CN102321044B - Preparation method of 3-(2-bromo propionyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-one - Google Patents
Preparation method of 3-(2-bromo propionyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-one Download PDFInfo
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Abstract
The invention relates to a preparation method of 3-(2-bromo propionyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-one. The preparation method comprises the following steps of: firstly preparing spiro[2H-1,3-benzoxazine-2,1'-cycloalkane]-4(3H)-one: respectively adding salicylamide, cyclohexanone, a solid acid catalyst and toluene in a reactor, heating and refluxing, stirring and reacting for 1-10 hours, cooling to room temperature for precipitating solids, filtering, washing and drying to obtain a solid product; and then preparing 3-(2-bromo propionyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-one: respectively adding toluene, a magnetic solid base catalyst and spiro[2H-1,3-benzoxazine-2,1'-cyclohexane]-4(3H)-one in the reactor, dropwise adding halogenated acyl halide, reacting at the reaction temperature of 10-80 DEG C for 1-10 hours, cooling, washing with water, drying, concentrating and crystallizing with isopropyl alcohol to obtain a solid product. Compared with the prior art, the solid acid catalyst and the magnetic solid base catalyst are used in the reaction processes; and the preparation method has the advantages of simple process operation, good technical performance, no environmental pollution and the like.
Description
Technical field
The present invention relates to a kind ofly prepare 3-(2 bromine propionyl)-spiral shell [2 with the heterogeneous catalysis technology
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
HThe method of)-ketone.
Background technology
Carbapenem antibiotic is a widest class 1 β-Nei Xiananleikangshengsu of antimicrobial spectrum, has has a broad antifungal spectrum, characteristics that anti-microbial activity is strong, the control resistant organism and zymogenic bacteria infects and immune deficiency person's infection aspect bringing into play important role.The carbapenems medicine that has now gone on the market has 6 kinds such as imipenum, panipenem, meropenem, ertapenem, S-4661 and biapenem, and wherein meropenem, ertapenem, S-4661 and biapenem are the l Beta-methyl carbapenem.Meropenem is by Dainippon Sumitomo Pharma research and development, goes on the market in Italy first in nineteen ninety-five, and it is first carbapenem antibiotic of medication separately, also is first l Beta-methyl carbapenem antibiotic simultaneously.Such microbiotic is stable to β-Nei Xiananmei and kidney dehydrogenation peptide-I enzyme, need not and the coupling of dehydropeptidase inhibitor, is one of important drugs for the treatment of at present severe and multi-drug resistant bacteria infection, has obtained utilization more and more widely clinically.Such microbiotic mainly is to prepare by chemistry is complete synthesis at present, and main processes comprises the synthetic of side chain and skeleton parent nucleus.Spiral shell [2
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
H)-ketone and 3-(2 bromine propionyl)-spiral shell [2
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
H)-ketone is the precursor of the important auxiliary reagent of preparation l Beta-methyl carbapenem antibiotic bicyclic mother nucleus, in building-up process, need to use a large amount of p-methyl benzenesulfonic acids and pyridine, environment there is certain pollution, therefore, the traditional technology of such medicine is improved had good economic benefit and important social benefit.
Summary of the invention
The object of the invention provides a kind of 3-(2 bromine propionyl)-spiral shell [2
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
HThe preparation method of)-ketone, it is synthetic spiral shell [2 under solid acid catalysis
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
H)-ketone, synthetic 3-(2 bromine propionyl)-spiral shell [2 under the magnetic retention base catalysis
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
H)-ketone.
The object of the present invention is achieved like this, described spiral shell [2
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
H)-ketone, structural formula is as follows:
Described 3-(2 bromine propionyl)-spiral shell [2
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
H)-ketone, structural formula is as follows:
At first prepare spiral shell [2
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
H)-ketone: in reactor, add salicylic amide, pimelinketone, solid acid catalyst and toluene respectively, reflux, stirring reaction 1～10 hour, be cooled to room temperature and separate out solid, filter, solid is used toluene and washed with isopropyl alcohol respectively, drying gets solid product, yield 90%.The consumption of described solid acid catalyst is 1～10% of salicylic amide and pimelinketone mass percent, is preferably 2～5%.Refabrication 3-(2 bromine propionyl)-spiral shell [2
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
H)-ketone: in reactor, add toluene, magnetic solid base catalyst and spiral shell [2 respectively
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
H)-ketone drips halogen acyl halide, control temperature of reaction at 10～80 ℃, reacts 1～10 hour, and cooling adds suitable quantity of water, and organic layer is told in washing, and drying concentrates, and gets solid product with the Virahol crystallization, and yield is greater than 80%.The consumption of described magnetic solid base catalyst is spiral shell [2
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
H1～10% of)-ketone mass percent is preferably 2～5%.
Described halogen acyl halide is chloro acyl chlorides or bromacyl bromide, is preferably the chloro acyl chlorides.
Described solid acid catalyst is one of following: SO
4 2-/ SnO
2-Fe
2O
3, S
2O
8 2-/ SnO
2-Fe
2O
3, SO
4 2-/ SnO
2-ZnO, S
2O
8 2-/ SnO
2-ZnO, O
4 2-/ SnO
2-TiO
2Or S
2O
8 2-/ SnO
2-TiO
2
The preparation method of solid acid catalyst uses co-precipitation-pickling process, detailed process is as follows: any corresponding soluble salt solution in solubility tin-salt solution and iron (Fe) or zinc (Zn) or the titanium (Ti) is dissolved in the distilled water by the mole proportioning of 1:2～1:9, transferring pH through strong aqua is 8, room temperature ageing 24h, after suction filtration, removal of impurities, oven dry, grinding, with the H of 0.2～5mol/L
2SO
4Or (the NH of 1～2mol/L
4)
2S
2O
8Solution carries out dip treating, filters, after the drying, and at 500～600 ℃ of roasting temperatures, roasting time is to obtain solid acid catalyst in 3～8 hours.
Described solubility pink salt is SnCl
45H
2O; Described soluble ferric iron salt FeCl
36H
2O, soluble zinc salt are ZnCl
2, the solubility titanium salt is TiCl
4
Solid acid catalyst adopts the Hammett indicator method to measure strength of acid.Concrete operations are as follows: quick weighing 0.2g new system catalyst sample, put into dry small test tube, and add 4～5 thionyl chlorides, drip the benzole soln that 3～4 1g/ L contain indicator then, observe the sample surfaces change in color.Can make the indicator flavescence as if the super acids sample, so its surperficial H
oFunction numerical value is equal to or less than the pKa of this indicator.Indicator can adopt meta-nitrotoluene (pKa=-11. 99), p-Nitrophenyl chloride (pKa=-12. 70), m-nitrochlorobenzene (pKa=-13.16), 2,4-dinitrochlorobenzene (pKa=-14. 52).
Described magnetic solid base catalyst is the magnetic solid base that magnetic mg_al hydrotalcite makes, the preparation method of magnetic solid base catalyst is as follows: get a certain amount of magnetic colloidal sol and join in the reaction flask, add distilled water again, stirring at room, magnesium nitrate and the aluminum nitrate getting the magnalium ratio and be 1: 2 are mixed with solution, other joins the sodium hydroxide solution of pH=10～13, two kinds of solution are added in the reaction flask, 110 ℃ of stirrings, washing and drying makes magnetic mg_al hydrotalcite, forms magnetic solid base 450～500 ℃ of high-temperature roastings then.Magnetic colloidal sol is to adopt chemical coprecipitation, with Fe
3+And Fe
2+Vitriol or muriate in excessive alkali, mix to stir in the ratio of 1:1 and make.
The present invention is exactly in reaction process compared with prior art, has used solid acid catalyst and magnetic solid base catalyst, and it is simple to have a technological operation, technological performance, advantages such as environmentally safe.
Embodiment
The invention will be further described below in conjunction with embodiment, but protection scope of the present invention is not limited to this.
Embodiment 1
Spiral shell [2
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
HThe preparation of)-ketone (I): in reactor, add 1000 kilograms of 137 kilograms of salicylic amides, 118 kilograms of pimelinketone, 5 kilograms of solid acid catalysts and toluene respectively, reflux, stirring reaction 8 hours, be cooled to room temperature and separate out solid, filter, solid is used toluene and washed with isopropyl alcohol respectively, dry 200 kilograms of white solid product, the yield 90% of getting.
mp：189～192℃；
1H?NMR(DMSO-d
6)δ:?1.20～1.30(m,?1H),?1.50～1.70(m,?6H),?1.90～2.10(m,?3H),?6.90～7.10(m,?2H),?7.40～7.50(m,?1H),?7.70～7.80(m,?1H),?8.64(brs,?1H);?MS(m/z):?217[M
+]。
3-(2-chlorine propionyl)-spiral shell [2
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
HThe preparation of)-ketone (II): in reactor, add 1000 kilograms of toluene, spiral shell [2 respectively
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
H200 kilograms of)-ketone (I), 10 kilograms of magnetic solid base catalysts drip 127 kilograms of chloro acyl chlorides, the control temperature of reaction is at 10 ℃, reacted 10 hours, cooling adds suitable quantity of water, washing, which floor has been told, and anhydrous sodium sulfate drying concentrates, get 243 kilograms of solid products, yield 86% with the Virahol crystallization.
1H?NMR(CDCl
3)δ:?1.20～2.50(m,?10H),?1.92(d,?
J?=?6.6Hz,3H),?5.14(q,
?J?=?6.6Hz,1H),?7.01(m,1H),?7.11(m,?1H),?7.55(m,?1H),?7.92(m,1H);?MS(m/z):?307[M
+]。
Embodiment 2
Spiral shell [2
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
HThe preparation of)-ketone (I): in reactor, add 1000 kilograms of 137 kilograms of salicylic amides, 118 kilograms of pimelinketone, 13.7 kilograms of solid acid catalysts and toluene respectively, reflux, stirring reaction 2 hours, be cooled to room temperature and separate out solid, filter, solid is used toluene and washed with isopropyl alcohol respectively, dry 200 kilograms of white solid product, the yield 90% of getting.
3-(2-bromine propionyl)-spiral shell [2
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
HThe preparation of)-ketone (II): in reactor, add 1000 kilograms of toluene, spiral shell [2 respectively
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
H200 kilograms of)-ketone (I), 4 kilograms of magnetic solid base catalysts drip 216 kilograms of bromacyl bromides, the control temperature of reaction is at 10 ℃, reacted 10 hours, cooling adds suitable quantity of water, washing, which floor has been told, and anhydrous sodium sulfate drying concentrates, get 243 kilograms of solid products, yield 86% with the Virahol crystallization.
mp：64～66℃；MS(m/z):?352[M
+]。
Claims (1)
1. a 3-(2 bromine propionyl)-spiral shell [2
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
HThe preparation method of)-ketone is characterized in that at first preparing spiral shell [2
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
H)-ketone, its preparation method is: in reactor, add 1000 kilograms of 137 kilograms of salicylic amides, 118 kilograms of pimelinketone, 13.7 kilograms of solid acid catalysts and toluene respectively, reflux, stirring reaction 2 hours is cooled to room temperature and separates out solid, filter, solid is used toluene and washed with isopropyl alcohol respectively, dry 200 kilograms of white solid product, the yield 90% of getting; Refabrication 3-(2-bromine propionyl)-spiral shell [2
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
H)-ketone, its preparation method is: in reactor, add 1000 kilograms of toluene, spiral shell [2 respectively
H-1,3-benzoxazine-2,1 '-hexanaphthene]-4 (3
H200 kilograms of)-ketone, 4 kilograms of magnetic solid base catalysts, dripping bromine is for 216 kilograms of propionyl bromide, and the control temperature of reaction was reacted 10 hours at 10 ℃, cooling adds suitable quantity of water, and organic layer is told in washing, anhydrous sodium sulfate drying concentrates, and gets 243 kilograms of solid products, yield 86% with the Virahol crystallization; The preparation method of solid acid catalyst uses co-precipitation-pickling process, detailed process is as follows: any corresponding soluble salt solution in solubility tin-salt solution and iron or zinc or the titanium is dissolved in the distilled water by the mole proportioning of 1:2～1:9, transferring pH through strong aqua is 8, room temperature ageing 24h, after suction filtration, removal of impurities, oven dry, grinding, with the H of 0.2～5mol/L
2SO
4Or (the NH of 1～2mol/L
4)
2S
2O
8Solution carries out dip treating, filters, after the drying, and at 500～600 ℃ of roasting temperatures, roasting time is to obtain solid acid catalyst in 3～8 hours; Described solubility pink salt is SnCl
45H
2O; Described soluble ferric iron salt FeCl
36H
2O, soluble zinc salt are ZnCl
2, the solubility titanium salt is TiCl
4Magnetic solid base catalyst is the magnetic solid base that magnetic mg_al hydrotalcite makes, the preparation method of magnetic solid base catalyst is as follows: get a certain amount of magnetic colloidal sol and join in the reaction flask, add distilled water again, stirring at room, magnesium nitrate and the aluminum nitrate getting the magnalium ratio and be 1: 2 are mixed with solution, other joins the sodium hydroxide solution of pH=10～13, two kinds of solution are added in the reaction flask, 110 ℃ of stirrings, washing and drying makes magnetic mg_al hydrotalcite, form magnetic solid base 450～500 ℃ of high-temperature roastings then, magnetic colloidal sol is to adopt chemical coprecipitation, with Fe
3+And Fe
2+Vitriol or muriate in excessive alkali, mix to stir in the ratio of 1:1 and make.
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| CN110025619A (en) * | 2019-04-29 | 2019-07-19 | 江苏汉阔生物有限公司 | Meropenem intermediate is preparing the application in anti-oxidation medicine |
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| CN106478538A (en) * | 2015-08-28 | 2017-03-08 | 曹子领 | Chlorine propionyl spiral shell benzimidazole dihydrochloride hexamethylene and its synthesis and application |
| CN106432122B (en) * | 2016-09-08 | 2018-12-07 | 新乡海滨药业有限公司 | A kind of preparation method of meropenem intermediate chlorine propionyl spiral shell benzoxazine hexamethylene |
| CN106397473B (en) * | 2016-09-08 | 2018-09-28 | 新乡海滨药业有限公司 | A kind of preparation method of meropenem intermediate 4-BMA |
| CN106967003A (en) * | 2017-03-20 | 2017-07-21 | 北京理工大学 | A kind of method for synthesizing the assimilation compound of 1,3 benzoxazine 4 |
| CN108774188A (en) * | 2018-07-23 | 2018-11-09 | 湖北宇阳药业有限公司 | A kind of preparation method of meropenem intermediate |
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| CN110025619A (en) * | 2019-04-29 | 2019-07-19 | 江苏汉阔生物有限公司 | Meropenem intermediate is preparing the application in anti-oxidation medicine |
| CN110025619B (en) * | 2019-04-29 | 2022-03-22 | 江苏汉阔生物有限公司 | Application of meropenem intermediate in preparation of antioxidant drugs |
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