A new method for synthesis of key intermediate of heptamibi

Abstract

A sea berm intermediate and a preparation method thereof, wherein the improvement of carboxylation process and carboxyl reduction process makes the total yield of intermediate (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid increase by 75.3%, and the total yield of sea berm also increases by 75.3%.

Description

A new method for synthesizing a key intermediate of Hebomib Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to the preparation of Hebombe and its key intermediate (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid, an intermediate compound of formula III for preparing the key intermediate (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid, and a preparation method of the intermediate compound of formula III. Background Art

[0002] Hebomib (HS-25) is a cholesterol-lowering drug with the following structure:

[0003] Hebomeb

[0004] The synthesis route of Hebomib (HS-25) disclosed in WO2011017907 is long, which limits the industrial production of Hebomib.

[0005] WO2015188727 discloses a method for preparing Hebomib and an intermediate (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid represented by formula V.

[0006] The synthesis method of the intermediate (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid disclosed in WO2015188727 has the problems of high risk, complex operation, low yield and high cost.

[0007] The intermediate (Z) -5- (4- fluorophenyl) -6-hydroxy - hex -4- enoic acid disclosed in WO2022262768 adopts Shapiro reaction, using dimethyl sulfone as carbon dioxide absorbent, normal pressure reaction, long reaction and post-processing time, and produces a large amount of solid waste. In the carboxylic acid reduction process, the first method is to first make anhydride and then reduce, and the anhydride method is used to prepare formula V, with a molar yield of only 40.9%, which is too low; the second method is to first make carboxylic acid into acyl chloride, and the post-processing is relatively complicated, and in the post-processing process, the product is easily degraded, and the subsequent acyl chloride reduction needs to be carried out at a low temperature of -50 ° C, the reaction conditions are harsh, and the total molar yield is low. Therefore, the synthetic method of the intermediate (Z) -5- (4- fluorophenyl) -6-hydroxy - hex -4- enoic acid disclosed in WO2022262768 has the problems of complex operation, easy degradation of intermediate products, harsh reaction conditions, high equipment requirements, huge energy consumption, and high cost, thereby limiting the application of the method in the large-scale production of hezemeb.

[0008] Therefore, it is necessary to develop a new preparation method of Hebomib and Hebomib key intermediate (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid to overcome the problems of the existing methods.

[0009] Summary of the Invention

[0010] One of the purposes of the present invention is to provide a novel intermediate compound of formula III of Hebombe and a preparation method thereof:

[0011] Hebomeb

[0012] In the first aspect of the present invention, there is provided a compound of formula III:

[0013] Wherein, R is selected from C1-C7 alkyl, -CH2CH=CH2 or -CH2-C6H5, preferably C1-C4 alkyl, -CH2CH=CH2 or -CH2-C6H5, more preferably -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH=CH2 or -CH2-C6H5.

[0014] In another aspect of the present invention, a method for preparing a compound of formula III is provided, the method comprising: reacting a compound of formula II with cyanuric chloride to obtain a compound of formula III:

[0015] Wherein, R is selected from C1-C7 alkyl, -CH2CH=CH2 or -CH2-C6H5, preferably C1-C4 alkyl, -CH2CH=CH2 or -CH2-C6H5, more preferably -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH=CH2 or -CH2-C6H5.

[0016] In the reaction, the molar ratio of the compound of formula II to cyanuric chloride is 1:1 to 3, preferably 1:1.

[0017] The reaction temperature is -10°C to 50°C, preferably 0°C to 30°C.

[0018] The solvent for the reaction is dichloromethane, toluene or tetrahydrofuran, preferably dichloromethane or toluene.

[0019] In another aspect of the present invention, a method for preparing a compound of formula II is provided, comprising: reacting a compound of formula I with CO2 under alkaline conditions under heating and pressure to obtain a compound of formula II:

[0020] Wherein, R is selected from C1-C7 alkyl, -CH2CH=CH2 or -CH2-C6H5, preferably C1-C4 alkyl, -CH2CH=CH2 or -CH2-C6H5, more preferably -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH=CH2 or -CH2-C6H5; R' is an alkyl, substituted or unsubstituted aryl, preferably a C1-C3 alkyl, substituted or unsubstituted phenyl, more preferably p-tolyl or methyl, most preferably p-tolyl.

[0021] The reaction pressure is increased to 0.3-2.0 MPa, preferably 1.0 MPa.

[0022] The base used in the reaction is an inorganic base or an organic base. Preferably, the inorganic base is cesium carbonate (Cs2CO3), potassium phosphate (K3PO4), potassium carbonate (K2CO3), sodium hydroxide, potassium hydroxide or sodium hydride (NaH). Preferably, the organic base is sodium methoxide, sodium ethoxide, potassium tert-butoxide, butyl lithium, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide (LDA), 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), triethylenediamine or tetramethylguanidine; more preferably, the base used is 1,8-diazabicycloundec-7-ene (DBU).

[0023] The molar ratio of the base used in the reaction to the compound of formula I is 2.0-3.0:1, preferably 2.6:1.

[0024] The reaction temperature is 50 to 95°C, preferably 80 to 85°C.

[0025] The reaction time is 4 to 5 hours.

[0026] The solvent used in this reaction was N-methylpyrrolidone.

[0027] In another aspect of the present invention, there is provided a method for preparing a compound of formula V from a compound of formula III, the method comprising:

[0028] Step 1: Reduction of the compound of formula III to obtain the compound of formula IV;

[0029] Step 2: The compound of formula IV obtained in step 1 is hydrolyzed to obtain the compound of formula V:

[0030] Wherein, R is selected from C1-C7 alkyl, -CH2CH=CH2 or -CH2-C6H5, preferably C1-C4 alkyl, -CH2CH=CH2 or -CH2-C6H5, more preferably -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH=CH2 or -CH2-C6H5.

[0031] In the above reaction, in step 1, the reducing agent for the reduction reaction is sodium borohydride or potassium borohydride, preferably sodium borohydride; the molar ratio of the reducing agent for the reduction reaction to the compound of formula III is 1 to 10:1, preferably 1.1 to 3.0:1; and the temperature for the reduction reaction is: -10°C to 50°C, preferably -5°C to 30°C, and more preferably -5°C to 5°C.

[0032] In step 2, the base used in the hydrolysis reaction is sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.

[0033] The advantages of the present invention are: 1. The process for preparing formula II of the present invention adopts pressurization, which first shortens the corresponding reaction time in WO2022262768 from 13 hours to 5 hours of the present invention; secondly, the use of pressurization not only does not use dimethyl sulfone, but also reduces the amount of base DBU, greatly reducing the amount of auxiliary materials, thereby reducing costs; furthermore, dimethyl sulfone is not used in the process, and there is no need to filter and recover dimethyl sulfone during the post-reaction treatment, which reduces the operation of post-processing, simplifies the complexity of post-processing, and reduces the large-scale generation of solid waste. After experiments, it was unexpectedly found that the product purity (92%) of the process of the present invention was slightly higher than the product purity (90%) of the prior art process; at the same time, the E-isomer impurity was reduced from 5% to 2%, and the E-isomer impurity was significantly reduced, which is beneficial to the improvement of the quality and yield of the subsequent steps; and the molar yield of the product was increased from 71% of the prior art to 81% (molar yield) of the present invention, an increase of 14%.

[0034] 2. More importantly, the present invention provides a novel intermediate compound of formula III of Hebombe and a preparation method thereof. The method converts carboxylic acid into the intermediate compound of formula III, and the post-processing thereof is simple, thus avoiding the disadvantages of the complex post-processing using water washing and alkali washing and the easy degradation of the intermediate product in the route of preparing acyl chloride in the process of WO2022262768; the reaction to generate the intermediate compound of formula III is carried out at room temperature, and the reduction reaction of the intermediate compound of formula III only needs to be carried out at -5 to 5°C, which overcomes the problem that the reaction to generate acyl halide or mixed anhydride in WO2022262768 is carried out at a low temperature of 0 to 10°C or -10 to 0°C; the reduction reaction is carried out at a low temperature of -50 to -40°C, requiring a low-temperature reaction tank and consuming huge energy. In addition, the synthetic method of the present invention for preparing (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid V from the intermediate compound of formula III reduces side reactions and improves the reaction yield. The molar yield is increased from 43.9% (calculated according to the data disclosed in Example 10) of the acyl chloride method of WO2022262768 to 67.5%, an increase of 53.7%.

[0035] In summary, the present invention has mild reaction conditions, short reaction time, simple post-processing operation, good product quality, high yield, and the total molar yield of the reaction from Formula I to Formula V is increased by 75.3% (the total yield of Hebomimbe is also increased by 75.3% accordingly). The reaction process is easy to control, low cost, and less solid waste is suitable for large-scale commercial production. DETAILED DESCRIPTION

[0036] The present invention is further described below by means of specific examples and specific operating modes, but the present invention is not limited to the scope of the described examples.

[0037] Sources and specifications of raw materials and reagents:

[0038] The preparation method of the compound of formula I-1 is described in WO2022262768. Solvents such as ethyl acetate and dichloromethane, bases such as sodium borohydride, sodium chloride, and sodium hydroxide, acids such as hydrochloric acid, cyanuric chloride, and N-methylmorpholine are all commercially available products and are chemically pure or analytically pure.

[0039] The following abbreviations are used throughout this invention:

[0040] NMP: N-methylpyrrolidone

[0041] DBU: 1,8-diazabicycloundec-7-ene

[0042] EA: ethyl acetate

[0043] Room temperature: 0℃~30℃

[0044] Comparative Example 1: Repeat the process of Example 5 of WO2022262768 to prepare Z-5-methoxycarbonyl-2-(4-fluorophenyl)-2-enepentanoic acid (II-1)

[0045] To a 500L dry reaction tank, 200L of N-methylpyrrolidone, 125Kg of dimethyl sulfone, and 70Kg of DBU were added, followed by 45Kg of 5-(4-fluorophenyl)-5-toluenesulfonylhydrazine-valeric acid methyl ester (I-1), continuous CO2 flow and heating to 80-83°C. The reaction was continued until the raw material disappeared by HPLC detection, which was the end point. The mixture was cooled to room temperature, and the dimethyl sulfone was filtered and recovered. The mixture was acidified with 400L of 3M dilute hydrochloric acid, extracted three times with 120L of EA, and the EA phases were combined, washed with 50L of saturated brine, and salted with 60Kg / 200L of potassium carbonate aqueous solution. The separated aqueous phase was acidified to pH-4 with 5M hydrochloric acid, extracted with 120L of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain 20.75Kg. Z-5-Methoxycarbonyl-2-(4-fluorophenyl)-2-enepentanoic acid (II-1) [HPLC purity 90%, E-isomer of II-1 5.0%, molar yield 71%].

[0046] The reaction requires more than 13 hours to reach the endpoint; the reaction requires filtration and recovery of dimethyl sulfone, making post-processing complex; and the HPLC content of the E-isomer in the concentrated solution of Compound II-1 prepared by this process is as high as 5%. Therefore, the reaction for preparing Compound II-1 disclosed in WO2022262768 suffers from long reaction times and complex post-processing.

[0047] To address the above-mentioned issues, the present invention improved the process for preparing compound II-1. The effects of reaction time, reaction pressure, and DBU dosage on the reaction were studied, primarily focusing on the purity of the product and the content of the E-isomer. This is shown below:

[0048] Preparation of Z-5-methoxycarbonyl-2-(4-fluorophenyl)-2-enepentanoic acid (II-1)

[0049] Example A: Effect of reaction time on the reaction

[0050] Accurately weigh 4 portions of 115 g (0.29 mol) of I-1 and add them to four autoclaves respectively. Then, add 300 mL of NMP and 192 g (1.26 mol) of DBU respectively and stir evenly. After the autoclave is sealed and replaced with carbon dioxide three times, the carbon dioxide is pressurized to 1.0 MPa. Stirring is started and the temperature is raised to 80-85°C for reaction. Samples are taken and tested after 3, 4, 5, and 6 hours of pressurization. The test results are as follows:

[0051] When the pressure and the amount of alkali remain unchanged, the product purity is higher when the reaction time is 4 to 5 hours. If the reaction time is further extended, the increase in product purity is far less than the increase in E-formula impurities. Since E-formula impurities are difficult to remove in subsequent reactions, the reaction time is selected to be 4 to 5 hours.

[0052] Example B: Investigating the effect of reaction pressure on the reaction

[0053] Accurately weigh 5 portions of 115g (0.29mol) of I-1 and add them to four autoclaves. Then, add 300mL of NMP and 192g (1.26mol) of DBU, respectively, and stir evenly. After sealing the autoclaves and replacing with carbon dioxide three times, the four autoclaves are pressurized with carbon dioxide to 0.3Mpa, 0.6Mpa, 0.8Mpa, 1.0Mpa, and 1.2Mpa, respectively. Stirring is started, and the temperature is raised to 80-85°C for reaction. After reacting for 5 hours, samples are taken and tested. The test results are as follows:

[0054] Reaction tests at different pressures ranging from 0.3Mpa to 1.2Mpa were tried respectively. The results showed that with the increase of pressure, the purity of the product also increased, and the E-formula impurities also increased. The product purity was higher at pressures of 1.0Mpa and 1.2Mpa, but when comparing the reaction conditions at pressures of 1.0Mpa and 1.2Mpa, with the increase of pressure, the increase in product purity was much smaller than the increase in E-formula impurities, and the subsequent purification difficulty of E-formula impurities also increased. Therefore, the reaction pressure was selected to be 1.0Mpa.

[0055] Example C: Investigating the Effect of DBU Reduction on Pressurized Reaction

[0056] Accurately weigh 3 portions of 115 g (0.29 mol) of I-1 and add them to three autoclaves respectively. Add 300 mL of NMP to each autoclave, then add 192 g (1.26 mol, 4.3 eq), 112 g (0.74 mol, 2.6 eq), and 67 g (0.44 mol, 1.5 eq) of DBU respectively, and stir evenly. After the autoclave is sealed, carbon dioxide is replaced three times. After the carbon dioxide is pressurized to 1.0 MPa, stirring is started, the temperature is raised to start the reaction, and the temperature is raised to 80-85 ° C. After reacting for 5 hours, samples are taken and tested. The test results are as follows:

[0057] Experiments with base dosages of 4.3 eq, 2.6 eq, and 1.5 eq (DBU to I-1 molar ratio) showed that at 2.6 eq, product purity was higher and the amount of E-formula byproducts was lower. At 4.3 eq, product purity was slightly higher, but the amount of E-formula byproducts was also higher, and the higher DBU dosage resulted in higher costs. At 1.5 eq, the product purity was only 54.42%, indicating low product purity. Taking into account product purity, cost, and the difficulty of subsequent removal of the E-formula impurity, the base dosage of 2.6 eq was selected.

[0058] By screening the parameters of the pressurized reaction, such as pressure, time and alkali dosage, the optimal reaction conditions were determined to be pressure 1.0 MPa, reaction time 4-5 hours and DBU dosage 2.6 eq.

[0059] Example 1: Preparation of Z-5-methoxycarbonyl-2-(4-fluorophenyl)-2-enepentanoic acid (II-1)

[0060] 115g (0.29mol) of I-1 was added to the autoclave, and then 300mL of NMP and 112g (0.74mol) of DBU were added respectively, and stirred evenly. After the autoclave was sealed and replaced with carbon dioxide three times, the carbon dioxide was pressurized to 1.0MPa, stirring was turned on, the temperature was raised to 80-85°C, and the reaction was carried out for 5 hours. The reaction was carried out until the raw material disappeared by HPLC detection, and then the temperature was cooled to room temperature and 600mL of ethyl acetate was added. The temperature was controlled to <20°C, and the pH was adjusted to 3-4 with 500ml of 3M hydrochloric acid solution. The solution was allowed to stand and separated, and the aqueous phase was extracted once with 300mL of ethyl acetate. The organic phases were combined, washed with 130mL of saturated brine, and 150g / 500mL of potassium carbonate aqueous solution was added to form a salt. The separated aqueous phase was acidified to pH 3-4 with 5M hydrochloric acid, extracted with 300mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain 60g. 60 g of Z-5-methoxycarbonyl-2-(4-fluorophenyl)-2-enepentanoic acid (II-1) [HPLC purity 92%, E isomer 2.0%, molar yield 81%. Comparative Example 1 above, based on the process of WO2022262768, HPLC purity 90%, E isomer 5.0%, molar yield 71%].

[0061] Example 2:

[0062] Add 300L of N-methylpyrrolidone and DBU to a 1000L dry reaction tank. 112Kg (730mol), then add 5-(4-fluorophenyl)-5-toluenesulfonylhydrazine-pentanoic acid methyl ester (I-1) 115Kg (290mol), stir evenly, after the autoclave is sealed and replaced with carbon dioxide three times, the carbon dioxide is pressurized to 1.0MPa, stirring is turned on, the temperature is raised to 80-85°C for reaction, and the reaction is carried out for 5 hours. The reaction is terminated when the raw material disappears by HPLC detection, and the reaction is cooled to room temperature, 600L of ethyl acetate is added, and the temperature is controlled to <20°C. 500L of 3M hydrochloric acid solution is adjusted to pH = 3-4, and the liquid is allowed to stand for separation. The aqueous phase is extracted once with 300L of ethyl acetate, the organic phases are combined, washed with 180L of saturated brine, and 150kg / 500L of potassium carbonate aqueous solution is added to form a salt. The separated aqueous phase is acidified to pH = 3-4 with 5M hydrochloric acid, extracted with 300L of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain 60g. Z-5-Methoxycarbonyl-2-(4-fluorophenyl)-2-enepentanoic acid (II-1) 60 kg [HPLC purity 92%, E isomer 2.0%, molar yield 81%]

[0063] Example 3: Preparation of (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid (V)

[0064] Step A: Add 39.4 (214.3 mmol) g of cyanuric chloride and 400 mL of dichloromethane to a 1500 mL reactor, stir to dissolve, then add 23.5 mL (214.3 mmol) of N-methylmorpholine, and stir at room temperature for 1 h. Then 60g (HPLC purity 92%, 214.3mmol) Z-5-methoxycarbonyl-2-(4-fluorophenyl)-2-enepentanoic acid (Compound II-1) was dissolved in 300mL of dichloromethane, and the dissolved solution was added to the above-mentioned reaction solution. After reacting at room temperature for 3h, TLC detection was performed. The reaction was completed, filtered, and the filtrate was cooled to -5~5°C. A mixed solution of 8.0g of sodium borohydride and 200mL of drinking water was added, and the temperature was maintained at -5~5°C for 30min. TLC detection was performed. After the reaction was completed, 200mL of water was added dropwise to quench the reaction, and the liquids were separated. The aqueous phase was extracted once with 200mL of dichloromethane. The organic phases were combined, concentrated to dryness under reduced pressure, and then 200mL of toluene was added to obtain the feed solution to be used.

[0065] Compound III-1 1 H NMR (400MHz, DMSO-d6): δ2.33~2.38(m,2H), 2.47~2.55(m,2H), 3.68(s,3H), 6. 52(t,1H,J=7.2Hz)7.19(t,2H,J=8.6Hz), 7.34-7.38(m,2H); MS(m / z): 400[M+H]+ .

[0066] Step B: The liquid to be used obtained in step A was placed in a 500 mL reactor, and 100 mL of sodium hydroxide aqueous solution (preparation method: 10.5 g of sodium hydroxide was dissolved in 130 mL of water) was added. The reaction was stirred at 10-20° C. until the raw materials reacted completely. After standing and stratification, the organic phase was extracted once with 30 mL of drinking water. The aqueous phases were combined and adjusted to pH 3-4 with dilute hydrochloric acid. The extracts were then extracted twice with ethyl acetate (70 mL / time). The ethyl acetate phases were combined, washed once with 50 mL of saturated sodium chloride solution, and then dehydrated with anhydrous sodium sulfate. The extracts were filtered and concentrated to dryness under reduced pressure. A mixed solvent of toluene and ethyl acetate was then added for crystallization. The extracts were filtered and dried under vacuum to obtain approximately 36.0 g of compound V (content: 99.50%; molar yield: 67.5%).

[0067] Example 4: Preparation of (Z)-5-(4-fluorophenyl)-6-hydroxy-hex-4-enoic acid (V)

[0068] Step A: Add 39.4 (214.3 mol) kg of cyanuric chloride and 400 L of dichloromethane to a 1500 L reactor, stir to dissolve, then add 23.5 L (214.3 mol) of N-methylmorpholine, and stir at room temperature for 1 h. Then 60 kg (HPLC purity 92%, 214.3 mol) of Z-5-methoxycarbonyl-2-(4-fluorophenyl)-2-enepentanoic acid (Compound II-1) was dissolved in 300 L of dichloromethane, and the dissolved solution was added to the above-mentioned reaction solution. After reacting at room temperature for 3 hours, TLC detection was performed. The reaction was completed, filtered, and the filtrate was cooled to -5 to 5°C. A mixed solution of 8.0 kg of sodium borohydride and 200 L of drinking water was added, and the temperature was maintained at -5 to 5°C for 30 minutes. TLC detection was performed. After the reaction was completed, 200 L of water was added dropwise to quench the mixture, the liquids were separated, and the aqueous phase was extracted once with 200 L of dichloromethane. The organic phases were combined, concentrated to dryness under reduced pressure, and then 200 L of toluene was added to obtain the ready-to-use feed liquid.

[0069] Step B: The unused liquid obtained in Step A was placed in a 500L reactor, and 100L of sodium hydroxide aqueous solution (preparation method: 10.5kg sodium hydroxide dissolved in 130L water) was added. The temperature was controlled at 10-20°C and stirred to react until the raw materials reacted completely. After standing and stratification, the organic phase was extracted once with 30L of drinking water. The aqueous phases were combined, adjusted to pH = 3-4 with dilute hydrochloric acid, and then extracted twice with ethyl acetate (70L / time); the ethyl acetate phases were combined, washed once with 50L of saturated sodium chloride solution, and then dehydrated with 8kg of anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. A mixed solvent of toluene and ethyl acetate was then added for crystallization. The mixture was filtered and dried under vacuum to obtain approximately 36kg of compound V (content: 99.50%, molar yield: 67.5%).

[0070] Example 5: Preparation of Compound VIIIa

[0071] Step A: Under N2 protection, add 36 kg of compound V (160 mol) and 180 L of N,N-dimethylacetamide to a 500 L reaction tank, stir to dissolve, cool, and add 35.6 kg (192 mol) of m-nitrobenzoyl chloride at 25°C to 30°C. Incubate for 2 hours. The reaction is complete when detected by HPLC. The reaction solution is reserved for later use.

[0072] Step B: 360L of dichloromethane and 32.6kg (176mol) of 3-nitrobenzoyl chloride were added to a 1000L reaction flask under nitrogen protection. 64.8g (640mol) of triethylamine was added dropwise at a temperature of 25°C to 30°C, and then the reaction solution of step A was added dropwise at a temperature of 25°C to 30°C (1 to 2 hours). After the addition was complete, the mixture was kept warm for 5 minutes, and then 23.5kg (0.072mol) of (S)-4-phenyl-2-oxazolidinone and 8.8kg (72mol) of 4-dimethylaminopyridine were added. The mixture was kept warm for 6 to 7 hours. The reaction was completed by HPLC.

[0073] 180 L of water was added to the reaction solution, and the mixture was allowed to stand and separate. The organic phase was collected, and the aqueous phase was extracted with dichloromethane (100 L × 2 times). The organic phases were combined, and the organic phase was adjusted to pH = 4-6 with 2M hydrochloric acid, and then washed with 180 L of water until neutral. Then, an imidazole aqueous solution (54 kg of imidazole dissolved in 100 L of water) was added, stirred for 30 minutes, and allowed to stand and separate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was recrystallized with a mixed solvent of ethyl acetate / petroleum ether (2 / 3), filtered, and dried to obtain 60 kg of compound VIIIa (HPLC purity: 97.5%; yield 74.0%).

[0074] Example 6: Preparation of [(Z,5R)-5-[(S)-(4-fluoroanilino)-[4-(3-nitrobenzoyloxy)phenyl]methyl]-2-(4-fluorophenyl)-6-oxo-6-[(4S)-2-oxo-4-phenyl-oxazolidinone-3-yl]hex-2-enyl] 3-nitrobenzoate (XIa)

[0075] To a 500L reaction tank, add 240L of dichloromethane and 24.0Kg (126.4mol) of titanium tetrachloride, protect with nitrogen, stir, cool, add 12.0Kg (42.6mol) of tetraisopropoxytitanium at a temperature of -5 to 0°C, and then stir at a temperature of -5 to 0°C for 30 minutes to obtain a titanium reagent. To a 2000L reaction tank, add 60.0Kg (106.4mol) of the compound of formula VIIIa, 42.4Kg (116.4mol) of the imine of formula IXa, and 880L of dichloromethane, stir and dissolve, add 33.2Kg (257.2mol) of diisopropylethylamine, stir for 10 minutes, cool, and slowly add the titanium reagent dropwise at a temperature of -25 to -20°C. After the addition is complete and the reaction is continued with insulation for 1 to 2 hours, sample and HPLC test are performed until the content of the raw material (compound VIIIa) is less than 5%.

[0076] 72 L of acetic acid was added dropwise at a temperature of -25 to -20°C, followed by stirring for 5 minutes; 360 L of sulfuric acid (2 M) was added dropwise at a temperature below 10°C, followed by stirring for 10 minutes; the mixture was allowed to stand for stratification, and the organic phase was collected. The aqueous phase was then extracted with 120 L of dichloromethane. The combined organic phases were washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was recrystallized from toluene, filtered, and dried to obtain 49.2 kg of compound XIa (HPLC purity: 92.1%; yield: 48.4%).

[0077] Example 7

[0078] Preparation of (3R, 4S)-4-[4-(3-nitrobenzoyloxy)phenyl]-3-[3-(4-fluorophenyl)-4-(3-nitrobenzoyloxy)but-2(Z)-enyl]-1-(4-fluorophenyl)-2-azetidinone (XIIa), (3R, 4S)-4-(4-hydroxyphenyl)-3-[3-(4-fluorophenyl)-4-(3-nitrobenzoyloxy)but-2(Z)-enyl]-1-(4-fluorophenyl)-2-azetidinone (XIIIa), and (3R, 4S)-4-(4-trimethylsilyloxyphenyl)-3-[3-(4-fluorophenyl)-4-(3-nitrobenzoyloxy)but-2(Z)-enyl]-1-(4-fluorophenyl)-2-azetidinone (XIVa)

[0079] To a 1000L reactor, add 49.2kg of XIa and 490L of toluene and stir. Raise the temperature to 50-60°C, add 41.8kg (205mol) of N,O-bis(trimethylsilyl)acetamide (BSA), and incubate for 2-3 hours. Then, add 2.5kg (7.8mol) of tetrabutylammonium fluoride and continue incubating for 2 hours. HPLC analysis is performed until the intermediate XIa meets the requirements. The reaction is terminated. Cool below 25°C, add 120L of ice water dropwise, stir for 10 minutes, then add 410L of n-heptane and continue stirring for 30 minutes. A solid precipitates and is filtered. The filtrate is allowed to stand for separation. The organic phase is collected and the aqueous phase is extracted with toluene (40L x 2). The combined organic phases are concentrated in vacuo to dryness to yield a mixture. A small amount of this mixture is separated to yield three products: compounds XIIa, XIIIa, and XIVa.

[0080] Example 8: Preparation of (3R, 4S)-4-(4-hydroxyphenyl)-3-[3-(4-fluorophenyl)-4-hydroxybutyl-2(Z)-ene]-1-(4-fluorophenyl)-2-azetidinone (Hebomib)

[0081] To a 500 L reactor, add the entire product from Example 7, add 200 L of acetone, and stir to dissolve. Then, add 53.3 L (159.9 mol) of a 3 M aqueous lithium hydroxide solution at room temperature and stir for 0.5 to 1 hour. Samples were taken for TLC analysis until the spots of the starting materials (Compounds XIIa, XIIIa, and XIVa) disappeared.

[0082] The pH was adjusted to 4-6 with 2M hydrochloric acid at room temperature, followed by vacuum concentration (temperature 30-40°C) to a small volume, 250L of ethyl acetate was added, stirred for 5 minutes, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (40L×2 times), the organic phases were combined, and an aqueous sodium bicarbonate solution (8.2Kg of sodium bicarbonate dissolved in 80L of water) was added, stirred for 30 minutes, and the organic phase was adjusted to pH 6 with 2M hydrochloric acid. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, separated by column chromatography, and then crystallized twice with a mixed solvent of ethyl acetate and n-heptane, filtered, and dried to give 8.6Kg of Hebomib (HPLC purity: 98.9%; yield: 39.4% (calculated based on the amount of compound XIa in Example 7)).

Claims

1. A compound of formula III: in, R is selected from C1-C7 alkyl, -CH2CH=CH2 or -CH2-C6H5, preferably C1-C4 alkyl, -CH2CH=CH2 or -CH2-C6H5, more preferably -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH=CH2 or -CH2-C6H5.

2. A method for preparing the compound of formula III according to claim 1, the method comprising: The compound of formula II reacts with cyanuric chloride to obtain a compound of formula III: Among them, R is selected from C1-C7 alkyl, -CH2CH=CH2 or -CH2-C6H5, preferably C1-C4 alkyl, -CH2CH=CH2 or -CH2-C6H5, more preferably -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH=CH2 or -CH2-C6H5.

3. The method according to claim 2, characterized in that The molar ratio of the compound of formula II to cyanuric chloride is 1:1-3, preferably 1:

1.

4. The method according to claim 2 or 3, characterized in that The reaction temperature is -10°C to 50°C, preferably 0°C to 30°C.

5. The method according to any one of claims 2 to 4, characterized in that: The solvent for the reaction is dichloromethane, toluene or tetrahydrofuran, preferably dichloromethane or toluene.

6. A method for preparing a compound of formula V from a compound of formula III according to claim 1, the method comprising: Step 1: The compound of formula III is subjected to reduction reaction to obtain the compound of formula IV; Step 2: The compound of formula IV obtained in step 1 is subjected to hydrolysis to obtain the compound of formula V: Among them, R is selected from C1-C7 alkyl, -CH2CH=CH2 or -CH2-C6H5, preferably C1-C4 alkyl, -CH2CH=CH2 or -CH2-C6H5, more preferably -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH=CH2 or -CH2-C6H5.

7. The method according to claim 6, characterized in that In step 1, the reducing agent for the reduction reaction is sodium borohydride or potassium borohydride, preferably sodium borohydride.

8. The method according to claim 6 or 7, characterized in that In step 1, the molar ratio of the reducing agent in the reduction reaction to the compound of formula III is 1 to 10:1, preferably 1.1 to 3.0:

1.

9. The method according to any one of claims 6 to 8, characterized in that: In step 1, the temperature of the reduction reaction is: -10°C to 50°C, preferably -5°C to 30°C, more preferably -5°C to 5°C.

10. The method according to any one of claims 6 to 9, characterized in that: In step 2, the base used in the hydrolysis reaction is sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.

11. The method according to claim 6, characterized in that Before step 1, the following steps are also included: Step 1": The compound of formula II is reacted with cyanuric chloride to obtain the compound of formula III: Among them, R is selected from C1-C7 alkyl, -CH2CH=CH2 or -CH2-C6H5, preferably C1-C4 alkyl, -CH2CH=CH2 or -CH2-C6H5, more preferably -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH=CH2 or -CH2-C6H5.

12. The method according to claim 11, characterized in that The molar ratio of the compound of formula II to cyanuric chloride is 1:1-3, preferably 1:

1.

13. The method according to claim 11 or 12, characterized in that: The reaction temperature is -10°C to 50°C, preferably 0°C to 30°C.

14. The method according to any one of claims 11 to 13, characterized in that: The solvent for the reaction is dichloromethane, toluene or tetrahydrofuran, preferably dichloromethane or toluene.

15. The method according to claim 11, characterized in that The following steps are also included before step 1: Step 1': The compound of formula I is reacted with CO2 under alkaline conditions by heating and pressurization to obtain the compound of formula II: Wherein, R is selected from C1-C7 alkyl, -CH2CH=CH2 or -CH2-C6H5, preferably C1-C4 alkyl, -CH2CH=CH2 or -CH2-C6H5, more preferably -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH=CH2 or -CH2-C6H5; R' is alkyl, substituted or unsubstituted aryl, preferably C1-C3 alkyl, substituted or unsubstituted phenyl, more preferably p-tolyl or methyl, most preferably p-tolyl.

16. The method according to claim 15, characterized in that The reaction pressure is increased to 0.3-2.0 MPa, preferably 1.0 MPa.

17. The method according to claim 15 or 16, characterized in that The base used in the reaction is an inorganic base or an organic base. Preferably, the inorganic base is cesium carbonate (Cs2CO3), potassium phosphate (K3PO4), potassium carbonate (K2CO3), sodium hydroxide, potassium hydroxide or sodium hydride (NaH). Preferably, the organic base is sodium methoxide, sodium ethoxide, potassium tert-butoxide, butyl lithium, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide (LDA), 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), triethylenediamine or tetramethylguanidine; more preferably, the base used is 1,8-diazabicycloundec-7-ene (DBU).

18. The method according to any one of claims 15 to 17, characterized in that: The molar ratio of the base to the compound of formula I is 2.0-3.0:1, preferably 2.6:

1.

19. The method according to any one of claims 15 to 18, characterized in that: The reaction time is 4 to 5 hours.

20. The method according to any one of claims 15 to 19, characterized in that: The reaction temperature is 50 to 95°C, preferably 80 to 85°C.

21. The method according to any one of claims 15 to 20, characterized in that: The solvent used in the reaction is N-methylpyrrolidone.