Preparation method of penem antibiotic intermediate 4-BMA

Abstract

The invention belongs to the technical field of pharmaceutical chemical processes, and particularly relates to a preparation method of a penem antibiotic intermediate 4-BMA, which comprises the following steps: adding Zn powder, chlorosilane, aliphatic tertiary amine, zinc salt and 4-AA in a formula (I) into THF (tetrahydrofuran), uniformly stirring, dropwise adding a THF solution of alpha-haloamide with an induction group in a formula (II) for reaction, filtering the reaction solution, removing the zinc powder, and drying to obtain the penem antibiotic intermediate 4-BMA. Extracting the filtrate to obtain a THF phase, washing with an aqueous solution of potassium oxalate, and recovering THF to obtain a formula (III); and carrying out oxidative hydrolysis, sulfur dioxide quenching, sulfur dioxide acid regulation crystallization and recrystallization on the formula (III) to obtain the intermediate 4-BMA. According to the preparation method disclosed by the invention, a zinc salt is used as a catalyst during preparation of the formula (III), potassium oxalate is used for removing residual Zn (II) in a THF phase, SO2 is used for quenching hydrogen peroxide and acid regulation and crystallization of 4-BMA, the oxygenolysis problem of 4-BMA is solved, and the preparation method has the characteristics of greenness, safety and high efficiency, is strong in product competitive advantage and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine and chemical industry, and particularly relates to a preparation method of 4-BMA, an intermediate of penam antibiotics. BACKGROUND

[0002] Penam antibiotics are the most widely used and the most active non-typical beta-lactam antibiotics, and are one of the most important antibacterial drugs for treating serious bacterial infections. The annual sales of penam antibiotics exceed 10 billion yuan, and the market share increases by nearly 20% per year. However, the synthesis of penam antibiotics is mainly achieved by a chemical total synthesis method, that is, 4-BMA ((3S, 4S)-3-((R)-1-(tert-butyldimethylsiloxy) ethyl)-4((R)-1-formyl ethyl)-2-azetidinone) is prepared from 4-AA ((3R, 4R)-4-acetyloxy-3-[(R)-1-(tert-butyldimethylsiloxy) ethyl]-2-azetidinone), then a mother nucleus MAP (hetero nitrogen bicyclic phosphonate) is synthesized, and finally a series of penam antibiotics are obtained by reacting with different side chains.

[0003] 4-BMA is a key intermediate for preparing penam antibiotics, and the synthesis process has the characteristics of difficult construction of multiple chiral centers, great difficulty in synthesis, and many dangerous processes. The currently reported synthesis methods of 4-BMA mainly adopt the method of preparing the target product by two-step reactions of Reformatsky and oxidative hydrolysis of 4-AA and a pre-constructed large steric hindrance type 2-chloro / bromo propionamide derivative. A relatively mature method (CN109970784A, CN106632453A, IN2008CH00177A, CN101348486A, WO2007145260A1, CN1948312A, Chinese Journal of Pharmaceuticals, 2010, 41, 891-894, Chinese Journal of Pharmaceuticals, 2001, 32, 512-514, Organic Process Research&Development, 2001, 5, 186-188, Chinese Journal of Pharmaceuticals, 2012, 31, 20-21.) is that 4-AA and 3-(2-chloro-1-oxopropyl)spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-ketone or 3-(2-bromo-1-oxopropyl)spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-ketone are subjected to Reformatsky reaction to obtain 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethylsiloxy ethyl] azetidin-2-one-4-yl] propionyl} spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-ketone, and then one-step oxidative hydrolysis reaction is performed to obtain 4-BMA. The whole reaction process is as follows: .

[0004] However, the existing method still has the following problems unsolved, which is the technical bottleneck restricting the green, safe and efficient production of 4-BMA: (1) Reformatsky reaction is difficult to initiate, and the product is prone to isomerization, and there is no effective method to inhibit the generation of isomer impurities.

[0005] (2) There is no efficient anhydrous system preparation method, and the existing method is prone to produce de-tert-butyldimethylsilyl protecting group impurities.

[0006] (3) A large amount of sodium sulfite, sodium thiosulfate and other reducing agents are used in the quenching process of hydrogen peroxide, and the atomic utilization rate is low.

[0007] All the above lead to low yield of product, which affects the production of high-quality penam antibiotic raw materials. SUMMARY

[0008] In order to overcome the shortcomings of the prior art, the present application provides a preparation method of penam antibiotic intermediate 4-BMA.

[0009] In order to achieve the above purpose, the following technical scheme is adopted: A preparation method of penam antibiotic intermediate 4-BMA, comprising the following steps: (1) Preparation of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethylsilyloxyethyl] azetidin-2-one-4-yl] propanoyl} spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-ketone: Zn powder, chlorosilane, aliphatic tertiary amine, zinc salt, formula (I) 4-AA are added into THF, and then THF solution of formula (II) α-haloamide with inducing group is added dropwise for reaction; the above reaction liquid is filtered to remove zinc powder, the filtrate is extracted to obtain THF phase, which is washed with potassium oxalate aqueous solution, THF is recovered, and light yellow oil 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethylsilyloxyethyl] azetidin-2-one-4-yl] propanoyl} spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-ketone of formula (III) is obtained; (2) Preparation of 4-BMA 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethylsilyl]ethyl]azetidin-2-one-4-yl}propionyl}spiro-[2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexan]-4-one is obtained by oxidative hydrolysis, sulfur dioxide quenching, sulfur dioxide acidification crystallization and recrystallization from 4-BMA; The reaction equation is as follows: .

[0010] After the chlorosilane is added, it reacts with the moisture in the system to achieve the construction of anhydrous system, thereby promoting the initiation of the Reformatsky reaction and realizing the uniform progress of the reaction. Meanwhile, the addition of zinc salt reduces the generation of isomer impurities.

[0011] Preferably, the α-haloamide with an inducing group in step (1) has a halogen atom X selected from Cl and Br.

[0012] Preferably, the reaction temperature in step (1) is 10-30°C, and the reaction time is 3-5 hours.

[0013] Preferably, the chlorosilane in step (1) is one of trimethylchlorosilane, triethylchlorosilane, triisopropylchlorosilane, tert-butyldimethylchlorosilane, trimethoxysilane and triethoxysilane, and the amount of the chlorosilane is 0.01-0.05 times the mass of 4-AA.

[0014] Further preferably, the chlorosilane in step (1) is one of trimethylchlorosilane, triethylchlorosilane, tert-butyldimethylchlorosilane and triethoxysilane.

[0015] Preferably, the aliphatic tertiary amine in step (1) is one of triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N,N-dimethylbutylamine, N,N,N',N'-tetramethylethylenediamine, N-methylpiperidine and N-methylmorpholine, and the amount of the aliphatic tertiary amine is 1-1.05 times the amount of substance of the chlorosilane.

[0016] Further preferably, the aliphatic tertiary amine in step (1) is one of triethylamine, diisopropylethylamine, N,N,N',N'-tetramethylethylenediamine and N-methylmorpholine.

[0017] Preferably, the zinc salt in step (1) is one of zinc chloride, zinc bromide, zinc iodide, zinc sulfate, zinc nitrate and zinc acetate, and the amount of the zinc salt is 0.001-0.01 times the mass of 4-AA.

[0018] Further preferably, the zinc salt in step (1) is one of zinc chloride, zinc bromide, zinc sulfate and zinc acetate.

[0019] Preferably, in step (1), the specific steps of obtaining the THF phase from the filtrate are as follows: saturated brine is added to the filtrate, the pH of the system is adjusted to 4-6 with glacial acetic acid, and after stirring for 10-30 minutes, the THF phase is obtained by liquid separation.

[0020] Preferably, the specific steps of washing with the aqueous potassium oxalate solution in step (1) are as follows: the THF phase is added with an aqueous potassium oxalate solution, stirred for 10-30 minutes, and then separated by liquid separation to remove residual Zn(II) ions in the THF phase. The mass fraction of the aqueous potassium oxalate solution is 5%-20%, and the amount of the aqueous potassium oxalate solution is 1-3 times the mass of 4-AA.

[0021] Preferably, the oxidation hydrolysis in step (2) is as follows: methanol, purified water and a catalyst are added to the light yellow oily substance obtained in step (1), hydrogen peroxide is added dropwise after cooling, and then sodium hydroxide solid is added in batches after the dropwise addition is completed to obtain an oxidation hydrolysis reaction solution.

[0022] Preferably, the sulfur dioxide quenching in step (2) is as follows: sulfur dioxide gas is passed through the prepared oxidation hydrolysis reaction solution to adjust the pH of the system to 8-10, the methanol is evaporated, and then the quenched filtrate is obtained by filtration.

[0023] Preferably, the sulfur dioxide acid-adjusted crystallization in step (2) is as follows: sulfur dioxide gas is passed through the obtained quenched filtrate to adjust the pH to 3-3.5, and then the filter cake is collected by filtration after crystallization and filtration.

[0024] Preferably, the recrystallization in step (2) is as follows: methanol is added to the filter cake, stirring is performed until the solution is clear, purified water is added dropwise, and then the product 4-BMA is obtained by recrystallization and drying.

[0025] Further preferably, in the oxidation hydrolysis process, the mass fraction of the hydrogen peroxide is 27%, the amount of the hydrogen peroxide is 2-4 times the mass of 4-AA, the amount of sodium hydroxide added is 0.4-0.6 times the mass of 4-AA, the reaction temperature is -25 to -15°C, and the reaction time is 2-5 hours after the sodium hydroxide solid is added in batches.

[0026] Preferably, in the oxidation hydrolysis process, the amount of methanol is 1-4 times the mass of 4-AA, the amount of purified water is 1-5 times the mass of 4-AA, and the catalyst is one of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800 and polyethylene glycol 1200, and the amount of the catalyst is 0.01-0.05 times the mass of 4-AA.

[0027] Preferably, in the sulfur dioxide quenching and sulfur dioxide acid-adjusted crystallization processes, the mass flow rate of the sulfur dioxide gas is 0.5-1 kg / (m 2 ·s).

[0028] Preferably, in the recrystallization process, the amount of methanol is 1-2 times the mass of 4-AA, and the amount of purified water is 2-5 times the mass of 4-AA.

[0029] Preferably, the recrystallization process is: cooling from 30°C to 5°C within 1 hour, and crystal growth for 2 hours.

[0030] Compared with the prior art, the present application mainly has the following beneficial technical effects: (1) The paired use of chlorosilane and aliphatic tertiary amine avoids the occurrence of side reactions of the desilyl protecting group of 4-BMA, thereby improving the yield of 4-BMA: chlorosilane reacts with water in the system to generate hydrogen chloride, and after the addition of aliphatic tertiary amine, the hydrogen chloride can react with the amine to form a hydrochloride salt, thereby avoiding the removal of the tertiary butyldimethylsilyl protecting group of the silicon group caused by the reaction of hydrogen chloride with 4-BMA.

[0031] (2) The zinc salt catalyst can promote the stereoselective nucleophilic addition reaction of the product of the reaction of zinc powder and the α-halogenated amide with an induced group to the enamine intermediate state, thereby reducing the content of the isomer of the product and improving the yield of 4-BMA.

[0032] (3) The present application finds that when 4-BMA is prepared by hydrolysis in a hydrogen peroxide / NaOH system, the residual Zn(II) ions in the THF phase of the Reformatsky reaction become active centers for the catalytic decomposition of hydrogen peroxide, causing rapid decomposition of hydrogen peroxide, which poses a high safety hazard. The present application uses potassium oxalate to remove the residual Zn(II) in the THF phase, thereby overcoming the problem of catalytic decomposition of hydrogen peroxide during hydrolysis, and the process has high safety.

[0033] (4) The use of SO2 to quench hydrogen peroxide and 4-BMA has high atomic utilization rate, effectively overcomes the problem of oxidative decomposition of 4-BMA, and has the characteristics of greenness, safety, and high efficiency, and strong product competitive advantage, which is suitable for industrial production. Compared with the use of sodium sulfite and other quenching agents, the amount of sulfur dioxide used to directly quench hydrogen peroxide is lower, and the economic benefit is also higher.

[0034] (5) The present application adopts a crystallization process of reducing the temperature from 30°C to 5°C within 1 hour, thereby fully removing the spiro ring and improving the purity and content of 4-BMA. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 The following is a detailed description of the preparation of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one-4-yl]propanoyl}spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexan]-4-one prepared in Example 1 of the present application.1 H NMR spectrum; Figure 2 The 4-BMA obtained after recrystallization in Example 1 of this invention 1 H NMR spectrum; Figure 3 This is a high-performance liquid chromatogram of 4-BMA obtained after recrystallization in Example 1 of the present invention. Detailed Implementation

[0036] The technical solutions in the embodiments of the present invention will be fully described below to enable those skilled in the art to better understand the advantages and features of the present invention, thereby providing a clearer definition of the scope of protection of the present invention. The embodiments described in this invention are only a part of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0037] Example 1: (1) Preparation of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethoxyethyl]azacyclobutane-2-one-4-yl]propionyl}spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-one At 25°C, Zn powder (285g), trimethylchlorosilane (5g), triethylamine (4.66g), zinc chloride (0.5g), and 4-AA (500g) were added to THF (1000g). After stirring for 20 minutes, a THF solution of 3-(2-chloro-1-oxopropyl)spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-one (642g dissolved in 1000g THF) was added dropwise. After the addition was complete, the reaction was kept at the temperature for 4 hours. Zn powder was filtered, and saturated saline solution was added to the filtrate. The pH of the system was adjusted to 5 with glacial acetic acid. After stirring for 10 minutes, the THF phase was separated and washed (1500 g of a 5% potassium oxalate aqueous solution was added to the THF phase, and the mixture was stirred for 15 minutes before separation). The THF was recovered to obtain crude 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethoxyethyl]azacyclobutane-2-one-4-yl]propionyl}spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-one, which was a pale yellow oil. 1 See H NMR spectrum Figure 1 The analysis is as follows: 1H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 7.7 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 5.93 (s, 1H), 4.21 (t, J = 5.7 Hz, 1H), 4.03 (s, 1H), 3.54 (t, J = 5.5 Hz,1H), 3.20 (s, 1H), 2.28 (t, J = 12.1 Hz, 1H), 2.15 (s, 2H), 1.97 (d, J = 13.3Hz, 1H), 1.71 (d, J = 14.6 Hz, 3H), 1.58 (s, 5H), 1.24 (dd, J = 17.2, 6.6 Hz, 6H), 0.85 (s, 8H), 0.07 (s, 5H); (2) Preparation of 4-BMA Add methanol (500g), purified water (2500g), and polyethylene glycol 200 (25g) to the pale yellow oily substance obtained in step (1). After cooling to -20℃, add hydrogen peroxide (27% by mass, 1100g) dropwise. After the addition is complete, add sodium hydroxide solid (210g) in batches. Keep the reaction at this temperature for 3 hours. Pass sulfur dioxide gas (mass flow rate of 1kg / (m³)) into the reaction solution. 2 Adjust the pH of the system to 8, evaporate methanol, filter to remove the spiro ring, and pass sulfur dioxide (at a mass flow rate of 1 kg / (m³)) through the filtrate. 2 The pH of the gas was adjusted to 3, stirred for 20 minutes, and then filtered. Methanol (1000g) was added to the filter cake, and the mixture was heated to 30°C and stirred until dissolved. Purified water (2500g) was added dropwise. After the addition was complete, the temperature was lowered to 5°C within 1 hour, and crystals were grown for 2 hours. The mixture was then filtered, the filter cake was washed with purified water, and dried to obtain 507.68g of product 4-BMA (molar yield 96.81%, purity 98.08%).

[0038] The structural formula of the helical ring is shown below:

[0039] Formula (IV) Figure 2 For 4-BMA 1 H NMR spectrum. 1H NMR (400 MHz, Chloroform-d) δ 6.30 (s, 1H), 4.25 - 4.15 (m, 1H), 3.95 (d, J = 3.1 Hz, 1H), 3.03 (s, 1H), 2.75 (t, J = 6.4 Hz, 1H), 1.26 (d, J = 7.1 Hz, 3H), 1.19 (d, J = 6.2 Hz, 3H), 0.87 (s, 9H), 0.07 (d, J = 2.9 Hz, 6H); Figure 3 HPLC of 4-BMA. Spirocycle (ret. time: 9.797 min): 0.394%, 4-BMA (ret. time: 12.783 min).

[0040] Example 2: Zn powder (285 g), triethylchlorosilane (15 g), diisopropylethylamine (12.86 g), zinc bromide (1.5 g), 4-AA (500 g) were added into THF (1000 g) at 25 °C, after stirring for 20 minutes, 3-(2-chloro-l-oxopropyl)spiro[2H-l,3-benzoxazin-2,l'- cyclohexane]-4(3H)-one THF solution (642 g dissolved in 1000 g THF) was added dropwise, and the reaction was maintained for 4 hours after the dropwise addition was completed. The Zn powder was filtered, saturated brine was added to the filtrate, and the pH of the system was adjusted to 5 with glacial acetic acid. After stirring for 10 minutes, the THF phase was separated and washed (1100 g of a 10% potassium oxalate aqueous solution was added to the THF phase, stirring was performed for 15 minutes, and then the phases were separated), and the THF was recovered to obtain a crude product of 3-{(2R)-2-[(3S,4R)-3-[(lR)-l-tert-butyldimethylsilyl]ethyl]azetidin-2-one-4-yl]propionyl}spiro-[2,3-dihydro-4H-l,3-benzoxazin-2,l'-cyclohexane]-4-one, which was a light yellow oil; (2) Preparation of 4-BMA Methanol (1000 g), purified water (1750 g), and polyethylene glycol 400 (20 g) were added to the light yellow oil obtained in step (1), and the temperature was lowered to -20 °C, then hydrogen peroxide (mass fraction 27%, 1100 g) was added dropwise, and after the dropwise addition was completed, sodium hydroxide solid (210 g) was added portionwise, and the reaction was maintained for 3 hours. Sulfur dioxide gas (mass flow rate 0.9 kg / (m 2 s)) was passed through the reaction solution to adjust the pH of the system to 8.6, methanol was distilled off, the spirocycle was removed by filtration, and sulfur dioxide gas (mass flow rate 0.9 kg / (m 2The pH of the gas was adjusted to 3, stirred for 20 minutes, and then filtered. Methanol (850g) was added to the filter cake, and the mixture was heated to 30°C and stirred until dissolved. Purified water (2000g) was added dropwise. After the addition was complete, the temperature was lowered to 5°C within 1 hour, and crystals were grown for 2 hours. The mixture was then filtered, the filter cake was washed with purified water, and dried to obtain 508.73g of product 4-BMA (molar yield 97.01%, purity 98.07%).

[0041] Example 3: At 25°C, Zn powder (285g), tert-butyldimethylchlorosilane (20g), N,N,N',N'-tetramethylethylenediamine (15.42g), zinc sulfate (3.5g), and 4-AA (500g) were added to THF (1000g). After stirring for 20 minutes, a THF solution of 3-(2-chloro-1-oxopropyl)spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-one (642g dissolved in 1000g THF) was added dropwise. After the addition was complete, the reaction was kept at the temperature for 4 hours. Zn powder was filtered, saturated saline was added to the filtrate, the pH of the system was adjusted to 5 with glacial acetic acid, and the mixture was stirred for 10 minutes before separation to obtain the THF phase and washing it (800g of 15% potassium oxalate aqueous solution was added to the THF phase, and the mixture was stirred for 15 minutes before separation). The THF was recovered to obtain crude 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethoxyethyl]azacyclobutane-2-one-4-yl]propionyl}spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-one, which was a pale yellow oil. (2) Preparation of 4-BMA Add methanol (1500g), purified water (1000g), and polyethylene glycol 800 (10g) to the pale yellow oily substance obtained in step (1). After cooling to -20℃, add hydrogen peroxide (27% by mass, 1100g) dropwise. After the addition is complete, add sodium hydroxide solid (210g) in batches. Keep the reaction at this temperature for 3 hours. Pass sulfur dioxide gas (mass flow rate of 0.7kg / (m³)) into the reaction solution. 2 The pH of the system was adjusted to 9.3, methanol was evaporated, spirocyclic rings were removed by filtration, and sulfur dioxide was passed through the filtrate at a flow rate of 0.7 kg / (m³). 2 The pH of the gas was adjusted to 3, stirred for 20 minutes, and then filtered. Methanol (650g) was added to the filter cake, and the mixture was heated to 30°C and stirred until dissolved. Purified water (1500g) was added dropwise. After the addition was complete, the temperature was lowered to 5°C within 1 hour, and crystals were grown for 2 hours. The mixture was then filtered, the filter cake was washed with purified water, and dried to obtain 510.88g of product 4-BMA (molar yield 97.42%, purity 97.93%).

[0042] Example 4: At 25°C, Zn powder (285g), triethoxychlorosilane (25g), N-methylmorpholine (12.73g), zinc acetate (5g), and 4-AA (500g) were added to THF (1000g). After stirring for 20 minutes, a THF solution of 3-(2-chloro-1-oxopropyl)spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-one (642g dissolved in 1000g THF) was added dropwise. After the addition was complete, the reaction was kept at the temperature for 4 hours. Zn powder was filtered, saturated saline was added to the filtrate, the pH of the system was adjusted to 5 with glacial acetic acid, and the mixture was stirred for 10 minutes before separation to obtain the THF phase and washing it (500g of 20% potassium oxalate aqueous solution was added to the THF phase, and the mixture was stirred for 15 minutes before separation). The THF was recovered to obtain crude 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethoxyethyl]azacyclobutane-2-one-4-yl]propionyl}spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-one, which was a pale yellow oil. (2) Preparation of 4-BMA Add methanol (2000g), purified water (500g), and polyethylene glycol 1200 (5g) to the pale yellow oily substance obtained in step (1). After cooling to -20℃, add hydrogen peroxide (27% by mass, 1100g) dropwise. After the addition is complete, add sodium hydroxide solid (210g) in batches. Keep the reaction at this temperature for 3 hours. Pass sulfur dioxide gas (mass flow rate of 0.5kg / (m³)) into the reaction solution. 2 Adjust the pH of the system to 10, evaporate methanol, filter to remove the spiro ring, and pass sulfur dioxide through the filtrate at a mass flow rate of 0.5 kg / (m³). 2 The pH of the gas was adjusted to 3, stirred for 20 minutes, and then filtered. Methanol (500g) was added to the filter cake, and the mixture was heated to 30°C and stirred until dissolved. Purified water (1000g) was added dropwise. After the addition was complete, the temperature was lowered to 5°C within 1 hour, and crystals were grown for 2 hours. The mixture was then filtered, the filter cake was washed with purified water, and dried to obtain 506.42g of product 4-BMA (molar yield 96.57%, purity 97.85%).

[0043] Example 5: (1) Preparation of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethoxyethyl]azacyclobutane-2-one-4-yl]propionyl}spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-one At 25°C, Zn powder (285g), trimethylchlorosilane (5g), triethylamine (4.66g), zinc chloride (0.5g), and 4-AA (500g) were added to THF (1000g). After stirring for 20 minutes, a THF solution of 3-(2-chloro-1-oxopropyl)spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-one (642g dissolved in 1000g THF) was added dropwise. After the addition was complete, the reaction was kept at the temperature for 4 hours. Zn powder was filtered, saturated saline was added to the filtrate, and the pH of the system was adjusted to 5 with glacial acetic acid. After stirring for 10 minutes, the THF phase was separated and washed (1500 g of 5% potassium oxalate aqueous solution was added to the THF phase, and the mixture was stirred for 15 minutes and then separated). The THF was recovered to obtain crude 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethoxyethyl]azacyclobutane-2-one-4-yl]propionyl}spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-one, which was a pale yellow oil. (2) Preparation of 4-BMA Add methanol (500g), purified water (2500g), and polyethylene glycol 200 (25g) to the pale yellow oily substance obtained in step (1). After cooling to -20℃, add hydrogen peroxide (27% by mass, 1100g) dropwise. After the addition is complete, add sodium hydroxide solid (210g) in batches. Keep the reaction at this temperature for 3 hours. Pass sulfur dioxide gas (mass flow rate of 1kg / (m³)) into the reaction solution. 2 Adjust the pH of the system to 8, evaporate methanol, filter to remove the spiro ring, and pass sulfur dioxide (at a mass flow rate of 1 kg / (m³)) through the filtrate. 2 The pH of the gas was adjusted to 3, stirred for 20 minutes, and then filtered. Methanol (1000g) was added to the filter cake, and the mixture was heated to 30°C and stirred until dissolved. Purified water (2500g) was added dropwise. After the addition was complete, the temperature was lowered to 5°C within 0.5 hours, and crystals were grown for 2 hours. The mixture was then filtered, the filter cake was rinsed with purified water, and dried to obtain 506.84 g of product 4-BMA.

[0044] The molar yield and purity of 4-BMA were 96.65% and 97.3%, respectively.

[0045] Comparative Example 1 (1) Preparation of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethoxyethyl]azacyclobutane-2-one-4-yl]propionyl}spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-one At 25°C, Zn powder (285g), trimethylchlorosilane (5g), triethylamine (4.66g), and 4-AA (500g) were added to THF (1000g). After stirring for 20 minutes, a THF solution of 3-(2-chloro-1-oxopropyl)spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-one (642g dissolved in 1000g THF) was added dropwise. After the addition was complete, the reaction was kept at the temperature for 4 hours. Zn powder was filtered, saturated saline was added to the filtrate, and the pH of the system was adjusted to 5 with glacial acetic acid. After stirring for 10 minutes, the THF phase was separated and washed (1500 g of 5% potassium oxalate aqueous solution was added to the THF phase, and the mixture was stirred for 15 minutes and then separated). The THF was recovered to obtain crude 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethoxyethyl]azacyclobutane-2-one-4-yl]propionyl}spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-one, which was a pale yellow oil. (2) Preparation of 4-BMA Add methanol (500g), purified water (2500g), and polyethylene glycol 200 (25g) to the pale yellow oily substance obtained in step (1). After cooling to -20℃, add hydrogen peroxide (27% by mass, 1100g) dropwise. After the addition is complete, add sodium hydroxide solid (210g) in batches. Keep the reaction at this temperature for 3 hours. Pass sulfur dioxide gas (mass flow rate of 1kg / (m³)) into the reaction solution. 2 Adjust the pH of the system to 8, evaporate methanol, filter to remove the spiro ring, and pass sulfur dioxide (at a mass flow rate of 1 kg / (m³)) through the filtrate. 2 The pH of the gas was adjusted to 3, stirred for 20 minutes, and then filtered. Methanol (1000g) was added to the filter cake, and the mixture was heated to 30°C and stirred until dissolved. Purified water (2500g) was added dropwise. After the addition was complete, the temperature was lowered to 5°C within 1 hour, and crystals were grown for 2 hours. The mixture was then filtered, the filter cake was rinsed with purified water, and dried to obtain 464.26g of product 4-BMA.

[0046] The molar yield and purity of 4-BMA were 88.53% and 97.12%, respectively.

[0047] Comparative Example 2 (1) Preparation of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethoxyethyl]azacyclobutane-2-one-4-yl]propionyl}spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-one At 25°C, Zn powder (285g), trimethylchlorosilane (5g), triethylamine (4.66g), zinc chloride (0.5g), and 4-AA (500g) were added to THF (1000g). After stirring for 20 minutes, a THF solution of 3-(2-chloro-1-oxopropyl)spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-one (642g dissolved in 1000g THF) was added dropwise. After the addition was complete, the reaction was kept at the temperature for 4 hours. Zn powder was filtered, saturated saline was added to the filtrate, the pH of the system was adjusted to 5 with glacial acetic acid, and the mixture was stirred for 10 minutes. The THF phase was separated, and the THF was recovered to obtain crude 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethoxyethyl]azacyclobutane-2-one-4-yl]propionyl}spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-one, which was a pale yellow oil. (2) Preparation of 4-BMA Add methanol (500g), purified water (2500g), and polyethylene glycol 200 (25g) to the pale yellow oily substance obtained in step (1). After cooling to -20℃, add hydrogen peroxide (27% by mass, 1100g) dropwise. After the addition is complete, add sodium hydroxide solid (210g) in batches. Keep the reaction at this temperature for 3 hours. Pass sulfur dioxide gas (mass flow rate of 1kg / (m³)) into the reaction solution. 2 Adjust the pH of the system to 8, evaporate methanol, filter, and pass sulfur dioxide through the filtrate at a mass flow rate of 1 kg / (m³). 2 The pH of the gas was adjusted to 3, stirred for 20 minutes, and then filtered. Methanol (1000g) was added to the filter cake, and the mixture was heated to 30°C and stirred until dissolved. Purified water (2500g) was added dropwise. After the addition was complete, the temperature was lowered to 5°C within 1 hour, and crystals were grown for 2 hours. The mixture was then filtered, the filter cake was washed with purified water, and dried to obtain 486.96g of product 4-BMA.

[0048] The molar yield and purity of 4-BMA were 92.86% and 96.98%, respectively.

[0049] Comparative Example 3: (1) Preparation of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethoxyethyl]azacyclobutane-2-one-4-yl]propionyl}spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-one At 25°C, Zn powder (285g), trimethylchlorosilane (5g), triethylamine (4.66g), zinc chloride (0.5g), and 4-AA (500g) were added to THF (1000g). After stirring for 20 minutes, a THF solution of 3-(2-chloro-1-oxopropyl)spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-one (642g dissolved in 1000g THF) was added dropwise. After the addition was complete, the reaction was kept at the temperature for 4 hours. Zn powder was filtered, saturated saline was added to the filtrate, and the pH of the system was adjusted to 5 with glacial acetic acid. After stirring for 10 minutes, the THF phase was separated and washed (1500 g of 5% potassium oxalate aqueous solution was added to the THF phase, and the mixture was stirred for 15 minutes and then separated). The THF was recovered to obtain crude 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethoxyethyl]azacyclobutane-2-one-4-yl]propionyl}spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-one, which was a pale yellow oil. (2) Preparation of 4-BMA Add methanol (500g), purified water (2500g), and polyethylene glycol 200 (25g) to the pale yellow oily substance obtained in step (1). After cooling to -20℃, add hydrogen peroxide (27% by mass, 1100g) dropwise. After the addition is complete, add sodium hydroxide solid (210g) in batches. Keep the reaction at this temperature for 3 hours. Add sodium sulfite solution (10% by mass) to the reaction solution to quench the hydrogen peroxide. Then add hydrochloric acid (6mol / L) to the system to adjust the pH to 8. Evaporate methanol and filter. Continue to add hydrochloric acid (6mol / L) dropwise to the filtrate until the pH of the system reaches 3. Stir for 20 minutes and then filter. Add methanol (1000g) to the filter cake, heat to 30℃ and stir until dissolved. Add purified water (2500g) dropwise. After the addition is complete, cool to 5℃ within 1 hour, grow crystals for 2 hours, filter, wash the filter cake with purified water, and dry to obtain 492.78g of product 4-BMA.

[0050] The molar yield and purity of 4-BMA were 93.97% and 96.93%, respectively.

Claims

1. A process for the preparation of an imipenem antibiotic intermediate 4-BMA, characterized by, Comprising the following steps: (1) Preparation of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethylsilyl ethyl] azetidin-2-one-4-yl] propanoyl} spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-ketone: Zinc powder, chlorosilane, aliphatic tertiary amine, zinc salt, 4-AA of formula (I) are added into THF, and then a THF solution of the alpha-halogenated amide of formula (II) with an inducing group is added dropwise for reaction; the above reaction solution is filtered to remove zinc powder, and the filtrate is extracted to obtain a THF phase, which is washed with an aqueous potassium oxalate solution, and THF is recovered to obtain a crude product of 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethylsilyl ethyl] azetidin-2-one-4-yl] propanoyl} spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-ketone in light yellow oil form of formula (III); (2) Preparation of 4-BMA The 3-{(2R)-2-[(3S,4R)-3-[(1R)-1-tert-butyldimethylsilyl ethyl] azetidin-2-one-4-yl] propanoyl} spiro-[2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane]-4-ketone of formula (III) is subjected to oxidative hydrolysis, sulfur dioxide quenching, sulfur dioxide acid adjustment crystallization, and recrystallization to obtain 4-BMA; The reaction equation is as follows: 。 2. The process for the preparation of the imidazole intermediate 4-BMA of the penam antibiotic according to claim 1, characterized in that, In step (1), the alpha-halogenated amide with an inducing group has a halogen atom X selected from Cl and Br; the reaction temperature in step (1) is 10-30°C, and the reaction time is 3-5 hours.

3. The process for the preparation of the imidazole intermediate 4-BMA of the penam antibiotic according to claim 1, characterized in that, In step (1), the chlorosilane is one of trimethylchlorosilane, triethylchlorosilane, triisopropylchlorosilane, tert-butyldimethylchlorosilane, trimethoxysilane, and triethoxysilane; the aliphatic tertiary amine is one of triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N,N-dimethylbutylamine, N,N,N',N'-tetramethylethylenediamine, N-methylpiperidine, and N-methylmorpholine; and the zinc salt is one of zinc chloride, zinc bromide, zinc iodide, zinc sulfate, zinc nitrate, and zinc acetate.

4. The process for the preparation of the imidazole intermediate 4-BMA of the penam antibiotic according to claim 1, characterized in that, In step (1), the amount of the chlorosilane is 0.01-0.05 times the mass of 4-AA; the amount of the aliphatic tertiary amine is 1-1.05 times the amount of substance of the chlorosilane; and the amount of the zinc salt is 0.001-0.01 times the mass of 4-AA.

5. The process for the preparation of the imidazole intermediate 4-BMA of the penam antibiotic according to claim 1, characterized by, In step (1), the specific steps for obtaining the THF phase from the filtrate are as follows: saturated brine is added to the filtrate, the pH of the system is adjusted to 4-6 with glacial acetic acid, and the THF phase is obtained after stirring for 10-30 minutes; and the specific steps for washing with the aqueous potassium oxalate solution are as follows: the THF phase is added with the aqueous potassium oxalate solution, and the THF phase is separated after stirring for 10-30 minutes to remove residual Zn(II) ions.

6. The process for the preparation of the imidazole intermediate 4-BMA of the penam antibiotic according to claim 5, characterized in that, The mass fraction of the aqueous potassium oxalate solution is 5%-20%, and the amount of the aqueous potassium oxalate solution is 1-3 times the mass of 4-AA.

7. The method of claim 1, wherein the preparation of the imidazole penam intermediate 4-BMA is characterized by, the oxidation hydrolysis of step (2) is: adding methanol, purified water and catalyst to the light yellow oily substance obtained in step (1), then adding hydrogen peroxide after cooling, and then adding sodium hydroxide solid in batches to obtain an oxidation hydrolysis reaction solution; the sulfur dioxide quenching of step (2) is: adjusting the pH of the oxidation hydrolysis reaction solution obtained above to 8-10 by passing sulfur dioxide gas, evaporating the methanol, and filtering to obtain a quenched filtrate; the sulfur dioxide acid adjusting crystallization of step (2) is: adjusting the pH of the quenched filtrate obtained to 3-3.5 by passing sulfur dioxide gas, crystallizing, filtering, and collecting the filter cake; the recrystallization of step (2) is: adding methanol to the filter cake, stirring to dissolve, adding purified water dropwise, and then recrystallizing and drying to obtain the product 4-BMA.

8. The process for the preparation of the imidazole intermediate 4-BMA of the penam antibiotic according to claim 7, characterized by, In the oxidation hydrolysis process, the mass fraction of hydrogen peroxide is 27%, the amount of hydrogen peroxide is 2-4 times the mass of 4-AA, the amount of sodium hydroxide added is 0.4-0.6 times the mass of 4-AA, the reaction temperature is -25 to -15°C, the reaction time is 2-5 hours after the batch addition of sodium hydroxide solid, the amount of methanol is 1-4 times the mass of 4-AA, the amount of purified water is 1-5 times the mass of 4-AA, and the catalyst is one of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800, and polyethylene glycol 1200, and the amount of catalyst is 0.01-0.05 times the mass of 4-AA.

9. The process for the preparation of the imidazole intermediate 4-BMA of the penam antibiotic according to claim 7, characterized by, The mass flow rate of sulfur dioxide gas is 0.5-1 kg / (m 2 2 during the sulfur dioxide quenching and sulfur dioxide acid-adjusting crystallization process; the amount of methanol is 1-2 times the mass of 4-AA, and the amount of purified water is 2-5 times the mass of 4-AA during the recrystallization process.

10. The process for the preparation of the imidazole intermediate 4-BMA of the penam antibiotic according to claim 7, characterized by, The recrystallization process is: cooling from 30°C to 5°C in 1 hour, and crystallizing for 2 hours.

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