A method for purifying and preparing an intermediate of a beta-lactam compound

Abstract

The present application provides a purification method and a preparation method of an intermediate of a β-lactam compound, namely a compound of formula (I), the method comprising sequentially adding a first portion of isopropyl ether, water and a second portion of isopropyl ether to a crude product of the compound of formula (I), and then eluting the filter cake obtained by filtration with a mixed solution of isopropyl ether and petroleum ether to obtain the compound of formula (I), wherein the volume ratio of the first portion of isopropyl ether to water is 1:3 to 7. The method of the present application can obtain the compound of formula (I) with high yield and high purity, and the compound can be directly used for the preparation of monocyclic β-lactam antibiotics without preparatory separation.

Description

Technical Field

[0001] The present application relates to a purification method and a preparation method of an intermediate of a β-lactam compound. Background Art

[0002] Monocyclic β-lactam antibiotics have good antibacterial activity, among which (S,Z) 1-(((1-(2-amino-4-thiazole)-2-((2,2-dimethyl-4-oxo-1-(sulfonyloxy)azetidin-3-yl)-amino)-2-oxo-ethylidene)amino)oxy)cyclopropane-1-carboxylic acid-disodium trihydrate (molecular formula C) having a structure of formula (II) 14 H 15 N5Na2O9S2·3H2O) is a fully synthetic monocyclic β-lactam antibiotic with better antibacterial effect than aztreonam.

[0003]

[0004] The compound (S)-2-(N-tert-butyloxycarbonyl-amino)-N-benzyloxy-3-hydroxy-3-methylbutanamide (molecular formula C 17 H 26 N2O5) is an important intermediate for preparing the monocyclic β-lactam antibiotics of the above-mentioned formula (II) structure (corresponding to the part in the wireframe in the above-mentioned formula (II) structure). Therefore, obtaining the compound of formula (I) with higher purity and yield is of great significance for obtaining high-quality monocyclic β-lactam antibiotics.

[0005] Summary of the invention

[0006] The purpose of the present application is to provide a purification method and a preparation method of an intermediate of a β-lactam compound, namely a compound of formula (I), by which the crystals of the compound of formula (I) can be directly obtained without preparatory separation, while having high yield and purity, which is beneficial to the subsequent preparation of β-lactam antibiotics.

[0007] In order to achieve the above object, the first aspect of the present application provides a method for purifying a compound of formula (I), the method comprising the following steps:

[0008]

[0009] (S1) providing a crude product of the compound of formula (I);

[0010] (S2) adding a first portion of C2-C6 ether, water and a second portion of C2-C6 ether to the crude product in sequence, and then rinsing the filter cake obtained by filtration with a mixed solution of isopropyl ether and petroleum ether to obtain a compound of formula (I), wherein the volume ratio of the first portion of C2-C6 ether to water is 1:3 to 7, preferably 1:4 to 6, and more preferably 1:5.

[0011] Therefore, compared with the prior art, the present application at least includes the following beneficial effects: the production process is simple and low-cost, the crystals of the compound of formula (I) are directly obtained without preparatory separation, and the yield is as high as 69.51% and the purity is as high as 99.17%, which is conducive to the subsequent production of β-lactam antibiotics.

[0012] In any embodiment, the method for purifying the compound of formula (I) further comprises: after eluting the obtained filter cake with a mixed solution of isopropyl ether and petroleum ether, drying it under reduced pressure.

[0013] In any embodiment, the first C2-C6 ether is isopropyl ether and the second C2-C6 ether is isopropyl ether, and the volume ratio of the first C2-C6 ether to the second C2-C6 ether is 1:0.5-3, preferably 1:1-2, and more preferably 1:1.5.

[0014] In any embodiment, the temperature is lowered to 2-8°C when the second portion of the C2-C6 ether is added.

[0015] In any embodiment, the volume ratio of isopropyl ether to petroleum ether in the mixed solution of isopropyl ether and petroleum ether is 1:3-7, preferably 1:4-6, and more preferably 1:5.

[0016] The second aspect of the present application provides a method for preparing a compound of formula (I), the method comprising:

[0017]

[0018] N-tert-butyloxycarbonyl-3-hydroxy-D-valine is reacted with O-benzyloxyammonium hydrochloride in N,N-dimethylformamide, and the product solution is separated to obtain a crude product of the compound of formula (I), which is then purified by the method of the first aspect of the present application to obtain the compound of formula (I).

[0019] In any embodiment, the separation comprises extracting, washing, drying, filtering and concentrating the product solution under reduced pressure in sequence.

[0020] In any embodiment, the extraction is to add a mixed solution of water and dichloromethane to the product solution, then stand for stratification extraction, extract the aqueous phase with dichloromethane again, and combine the organic phases, wherein the volume ratio of water to dichloromethane in the mixed solution of water and dichloromethane is 1:0.5 to 1.5, preferably 1:0.8 to 1.2, and more preferably 1:1;

[0021] The washing is to wash the organic phase obtained by extraction with an acidic solution, an alkaline solution and a neutral solution in sequence;

[0022] The drying step is to dry the product solution after extraction and washing with anhydrous sodium sulfate and / or anhydrous magnesium sulfate;

[0023] The reduced pressure concentration is performed at a temperature of 30 to 45°C, preferably 35 to 40°C.

[0024] In any embodiment, based on the weight of the N-tert-butyloxycarbonyl-3-hydroxy-D-pyrimidine, the amount of water added in step (S2) is 10 to 12 times, preferably 10 times, the amount of the N-tert-butyloxycarbonyl-3-hydroxy-D-pyrimidine.

[0025] The third aspect of the present application provides a method for preparing a β-lactam compound, wherein the compound of formula (I) obtained according to the purification method of the first aspect of the present application or the preparation method of the second aspect of the present application is used to prepare a β-lactam compound. DETAILED DESCRIPTION

[0026] The following is a detailed description of the purification and preparation methods of the compound of formula (I) of the present application. However, there may be cases where unnecessary detailed descriptions are omitted. For example, there are cases where the detailed description of well-known matters and the repeated description of the actual same structure are omitted. This is to avoid the following description from becoming unnecessarily lengthy and to facilitate the understanding of those skilled in the art. In addition, the following description is provided for those skilled in the art to fully understand the present application and is not intended to limit the subject matter described in the claims.

[0027] "Scope" disclosed in the present application is limited in the form of lower limit and upper limit, and a given range is limited by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundary of a special range. The scope limited in this way can be including end values ​​or not including end values, and can be arbitrarily combined, that is, any lower limit can be combined with any upper limit to form a scope. For example, if the scope of 60-120 and 80-110 is listed for a specific parameter, it is understood that the scope of 60-110 and 80-120 is also expected. In addition, if the minimum range values ​​1 and 2 are listed, and if the maximum range values ​​3, 4 and 5 are listed, the following scope can be all expected: 1-3, 1-4, 1-5, 2-3, 2-4 and 2-5. In the present application, unless otherwise specified, the numerical range "ab" represents the abbreviation of any real number combination between a and b, wherein a and b are real numbers. For example, the numerical range "0-5" means that all real numbers between "0-5" are listed in this document, and "0-5" is just an abbreviation of these numerical combinations. In addition, when a parameter is expressed as an integer ≥ 2, it is equivalent to disclosing that the parameter is, for example, an integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0028] Unless otherwise specified, all embodiments and optional embodiments of the present application can be combined with each other to form a new technical solution.

[0029] Unless otherwise specified, all technical features and optional technical features of this application can be combined with each other to form a new technical solution.

[0030] If there is no special explanation, all steps of the present application can be performed sequentially or randomly, preferably sequentially. For example, the method includes steps (a) and (b), which means that the method may include steps (a) and (b) performed sequentially, or may include steps (b) and (a) performed sequentially. For example, the method may further include step (c), which means that step (c) may be added to the method in any order. For example, the method may include steps (a), (b) and (c), or may include steps (a), (c) and (b), or may include steps (c), (a) and (b), etc.

[0031] If there is no special explanation, the "include" and "comprising" mentioned in this application are open-ended or closed-ended. For example, the "include" and "comprising" may mean that other components not listed may also be included or only the listed components may be included or only the listed components may be included.

[0032] If not specifically stated, in this application, the term "or" is inclusive. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, any of the following conditions satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0033] The first aspect of the present application provides a method for purifying a compound of formula (I), the method comprising the following steps:

[0034]

[0035] (S1) providing a crude product of the compound of formula (I);

[0036] (S2) adding a first portion of C2-C6 ether, water and a second portion of C2-C6 ether to the crude product in sequence, and then rinsing the filter cake obtained by filtration with a mixed solution of isopropyl ether and petroleum ether to obtain a compound of formula (I), wherein the volume ratio of the first portion of C2-C6 ether to water is 1:3 to 7, preferably 1:4 to 6, and more preferably 1:5.

[0037] In the prior art, it is difficult to obtain crystals of the compound of formula (I) with higher purity and higher yield, because the crude product solution of the compound of formula (I) is unstable / difficult to crystallize, and even if the crystals of the compound of formula (I) are obtained, the crystals contain a large amount of oily viscous impurities, which will adversely affect the subsequent preparation of monocyclic β-lactam antibiotics.

[0038] However, the method of the present application obtains a compound of formula (I) with high yield and high purity. Although not bound by any principle, the reasons are analyzed as follows:

[0039] The crude product of the compound of formula (I) is purified by adding a first portion of C2-C6 ether, which can dissolve the oily impurities in the product but has a low solubility in the product (primary purification), and then the product is stably precipitated into the aqueous phase by water while the impurities are retained in the organic phase. Then, a second portion of C2-C6 ether is added, which can purify the product again by dissolving the oily impurities that may still remain on the precipitated product (secondary purification). Finally, the filtered filter cake is rinsed with a mixed solution of isopropyl ether and petroleum ether to remove the oily impurities and purified again (tertiary purification), thereby directly obtaining crystals of the compound of formula (I) with high yield and high purity, so that the compound of formula (I) can be directly used for the preparation of monocyclic β-lactam antibiotics without preparatory separation.

[0040] In the present application, the purity of the compound of formula (I) is obtained by high performance liquid chromatography (HPLC) using Thermo Fisher Ultimate 3000 (with UV detector); the yield of the compound of formula (I) is obtained as follows: yield = (moles of product ÷ moles of reactants) × 100%.

[0041] In the method of the present application, during operation, unless otherwise specified, the temperature is room temperature, the pressure is atmospheric pressure, and the water is purified water.

[0042] In some embodiments, the volume ratio of the first C2-C6 ether to water is 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5 or 1:7.

[0043] In some embodiments, the method for purifying the compound of formula (I) further comprises drying under reduced pressure after rinsing the obtained filter cake with a mixed solution of isopropyl ether and petroleum ether. The temperature of the reduced pressure drying is 35-50°C, preferably 40-45°C, and the drying time is 8-12h. Thus, the moisture content in the product can be reduced, which is beneficial to the preservation of the obtained compound of formula (I), and the purity and yield of the obtained compound of formula (I) are significantly improved.

[0044] In some embodiments, the first C2-C6 ether is isopropyl ether and the second C2-C6 ether is isopropyl ether, and the volume ratio of the first C2-C6 ether to the second C2-C6 ether is 1:0.5-3, preferably 1:1-2, more preferably 1:1.5. Thus, the purity and yield of the obtained compound of formula (I) can be further improved.

[0045] In some embodiments, the volume ratio of the first C2-C6 ether to the second C2-C6 ether is 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5 or 1:3.

[0046] In some embodiments, when the second portion of C2-C6 ether is added, the temperature is lowered to 2-8° C., preferably 5° C. Thus, the yield of the compound of formula (I) can be further improved.

[0047] In some embodiments, the volume ratio of isopropyl ether to petroleum ether in the mixed solution of isopropyl ether and petroleum ether is 1:3-7, preferably 1:4-6, more preferably 1:5. Thus, the yield and purity of the compound of formula (I) can be further improved.

[0048] In some embodiments, the volume ratio of isopropyl ether to petroleum ether in the mixed solution of isopropyl ether and petroleum ether is 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5 or 1:7.

[0049] In some embodiments, the volume ratio of the first C2-C6 ether, the second C2-C6 ether, and the isopropyl ether in the mixed solution of isopropyl ether and petroleum ether is 2.5-7:1.5-12.5:1, preferably 3-6:3-10:1, more preferably 3-5:5-7:1, and most preferably 4:6:1.

[0050] The second aspect of the present application provides a method for preparing a compound of formula (I), the method comprising:

[0051]

[0052] N-tert-butyloxycarbonyl-3-hydroxy-D-valine is reacted with O-benzyloxyammonium hydrochloride in N,N-dimethylformamide, and the product solution is separated to obtain a crude product of the compound of formula (I), which is then purified by the first aspect of the present application to obtain the compound of formula (I).

[0053] In some embodiments, N-tert-butyloxycarbonyl-3-hydroxy-D-valine is reacted with O-benzyloxyammonium hydrochloride in the presence of N,N-dimethylformamide, sodium bicarbonate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole to obtain a solution containing a crude product of the compound of formula (I).

[0054] In some embodiments, the separation comprises extracting, washing, drying, filtering and concentrating the product solution under reduced pressure in sequence.

[0055] In some embodiments, the extraction is to add a mixed solution of water and dichloromethane to the product solution, then stand for stratification extraction, extract the aqueous phase with dichloromethane again, and combine the organic phases, wherein the volume ratio of water to dichloromethane in the mixed solution of water and dichloromethane is 1:0.5-1.5, preferably 1:0.8-1.2, and more preferably 1:1;

[0056] The washing is to wash the organic phase obtained by extraction with an acidic solution, an alkaline solution and a neutral solution in sequence;

[0057] The drying step is to dry the product solution after extraction and washing with anhydrous sodium sulfate and / or anhydrous magnesium sulfate;

[0058] The reduced pressure concentration is performed at a temperature of 30 to 45°C, preferably 35 to 40°C.

[0059] In some embodiments, the acidic solution may be a 0.8-1.2 mol / L, preferably a 1 mol / L hydrochloric acid solution, the alkaline solution may be a 4-6 wt %, preferably a 5 wt % sodium bicarbonate solution, and the neutral solution may be a saturated sodium chloride solution.

[0060] In some embodiments, based on the weight of the N-tert-butyloxycarbonyl-3-hydroxy-D-valine, the amount of water added in step (S2) is 10 to 12 times, preferably 10 times, of the N-tert-butyloxycarbonyl-3-hydroxy-D-valine. For example, when 1 kg of the crude product of the compound of formula (I) of N-tert-butyloxycarbonyl-3-hydroxy-D-valine is used, in step (S2), the amount of water used is 10 kg (i.e., the volume of water used is 10 L), then based on the above definition of the volume ratio of each reagent used, it can be determined that the volume of the first portion of C2-C6 ether used is 2 L, and the volume of the second portion of C2-C6 ether used is 3 L.

[0061] The third aspect of the present application provides a method for preparing a β-lactam compound, wherein the compound of formula (I) obtained according to the purification method of the first aspect of the present application or the preparation method of the second aspect of the present application is used to prepare a β-lactam compound. For example, the compound of formula (I) obtained in the present application can be used to prepare the β-lactam compound in CN 113754651A, which is hereby incorporated by reference in its entirety into the present application.

[0062] Example

[0063] Hereinafter, the embodiments of the present application will be described. The embodiments described below are exemplary and are only used to explain the present application, and should not be construed as limiting the present application. If no specific techniques or conditions are indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. If the manufacturer is not indicated in the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0064] I. Raw materials

[0065] N-tert-Butyloxycarbonyl-3-hydroxy-D-valine (CAS: 288159-40-0, self-produced, the specific preparation process can be seen below)

[0066] O-Benzyloxyammonium hydrochloride (CAS: 2687-43-6, purchased from Ningbo Siming)

[0067] N,N-dimethylformamide (CAS: 68-12-2, purchased from Luxi Chemical Group)

[0068] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS: 25952-53-8, purchased from Jinan Daen Pharmaceutical)

[0069] 1-Hydroxybenzotriazole (CAS: 2592-95-2, purchased from Suzhou Haofan Biotechnology)

[0070] Dichloromethane (CAS: 75-09-2, purchased from Luxi Chemical Group)

[0071] Isopropyl ether (CAS: 108-20-3, purchased from Zhejiang Hengtong Chemical)

[0072] Petroleum ether (CAS: 8032-32-4, purchased from Shandong Zhongqiang Chemical)

[0073] II. Method for detecting the purity of the compound of formula (I)

[0074] The purity of the compound of formula (I) was determined by high performance liquid chromatography (HPLC). An appropriate amount of sample was taken, accurately weighed, and prepared into a solution containing about 0.5 mg per 1 ml using 30% acetonitrile solution. The test was performed as follows:

[0075] Instrument model: Thermo Fisher Ultimate3000 (with UV detector)

[0076] Column: Inertsil ODS-SP, 150×4.6 mm, 5 μm;

[0077] Mobile phase A: 0.01 mol / L tetrabutylammonium hydrogen sulfate (adjust pH to 8.0 with ammonia)

[0078] Mobile phase B: acetonitrile

[0079] Gradient elution sequence:

[0080] 0min, 90% mobile phase A, 10% mobile phase B; 5min, 90% mobile phase A, 10% mobile phase B; 30min, 40% mobile phase A, 60% mobile phase B; 30.1min, 90% mobile phase A, 10% mobile phase B; 45min, 90% mobile phase A, 10% mobile phase B

[0081] Flow rate: 1.0ml / min

[0082] Wavelength: 210nm

[0083] Column temperature: 35°C

[0084] Injection volume: 20 μL

[0085] III. Preparation of N-tert-butyloxycarbonyl-3-hydroxy-D-valine

[0086] At 25°C, 360L of acetonitrile and 2-(N-tert-butyloxycarbonyl)-amino-3-methyl-1,3-butanediol (36.00kg) were added to the reactor, 288L of phosphate buffer solution with a pH of 6.7, 2,2,6,6-tetramethylpiperidinium nitrogen oxide (2.57kg), sodium chlorite solution (44.57kg of sodium chlorite dissolved in 144kg of purified water) and sodium hypochlorite solution (7.34L of 5% sodium hypochlorite solution diluted to 101L of purified water) were added, the reactor was sealed, the material temperature was controlled at 42-48°C, and the reaction was carried out for 24 hours. The reaction of 2-(N-tert-butyloxycarbonyl)-amino-3-methyl-1,3-butanediol was completely detected by thin layer chromatography (TLC).

[0087] After the reaction is completed, the temperature is lowered to 25°C, 36L of saturated citric acid aqueous solution is added to adjust the pH to 3-4, the aqueous phase is extracted with ethyl acetate 3 times (108L of ethyl acetate is added each time), and the organic phase is collected and concentrated under reduced pressure at 42°C until no extraction is produced. 288L of dichloromethane is added to the concentrate to dissolve, 108L of saturated brine is added to wash, and the layers are separated. 5kg of anhydrous sodium sulfate is added to the organic phase for drying and dehydration, 10kg of anhydrous magnesium sulfate is added to the filter, and the filter cake is washed with 36L of dichloromethane, and the filtrate is collected and concentrated under reduced pressure at 38°C until no extraction is produced. 108L of petroleum ether is added to the concentrate for pulping and crystallization, and the filter cake is washed with 36L of petroleum ether. After the filter cake is dried under reduced pressure at 40°C for 8 hours, a sample is taken for detection, and the drying loss is less than 5%, and a powder is obtained to obtain an off-white solid (i.e., N-tert-butyloxycarbonyl-3-hydroxy-D-valine).

[0088] IV. Preparation of crude product of compound of formula (I)

[0089] At 20°C, N-tert-butyloxycarbonyl-3-hydroxy-D-valine (21.00 kg) and N,N-dimethylformamide (84 L) were added to the reactor, the temperature was lowered to 0°C, sodium bicarbonate (26.27 kg) was slowly added with stirring, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (18.94 kg) and 1-hydroxybenzotriazole (13.38 kg) were added in sequence, the reaction was stirred for 30 minutes, and then O-benzyloxyammonium hydrochloride (15.81 kg) was added. The temperature was raised to 30°C and the reaction was carried out for 16 hours. The intermediate control reaction was completed to obtain a product solution.

[0090] Purified water (210 L) and dichloromethane (210 L) were added to the product solution, stirred, and the mixture was allowed to stand for stratification and extraction. The aqueous phase was extracted twice with dichloromethane (84 L) each time, and the organic phases were combined. The mixture was then washed with 1 mol / L hydrochloric acid (150 L), 5 wt% sodium bicarbonate solution (150 L), and saturated brine (105 L) in that order. Anhydrous sodium sulfate (5 kg) was added to the washed solution for drying and dehydration, and anhydrous magnesium sulfate (10 kg) was added to the filter for filtration. The filtrate was concentrated under reduced pressure at 38° C. until there was no extraction from the condenser to obtain a crude product of the compound of formula (I) as a light yellow oil.

[0091] V. Purification of the crude product of the compound of formula (I)

[0092] Example 1

[0093] At 20°C, the first portion of isopropyl ether (42 L) was added to the crude product of the compound of formula (I) prepared in IV and stirred, and then purified water (210 L) was added to precipitate a white solid, and then the second portion of isopropyl ether (63 L) was added and stirred at 5°C for 2 hours, followed by filtration, and the filter cake was rinsed with a mixed solution of isopropyl ether and petroleum ether (10.5 L / 52.5 L). It was then dried at room temperature (25°C) for 8 hours to obtain a white solid.

[0094] Example 2

[0095] Purification was carried out in the same manner as in Example 1, except that after the filter cake was washed, the filter cake was dried under reduced pressure at 42° C. for 8 h, thereby obtaining a white solid.

[0096] Example 3

[0097] Purification was carried out in the same manner as in Example 2, except that 30 L of the first portion of isopropyl ether was added (ie, the volume ratio of the first portion of isopropyl ether to water was 1:7).

[0098] Example 4

[0099] Purification was carried out in the same manner as in Example 2, except that the amount of the first portion of isopropyl ether added was 70 L (ie, the volume ratio of the first portion of isopropyl ether to water was 1:3).

[0100] Example 5

[0101] Purification was carried out in the same manner as in Example 2, except that 21 L of the second portion of isopropyl ether was added (ie, the volume ratio of the first portion of isopropyl ether to the second portion of isopropyl ether was 1:0.5).

[0102] Example 6

[0103] Purification was carried out in the same manner as in Example 2, except that 42 L of the second portion of isopropyl ether was added (ie, the volume ratio of the first portion of isopropyl ether to the second portion of isopropyl ether was 1:1).

[0104] Example 7

[0105] Purification was carried out in the same manner as in Example 2, except that the amount of the first portion of isopropyl ether added was 126 L (ie, the volume ratio of the first portion of isopropyl ether to the second portion of isopropyl ether was 1:3).

[0106] Example 8

[0107] Purification was performed in the same manner as in Example 2, except that a mixed solution of isopropyl ether and petroleum ether (10.5 L / 32.5 L) was used (ie, the volume ratio of isopropyl ether to petroleum ether was 1:3).

[0108] Example 9

[0109] Purification was performed in the same manner as in Example 2, except that a mixed solution of isopropyl ether and petroleum ether (10.5 L / 73.5 L) was used (ie, the volume ratio of isopropyl ether to petroleum ether was 1:7).

[0110] Comparative Example 1

[0111] At 20°C, add isopropyl ether (21 L) to the crude product of the compound of formula (I) obtained in IV and stir, then add the first portion of petroleum ether (126 L) (if no solid is precipitated, distill once), after solid is precipitated, stir for 1 h and then add the second portion of petroleum ether (63 L), cool to 10°C and grow crystals for 4 h, then filter, and rinse the filter cake with the third portion of petroleum ether (42 L).

[0112] The moisture content, yield and purity of the compound of formula (I) obtained in Examples 1-9 of the present application and Comparative Example 1 are shown in Table 1 below.

[0113] Table 1 Moisture content, yield and purity of the products of Examples 1-9 of the present application and Comparative Example 1

[0114]

[0115] It can be seen from Table 1 that compared with the purification method in the prior art (i.e., Comparative Example 1), the method of the present application can obtain a higher yield and purity - the yield can be as high as 69.51% and the purity can be as high as 99.17%. The crude product of the compound of formula (I) is purified by adding a first portion of isopropyl ether (which can dissolve the oily impurities in the product but has a low solubility in the product); then the product is stably precipitated into the aqueous phase by water and the impurities are left in the organic phase, and then isopropyl ether is added again, which can dissolve the oily impurities that may still remain on the precipitated product and purify the product in the second stage; finally, the filtered filter cake is rinsed with a mixed solution of isopropyl ether and petroleum ether to remove the oily impurities for tertiary purification, thereby finally obtaining a crystal of the compound of formula (I) with a high yield and purity, and the crystal of the compound of formula (I) can be directly used for subsequent preparation, such as the preparation of β-lactam compounds without preparatory separation.

[0116] It should be noted that the present application is not limited to the above-mentioned embodiments. The above-mentioned embodiments are only examples, and the embodiments having the same structure as the technical idea and exerting the same effect within the scope of the technical solution of the present application are all included in the technical scope of the present application. In addition, without departing from the scope of the main purpose of the present application, various modifications that can be thought of by those skilled in the art to the embodiments and other methods of combining some of the constituent elements in the embodiments are also included in the scope of the present application.

Claims

1. A method for purifying a compound of formula (I), characterized in that: The method comprises the following steps: (S1) reacting N-tert-butyloxycarbonyl-3-hydroxy-L-valine with O-benzyloxyammonium hydrochloride in N,N-dimethylformamide, and separating the product solution to provide a crude product of the compound of formula (I); (S2) adding a first portion of C2-C6 ether, water and a second portion of C2-C6 ether to the crude product in sequence, and then rinsing the filter cake obtained by filtration with a mixed solution of isopropyl ether and petroleum ether to obtain a compound of formula (I), wherein the volume ratio of the first portion of C2-C6 ether to water is 1:3-7, and the volume ratio of the first portion of C2-C6 ether to the second portion of C2-C6 ether is 1:0.5-3.

2. The method for purifying the compound of formula (I) according to claim 1, characterized in that: The volume ratio of the first portion of C2-C6 ether to water is 1:4-6.

3. The method for purifying the compound of formula (I) according to claim 1, characterized in that: The volume ratio of the first portion of C2-C6 ether and water is 1:

5.

4. The method for purifying the compound of formula (I) according to claim 1, characterized in that: The method further comprises: drying under reduced pressure after rinsing the obtained filter cake with a mixed solution of isopropyl ether and petroleum ether.

5. A method for purifying a compound of formula (I) according to any one of claims 1 to 4, characterized in that: The first C2-C6 ether is isopropyl ether and the second C2-C6 ether is isopropyl ether.

6. A method for purifying a compound of formula (I) according to any one of claims 1 to 4, characterized in that: The volume ratio of the first portion of C2-C6 ether to the second portion of C2-C6 ether is 1:1-2.

7. A method for purifying a compound of formula (I) according to any one of claims 1 to 4, characterized in that: The volume ratio of the first portion of C2-C6 ether to the second portion of C2-C6 ether is 1:1.

5.

8. A method for purifying a compound of formula (I) according to any one of claims 1 to 4, characterized in that: When the second portion of the C2-C6 ether was added, the temperature dropped to 2-8°C.

9. A method for purifying a compound of formula (I) according to any one of claims 1 to 4, characterized in that: The volume ratio of isopropyl ether to petroleum ether in the mixed solution of isopropyl ether and petroleum ether is 1:3-7.

10. The method for purifying the compound of formula (I) according to claim 9, characterized in that: The volume ratio of isopropyl ether to petroleum ether in the mixed solution of isopropyl ether and petroleum ether is 1:4-6.

11. The method for purifying the compound of formula (I) according to claim 9, characterized in that: The volume ratio of isopropyl ether to petroleum ether in the mixed solution of isopropyl ether and petroleum ether is 1:

5.

12. The method for purifying the compound of formula (I) according to claim 1, characterized in that: The separation comprises extracting, washing, drying, filtering and concentrating the product solution under reduced pressure in sequence.

13. The method for purifying the compound of formula (I) according to claim 12, characterized in that: The extraction is to add a mixed solution of water and dichloromethane to the product solution, then stand for stratification extraction, extract the aqueous phase with dichloromethane again, and combine the organic phases, wherein the volume ratio of water to dichloromethane in the mixed solution of water and dichloromethane is 1:0.5-1.5; The washing is to wash the organic phase obtained by extraction with an acidic solution, an alkaline solution and a neutral solution in sequence; The drying step is to dry the product solution after extraction and washing with anhydrous sodium sulfate and / or anhydrous magnesium sulfate; The reduced pressure concentration is carried out at a temperature of 30-45°C.

14. The method for purifying the compound of formula (I) according to claim 13, characterized in that: The volume ratio of water to dichloromethane in the mixed solution of water and dichloromethane is 1:0.8-1.

2.

15. The method for purifying the compound of formula (I) according to claim 13, characterized in that: The volume ratio of water to dichloromethane in the mixed solution of water and dichloromethane is 1:

1.

16. The method for purifying the compound of formula (I) according to claim 13, characterized in that: The reduced pressure concentration is carried out at a temperature of 35-40°C.

17. The method for purifying the compound of formula (I) according to claim 1, characterized in that: Based on the weight of the N-tert-butyloxycarbonyl-3-hydroxy-L-valine, the amount of water added in step (S2) is 10 to 12 times the amount of the N-tert-butyloxycarbonyl-3-hydroxy-L-valine.

18. The method for purifying the compound of formula (I) according to claim 17, characterized in that: The amount of water added in step (S2) is 10 times that of the N-tert-butyloxycarbonyl-3-hydroxy-L-valine.

19. A process for preparing a β-lactam compound, wherein the compound of formula (I) obtained according to the process of any one of claims 1 to 18 is used to prepare a β-lactam compound.

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