Preparation method of sitafloxacin intermediate 5-benzyl-7 (S)-tertiary butyl carbonyl amino-5-azaspiro [2, 4] heptane

Abstract

The invention provides a preparation method of sitafloxacin intermediate 5-benzyl-7 (S)-tertiary butyl carbonyl amino-5-azaspiro [2, 4] heptane, which comprises the following steps: carrying out condensation reaction on 5-benzyl-4, 7-dioxo-5-azaspiro [2, 4] heptane serving as an initial raw material and (S)-tertiary butyl sulfinamide to obtain imine, reducing the imine and reducing amide under the action of a reducing agent to obtain 5-benzyl-7 (S)-tertiary butyl carbonyl amino-5-azaspiro [2, 4] heptane. And removing tert-butyl sulfinyl from the obtained reduction product under an acidic condition, and finally, carrying out protection by tert-butyloxycarboryl to obtain the 5-benzyl-7 (S)-tert-butyl carbonyl amino-5-azaspiro [2, 4] heptane. The synthesis method provided by the invention is simple and convenient to operate, mild in reaction condition, relatively short in production period, good in stereoselectivity and more suitable for industrial production, and the obtained product has high yield and optical purity.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and particularly to a preparation method of a sitafloxacin intermediate 5-benzyl-7(S)-tert-butylcarbonylamino-5-azaspiro[2,4]heptane. Background Art

[0002] Sitafloxacin was developed by Daiichi Sankyo Co., Ltd. of Japan as early as 1992, and its oral tablets and fine granules were launched in Japan in June 2008. Sitafloxacin monohydrate is a new type of oral quinolone antibacterial drug with excellent broad-spectrum antibacterial activity, and is clinically used for bacterial pneumonia, acute and chronic respiratory tract infections, skin infections, and hemophilia bacterial infections, etc. Since its first launch in Japan, sitafloxacin has the advantages of good oral absorption, a bioavailability greater than 70%, wide distribution in many tissues, and drug concentrations higher than serum drug concentrations in various tissues except the central nervous system. For diseases of the urogenital tract, respiratory tract, abdominal cavity, and skin and soft tissues caused by single or mixed bacterial infections, it is expected to become an important specific drug for treatment, with great development potential and an increasing market share in the Japanese market year by year.

[0003] Sitafloxacin, chemically named 7-[(7S)-7-amino-5-azaspiro[2,4]hept-5-yl]-8-chloro-6-fluoro-1-

[0004] [(1R,2S)-cis-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, and its monohydrate is used clinically. Its structural formula is shown in Formula 1. Due to the presence of the (S)-7-amino-5-azaspiro[2,4]heptane structure in its chemical structure, sitafloxacin has good liposolubility and also affects the pharmacokinetics of its antibacterial spectrum against Gram-negative bacteria. 7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane is a key intermediate for the synthesis of sitafloxacin. However, due to its instability, the preservation of this intermediate is greatly restricted. And the compound 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane (whose structure is shown in Formula 2) is very stable, and after the benzyl protecting group is removed immediately during use, it directly participates in the next reaction.

[0005]

[0006] For the synthesis of this compound, according to the reported synthetic routes and the methods for constructing chiral amines, there are mainly the following several synthetic methods:

[0007] One is to obtain the chiral amine compound 2 through chemical resolution methods. For example, a preparation method of 5-benzyl-7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane disclosed in Chinese Patent CN201310329592 has the following synthetic route:

[0008]

[0009] The chemical resolution method requires the use of a large amount of resolving agents, generating a large amount of waste due to the difficulty of recycling; moreover, the isomers cannot be racemized and recycled, resulting in low yields and high material costs.

[0010] The other is to achieve the selective asymmetric reduction of imines to obtain chiral amines by using chiral auxiliary reagents for induction. For example, the preparation method reported in US2004235928A1 has the following specific synthetic route:

[0011]

[0012] This route uses R-α-phenylethylamine as a chiral auxiliary reagent and platinum dioxide as a catalyst to hydrogenate and reduce the imine, and the obtained product has a d.e. value of only 79%. Subsequent L-tartaric acid resolution and purification are also required. Palladium-carbon catalyzed hydrogenation is used to remove the phenethyl group, and due to the presence of a benzyl group in the structure, there is a selectivity problem, so the overall yield is relatively low. The entire reaction route undergoes two high-pressure hydrogenation reductions catalyzed by precious metals, with high material costs and production costs, and there are also relatively large safety risks.

[0013] In addition, Chinese Patent CN200910028384 discloses a preparation method of 7(S)-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane. Using S-α-phenylethylamine as a chiral auxiliary reagent, the imine is catalytically hydrogenated and reduced by Raney nickel to obtain two diastereoisomers, which need to be separated by silica gel column chromatography to obtain a single optically pure compound amine. Then, palladium-carbon catalyzed hydrogenation is used to selectively remove the phenethyl group, lithium aluminum hydride is used to reduce the amide, and finally the tert-butoxycarbonyl group is used to protect the amino group to obtain the intermediate formula 2 compound related to the present invention. This method requires the use of a large amount of lithium aluminum hydride, which is not only expensive but also has great safety risks, and silica gel column chromatography is required, making it difficult to industrialize.

[0014] The third is to construct chiral amines through asymmetric synthesis methods. For example, Chem.Pharm.Bull.,1998,46,587 reports that starting from 5-benzyl-4,7-dioxo-5-azaspiro[2,4]heptane, the intermediate formula 2 compound related to the present invention is obtained through enzymatic catalytic asymmetric reduction of the carbonyl group, Mitsunobu reaction, and amino protection. The synthetic route is as follows:

[0015]

[0016] This route introduces a chiral center through biocatalytic asymmetric reduction. Although the route is short, the enzyme-catalyzed reaction time mentioned in the literature is long (10 days), and the post-treatment operation is complex. The Mitsunobu reaction uses triphenylphosphine, generating a large amount of by-product triphenylphosphine oxide, which is difficult to completely remove from the product and is difficult to handle. Diethyl azodicarboxylate is sensitive to light, heat, and vibration, and requires the use of azides, presenting certain safety risks. Most intermediates need to be purified by silica gel column chromatography, limiting its industrial application.

[0017] In summary, the current preparation process of the key intermediate of sitafloxacin involves the application of chiral resolution technology, resulting in serious waste of related raw materials and low yields. At the same time, the large-scale use of resolving agents, which are not easily recyclable, also increases production costs. Using chiral α-phenylethylamine as a chiral auxiliary reagent has poor selectivity and a cumbersome refining process. The asymmetric synthesis method has low production efficiency and requires the use of highly hazardous azo and azide reagents.

[0018] Therefore, it remains an urgent problem to explore a process route for the key intermediate of sitafloxacin, 5-benzyl-7(S)-tert-butylcarbonylamino-5-azaspiro[2.4]heptane, which is simple to operate, has a shorter production cycle, higher yield, and is more suitable for industrial production. Summary of the Invention

[0019] Aiming at the problems in the prior art that the process for preparing the sitafloxacin intermediate 5-benzyl-7(S)-tert-butylcarbonylamino-5-azaspiro[2.4]heptane (compound of formula 2) is complex, has a long production cycle, low yield, high cost, and significant safety risks, the present invention provides an efficient asymmetric synthesis strategy. This method is simple to operate, has mild reaction conditions, a shorter production cycle, good stereoselectivity, is more suitable for industrial production, and the obtained product has a high yield and optical purity.

[0020] To achieve the above technical objectives, the technical solution adopted by the present invention is as follows:

[0021] A preparation method of a sitafloxacin intermediate 5-benzyl-7(S)-tert-butylcarbonylamino-5-azaspiro[2.4]heptane, and its synthetic route is as follows:

[0022]

[0023] Among them, x is 1 or 2; HA is an organic acid or an inorganic acid.

[0024] Furthermore, the preparation method of the sitafloxacin intermediate 5-benzyl-7(S)-tert-butylcarbonylamino-5-azaspiro[2.4]heptane includes the following steps:

[0025] (1) Under the protection of inert gas, 5-benzyl-4,7-dioxo-5-azaspiro[2.4]heptane (Compound of Formula 3) reacts with (S)-tert-butanesulfinamide (Compound of Formula 4) under the action of a dehydrating agent through a condensation reaction to obtain a Compound of Formula 5;

[0026] (2) The imine of the Compound of Formula 5 is reduced in the presence of a reducing agent to obtain an optically pure Compound of Formula 6;

[0027] (3) The amide of the Compound of Formula 6 is reduced by reacting with a reducing agent in a dry organic solvent to obtain a Compound of Formula 7;

[0028] (4) The tert-butanesulfinyl group of the Compound of Formula 7 is removed under acidic conditions to obtain a Compound of Formula 8;

[0029] (5) The Compound of Formula 8 is freed by a base and then reacts in situ with di-tert-butyl dicarbonate to protect the amino group to obtain a Compound of Formula 2.

[0030] Furthermore, the reaction temperature of step (1) is 40 - 120 °C, preferably 60 - 80 °C; the reaction medium is selected from organic solvents including at least one of toluene, tetrahydrofuran, 1,4-dioxane, dichloromethane, and chloroform; the molar ratio of the Compound of Formula 3 to (S)-tert-butanesulfinamide and the dehydrating agent is 1:1.0 - 2.0:1.2 - 2.5, preferably 1:1.2 - 1.5:1.6 - 2.0; the dehydrating agent is selected from one or more of titanates, copper sulfate, magnesium sulfate, and molecular sieves.

[0031] Furthermore, the dehydrating agent is preferably a titanate, and the titanate is selected from at least one of tetraethyl titanate, tetraisopropyl titanate, and tetrabutyl titanate.

[0032] Furthermore, in step (2), the reducing agent is selected from one of lithium borohydride, lithium tri-sec-butylborohydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and potassium borohydride; the molar ratio of the Compound of Formula 5 to the reducing agent is 1:1.0 - 2.2, preferably 1:1.1 - 1.5; the reaction solvent is selected from at least one of methanol, ethanol, isopropanol, tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, and dichloromethane; the controlled temperature during feeding is -20 - 20 °C, preferably -10 - 5 °C; the reaction temperature is 10 - 50 °C, preferably 20 - 30 °C.

[0033] Preferably, in step (2), the reducing agent is lithium tri-sec-butylborohydride, and the solvent is a mixture of tetrahydrofuran, toluene, and dichloromethane in a volume ratio of 5-10:1-2:1-2. The inventors unexpectedly found that by selecting the above specific reducing agent and mixed solvent system, the yield and stereoselectivity of product 6 can be improved simultaneously. The possible reason is that the unique cavity environment of lithium tri-sec-butylborohydride enables it to further act on the chiral substrate. In addition, the use of the mixed solvent changes the polarity and coordination effect of the original single solvent, which can further improve the reaction conversion rate and stereoselectivity, and also make the product easier to precipitate.

[0034] Furthermore, in step (3), the reducing agent is selected from red aluminum, borane, lithium aluminum hydride, and a Lewis acid, a complex of sodium borohydride and a Lewis acid, preferably a complex of lithium aluminum hydride and a Lewis acid; the reaction medium is selected from at least one of toluene, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, and dioxane; the reaction temperature is 30-80 °C, preferably 40-70 °C.

[0035] Furthermore, in step (3), the molar ratio of the compound of formula 6 to the reducing agent is 1:1.0-4.5, preferably 1:1.5-3.5.

[0036] Furthermore, in step (4), the acid is selected from inorganic acids or organic acids, such as any one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; the reaction solvent is selected from one or more of n-heptane, cyclohexane, toluene, dichloromethane, methanol, ethanol, isopropanol, tert-butyl methyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, and water.

[0037] Furthermore, in step (4), the molar ratio of the compound of formula 7 to the acid is 1:1.0-10.0, preferably 1:3.0-7.0; the reaction temperature is 0-60 °C, preferably 20-30 °C.

[0038] Furthermore, in step (5), the base is an inorganic base or an organic base; preferably, the inorganic base is selected from hydroxides, carbonates, bicarbonates, phosphates of alkali metals or alkaline earth metals, or any combination thereof, such as at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and potassium bicarbonate; the organic base is selected from at least one of alcoholates and organic amines; the alcoholates are selected from at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; the organic amines are selected from at least one of triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, 4-dimethylaminopyridine, tetramethylethylenediamine, 1,8-diazabicyclo

[0039] [5.4.0] At least one of undec-7-ene. The amount of the base is such that the pH of the system is 9 - 10; the molar ratio of the compound of formula 8 to di-tert-butyl dicarbonate is 1:1.1 - 1.5.

[0040] In the present invention, the inert gas is selected from nitrogen or argon, and nitrogen is preferably used; the drying refers to obtaining anhydrous solvent or solvent with water content that does not affect the reaction by means such as removing water with molecular sieve or rectification.

[0041] Compared with the prior art, the beneficial technical effects achieved by the present invention are as follows:

[0042] First, the method of the present invention uses an easily obtainable chiral amine as a chiral auxiliary reagent for the asymmetric synthesis strategy to prepare 5-benzyl-7(S)-tert-butylcarbonylamino-5-azaspiro[2.4]heptane. Compared with the traditional chemical resolution method, the production efficiency is improved. At the same time, process units such as optical isomer resolution and racemization are reduced, the production cost is lowered, the discharge amount of three wastes is reduced, and the production process is green and environmentally friendly.

[0043] Second, the method of the present invention does not use reagents with great safety risks such as azides. The reaction conditions are mild and the production process is easy to control.

[0044] Third, when the present invention prepares compound 6 from compound 5, lithium tri-sec-butylborohydride is used as a reducing agent, and a compound solvent of tetrahydrofuran, toluene, and dichloromethane can improve the yield and stereoselectivity of product 6 at the same time. Further strengthen the industrial advantages of the preparation process of the present invention.

[0045] Fourth, the preparation method provided by the present invention has short steps, good stereoselectivity, and high reaction yield. The intermediate obtained during the reaction is easy to separate and purify, and the chiral purity and chemical purity of the obtained product are high, having practical industrial application prospects. Description of the Drawings

[0046] Figure 1 It is the nuclear magnetic resonance hydrogen spectrum of the product compound 2 in Example 5. Detailed Embodiments

[0047] The present invention will be further described below in conjunction with specific embodiments, but is not limited to the specific embodiments.

[0048] In the following embodiments, the experimental methods are all conventional methods unless otherwise specified; the reagents and materials can all be obtained from commercial channels unless otherwise specified.

[0049] Example 1: Preparation of Compound 5

[0050]

[0051] Under nitrogen protection, in a 250 mL reaction flask, the compound of formula 3 (10.0 g, 46.5 mmol) was added to dry tetrahydrofuran (100 mL), and the mixture was stirred until clear. Subsequently, S-tert-butylsulfinamide (8.4 g, 69.7 mmol) and tetraethyl titanate (21.2 g, 92.9 mmol) were added successively. The temperature was raised to 60 - 65 °C, and the mixture was stirred and reacted for 18 hours. TLC detection showed that the raw materials had completely reacted. The reaction system was cooled to room temperature, 100 mL of water was added, and a large amount of solid precipitated. The mixture was extracted with 100 mL × 3 of methyl tert-butyl ether. The combined organic phases were washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 14.3 g of a red oil, which was the compound of formula 5, with a yield of 95.3%. 1 HNMR(600MHz,CDCl 3 )δppm 7.33–7.24(m,5H),4.67(d,J=14.6Hz,1H),4.65(d,J=18.7Hz,1H),4.46(d,J=14.6Hz,1H),4.30(d,J=18.7Hz,1H),1.74–1.71(m,2H),1.54-1.51(m,1H),1.40-1.37(m,1H),1.17(s,9H).ESI-HRMS(m / z):319.1511

[0052] [M+H] + 。

[0053] Example 2-1: Preparation of Compound 6

[0054]

[0055] Under nitrogen protection, in a 100 mL reaction flask, the compound of formula 5 (5.0 g, 15.7 mmol) was added to a mixture of tetrahydrofuran, toluene, and dichloromethane in a volume ratio of 6:2:2 (50 mL), and the mixture was stirred until clear. The temperature was cooled to 0 - 5 °C in an ice bath, and lithium tri-sec-butylborohydride (3.6 g, 18.8 mmol) was added in portions while maintaining the temperature below 5 °C. After addition, the mixture was stirred and reacted for 1 hour while maintaining the temperature. TLC detection showed that no raw materials remained. 50 mL of water was added to the reaction system, and the mixture was extracted with 30 mL × 3 of ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 4.8 g of a pale yellow oil, which was the compound of formula 6, with a yield of 95.4%. The d.e. value was 99.1%. 1 HNMR(600MHz,CDCl 3 )δppm 7.29–

[0056] 7.19(m,5H),4.53(d,J=14.8Hz,1H),4.35(d,J=14.8Hz,1H),3.75–

[0057] 3.71 (m, 1H), 3.55 (dd, J = 10.5, 6.4 Hz, 1H), 3.39 (d, J = 5.1 Hz, 1H), 3.19 (dd, J = 10.5, 2.7 Hz, 1H), 1.18 - 1.17 (m, 2H), 1.09 (s, 9H), 1.02 - 1.00 (m, 2H). ESI-HRMS (m / z): 343.1476 [M+Na] + 。

[0058] Example 2-2

[0059] Other conditions were the same as in Example 2-1, except that the reducing agent was changed from lithium tri-sec-butylborohydride to an equimolar amount of sodium borohydride. The yield of Compound 6 was 92.7%. The d.e. value was 97.4%.

[0060] Example 2-3

[0061] Other conditions were the same as in Example 2-1, except that the reducing agent was changed from lithium tri-sec-butylborohydride to an equimolar amount of sodium triacetoxyborohydride. The yield of Compound 6 was 93.5%. The d.e. value was 96.6%.

[0062] Example 2-4

[0063] Other conditions were the same as in Example 2-1, except that the solvent was a 3:1 volume ratio mixture of tetrahydrofuran and toluene. The yield of Compound 6 was 94.4%. The d.e. value was 97.2%.

[0064] Example 2-5

[0065] Other conditions were the same as in Example 2-1, except that the solvent was a 3:1 volume ratio mixture of tetrahydrofuran and dichloromethane. The yield of Compound 6 was 94.7%. The d.e. value was 96.0%.

[0066] Example 2-6

[0067] Other conditions were the same as in Example 2-1, except that the solvent was a 1:1 volume ratio mixture of toluene and dichloromethane. The yield of Compound 6 was 92.8%. The d.e. value was 95.6%.

[0068] Example 3: Preparation of Compound 7

[0069]

[0070] Under nitrogen protection, 2.0 g (6.2 mmol) of the compound of formula 6 (prepared in Example 2-1) was added to dry toluene (20 mL) in a 100 mL reaction flask. The temperature was lowered to 0-10 °C in an ice bath, and a 70% toluene solution of red aluminum (4.5 g, 15.6 mmol) was added dropwise. The system exothermed and released gas violently. After the addition was completed, the temperature was raised to 40 °C, and the reaction was stirred for another 2 hours. TLC detection showed that the raw materials disappeared. The system was cooled to 0-5 °C, and a 20% aqueous sodium hydroxide solution (10 mL) was added dropwise to quench the reaction. The mixture was allowed to stand and separated. The aqueous phase was extracted once with toluene (20 mL). The organic phases were combined and washed successively with water and saturated brine. Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 1.8 g of a off-white solid crude product with a yield of 93.5%. 1 HNMR(600MHz,CDCl 3 )δppm 7.27–7.18(m,5H),3.57(dd,J=19.8,12.8Hz,2H),3.51-3.48(m,1H),3.45(br,1H),2.96(dd,J=9.7,5.9Hz,1H),2.66(d,J=9.0Hz,1H),2.60(dd,J=9.6,3.9Hz,1H),2.38(d,J=9.0Hz,1H),1.13(s,9H),0.93-0.89(m,1H),0.77-0.74(m,1H),0.62-0.59(m,1H),0.48-0.44(m,1H).ESI-HRMS(m / z):307.1876[M+H] + 。

[0071] Example 4: Preparation of Compound 8

[0072]

[0073] At room temperature, 10.0 g (32.6 mmol) of the compound of formula 7 was added to ethyl acetate (100 mL) in a 100 mL reaction flask and stirred until dissolved. A solution of hydrogen chloride in ethyl acetate (50 mL, containing 142.7 mmol HCl) was added dropwise. After the addition was completed, a solid began to precipitate. The mixture was stirred at a constant temperature for 2 hours. TLC detection showed no remaining raw materials. The reaction system was cooled to 0-5 °C and stirred for another 2 h. Filtered, and the filter cake was dried at 50-55 °C to obtain 7.9 g of a white solid with a yield of 88.3%. 1 HNMR(600MHz,CDCl 3)δ ppm 7.28–7.19 (m, 5H), 3.56 (dd, J = 26.9, 12.7 Hz, 2H), 3.02–2.99 (m, 2H), 2.61 (d, J = 8.9 Hz, 1H), 2.43–2.40 (m, 2H), 1.72 (br, 2H), 0.70–0.67 (m, 1H), 0.56 - 0.52 (m, 2H), 0.36–0.33 (m, 1H).

[0074] Example 5: Preparation of Compound 2

[0075]

[0076] In a 250 mL three-necked flask, dissolve the compound of formula 8 (7.0 g, 25.4 mmol) in a mixed solvent of methanol (70 mL) and water (30 mL). Dropwise add di-tert-butyl dicarbonate (5.8 g, 26.7 mmol) and 30% sodium hydroxide solution at room temperature, control the pH of the system to 9 - 10, and stir the reaction for 3 hours after dropping. Recover methanol under reduced pressure, cool to room temperature, filter to obtain a white solid-like compound of formula 2. After slurrying with n-heptane and drying, 7.1 g of white solid is obtained, with a yield of 93.4% and a purity of 99.1%. 1 HNMR(600MHz,CDCl 3 )δ ppm 1 H NMR(600MHz,CDCl 3 )δ 7.29–7.18 (m, 5H), 4.90 (d, J = 9.3 Hz, 1H), 3.78–3.76 (m, 1H), 3.55 (dd, J = 26.9, 13.0 Hz, 2H), 2.85 (dd, J = 9.6, 5.9 Hz, 1H), 2.62 (dd, J = 10.0, 4.5 Hz, 2H), 2.28 (d, J = 9.0 Hz, 1H), 1.37 (s, 9H), 0.76 - 0.73 (m, 1H), 0.68 - 0.64 (m, 1H), 0.55 - 0.52 (m, 1H), 0.41–0.37 (m, 1H). LC-MS(EI)(m / z): 303.27[M + H] + . Figure 1 It is the 1H NMR spectrum of the product Compound 2 in Example 5.

Claims

1. A method for preparing a sitafloxacin intermediate 5-benzyl-7(S)-tert-butylcarbonylamino-5-azaspiro[2,4]heptane, characterized in that: Its synthetic route is as follows: Wherein, x is 1 or 2; HA is an organic acid or an inorganic acid.

2. The preparation method according to claim 1, characterized in that: The following steps are involved: (1) Under the protection of an inert gas, 5-benzyl-4,7-dioxo-5-azaspiro[2,4]heptane (compound of formula 3) is subjected to a condensation reaction with (S)-tert-butylsulfenamide (compound of formula 4) in the presence of a dehydrating agent to obtain a compound of formula 5; (2) reducing the imine with the compound of formula 5 in the presence of a reducing agent to obtain an optically pure compound of formula 6; (3) reducing the amide of the compound of formula 6 with a reducing agent in a dry organic solvent to obtain a compound of formula 7; (4) removing the tert-butylsulfinyl group from the compound of formula 7 under acidic conditions to obtain a compound of formula 8; (5) The compound of formula 8 is freed by alkali and then reacted with di-tert-butyl dicarbonate in situ to protect the amino group to obtain the compound of formula 2.

3. The preparation method according to claim 2, characterized in that: The reaction temperature of step (1) is 40-120° C., preferably 60-80° C.; the reaction medium is selected from at least one of the organic solvents selected from toluene, tetrahydrofuran, 1,4-dioxane, dichloromethane, and chloroform; the molar ratio of the compound of formula 3 to (S)-tert-butylsulfenamide and the dehydrating agent is 1:1.0-2.0:1.2-2.5, preferably 1:1.2-1.5:1.6-2.0; the dehydrating agent is selected from one or more of titanate, copper sulfate, magnesium sulfate, and molecular sieve; The dehydrating agent is preferably a titanate, and the titanate is selected from at least one of tetraethyl titanate, tetraisopropyl titanate, and tetrabutyl titanate.

4. The preparation method according to claim 2, characterized in that: In step (2), the reducing agent is selected from one of lithium borohydride, lithium tri-sec-butyl borohydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and potassium borohydride; the molar ratio of the compound of formula 5 to the reducing agent is 1:1.0-2.2, preferably 1:1.1-1.5; the reaction solvent is selected from at least one of methanol, ethanol, isopropanol, tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, and dichloromethane; the control temperature during the addition is -20-20°C, preferably -10-5°C; the reaction temperature is 10-50°C, preferably 20-30°C.

5. The preparation method according to claim 2, characterized in that: In step (2), the reducing agent is lithium tri-sec-butylborohydride, and the solvent is tetrahydrofuran, toluene, and dichloromethane in a volume ratio of 5-10:1-2:1-2.

6. The preparation method according to claim 2, characterized in that: In step (3), the reducing agent is selected from red aluminum, borane, lithium aluminum hydride and Lewis acid, sodium borohydride and Lewis acid complex, wherein lithium aluminum hydride and Lewis acid complex is preferred; the reaction medium is selected from at least one of toluene, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, and dioxane; the reaction temperature is 30-80°C, preferably 40-70°C.

7. The preparation method according to claim 2, characterized in that: In step (3), the molar ratio of the compound of formula 6 to the reducing agent is 1:1.0 to 4.5, preferably 1:1.5 to 3.

5.

8. The preparation method according to claim 2, characterized in that: In step (4), the acid is selected from an inorganic acid or an organic acid, for example, any one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; the reaction solvent is selected from one or more of n-heptane, cyclohexane, toluene, dichloromethane, methanol, ethanol, isopropanol, tert-butyl methyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, ethyl acetate, isopropyl acetate, and water.

9. The preparation method according to claim 2, characterized in that: In step (4), the molar ratio of the compound of formula 7 to the acid is 1:1.0-10.0, preferably 1:3.0-7.0; the reaction temperature is 0-60°C, preferably 20-30°C.

10. The preparation method according to claim 2, characterized in that: In step (5), the base is an inorganic base or an organic base; preferably, the inorganic base is selected from the hydroxide, carbonate, bicarbonate, phosphate or any combination thereof of an alkali metal or alkaline earth metal, such as at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; the organic base is selected from at least one of alkoxide and organic amine; the alkoxide is selected from at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; the organic amine is selected from at least one of triethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, 4-dimethylaminopyridine, tetramethylethylenediamine and 1,8-diazabicyclo[5.4.0]undec-7-ene. The amount of the base is such that the system pH is 9-10; the molar ratio of the compound of formula 8 to di-tert-butyl dicarbonate is 1:1.1-1.5.

Images