CN112898217B - Trifluoromethyl oxazolone compound, preparation method thereof and application thereof in anti-cancer drugs - Google Patents
Trifluoromethyl oxazolone compound, preparation method thereof and application thereof in anti-cancer drugs Download PDFInfo
- Publication number
- CN112898217B CN112898217B CN202010034625.5A CN202010034625A CN112898217B CN 112898217 B CN112898217 B CN 112898217B CN 202010034625 A CN202010034625 A CN 202010034625A CN 112898217 B CN112898217 B CN 112898217B
- Authority
- CN
- China
- Prior art keywords
- trifluoromethyl
- oxazolone
- reaction
- carried out
- containing compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/38—One oxygen atom attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a trifluoromethyl oxazolone-containing compound, a preparation method thereof and application thereof in anticancer drugs, belonging to the field of organic chemistry. 4-substituted-2-trifluoromethyl oxazolone (1) and alpha, beta-unsaturated ketone (2) are adopted to react with high stereoselectivity and high enantioselectivity under the catalysis of thiourea catalyst to obtain trifluoromethyl oxazolone compound (3). The compounds have certain inhibiting effect on HepG2 liver cancer cells, MGC-803 stomach cancer cells and PC-9 lung cancer cells. The method has the advantages of mild conditions, short reaction path, simple post-treatment and high selectivity, and two trifluoromethyl oxazolone compounds containing chiral centers can be obtained in one step.
Description
Technical Field
The invention belongs to the technical field of asymmetric synthesis in organic chemistry, and particularly relates to a trifluoromethyl oxazolone-containing compound, a preparation method thereof and application thereof in anticancer drugs.
Background
Organofluorine compounds are important in agrochemicals, diagnostic tools, biological research, new materials and pharmaceuticals. CF 3 The introduction of groups can change the properties of pKa, lipophilicity, molecular recognition, conformation, metabolic oxidation potential and the like of molecules to a certain extent, thereby influencing the efficacy, selectivity, absorption and metabolism of the molecules. The candidate drug containing the chiral trifluoromethyl group has important medicinal value, and according to statistics, 28 percent of all newly approved drugs approved by the U.S. Food and Drug Administration (FDA) in 2018 contain fluorine atoms or fluoroalkyl groups. More importantly, the 18 fluorine-containing drugs contain 49F atoms in total. Therefore, the introduction of trifluoromethyl groups into organic chiral molecules has been the focus of attention of chemists.
In 2005, the Ishihara group reported an alpha-CF with a chiral auxiliary 3 The Aldol reaction of the imine is carried out,α-CF 3 the imine is converted to the corresponding silanol, titanium enol and aldehyde respectively to give good diastereoselective products (Shimada, T.; yoshioka, M.; konno, T.; ishihara, T. Org. Lett.2006,8, 1129-1131.). In 2006, the Franck group reported a similar strategy, i.e. using TiCl 4 TMEDA promotes alpha-CF with chiral auxiliary 3 Aldol reaction of imines and aldehydes (Franck, X.; seon-Meniel, B.; figade re, B.Angew. Chem., int. Ed.2006,45, 5174-5176.). However, alpha-CF 3 There is no general method for enolates to participate catalytically in asymmetric reactions.
Although the above construction contains CF at the chiral center 3 The strategy of class of compounds has made great progress, but alpha-CF 3 Nucleophiles of this kind are limited to only alpha-CF 3 Imine, alpha-CF 3 Thioesters and trifluoromethylimines. Thus, a novel alpha-CF was developed 3 The nucleophilic reagent has important research value when being applied to the organic asymmetric catalytic reaction and needs to be researched.
Disclosure of Invention
The invention aims to provide a trifluoromethyl oxazolone compound, a preparation method thereof and application thereof in anticancer drugs. 4-substituted-2-trifluoromethyl oxazolone (1) and alpha, beta-unsaturated ketone (2) are adopted to react with high stereoselectivity and high enantioselectivity under the catalysis of thiourea catalyst to obtain trifluoromethyl oxazolone compound (3). The compounds have certain inhibiting effect on HepG2 liver cancer cells, MGC-803 stomach cancer cells and PC-9 lung cancer cells. The method has the advantages of mild conditions, short reaction path, simple post-treatment and high selectivity, and two trifluoromethyl oxazolone compounds containing chiral centers can be obtained in one step.
The invention relates to a trifluoromethyl oxazolone-containing compound, which has a structural formula as follows:
wherein Ar is phenyl, halophenyl, trifluoromethylphenyl, nitrophenyl, C1-C3 alkylphenyl, C1-C3 alkoxyphenyl, thienyl, furyl, or naphthyl; r is 1 Is carboxylic acid ester, alkyl carbonyl, phenyl carbonylPhenyl, quinolyl or phenylalkyl; r 2 Is C1-C6 alkyl, phenyl or benzyl.
Further, in the above technical scheme, ar is C 6 H 5 、4-CF 3 C 6 H 5 、4-FC 6 H 5 、4-ClC 6 H 5 、4-BrC 6 H 5 、4-NO 2 C 6 H 5 、4-MeC 6 H 5 、3-CF 3 C 6 H 5 、3-FC 6 H 5 、3-ClC 6 H 5 、3-MeOC 6 H 5 、3-MeC 6 H 5 、2-BrC 6 H 5 、2-MeC 6 H 5 、3,4-Cl 2 C 6 H 5 2-thienyl, 3-thienyl, 2-furyl or 2-naphthyl; r is 1 Is C (O) OEt, C (O) OMe, C (O) C 6 H 5 、CH 2 CH 2 C 6 H 5 、C 6 H 5 Or a quinolyl group; r is 2 Is CH 3 、C 2 H 5 、C 4 H 9 、C 6 H 5 、CH 2 C 6 H 5 Or C 6 H 11 。
The invention provides a preparation method of the trifluoromethyl oxazolone-containing compound, and the synthetic route is as follows:
the method comprises the following steps:
reacting 4-substituted-2-trifluoromethyl oxazolone (1) with alpha, beta-unsaturated ketone (2) in an organic solvent in the presence of a thiourea catalyst to obtain a trifluoromethyl oxazolone-containing compound (3).
Further, in the above technical scheme, the thiourea catalyst is selected from C1-C10, and has the following specific structure:
wherein: ar is 3,5- (CF) 3 ) 2 Ph。
Further, in the above technical solution, the thiourea catalyst is preferably C10.
Further, in the above technical scheme, the molar ratio of the 4-substituted-2-trifluoromethyl oxazolone (1), the α, β -unsaturated ketone (2), and the thiourea catalyst is 1.2-1.5.
Further, in the above technical solution, the organic solvent is selected from toluene, pentafluorobenzene, chlorobenzene, bromobenzene, trifluoromethylbenzene, xylene, bromotoluene or trimethylbenzene.
Furthermore, in the technical scheme, the reaction temperature is 20-30 ℃, and the reaction time is 1-96 hours.
The invention further provides application of the trifluoromethyl oxazolone-containing compound (3) in anticancer drugs.
Further, in the above technical scheme, the anti-cancer drug is a liver cancer, lung cancer or stomach cancer drug, more preferably a HepG2 liver cancer, PC-9 lung cancer or MGC-803 stomach cancer drug.
The invention has the beneficial effects that:
the invention adopts 4-substituted-2-trifluoromethyl oxazolone (1) and alpha, beta-unsaturated ketone (2) to react under the catalysis of thiourea catalyst to obtain trifluoromethyl oxazolone compound (3). The method has the advantages of mild conditions, short reaction path, simple post-treatment and high selectivity, and two trifluoromethyl oxazolone compounds containing chiral centers are obtained in one step. The compounds can be applied to anti-cancer drugs HepG2 liver cancer, PC-9 lung cancer or MGC-803 stomach cancer drugs.
Detailed Description
The technical solution of the present invention is further described in detail with reference to the following specific examples, but the scope of the present invention is not limited thereto. In all examples, the d.r. values are > 20.
Instruments and primary chemical reagents
Nuclear magnetic resonance apparatus of the type Bruker AVANCE NEO (switzerland) and Bruker AVANCE III HD600MHZ (switzerland); ultiMate3000 siemer on-the-fly high performance liquid chromatograph (usa).
The raw materials and solvents used in the implementation process of the invention are all purchased from commercial sources.
Example 1:
the synthesis steps of racemic compound 3 are as follows:
compound 1 (0.15mmol, 1.5equiv), a catalyst (0.01mmol, 0.1equiv), 1mL of a solvent, and compound 2 (0.1mmol, 1.0 equiv) were charged into a reaction flask to react at 25 ℃, the reaction was monitored by thin layer plate (TLC), and after completion of the reaction, column chromatography (eluent: PE: EA = 50.
The catalyst is selected from organic base or inorganic base such as triethylamine, tetramethylguanidine, DBU, sodium hydroxide, etc. The solvent is selected from halogenated alkane, nitrile, ether, benzene and other solvents, the amount of the solvent only influences the reaction rate, and no other influence is caused.
Example 2:
a 1a (0.075 mmol), cat. (0.005 mmol), 2a (0.05 mmol), solvent (0.5 mL) unless otherwise noted. b Isolated yield. c The dr values were obtained by hydrogen spectroscopic analysis of the crude product. d The ee value was obtained by chiral column HPLC analysis.
In the process of screening reaction conditions, the influence of different chiral catalysts on the reaction is firstly examined (entries 1-10), and C10 is found to be the best chiral catalyst. Subsequently, the influence of various solvents on the reaction was examined (entries 11-18), and pentafluorobenzene was finally determined as the optimum solvent.
Examination of reaction conditions (taking entry 11 as an example), the synthesis procedure of compound 3a is as follows:
1a (0.075mmol, 1.5eq), catalyst C10 (0.0055mmol, 0.1eq), 0.5mL of pentafluorobenzene, and 2a (0.05mmol, 1.0eq) were added to a reaction flask, reacted at 25 ℃, the reaction was monitored by thin layer plate (TLC), and after 1h of reaction, column chromatography (eluent PE: EA = 50. 1 H NMR(600MHz,CDCl 3 )δ7.91-7.86(m,2H),7.54-7.50(m,1H),7.43-7.38(m,2H),4.11-3.98(m,2H),3.96(dd,J＝10.5,3.4Hz,1H),3.63(dd,J＝18.1,10.5Hz,1H),3.48(dd,J＝18.1,3.4Hz,1H),1.29(s,9H),1.20(t,J＝7.2Hz,3H).
Example 3:
1a (0.15mmol, 1.5eq), catalyst C10 (0.01mmol, 0.1eq), 1mL of pentafluorobenzene, and 2b (0.1mmol, 1.0eq) were added to a reaction flask, reacted at 25 ℃, the reaction was monitored by thin layer plate (TLC), and after 1h of reaction completion, column chromatography (eluent: PE: EA =50: 1-10) was separated to give 3b,87% ee in 87% yield. 1 H NMR(400MHz,CDCl 3 )δ8.07(d,J＝8.2Hz,2H),7.76(d,J＝8.2Hz,2H),4.21-4.06(m,2H),4.04(dd,J＝10.3,3.5Hz,1H),3.73(dd,J＝18.3,10.3Hz,1H),3.57(dd,J＝18.3,3.5Hz,1H),1.37(s,9H),1.28(t,J＝7.1Hz,3H).
Example 4:
the reaction was carried out for 1 hour by replacing the starting material 2a with 2c in example 3, and the other experimental procedures and purification were carried out in accordance with example 3 to give 3c as a colorless oil, 90% ee, 81% yield. 1 H NMR(400MHz,CDCl 3 )δ8.02-7.95(m,2H),7.19-7.11(m,2H),4.20-4.05(m,2H),4.01(dd,J＝10.4,3.5Hz,1H),3.67(dd,J＝18.1,10.4Hz,1H),3.52(dd,J＝18.1,3.5Hz,1H),1.35(s,9H),1.27(t,J＝7.2Hz,3H).
Example 5:
the starting material 2a in example 3 was replaced with 2d, reaction was carried out for 2h, and other experimental procedures and purification were carried out with reference to example 3, to give a white solid 3d,91% ee, 81% yield. 1 H NMR(600MHz,CDCl 3 )δ7.89(d,J＝8.1Hz,2H),7.46(d,J＝8.1Hz,2H),4.18-4.11(m,1H),4.11-4.04(m,1H),4.01(dd,J＝10.5,3.3Hz,1H),3.66(dd,J＝18.1,10.5Hz,1H),3.51(dd,J＝18.1,3.3Hz,1H),1.36(s,9H),1.27(t,J＝7.2Hz,3H).
Example 6:
the reaction was carried out for 3h by changing the starting material 2a to 2e in example 3, and the other experimental procedures and purification were carried out with reference to example 3, to give 3e as a colorless oil, 92% ee, in 94% yield. 1 H NMR(400MHz,CDCl 3 )δ7.82(d,J＝8.3Hz,2H),7.63(d,J＝8.3Hz,2H),4.20-4.11(m,1H),4.11-4.04(m,1H),4.01(dd,J＝10.4,3.5Hz,1H),3.66(dd,J＝18.2,10.4Hz,1H),3.51(dd,J＝18.2,3.5Hz,1H),1.36(s,9H),1.27(t,J＝7.1Hz,3H).
Example 7:
the starting material 2a in example 3 was changed to 2f, reaction was carried out for 3h, and other experimental procedures and purification were carried out with reference to example 3, to obtain white crystals 3f,85% ee, 90% yield. 1 H NMR(600MHz,CDCl 3 )δ8.33(d,J＝8.1Hz,2H),8.12(d,J＝8.1Hz,2H),4.20-4.13(m,1H),4.12-4.05(m,1H),4.02(dd,J＝10.4,3.4Hz,1H),3.75(dd,J＝18.2,10.4Hz,1H),3.59(dd,J＝18.2,3.4Hz,1H),1.36(s,9H),1.28(t,J＝7.1Hz,3H).
Example 8:
the reaction was carried out for 1h by changing the starting material 2a from example 3 to 2g, and the other experimental procedures and purification were carried out with reference to example 3, to give 3g as a pale yellow oil, 94% ee, 82% yield. 1 H NMR(600MHz,CDCl 3 )δ7.85(d,J＝7.9Hz,2H),7.27(d,J＝7.9Hz,2H),4.17-4.11(m,1H),4.10-4.04(m,1H),4.02(dd,J＝10.6,3.4Hz,1H),3.66(dd,J＝18.1,10.6Hz,1H),3.53(dd,J＝18.1,3.4Hz,1H),2.42(s,3H),1.36(s,9H),1.27(t,J＝7.1Hz,3H).
Example 9:
the starting material 2a in example 3 was changed to 2h, the reaction was carried out for 2h, and other experimental procedures and purification were carried out with reference to example 3, to obtain a white solid 3h,84% ee, 74% yield. 1 H NMR(400MHz,CDCl 3 )δ8.20(s,1H),8.14(d,J＝7.8Hz,1H),7.86(d,J＝7.8Hz,1H),7.64(t,J＝7.8Hz,1H),4.21-4.05(m,2H),4.05-4.01(m,1H),3.72(dd,J＝18.2,10.4Hz,1H),3.56(dd,J＝18.2,3.4Hz,1H),1.36(s,9H),1.28(t,J＝7.1Hz,3H).
Example 10:
the reaction was carried out for 2h by replacing the compound 2a in example 3 with 2i, and the other experimental procedures and purification were carried out in accordance with example 3 to give 3i as a colorless oil, 88% ee, 81% yield. 1 H NMR(400MHz,CDCl 3 )δ7.76-7.72(m,1H),7.65-7.60(m,1H),7.51-7.43(m,1H),7.33-7.26(m,1H),4.20-4.03(m,2H),4.01(dd,J＝10.4,3.5Hz,1H),3.67(dd,J＝18.2,10.4Hz,1H),3.52(dd,J＝18.2,3.5Hz,1H),1.36(s,9H),1.27(t,J＝7.1Hz,3H).
Example 11:
the reaction was carried out for 2h by replacing the starting material 2a in example 3 with 2j, and the other experimental procedures and purification were carried out in accordance with example 3 to obtain a white solid 3j,88% ee at 97% yield. 1 H NMR(400MHz,CDCl 3 )δ7.94-7.89(m,1H),7.85-7.80(m,1H),7.59-7.54(m,1H),7.43(t,J＝7.8Hz,1H),4.20-4.04(m,2H),4.01(dd,J＝10.3,3.5Hz,1H),3.67(dd,J＝18.3,10.3Hz,1H),3.52(dd,J＝18.3,3.5Hz,1H),1.36(s,9H),1.27(t,J＝7.1Hz,3H).
Example 12:
the starting material 2a in example 3 was changed to 2k, reacted for 2h, and the other experimental procedures and purification were carried out with reference to example 3, to obtain white crystals 3k,90% ee, yield 79%. 1 H NMR(600MHz,CDCl 3 )δ7.56-7.52(m,1H),7.46(s,1H),7.41-7.36(m,1H),7.16-7.12(m,1H),4.18-4.11(m,1H),4.11-4.05(m,1H),4.02(dd,J＝10.5,3.4Hz,1H),3.86(s,3H),3.67(dd,J＝18.1,10.5Hz,1H),3.54(dd,J＝18.1,3.4Hz,1H),1.36(s,9H),1.28(t,J＝7.1Hz,3H).
Example 13:
the starting material 2a in example 3 was replaced with 2l, reaction was carried out for 2h, and other experimental procedures and purification were carried out in accordance with example 3 to obtain 3l of a white solid, 92% ee, 92% yield. 1 H NMR(600MHz,CDCl 3 )δ7.75(m,2H),7.40(d,J＝7.5Hz,1H),7.36(t,J＝7.5Hz,1H),4.19-4.05(m,2H),4.03(dd,J＝10.7,3.3Hz,1H),3.68(dd,J＝18.2,10.7Hz,1H),3.54(dd,J＝18.2,3.3Hz,1H),2.41(s,3H),1.36(s,9H),1.27(t,J＝7.1Hz,3H).
Example 14:
the reaction was carried out for 1 hour by replacing the starting material 2a in example 3 with 2m, and the other experimental procedures and purification were carried out in accordance with example 3 to give 3m as a colorless oil, 89% ee, 86% yield. 1 H NMR(400MHz,CDCl 3 )δ8.05-7.01(m,1H),7.80-7.75(m,1H),7.60-7.55(m,1H),4.20-4.03(m,2H),4.00(dd,J＝10.3,3.5Hz,1H),3.66(dd,J＝18.3,10.3Hz,1H),3.50(dd,J＝18.3,3.5Hz,1H),1.36(s,9H),1.28(t,J＝7.2Hz,3H).
Example 15:
the reaction was carried out for 1h by changing the starting material 2a to 2n in example 3, and the other experimental procedures and purification were carried out with reference to example 3, to give 3n as a yellow oil, 67% ee, in 87% yield. 1 H NMR(400MHz,CDCl 3 )δ7.66-7.60(m,1H),7.49-7.44(m,1H),7.42-7.36(m,1H),7.36-7.30(m,1H),4.24-4.06(m,2H),4.00(dd,J＝10.3,3.7Hz,1H),3.62(dd,J＝18.5,10.3Hz,1H),3.51(dd,J＝18.5,3.7Hz,1H),1.36(s,9H),1.30(t,J＝7.2Hz,3H).
Example 16:
the reaction was carried out for 2h by replacing the starting material 2a in example 3 with 2o, and the other experimental procedures and purification were carried out in accordance with example 3 to give 3o as a colorless oil, 65% ee, and 99% yield. 1 H NMR(400MHz,CDCl 3 )δ7.69(d,J＝7.6Hz,1H),7.41(t,J＝7.6Hz,1H),7.33-7.23(m,2H),4.24-4.05(m,2H),4.02(dd,J＝10.5,3.5Hz,1H),3.62(dd,J＝18.1,10.5Hz,1H),3.43(dd,J＝18.1,3.5Hz,1H),2.48(s,3H),1.36(s,9H),1.28(t,J＝7.1Hz,3H).
Example 17:
the starting material 2a in example 3 was changed to 2p, the reaction was carried out for 3 hours, and other experimental procedures and purification were carried out with reference to example 3, to obtain white crystals 3p,92% ee, 92% yield. 1 H NMR(600MHz,CDCl 3 )δ8.49(s,1H),8.02-7.97(m,2H),7.92-7.86(m,2H),7.63(t,J＝7.5Hz,1H),7.58(t,J＝7.5Hz,1H),4.20-4.13(m,1H),4.13-4.06(m,2H),3.85(dd,J＝17.9,10.4Hz,1H),3.71(dd,J＝17.9,3.4Hz,1H),1.38(s,9H),1.28(t,J＝7.2Hz,3H).
Example 18:
the reaction was carried out for 3 hours by changing the starting material 2a from example 3 to 2q, and the other experimental procedures and purification were carried out with reference to example 3, to obtain a white solid 3q,91% ee, at a yield of 85%. 1 H NMR(400MHz,CDCl 3 )δ8.10(dd,J＝2.9,1.3Hz,1H),7.53(dd,J＝5.1,1.3Hz,1H),7.34(dd,J＝5.1,2.9Hz,1H),4.18-4.10(m,1H),4.10-4.04(m,1H),4.00(dd,J＝10.3,3.6Hz,1H),3.59(dd,J＝17.9,10.3Hz,1H),3.46(dd,J＝17.9,3.6Hz,1H),1.35(s,9H),1.26(t,J＝7.1Hz,3H).
Example 19:
the reaction was carried out for 3 hours by changing the starting material 2a from example 3 to 2r, and the other experimental procedures and purification were carried out with reference to example 3, to give 3r as a colorless oil, 94% ee, 96% yield. 1 H NMR(600MHz,CDCl 3 )δ7.78-7.75(m,1H),7.69-7.66(m,1H),7.17-7.14(m,1H),4.17-4.10(m,1H),4.10-4.04(m,1H),4.01(dd,J＝10.5,3.4Hz,1H),3.62(dd,J＝17.6,10.5Hz,1H),3.50(dd,J＝17.6,3.4Hz,1H),1.36(s,9H),1.26(t,J＝7.3Hz,3H).
Example 20:
the reaction was carried out for 1h by changing the starting material 2a from example 3 to 2s, and the other experimental procedures and purification were carried out with reference to example 3, to give yellow oil 3s,75% ee, 81% yield. 1 H NMR(600MHz,CDCl 3 )δ7.60(d,J＝1.7Hz,1H),7.24(d,J＝3.6Hz,1H),6.56(dd,J＝3.6,1.7Hz,1H),4.17-4.04(m,2H),3.98(dd,J＝10.5,3.7Hz,1H),3.52(dd,J＝18.0,10.5Hz,1H),3.42(dd,J＝18.0,3.7Hz,1H),1.36(s,9H),1.26(t,J＝7.1Hz,3H).
Example 21:
the reaction was carried out for 4 hours by changing the starting material 2a from example 3 to 2t, and the other experimental procedures and purification were carried out in accordance with example 3 to obtain a white solid 3t,89% ee, 83% yield. 1 H NMR(400MHz,CDCl 3 )δ7.98-7.92(m,2H),7.63-7.56(m,1H),7.52-7.44(m,2H),4.05(dd,J＝10.5,3.5Hz,1H),3.76-3.66(m,4H),3.57(dd,J＝18.3,3.5Hz,1H),1.36(s,9H).
Example 22:
the reaction was carried out for 60 hours by replacing the starting material 2a in example 3 with 2u, and the other experimental procedures and purification were carried out in accordance with example 3 to give a white solid 3u,80% ee, 65% yield. 1 H NMR(600MHz,CDCl 3 )δ8.07(d,J＝7.7Hz,2H),7.96(d,J＝7.7Hz,2H),7.66-7.56(m,2H),7.51(t,J＝7.7Hz,2H),7.46(t,J＝7.7Hz,2H),5.23(dd,J＝10.4,2.9Hz,1H),4.10(dd,J＝18.5,10.4Hz,1H),3.80(dd,J＝18.5,2.9Hz,1H),1.06(s,9H).
Example 23:
the starting material 2a in example 3 was changed to 2v, the reaction was carried out for 96h, and the other experimental procedures and purification were carried out with reference to example 3, to obtain a white solid 3v,94% ee, 90% yield. 1 H NMR(400MHz,CDCl 3 )δ7.96-7.91(m,2H),7.61-7.55(m,1H),7.51-7.44(m,2H),7.25-7.20(m,2H),7.19-7.13(m,1H),7.03-7.07(m,2H),3.59-3.48(m,1H),3.23-3.12(m,1H),3.07-2.96(m,1H),2.71-2.61(m,2H),2.02-1.90(m,1H),171-1.59(m,1H),1.34(s,9H).
Example 24:
the reaction was carried out for 96h by changing the starting material 2a from example 3 to 2w, and the other experimental procedures and purification were carried out with reference to example 3, to give yellow oil 3w,85% ee, 79% yield. 1H NMR (600mhz, cdcl3) δ 8.09-8.02 (m, 1H), 8.00-7.94 (m, 2H), 7.91-783 (m, 1H), 7.76-7.69 (m, 1H), 7.65-7.57 (m, 1H), 7.56-7.48 (m, 2H), 7.48-7.38 (m, 3H), 4.81 (dd, J =10.4,2.5hz, 1h), 4.47 (dd, J =18.5,10.4hz, 1h), 3.87 (dd, J =18.5,2.5hz, 1h), 0.74 (s, 9H).
Example 25:
the reaction was carried out for 96 hours by replacing the starting material 2a in example 3 with 2X, and the other experimental procedures and purification were carried out in accordance with example 3, to give a colorless oily compound, 3X,86% ee, 67% yield. 1H NMR (400MHz, CDCl3). Delta.7.95-7.88 (m, 2H), 7.60-7.53 (m, 1H), 7.49-7.41 (m, 2H), 7.25-7.13 (m, 5H), 4.65-4.59 (m, 1H), 3.86-3.70 (m, 2H), 0.97 (s, 9H).
Example 26
Determining toxicity of high optical purity compound for 3h on HepG2 hepatocarcinoma cell, MGC-803 gastric cancer cell and PC-9 lung cancer cell by MTT method, and calculating half Inhibitory Concentration (IC) of each compound 50 )。
The determination method comprises the following specific steps:
maintaining the tumor cell line at a concentration ofIn comparison with 10% fetal bovine serum and 2mM glutamine RPMI1640, the cells were caused to be at 5% by volume CO 2 Grown at 37 ℃ in a humidified incubator. 40uL of cells were seeded (10000 cells/well) in growth medium in Corning black clear bottom 384-well plates at 37 ℃ CO 5% by volume 2 Cultured overnight in the medium. The compounds of the invention, diluted 100% by mass in dmso serially, were added to the cells using Echo555 sonification (Cacous tail). The plates were incubated for an additional 2 hours and after gentle mixing of the medium, 40uL of lysis buffer was added to each well. Greiner black high binding 384-well plates were covered with capture antibody and then blocked with 3% by mass BAS. The blocking solution was then removed and 15uL of lysate was transferred to Greiner black high binding 384 well plates and incubated for 2 hours. After gentle mixing and washing of the plates with PBS, 20uL of detection antibody was added and incubated for 2 hours. After gently mixing and washing the plates with PBS, 20uL of QuantaBlu fluorescent peroxidase substrate was added and incubated for 1 hour. 20uL of QuantaBlu stop solution was added to the plates and fluorescence read using an Envision microplate detector with an excitation wavelength of 352nm and an emission wavelength of 460 nm. The data obtained for each compound was entered into an appropriate software package to perform curve fitting analysis. IC was determined based on this data and by calculating the concentration of compound required to obtain 50% effect 50 The value of (c).
IC of H22 liver cancer cell in 3H 50 The values are respectively 50.17,>100 and 70.06.
The above experimental results show that: the compound has certain inhibition effect on HepG2 liver cancer cells, MGC-803 stomach cancer cells and PC-9 lung cancer cells after 3 hours, so that the compound can be used for preparing a new anti-tumor medicament by salifying with an acid acceptable for a human body or mixing with a medicinal carrier according to a general way of medicament development (carrying out conventional anti-tumor in vitro screening and then carrying out targeted research).
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (10)
1. A trifluoromethyl oxazolone-containing compound is characterized in that the structural formula is as follows:
wherein Ar is phenyl, halophenyl, trifluoromethylphenyl, nitrophenyl, C1-C3 alkylphenyl, C1-C3 alkoxyphenyl, thienyl, furyl, or naphthyl; r is 1 Is C (O) OEt, C (O) OMe, C (O) C 6 H 5 、CH 2 CH 2 C 6 H 5 Phenyl or quinolinyl; r 2 Is C1-C6 alkyl, phenyl or benzyl.
2. The trifluoromethyl oxazolone-containing compound according to claim 1, characterized in that: ar is C 6 H 5 、4-CF 3 C 6 H 5 、4-FC 6 H 5 、4-ClC 6 H 5 、4-BrC 6 H 5 、4-NO 2 C 6 H 5 、4-MeC 6 H 5 、3-CF 3 C 6 H 5 、3-FC 6 H 5 、3-ClC 6 H 5 、3-MeOC 6 H 5 、3-MeC 6 H 5 、2-BrC 6 H 5 、2-MeC 6 H 5 、3,4-Cl 2 C 6 H 5 2-thienyl, 3-thienyl, 2-furyl or 2-naphthyl; r 2 Is CH 3 、C 2 H 5 、C 4 H 9 、C 6 H 5 、CH 2 C 6 H 5 Or C 6 H 11 。
3. The process for producing trifluoromethyl oxazolone-containing compounds as claimed in claim 1 or 2, characterized by the following synthetic route:
the method comprises the following steps:
reacting 4-substituted-2-trifluoromethyl oxazolone (1) with alpha, beta-unsaturated ketone (2) in an organic solvent in the presence of a thiourea catalyst to obtain trifluoromethyl oxazolone-containing compounds (3).
4. The method for producing trifluoromethyl oxazolone-containing compounds according to claim 3, characterized in that: the thiourea catalyst is selected from
Wherein Ar is 3,5- (CF) 3 ) 2 Ph。
5. The method for preparing trifluoromethyl oxazolone-containing compounds according to claim 3, characterized in that: the molar ratio of the 4-substituted-2-trifluoromethyl oxazolone (1), the alpha, beta-unsaturated ketone (2) and the thiourea catalyst is 1.2-1.5.
6. The method for preparing trifluoromethyl oxazolone-containing compounds according to claim 3, characterized in that: the organic solvent is selected from toluene, pentafluorobenzene, chlorobenzene, bromobenzene, trifluoromethylbenzene, xylene, bromotoluene or trimethylbenzene.
7. The method for producing trifluoromethyl oxazolone-containing compounds according to claim 3, characterized in that: the reaction temperature is 20-30 ℃, and the reaction time is 1-96 hours.
8. The use of trifluoromethyl oxazolone containing compounds of claim 1 in the preparation of anti-cancer drugs.
9. The use of the trifluoromethyl oxazolone-containing compound according to claim 8 in the preparation of an anticancer drug, characterized in that: the anticancer drug is HepG2 liver cancer, PC-9 lung cancer or MGC-803 stomach cancer drug.
10. The use of the trifluoromethyl oxazolone-containing compound according to claim 9 in the preparation of an anticancer drug, characterized in that: the trifluoromethyl oxazolone compound is
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010034625.5A CN112898217B (en) | 2020-01-14 | 2020-01-14 | Trifluoromethyl oxazolone compound, preparation method thereof and application thereof in anti-cancer drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010034625.5A CN112898217B (en) | 2020-01-14 | 2020-01-14 | Trifluoromethyl oxazolone compound, preparation method thereof and application thereof in anti-cancer drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112898217A CN112898217A (en) | 2021-06-04 |
| CN112898217B true CN112898217B (en) | 2022-12-02 |
Family
ID=76110894
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010034625.5A Active CN112898217B (en) | 2020-01-14 | 2020-01-14 | Trifluoromethyl oxazolone compound, preparation method thereof and application thereof in anti-cancer drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112898217B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114835655A (en) * | 2022-04-14 | 2022-08-02 | 河南师范大学 | Method for synthesizing optically active trifluoromethyl acrylate compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294591A (en) * | 2015-11-17 | 2016-02-03 | 河南大学 | High-stereo and highly-enantioselective oxazolinedione compound, preparation method and application thereof |
| CN107652255A (en) * | 2017-11-03 | 2018-02-02 | 宁夏大学 | 2 (5H) furanone derivatives of a kind of chirality and its preparation method and the application in anti-cervical cancer and medicines resistant to liver cancer is prepared |
-
2020
- 2020-01-14 CN CN202010034625.5A patent/CN112898217B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294591A (en) * | 2015-11-17 | 2016-02-03 | 河南大学 | High-stereo and highly-enantioselective oxazolinedione compound, preparation method and application thereof |
| CN107652255A (en) * | 2017-11-03 | 2018-02-02 | 宁夏大学 | 2 (5H) furanone derivatives of a kind of chirality and its preparation method and the application in anti-cervical cancer and medicines resistant to liver cancer is prepared |
Non-Patent Citations (2)
| Title |
|---|
| Acyl Phosphonates: Good Hydrogen Bond Acceptors and;Hao Jiang 等;《JACS》;20100204;全文 * |
| Organocatalytic regioselective asymmetric Michael addition of azlactones to o-hydroxy chalcone derivatives;Shao-Yun Zhang 等;《Organic & Biomolecular Chemistry》;20150121;全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112898217A (en) | 2021-06-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| O’Mahony et al. | Copper-catalyzed asymmetric oxidation of sulfides | |
| Nakamura et al. | Catalytic enantioselective reaction of 2 H-azirines with thiols using cinchona alkaloid sulfonamide catalysts | |
| CN110099893B (en) | Preparation method of droxidopa and intermediate thereof | |
| CN112898217B (en) | Trifluoromethyl oxazolone compound, preparation method thereof and application thereof in anti-cancer drugs | |
| CN104447604B (en) | A kind of synthetic method of chirality quaternary carbon oxazoline ketonic compound | |
| CN113979975B (en) | Chiral phosphoric acid catalyzed aryl allyl tertiary alcohol kinetic resolution method | |
| CN1290818C (en) | Method for asymmetrical hydrogen transfer of alpha-imino keton for synthesizing chirality salbutamol | |
| CN112898218B (en) | Method for synthesizing trifluoromethyl oxazolone compound by one-pot method | |
| Jiang et al. | Asymmetric Synthesis of Hydroquinazolines Bearing C4-Tetrasubstituted Stereocenters via Kinetic Resolution of α-Tertiary Amines | |
| Hu et al. | Organocatalytic enantioselective sulfa-Michael addition of thiocarboxylic acids to β-trifluoromethyl-α, β-unsaturated ketones for the construction of stereogenic carbon center bearing a sulfur atom and a trifluoromethyl group | |
| Fang et al. | Highly enantioselective copper-catalyzed allylic alkylation with atropos phosphoramidites bearing a D2-symmetric biphenyl backbone | |
| Kimura et al. | Practical synthesis of chiral emopamil left hand as a bioactive motif | |
| CN112898285B (en) | Trifluoromethyl-containing bisoxazole compound, and synthesis method and application thereof in anti-cancer drugs | |
| TWI607803B (en) | Catalyst, and method for producing optically active anti-1,2-nitroalkanol compound | |
| Ye et al. | Enantioselective Construction of Sulfur‐Containing Tetrasubstituted Stereocenters via Asymmetric Functionalizations of α‐Sulfanyl Cyclic Ketones | |
| CN102336769A (en) | Simple and novel method for synthesizing spiro[oxoindole-3,5'-oxazoline] heterocyclic compound | |
| CN113444101A (en) | Cyclopentane chromanone spliced bis-spiro-indene dione oxoindole compound and preparation method and application thereof | |
| JP6057257B2 (en) | Method for producing optically active carboxylic acid ester | |
| CN104860911A (en) | Synthesis method of chiral 3,4-dihydrocoumarin derivative compound | |
| CN110668943A (en) | Simple synthesis method of palladium metal catalyzed polysubstituted aryl ketone compound | |
| CN111116434B (en) | Synthesis method of chiral chlorosulfonylnaphthone compound | |
| CN113307815B (en) | Trifluoromethyl spliced double-spiro chromanone skeleton pyrrole oxindole compound and preparation method and application thereof | |
| CN111187184B (en) | Novel method for synthesizing sulfonyl ketoamide | |
| CN108912077B (en) | Preparation method of chiral phthalide derivative | |
| JP5179430B2 (en) | Method for producing optically active alcohol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |