CN105384688A - Novel environment-friendly method for preparing pleuromulin Beckmann rearrangement product - Google Patents
Novel environment-friendly method for preparing pleuromulin Beckmann rearrangement product Download PDFInfo
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- CN105384688A CN105384688A CN201510827996.8A CN201510827996A CN105384688A CN 105384688 A CN105384688 A CN 105384688A CN 201510827996 A CN201510827996 A CN 201510827996A CN 105384688 A CN105384688 A CN 105384688A
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- China
- Prior art keywords
- oxime
- pleuromutilin
- beckmann rearrangement
- rearrangement product
- chloride
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- 238000006237 Beckmann rearrangement reaction Methods 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 20
- ZRZNJUXESFHSIO-BKUNHTPHSA-N 3de4a80mz1 Chemical compound C([C@H]([C@@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-BKUNHTPHSA-N 0.000 title abstract 3
- 229950009961 pleuromulin Drugs 0.000 title abstract 3
- 239000002904 solvent Substances 0.000 claims abstract description 26
- 239000002608 ionic liquid Substances 0.000 claims abstract description 16
- 239000002841 Lewis acid Substances 0.000 claims abstract description 10
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 10
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 239000002131 composite material Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 63
- ZRZNJUXESFHSIO-UHFFFAOYSA-N Pleuromutilin Natural products CC1C(O)C(C)(C=C)CC(OC(=O)CO)C2(C)C(C)CCC31C2C(=O)CC3 ZRZNJUXESFHSIO-UHFFFAOYSA-N 0.000 claims description 23
- -1 pleuromutilin oxime Chemical class 0.000 claims description 23
- 238000010992 reflux Methods 0.000 claims description 20
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- GFHNAMRJFCEERV-UHFFFAOYSA-L cobalt chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Co+2] GFHNAMRJFCEERV-UHFFFAOYSA-L 0.000 claims description 8
- JHXKRIRFYBPWGE-UHFFFAOYSA-K bismuth chloride Chemical compound Cl[Bi](Cl)Cl JHXKRIRFYBPWGE-UHFFFAOYSA-K 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- ONDPHDOFVYQSGI-UHFFFAOYSA-N zinc nitrate Chemical compound [Zn+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ONDPHDOFVYQSGI-UHFFFAOYSA-N 0.000 claims description 6
- 235000005074 zinc chloride Nutrition 0.000 claims description 5
- 239000011592 zinc chloride Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 3
- 239000011790 ferrous sulphate Substances 0.000 claims description 3
- HTUOOVUNNYVZGP-UHFFFAOYSA-N imidazolidine-1-sulfonic acid Chemical compound OS(=O)(=O)N1CCNC1 HTUOOVUNNYVZGP-UHFFFAOYSA-N 0.000 claims description 3
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 3
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 3
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 claims description 3
- 235000011285 magnesium acetate Nutrition 0.000 claims description 3
- 239000011654 magnesium acetate Substances 0.000 claims description 3
- 229940069446 magnesium acetate Drugs 0.000 claims description 3
- 235000011147 magnesium chloride Nutrition 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- LAIZPRYFQUWUBN-UHFFFAOYSA-L nickel chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ni+2] LAIZPRYFQUWUBN-UHFFFAOYSA-L 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- MQRWBMAEBQOWAF-UHFFFAOYSA-N acetic acid;nickel Chemical compound [Ni].CC(O)=O.CC(O)=O MQRWBMAEBQOWAF-UHFFFAOYSA-N 0.000 claims description 2
- 229940063656 aluminum chloride Drugs 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- 229960003280 cupric chloride Drugs 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229940032950 ferric sulfate Drugs 0.000 claims description 2
- 229960001781 ferrous sulfate Drugs 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 2
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 claims description 2
- 229910000360 iron(III) sulfate Inorganic materials 0.000 claims description 2
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 claims description 2
- 229940078494 nickel acetate Drugs 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 22
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 230000008707 rearrangement Effects 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 238000007796 conventional method Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 239000000047 product Substances 0.000 description 28
- 239000012043 crude product Substances 0.000 description 18
- 239000000284 extract Substances 0.000 description 18
- 238000001914 filtration Methods 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 18
- 150000002923 oximes Chemical class 0.000 description 18
- 238000005292 vacuum distillation Methods 0.000 description 18
- 238000005406 washing Methods 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- LXSLZSJZGMWGOL-UHFFFAOYSA-N butane-1-sulfonate;pyridin-1-ium Chemical compound C1=CC=[NH+]C=C1.CCCCS([O-])(=O)=O LXSLZSJZGMWGOL-UHFFFAOYSA-N 0.000 description 16
- QDHFHIQKOVNCNC-UHFFFAOYSA-N butane-1-sulfonic acid Chemical compound CCCCS(O)(=O)=O QDHFHIQKOVNCNC-UHFFFAOYSA-N 0.000 description 4
- 150000002460 imidazoles Chemical class 0.000 description 4
- 238000000926 separation method Methods 0.000 description 3
- VEZUQRBDRNJBJY-UHFFFAOYSA-N cyclohexanone oxime Chemical compound ON=C1CCCCC1 VEZUQRBDRNJBJY-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- ZRZNJUXESFHSIO-VYTKZBNOSA-N pleuromutilin Chemical compound C([C@H]([C@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-VYTKZBNOSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102000057234 Acyl transferases Human genes 0.000 description 1
- 108700016155 Acyl transferases Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- VZFZLSMQLKEYFV-UHFFFAOYSA-N butane-1-sulfonate trimethylazanium Chemical compound C[NH+](C)C.CCCCS([O-])(=O)=O VZFZLSMQLKEYFV-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000010977 jade Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0272—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/04—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing carboxylic acids or their salts
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
- B01J31/28—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of the platinum group metals, iron group metals or copper
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
- B01J31/28—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of the platinum group metals, iron group metals or copper
- B01J31/30—Halides
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J35/00—Catalysts, in general, characterised by their form or physical properties
- B01J35/19—Catalysts containing parts with different compositions
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing a pleuromulin Beckmann rearrangement product. The method is characterized in that pleuromulin is taken as a raw material, and a sulfonic acid funtionalized ionic liquid and Lewis acid are taken as a composite catalysis system to perform rearrangement in a solvent under a heating condition, wherein the sulfonic acid funtionalized ionic liquid is pyridinealkylsulfonatehydrosulfate and imidazolidinylsulfonatehydrosulfate. Compared with the conventional method, the method has the advantages of less side reactions and higher yield. At the end of a reaction, both the solvent and the composite catalysis system can be recycled and reused. The method can be suitable for industrial production.
Description
Technical field
The present invention relates to a kind of method preparing pleuromutilin oxime Beckmann rearrangement product, particularly relate to a kind of with pleuromutilin oxime for raw material, with sulfonic acid funtionalized ionic liquid and Lewis acid for composite catalyst, the green novel method heated in a solvent.
Background technology
Pleuromutilin is a kind of tricyclic diterpene compounds produced by higher fungi.Pleuromutilin and derivative thereof can selectively acting in bacterial ribosome 50s subunit, hinder bacterioprotein synthesis by the activity of inhibiting peptide acyltransferase, thus reach bacteriostatic action, have strong anti-microbial activity to gram positive organism and mycoplasma.The subject matter that current pleuromulins medicine exists is water-soluble poor, and internal metabolism is fast, therefore needs to carry out structure of modification to it.
Patent (201310222047.8) discloses the Beckmann rearrangement product of pleuromutilin oxime, i.e. 2-oxyacetic acid-2-oxygen-(4aS, 5R, 6S, 7S, 9R, 10R, 10aR, 11R)-6-hydroxyl-5,7,10,11-tetramethyl--7-vinyl-4a, 10-n-propyl-piperazine the preparation method of cyclooctane-9-base ester.The process employs the strong acid such as traditional vitriol oil, chlorsulfonic acid as catalyzer, have severe corrosive, product separation purification difficult, catalyzer is not recyclable, is difficult to the shortcomings such as industrialization.
Ionic liquid (IonLiquid, IL) is the salt for liquid under room temperature or low temperature, has become the important research content of Green Chemistry as environmentally friendly solvent.Particularly sulfonic acid funtionalized ionic liquid has the advantages such as non-volatile, non-corrosiveness, at esterification (Catal.Commun.2004,5 (9), 473-477) with selective alkylation (petrochemical complex Journal of Chinese Universities, 2005,18 (2), 1-4) etc. in organic reaction, there is good application potential.In recent years, Chinese scholars catalysis of pimelinketone oxime rearrangement under ionic liquid condition is prepared in hexanolactam and is achieved certain progress [GreenChem.2006,8 (3), 296; Catal.Commun.2005,6 (3), 225; TetrahydronLett.2007,48 (40), 7218].The people such as Hebei University of Technology Zhao Jiang a kind of jade are by ionic liquid trimethyl ammonium butyl sulfonic acid hydrosulfate ([HSO
3-b-N (CH
3)
3] HSO
4) and ZnCl
2composite catalyst system introduces using cyclohexanone-oxime Beckmann rearrangement reaction (colleges and universities' chemical engineering journal, 2011,25 (5), 838-843), has good result.But by the ionic liquid [HSO of above-mentioned bibliographical information
3-b-N (CH
3)
3] HSO
4with ZnCl
2when the catalyst system formed is applied in the Beckmann rearrangement reaction of pleuromutilin oxime, but find that byproduct of reaction is a lot, be difficult to separation and obtain expecting product.Therefore, develop a kind of newly, green pleuromutilin oxime Beckmann rearrangement product method of preparing is very important.
Summary of the invention
The technical problem to be solved in the present invention be the pleuromutilin oxime Beckmann rearrangement product that there is complex construction for preparation provide a kind of newly, green method, for solving this technical problem, the technical solution used in the present invention is as follows:
Prepare a method for pleuromutilin oxime Beckmann rearrangement product, it is characterized in that the method with pleuromutilin oxime for raw material, with sulfonic acid funtionalized ionic liquid and Lewis acid for composite catalyst system, carry out under the condition heated in a solvent.
Wherein said sulfonic acid funtionalized ionic liquid is pyridine alkylsulphonic acid hydrosulfate (1) and imidazolidyl sulfonic acid hydrosulfate (2), and they have following general structure:
Preferred sulfonic acid funtionalized ionic liquid is pyridine butyl sulfonic acid hydrosulfate (1b) and imidazoles butyl sulfonic acid hydrosulfate (2b).
Wherein said Lewis acid is zinc chloride, bismuth chloride, cobalt chloride hexahydrate, Magnesium dichloride hexahydrate, magnesium chloride, iron(ic) chloride, iron protochloride, aluminum chloride, cupric chloride, cuprous chloride, Nickel dichloride hexahydrate, ferrous sulfate, ferric sulfate, magnesium acetate, nickel acetate, zinc nitrate.Preferred Lewis acid is cobalt chloride hexahydrate.
Wherein said reaction solvent is acetonitrile, acetone, tetrahydrofuran (THF), methyl alcohol, chloroform, Virahol.Preferred solvent is acetonitrile.
The amount of substance of wherein said ionic liquid and pleuromutilin oxime is than the 1:20 ~ 1:5 being; The ratio of the amount of substance of described lewis acid and pleuromutilin oxime is 1:10 ~ 1:1.
The type of heating of wherein said reaction is passable, but is not limited to traditional reflux mode, also comprises the unconventional type of heating such as microwave heating.
The present invention with pyridine alkylsulphonic acid hydrosulfate (1) and imidazolidyl sulfonic acid hydrosulfate (2) with Lewis acid for catalyst system, side reaction is few, improves productive rate; Because product is at room temperature insoluble to ionic liquid, make the separation of product become simple, saved cost; After reaction terminates, solvent and catalyst system are all recyclable, and reusable, are more conducive to suitability for industrialized production.
Embodiment
Embodiment 1
By oxime (197mg, 0.5mmol) in 50mL two-mouth bottle, pyridine butyl sulfonic acid hydrosulfate [PyBSO
3h] HSO
4(15.8mg, 0.05mmol), bismuth chloride (15.8mg, 0.05mmol), is dissolved in 10mL acetonitrile, and reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, add 30mL water washing residue, and extract with methylene dichloride (15mL × 3), merge organic phase, the rear concentrating under reduced pressure of dry, filtration, crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 50.0mg (mp259-262 DEG C), productive rate 25.2%.
1HNMR(600MHz,CDCl
3)δ:6.48(dd,J
1＝10.8Hz,J
2＝17.4Hz,1H),5.98(d,J＝9.6Hz,1H),5.73(s,1H),5.39(d,J＝10.8Hz,1H),5.22(m,1H),4.05(q,2H),3.41(s,2H),2.35(m,4H),2.09(q,1H),1.98(m,1H),1.67(m,2H),1.50(m,6H),1.35(d,2H),1.17(m,5H),0.85(m,3H),0.74(m,3H).
13CNMR(150MHz,CDCl
3)δ:172.92,171.98,137.81,117.90,73.50,69.98,61.23,59.69,44.36,43.67,37.89,35.34,29.67,27.40,27.14,26.13,25.90,25.78,24.47,16.86,16.26,10.77.
HRMS(ESI):m/zCalcdforC
22H
36NO
5:394.25880.Found:394.25839(M+H
+).
Embodiment 2
By oxime (197mg, 0.5mmol) in 50mL two-mouth bottle, pyridine butyl sulfonic acid hydrosulfate [PyBSO
3h] HSO
4(15.8mg, 0.05mmol), magnesium chloride (4.6mg, 0.05mmol), is dissolved in 10mL acetonitrile, and reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, add 30mL water washing residue, and extract with methylene dichloride (15mL × 3), merge organic phase, the rear concentrating under reduced pressure of dry, filtration, crude product ethyl acetate crystallization, obtains Beckmann rearrangement product 47.3mg (mp259-262 DEG C), productive rate 24.0%.
Embodiment 3
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, pyridine butyl sulfonic acid hydrosulfate [PyBSO
3h] HSO
4(15.8mg, 0.05mmol), Nickel dichloride hexahydrate (11.9mg, 0.05mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 30mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 17.9mg (mp259-262 DEG C), productive rate 9.1%.
Embodiment 4
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, pyridine butyl sulfonic acid hydrosulfate [PyBSO
3h] HSO
4(15.8mg, 0.05mmol), ferrous sulfate (13.9mg, 0.05mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 100mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 22.7mg (mp259-262 DEG C), productive rate 11.5%.
Embodiment 5
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, pyridine butyl sulfonic acid hydrosulfate [PyBSO
3h] HSO
4(15.8mg, 0.05mmol), zinc nitrate (14.9mg, 0.05mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 100mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 30.7mg (mp259-262 DEG C), productive rate 15.6%.
Embodiment 6
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, pyridine butyl sulfonic acid hydrosulfate [PyBSO
3h] HSO
4(15.8mg, 0.05mmol), magnesium acetate (10.7mg, 0.05mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 100mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 41.8mg (mp259-262 DEG C), productive rate 21.2%.
Embodiment 7
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, pyridine butyl sulfonic acid hydrosulfate [PyBSO
3h] HSO
4(15.8mg, 0.05mmol), cobalt chloride hexahydrate (11.9mg, 0.05mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 100mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 43.7mg (mp259-262 DEG C), productive rate 22.2%.
Embodiment 8
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, pyridine butyl sulfonic acid hydrosulfate [PyBSO
3h] HSO
4(15.8mg, 0.05mmol), cobalt chloride hexahydrate (23.8mg, 0.1mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 100mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 67.2mg (mp259-262 DEG C), productive rate 34.1%.
Embodiment 9
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, pyridine butyl sulfonic acid hydrosulfate [PyBSO
3h] HSO
4(15.8mg, 0.05mmol), cobalt chloride hexahydrate (59.5mg, 0.25mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 100mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 95.2mg (mp259-262 DEG C), productive rate 48.3%.
Embodiment 10
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, pyridine butyl sulfonic acid hydrosulfate [PyBSO
3h] HSO
4(15.8mg, 0.05mmol), cobalt chloride hexahydrate (119mg, 0.5mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 100mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 108.8mg (mp259-262 DEG C), productive rate 55.1%.
Embodiment 11
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, pyridine butyl sulfonic acid hydrosulfate [PyBSO
3h] HSO
4(15.8mg, 0.05mmol), bismuth chloride (31.5mg, 0.1mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 100mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 53.4mg (mp259-262 DEG C), productive rate 27.1%.
Embodiment 12
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, pyridine butyl sulfonic acid hydrosulfate [PyBSO
3h] HSO
4(15.8mg, 0.05mmol), bismuth chloride (78.8mg, 0.25mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 100mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 66.6mg (mp259-262 DEG C), productive rate 33.8%.
Embodiment 13
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, pyridine butyl sulfonic acid hydrosulfate [PyBSO
3h] HSO
4(15.8mg, 0.05mmol), bismuth chloride (158mg, 0.5mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 100mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 74.6mg (mp259-262 DEG C), productive rate 37.9%.
Embodiment 14
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, pyridine butyl sulfonic acid hydrosulfate [PyBSO
3h] HSO
4(15.8mg, 0.05mmol), zinc chloride (34.1mg, 0.25mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 100mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 118.8mg (mp259-262 DEG C), productive rate 60.3%.
Embodiment 15
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, pyridine butyl sulfonic acid hydrosulfate [PyBSO
3h] HSO
4(15.8mg, 0.05mmol), zinc chloride (68.2mg, 0.5mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 100mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 136.5mg (mp259-262 DEG C), productive rate 69.3%.
Embodiment 16
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, imidazoles butyl sulfonic acid hydrosulfate [ImBSO
3h] HSO
4(15.1mg, 0.05mmol), bismuth chloride (158mg, 0.5mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 100mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 60.9mg (mp259-262 DEG C), productive rate 30.9%.
Embodiment 17
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, imidazoles butyl sulfonic acid hydrosulfate [ImBSO
3h] HSO
4(15.1mg, 0.05mmol), cobalt chloride hexahydrate (119mg, 0.5mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 100mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 75.1mg (mp259-262 DEG C), productive rate 38.1%.
Embodiment 18
By oxime (197mg, 0.5mmol) in 100mL two-mouth bottle, imidazoles butyl sulfonic acid hydrosulfate [ImBSO
3h] HSO
4(15.1mg, 0.05mmol), zinc chloride (34.1mg, 0.25mmol), is dissolved in 50mL acetonitrile.Reflux, to reacting completely, is cooled to room temperature.Reaction solution vacuum distillation recovered solvent, with 100mL water washing residue, methylene dichloride (50mL × 4) extracts, and merges organic phase, the rear concentrating under reduced pressure of dry, filtration.Crude product re-crystallizing in ethyl acetate, obtains Beckmann rearrangement product 92.4mg (mp259-262 DEG C), productive rate 46.9%.
Claims (6)
1. prepare a method for pleuromutilin oxime Beckmann rearrangement product, wherein pleuromutilin oxime Beckmann rearrangement product, i.e. 2-oxyacetic acid-2-oxygen-(4aS, 5R, 6S, 7S, 9R, 10R, 10aR, 11R)-6-hydroxyl-5,7,10,11-tetramethyl--7-vinyl-4a, 10-n-propyl-piperazine cyclooctane-9-base ester, have following structural formula:
The method is characterized in that with pleuromutilin oxime for raw material, with sulfonic acid funtionalized ionic liquid and Lewis acid for composite catalyst system, carry out under the condition heated in a solvent.
2. a kind of method preparing pleuromutilin oxime Beckmann rearrangement product according to claim 1, it is characterized in that described sulfonic acid funtionalized ionic liquid is the one in pyridine alkylsulphonic acid hydrosulfate (1) and imidazolidyl sulfonic acid hydrosulfate (2), they have following general structure:
。
3. a kind of method preparing pleuromutilin oxime Beckmann rearrangement product according to claim 1, is characterized in that Lewis acid can be the one in zinc chloride, bismuth chloride, cobalt chloride hexahydrate, Magnesium dichloride hexahydrate, magnesium chloride, iron(ic) chloride, iron protochloride, aluminum chloride, cupric chloride, cuprous chloride, Nickel dichloride hexahydrate, ferrous sulfate, ferric sulfate, magnesium acetate, nickel acetate, zinc nitrate.
4. a kind of method preparing pleuromutilin oxime Beckmann rearrangement product according to claim 1, is characterized in that reaction solvent can be the one of acetonitrile, acetone, tetrahydrofuran (THF), methyl alcohol, chloroform, Virahol.
5. a kind of method preparing pleuromutilin oxime Beckmann rearrangement product according to claim 1, is characterized in that the amount of substance of described ionic liquid and pleuromutilin oxime is than the 1:20 ~ 1:5 being; The ratio of the amount of substance of described lewis acid and pleuromutilin oxime is 1:10 ~ 1:1.
6. a kind of method preparing pleuromutilin oxime Beckmann rearrangement product according to claim 1, is characterized in that the type of heating reacted is passable, but is not limited to traditional reflux mode, also comprise the unconventional type of heating such as microwave heating.
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| CN115636787A (en) * | 2022-11-07 | 2023-01-24 | 北京理工大学 | Compound with Tau protein inhibitory activity and preparation method thereof |
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| CN103265487A (en) * | 2013-06-05 | 2013-08-28 | 北京理工大学 | Pleuromutilin expansion ring derivative, and preparation method and application thereof |
| CN103265442A (en) * | 2013-06-05 | 2013-08-28 | 北京理工大学 | Novel pleuromutilin derivatives, as well as preparation method and anti-tumour application thereof |
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| CN103265487A (en) * | 2013-06-05 | 2013-08-28 | 北京理工大学 | Pleuromutilin expansion ring derivative, and preparation method and application thereof |
| CN103265442A (en) * | 2013-06-05 | 2013-08-28 | 北京理工大学 | Novel pleuromutilin derivatives, as well as preparation method and anti-tumour application thereof |
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Cited By (1)
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| CN115636787A (en) * | 2022-11-07 | 2023-01-24 | 北京理工大学 | Compound with Tau protein inhibitory activity and preparation method thereof |
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