CN114133384A - Preparation method of chiral isoxazolone compound - Google Patents
Preparation method of chiral isoxazolone compound Download PDFInfo
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- CN114133384A CN114133384A CN202111492522.4A CN202111492522A CN114133384A CN 114133384 A CN114133384 A CN 114133384A CN 202111492522 A CN202111492522 A CN 202111492522A CN 114133384 A CN114133384 A CN 114133384A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- -1 isoxazolone compound Chemical class 0.000 title abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 14
- FUOSTELFLYZQCW-UHFFFAOYSA-N 1,2-oxazol-3-one Chemical compound OC=1C=CON=1 FUOSTELFLYZQCW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 7
- 229940125904 compound 1 Drugs 0.000 claims abstract description 5
- 229940125782 compound 2 Drugs 0.000 claims abstract description 5
- 229940126214 compound 3 Drugs 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 150000003738 xylenes Chemical class 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 229930014626 natural product Natural products 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000000758 substrate Substances 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 238000001514 detection method Methods 0.000 description 15
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-dimethylbenzene Natural products CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- PCKPVGOLPKLUHR-UHFFFAOYSA-N indoxyl Chemical group C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- QXDOFVVNXBGLKK-UHFFFAOYSA-N 3-Isoxazolidinone Chemical compound OC1=NOCC1 QXDOFVVNXBGLKK-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002545 isoxazoles Chemical class 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 238000007366 cycloisomerization reaction Methods 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 230000000668 effect on calcium Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a preparation method of a chiral isoxazolone compound, which comprises the following steps: chiral phosphoric acid CPA is used as a catalyst, the temperature is set to be-20 ℃ to 0 ℃, and a compound 1 and a compound 2 in a reaction solvent are used as reaction raw materials to react to obtain a chiral isoxazolone compound 3. The preparation method has mild reaction conditions, easily available and cheap raw materials, simple reaction operation and higher yield, provides a key framework structure for the synthesis of a plurality of natural products and medicines, and can be widely applied to industrial mass production.
Description
Technical Field
The invention relates to the field of organic compound process application, in particular to a preparation method of a chiral isoxazolone compound.
Background
Isoxazoles and derivatives thereof are important heterocyclic compounds, which are used as important intermediates in organic synthesis and are greatly developed in organic synthesis reactions. In addition, isoxazole derivatives have a broad spectrum of pharmacological and biological activities. The main pharmacological activities of the compounds include pain relieving, inflammation diminishing, tuberculosis resisting, convulsion resisting, bacteria resisting, nerve exciting, Alzheimer disease treating and the like, and the compounds also have good curative effect on calcium regulation. In addition, isoxazole and its derivatives have been widely used in the field of agricultural chemicals, and have been developed into various agricultural chemicals such as antibacterial agents, herbicides, insecticides, and the like.
At present, various construction methods for the isoxazole ring skeleton mainly include cycloaddition reaction, condensation reaction, cycloisomerization reaction and the like, but these methods have corresponding problems, such as harsh reaction conditions, environmental pollution, low yield, and excessively long synthesis time, so that the isoxazole ring skeleton cannot be effectively and reasonably constructed.
Therefore, in combination with the above problems, it is an urgent need to solve the problems of the art to research a preparation method of a chiral isoxazolone compound that is green, environment-friendly, simple and efficient.
Disclosure of Invention
In view of the above, the present invention provides a method for preparing a chiral isoxazolone compound, which can efficiently achieve conversion of a reaction by using Chiral Phosphoric Acid (CPA) as a catalyst, and has advantages of mild reaction conditions, no metal residue, simple operation, low cost, and the like.
The invention utilizes isoxazolone and indoxyl as reaction raw materials, takes chiral phosphoric acid as a catalyst, and reacts in a reaction solvent to synthesize the novel chiral isoxazolone compound.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a preparation method of chiral isoxazolone compounds comprises the following steps: chiral phosphoric acid CPA is used as a catalyst, the temperature is set to be-20 ℃ to 0 ℃, a compound 1 and a compound 2 in a reaction solvent are used as reaction raw materials, and the reaction is carried out for 24-72h to obtain a chiral isoxazolone compound 3, wherein the reaction process is shown as a formula I;
wherein R is1、R2、R3One or more selected from alkyl, aryl, substituted aromatic ring and substituted hetero atom.
Preferably, the catalyst is used in a proportion of 1 to 100 mol% with respect to the reactants.
Preferably, the reaction solvent is selected from one of toluene, chloroform, carbon tetrachloride, dichloromethane, trifluorotoluene, tetrahydrofuran, xylene compounds, tert-butyl methyl ether and diethyl ether.
Preferably, the molar ratio of compound 1 to compound 2 is 1.2: 1.
preferably, the preparation method of the chiral isoxazolidone compound takes isoxazolidone and indoxyl as reaction raw materials, and the reaction process is shown as formula II:
preferably, in the reaction process, the indole alcohol and the isoxazolidone are respectively dissolved in a reaction solvent, chiral phosphoric acid is added at room temperature to react for 36 hours at the temperature of-20-0 ℃, TLC is used for detecting the reaction process, and after the reaction is finished, silica gel is added, and the product is obtained by spin-dry column chromatography and separation.
Preferably, the molar ratio of isoxazolone to indole alcohol is 1: 1-1.2.
Preferably, the molar ratio of isoxazolone to indole is 1: 1.2.
Preferably, in the reaction process, 0.3mL of xylene compounds are added into a 10mL test tube reactor, 0.06mmol of indoxyl, 0.05mmol of isoxazolone and 0.0005mmol of CPA are respectively dissolved in a reaction solvent, a reaction system is reacted for 36 hours at the temperature of-20 ℃ to 0 ℃, the reaction process is detected by TLC, after the reaction is finished, silica gel is added, and the product is obtained by spin-dry column chromatography and separation.
Through the technical scheme, compared with the prior art, the invention has the following beneficial effects:
the raw materials selected by the method are all industrial commodities, are simple and easy to obtain, have wide sources and very stable performance, do not need special storage conditions, and the used catalyst is also a common commercial reagent and has very stable performance. The invention takes simple and easily obtained indoxyl and isoxazolidone as reaction raw materials, and the novel chiral isoxazolidone compound is obtained by reaction under the action of chiral phosphoric acid CPA, and the invention has the advantages of simple reaction operation, mild reaction condition and higher yield, and is suitable for large-scale industrial production. The chiral isoxazolidone compounds obtained by the invention are core skeletons of a plurality of natural products and active drug molecules, and a reaction route innovatively designed by the invention provides a widely applicable preparation method for synthesizing the compounds.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
the embodiment 1 of the invention discloses a preparation method of a chiral isoxazolone compound, which adopts the following technical scheme:
adding 0.3mL of dimethylbenzene compound into a 10mL test tube reactor, and sequentially adding 0.06mmol of substrate 1a, 0.05mmol of substrate 2a and 0.0005mmol of CPA into the reaction tube; reacting the reaction system at-20 ℃ to 0 ℃ for 36 hours; after the TLC detection reaction, silica gel is added directly, and the column chromatography is performed in a spin-drying manner to obtain 3aa (81%) of a white solid.1H NMR(DMSO-d6,400MHz):δ(ppm)11.41(s,1H),7.82(d,J＝8.0Hz,1H),7.78-7.77(m,1H),7.73-7.71(m,2H),7.65-7.60(m,3H),7.46-7.39(m,4H),7.26-7.20(m,4H),6.98-6.96(m,2H),6.84-6.81(m,1H),6.75-6.73(m,2H),6.39-6.37(m,2H),6.05(s,1H),3.79(s,3H),3.40(s,2H),2.11(s,3H).13C NMR(DMSO-d6,100MHz):δ(ppm)171.6,165.8,159.5,137.2,136.2,135.6,135.4,131.9,130.2,130.1,129.4,129.3,129.3,129.2,128.4,128.2,127.5,127.0,125.9,125.3,124.8,121.0,119.3,116.3,114.1,112.9,106.5,71.0,55.6,27.2,20.9.HRMS(ESI):exact mass calculated for[M+Na]+(C39H32N2O3Na)requires m/z 599.2305,found m/z 599.2299。
Example 2:
the embodiment 1 of the invention discloses a preparation method of a chiral isoxazolone compound, which adopts the following technical scheme:
adding 0.3mL of dimethylbenzene compound into a 10mL test tube reactor, and sequentially adding 0.06mmol of substrate 1a, 0.05mmol of substrate 2b and 0.0005mmol of CPA into the reaction tube; reacting the reaction system at-20 ℃ to 0 ℃ for 36 hours; after TLC detection, silica gel was added directly and column chromatography was performed to obtain 3ac (70%) as a white solid.1H NMR(DMSO-d6,400MHz):δ(ppm)11.41(s,1H),7.82(d,J＝8.0Hz,1H),7.78-7.77(m,1H),7.73-7.71(m,2H),7.65-7.60(m,3H),7.46-7.39(m,4H),7.26-7.20(m,4H),6.98-6.96(m,2H),6.84-6.81(m,1H),6.75-6.73(m,2H),6.39-6.37(m,2H),6.05(s,1H),3.79(s,3H),3.40(s,2H),2.11(s,3H).13C NMR(DMSO-d6,100MHz):δ(ppm)171.6,165.8,159.5,137.2,136.2,135.6,135.4,131.9,130.2,130.1,129.4,129.3,129.3,129.2,128.4,128.2,127.5,127.0,125.9,125.3,124.8,121.0,119.3,116.3,114.1,112.9,106.5,71.0,55.6,27.2,20.9.HRMS(ESI):exact mass calculated for[M+Na]+(C39H32N2O3Na)requires m/z 599.2305,found m/z 599.2299。
Example 3:
the embodiment 3 of the invention discloses a preparation method of a chiral isoxazolone compound, which adopts the following technical scheme:
adding 0.3mL of dimethylbenzene compound into a 10mL test tube reactor, and sequentially adding 0.06mmol of substrate 1a, 0.05mmol of substrate 2c and 0.0005mmol of CPA into the reaction tube; reacting the reaction system at-20 ℃ to 0 ℃ for 36 hours; after the TLC detection reaction, silica gel was added directly and the column chromatography was performed to obtain 3ac (79%) as a white solid.1H NMR(DMSO-d6,400MHz):δ(ppm)11.45(s,1H),7.83(d,J＝8.0Hz,1H),7.79-7.78(m,1H),7.73-7.71(m,2H),7.66-7.59(m,3H),7.46-7.43(m,2H),7.39-7.37(m,2H),7.27-7.21(m,4H),7.09-7.07(m,2H),6.99-6.97(m,2H),6.82-6.80(m,1H),6.42-6.40(m,2H),6.06(s,1H),3.79(s,3H),3.42(s,2H).13C NMR(DMSO-d6,100MHz):δ(ppm)171.5,166.1,159.4,138.2,137.1,136.0,132.1,131.4,130.2,130.2,129.8,129.3,129.2,129.2,128.4,128.0,127.1,125.9,125.3,124.9,121.1,119.6,119.2,116.3,114.1,112.9,105.9,71.1,55.6,27.1.HRMS(ESI):exact mass calculated for[M+Na]+(C38H29BrN2O3Na)requires m/z 663.1254,found m/z 663.1249。
Example 4:
the embodiment 4 of the invention discloses a preparation method of a chiral isoxazolone compound, which adopts the following technical scheme:
adding 0.3mL of dimethylbenzene compound into a 10mL test tube reactor, and sequentially adding 0.06mmol of substrate 1a, 0.05mmol of substrate 2d and 0.0005mmol of CPA into the reaction tube; reacting the reaction system at-20 ℃ to 0 ℃ for 36 hours; after TLC detection, silica gel was added directly and column chromatography was performed to obtain 3ad (82%) as a white solid.1H NMR(DMSO-d6,400MHz):δ(ppm)11.45(s,1H),7.87(d,J＝8.0Hz,1H),7.82-7.81(m,1H),7.75-7.73(m,2H),7.66-7.63(m,2H),7.61-7.59(m,1H),7.45-7.43(m,1H),7.41-7.39(m,3H),7.25-7.23(m,2H),,7.22(s,2H),6.99-6.97(m,2H),6.85-6.82(m,1H),6.46-6.44(m,2H),6.36-6.34(m,2H),6.06(s,1H),3.80(s,3H),3.50(s,3H),3.38(s,2H).13C NMR(DMSO-d6,100MHz):δ(ppm)171.6,165.9,159.4,157.9,137.2,136.1,132.0,130.7,130.4,130.2,129.3,129.2,128.6,128.4,128.2,126.8,125.8,125.2,125.0,121.1,119.3,116.1,114.1,113.9,113.0,106.8,71.0,55.6,55.1,26.7.HRMS(ESI):exact mass calculated for[M+Na]+(C39H32N2O4Na)requires m/z 615.2254,foundm/z 615.2251。
Example 5:
the embodiment 5 of the invention discloses a preparation method of a chiral isoxazolone compound, which adopts the following technical scheme:
adding 0.3mL of dimethylbenzene compound into a 10mL test tube reactor, and sequentially adding 0.06mmol of substrate 1a, 0.05mmol of substrate 2e and 0.0005mmol of CPA into the reaction tube; reacting the reaction system at-20 ℃ to 0 ℃ for 36 hours; after TLC detection, silica gel was added directly and spin-dry column chromatography gave 3ae as a white solid (74%).1H NMR(DMSO-d6,400MHz):δ(ppm)11.46(s,1H),7.85(d,J＝8.0Hz,1H),7.81-7.79(m,3H),7.74-7.72(m,2H),7.67-7.65(m,1H),7.63-7.59(m,2H),7.46-7.42(m,2H),7.40-7.38(m,2H),7.26-7.24(m,2H),,7.23-7.21(m,2H),7.00-6.97(m,2H),6.86-6.84(m,1H),6.77-6.74(m,2H),6.09(s,1H),3.80(s,3H),3.61(s,2H).13C NMR(DMSO-d6,100MHz):δ(ppm)171.4,166.4,159.5,147.0,146.4,137.1,136.0,132.2,130.2,130.1,129.3,129.2,129.0,128.9,128.5,127.8,127.0,125.9,125.3,125.0,123.7,121.1,119.3,116.3,114.1,112.8,105.2,71.1,55.6,27.7.HRMS(ESI):exact mass calculated for[M+Na]+(C38H29N3O5Na)requires m/z 630.1999,found m/z 630.1993。
Example 6:
the embodiment 6 of the invention discloses a preparation method of a chiral isoxazolone compound, which adopts the following technical scheme:
adding 0.3mL of dimethylbenzene compound into a 10mL test tube reactor, and sequentially adding 0.06mmol of substrate 1a, 0.05mmol of substrate 2f and 0.0005mmol of CPA into the reaction tube; reacting the reaction system at-20 ℃ to 0 ℃ for 36 hours; after TLC detection, silica gel was added directly and column chromatography was performed to obtain 3af (79%) as a white solid.1H NMR(DMSO-d6,400MHz):δ(ppm)11.43(s,1H),7.85(d,J＝8.0Hz,1H),7.76-7.76(m,1H),7.71-7.69(m,2H),7.66-7.64(m,2H),7.62-7.59(m,1H),7.45-7.40(m,4H),7.27(s,1H),7.25-7.21(m,1H),7.17-7.15(m,3H),6.98-6.97(m,2H),6.95(s,1H),6.90-6.88(m,2H),6.43(d,J＝8.0Hz,1H),6.09(s,1H),3.78(s,3H),3.50(s,2H).13C NMR(DMSO-d6,100MHz):δ(ppm)171.3,166.0,159.5,141.4,137.2,136.1,133.6,132.1,130.4,130.3,130.2,129.8,129.3,128.9,128.5,127.9,127.8,126.9,126.7,126.2,125.9,125.2,124.8,120.7,119.3,116.3,114.1,112.6,105.0,70.6,55.6,27.4.HRMS(ESI):exact mass calculated for[M+Na]+(C38H29ClN2O3Na)requires m/z 619.1759,found m/z 619.1752。
Example 7:
the embodiment 7 of the invention discloses a preparation method of a chiral isoxazolone compound, which adopts the following technical scheme:
adding 0.3mL of dimethylbenzene compound into a 10mL test tube reactor, and sequentially adding 0.06mmol of substrate 1a, 0.05mmol of substrate 2g and 0.0005mmol of CPA into the reaction tube; reacting the reaction system at-20 ℃ to 0 ℃ for 36 hours; after TLC detection, silica gel was added directly and column chromatography was performed to obtain 3ag (79%) as a white solid.1H NMR(DMSO-d6,400MHz):δ(ppm)11.43(s,1H),7.85(d,J＝8.0Hz,1H),7.76-7.76(m,1H),7.71-7.69(m,2H),7.66-7.60(m,3H),7.45-7.40(m,4H),7.30-7.21(m,3H),7.17-7.15(m,2H),7.09(s,1H),,6.97-6.95(m,2H),6.90-6.86(m,2H),6.42(d,J＝8.0Hz,1H),6.09(s,1H),3.78(s,3H),3.50(s,2H).13C NMR(DMSO-d6,100MHz):δ(ppm)171.3,166.0,159.5,141.7,137.1,136.1,132.1,130.8,130.7,130.2,130.1,129.8,129.6,129.3,128.9,128.5,127.8,127.0,126.5,125.9,125.2,124.8,122.2,120.7,119.3,116.2,114.1,112.6,104.9,70.6,55.6,27.4.HRMS(ESI):exact mass calculated for[M+Na]+(C38H29BrN2O3Na)requires m/z 663.1254,found m/z 663.1249。
Example 8:
the embodiment 8 of the invention discloses a preparation method of a chiral isoxazolone compound, which adopts the following technical scheme:
adding 0.3mL of dimethylbenzene compound into a 10mL test tube reactor, and sequentially adding 0.06mmol of substrate 1a, 0.05mmol of substrate for 2h and 0.0005mmol of CPA into the reaction tube; reacting the reaction system at-20 ℃ to 0 ℃ for 36 hours; after TLC detection, silica gel was added directly and column chromatography was performed to obtain 3ah (79%) as a white solid.1H NMR(DMSO-d6,400MHz):δ(ppm)11.44(s,1H),7.84(d,J＝8.0Hz,1H),7.76-7.76(m,1H),7.71-7.69(m,2H),7.65-7.62(m,2H),7.60-7.58(m,1H),7.45-7.41(m,4H),7.28(s,1H),7.25-7.21(m,1H),7.18-7.16(m,2H),6.97-6.95(m,2H),6.89-6.84(m,3H),6.56(s,1H),6.29-6.27(m,1H),6.08(s,1H),3.78(s,3H),3.43(s,2H),2.05(s,3H).13C NMR(DMSO-d6,100MHz):δ(ppm)176.3,170.5,164.2,143.5,142.7,141.9,140.9,136.7,135.1,134.9,134.6,134.0,133.8,133.3,133.2,133.1,132.9,132.0,131.7,130.6,129.9,129.6,129.4,125.6,124.1,121.0,118.8,117.4,110.5,75.3,60.3,32.4,26.0.HRMS(ESI):exact mass calculated for[M+Na]+(C39H32N2O3Na)requires m/z 599.2311,found m/z 599.2298。
Example 9:
embodiment 9 of the invention discloses a preparation method of a chiral isoxazolone compound, which adopts the following technical scheme:
adding 0.3mL of dimethylbenzene compound into a 10mL test tube reactor, and sequentially adding 0.06mmol of substrate 1b, 0.05mmol of substrate 2a and 0.0005mmol of CPA into the reaction tube; reacting the reaction system at-20 ℃ to 0 ℃ for 36 hours; after TLC detection, silica gel was added directly and column chromatography was performed to obtain 3ba (77%) as a white solid.1H NMR(DMSO-d6,400MHz):δ(ppm)11.44(s,1H),7.83(d,J＝8.0Hz,1H),7.80-7.79(m,1H),7.74-7.72(m,2H),7.65-7.61(m,2H),7.59-7.58(m,1H),7.47-7.45(m,2H),7.43-7.41(m,2H),7.40-7.38(m,2H),7.27-7.23(m,3H),7.20-7.19(m,1H),6.78-6.75(m,1H),6.72-6.70(m,2H),6.36-6.34(m,2H),6.13(s,1H),3.40(s,2H),2.09(s,3H).13C NMR(DMSO-d6,100MHz):δ(ppm)171.5,165.8,162.2(d,J＝972.0Hz),137.2,136.1,135.5(d,J＝52.0Hz),134.0(d,J＝8.0Hz),132.0,130.9(d,J＝32.0Hz),130.1,129.3,129.3,128.5,128.4,128.1,127.4,127.0,125.9,125.5,125.0,121.2,119.3,116.3,115.6(d,J＝88.0Hz),113.1,106.8,70.7,27.2,20.9.HRMS(ESI):exact mass calculated for[M+Na]+(C38H29FN2O2Na)requires m/z 587.2111,found m/z 587.2100。
Example 10:
the embodiment 10 of the invention discloses a preparation method of a chiral isoxazolone compound, which adopts the following technical scheme:
adding 0.3mL of dimethylbenzene compound into a 10mL test tube reactor, and sequentially adding 0.06mmol of substrate 1c, 0.05mmol of substrate 2a and 0.0005mmol of CPA into the reaction tube; reacting the reaction system at-20 ℃ to 0 ℃ for 36 hours; after the TLC detection reaction, silica gel is directly added, and the obtained product is subjected to spin-dry column chromatography to obtain a white solid 3ca (70%).1H NMR(DMSO-d6,400MHz):δ(ppm)11.46(s,1H),7.83(d,J＝8.0Hz,1H),7.81-7.81(m,1H),7.75-7.73(m,2H),7.66-7.64(m,1H),7.62-7.61(m,2H),7.48-7.48(m,2H),7.46-7.44(m,3H),7.42-7.40(m,2H),7.36-7.34(m,1H),7.28-7.24(m,1H),7.15(s,1H),6.74-6.72(m,1H),6.70-6.68(m,2H),6.33-6.31(m,2H),6.18(s,1H),3.41(s,2H),2.08(s,3H).13C NMR(DMSO-d6,100MHz):δ(ppm)171.4,165.8,140.6,137.1,136.0,135.5,135.4,133.5,132.0,130.7,130.1,129.3,128.5,128.4,128.3,128.0,127.8,127.4,127.4,127.0,125.9,125.6,125.1,121.3,119.4,116.4,113.4,106.9,70.8,27.2,20.9.HRMS(ESI):exact mass calculated for[M+Na]+(C38H29ClN2O2Na)requires m/z603.1810,foundm/z 603.1817。
Example 11:
the embodiment 11 of the invention discloses a preparation method of a chiral isoxazolone compound, which adopts the following technical scheme:
adding 0.3mL of dimethylbenzene compound into a 10mL test tube reactor, and sequentially adding 0.06mmol of substrate 1d, 0.05mmol of substrate 2a and 0.0005mmol of CPA into the reaction tube; reacting the reaction system at-20 ℃ to 0 ℃ for 36 hours; after the TLC detection reaction, silica gel was added directly and the column chromatography was performed to obtain 3da (70%) as a white solid.1H NMR(DMSO-d6,400MHz):δ(ppm)11.43(s,1H),7.83(d,J＝8.0Hz,1H),7.79-7.78(m,1H),7.74-7.72(m,2H),7.65-7.58(m,3H),7.47-7.40(m,4H),7.35-7.31(m,1H),7.27-7.20(m,2H),7.00-6.98(m,1H),6.90-6.89(m,2H),6.81-6.79(m,1H),6.74-6.72(m,2H),6.37-6.35(m,2H),6.09(s,1H),3.72(s,3H),3.38(s,2H),2.10(s,3H).13C NMR(DMSO-d6,100MHz):δ(ppm)171.6,165.8,159.6,139.2,137.1,136.1,135.6,135.4,132.0,130.1,129.9,129.3,128.6,128.4,128.1,128.1,127.5,127.0,125.9,125.4,124.9,121.2,121.1,119.3,116.3,114.7,113.5,113.2,106.6,71.2,55.5,27.3,20.9.HRMS(ESI):exact mass calculated for[M+Na]+(C39H32N2O3Na)requires m/z 599.2305,found m/z 599.2299。
Example 12:
embodiment 12 of the invention discloses a preparation method of a chiral isoxazolone compound, which adopts the following technical scheme:
adding 0.3mL of dimethylbenzene compound into a 10mL test tube reactor, and sequentially adding 0.06mmol of substrate 1e, 0.05mmol of substrate 2a and 0.0005mmol of CPA into the reaction tube; reacting the reaction system at-20 ℃ to 0 ℃ for 36 hours; after the TLC detection reaction, silica gel is directly added, and the column chromatography is performed in a spin-drying mode to obtain white solid 3ea (70%).1H NMR(DMSO-d6,400MHz):δ(ppm)11.11(s,1H),7.64-7.56(m,3H),7.49(d,J＝8.0Hz,1H),7.39-7.38(m,3H),7.19(s,1H),7.14-7.12(m,2H),6.94-6.93(m,2H),6.79-6.75(m,3H),6.46-6.42(m,3H),6.01(s,1H),3.77(s,3H),3.39(s,2H),2.18(s,3H).13C NMR(CDCl3,100MHz):δ(ppm)172.4,165.4,159.3,135.7,135.5,135.4,131.1,130.1,129.9,129.4,129.1,129.0,128.5,128.4,127.7,127.4,125.3,120.8,120.3,113.6,111.6,106.9,102.3,71.0,55.3,27.4,21.0.HRMS(ESI):exact mass calculated for[M+Na]+(C33H28N2O3Na)requires m/z 523.1992,found m/z 523.2001。
Example 13:
the embodiment 13 of the invention discloses a preparation method of a chiral isoxazolone compound, which adopts the following technical scheme:
adding 0.3mL of dimethylbenzene compound into a 10mL test tube reactor, and sequentially adding 0.06mmol of substrate 1f, 0.05mmol of substrate 2a and 0.0005mmol of CPA into the reaction tube; reacting the reaction system at-20 ℃ to 0 ℃ for 36 hours; after TLC detection, silica gel was added directly and column chromatography was performed to obtain 3fa (79%) as a white solid.1H NMR(DMSO-d6,400MHz):δ(ppm)10.78(s,1H),7.64-7.57(m,3H),7.45-7.39(m,3H),7.18-7.15(m,3H),7.13(s,1H),6.96-6.94(m,2H),6.79-6.77(m,2H),6.74-6.72(m,1H),6.44-6.42(m,2H),6.01(s,1H),3.78(s,3H),3.40(s,2H),2.29(s,3H),2.19(s,3H).13C NMR(DMSO-d6,100MHz):δ(ppm)171.6,165.7,159.4,136.5,135.7,135.4,131.9,130.2,130.1,129.3,129.3,128.9,128.4,128.2,127.6,124.1,119.5,118.4,114.1,112.1,109.8,106.2,71.0,55.6,27.3,21.0,10.0.HRMS(ESI):exact mass calculated for[M+Na]+(C34H30N2O3Na)requires m/z 537.2149,found m/z 537.2159。
Example 14:
the embodiment 14 of the invention discloses a preparation method of a chiral isoxazolone compound, which adopts the following technical scheme:
adding 0.3mL of dimethylbenzene compound into a 10mL test tube reactor, and sequentially adding 0.06mmol of substrate 1g, 0.05mmol of substrate 2a and 0.0005mmol of CPA into the reaction tube; reacting the reaction system at-20 ℃ to 0 ℃ for 36 hours; after the TLC detection reaction, silica gel was added directly and the column chromatography was performed to obtain 3ga (81%) as a white solid.1H NMR(DMSO-d6,400MHz):δ(ppm)11.32(s,1H),7.77(d,J＝12.0Hz,1H),7.67-7.67(m,1H),7.65-7.63(m,2H),7.62-7.58(m,3H),7.41-7.39(m,2H),7.21-7.19(m,3H),7.03(d,J＝8.0Hz,2H),6.97(d,J＝8.0Hz,2H),6.82-6.79(m,1H),6.74(d,J＝8.0Hz,2H),6.36(d,J＝8.0Hz,2H),6.05(s,1H),3.79(s,3H),3.79(s,3H),3.39(s,2H),2.12(s,3H).13C NMR(DMSO-d6,100MHz):δ(ppm)171.6,165.8,159.4,157.8,137.0,135.6,135.4,131.9,130.2,130.1,129.3,129.2,129.2,128.6,128.4,128.2,127.5,125.4,124.0,120.8,119.2,116.1,114.8,114.1,112.7,106.5,71.0,55.6,55.6,27.2,21.0.HRMS(ESI):exact mass calculated for[M+Na]+(C40H34N2O4Na)requires m/z 629.2411,foundm/z 629.2405。
Example 15:
the embodiment 15 of the invention discloses a preparation method of a chiral isoxazolone compound, which adopts the following technical scheme:
adding 0.3mL of dimethylbenzene compound into a 10mL test tube reactor, and sequentially adding 0.06mmol of substrate for 1h, 0.05mmol of substrate 2a and 0.0005mmol of CPA into the reaction tube; reacting the reaction system at-20 ℃ to 0 ℃ for 36 hours; after TLC detection, silica gel was added directly and column chromatography was performed to obtain 3ha (81%) as a white solid.1H NMR(DMSO-d6,400MHz):δ(ppm)11.35(s,1H),7.66-7.62(m,3H),7.60-7.57(m,3H),7.41-7.39(m,2H),7.30-7.26(m,1H),7.23-7.21(m,3H),7.13(d,J＝8.0Hz,1H),7.06-7.03(m,1H),6.98(d,J＝8.0Hz,2H),6.79-6.74(m,3H),6.36(d,J＝8.0Hz,2H),6.05(s,1H),3.82(s,3H),3.80(s,3H),3.39(s,2H),2.13(s,3H).13C NMR(DMSO-d6,100MHz):δ(ppm)171.6,165.8,159.4,156.6,136.3,135.6,135.4,131.9,130.2,130.1,130.1,129.3,129.2,128.9,128.4,128.2,127.5,127.4,126.6,126.4,124.4,121.0,120.5,119.9,114.1,112.5,112.2,111.9,106.4,71.0,55.7,55.6,27.2,20.9.HRMS(ESI):exact mass calculated for[M+Na]+(C40H34N2O4Na)requires m/z 629.2411,found m/z 629.2404。
The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (4)
1. A preparation method of chiral isoxazolone compounds is characterized by comprising the following steps: chiral phosphoric acid CPA is used as a catalyst, the temperature is set to be-20 ℃ to 0 ℃, a compound 1 and a compound 2 in a reaction solvent are used as reaction raw materials, and the reaction is carried out for 24-72h to obtain a chiral isoxazolone compound 3, wherein the reaction process is shown as a formula I;
wherein R is1、R2、R3One or more selected from alkyl, aryl, substituted aromatic ring and substituted hetero atom.
2. The method for preparing chiral isoxazolones according to claim 1, wherein the ratio of the amount of the catalyst to the reactants is 1-100 mol%.
3. The method for preparing chiral isoxazolones according to claim 1, wherein the reaction solvent is one selected from toluene, chloroform, carbon tetrachloride, dichloromethane, trifluorotoluene, tetrahydrofuran, xylene compounds, tert-butyl methyl ether and diethyl ether.
4. The preparation method of chiral isoxazolone compounds according to claim 1, wherein the molar ratio of the compound 1 to the compound 2 is 1.2: 1.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104710359A (en) * | 2013-12-13 | 2015-06-17 | 中国科学院大连化学物理研究所 | Method for synthesizing tetrahydroquinoline containing three continuous chiral centers through asymmetric transfer hydrogenation |
| CN106365949A (en) * | 2015-07-23 | 2017-02-01 | 中国科学院上海有机化学研究所 | Chiral spirodihydroindene skeleton compound and preparation method thereof |
| CN106631702A (en) * | 2016-11-11 | 2017-05-10 | 南方科技大学 | Catalytic asymmetric synthetic method for chiral spirodiol derivative |
| CN109651282A (en) * | 2018-12-19 | 2019-04-19 | 深圳市众康动保科技有限公司 | A kind of synthesis four replaces the new method of connection alkene |
| CN109721564A (en) * | 2018-12-19 | 2019-05-07 | 深圳市众康动保科技有限公司 | A kind of new method synthesizing the polysubstituted alkene of sulfur-bearing |
| CN111763197A (en) * | 2020-07-08 | 2020-10-13 | 青岛大学 | Synthesis method of novel chiral indole compound |
-
2021
- 2021-12-08 CN CN202111492522.4A patent/CN114133384A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104710359A (en) * | 2013-12-13 | 2015-06-17 | 中国科学院大连化学物理研究所 | Method for synthesizing tetrahydroquinoline containing three continuous chiral centers through asymmetric transfer hydrogenation |
| CN106365949A (en) * | 2015-07-23 | 2017-02-01 | 中国科学院上海有机化学研究所 | Chiral spirodihydroindene skeleton compound and preparation method thereof |
| CN106631702A (en) * | 2016-11-11 | 2017-05-10 | 南方科技大学 | Catalytic asymmetric synthetic method for chiral spirodiol derivative |
| CN109651282A (en) * | 2018-12-19 | 2019-04-19 | 深圳市众康动保科技有限公司 | A kind of synthesis four replaces the new method of connection alkene |
| CN109721564A (en) * | 2018-12-19 | 2019-05-07 | 深圳市众康动保科技有限公司 | A kind of new method synthesizing the polysubstituted alkene of sulfur-bearing |
| CN111763197A (en) * | 2020-07-08 | 2020-10-13 | 青岛大学 | Synthesis method of novel chiral indole compound |
Non-Patent Citations (2)
| Title |
|---|
| DEYUN QIAN ET AL.: "Organocatalytic synthesis of chiral tetrasubstituted allenes from racemic propargylic alcohols", NATURE COMMUNICATIONS, vol. 8, pages 1 - 9 * |
| 刘财路等: "手性磷酸催化己内酯的动力学拆分", 中国科技论文, vol. 12, no. 18, pages 2041 - 2045 * |
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