A process for preparing chlorinated olefins

Abstract

The present invention provides a chlorination preparation process for olefins, and the process comprises the following operating steps: raw material 3-methyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester is added to a solvent to dissolve, and a catalyst and a chlorination reagent are added to react; after the reaction is completed, pH is adjusted to neutral, and after extraction and rotary evaporation of part of the solvent, an anti-solvent is added to stir and crystallize, and the target product 3-chloromethyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester is obtained, and the preparation method of the present invention is simple to operate, avoids the use of chlorine, and the solvent can be recycled, and the reaction process conditions are mild, and a high-purity and high-yield target product is finally obtained, which is suitable for industrialized amplification production.

Description

[0001] The present invention claims the priority of Chinese patent application CN202310716923.6, and the contents of the specification, drawings and claims of the priority document are fully incorporated into the specification of the present invention and are regarded as part of the original description of the present invention. The applicant further declares that the applicant has the right to modify the specification and claims of the present invention based on the priority document. Technical Field

[0002] The invention belongs to the technical field of pharmaceutical chemical industry, and in particular relates to a method for preparing a chlorinated oxycephem parent nucleus intermediate. Background Art

[0003] Oxocephalene nucleus intermediate is an important intermediate for the preparation of fluoxetine and latamoxetine:

[0004] Fluoxetine is a semisynthetic oxycephalosporin antibiotic and a broad-spectrum antibiotic. Similar to other β-lactam antibiotics, Fluoxetine may also bind to one or more penicillin-binding proteins to hinder bacterial cell wall biosynthesis, thereby achieving antibacterial effects.

[0005] The mechanism of action of Latamoxef is to inhibit the biosynthesis of bacterial cell walls and thus exert a bactericidal effect. Compared with the first and second generation cephalosporins, its antibacterial spectrum is further expanded and it is highly stable to β-lactamase, so it has antibacterial effects on strains resistant to penicillinase or some Gram-negative bacteria resistant to the first and second generation cephalosporins. Latamoxef is a 1-benzoazole-β-lactam antibiotic with a unique structure among β-lactam compounds.

[0006] At present, there is little research on the parent intermediate of oxocephem in China, and the existing technology has high preparation cost and is not suitable for industrial production. The literature Tetrahedron Letters, 1980, 21: 351-354. reported the synthesis routes of several key intermediates of oxocephem antibiotics, among which [1R-[1α, 5α]]-3-methyl-2-(7-oxo-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-ene-6-6yl)-3-butenoic acid diphenylmethyl ester was used as raw material and chlorinated with chlorine to obtain [1R-[1α, 5α]]-3-chloromethyl-2-(7-oxo-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-ene-6-6yl)-3-butenoic acid diphenylmethyl ester. The reaction process is as follows:

[0007]

[0008] The paper "Research on the Synthesis Process of Oxycephem Antibiotic Intermediates" published by Zhejiang University of Technology in 2018 involves the synthesis of the following oxycephem nucleus intermediate. The oxycephem nucleus intermediate and the oxycephem nucleus intermediate of the present invention have an o-methyl difference in molecular structure. However, after research and experiments, the research and development team of the present invention found that chlorination of the allylic position inevitably occurs during the addition of the double bond, resulting in more reaction impurities, lower yield, and the following side reactions:

[0009]

[0010] Patent CN103254215A discloses a method for preparing an oxycephem parent nucleus intermediate, which first reacts the double bond of the allylic position with chlorine to obtain a dichloro product through an addition reaction, and then undergoes elimination reaction, hydrolysis reaction, ring closure reaction and halogenation reaction to obtain the target product. It is worth noting that chlorine is used as a chlorination reagent for addition reaction in the above patents or documents, so the operating equipment requirements are too high, and the use control of chlorine should be more delicate, resulting in the need for attention and operation matters in industrial production becoming cumbersome, and the introduction and control of chlorine are demanding, which is not conducive to industrialized amplification production.

[0011] Zhengzhou University disclosed the following synthetic route of the oxycephem nucleus intermediate in patent CN106188097A. The allylic chlorination is a free radical reaction. The allylic chlorination of the synthetic route uses chlorosuccinimide as a chlorination reagent. The allylic chlorination compound 3 is obtained by reflux reaction with the participation of a free radical initiator. The allylic chlorination reaction time in this patent is long, requiring a reflux reaction of 6 hours. The addition of the initiator results in poor reaction stability, increased impurities, and poor reaction selectivity. Summary of the invention

[0012] In view of the above problems, it is necessary to improve and optimize the preparation method of the oxocephem nucleus intermediate, and develop a synthesis route of the oxocephem nucleus intermediate [1R-[1α,5α]]-3-chloromethyl-2-(7-oxo-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-ene-6-6yl)-3-butenoic acid diphenylmethyl ester with higher yield, lower cost and more suitable for industrial production.

[0013] The invention provides an olefin chlorination preparation process, comprising the steps of adding a raw material of 3-methyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester into a solvent for dissolution, adding a catalyst and a chlorination agent for reaction; adjusting the pH to neutral after the reaction is completed, extracting and rotary evaporating part of the solvent, adding an anti-solvent for stirring and crystallization, and separating and drying to obtain a target product.

[0014] The reaction process of the present invention is as follows:

[0015]

[0016] The method comprises the following steps: wherein 3-methyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-en-6-yl)-3-butenoic acid dibenzoyl ester is the raw material; and 3-chloromethyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-en-6-yl)-3-butenoic acid dibenzoyl ester is the target product.

[0017] As described above, in the technical solution of the present invention, the reaction process of using 3-methyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester as a raw material and reacting with a chlorinating agent to prepare 3-chloromethyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester is a free radical reaction. How to initiate the reaction at the beginning has become a key operation for controlling the reaction process and related to the purity and yield of the product.

[0018] In the prior art, the reaction is often initiated by the following two methods: one is to add an initiator, such as patent CN106188097A uses any one of cyclohexanone peroxide, dibenzoyl peroxide, tert-butyl hydroperoxide, azobisisobutyronitrile, and azobisisoheptanenitrile as an initiator to initiate the reaction; but it is worth noting that the free radical reaction initiated by the initiator is very intense, and the reaction rate usually increases rapidly in the initial stage of the free radical reaction. Therefore, the technical solution has poor reaction controllability and low operability, which will lead to a large number of side reactions and further reduce the purity and yield of the product. This method limits the large-scale industrial production; the second is to initiate the free radical reaction by ultraviolet irradiation. Considering the harmfulness of ultraviolet rays to the human body and the relatively expensive equipment cost and maintenance cost, this method is not convenient for use in industrial production.

[0019] Faced with the wide application prospects and growing market demand of oxycephem antibiotics, the research and development team of the present invention tried to find a new way to explore a method for preparing oxycephem parent core intermediates with high purity, high yield, more controllability and suitable for industrial production. Based on a large number of experimental studies, the research and development team of the present invention unexpectedly found that adding a catalyst to the chlorination reaction in the existing technical route can significantly improve the product yield and optimize the product appearance, while significantly shortening the reaction time, and the reaction conditions are milder; more importantly, the purity and product state of the prepared target product are better, that is, the product quality is better, thus proposing the technical solution of the present invention.

[0020] Based on the above technical solution, the research and development team carried out exploratory experiments on different types of catalysts. Specifically, when the lanthanum chloride, zinc chloride or tellurium tetrachloride or copper chloride is used, the product purity and product yield obtained by the preparation process are high, and the side reactions occur less, the reaction conditions are mild, and the reaction efficiency is high; the catalyst used can further be selected as zinc chloride.

[0021] Based on the above technical solution, the research and development team of the present invention has conducted a large number of exploratory experiments on the amount of catalyst used. Specifically, the amount of the catalyst added can be selected to be 5%-10% of the molar amount of the raw material. Within this catalyst addition range, the target product prepared has high purity and high yield; further optionally, the amount of the catalyst added is 8% of the molar amount of the raw material.

[0022] Based on the above technical scheme, the research and development team of the present invention has carried out a large number of exploratory experiments on the type and addition amount of the chlorinating agent used. Optionally, the chlorinating agent includes one of oxalyl chloride, triphosgene, and chlorosuccinimide, and can further be selected from chlorosuccinimide. Optionally, the molar ratio of the chlorinating agent to the raw material is 1.0-1.1:1, further can be selected as 1.05-1.1:1, and further can be selected as 1.05:1. The purity and product state of the target product prepared under the condition of the chlorinating agent in this dosage are better, that is, the product quality is better.

[0023] Based on the above technical scheme, the research and development team of the present invention has conducted a large number of exploratory experiments on the type of solvent used and the amount of solvent added. The solvent can be selected from one of ethyl acetate, dichloromethane, chloroform, dichloroethane, and tetrahydrofuran. When tetrahydrofuran and ethyl acetate are used, the yield and purity of the target product are higher, so the solvent can be further selected from tetrahydrofuran or ethyl acetate; in order to reduce the difficulty of the subsequent extraction operation process, the solvent can be further selected from ethyl acetate.

[0024] Based on the above technical solution, the research and development team of the present invention explored the amount of the solvent. Specifically, the mass ratio of the solvent to the raw material can be selected as 10-20:1; further selected as 12-16:1, and the purity and yield of the target product obtained within this range are better; further selected as 14:1. The preparation results of different types of solvents and different amounts of solvents are given in the examples of the present invention.

[0025] In the above technical scheme, after adjusting the pH value of the reacted material, the product only needs to be extracted into an organic solvent, and then the solvent is concentrated and part of the solvent is evaporated, and then an anti-solvent is added for stirring and crystallization to obtain the target product. The overall process is simple to operate and is conducive to industrial production.

[0026] Based on the above technical scheme, the research and development team of the present invention explored and optimized the types of anti-solvents. Specifically, the anti-solvent can be selected from methanol, ethanol, isopropanol, n-hexane, and one of petroleum ether, and can be further selected from methanol or ethanol, and can be further selected from methanol.

[0027] Based on the above technical solution, the research and development team of the present invention explored the dosage of the anti-solvent. Specifically, the mass ratio of the anti-solvent to the raw material is (3-7):1.

[0028] Based on the above technical scheme, the research and development team explored and optimized the reaction temperature and reaction time. The temperature can be optionally controlled to 0-30°C, preferably 15-20°C. The reaction conditions of the olefin chlorination process of the present invention are mild and can react at room temperature. In addition, the reaction time can be selected to be 2-6h, and further selected to be 2h. The efficiency of the olefin chlorination process of the present invention is high.

[0029] Based on the above technical scheme, the method further includes rotary evaporation of the organic phase after extraction; further, the method further includes washing the extracted solvent with water and / or saturated brine before rotary evaporation.

[0030] Based on the above technical scheme, the solvent is also recycled after rotary evaporation, for example, the solvent of rotary evaporation can be partially evaporated and reused, so as to further reduce production costs and improve operability. It should be noted that the present invention does not limit the specific evaporation amount of rotary evaporation, which can be selected to be evaporated until about half of the solution is retained. Those skilled in the art can determine the specific evaporation amount through non-creative labor and for the principle of convenience of process use, and the technical schemes formed thereby are all within the scope of protection of the present invention.

[0031] Beneficial effects of the present invention:

[0032] The invention provides an olefin chlorination preparation process. Under the action of a catalyst, 3-methyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester is reacted with a chlorination reagent to prepare a target product, 3-chloromethyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester. The process of the invention is simple to operate, avoids the use of highly toxic chlorine, does not use chlorine-resistant equipment and light-proof equipment, and reduces production costs; and the applicable reaction conditions are milder, no reflux reaction is required, energy consumption is reduced, and process efficiency is improved; the process of the invention has high product yield, high product purity, simple post-processing, and improved optical purity and chemical purity of the product compared with the prior art, and is more suitable for industrial-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1The HPLC spectrum of the target product prepared in Example 1. DETAILED DESCRIPTION

[0034] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0035] In order to facilitate the understanding of the present invention, the present invention will be described more comprehensively below, and preferred embodiments of the present invention are given. However, it should be understood that these embodiments are only used for more detailed description and should not be understood as limiting the present invention in any form, i.e., not intended to limit the scope of protection of the present invention.

[0036] Sources of raw materials in the following examples:

[0037]

[0038] HPLC detection conditions: chromatographic column model: liquid column model: l unaC18, 5um, 250*4.6; column temperature: 25℃; mobile phase: acetonitrile: water = 70:30; flow rate: 1ml / min; absorption wavelength: 254nm; injection volume: 0.1ul;

[0039] The present invention adopts HPLC to detect the purity of the product; the product yield is the molar ratio of the weight converted into mole number after drying to the raw material.

[0040] The present invention will be further described below in conjunction with the embodiments.

[0041] Example 1

[0042] Add 90g 3-methyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester (raw material) (0.19mol, 1eq) and 1200g ethyl acetate to the reactor, stir until completely dissolved, add 2g zinc chloride (0.015mol, 8%eq) to the reactor, add 26.6g chlorosuccinimide (0.199mol, 1.05eq), control the temperature at 20-25℃, stir the reaction liquid for 2h. HPLC detection raw material residue <0.5%, add saturated sodium bicarbonate solution for washing. The reaction solution was allowed to stand and stratified, the organic phase was separated and the ethyl acetate phase was washed with purified water and saturated brine, the ethyl acetate was concentrated to one third, 350 g of methanol was added, and the crystallization temperature was controlled at -5°C-0°C, and the target product, oxacephem parent core intermediate 3-chloromethyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester, was obtained as a white powder of 90.25 g with a purity of 99.2% and a yield of 95.2%.

[0043] Comparative Example 1

[0044] Comparative Example 1.1: Add 90g of 3-methyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester (raw material) (0.19 mol, 1 eq) and 1200g of ethyl acetate to the reactor, stir until completely dissolved, add 26.6g of chlorosuccinimide (0.199 mol, 1.05 eq), control the temperature at 20-25°C, stir the reaction liquid for 6h. Raise the temperature to reflux state, reflux the reaction for 8h, HPLC detection raw material residue <0.5%, add saturated sodium bicarbonate solution for washing. The reaction solution was allowed to stand and stratified, the organic phase was separated and the ethyl acetate phase was washed with purified water and saturated brine, the ethyl acetate was concentrated to one third, 350 g of methanol was added, and the crystallization temperature was controlled at -5°C-0°C, and the target product, oxacephem parent core intermediate 3-chloromethyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester, was obtained as a white powder of 60.3 g with a purity of 95.1% and a yield of 63.4%.

[0045] Further, based on Comparative Example 1.1, the present Comparative Examples 1.2-1.5 explored the reproducibility of the experimental results of preparing the oxacephem parent core intermediate 3-chloromethyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester by chlorination reaction under the same experimental conditions when no catalyst was used. The comparative results are shown in Table 1.

[0046] Table 1

[0047]

[0048] Combining Example 1 with Table 1, it can be confirmed that when no catalyst is added, the properties of the prepared target product are unstable, with low purity, many impurities, or it is difficult to precipitate solid products, etc., reflecting that the process shown in Comparative Example 1 not only has low product selectivity, but also poor experimental repeatability.

[0049] Comparative Example 2

[0050] Add 90g of 3-methyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester (raw material) (0.19mol, 1eq) and 1200g of ethyl acetate to the reactor, stir until completely dissolved, add a catalyst and / or an initiator to the reactor, then introduce chlorine (0.18mol, 0.95eq), control the temperature at 35-40°C, and stir the reaction liquid for 3-6h. HPLC detection shows that the raw material residue is less than 0.5%, and a saturated sodium bicarbonate solution and sodium sulfite are added dropwise for washing. The reaction solution was allowed to stand and stratified, the organic phase was separated and the ethyl acetate phase was washed with purified water and saturated brine, the ethyl acetate was concentrated to one third, 350 g of methanol was added, stirred and crystallized, the temperature was controlled at -5°C-0°C, and centrifuged and dried to obtain the target product, oxacephem nucleus intermediate 3-chloromethyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester

[0051] The experimental results are shown in Table 2. The free radical initiator added was azobisisobutyronitrile (AI BN), and the added ratio was 0.6% of the raw material; the catalyst added was 2 g of zinc chloride, and the ratio was 8% of the raw material.

[0052] Table 2

[0053]

[0054] The above Table 2 can verify that the products obtained by the reaction with the addition of chlorine are all light yellow solids, and the yield is much lower than that of Example 1; under the same reaction control conditions, the chlorine reaction yield of Comparative Examples 2.1-2.7 is much lower than that of Example 1.

[0055] Example 2

[0056] Add 90g 3-methyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester (raw material) (0.19mol, 1eq) to the reactor, add 1260ml ethyl acetate, stir until completely dissolved, add different catalysts (0.019mol, 10%eq) to the reactor, add 26.6g chlorosuccinimide (0.199mol, 1.05eq), control the temperature at 20-25℃, stir the reaction liquid for 2h. HPLC detection raw material residue <0.5%, add saturated sodium bicarbonate solution for washing. The reaction solution was allowed to stand for stratification, the organic phase ethyl acetate phase was separated and washed with purified water, washed with saturated brine, concentrated to one third of the ethyl acetate, added with 400g methanol, stirred and crystallized at a temperature of -5°C-0°C, and centrifuged and dried to obtain the target product oxacephem parent core intermediate 3-chloromethyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester. Examples 2.1-2.4 respectively used different catalysts for chlorination reaction, and the experimental results are shown in Table 3.

[0057] Table 3

[0058] Example Catalyst (10%) purity Yield 2.1 Cupric chloride 97.50％ 87.50％ 2.2 Zinc chloride 98.40％ 93.50％ 2.3 Lanthanum chloride 98.20％ 89.50％ 2.4 Tellurium tetrachloride 96.80％ 88.50％

[0059] As can be confirmed from Table 3, the catalyst may optionally include zinc chloride, lanthanum chloride, tellurium tetrachloride or copper chloride, and may further optionally be zinc chloride.

[0060] This embodiment further explores the amount of catalyst used. Examples 2.5-2.10 explore the purity and yield of the target product obtained under the conditions of different mass fractions of the catalyst to the raw materials, wherein the catalyst used is zinc chloride. The experimental results are shown in Table 4.

[0061] Table 4

[0062] Examples Catalyst zinc chloride dosage (%) purity Yield 2.5 5 98.70％ 90.50％ 2.6 6 98.10％ 93.20％ 2.7 7 98.40％ 93.50％ 2.8 8 99.20％ 96.60％ 2.9 9 98.50％ 93.50％ 2.10 10 98.40％ 93.50％

[0063] It can be confirmed from Table 3 that the amount of the catalyst added in the technical solution of the present invention can be selected to be 5%-10% of the molar amount of the raw material, and can further be selected to be 8%.

[0064] Example 3

[0065] Add 90g 3-methyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester (starting material) (0.19mol, 1eq) to the reactor, add 1260ml ethyl acetate, stir until completely dissolved, add 2.1mol zinc chloride (0.015mol, 8%eq) to the reactor, add different chlorination reagents (0.199mol, 1.05eq), control the temperature at 20-25℃, stir the reaction liquid for 2h. HPLC detection raw material residue <0.5%, add saturated sodium bicarbonate solution to wash. The reaction solution was allowed to stand and stratified, the organic phase was separated and the ethyl acetate phase was washed with purified water and saturated brine, the ethyl acetate was concentrated to one third, 420 g of methanol was added and stirred for crystallization, the temperature was controlled at -5°C-0°C, and the target product, oxacephem parent core intermediate 3-chloromethyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester, was obtained as a white powder. Examples 3.1-3.9 were reacted with different chlorination reagents and different amounts of chlorination reagents, and the experimental results are shown in Table 5.

[0066] Table 5

[0067]

[0068] It can be confirmed from Table 5 that the chlorinating agent optionally includes oxalyl chloride, triphosgene or chlorosuccinimide, and further optionally chlorosuccinimide. In addition, the molar ratio of the chlorinating agent to the raw material can be 1.0-1.1:1, further can be 1.05-1.1:1, and further can be 1.05:1.

[0069] Example 4

[0070] Add 90g 3-methyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester (raw material) (0.19mol, 1eq) to the reactor, add 1200ml of different solvents, stir until completely dissolved, add 2g zinc chloride (0.015mol, 8%eq) to the reactor, add 26.6g chlorosuccinimide (0.199mol, 1.05eq), control the temperature at 20-25℃, stir the reaction liquid for 2h. HPLC detection raw material residue <0.5%, add saturated sodium bicarbonate solution for washing. The reaction solution was allowed to stand and stratified, the organic phase was separated and the ethyl acetate phase was washed with purified water and saturated brine, the ethyl acetate was concentrated to one third, 350 g of methanol was added and stirred for crystallization, the temperature was controlled at -5°C-0°C, and the target product, oxacephem parent core intermediate 3-chloromethyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester, was obtained as a white powder. Examples 4.1-4.4 were reacted using different solvents, and the results are shown in Table 6.

[0071] Table 6

[0072] Example Solvents purity Yield 4.1 Dichloromethane 98.20％ 89.50％ 4.2 Ethylene dichloride 98.50％ 89.80％ 4.3 Ethyl acetate 99.20％ 95.20％ 4.4 Tetrahydrofuran 99.10％ 93.20％

[0073] As can be verified in Table 6, the solvent can be selected from one of ethyl acetate, dichloromethane, chloroform, dichloroethane, and tetrahydrofuran; when tetrahydrofuran and ethyl acetate are used, the yield and purity of the target product are higher. Compared with tetrahydrofuran, ethyl acetate can greatly reduce the workload of the reaction in the subsequent extraction process, so the solvent can further be selected from ethyl acetate or tetrahydrofuran, and further can be selected from ethyl acetate.

[0074] Furthermore, the amount of the solvent used was optimized in this example. Examples 4.5-4.10 explored the purity and yield of the target product prepared under different mass ratios of solvent to raw material, wherein the solvent used was ethyl acetate, and the experimental results are shown in Table 7.

[0075] Table 7

[0076] Example Solvent amount purity Yield 4.5 10:1 98.40％ 94.70％ 4.6 12:1 98.70％ 95.40％ 4.7 14:1 99.20％ 96.60％ 4.8 16:1 98.20％ 95.80％ 4.9 18:1 98.20％ 94.20％ 4.10 20:1 97.90％ 93.90％

[0077] It can be confirmed from Table 7 that when the solvent used is ethyl acetate, the mass ratio of the solvent to the raw material can be selected as 10-20:1, further selected as 12-16:1, and further preferably 14:1.

[0078] Example 5

[0079] Add 90g 3-methyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester (raw material) (0.19mol, 1eq) to the reactor, add 1260ml ethyl acetate, stir until completely dissolved, add 2.1g zinc chloride (0.015mol, 8%eq) to the reactor, add 26.6g chlorosuccinimide (0.199mol, 1.05eq), control the temperature at 20-25℃, stir the reaction liquid for 2h. HPLC detection raw material residue <0.5%, add saturated sodium bicarbonate solution to wash. The reaction solution was allowed to stand and stratified, the organic phase and ethyl acetate phase were separated and washed with purified water and saturated brine, the ethyl acetate was concentrated to one third, 420 g of different anti-solvents were added, and the crystallization temperature was controlled at -5°C-0°C, and the target product, oxacephem parent core intermediate 3-chloromethyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-ene-6-yl)-3-butenoic acid dibenzoyl ester, was obtained as a white powder; Examples 5.1-5.5 explored different types of anti-solvents added to the rotary evaporator for stirring and crystallization, and the experimental results are shown in Table 8.

[0080] Table 8

[0081] Examples Solvents purity Yield 5.1 Methanol 99.20％ 96.60％ 5.2 Ethanol 99.20％ 95.10％ 5.3 n-Hexane 95.30％ 96.20％ 5.4 Petroleum ether 95.40％ 96.20％ 5.5 Isopropyl alcohol 99.50％ 88.30％

[0082] As can be verified in Table 8, the anti-solvent described in the technical solution of the present invention can be selected from methanol, ethanol, isopropanol, n-hexane or petroleum ether. The research and development team found in the experiment that when n-hexane or petroleum ether is used as the anti-solvent, the stirring crystallization is faster and the color is darker, and the solid is precipitated faster, resulting in a decrease in purity; when isopropanol is used as the anti-solvent, although a high-purity product can be obtained, the yield is significantly lower. Considering the purity and yield performance, the anti-solvent used in the present invention can be further selected from methanol or ethanol. Considering that in the industrial production process, methanol is lower in cost and easier to recover than ethanol, the anti-solvent used in the present invention can be further selected from methanol. The proportion of methanol addition is further discussed as shown in Table 9 below.

[0083] Table 9

[0084]

[0085] As can be verified in Table 9, when the anti-solvent described in the technical solution of the present invention is methanol, the mass ratio of the added solvent to the starting material is (3-7):1, the purity obtained is 99%+, the yield is about 96%, and the optimal ratio is (4-5):1.

[0086] The examples described above only express several embodiments of the present invention, which are described in detail. The above are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent substitutions, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be based on the attached claims.

Claims

1. A process for preparing chlorinated olefins, characterized in that: The target product 3-chloromethyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-en-6-yl)-3-butenoic acid dibenzoyl ester was prepared using 3-methyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-en-6-yl)-3-butenoic acid dibenzoyl ester as a raw material. The reaction steps are as follows: The raw material 3-methyl-2-(7-oxo-3-p-tolyl-4-oxa-2,6-diazabicyclo[3.2.0]-hept-2-en-6-yl)-3-butenoic acid dibenzoyl ester is added to a solvent to dissolve, and a catalyst and a chlorination agent are added to react; after the reaction is completed, the pH is adjusted to neutral, and after extraction and rotary evaporation of part of the solvent, an anti-solvent is added and stirred for crystallization, and the target product is separated and dried to obtain; Wherein, the catalyst is selected from one of zinc chloride, lanthanum chloride, tellurium tetrachloride, and copper chloride; the chlorination reagent is selected from one of oxalyl chloride, triphosgene, and chlorosuccinimide.

2. A process for preparing olefin chlorination according to claim 1, characterized in that: The catalyst is zinc chloride.

3. A process for preparing olefin chlorination according to claim 1, characterized in that: The amount of the catalyst added is 5%-10% of the molar amount of the raw material.

4. A process for preparing olefin chlorination according to claim 3, characterized in that: The amount of the catalyst added is 8% of the molar amount of the raw material.

5. A process for preparing olefin chlorination according to claim 1, characterized in that: The chlorination agent is chlorosuccinimide.

6. A process for preparing olefin chlorination according to claim 1, characterized in that: The molar ratio of the chlorination agent to the raw material is 1.0-1.1:

1.

7. A process for preparing olefin chlorination according to claim 6, characterized in that: The molar ratio of the chlorination agent to the raw material is 1.05:

1.

8. A process for preparing chlorinated olefins according to claim 1, characterized in that: The solvent is selected from one of ethyl acetate, dichloromethane, chloroform, dichloroethane and tetrahydrofuran.

9. A process for preparing olefin chlorination according to claim 8, characterized in that: The solvent is ethyl acetate.

10. The process for preparing olefin chlorination according to claim 1, characterized in that: The mass ratio of the solvent to the raw material is 10-20:

1.

11. A process for preparing olefin chlorination according to claim 10, characterized in that: The mass ratio of the solvent to the raw material is 12-16:

1.

12. A process for preparing olefin chlorination according to claim 11, characterized in that: The mass ratio of the solvent to the raw material is 14:

1.

13. The process for preparing olefin chlorination according to claim 1, characterized in that: The anti-solvent is selected from one of methanol, ethanol, isopropanol, n-hexane and petroleum ether.

14. A process for preparing olefin chlorination according to claim 13, characterized in that: The anti-solvent is methanol.

15. The process for preparing olefin chlorination according to claim 1, characterized in that: The mass ratio of the added amount of the anti-solvent to the raw material is (3-7):

1.

16. The process for preparing olefin chlorination according to claim 1, characterized in that: The reaction temperature is 0-30°C.

17. A process for preparing olefin chlorination according to claim 16, characterized in that: The reaction temperature is 15-20°C.

18. The process for preparing olefin chlorination according to claim 16, characterized in that: The reaction time is 2-6h.

19. The process for preparing olefin chlorination according to claim 18, characterized in that: The reaction time is 2h.

20. The process for preparing olefin chlorination according to claim 1, characterized in that: It also includes recycling the solvent after rotary evaporation.

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