A process for the preparation of 4-acetyloxy-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-2-azetidinone

Abstract

The application belongs to the technical field of organic synthesis and medicine intermediate preparation, and relates to a preparation method of 4-acetyloxy-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-2-azetidinone. The method takes (S)-methyl lactate as a starting material, and 4-AA is prepared through six steps of hydroxyl silicon group protection, selective reduction, imine condensation, palladium catalysis carbonylation ring formation, acetylation and N-PMB deprotection. In the ring formation stage, the 4-hydroxy beta-lactam intermediate is obtained, and the 4-position oxygen functional group is avoided to be introduced by using a strong oxidation method in the later stage. According to the (S)-methyl lactate, the total yield of 4-AA obtained in the embodiment 1 is 64.66%, and the HPLC purity is 99.36%.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and pharmaceutical intermediate preparation technology, specifically relating to a method for preparing 4-acetoxy-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-2-azacyclobutanone. Background Technology

[0002] 4-Acetoxy-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-2-azacyclobutanone, CAS No. 76855-69-1, often simply referred to as 4-AA or 4-acetoxyazacyclobutanone derivatives, is a key chiral intermediate commonly used in the synthesis of β-lactam drugs such as penicillin and carbapenem. This type of intermediate simultaneously contains a β-lactam four-membered ring, a chiral silyl ether side chain at the 3-position, and an acetoxy leaving group at the 4-position. Its stereopurity, the introduction of the 4-position functional group, and the removal of the N-protecting group directly affect subsequent side chain coupling, impurity profile control, and the safety of industrial scale-up.

[0003] The publicly disclosed techniques for synthesizing 4-AA intermediates mainly include the following categories:

[0004] The first type involves a cyclization followed by oxidation / acetylation. For example, in a method for synthesizing 4-acetoxy-2-azacyclobutanone disclosed in CN102002066A, N-PMP imine and a chiral thioester are cyclized at low temperature in TiCl4 / Et3N / chloroform to obtain a (3S,4S)-azacyclobutanone intermediate. This intermediate is then oxidized with peracetic acid / phase transfer catalyst to obtain a 4-acetoxy intermediate, and finally, PMP protection is removed by ozone to yield 4-AA. However, this route uses highly corrosive TiCl4, hydrothermal and highly hazardous peracetic acid, and ozone, which requires sophisticated equipment, thus limiting process safety and scale-up applicability.

[0005]

[0006] The second type is the Kinugasa-type nitrone / alkyne cyclization route. Grzeszczyk et al. (J. Antibiot. 2013, 66(3), 161–163) reported a practical method for constructing β-lactam rings with nitrones and alkynes under copper salt mediation to prepare key intermediates of penicillene and carbapenem. However, the stability and storage conditions of the nitrone substrate in this route need to be strictly controlled; the amount of copper salt and the post-treatment method will increase the burden of copper-containing wastewater treatment; in order to control the configuration of the chiral center, specific chiral nitrones or chiral alkynes are usually required, which limits the applicability of raw materials and cost control; in addition, the system is sensitive to moisture, and the requirements for anhydrous operation and process control are high during scale-up.

[0007]

[0008] The third category is the ring-expansion route via carbonylation of aziridines. For example, Chamchaang and Pinhas (J. Org. Chem. 1990, 55(9), 2943–2950) reported a method for converting aziridines to β-lactams. This type of route provides another approach for the construction of β-lactams, but the preparation steps of the precursor aziridine are usually lengthy, and the reaction depends on highly reactive small-ring substrates and carbonylation conditions. It does not directly solve the problem of the controllable removal of the 3-position (1R)-silyl ether side chain, the 4-position acetoxy group, and the N protecting group required for 4-AA.

[0009]

[0010] The fourth category comprises post-oxidation routes centered around the 4-position functional group, encompassing variants such as Baeyer-Villiger oxidation, peroxide oxidation, and electrochemical oxidation. Their common characteristic is the initial acquisition of a β-lactam intermediate with acyl or alkyl substitution at the 4-position, followed by the introduction of a 4-acetoxy group through oxidative rearrangement, oxidative substitution, or acetylation. While this type of method is frequently reported in the literature and patents, its main focus is on the selection of oxidants, phase-transfer catalysts, solvents, or post-treatment conditions, with no substantial breakthroughs in the core cyclization strategy and the simultaneous construction of the 4-position oxygen functional group.

[0011] Furthermore, although Nature Catalysis 2024, 7, 132-138 (Tobisu et al.) first demonstrated that acylsilanes can undergo carbonylation cycloaddition with imines as Fischer carbene equivalents under palladium catalysis to construct β-lactam skeletons, this literature falls within the scope of general methodologies. Its entire substrate range is limited to combinations of aromatic acylsilanes (Ar-CO-SiMe3) and simple aryl imines, and it does not involve specific combination schemes using formyltrimethylsilane as the acylsilane component and (1R)-silyl ether chiral imines derived from lactate as the electrophilic component.

[0012]

[0013] In summary, while existing technologies can obtain β-lactam intermediates through methods such as cyclization followed by oxidation, Kinugasa cyclization, carbonylation of aziridines, or subsequent oxidation modification, they still suffer from drawbacks including outdated key cyclization logic, reliance on strong subsequent oxidation for the 4-acetoxy group, frequent use of hazardous or highly corrosive reagents, and heavy burdens on process scale-up. Therefore, a novel preparation method is needed that can form a suitable 4-hydroxyl β-lactam for subsequent acetylation during the critical cyclization stage, and that matches the sequence of removal of the target 3-chiral silane ether side chain and N-protecting group. Summary of the Invention

[0014] The purpose of this invention is to provide a method for preparing 4-acetoxy-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-2-azacyclobutanone, which differs from the existing Kinugasa route, Staudinger route, and azacyclopropane carbonylation route. This method involves a palladium-catalyzed carbonylation cyclization reaction of a Schiff base intermediate (compound VI) with a purified acylsilane (compound VII), forming a 4-hydroxyl group while simultaneously forming a β-lactam skeleton. Subsequently, the target compound I is obtained by non-column chromatography purification, acetylation, crystallization purification, and deprotection.

[0015] The technical solution adopted by this invention to solve its technical problem is: a method for preparing 4-acetoxy-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-2-azacyclobutanone, comprising the following steps:

[0016] S1. Starting with (S)-methyl lactate (compound II), the hydroxyl groups of compound II were protected with a tert-butyldimethylsilyl group using a hydroxyl protecting agent in the presence of a base to obtain (S)-2-(tert-butyldimethylsiloxy)propionate methyl ester (compound III).

[0017] S2. Selectively reduce compound III obtained in step S1 to obtain (1R)-1-(tert-butyldimethylsiloxy)acetaldehyde (compound IV), and use compound IV directly in the next condensation reaction without separation and purification.

[0018] S3. Compound IV obtained in step S2 undergoes a condensation reaction with p-methoxybenzylamine (compound V) to obtain a Schiff base intermediate, namely a chiral imine intermediate (compound VI).

[0019] S4. Compound VI obtained in step S3 and compound VII acylsilane undergo a cyclization reaction in a palladium catalyst, phosphine ligand, and carbon monoxide atmosphere to obtain an N-PMB protected 4-hydroxyβ-lactam intermediate (compound VIII).

[0020] S5. After removing palladium and decolorizing the obtained compound VIII in step S4, it is acetylated to obtain a β-lactam intermediate protected by 4-acetoxy-N-PMB (compound IX).

[0021] S6. The compound IX obtained in step S5 was deprotected by the 4-methoxybenzyl protecting group and purified by crystallization in an ethyl acetate / n-heptane system to obtain 4-acetoxy-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-2-azacyclobutanone (compound I).

[0022] Further, in step S1, the hydroxyl protecting agent is tert-butyldimethylchlorosilane, and the base is imidazole; the molar ratio of (S)-methyl lactate, the hydroxyl protecting agent, and the base is 1.0:(1.05-1.20):(1.5-2.5).

[0023] Step S1 is as follows:

[0024] (S)-methyl lactate (compound II), anhydrous DMF, and imidazole were added to a dry reaction flask and cooled to 0°C in an ice bath. Tert-butyldimethylchlorosilane was added in portions under nitrogen protection, and the mixture was allowed to rise to room temperature for 4 hours after the addition was complete. After the reaction was monitored by TLC until complete, water was added to quench the reaction, and the mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate, and the combined organic phases were washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and distilled under reduced pressure to obtain methyl (S)-2-(tert-butyldimethylsiloxy)propionate (compound III).

[0025] Furthermore, in step S2, the reagent used for selective reduction is DIBAL-H (diisobutylaluminum hydride), the molar ratio of DIBAL-H to compound III is 1.27:1, and the reaction temperature is -78℃ to -65℃; after the reaction is completed, it is quenched with methanol and the aluminum salt is treated with an aqueous solution of potassium sodium tartrate.

[0026] Step S2 is as follows:

[0027] Compound III obtained in step S1 was dissolved in anhydrous dichloromethane and cooled to -70°C. A 1.0 mol / L DIBAL-H toluene solution was slowly added dropwise, maintaining the internal temperature between -78°C and -65°C. After the addition was complete, stirring was continued for 1.5 h. After the reaction was complete, methanol was slowly added dropwise at -70°C to -60°C to quench the reaction. After the addition was complete, the temperature was raised to 0°C, and a 20% potassium sodium tartrate aqueous solution was added. The mixture was stirred for 30 min and allowed to stand before separation. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature to obtain the chiral aldehyde intermediate (compound IV). Because this intermediate has moderate stability, it was used directly in the next reaction without further purification.

[0028] Further, in step S3, the molar ratio of compound IV to p-methoxybenzylamine (compound V) is 1:1.0; the condensation reaction is carried out in the presence of 4A molecular sieve; after the reaction is completed, the molecular sieve is removed by filtration, and the mixture is concentrated under reduced pressure at 0-10°C; toluene is then added for replacement, and the mixture is concentrated under reduced pressure until no low-boiling substances are distilled off, to obtain a toluene solution of compound VI.

[0029] Step S3 is as follows:

[0030] The chiral aldehyde intermediate (compound IV) obtained in step S2 was dissolved in anhydrous dichloromethane, and p-methoxybenzylamine (compound V) and 4A molecular sieve were added. The mixture was stirred at room temperature for 6 hours. After the reaction was completed as monitored by HPLC or TLC, the molecular sieve was removed by filtration, and the filter cake was washed with dichloromethane. The filtrates were combined. The filtrate was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 0–10 °C. Toluene was then added to replace the filtrate, and the mixture was concentrated under reduced pressure until no low-boiling substances distilled off, yielding a toluene solution of compound VI.

[0031] Furthermore, in step S4, compound VII is formyltrimethylsilane; the formyltrimethylsilane is prepared separately without purification, and is immediately used in the cyclization reaction after passing the moisture and content tests.

[0032] Further, in step S4, the palladium catalyst is Pd(OAc)2, the phosphine ligand is tri-o-tolylphosphine (P(o-tol)3), the molar ratio of compound VI, compound VII, and palladium catalyst is 1.0:(1.05-1.20):(0.02-0.10), and the molar ratio of palladium catalyst to phosphine ligand is 1:2.

[0033] Furthermore, in step S4, the reaction solvent for the cyclization reaction is toluene, the reaction temperature is 55℃-65℃, and the reaction time is 8-16h; after the reaction is completed, the mixture is filtered through diatomaceous earth and decolorized with activated carbon.

[0034] Step S4 is as follows:

[0035] Pd(OAc)₂, tri-o-tolylphosphine, and toluene were added to a dry, pressure-resistant reactor. The mixture was replaced three times with carbon monoxide while maintaining a carbon monoxide atmosphere, and pre-stirred at room temperature for 20 min to form a catalytic system. Separately, a toluene solution of compound VI obtained in step S3 was mixed with a toluene solution of compound VII (formyltrimethylsilane) VII (which passed testing), and added to the aforementioned catalytic system. The mixture was heated to 60°C and reacted for 12 h under a carbon monoxide atmosphere. After the reaction, the mixture was cooled to room temperature, filtered through diatomaceous earth to remove palladium black and insoluble matter, and the filter cake was washed with toluene. The filtrates were combined, activated carbon was added, and the mixture was stirred at room temperature for 30 min before filtration. The filtrate was concentrated under reduced pressure, and ethyl acetate was added and stirred at 40-45°C until dissolved. While maintaining 40-45°C, n-heptane was slowly added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 30 min, then cooled to 0-5°C and stirred for 2 h. The filter cake was filtered, washed with a pre-cooled ethyl acetate / n-heptane = 1 / 3 (v / v) mixed solvent, and dried under reduced pressure below 40°C to obtain an N-PMB protected 4-hydroxyβ-lactam intermediate (compound VIII).

[0036] Further, in step S5, the acetylation reagent used is acetic anhydride, and the acetylation reaction is carried out in the presence of triethylamine and 4-dimethylaminopyridine (DMAP); the molar ratio of compound VIII, acetic anhydride, triethylamine and 4-dimethylaminopyridine is 1:1.2-1.6:1.2-1.6:0.06; compound IX is purified by crystallization in an ethyl acetate / n-heptane system and then used in step S6.

[0037] Step S5 is as follows:

[0038] Compound VIII obtained in step S4 was dissolved in anhydrous dichloromethane and cooled to 0°C. Triethylamine and DMAP were added, and acetic anhydride was slowly added dropwise, controlling the internal temperature to not exceed 10°C. After the addition was complete, the mixture was brought to room temperature and the reaction continued for 3 hours. After the reaction was completed by HPLC monitoring, water was added to the reaction solution, and the mixture was stirred for 10 minutes and allowed to stand before separation. The organic phase was washed successively with 1 mol / L hydrochloric acid, 5% sodium bicarbonate aqueous solution, and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate was added to the concentrated residue, and the mixture was heated to 45-50°C and stirred until dissolved. While maintaining the temperature at 45-50°C, n-heptane was slowly added dropwise. After the addition was complete, the mixture was kept at this temperature and stirred for 30 minutes. Then, the temperature was lowered to 0-5°C at a rate of 5-10°C / h and kept at this temperature and stirred for 2 hours. The mixture was filtered, and the filter cake was washed with a pre-cooled ethyl acetate / n-heptane = 1 / 3 (v / v) mixed solvent and dried under reduced pressure below 40°C to obtain the 4-acetoxy N-PMB protected product (compound IX).

[0039] Further, in step S6, the deprotecting agent used to remove the 4-methoxybenzyl protecting group from compound IX is DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone), and the molar ratio of compound IX to DDQ is 1:1.0-1.5; the reaction solvent is a dichloromethane / water mixed solvent, the volume ratio of dichloromethane to water is 10:1, and the reaction temperature is 5℃-15℃; after the reaction is completed, it is quenched with sodium bisulfite aqueous solution, and then decolorized by activated carbon and purified by crystallization in an ethyl acetate / n-heptane system.

[0040] Step S6 is as follows:

[0041] Compound IX obtained in step S5 was dissolved in dichloromethane, water was added, and the mixture was cooled to 5°C. DDQ was added in portions, maintaining an internal temperature of 5-15°C. After the addition was complete, the reaction was continued at 5-15°C for 2 hours. After the reaction was completed by HPLC monitoring, a saturated sodium bisulfite aqueous solution was added to the reaction mixture, and the mixture was stirred at 5-15°C for 30 minutes to quench the reaction. The mixture was then allowed to stand and separated. The aqueous layer was extracted with dichloromethane, and the combined organic phases were washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Activated carbon was added to the organic phase, and the mixture was stirred at room temperature for 30 minutes before filtration. The filtrate was concentrated under reduced pressure. Ethyl acetate was added to the concentrated residue and stirred at 35-40°C to dissolve it. While maintaining the temperature at 35-40°C, n-heptane was slowly added dropwise. After the addition was complete, the mixture was stirred at this temperature for 30 minutes, then cooled to 0-5°C and stirred at this temperature for 2 hours. The filter cake was filtered and washed with a pre-cooled ethyl acetate / n-heptane = 1 / 4 (v / v) mixed solvent and dried under reduced pressure below 40°C to obtain the target compound 4-acetoxy-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-2-azacyclobutanone (compound I, 4-AA).

[0042] The reaction formula of this invention is as follows:

[0043] .

[0044] The key cyclization step of this invention can be understood as a palladium-catalyzed carbonylation cyclization process, which mainly includes three stages: palladium-catalyzed activation of acylsilane compound VII, silicon migration, CO coordination and insertion, and cyclization of the obtained active intermediate with compound VI and release of palladium catalyst.

[0045] First, the chiral aldehyde compound IV obtained in step S2 undergoes dehydration condensation with p-methoxybenzylamine (compound V) to generate a Schiff base intermediate, namely the chiral imine intermediate (compound VI). The C=N bond in compound VI is the reactive site for the subsequent cyclization reaction, and the (1R)-1-(tert-butyldimethylsiloxy)ethyl side chain in the molecule provides a chiral environment for the cyclization process.

[0046] Second, in the presence of a palladium catalyst and a phosphine ligand, the palladium catalyst is first converted in situ to a zero-valent palladium active species in the reaction system. The zero-valent palladium further undergoes oxidative addition with the acyl carbon-silicon bond in acylsilane compound VII, generating intermediate VII-A, which contains both acyl palladium and silicon-palladium bonds. Due to the strong affinity of silicon atoms for oxygen atoms and the thermodynamically favorable formation of stable Si-O bonds, the silicon group in intermediate VII-A migrates to the acyl oxygen, undergoing [1,3]-silicon migration, transforming into a silicon-oxygen substituted palladium carbene intermediate VII-B. Subsequently, under a carbon monoxide atmosphere, carbon monoxide coordinates with the palladium center in intermediate VII-B to form intermediate VII-C, and further undergoes CO insertion to form the palladium-enone type active intermediate VII-D.

[0047] Third, intermediate VII-D undergoes a [2+2] cycloaddition reaction with the C=N bond in compound VI to form new CC and CN bonds, which then close into a four-membered β-lactam ring, yielding an N-PMB-protected 4-hydroxyβ-lactam intermediate (compound VIII). Simultaneously, the palladium catalyst dissociates and releases from the organic intermediate, regenerating palladium active species that can participate in the next round of reaction, thus completing the catalytic cycle of "oxidative addition – [1,3]-silicon migration – CO coordination – CO insertion – imine cyclization – palladium release".

[0048]

[0049] Compound VIII is then acetylated to a 4-acetoxy N-PMB protecting intermediate (compound IX), followed by removal of the N-PMB protecting group to obtain the target compound I. Compared to routes involving cyclization followed by oxidation, the difference in this invention lies in the direct formation of compound VIII, suitable for subsequent acetylation, via the aforementioned palladium-catalyzed cycle, rather than relying on a strong oxidative transformation in the later stage of a pre-cyclized β-lactam.

[0050] The present invention has the following beneficial effects:

[0051] 1. The formation of 4-hydroxyβ-lactam during the key cyclization stage changes the existing technology which mostly relies on oxidation or substitution after cyclization to introduce oxygen-containing functional groups at the 4-position.

[0052] 2. Chiral information is pre-established in the precursor to avoid complex three-dimensional control after the quaternary ring is formed.

[0053] 3. Compounds VI, VIII, IX, and target compound I were obtained from the same continuous route, and the route connection is clear.

[0054] 4. Except for the aldehyde intermediate IV, which has general stability, which uses short-path continuous injection, compounds VI, VIII, IX, and target compound I all have non-column chromatography purification or quality control nodes suitable for scale-up, and the routes are clearly connected.

[0055] 5. Unlike existing routes that involve cyclization followed by oxidation or the introduction of 4-acetoxy groups by strong oxidants, this invention directly constructs the 4-hydroxy β-lactam skeleton via a palladium-catalyzed acylsilane-imine carbonylation cycloaddition reaction. Based on methyl lactate, the overall yield of Example 1 was 64.66%, and the HPLC purity was 99.36%. Attached Figure Description

[0056] Figure 1 This is the HPLC spectrum of compound III prepared in step S1 of Example 1 of the present invention.

[0057] Figure 2This is the HPLC spectrum of compound VI prepared in step S3 of Example 1 of the present invention.

[0058] Figure 3 This is the HPLC spectrum of compound VIII prepared in step S4 of Example 1 of the present invention.

[0059] Figure 4 It is compound VIII prepared in step S4 of Example 1 of this invention. 1 H NMR spectrum.

[0060] Figure 5 It is compound VIII prepared in step S4 of Example 1 of this invention. 13 C10 NMR spectrum.

[0061] Figure 6 This is the HPLC spectrum of compound I prepared in step S6 of Example 1 of the present invention.

[0062] Figure 7 It is compound I prepared in step S6 of Example 1 of this invention. 1 H NMR spectrum.

[0063] Figure 8 It is compound I prepared in step S6 of Example 1 of this invention. 13 C10 NMR spectrum. Detailed Implementation

[0064] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention. However, the scope of protection of the present invention is not limited to these embodiments. All changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention.

[0065] Example 1

[0066] Step S1:

[0067]

[0068] In a dry reaction flask, 11.56 g (111.0 mmol) of (S)-methyl lactate (compound II), 80 mL of anhydrous DMF, and 15.11 g (222.0 mmol, 2.0 eq) of imidazole were added, and the mixture was cooled to 0°C in an ice bath. Under nitrogen protection, 18.40 g (122.1 mmol, 1.1 eq) of tert-butyldimethylchlorosilane was added in portions, and the mixture was allowed to rise to room temperature for 4 h after the addition was complete. After the reaction was monitored by TLC until complete, 10 g of water was added to quench the reaction, and the mixture was stirred for 10 min. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The mixture was washed successively with 50 g of water and 50 g of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and distilled under reduced pressure to obtain 22.78 g of (S)-2-(tert-butyldimethylsiloxy)propionate (compound III), with a yield of 94.0% and an HPLC purity of 99.84%. The HPLC chromatogram of compound III is shown below. Figure 1 As shown in the figure, the specific peaks and their related data are shown in the table below.

[0069] Step S2: Preparation of chiral aldehyde intermediate compound IV

[0070]

[0071] 22.78 g (104.34 mmol) of compound III obtained in step S1 was dissolved in 40 mL of anhydrous dichloromethane and cooled to -70 °C. 133 mL (133.0 mmol, 1.27 eq) of 1.0 mol / L DIBAL-H toluene solution was slowly added dropwise, maintaining an internal temperature of -73 °C to -69 °C. After the addition was complete, stirring was continued for 1.5 h. After the reaction was complete, 10 mL of methanol was slowly added dropwise at -73 °C to -69 °C to quench the reaction. After the addition was complete, the temperature was raised to 0 °C, and 100 g of 20% potassium sodium tartrate aqueous solution was added. The mixture was stirred for 30 min and allowed to stand for separation. The organic phase was washed with 50 g of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature to obtain the chiral aldehyde intermediate (compound IV). Because this intermediate has moderate stability, it was used directly in the next reaction without further purification.

[0072] Step S3: Preparation of chiral imine intermediate compound VI

[0073]

[0074] The chiral aldehyde intermediate (compound IV) obtained in step S2 was dissolved in 60 mL of anhydrous dichloromethane. 14.31 g (104.34 mmol, 1.0 eq) of p-methoxybenzylamine (compound V) and 15 g of 4A molecular sieve were added, and the mixture was stirred at room temperature for 6 h. After the reaction was monitored by HPLC or TLC, the molecular sieve was removed by filtration. The filter cake was washed with 20 mL of dichloromethane, and the filtrates were combined. The filtrate was washed successively with 50 g of water and 50 g of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at low temperature (0–10 °C). Then, 50 mL of toluene was added to replace the dichloromethane, and the mixture was concentrated under reduced pressure until no low-boiling substances distilled off, yielding a toluene solution of compound VI. After sampling and content determination, the yield was converted to 29.45 g of compound VI. The yield of steps 2 and 3 was 91.8%, and the HPLC purity was 95.4%. The HPLC chromatogram of compound VI is shown below. Figure 2 As shown in the figure, the specific peaks and their related data are presented in the table. This toluene solution, after passing the moisture test (≤1%), was used for the next step of the cyclization reaction.

[0075] Step S4:

[0076]

[0077] In a dry, pressure-resistant reactor, 1.075 g (4.79 mmol, 5 mol%) of Pd(OAc)2, 2.915 g (9.58 mmol, 10 mol%) of P(o-tol)3, and 80 mL of toluene were added. The mixture was replaced three times with carbon monoxide while maintaining a carbon monoxide atmosphere, and pre-stirred at room temperature for 20 min to form a catalytic system. Separately, a toluene solution of compound VI obtained in step S3 (equivalent to 29.45 g of compound VI, approximately 95.77 mmol) and a toluene solution of compound VII (formyltrimethylsilane) VII (10.77 g, 105.34 mmol, 1.1 eq) that passed the test were mixed and added to the aforementioned catalytic system. The mixture was heated to 60 °C and reacted for 12 h under a carbon monoxide atmosphere. After the reaction was complete, the mixture was cooled to room temperature, filtered through diatomaceous earth to remove palladium black and insoluble matter, and the filter cake was washed with 30 mL of toluene. The filtrates were combined, 1.5 g of activated carbon was added, and the mixture was stirred at room temperature for 30 min before filtration. The filtrate was concentrated under reduced pressure to approximately 45 g, and 60 mL of ethyl acetate was added. The mixture was stirred at 40-45 °C until dissolved. While maintaining the temperature at 40-45 °C, 180 mL of n-heptane was slowly added dropwise. After the addition was complete, the mixture was stirred at this temperature for 30 min, then cooled to 0-5 °C and stirred for 2 h. The mixture was filtered, and the filter cake was washed with 30 mL of a pre-cooled ethyl acetate / n-heptane = 1 / 3 (v / v) mixed solvent. The mixture was dried under reduced pressure below 40 °C to obtain 28.71 g of N-PMB-protected 4-hydroxyβ-lactam intermediate (compound VIII), with a yield of 82.0% and an HPLC purity of 98.42%. The HPLC chromatogram of compound VIII is shown below. Figure 3As shown in the figure, the specific peaks and their related data are shown in the table in the figure. Compound VIII 1 H NMR spectrum as shown Figure 4 As shown, 13 The C NMR spectrum is as follows Figure 5 As shown.

[0078] Step S5:

[0079]

[0080] 28.71 g (78.53 mmol) of compound VIII obtained in step S4 was dissolved in 80 mL of anhydrous dichloromethane and cooled to 0 °C. 11.13 g (109.94 mmol, 1.4 eq) of triethylamine and 0.575 g (4.71 mmol, 0.06 eq) of DMAP were added, followed by the slow addition of 11.22 g (109.94 mmol, 1.4 eq) of acetic anhydride, maintaining the internal temperature below 10 °C. After the addition was complete, the mixture was allowed to rise to room temperature and the reaction continued for 3 h. After the reaction was completed as monitored by HPLC, 50 g of water was added to the reaction mixture, and the mixture was stirred for 10 min and allowed to stand before separation. The organic phase was washed successively with 50 g of 1 mol / L hydrochloric acid, 50 g of 5% sodium bicarbonate aqueous solution, and 50 g of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to approximately 45 g. Add 45 mL of ethyl acetate to the concentrated residue, heat to 45-50 °C and stir until dissolved; maintain 45-50 °C and slowly add 135 mL of n-heptane dropwise. After the addition is complete, keep warm and stir for 30 min, then cool to 0-5 °C at 5-10 °C / h and keep warm and stir for 2 h. Filter, wash the filter cake with 30 mL of pre-cooled ethyl acetate / n-heptane = 1 / 3 (v / v) mixed solvent, and dry under reduced pressure below 40 °C to obtain 30.57 g of the 4-acetoxy N-PMB protected product (compound IX), yield 95.5%, HPLC purity 96.82%.

[0081] Step S6:

[0082]

[0083] The compound IX3 obtained in step S5, 0.57 g (75.00 mmol), was dissolved in 100 mL of dichloromethane. 10 mL of water was added, and the mixture was cooled to 5 °C. DDQ2, 0.43 g (90.0 mmol, 1.2 eq), was added in portions, maintaining an internal temperature of 5–15 °C. After the addition was complete, the reaction was continued at 5–15 °C for 2 h. After the reaction was completed as monitored by HPLC, 80 g of saturated sodium bisulfite aqueous solution was added to the reaction mixture. The mixture was stirred for 30 min at 5–15 °C to quench the reaction, and then allowed to stand for separation. The aqueous layer was extracted with dichloromethane (20 mL × 3). The organic phases were combined and washed successively with 50 g of water and 50 g of saturated brine, and dried over anhydrous sodium sulfate. 1.0 g of activated carbon was added to the organic phase, and the mixture was stirred at room temperature for 30 min, then filtered. The filtrate was concentrated under reduced pressure to approximately 30 g. Add 30 mL of ethyl acetate to the concentrated residue and stir to dissolve at 35-40 °C. Maintain the temperature at 35-40 °C and slowly add 120 mL of n-heptane dropwise. After the addition is complete, keep the mixture warm and stir for 30 min, then cool to 0-5 °C and keep warm and stir for 2 h. Filter the mixture, wash the filter cake with 20 mL of pre-cooled ethyl acetate / n-heptane = 1 / 4 (v / v) mixed solvent, and dry under reduced pressure below 40 °C to obtain 20.63 g of the target compound 4-acetoxy-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-2-azacyclobutanone (compound I, 4-AA), with a separation yield of 95.7% and an HPLC purity of 99.36%. The HPLC chromatogram of compound I is shown below. Figure 6 As shown in the figure, the specific peaks and their related data are shown in the table in the figure. Compound I 1 H NMR spectrum as shown Figure 7 As shown, 13 The C NMR spectrum is as follows Figure 8 As shown; the overall yield was 64.66% based on methyl lactate.

[0084] Preparation Example 1: Preparation of formyltrimethylsilane (compound VII)

[0085] Prepared according to the protocol in J. Org. Chem. 1985, 50, 2198–2200: 1.76 L of anhydrous toluene (dichloromethane in the literature) was added to a dry 5 L three-necked flask, and the mixture was cooled to an internal temperature of -78 °C under nitrogen protection. 28.8 mL (330 mmol) of oxalyl chloride was slowly added dropwise, keeping the internal temperature below -70 °C; then 26.6 mL (374 mmol) of dimethyl sulfoxide was slowly added dropwise, and the mixture was stirred at -78 °C for 10 min. 22.9 g (220 mmol, CAS 3219-63-4) of trimethylsilylmethanol was dissolved in 440 mL of anhydrous dichloromethane and slowly added dropwise to the reaction mixture at -78 °C (approximately 15 min), and the mixture was stirred at -78 °C for another 15 min. Subsequently, 114 mL (814 mmol) of triethylamine was slowly added dropwise at -78 °C to completely neutralize the acidic substance. After the addition was complete, the mixture was stirred at -78 °C for another 5 min to obtain a low-temperature toluene reaction solution containing formyltrimethylsilane (compound VII). The obtained compound VII, after GC analysis to a purity of not less than 98.0% and Karl Fischer determination to a moisture content of not more than 0.10%, was immediately used for the cyclization reaction in step S4 and must not be heated, distilled, or stored.

[0086] Examples 2-3

[0087] The amount of (S)-methyl lactate (compound II) 11.56 g (111.0 mmol) remained unchanged. The molar ratio of (S)-methyl lactate, tert-butyldimethylchlorosilane and imidazole in step S1 of Example 1 was adjusted to 1.0:1.05:1.5 (Example 2) and 1.0:1.20:2.5 (Example 3), respectively. The remaining steps were the same as in Example 1. The separation yield of compound III and the final total yield and purity data of 4-AA for each example are shown in Table 1. As can be seen from Table 1, under the molar ratio conditions investigated, the yield of compound III reached more than 94%, the final total yield of 4-AA was ≥64%, and the purity was not less than 99.1%.

[0088] Table 1. Effect of the molar ratio of (S)-methyl lactate, tert-butyldimethylchlorosilane, and imidazole on the reaction in Examples 2-3.

[0089]

[0090] Examples 4-5

[0091] The temperature of the DIBAL-H reduction reaction in step S2 of Example 1 was adjusted to -78℃ to -73℃ (Example 4) and -69℃ to -65℃ (Example 5), respectively, while the remaining steps were the same as in Example 1. The combined yields of steps S2-S3 and the final total yield and purity data of 4-AA for each example are shown in Table 2.

[0092] Table 2 shows the effect of the DIBAL-H reduction reaction temperature on the reaction in step S2 of Examples 4-5.

[0093]

[0094] Examples 6-7

[0095] While maintaining the same compound VI, toluene, carbon monoxide atmosphere, and reaction conditions of 60°C as in step S4 of Example 1, the molar ratio of palladium catalyst to phosphine ligand was 1:2. The molar ratios of Pd(OAc)2, compound VII, and compound VI were adjusted, and the amount of Pd(OAc)2 was adjusted to 2 mol% (Example 6, corresponding to 4 mol% of P(o-tol)3) and 10 mol% (Example 7, corresponding to 20 mol% of P(o-tol)3), respectively. The remaining steps were the same as in Example 1. The cyclization yield, final total yield of 4-AA, and purity data for each example are shown in Table 3. As shown in Table 3, satisfactory cyclization yields (≥79%) can be obtained in the range of 1:2 between the molar ratio of compound VI, compound VII, and palladium catalyst (1.0:(1.05-1.20):(0.02-0.10) and palladium catalyst to phosphine ligand (1:2). The final total yield of 4-AA is ≥62%, and the purity is not less than 99.10%, which confirms that the catalyst / ligand ratio range has good process applicability.

[0096] Table 3. Effects of palladium catalyst and phosphine ligand on the reaction in steps S4 of Examples 6-7.

[0097]

[0098] Examples 8-9

[0099] The cyclization reaction temperature in step S4 of Example 1 was adjusted to 55℃ (Example 8) and 65℃ (Example 9), respectively, while the remaining steps were the same as in Example 1. The cyclization yield, final total yield of 4-AA, and purity data for each example are shown in Table 4. As can be seen from Table 4, the cyclization reaction can still proceed smoothly at 55℃ and 65℃, with yields both above 75%, and the final 4-AA purity is not less than 99.10%, indicating that the cyclization reaction has good temperature tolerance in the range of 55~65℃.

[0100] Table 4. Effect of cyclization reaction temperature on the reaction in steps S4 of Examples 8-9.

[0101]

[0102] Examples 10-11

[0103] In Example 1, step S5, the amount of acetic anhydride (Ac2O) was adjusted to 1.2 eq (Example 10) and 1.6 eq (Example 11), respectively. The amount of triethylamine was correspondingly adjusted to 1.2 eq and 1.6 eq, while the amount of DMAP remained unchanged at 0.06 eq. The remaining steps were the same as in Example 1. The acetylation yield, final total yield of 4-AA, and purity data for each example are shown in Table 5. As can be seen from Table 5, within the range of Ac2O dosage from 1.2 eq to 1.6 eq, the acetylation yield was consistently above 94%, and the final purity of 4-AA was consistently not less than 99.15%.

[0104] Table 5. Effect of the amounts of acetic anhydride and triethylamine on the reaction in steps S5 of Examples 10-11.

[0105]

[0106] Examples 12-13

[0107] The amount of DDQ used in step S6 of Example 1 was adjusted to 1.0 eq (Example 12) and 1.5 eq (Example 13), respectively, while the remaining steps were the same as in Example 1. The deprotection yield, final total 4-AA yield, and purity data for each example are shown in Table 6.

[0108] Table 6. Effect of DDQ dosage on the reaction in steps S6 of Examples 12-13.

[0109]

[0110] Effect of deviation on the deprotection of N-PMB deprotection system in comparison samples 1-2

[0111] Using compound IX obtained in Example 1 as a substrate, the deprotection system was modified to illustrate the necessity of the DDQ / dichloromethane / water system for retaining 4-acetoxy groups and controlling final impurities. The results are shown in Table 7.

[0112] Table 7. Effects of different deprotection systems on the reaction in Comparative Examples 1-2

[0113]

[0114] Comparative Example 3: Synthesis of 4-AA via the conventional TiCl4 / peracetic acid / ozone route (refer to CN102002066A)

[0115] Following the route disclosed in CN102002066A, N-PMP imine and chiral thioester were cyclized at low temperature in TiCl4 / Et3N / chloroform to obtain a (3S,4S)-azacyclobutanone intermediate (yield 73.4%). This intermediate was then oxidized with peracetic acid / phase transfer catalyst to obtain a 4-acetoxy intermediate (yield 85.2%), and finally deprotected with ozone to obtain 4-AA (yield 79.7%). The overall yield of the three steps was 49.8% based on lactic acid derivatives, and the HPLC purity of the obtained 4-AA was 97.2%. This route uses TiCl4, peracetic acid, and ozone, and the three steps require switching between different reaction apparatuses. In contrast, Example 1 of this application has an overall yield of 64.66% and an HPLC purity of 99.36%, avoiding column chromatography purification throughout the process.

[0116] Comparative Example 4: Condensation reaction without the use of molecular sieves

[0117] The 4A molecular sieve in step S3 of Example 1 was omitted, and the remaining steps were the same as in Example 1. The water generated in the condensation reaction was not removed in time, resulting in incomplete iminolation. NMR monitoring showed that approximately 8%–10% of the crude product from step S3 contained residual aldehyde intermediates. This crude product was directly introduced into the cyclization reaction in step S4 without further processing, ultimately reducing the total yield of 4-AA to 47.3%, with an HPLC purity of 93.5%.

[0118] Comparative Example 5: Acetylation reaction without the use of DMAP

[0119] DMAP in step S5 of Example 1 was omitted, and the remaining steps were the same as in Example 1. Due to the lack of a nucleophilic catalyst to activate acetic anhydride, the conversion rate was only about 72% within the same reaction time (3 h at room temperature); even after extending to 8 h, the acetylation yield was still only 82.1%. Finally, the total yield of 4-AA decreased to 55.7%, and the HPLC purity was 97.8%.

[0120] Comparative Example 6: Deprotection of DDQ using cerium ammonium nitrate instead of DDQ

[0121] In Example 1, step S6, DDQ was replaced with cerium ammonium nitrate (CAN, 3.0 eq), and N-PMB deprotection was performed by reacting the mixture in acetonitrile / water (4:1, v / v) at 0°C for 3 h. The remaining steps were the same as in Example 1. HPLC monitoring showed that the reaction produced a 4-hydroxyl impurity, the deprotection yield was only 65.3%, and the final total yield of 4-AA decreased to 44.2%, with an HPLC purity of 91.5%.

[0122] This invention is not limited to the above-described embodiments. Anyone should know that any structural changes made under the guidance of this invention, and any technical solutions that are the same as or similar to this invention, fall within the protection scope of this invention.

[0123] The technologies, shapes, and structures not described in detail in this invention are all known technologies.

Claims

1. A method for preparing 4-acetoxy-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-2-azacyclobutanone, characterized in that, Includes the following steps: S1. Starting with compound II (S)-methyl lactate, the hydroxyl groups of compound II are protected with a tert-butyldimethylsilyl group using a hydroxyl protecting agent in the presence of a base to obtain compound III (S)-2-(tert-butyldimethylsiloxy)propionate methyl ester. S2. Selectively reduce compound III obtained in step S1 to obtain compound IV (1R)-1-(tert-butyldimethylsiloxy)acetaldehyde, and use compound IV directly in the next condensation reaction without separation and purification. S3. Compound IV obtained in step S2 undergoes a condensation reaction with compound V to obtain a Schiff base intermediate, namely the chiral imine intermediate of compound VI. S4. Compound VI obtained in step S3 and compound VII acylsilane undergo a cyclization reaction in a palladium catalyst, phosphine ligand and carbon monoxide atmosphere to obtain N-PMB protected 4-hydroxyβ-lactam intermediate compound VIII. S5. After removing palladium and decolorizing the obtained compound VIII in step S4, it is acetylated to obtain β-lactam intermediate compound IX protected by 4-acetoxy-N-PMB. S6. The compound IX obtained in step S5 was deprotected by the 4-methoxybenzyl protecting group and purified by crystallization in an ethyl acetate / n-heptane system to obtain compound I 4-acetoxy-3-[(1R)-1-(tert-butyldimethylsiloxy)ethyl]-2-azacyclobutanone.

2. The preparation method according to claim 1, characterized in that, The reaction formulas for steps S1-S6 are as follows: 。 3. The preparation method according to claim 1, characterized in that, In step S1, the hydroxyl protecting agent is tert-butyldimethylchlorosilane, and the base is imidazole; the molar ratio of (S)-methyl lactate, the hydroxyl protecting agent, and the base is 1.0:(1.05-1.20):(1.5-2.5).

4. The preparation method according to claim 1, characterized in that, In step S2, selective reduction is performed using DIBAL-H, with a molar ratio of DIBAL-H to compound III of 1.27:1, and the reaction temperature is -78°C to -65°C. After the reaction is completed, the reaction is quenched with methanol and the aluminum salt is treated with an aqueous solution of potassium sodium tartrate.

5. The preparation method according to claim 1, characterized in that, In step S3, the molar ratio of compound IV to p-methoxybenzylamine is 1:1.0; the condensation reaction is carried out in the presence of molecular sieve 4A; after the reaction is completed, the molecular sieve is removed by filtration, and the mixture is concentrated under reduced pressure at 0-10°C; toluene is then added for replacement, and the mixture is concentrated under reduced pressure until no low-boiling substances are distilled off, to obtain a toluene solution of compound VI.

6. The preparation method according to claim 1, characterized in that, In step S4, compound VII is formyltrimethylsilane.

7. The preparation method according to claim 1, characterized in that, In step S4, the palladium catalyst is Pd(OAc)2, the phosphine ligand is tri-o-tolylphosphine, the molar ratio of compound VI, compound VII and palladium catalyst is 1.0:(1.05-1.20):(0.02-0.10), and the molar ratio of palladium catalyst to phosphine ligand is 1:

2.

8. The preparation method according to claim 1, characterized in that, In step S4, the cyclization reaction is carried out using toluene as the solvent, at a temperature of 55℃-65℃, for a time of 8-16 hours. After the reaction is completed, the mixture is filtered through diatomaceous earth and decolorized with activated carbon.

9. The preparation method according to claim 1, characterized in that, In step S5, acetylation is performed using acetic anhydride, and the acetylation reaction is carried out in the presence of triethylamine and 4-dimethylaminopyridine; the molar ratio of compound VIII, acetic anhydride, triethylamine and 4-dimethylaminopyridine is 1:1.2-1.6:1.2-1.6:0.

06.

10. The preparation method according to claim 1, characterized in that, In step S6, DDQ is used to remove the 4-methoxybenzyl protecting group of compound IX, and the molar ratio of compound IX to DDQ is 1:1.0-1.5; the reaction solvent is a dichloromethane / water mixed solvent, and the volume ratio of dichloromethane to water is 10:1; after the reaction is completed, it is quenched with sodium bisulfite aqueous solution, and then decolorized by activated carbon and purified by crystallization in an ethyl acetate / n-heptane system.

Images