CN117402029A - Synthesis method of chiral quinoxalinone - Google Patents
Synthesis method of chiral quinoxalinone Download PDFInfo
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- CN117402029A CN117402029A CN202311273014.6A CN202311273014A CN117402029A CN 117402029 A CN117402029 A CN 117402029A CN 202311273014 A CN202311273014 A CN 202311273014A CN 117402029 A CN117402029 A CN 117402029A
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- chiral
- quinoxalinone
- reaction
- synthesizing
- phenylenediamine
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- FFRYUAVNPBUEIC-UHFFFAOYSA-N quinoxalin-2-ol Chemical compound C1=CC=CC2=NC(O)=CN=C21 FFRYUAVNPBUEIC-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- -1 quinoxalinone compound Chemical class 0.000 claims abstract description 19
- 239000003446 ligand Substances 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- 150000001879 copper Chemical class 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 230000003197 catalytic effect Effects 0.000 claims abstract description 4
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 claims description 16
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 16
- 239000012046 mixed solvent Substances 0.000 claims description 16
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims description 15
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- FUPAJKKAHDLPAZ-UHFFFAOYSA-N 1,2,3-triphenylguanidine Chemical compound C=1C=CC=CC=1NC(=NC=1C=CC=CC=1)NC1=CC=CC=C1 FUPAJKKAHDLPAZ-UHFFFAOYSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000000741 silica gel Substances 0.000 claims description 8
- 229910002027 silica gel Inorganic materials 0.000 claims description 8
- 239000010949 copper Substances 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-Cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical group C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 238000012512 characterization method Methods 0.000 description 6
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 6
- 239000012264 purified product Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical compound NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- KELNNWMENBUHNS-NSHDSACASA-N isopropyl (2s)-2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxaline-1(2h)-carboxylate Chemical compound FC1=CC=C2NC(=O)[C@H](CC)N(C(=O)OC(C)C)C2=C1 KELNNWMENBUHNS-NSHDSACASA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- 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
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
-
- 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
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
- B01J2531/16—Copper
-
- 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)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of chiral quinoxalinone, which comprises the steps of taking copper salt, chiral ligand and alkali as a catalytic system, and reacting in an organic solvent to obtain a target chiral quinoxalinone compound; the method has the advantages of good substrate universality, high yield, good enantioselectivity, easy realization of industrial production and the like. The synthesis method of the invention does not need to use special and expensive catalysts, has simple reaction conditions, does not need special reaction environments such as high-pressure hydrogen and the like, has low requirements on reaction equipment, and is easy for industrialized mass production.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of chiral quinoxalinone, which is suitable for synthesizing unnatural chiral quinoxalinone.
Background
Chiral quinoxalinone and its derivatives play a very important role in medicine, biology, materials and the like. In the field of medical research, chiral quinoxalinones are not only intermediates in the synthesis of many drug molecules, but also important backbone structures of many drug molecules. For example, GW420867X containing a chiral quinoxalinone backbone is a molecule having anti-HIV activity (HIV Clin. Trials 2001,2,307-316). Currently, strategies for synthesizing chiral quinoxalinones fall into two main categories: (1) Synthetic strategies based on chiral starting prosthetic groups, which require the use of equivalent amounts of chiral starting or prosthetic groups; (2) An asymmetric catalytic synthesis strategy that requires the construction of a quinoxalinone backbone in advance and the use of a noble metal catalyst. Therefore, development of a chiral quinoxalinone synthesis strategy which is simple to operate, economical and inexpensive has received a great deal of attention.
In 2015, the De Brabender team uses 2-iodoaniline and derivatives thereof and alpha-chiral amino acid as raw materials, and a series of chiral quinoxalinones are obtained through two-step reactions of copper-catalyzed cross-coupling and intramolecular cyclization (Tetrahedron Lett.2015,56, 3179-3182).
The reaction needs to use equivalent alpha-chiral amino acid as a raw material, and can be completed in two steps, so that the reaction flow is complex and is not beneficial to operation.
In 2023, chen Fener team used quinoxalinone as starting material, and performed asymmetric hydrogenation of quinoxalinone backbone under the catalysis of rhodium catalyst and chiral thiourea ligand to give chiral quinoxalinone product (chem. Sci.2023,10.1039/D3SC 00803G).
This type of reaction requires the construction of a quinoxalinone framework in advance and the use of high pressure hydrogen, and also requires the use of expensive rhodium catalysts in the hydrogenation process, which is a complex and costly synthetic strategy to operate.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a synthesis method of chiral quinoxalinone, which aims to solve the technical problems that the synthesis method in the prior art is complex in operation, the used reaction materials are not easy to obtain and the cost is high.
In order to achieve the above purpose, the invention is realized by adopting the following technical scheme:
the invention discloses a synthesis method of chiral quinoxalinone, which is characterized in that propargyl ester compound and o-phenylenediamine are used as reaction raw materials, copper salt, chiral ligand and alkali are used as a catalytic system, and the reaction is carried out in an organic solvent to prepare the chiral quinoxalinone compound. The reaction general formula is as follows:
preferably, the structural formula of the o-phenylenediamine and propargyl ester compound is as follows:
R 1 and R is 2 Is alkyl or aryl.
Preferably, the copper salt is CuI, cu (OTf) 2 、Cu(ACN) 4 PF 6 、Cu(OAc )2 、CuCl、Cu(ACN) 4 BF 4 、CuBr 2 、CuSO 4 ·5H 2 O or CuBr.
Preferably, the chiral ligand is:
wherein X is H or alkyl.
Preferably, the base is quinuclidine, N-diisopropylethylamine, triphenylguanidine, or N-methyldicyclohexylamine.
Preferably, the molar amount of the o-phenylenediamine is 1.2 times the molar amount of the propargyl ester compound; the molar amount of the base is 1.2 times the molar amount of the propargyl ester compound.
Preferably, the organic solvent is a mixed solvent of trifluoroethanol and chloroacetonitrile, and the volume ratio of the trifluoroethanol to the chloroacetonitrile in the mixed solvent is (1-6): 1.
preferably, the specific reaction steps are as follows:
firstly adding copper salt and chiral ligand into organic solvent, stirring for 1 hour at room temperature, then adding propargyl ester compound, o-phenylenediamine and alkali, continuously reacting, then removing solvent, and separating by silica gel chromatographic column to obtain chiral quinoxalinone.
Further preferably, the reaction time is 24 to 72 hours.
Further preferably, the reaction temperature is-30 ℃.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, propargyl ester compound and o-phenylenediamine are used as reaction raw materials, copper salt, chiral ligand and alkali are used as a catalytic system, and the target chiral quinoxalinone compound is obtained by reaction in an organic solvent; the method has the advantages of good substrate universality, high yield, good enantioselectivity, easy realization of industrial production and the like. The synthesis method of the invention does not need to use special and expensive catalysts, has simple reaction conditions, does not need special reaction environments such as high-pressure hydrogen and the like, has low requirements on reaction equipment, and is easy for industrialized mass production.
Detailed Description
In order that the manner in which the invention may be better understood, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are, therefore, apparent to those skilled in the art, only partially but not completely. All other embodiments, which can be made by those skilled in the art based on the embodiments of the present invention without making any inventive effort, shall fall within the scope of the present invention.
It should be noted that the terms "first," "second," and the like in the description and in the claims are used for distinguishing between similar objects and not necessarily for describing a particular sequential or chronological order. It is to be understood that the data so used may be interchanged where appropriate such that the embodiments of the invention described herein may be implemented in sequences other than those described herein. Furthermore, the terms "comprises," "comprising," and "having," and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or apparatus that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.
The invention is described in further detail below in connection with specific examples:
example 1
To a 2mL reaction flask, 0.9mg of anhydrous copper acetate, 3.3mg of (4R, 5S) -L1 ligand and 0.5mL of a mixed solvent of trifluoroethanol and chloroacetonitrile (volume ratio: 3:1) were successively added, and the mixture was stirred at room temperature for 1 hour and then cooled to-30 ℃. 23.2mg of propargyl ester I-1, 13.0mg of o-phenylenediamine II-1 and 34.4mg of triphenylguanidine were dissolved in 0.5mL of a mixed solvent of trifluoroethanol and chloroacetonitrile (volume ratio: 3:1), and slowly added to the reaction flask via a microinjector. The reaction system was stirred at-30℃for 36 hours. The reaction solution is concentrated and dried, and the purified product (R) -III-1 is obtained through silica gel column separation. The yield was 88% and the ee value was 94%. The pure product structure characterization data are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.03(s,1H),7.85-7.76(m,2H),7.47-7.37(m,3H),6.99(td,J＝7.6,1.3Hz,1H),6.88(td,J＝7.6,1.2Hz,1H),6.79(dd,J＝7.1,4.9Hz,2H),4.42(s,1H),2.69(s,1H). 13 C NMR(100MHz,CDCl 3 )δ165.3,138.3,132.2,129.1,128.6,127.8,125.5,124.2,120.8,115.7,115.0,81.2,76.8,61.4.IR(neat,cm -1 )3288,3050,1675,1605,1499,1350,1312,912,731,689.HRMS(ESI):m/z:calcd for C 16 H 12 N 2 ONa[M+Na] + :271.0847,found:271.0852.
example 2
To a 2mL reaction flask, 0.9mg of anhydrous copper acetate, 3.3mg of (4R, 5S) -L1 ligand and 0.5mL of a mixed solvent of trifluoroethanol and chloroacetonitrile (volume ratio: 3:1) were successively added, and the mixture was stirred at room temperature for 1 hour and then cooled to-30 ℃. 24.6mg of propargyl ester I-2, 13.0mg of o-phenylenediamine II-1 and 34.4mg of triphenylguanidine were dissolved in 0.5mL of a mixed solvent of trifluoroethanol and chloroacetonitrile (volume ratio: 3:1), and slowly added to the reaction flask via a microinjector. The reaction system was stirred at-30℃for 36 hours. The reaction solution is concentrated and dried, and the purified product (R) -III-2 is obtained through silica gel column separation. The yield was 81% and the ee value was 92%. The pure product structure characterization data are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.34(s,1H),7.68(d,J＝8.2Hz,2H),7.23(d,J＝8.0Hz,2H),6.97(td,J＝7.6,1.3Hz,1H),6.86(td,J＝7.6,1.2Hz,1H),6.78(d,J＝7.8Hz,2H),4.40(s,1H),2.66(s,1H),2.37(s,3H). 13 C NMR(100MHz,CDCl 3 )δ165.3,139.0,135.4,132.3,129.3,127.6,125.5,124.1,120.7,115.5,115.0,81.3,76.6,61.2,21.3.IR(neat,cm -1 )3279,3057,1684,1607,1505,1447,1353,1311,1271,812,744.HRMS(ESI):m/z:calcd for C 17 H 14 N 2 ONa[M+Na] + :285.1004,found:285.1010.
example 3
To a 2mL reaction flask, 0.9mg of anhydrous copper acetate, 3.3mg of (4R, 5S) -L1 ligand and 0.5mL of a mixed solvent of trifluoroethanol and chloroacetonitrile (volume ratio: 3:1) were successively added, and the mixture was stirred at room temperature for 1 hour and then cooled to-30 ℃. 28.8mg of propargyl ester I-3, 13.0mg of o-phenylenediamine II-1 and 34.4mg of triphenylguanidine were dissolved in 0.5mL of a mixed solvent of trifluoroethanol and chloroacetonitrile (volume ratio: 3:1), and slowly added to the reaction flask via a microinjector. The reaction system was stirred at-30℃for 36 hours. The reaction solution was concentrated and spin-dried, and the purified product (R) -III-3 was obtained by separation on a silica gel column. The yield was 72% and the ee value was 93%. The pure product structure characterization data are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.74(s,1H),7.73(d,J＝8.5Hz,2H),7.44(d,J＝8.5Hz,2H),6.96(td,J＝7.6,1.2Hz,1H),6.84(t,J＝7.5Hz,1H),6.81-6.72(m,2H),4.42(s,1H),2.66(s,1H),1.33(s,9H). 13 C NMR(100MHz,CDCl 3 )δ165.5,152.0,135.4,132.3,127.4,125.6,125.5,124.1,120.6,115.7,114.9,81.4,76.5,61.1,34.7,31.4.IR(neat,cm -1 )3283,2962,1686,1608,1506,1459,1360,1311,1270,735,650.HRMS(ESI):m/z:calcd for C 20 H 20 N 2 ONa[M+Na] + :327.1473,found:327.1473.
example 4
To a 2mL reaction flask, 0.9mg of anhydrous copper acetate, 3.3mg of (4R, 5S) -L1 ligand and 0.5mL of a mixed solvent of trifluoroethanol and chloroacetonitrile (volume ratio: 3:1) were successively added, and the mixture was stirred at room temperature for 1 hour and then cooled to-30 ℃. 30.8mg of propargyl ester I-4, 13.0mg of o-phenylenediamine II-1 and 34.4mg of triphenylguanidine were dissolved in 0.5mL of a mixed solvent of trifluoroethanol and chloroacetonitrile (volume ratio: 3:1), and slowly added to the reaction flask via a microinjector. The reaction system was stirred at-30℃for 36 hours. The reaction solution was concentrated and spin-dried, and the purified product (R) -III-4 was obtained by separation on a silica gel column. The yield was 75% and the ee value was 93%. The pure product structure characterization data are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.67(s,1H),7.96-7.83(m,2H),7.74-7.54(m,4H),7.52-7.41(m,2H),7.41-7.34(m,1H),6.98(td,J＝7.6,1.5Hz,1H),6.86(td,J＝7.7,1.2Hz,1H),6.83-6.75(m,2H),4.47(s,1H),2.71(s,1H). 13 C NMR(100MHz,CDCl 3 )δ165.3,142.0,140.7,137.3,132.2,128.9,128.2,127.7,127.4,127.3,125.5,124.2,120.8,115.7,115.0,81.2,76.9,61.2.IR(neat,cm -1 )3283,3058,2925,1685,1607,1505,1355,1311,909,733.HRMS(ESI):m/z:calcd for C 22 H 16 N 2 ONa[M+Na] + :347.1160,found:347.1161.
example 5
To a 2mL reaction flask, 0.9mg of anhydrous copper acetate, 3.3mg of (4R, 5S) -L1 ligand and 0.5mL of a mixed solvent of trifluoroethanol and chloroacetonitrile (volume ratio: 3:1) were successively added, and the mixture was stirred at room temperature for 1 hour and then cooled to-30 ℃. 31.0mg of propargyl ester I-5, 13.0mg of o-phenylenediamine II-1 and 34.4mg of triphenylguanidine are dissolved in 0.5mL of a mixed solvent of trifluoroethanol and chloroacetonitrile (the volume ratio is 3:1), and the mixture is slowly added to a reaction flask by a microinjector. The reaction system was stirred at-30℃for 36 hours. The reaction solution was concentrated and spin-dried, and the purified product (R) -III-5 was obtained by separation on a silica gel column. The yield was 78% and the ee value 90%. The pure product structure characterization data are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.27(s,1H),7.69(d,J＝8.7Hz,2H),7.55(d,J＝8.7Hz,2H),6.99(td,J＝7.6,1.3Hz,1H),6.89(td,J＝7.6,1.2Hz,1H),6.80(t,J＝6.5Hz,2H),4.39(s,1H),2.69(s,1H). 13 C NMR(100MHz,CDCl 3 )one carbon signal was overlappedδ164.6,137.3,132.0,131.7,129.6,125.4,124.3,123.5,121.1,115.6,115.2,80.7,61.1.IR(neat,cm -1 )3287,1686,1608,1505,1486,1355,1312,1074,1011,748,659.HRMS(ESI):m/z:calcd for C 16 H 11 N 2 OBrNa[M+Na] + :348.9952,found:348.9958.
example 6
To a 2mL reaction flask, 0.9mg of anhydrous copper acetate, 3.3mg of (4R, 5S) -L1 ligand and 0.5mL of a mixed solvent of trifluoroethanol and chloroacetonitrile (volume ratio: 3:1) were successively added, and the mixture was stirred at room temperature for 1 hour and then cooled to-30 ℃. 17.0mg of propargyl ester I-6, 13.0mg of o-phenylenediamine II-1 and 34.4mg of triphenylguanidine are dissolved in 0.5mL of a mixed solvent of trifluoroethanol and chloroacetonitrile (the volume ratio is 3:1), and the mixture is slowly added to a reaction flask by a microinjector. The reaction system was stirred at-30℃for 36 hours. The reaction solution was concentrated and spin-dried, and the purified product (R) -III-6 was obtained by separation on a silica gel column. The yield was 60% and the ee value was 60%. The pure product structure characterization data are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.85(s,1H),6.96(td,J＝7.6,1.4Hz,1H),6.87(td,J＝7.6,1.3Hz,1H),6.79(dd,J＝8.9,4.4Hz,2H),4.16(s,1H),2.36(s,1H),1.80(s,3H). 13 C NMR(100MHz,CDCl 3 )one carbon signal was overlappedδ165.5,132.5,125.9,124.1,120.9,115.4,115.2,73.3,53.2,25.1.IR(neat,cm -1 )3325,3270,1664,1604,1507,1388,1314,1146,746,663.HRMS(ESI):m/z:calcd for C 11 H 11 N 2 O[M+H] + :187.0871,found:187.0874.
the above is only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited by this, and any modification made on the basis of the technical scheme according to the technical idea of the present invention falls within the protection scope of the claims of the present invention.
Claims (10)
1. A synthesis method of chiral quinoxalinone is characterized in that propargyl ester compound and o-phenylenediamine are used as reaction raw materials, copper salt, chiral ligand and alkali are used as a catalytic system, and the reaction is carried out in an organic solvent to prepare the chiral quinoxalinone compound.
2. The method for synthesizing chiral quinoxalinone according to claim 1, wherein said o-phenylenediamine and propargyl ester compound has the following structural formula:
R 1 and R is 2 Is alkyl or aryl.
3. The method for synthesizing chiral quinoxalinone according to claim 1, wherein said copper salt is CuI, cu (OTf) 2 、Cu(ACN) 4 PF 6 、Cu(OAc )2 、CuCl、Cu(ACN) 4 BF 4 、CuBr 2 、CuSO 4 ·5H 2 O or CuBr.
4. The method for synthesizing chiral quinoxalinone according to claim 1, wherein said chiral ligand is:
wherein X is H or alkyl.
5. The method for synthesizing chiral quinoxalinone according to claim 1, wherein said base is quinuclidine, N-diisopropylethylamine, triphenylguanidine or N-methyldicyclohexylamine.
6. The method for synthesizing chiral quinoxalinone according to claim 1, wherein the molar amount of o-phenylenediamine is 1.2 times the molar amount of propargyl ester compound; the molar amount of the base is 1.2 times the molar amount of the propargyl ester compound.
7. The method for synthesizing chiral quinoxalinone according to claim 1, wherein the organic solvent is a mixed solvent of trifluoroethanol and chloroacetonitrile, and the volume ratio of the trifluoroethanol to the chloroacetonitrile in the mixed solvent is (1-6): 1.
8. the method for synthesizing chiral quinoxalinone according to claim 1, wherein the specific reaction steps are as follows:
firstly adding copper salt and chiral ligand into organic solvent, stirring for 1 hour at room temperature, then adding propargyl ester compound, o-phenylenediamine and alkali, continuously reacting, then removing solvent, and separating by silica gel chromatographic column to obtain chiral quinoxalinone.
9. The method for synthesizing chiral quinoxalinone according to claim 8, wherein the reaction time is 24 to 72 hours.
10. The method for synthesizing chiral quinoxalinone according to claim 8, wherein the reaction temperature is-30 ℃.
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