CN116925103A - Olefin chlorination preparation process - Google Patents
Olefin chlorination preparation process Download PDFInfo
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- CN116925103A CN116925103A CN202310716923.6A CN202310716923A CN116925103A CN 116925103 A CN116925103 A CN 116925103A CN 202310716923 A CN202310716923 A CN 202310716923A CN 116925103 A CN116925103 A CN 116925103A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 238000005660 chlorination reaction Methods 0.000 title claims abstract description 22
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 150000001336 alkenes Chemical class 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 239000002904 solvent Substances 0.000 claims abstract description 30
- -1 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 Chemical class 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 238000002425 crystallisation Methods 0.000 claims abstract description 13
- 230000008025 crystallization Effects 0.000 claims abstract description 13
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 239000012296 anti-solvent Substances 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 238000004090 dissolution Methods 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 230000007935 neutral effect Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 98
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 30
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 24
- 239000007858 starting material Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 235000005074 zinc chloride Nutrition 0.000 claims description 12
- 239000011592 zinc chloride Substances 0.000 claims description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 239000012320 chlorinating reagent Substances 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 6
- 238000010025 steaming Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- OFDISMSWWNOGFW-UHFFFAOYSA-N 1-(4-ethoxy-3-fluorophenyl)ethanamine Chemical compound CCOC1=CC=C(C(C)N)C=C1F OFDISMSWWNOGFW-UHFFFAOYSA-N 0.000 claims description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 3
- ICAKDTKJOYSXGC-UHFFFAOYSA-K lanthanum(iii) chloride Chemical compound Cl[La](Cl)Cl ICAKDTKJOYSXGC-UHFFFAOYSA-K 0.000 claims description 3
- 238000004064 recycling Methods 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 abstract description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 5
- 239000000460 chlorine Substances 0.000 abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 abstract description 5
- 238000000605 extraction Methods 0.000 abstract description 3
- 238000013341 scale-up Methods 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 19
- QXNSHVVNEOAAOF-RXMQYKEDSA-N (6R)-4-oxa-5-thia-1-azabicyclo[4.2.0]oct-2-en-8-one Chemical compound S1OC=CN2[C@H]1CC2=O QXNSHVVNEOAAOF-RXMQYKEDSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 14
- 238000005406 washing Methods 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000012827 research and development Methods 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 239000009096 changqing Substances 0.000 description 3
- 229960002878 flomoxef Drugs 0.000 description 3
- UHRBTBZOWWGKMK-DOMZBBRYSA-N flomoxef Chemical compound O([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSC(F)F)OC)CC=1CSC1=NN=NN1CCO UHRBTBZOWWGKMK-DOMZBBRYSA-N 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000000746 allylic group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 2
- 210000002421 cell wall Anatomy 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 description 2
- 229940041006 first-generation cephalosporins Drugs 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229940041008 second-generation cephalosporins Drugs 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000002132 β-lactam antibiotic Substances 0.000 description 2
- 229940124586 β-lactam antibiotics Drugs 0.000 description 2
- WMIQCCDZARURRI-UHFFFAOYSA-N 1,1-dichloroethane Chemical compound CC(Cl)Cl.CC(Cl)Cl WMIQCCDZARURRI-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 108700020474 Penicillin-Binding Proteins Proteins 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 150000001782 cephems Chemical class 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 229940112669 cuprous oxide Drugs 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229950009506 penicillinase Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D507/00—Heterocyclic compounds containing a condensed beta-lactam ring system, not provided for by groups C07D463/00, C07D477/00 or C07D499/00 - C07D505/00; Such ring systems being further condensed
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides an olefin chlorination preparation process, which comprises the following operation steps: 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 into a certain solvent for dissolution, then a certain catalyst is added, then a chloro reagent is added, a certain temperature is controlled, after the chloro reaction is finished, a certain saturated sodium bicarbonate is adjusted to be neutral in pH, after extraction, a part of solvent is added into an antisolvent for stirring crystallization, and the target product is obtained after separation and drying. To obtain 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. The preparation method disclosed by the invention is simple to operate, avoids the use of chlorine, can recycle the solvent, is mild in reaction process condition, finally obtains the high-purity high-yield target product, and is suitable for industrial scale-up production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical industry, and particularly relates to a preparation method of a oxacephem parent nucleus intermediate chloro.
Background
The oxacephem parent nucleus intermediate is an important intermediate for preparing flomoxef and moxef:
the action mechanism of the Laroxb is to inhibit the biosynthesis of bacterial cell walls and play a role in sterilization. Compared with the first and second generation cephalosporins, the antibacterial spectrum is further expanded, and the antibacterial spectrum is highly stable to beta-lactamase, so that the antibacterial effect on penicillinase-resistant strains or gram-negative bacteria resistant to the first and second generation cephalosporins is achieved. Laroxb is a 1-benzoxazole-beta-lactam antibiotic, and has a unique structure in beta-lactam compounds.
The flomoxef semi-synthesized oxacephem antibiotic is a broad spectrum antibiotic. Similar to other beta-lactam antibiotics, flomoxef may also act as an antibacterial agent by binding to one or more penicillin binding proteins, which inhibit bacterial cell wall biosynthesis.
At present, the research on the oxacephem parent nucleus intermediate in China is less, and the preparation cost is high, so that the oxacephem parent nucleus intermediate is not suitable for industrial production. The synthesis of several key intermediates for oxacephem antibiotics is reported in document Tetrahedron Letters,1980,21:351-354, wherein [1R- [1 alpha, 5 alpha ] ] -3-methyl-2- (7-oxo-3-phenyl-4-oxa-2, 6-diazabicyclo [3.2.0] hept-2-en-6-yl) -3-butenoic acid dibenzoyl ester is used as a raw material and chlorine is used for chloro to obtain [1R- [1 alpha, 5 alpha ] ] -3-chloromethyl-2- (7-oxo-3-phenyl-4-oxa 2, 6-diazabicyclo [3.2.0] hept-2-en-6-yl) -3-butenoic acid dibenzoyl ester. The following figures
The paper "oxacephem antibiotic intermediate synthesis process research" published in the university of Zhejiang industry and 2018 relates to the fact that in the synthesis of the oxacephem parent intermediate, the oxacephem parent intermediate and the oxacephem parent intermediate have an ortho-methyl difference in molecular structure, but the applicant of the present invention finds that allyl chlorination inevitably occurs during double bond addition, reaction impurities are more, and the yield is lower. Patent CN103254215B discloses a synthesis reaction of a oxacephem parent nucleus intermediate, wherein the reaction is caused by adding chlorine gas to make an allyl double bond and the chlorine gas undergo an addition reaction to obtain a dichloro product, and the dichloro product is caused by excessive chlorine gas. The formation of excessive impurities may occur as a side reaction:
it can be seen from the above patent or literature that the reaction of chlorination by using chlorine gas is too high in requirement for operation equipment, and the control of chlorine gas use should be more fine, so that attention and operation matters in industrial production become complicated, and the requirement for introducing and controlling the chlorine gas is severe. The university of Zhengzhou in patent CN106188097A discloses a synthetic route of a cephem parent nucleus intermediate, allylic chlorination reaction of the synthetic route adopts chlorosuccinimide as a chlorination reagent, allylic chlorination reaction is a free radical reaction, the reaction proceeds slowly in a chemical reaction without adding a catalyst, and reflux reaction is required for 6h, so that the reaction selectivity is poor.
Disclosure of Invention
Aiming at the problems, the preparation method of the oxacephem parent nucleus intermediate is necessary to be improved and optimized, and a synthetic route which has higher yield, lower cost, no need of harsh process equipment and is more suitable for industrial production is developed.
The invention provides a preparation process of olefine chlorination, which comprises the steps of adding 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 into a solvent for dissolution, adding a catalyst and a chloro reagent for reaction; and after the reaction is finished, regulating the pH value to be neutral, extracting, rotationally steaming part of the solvent, adding an antisolvent, stirring for crystallization, separating and drying to obtain a target product.
The reaction process map of the invention is as follows:
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 used as a starting material.
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.
In the technical scheme, the research and development team of the invention unexpectedly discovers that the catalyst is added in the chlorination reaction in the prior art route, the reaction time is obviously shortened, the applicable reaction condition is milder, and more importantly, the purity and the product state of the prepared target product are better, namely the product quality is better, and the product yield is obviously improved. The embodiment of the invention verifies that the yield of the product is improved by more than 10% after the catalyst is added.
Based on the findings, research and development groups develop selectivity experiments of various catalysts, and find that when lanthanum chloride, zinc chloride or tellurium tetrachloride and copper chloride are prepared, the purity and the yield of the product obtained by the preparation process are high, side reactions are less, the reaction conditions are mild, and the reaction efficiency is high; zinc chloride is preferred.
Further, the research and development team selects the catalyst to perform a great deal of exploratory experiments on the amount of the catalyst added in the preparation process. Optionally, the adding amount of the catalyst is 5% -10% of the molar amount of the initial raw material, the purity of the prepared target product in the adding range of the catalyst is high, the yield reaches more than 94.3%, and the yield is far higher than 70.5% in the comparative example; preferably, the catalyst is added in an amount of 8% of the starting material molar amount.
In the technical scheme, the research and development team of the invention performs a large number of selectivity experiments on the types of solvents used in the reaction and the addition amount of the solvents, and the preference of the solvents. Optionally, one of ethyl acetate, dichloromethane, chloroform, dichloroethane and tetrahydrofuran. Optionally, the mass ratio of solvent to starting material is 10-20:1, preferably 12-16:1, more preferably 14:1.
The embodiment of the invention provides the preparation results of different solvents and different solvent dosages.
The invention relates to an olefin chlorination preparation process, which is characterized in that a research and development team performs a large number of selectivity experiments on the types and the addition amounts of chloridizing reagents used in the reaction and a preferred scheme. Optionally, the chlorinating agent is one of oxalyl chloride, triphosgene and chlorosuccinimide, and preferably one of chlorosuccinimide. Optionally, when the chlorinating agent is one of oxalyl chloride, triphosgene and chlorosuccinimide, the molar ratio of the chlorinating agent to the starting material is 1.0-1.1:1, preferably 1.05-1.1:1; more preferably, the purity and product state of the target product prepared at a ratio of 1.05:1 of chlorosuccinimide are better, i.e. the product quality is better. The embodiment of the invention provides the preparation results of different types of chlorinating agents and different chlorinating agent dosage.
In the olefin chlorination preparation process, a research and development team explores and optimizes the reaction temperature. The optional temperature is controlled to be 0-30 ℃, preferably 15-20 ℃.
According to the technical scheme, after the pH is adjusted, only the product is extracted to an organic solvent, then the solvent is concentrated and distilled to obtain a part of solvent, and an antisolvent is added for stirring crystallization. Further exploration and optimization of the antisolvent, wherein the antisolvent is selected from one of methanol, ethanol, isopropanol, n-hexane and petroleum ether, preferably methanol, and the mass ratio of the further addition amount to the initial raw materials is 1: (3-7). Further, the step (3) further comprises rotary steaming the extracted organic phase; further, the method also comprises the step of washing the solvent obtained by extraction with water and/or saturated salt water before rotary steaming.
The preferred solvent in the whole chlorination process is ethyl acetate, wherein the ethyl acetate solvent can be recycled after the reaction is completed. For example, the ethyl acetate solution which is distilled in a rotary way is partially evaporated for recycling. The specific evaporation is determined according to the principle of convenient process use, such as steaming to about half of the solution retention.
The invention has the beneficial effects that:
the preparation process of the olefin chlorination provided by the invention is characterized in that 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 used for preparing a target product, the operation is simple, the use of chlorine is reduced, the use of chlorine-resistant equipment and light-resistant equipment is avoided, the production cost is reduced, the reaction time can be obviously shortened by using a catalyst, the applicable reaction condition can be reacted at room temperature under milder temperature, the reflux reaction is not needed, the energy consumption is reduced, and the yield is improved. And the solvent can be recycled, the use of highly toxic chlorine is avoided in the reaction process, and finally the target product is obtained in high yield. The invention simultaneously improves the product yield by more than 95 percent, has single product and simple post-treatment, improves the optical purity and chemical purity of the product, and is more suitable for industrial scale production.
Drawings
FIG. 1 is an HPLC chart of the target product of example 1.1.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In order that the invention may be understood more fully, a more particular description of the invention will be rendered by reference to preferred embodiments thereof. It should be understood that these examples are for the purpose of more detailed description only and should not be construed as limiting the invention in any way, i.e., not intended to limit the scope of the invention.
Sources of raw materials in the following examples:
3-methyl-2- (7-oxo-3-p-tolyl-4-oxa-2, 6-diazabicyclo [3.2.0] -hept-2-en-6-one
Phenyl) -3-butenoic acid dibenzoyl ester (starting material) Shandong you group Biochemical Co., ltd
Sodium bicarbonate Henan gold Dascarification chemical industry Limited liability company
Sodium thiosulfate Shanxi Yinchang chemical industry Limited liability company
Dimethyl sulfoxide Hubei Xingfu chemical group Co., ltd
Cuprous oxide, qinghai county-femtoherba Oenotherae materials Co., ltd
Anhydrous magnesium sulfate Weifang Boyun chemical Co., ltd
Triphosgene Kang Disi chemical industry
Oxalyl chloride, division of Chengzhi county gold-handicapped Co., ltd
Sodium chloride Hubei Long boat salt Co.Ltd
Methyl alcohol Shanxi Changqing energy chemical Co.Ltd
Ethanol Shaanxi Changqing energy chemical Co.Ltd
Isopropanol Shanxi Changqing energy chemical Co.Ltd
New Material Co.Ltd. Shandong Jin Ling in dichloromethane
Dichloroethane Shandong Jin Ling New Material Co.Ltd
Ethyl acetate Jiangsu Jin Maoyuan biological chemical industry Limited liability company
New Material Co.Ltd. N-hexane Shandong Jin Ling
Tetrahydrofuran Shandong Boyuan pharmaceutical chemical Co., ltd
HPLC detection conditions: chromatographic column model: liquid phase column model: lunaC18,5um,250 x 4.6; column temperature: 25 ℃; mobile phase: acetonitrile: water=70:30; flow rate: 1ml/min; absorption wavelength: 254nm; sample injection amount: 0.1ul;
the invention adopts HPLC to detect the purity of the product; the product yield is the molar ratio of weight to moles of starting material after drying.
The invention is further illustrated below with reference to examples.
Example 1:
example 1.1
90g of dibenzoyl 3-methyl-2- (7-oxo-3-p-tolyl-4-oxa-2, 6-diazabicyclo [3.2.0] -hept-2-en-6-yl) -3-butenoic acid (starting material) (0.19 mol,1 eq) and 1200g of ethyl acetate were added to the reactor, stirred until completely dissolved, 2g of zinc chloride (0.015 mol,8% eq) was added to the reactor, and 26.6g of chlorosuccinimide (0.199mol, 1.05 eq) was added at a temperature of 20℃to 25℃and the reaction mixture was stirred for 2 hours. HPLC detection of residue of the material is less than 0.5%, and saturated sodium bicarbonate solution is added dropwise for washing. The reaction solution is stood for layering, an organic phase ethyl acetate phase is separated and washed by purified water, saturated brine is used for washing, ethyl acetate is concentrated to one third, 350g of methanol is added, stirring crystallization temperature is controlled at-5 ℃ to 0 ℃, centrifugal drying is carried out, and a target product of the oxacephem master nucleus intermediate 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 white powder is obtained, the purity is 99.2% by 90.25g, and the yield is 95.2%.
Comparative example 1.2 (without catalyst)
90g of dibenzoyl 3-methyl-2- (7-oxo-3-p-tolyl-4-oxa-2, 6-diazabicyclo [3.2.0] -hept-2-en-6-yl) -3-butenoic acid (starting material) (0.19 mol,1 eq) and 1200g of ethyl acetate were added to the reactor, stirred until completely dissolved, 26.6g of chlorosuccinimide (0.199mol, 1.05 eq) was added at a temperature of 20-25℃and the reaction mixture was stirred for 2h. Heating to reflux state, refluxing for 8h, detecting the residue of the raw material by HPLC to be less than 0.5%, and dripping saturated sodium bicarbonate solution for washing. The reaction solution is stood for layering, an organic phase ethyl acetate phase is separated and washed by purified water, saturated brine is used for washing, ethyl acetate is concentrated to one third, 350g of methanol is added, stirring crystallization temperature is controlled at-5 ℃ to 0 ℃, centrifugal drying is carried out, and a target product of the oxacephem master nucleus intermediate 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 white powder with the purity of 60.3g of 95.1 percent and the yield of 63.4 percent is obtained.
Example 1.3
After the reaction of the materials in example 1.2, no solid was obtained and no oil was separated out. Indicating that the selectivity of the reaction is lower without catalyst.
Example 2
To the reactor, 90g of dibenzoyl 3-methyl-2- (7-oxo-3-p-tolyl-4-oxa-2, 6-diazabicyclo [3.2.0] -hept-2-en-6-yl) -3-butenoic acid ester (starting material) (0.19 mol,1 eq) was added to 1200ml of a different solvent, stirred until completely dissolved, 2g of zinc chloride (0.015 mol,8% eq) was added to the reactor, and 26.6g of chlorosuccinimide (0.199mol, 1.05 eq) was added at a temperature of 20-25℃and the reaction mixture was stirred for 2 hours. HPLC detection of residue of the material is less than 0.5%, and saturated sodium bicarbonate solution is added dropwise for washing. The reaction solution is stood for layering, an organic phase ethyl acetate phase is separated and washed by purified water, saturated brine is used for washing, ethyl acetate is concentrated to one third, 350g of methanol is added, stirring crystallization temperature is controlled at-5 ℃ to 0 ℃, centrifugal drying is carried out, and a target product of oxacephem parent nucleus intermediate 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 white powder is obtained, and the yield and purity are compared with those of selected solvents under certain other conditions in the following table (as shown in table 1).
TABLE 1
| Examples | Solvent(s) | Purity of | Yield is good |
| 2.1 | Dichloromethane (dichloromethane) | 98.20％ | 89.50％ |
| 2.2 | Dichloroethane (dichloroethane) | 98.50％ | 89.80％ |
| 2.3 | Acetic acid ethyl ester | 99.20％ | 95.20％ |
| 2.4 | Tetrahydrofuran (THF) | 99.10％ | 93.20％ |
As can be seen from Table 1, the four solvents have higher yields and purities of tetrahydrofuran and ethyl acetate, and compared with tetrahydrofuran, the ethyl acetate can greatly reduce the workload of the reaction in the subsequent extraction process, so that ethyl acetate is selected as the reaction solvent, after the ethyl acetate is determined and is further optimized in quantity, the mass ratio of the ethyl acetate to the raw materials in the reaction solvent is 10-20:1, and the ethyl acetate is 12-16:1 is the yield remains substantially unchanged, more preferably 14:1, as in Table 2.
TABLE 2
| Examples | Amount of solvent | Purity of | Yield is good |
| 2.5 | 10:1 | 98.40％ | 94.70％ |
| 2.6 | 12:1 | 98.70％ | 95.40％ |
| 2.7 | 14:1 | 99.20％ | 96.60％ |
| 2.8 | 16:1 | 98.20％ | 95.80％ |
| 2.9 | 18:1 | 98.20％ | 94.20％ |
| 2.10 | 20:1 | 97.90％ | 93.90％ |
Example 3
90g of dibenzoyl 3-methyl-2- (7-oxo-3-p-tolyl-4-oxa-2, 6-diazabicyclo [3.2.0] -hept-2-en-6-yl) -3-butenoic acid ester (starting material) (0.19 mol,1 eq) was added to the reactor, 1260ml of ethyl acetate was added, stirred until completely dissolved, and various catalysts (0.019 mol,10% eq) were added to the reactor, 26.6g of chlorosuccinimide (0.199mol, 1.05 eq) was added at a temperature of 20℃to 25℃and the reaction mixture was stirred for 2h. HPLC detection of residue of the material is less than 0.5%, and saturated sodium bicarbonate solution is added dropwise for washing. The reaction solution is stood for layering, an organic phase ethyl acetate phase is separated and washed by purified water, saturated brine is used for washing, ethyl acetate is concentrated to one third, 400g of methanol is added, stirring crystallization temperature is controlled at-5 ℃ to 0 ℃, centrifugal drying is carried out, and a target product of oxacephem mother nucleus intermediate 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 white powder is obtained, and the yield and purity are shown in table 3: the influence of different catalysts used on the reaction is explored under certain other conditions of determining the dosage of ethyl acetate in a reaction system.
TABLE 3 Table 3
| Examples | Catalyst (10%) | Purity of | Yield is good |
| 3.1 | Copper chloride | 97.50％ | 87.50％ |
| 3.2 | Zinc chloride | 98.40％ | 93.50％ |
| 3.3 | Lanthanum chloride | 98.20％ | 89.50％ |
| 3.4 | Tellurium tetrachloride | 96.80％ | 88.50％ |
As can be seen from Table 3, the yield and purity of zinc chloride were optimal at 10% molar amount of the starting material, and after the catalyst zinc chloride was determined, the amount was further optimized to achieve the best yield and purity at 8%. As in table 4.
TABLE 4 Table 4
| Examples | Catalyst zinc chloride usage (%) | Purity of | Yield is good |
| 3.5 | 5 | 98.70％ | 90.50％ |
| 3.6 | 6 | 98.10％ | 93.20％ |
| 3.7 | 7 | 98.40％ | 93.50％ |
| 3.8 | 8 | 99.20％ | 96.60％ |
| 3.9 | 9 | 98.50％ | 93.50％ |
| 3.10 | 10 | 98.40％ | 93.50％ |
Example 4:
90g of dibenzoyl 3-methyl-2- (7-oxo-3-p-tolyl-4-oxa-2, 6-diazabicyclo [3.2.0] -hept-2-en-6-yl) -3-butenoic acid (starting material) (0.19 mol,1 eq) are introduced into a reactor, 1260ml of ethyl acetate are added, stirred until complete dissolution, no 2.1 zinc chloride (0.015 mol,8% eq) is added to the reactor, the temperature of the various chlorinating agents (0.199mol, 1.05 eq) is controlled between 20℃and 25℃and the reaction mixture is stirred for 2h. HPLC detection of residue of the material is less than 0.5%, and saturated sodium bicarbonate solution is added dropwise for washing. The reaction solution is stood for layering, an organic phase ethyl acetate phase is separated and washed by purified water, saturated brine is used for washing, ethyl acetate is concentrated to one third, 420g of methanol is added, stirring crystallization temperature is controlled at-5 ℃ to 0 ℃, and centrifugal drying is carried out to obtain a target product of oxacephem mother nucleus intermediate 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 white powder, and the yield and purity are shown in table 5.
TABLE 5
From Table 5, it can be seen that the yields of oxalyl chloride and triphosgene are less than 90% in the process of the three selection, the purity of triphosgene is lower, but chlorosuccinimide is obviously higher than that of chlorosuccinimide, and the best purity and the highest yield are obtained when the molar ratio of chlorosuccinimide to the starting material is 1.05:1.
Example 5:
90g of dibenzoyl 3-methyl-2- (7-oxo-3-p-tolyl-4-oxa-2, 6-diazabicyclo [3.2.0] -hept-2-en-6-yl) -3-butenoic acid (starting material) (0.19 mol,1 eq) are introduced into a reactor, 1260ml of ethyl acetate are added, stirred until complete dissolution, no 2.1 zinc chloride (0.015 mol,8% eq) is added to the reactor, the temperature is controlled between 20 and 25℃and 26.6g chlorosuccinimide (0.199mol, 1.05 eq) is added, and the reaction mixture is stirred for 2h. HPLC detection of residue of the material is less than 0.5%, and saturated sodium bicarbonate solution is added dropwise for washing. The reaction solution is stood for layering, an organic phase ethyl acetate phase is separated and washed by purified water, saturated brine is used for washing, ethyl acetate is concentrated to one third, 420g of different antisolvents are added, stirring crystallization temperature is controlled at-5 ℃ to 0 ℃, centrifugal drying is carried out, and a target product of the oxacephem parent nucleus intermediate 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 obtained, white powder is obtained, under the condition that other conditions are determined to be one, different antisolvents are selected, and the yield and purity obtained by adding the antisolvents into the rotary evaporation liquid are shown in the table 6.
TABLE 6
| Examples | Solvent(s) | Purity of | Yield is good |
| 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％ |
As can be seen from Table 6, when the stirring crystallization solvent was methanol ethanol, the effect was best, methanol was cheaper and easier to recycle than ethanol, and when n-hexane and petroleum ether were added in the experiment, the stirring crystallization was faster and darker in color, the precipitated solid was faster, resulting in a decrease in purity, and isopropyl alcohol was significantly decreased in yield although a high purity product was obtained. The use of methanol to agitate the crystallization is optimal.
The above examples merely represent a few embodiments of the present invention, which are described in detail and detail. The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention. It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope of the invention, which is defined in the appended claims.
Claims (11)
1. A process for preparing chloro-olefine, which is characterized in that 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 taken as a raw material to prepare a 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, and the reaction steps are as follows: adding 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 into a solvent for dissolution, and adding a catalyst and a chloro reagent for reaction; and after the reaction is finished, regulating the pH value to be neutral, extracting, rotationally steaming part of the solvent, adding an antisolvent, stirring for crystallization, separating and drying to obtain a target product.
2. The process for the preparation of an olefin by chlorination according to claim 1, wherein the solvent is one of ethyl acetate, dichloromethane, chloroform, dichloroethane and tetrahydrofuran, preferably ethyl acetate.
3. The process for the preparation of an olefin by chlorination according to claim 2, characterized in that when the solvent is ethyl acetate, the mass ratio of solvent to raw material is 10-20:1, preferably 12-16:1, more preferably 14:1.
4. The process for the preparation of an olefin chloride according to claim 1, wherein the catalyst is one of zinc chloride, lanthanum chloride, tellurium tetrachloride, and copper chloride, preferably zinc chloride.
5. The process for the preparation of an olefin by chlorination according to claim 1, characterized in that the catalyst is added in an amount of 5% to 10%, preferably 8% of the molar amount of the starting material.
6. The process for preparing olefin chloride according to claim 1, wherein the chlorinating agent is one of oxalyl chloride, triphosgene and chlorosuccinimide, preferably chlorosuccinimide.
7. The process for the preparation of an olefin by chlorination according to claim 1, characterized in that the molar ratio of the chlorinating agent to the starting material is 1.0-1.1:1, preferably 1.05:1.
8. The process for the preparation of an olefin by chlorination according to claim 1, wherein the antisolvent is one of methanol, ethanol, isopropanol, n-hexane, petroleum ether, preferably methanol.
9. The process for the preparation of an olefin by chlorination according to claim 1, characterized in that the mass ratio of the addition amount of the antisolvent to the starting material is 1: (3-7).
10. A process for the preparation of an olefin by chlorination according to claim 1, characterized in that the temperature is controlled between 0 and 30 ℃, preferably between 15 and 20 ℃.
11. The process for the preparation of an olefin by chlorination according to claim 1, further comprising recycling the solvent after rotary evaporation.
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