyl ether (50 mL) and dried under forced air at 40°C to obtain 110.2 g of purified compound 3, with a yield of 81.3% and a purity of 98.2%.

[0037] Example 3: Preparation of Compound 3 The specific operating steps are as follows: Compound 2 (30 g, 0.16 mol) was added to THF (300 mL) in a three-necked flask and stirred until dissolved. Solid sodium ethoxide (27.22 g, 0.4 mol) was added in portions at 5–15 °C, and the mixture was stirred for 2 h after the addition was complete. Then, 1,2-dibromoethane (31.56 g, 0.168 mol) was added dropwise. After the addition was complete, the temperature was slowly raised to 50–60 °C and the reaction was allowed to proceed for 12 h. The reaction was monitored by TLC until complete. Water (150 mL) and ethyl acetate (150 mL) were added to the system at 10–20 °C and stirred for 30 minutes. After standing, the upper organic phase was separated, and the lower aqueous phase was extracted with ethyl acetate (150 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 40–50 °C to obtain 33.41 g of crude compound 3, with a yield of 97% and an HPLC purity of 89%. The crude compound 3 obtained in this example can be used directly in the next oxime reaction without additional purification.

[0038] Example 4: Preparation of Compound 3

[0039] The specific operating steps are as follows: Compound 2 (189.21 g, 1 mol) was added to THF (1000 mL) in a three-necked flask and stirred until dissolved. At 5-15 °C, vinyl sulfate (310.3 g, 2.5 mol) was added sequentially, followed by sodium ethoxide (204.15 g, 3.0 mol) in portions. After the addition was complete, the mixture was stirred for 6 h, and the reaction was monitored by TLC to ensure completeness. At 5-20 °C, water (1000 mL) and ethyl acetate (1000 mL) were added to the reaction system and stirred for 30 minutes. The mixture was allowed to stand, and the upper organic phase was separated. The lower aqueous phase was extracted with ethyl acetate (600 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered through a Buchner funnel lined with silica gel (200-300 mesh, 95 g). The filtrate was concentrated under reduced pressure at 40-50 °C to obtain crude compound 3. 567 mL of methyl tert-butyl ether was added to the crude product, and the mixture was stirred at room temperature for 3 h. After filtration, the wet product was dried by forced air at 40 °C to obtain 202.34 g of compound 3 as a pure yellow solid with a yield of 94% and an HPLC purity of 96.5%.

[0040] Example 5: Preparation of Compound 4

[0041] The specific operating steps are as follows: Compound 3 (43.05 g, 0.2 mol) was added to pyridine (126 mL) in a three-necked flask and stirred until dissolved. Methoxyamine hydrochloride (17.54 g, 0.21 mol) was added in portions at 0–10 °C. After the addition was complete, the mixture was stirred at room temperature, and the reaction was monitored by TLC until complete. The reaction solution was concentrated under reduced pressure to remove pyridine, then dissolved in dichloromethane (430 mL), washed with process water (200 mL × 3), and the lower organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure at 30–50 °C to obtain 47.88 g of crude compound 4, a yellow oily liquid, with a yield of 98% and an HPLC purity of 95.5%. The crude compound 4 obtained in this example was used directly in the next reaction without further purification.

[0042] Example 6: Preparation of Compound 6

[0043] The specific operating steps are as follows: Toluene (150 mL), R-(+)-diphenylprolyl (2.58 g, 0.0102 mol), and trimethyl borate (1.06 g, 0.0102 mol) are added to a three-necked flask and stirred at 35-40 °C for 2 h. Then, 10 mol / L dimethyl sulfide borate (25.7 mL, 0.257 mol) is added dropwise to the mixture through a constant pressure dropping funnel over a period of 30 min. After the addition is complete, the temperature is lowered to 0-5 °C, and then a mixed solution of compound 4 (24.92 g, 0.102 mol) and toluene (50 mL) is added dropwise over a period of 30 min. After the addition is complete, the temperature is maintained at 0-5 °C for 1 h, and then the temperature is raised to 20-30 °C and stirred for 18 h. The reaction of the raw materials is controlled by TLC to ensure complete reaction. The reaction was quenched by slowly adding methanol (15 mL) dropwise to the reaction solution at 10 °C. After quenching, process water (250 mL) and hydrochloric acid (12 mol / L, 33 mL) were added to the reaction solution. The mixture was stirred at 40-50 °C for 1 h. The mixture was then filtered through a funnel lined with diatomaceous earth. The filtrate was transferred to a separatory funnel and allowed to stand to separate into layers. The upper organic phase was separated, and the lower aqueous phase was extracted with toluene (100 mL). The aqueous phase was then separated, and the pH was adjusted to 10-11 with 40% sodium hydroxide. Ethyl acetate (150 mL × 2) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was transferred to a vacuum concentration apparatus. The solution was concentrated under reduced pressure at 30 °C to obtain 18.21 g of compound 5, a pale yellow oily liquid with a chiral purity of 94%.

[0044] Compound 5 (18.21 g, 0.09 mol) was dissolved in ethanol (50 mL), and maleic acid (9.87 g, 0.085 mol) was added. The mixture was stirred at room temperature for 4 h, and then concentrated under reduced pressure to remove about 25 mL of ethanol. Heptane (50 mL) was slowly added dropwise to the system, and the mixture was stirred at 10-20 °C for 4 h to crystallize. The mixture was filtered, dried under reduced pressure, and 24.36 g of compound 6 was obtained, with a yield of 75% and a chiral purity of 96.4%.

[0045] Example 7: Preparation of Compound 6

[0046] The specific operating steps are as follows: Toluene (400 mL), (R)-BINOL (11.74 g, 0.041 mol), L-proline (4.72 g, 0.041 mol), and trimethyl borate (4.26 g, 0.041 mol) are added to a three-necked flask. The mixture is stirred at 50-60 °C for 2 h. Then, the temperature is controlled at 20-30 °C, and 10 mol / L dimethyl sulfide borate (102.5 mL, 1.025 mol) is added dropwise to the mixture through a constant pressure dropping funnel over a period of 30 min. After the addition is complete, the temperature is lowered to 0-5 °C, and then a mixed solution of compound 4 (100.16 g, 0.41 mol) and toluene (100 mL) is added dropwise over a period of 30 min. After the addition is complete, the temperature is maintained at 0-5 °C for 1 h, and then the temperature is raised to 20-30 °C and stirred for 24 h. The reaction of the starting materials is controlled by TLC to ensure complete reaction. The reaction was quenched by slowly adding methanol (60 mL) dropwise to the reaction solution at 10 °C. After quenching, process water (1000 mL) and hydrochloric acid (12 mol / L, 132 mL) were added to the reaction solution. The mixture was stirred at 40-50 °C for 1 h. The mixture was then filtered through a funnel lined with diatomaceous earth. The filtrate was transferred to a separatory funnel and allowed to stand to separate into layers. The upper organic phase was separated, and the lower aqueous phase was extracted with toluene (500 mL). The aqueous phase was then separated, and the pH was adjusted to 10-11 with 40% sodium hydroxide. Ethyl acetate (600 mL × 2) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was transferred to a vacuum concentration apparatus. The solution was concentrated under reduced pressure at 30 °C to obtain 78.9 g of compound 5, a pale yellow oily liquid with a chiral purity of 98.6%.

[0047] Compound 5 (78.9 g, 0.39 mol) was dissolved in ethanol (158 mL), and maleic acid (43.41 g, 0.374 mol) was added. The mixture was stirred at room temperature for 4 h, and then concentrated under reduced pressure to remove about 79 mL of ethanol. Heptane (120 mL) was slowly added dropwise to the system, and the mixture was stirred at 10-20 °C for 4 h to crystallize. The mixture was filtered, dried under reduced pressure, and 112 g of compound 6 was obtained as an off-white solid with a yield of 85.8% and a chiral purity of 99.5%.

[0048] Example 8: Preparation of Compound 1

[0049] The specific operating steps are as follows: Compound 6 (99.97 g, 0.314 mol) was added to process water (600 mL) in a three-necked flask and stirred until dissolved. Then, 10% NaOH solution was added dropwise to adjust the pH to 11. A mixed solution of di-tert-butyl dicarbonate (72.02 g, 0.33 mol) and tetrahydrofuran (500 mL) was then added dropwise. The mixture was stirred at 20-30°C until the reaction was complete. The solvent was removed by vacuum extraction at 30-45°C, and process water (600 mL) was added. The mixture was stirred and slurried for 2 hours, filtered, and dried under vacuum at 30-45°C to obtain crude compound 1.

[0050] Add crude compound 1 and n-heptane (500 mL) to the reaction flask, heat to 60-70 °C and stir for 2 h, then cool to 20-25 °C and stir to crystallize for 2 h. Filter, and dry the filter cake under vacuum at 40-45 °C to obtain 80.72 g of refined compound 1, an off-white solid, with a yield of 85.0%, chemical purity >99.0%, and chiral purity of 99.7%. 1 HNMR (400 MHz, CDCl3) δ7.33-7.25(m,5H) ,4.98(m ,1H) ,3.85(m ,1H) ,3.67-3.57(m ,2H) ,2.94-2.90(m ,1H) ,2.70-2.68(m ,2H) ,2.37-2.35(m ,1H) ,1.45(s ,9H) ,0.83-0.74(m ,2H) ,0.62-0.60(m ,1H) ,0.48–0.44(m ,1H).

[0051] The advantages of this invention are: (1) The present invention uses an asymmetric reduction reaction to directly construct the target chiral center without the need to synthesize a racemic mixture and then resolve it. This avoids the waste of another chiral isomer in the traditional racemic resolution method from the source, significantly improves the atom utilization rate, and reduces the cost increase caused by raw material loss. (2) The present invention adopts a chiral catalytic system formed by chiral ligands and boron reagents. The reaction conditions are easy to control and the requirements for production equipment and environmental stability are lower. It solves the technical bottleneck of poor stability and difficulty in scaling up bio-enzyme catalysis in industrial scale-up process, and is more suitable for large-scale industrial production. By optimizing the chiral catalytic system and process parameters, the chemical purity of 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane prepared by the present invention can reach more than 99%, and the chiral purity can reach up to 99.7%, which is better than the product purity level of some existing synthesis methods. (3) The synthesis steps provided by the present invention are simple and coherent, each reaction step is highly selective, with few by-products and mild conditions. The post-processing is all routine operation, without the need for complex equipment and special processes, which significantly reduces the difficulty of operation and cost input in the production process. (4) The present invention provides a variety of matching options for reagents in each step, which can be flexibly adjusted according to the raw material supply, cost budget and equipment conditions in actual production, without relying on a single special reagent, further improving the industrial adaptability of the process and reducing the supply chain risk in the production process.

[0052] In summary, this invention provides a synthesis method that combines high atom economy, good process scalability, simple operation, controllable cost, and high product purity. It effectively overcomes the shortcomings of existing technologies, such as chiral waste, difficulty in industrialization, and complex operation. It provides an efficient, stable, and economical technical solution for the industrialization of the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane, and has significant industrial application value and market prospects.

[0053] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications can still be made to the specific implementation of the present invention or equivalent substitutions can be made to some technical features without departing from the spirit of the technical solutions of the present invention, and all such modifications and substitutions should be covered within the scope of the technical solutions claimed in the present invention.

Claims

1. A method for synthesizing the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane, characterized in that: Starting from 1-benzylpyrrolidine-2,4-dione, 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane was prepared via cyclization, oximeization, chiral asymmetric reduction, salt formation, and amino protection reactions; the reaction equation is as follows: Among them, compound 2 is 1-benzylpyrrolidine-2,4-dione, compound 3 is 5-benzyl-4,7-dioxo-5-azaspiro[2,4]heptane, compound 4 is 5-benzyl-7-(methoxyimino)-5-azaspiro[2,4]hept-4-one, compound 5 is a chiral amine, compound 6 is a chiral amine maleate, and compound 1 is 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane.

2. The method for synthesizing the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane according to claim 1, characterized in that: Specifically, the following steps are included: (1) Compound 2 was cyclized with an alkylating agent under the action of a base to obtain compound 3; (2) Compound 3 undergoes an oxime reaction under the action of an oxime reagent and a base to give compound 4 containing a methoxyimino group; (3) Compound 4 obtained in step (2) was asymmetrically reduced by a chiral catalytic system formed by chiral ligand and boron reagent to prepare compound 5, which was then salted to obtain compound 6; (4) After the compound 6 obtained in step (3) is freed by alkali, it reacts with ditert-butyl dicarbonate to protect the amino group and obtain compound 1.

3. The method for synthesizing the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane according to claim 2, characterized in that: The alkylating agent in step (1) is one of 1,2-dibromoethane, 1-bromo-2-chloroethane, and vinyl sulfate; the base is one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, and sodium ethoxide; and the reaction solvent is one of toluene, DMF, THF, and 2-methyltetrahydrofuran.

4. The method for synthesizing the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane according to claim 2, characterized in that: In step (1), the molar ratio of compound 2, alkylating agent, and base is 1:1~3:2~3.

5. The method for synthesizing the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane according to claim 2, characterized in that: The oxime reagent in step (2) is methoxyamine hydrochloride, the base is one of pyridine, triethylamine, and diisopropylethylamine, and the reaction solvent is one of pyridine, dichloromethane, THF, and acetonitrile.

6. The method for synthesizing the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane according to claim 2, characterized in that: In step (2), the molar ratio of compound 3: oxime reagent: base is 1:1~1.5:1.5~3.

7. The method for synthesizing the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane according to claim 2, characterized in that: In step (3), the chiral ligand is one or more of R-(+)-diphenylproline, (R)-BINOL, and L-proline, the boron reagent is dimethyl sulfide borane, the chiral catalytic system also includes the activator trimethyl borate, the reaction solvent is one of toluene, THF, dichloromethane, and diethyl ether, and the molar ratio of compound 4: chiral ligand: boron reagent: activator is 1:0.1~0.2:2~3:0.1~0.

2.

8. The method for synthesizing the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane according to claim 1, characterized in that: The solvent used in the salt formation reaction in step (3) is one of ethanol, methanol, isopropanol, and acetonitrile. The molar ratio of compound 5 to maleic acid is 1:0.8~1. After salt formation, crystallization can be carried out by adding one of n-heptane, n-hexane, and petroleum ether.

9. The method for synthesizing the sitafloxacin intermediate 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane according to claim 2, characterized in that: The base used in step (4) is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate. The amount of base used is such that the pH of the reaction system is 9 to 11, and the molar ratio of compound 6 to ditert-butyl dicarbonate is 1:1 to 1.

2. The reaction solvent is one of THF, dichloromethane, ethyl acetate, and acetone.

Images