CN113956246B - 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivative and preparation and application thereof - Google Patents

3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivative and preparation and application thereof Download PDF

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CN113956246B
CN113956246B CN202111238509.6A CN202111238509A CN113956246B CN 113956246 B CN113956246 B CN 113956246B CN 202111238509 A CN202111238509 A CN 202111238509A CN 113956246 B CN113956246 B CN 113956246B
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胡文浩
吴琳娜
刘书豪
贾世琨
张芷菁
史滔达
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Sun Yat Sen University
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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to a 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3]]Oxazine derivative, preparation and application thereof, and the 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] provided by the invention]The oxazine derivative can be prepared by one-step reaction; the method takes the compounds which are available in the market or are easy to synthesize as raw materials, and has the characteristics of simple operation, mild conditions, few steps, high reaction speed, low cost, less waste, high atom economy and the like. Meanwhile, the derivative has certain inhibition activity on four tumor cells (human osteosarcoma cells, human colon cancer cells, human non-small cell lung cancer cells and human breast cancer cells), and is expected to be prepared into medicines for inhibiting tumor cells, in particular medicines for inhibiting non-small cell lung cancer cells.

Description

3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivative and preparation and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivative, and preparation and application thereof.
Background
4H- [1,3] -benzoxazines have excellent pharmaceutical activity and have the potential to be converted into more complex compounds. The biological activity of 4H- [1,3] benzoxazines and derivatives thereof is generally shown to be anti-tumor, postoperative analgesic, anti-inflammatory, antibacterial and the like. 4H- [1,3] benzoxazine is an important core skeleton, is widely used in medicines and natural products (such as anxiolytic agent Artemisia Fu Xin and fungicide), is often used as an important intermediate (such as herbicide and progesterone receptor agonist) in the synthesis of heterocyclic compounds with important biological activity, and meanwhile, the application of the benzoxazine in materials can enable the materials to have oxidation resistance and corrosion resistance, and meanwhile, the mechanical properties of the materials are improved.
Oxazine compounds have been attracting attention because of their wide range of uses. Currently, the synthesis of 4H-benzo [1,3] oxazine compounds mainly adopts a traditional synthesis method and a Lewis acid-mediated olefin synthesis method, wherein the traditional synthesis method of the benzoxazine is to carry out ring closure on aldehyde and o-glycollic aniline to generate the benzoxazine under a metal catalysis or non-metal reaction system, and the method cannot generate the benzoxazine with optical purity. The method for synthesizing benzoxazine by Lewis acid-mediated olefin is to carry out ring-closure reaction on styrene and amide at the ortho position of the styrene under the mediation of Lewis acid, so that benzoxazine is generated, and the method has long reaction time, usually requires one to three days and cannot realize stereoselective synthesis. Therefore, the current synthesis method of the 4H-benzo [1,3] oxazine compound has the defects of difficult realization of stereoselectivity control, long reaction time, need of additives, harsh and complex reaction conditions and the like. Therefore, the development of a rapid and simple synthetic route of oxazine compounds is particularly important.
Disclosure of Invention
In order to overcome the defects in the prior art, the primary aim of the invention is to provide a 2-phenyl-4H-benzo [1,3] oxazine derivative containing 3-phenyl furan.
The second object of the present invention is to provide a process for producing the above 3-phenylfuran-containing 2-phenyl-4H-benzo [1,3] oxazine derivative. The preparation method has the advantages of few steps, quick reaction and relatively simple and safe operation.
The third object of the present invention is to provide the use of the above-mentioned 3-phenylfuran-containing 2-phenyl-4H-benzo [1,3] oxazine derivative.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention provides a 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivative, which has a structure shown in a general formula (I):
in the formula (I), R 1 Is hydrogen, alkyl, alkoxy or halogen substituent; r is R 2 Is aryl, substituted aryl or heterocyclic aryl; r is R 3 Is aryl, substituted aryl or heterocyclic aryl; ar (Ar) 1 Is aryl or substituted aryl; ar (Ar) 2 Is aryl or substituted aryl; the aryl group is C 6-10 An aryl group; the heterocyclic aryl group being C containing a sulfur atom 5-6 C of aryl groups or nitrogen atoms 5-6 An aryl group; the substituted aryl is alkyl, alkoxyl nitro or halogen substituted aryl.
Preferably, said R 1 Is hydrogen, methyl, isopropyl or halogen substituent; r is R 2 Phenyl, p-tolyl, p-fluorophenyl or p-chlorophenyl; r is R 3 Phenyl, p-tolyl, p-chlorophenyl, naphthalene, or thiophene; ar (Ar) 1 Aryl or chloro substituted aryl; ar (Ar) 2 Is aryl or chloro substituted aryl.
More preferably, the R 1 Is hydrogen, methyl, isopropyl, fluorine atom substituent or chlorine atom substituent; r is R 2 Phenyl, p-tolyl, p-fluorophenyl or p-chlorophenyl; r is R 3 Phenyl, p-tolyl, p-chlorophenyl, naphthalene, or thiophene; ar (Ar) 1 Is chloro substituted aryl; ar (Ar) 2 Is phenyl.
More preferably, the R 1 Is hydrogen, methyl, isopropyl, fluorine atom substituent or chlorine atom substituent; r is R 2 Is phenyl or p-tolyl; r is R 3 Is phenyl or p-tolyl. Ar (Ar) 1 Is chloro substituted aryl; ar (Ar) 2 Is phenyl.
The invention also provides the 2-phenyl-4H-benzo [1,3] containing 3-phenyl furan]The preparation method of the oxazine derivative specifically comprises the following steps: according to the following reaction formula, using the compound 1a and the compound 1b as raw materials, chiral PA and Rh 2 (OAc) 4 As a catalyst and a molecular sieve as a water absorbent, firstly, the compound 1b and Rh are mixed 2 (OAc) 4 Mixing PA and molecular sieve in organic solvent to obtain solution A, protecting with argon, dissolving compound 1a in organic solvent to obtain solution B, and dripping the solution B into the solution A at-30-30deg.CAfter dripping, continuing to react for 0.5 to 3 hours to obtain a target product shown in a general formula (I);
preferably, compound 1a, compound 1b, chiral PA and Rh 2 (OAc) 4 The reaction molar ratio of (1.0-1.5:0.5-1.2:0.05-0.1:0.01-0.05). In the reaction process, when the amount of the compound 1a and the compound 1b is too large, the side reaction is increased, the byproducts are increased, the atom economy is not met, and the yield of the final target product is influenced; when the ratio of the amounts of the reaction raw materials is within the above range, the byproducts are minimized, and the yield of the final target product is higher, conforming to the atom economy.
More preferably, compound 1a, compound 1b, chiral PA and Rh 2 (OAc) 4 The reaction molar ratio of (2) is 1.0:1.2:0.1:0.01.
Preferably, the molecular sieve is added in an amount of 10.0mg/mmol based on the amount of the compound 1 a; the dosage of the organic solvent is 5 mL-10 mL/mmol.
More preferably, the organic solvent is used in an amount of 10mL/mmol.
Preferably, the reaction temperature after dripping is-30 ℃ and the reaction time is 0.5-3 h.
More preferably, the temperature of the dropwise addition reaction is 0 ℃, the reaction temperature is room temperature, and when the reaction time is 1.0h, the yield of the target product is higher, heating is not needed, the operation is simple, and the energy consumption is low.
Preferably, the organic solvent is dichloromethane or chloroform, and the molecular sieve isMolecular sieves.
The invention also provides application of the 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivatives in preparing medicaments for inhibiting the activity of tumor cells, wherein the tumor cells comprise human osteosarcoma cells, human colon cancer cells, human non-small cell lung cancer cells and human breast cancer cells.
Preferably, the tumor cells are human non-small cell lung cancer cells.
The invention discovers that the 2-phenyl-4H-benzo [1,3] oxazine derivative containing 3-phenyl furan has certain inhibition activity on four tumor cells (human osteosarcoma cells, human colon cancer cells, human non-small cell lung cancer cells and human breast cancer cells). The inhibition rate of the compounds 3,4, 5, 6, 7, 8, 11, 17 and 20 on the non-small cell lung cancer A549 cells is more than 60% at the concentration of 20 mu M, and the compounds are expected to be prepared into medicaments for inhibiting tumor cells, in particular medicaments for resisting the non-small cell lung cancer cells.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a 2-phenyl-4H-benzo [1,3] oxazine derivative containing 3-phenyl furan, which can be prepared by one-step reaction; the method takes the compounds which are available in the market or are easy to synthesize as raw materials, and has the characteristics of simple operation, mild conditions, few steps, high reaction speed, low cost, less waste, high atom economy and the like. Meanwhile, the derivative has certain inhibition activity on four tumor cells (human osteosarcoma cells, human colon cancer cells, human non-small cell lung cancer cells and human breast cancer cells), and is expected to be prepared into medicines for inhibiting tumor cells, in particular medicines for inhibiting non-small cell lung cancer cells.
Detailed Description
The following describes the invention in more detail. The description of these embodiments is provided to assist understanding of the present invention, but is not intended to limit the present invention. In addition, the technical features of the embodiments of the present invention described below may be combined with each other as long as they do not collide with each other.
The experimental methods in the following examples, unless otherwise specified, are conventional, and the experimental materials used in the following examples, unless otherwise specified, are commercially available.
EXAMPLE 1 preparation of 3-phenyl-furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivatives
The synthesis reaction formula is as follows:
in each structural formula of the above reaction formula, R 1 Is hydrogen, methyl, isopropyl or halogen substituent; r is R 2 Phenyl, p-tolyl, p-fluorophenyl or p-chlorophenyl; r is R 3 Phenyl, p-tolyl, p-chlorophenyl, naphthalene, or thiophene; ar (Ar) 1 Is aryl or substituted aryl; ar (Ar) 2 Is aryl or substituted aryl.
According to the chemical reaction formula, compound 1a and compound 1b are used as raw materials, chiral PA (chiral polyamide) and rhodium dimeric acetate Rh 2 (OAc) 4 In the form of a catalyst, the catalyst is,the molecular sieve is water absorbent (compound 1a, compound 1b, chiral PA and Rh 2 (OAc) 4 The reaction molar ratio of (1.0-1.5:0.5-1.2:0.05-0.1:0.01-0.05); taking the dosage of the compound 1a as a reference, the dosage of the molecular sieve is 10.0mg/mmol; the dosage of the organic solvent is 0.5 mL-1.0 mL/mmol), and the compound 1b, rhodium diacetate dimer, PA and +.>The molecular sieve is mixed and dissolved in an organic solvent (dichloromethane or chloroform) to prepare a solution A, and the solution A is protected by argon, the compound 1a is dissolved in the organic solvent (dichloromethane or chloroform) to prepare a solution B, then the solution B is dripped into the solution A at the temperature of minus 30 ℃ to 30 ℃, and the reaction is continued for 0.5 to 3 hours after the dripping, so that the target product shown in the general formula (I) can be prepared.
The specific synthetic process of the 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivative (compound 1-21) is as follows:
1. preparation of Compound 1
Compound 1 is R 1 Is hydrogen, R 2 Is phenyl, R 3 Is phenyl, ar 1 Is p-chlorophenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]The oxazine derivative has a structure shown in a formula (1):
the preparation process comprises the following steps:
(1) 1- (4-chlorophenyl) -N-phenyl-azomethine (0.1 mmol), rhodium diacetate dimer (0.001 mmol), PA (0.01 mmol) andmolecular sieves (1.0 mg) were dissolved in 1.0mL of dry dichloromethane to prepare a mixed solution a, and protected with argon;
(2) 3-diazo-2-phenylacetic acid-3- (2-benzoylaminophenyl) prop-2-yn-1-yl ester (0.12 mmol) was dissolved in 1.0mL dry dichloromethane to prepare solution B;
(3) Dropwise adding the solution B into the mixed solution A by using a syringe pump at the temperature of 0 ℃ for 1 hour, and vigorously stirring in the dropwise adding process; after the completion of the dropwise addition of the solution B, the reaction was continued at room temperature for 60 minutes with stirring.
After the reaction is finished, filtering, removing the solvent by rotary evaporation of the obtained filtrate, and purifying the obtained crude product by column chromatography (petroleum ether: ethyl acetate=5:1-3:1 is used as eluent) to obtain a pure product, wherein the separation yield of the product is 58%, the dr value of the compound is 93:7, and the ee value is 97%. Mass spectrum information of the compound is as follows:
1 H NMR(400MHz,Chloroform-d)δ7.89(d,J＝7.5Hz,2H),7.53–7.50(m,1H),7.45–7.37(m,6H),7.30–7.24(m,2H),7.19–7.05(m,5H),6.76(td,J＝7.4,1.9Hz,1H),6.71–6.67(m,3H),6.55(d,J＝7.7Hz,1H),6.42(d,J＝8.0Hz,2H),5.16(d,J＝7.3Hz,1H),4.58(d,J＝17.8Hz,1H),4.46(d,J＝7.3Hz,1H),3.93(d,J＝17.8Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ172.5,160.1,154.8,145.2,135.7,135.0,132.2,131.9,130.7,130.1,130.0,129.4,129.0,128.7,128.6,128.5,128.4,127.7,127.0,125.7,124.5,121.8,118.8,113.5,83.7,72.2,61.4.HRMS(ESI)Calcd.for C 37 H 27 N 2 O 3 Cl(M+H)+583.1783,found:583.1786.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝94:6,flow rate＝1.0mL/min),t major ＝15.33min,t minor ＝19.62min。
2. preparation of Compound 2
Compound 2 is R 1 Is methyl, R 2 Is phenyl, R 3 Is phenyl, ar 1 Is p-chlorophenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]The oxazine derivative and the structure of the compound 2 are shown as the formula (2):
the procedure for the preparation of this compound was as in example 1, except that: replacing 3-diazo-2-phenylacetic acid-3- (2-benzoylaminophenyl) prop-2-yn-1-yl ester in step (2) with 3- (2-benzamido-5-methylphenyl) prop-2-yn-1-yl 2-diazo-2-phenylacetic acid ester, i.e. R of Compound 1 1 R of hydrogen to Compound 2 1 Methyl, compound 2 was prepared in 54% isolated yield with a dr of 89:11 and an ee of 91%. Mass spectrum information of the compound is as follows:
1 H NMR(400MHz,Chloroform-d)δ7.91(d,J＝7.6Hz,2H),7.53–7.38(m,7H),7.23–7.16(m,4H),7.09–7.05(m,3H),6.75–6.66(m,3H),6.41(d,J＝7.9Hz,2H),6.28(s,1H),5.15(d,J＝7.2Hz,1H),4.55–4.46(m,2H),3.84(d,J＝17.9Hz,1H),1.93(s,3H). 13 C NMR(101MHz,Chloroform-d)δ172.6,160.6,154.1,145.4,137.4,137.1,135.9,134.9,132.0,131.6,130.9,130.8,130.2,129.5,129.3,129.0,128.7,128.7,128.5,128.2,127.6,125.5,125.5,121.5,118.7,113.6,83.7,72.4,61.5,21.3.HRMS(ESI)Calcd.for C 38 H 29 N 2 O 3 Cl(M+H)+597.1939,found:597.1931.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝94:6,flow rate＝1.0mL/min),t major ＝22.61min,t minor ＝18.99min。
3. preparation of Compound 3
Compound 3 is R 1 Is isopropyl, R 2 Is phenyl, R 3 Is phenyl, ar 1 Is p-chlorophenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, the structure of the compound 3 is shown as (3):
the procedure for the preparation of this compound was as in example 1, except that: replacing 3-diazo-2-phenylacetic acid-3- (2-benzoylaminophenyl) prop-2-yn-1-yl ester in step (2) with 3- (2-benzamido-5-isopropylphenyl) prop-2-yn-1-yl 2-diazo-2-phenylacetic acid ester, i.e. R of Compound 1 1 R of hydrogen to Compound 3 1 Isopropyl, compound 3 was prepared in a product isolation yield of 56%, with a dr value of 95:5 and an ee value of 91%. Mass spectrum information of the compound is as follows:
1 H NMR(500MHz,Chloroform-d)δ7.85(d,J＝7.7Hz,2H),7.50–7.33(m,7H),7.24–7.04(m,7H),6.73–6.66(m,3H),6.43–6.39(m,3H),5.12(d,J＝6.3Hz,1H),4.67(d,J＝17.8Hz,1H),4.43(d,J＝7.1Hz,1H),4.07(d,J＝17.8Hz,1H),2.44(p,J＝7.0Hz,1H),1.02(d,J＝6.9Hz,3H),0.85(d,J＝7.0Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ172.7,159.8,154.2,148.0,145.7,137.7,136.0,134.8,131.9,131.7,131.0,130.1,129.5,129.4,128.9,128.7,128.6,128.2,127.8,127.5,125.7,123.1,121.3,118.8,113.4,83.8,72.0,61.9,33.4,24.4,22.6.HRMS(ESI)Calcd.for C 40 H 33 N 2 O 3 Cl(M+H)+625.2252,found:625.2254.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝94:6,flow rate＝1.0mL/min),t major ＝20.02min,t minor ＝12.59min。
4. preparation of Compound 4
Compound 4 is R 1 Is fluorine, R 2 Is phenyl, R 3 Is phenyl, ar 1 Is p-chlorophenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, the structure of the compound 4 is shown as (4):
the procedure for the preparation of this compound was as in example 1, except that: replacing 3-diazo-2-phenylacetic acid-3- (2-benzoylaminophenyl) prop-2-yn-1-yl ester in step (2) with 3-diazo-2-phenylacetic acid 3- (2-benzoylamino-5-fluorophenyl) prop-2-yn-1-yl ester, i.e. R of Compound 1 1 R of hydrogen to Compound 4 1 Fluorine produced compound 4 in 65% isolated yield with 93:7 dr and 91% ee. Mass spectrum information of the compound is as follows:
1 H NMR(400MHz,Chloroform-d)δ7.92(d,J＝7.7Hz,2H),7.56–7.39(m,7H),7.29–7.21(m,4H),7.08(t,J＝7.7Hz,2H),6.95(dt,J＝8.6,4.3Hz,1H),6.76–6.68(m,3H),6.43(d,J＝7.9Hz,2H),6.17(d,J＝8.0Hz,1H),5.11(d,J＝7.9Hz,1H),4.51–4.47(m,2H),3.78(d,J＝17.9Hz,1H). 13 C NMR(101MHz,CDCl3)δ172.57,160.59,154.14,145.40,137.36,137.05,135.86,134.90,132.04,131.56,130.85,130.79,130.17,129.49,129.31,129.02,128.72,128.69,128.54,128.24,127.58,125.50,125.45,121.53,118.67,113.62,83.70,72.38,61.48,21.33. 19 F NMR(376MHz,Chloroform-d)δ-112.77(td,J＝8.4,5.2Hz).HRMS(ESI)Calcd.For C 37 H 26 N 2 OFCl(M+H)+601.1689,found:601.1686.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝9:1,flow rate＝1.0mL/min),t major ＝12.37min,t minor ＝9.28min。
5. preparation of Compound 5
Compound 5 is R 1 Is chlorine, R 2 Is phenyl, R 3 Is phenyl, ar 1 Is p-chlorophenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, the structure of the compound 5 is shown as (5):
the procedure for the preparation of this compound was as in example 1, except that: replacing 3-diazo-2-phenylacetic acid-3- (2-benzoylaminophenyl) prop-2-yn-1-yl ester in step (2) with 3-diazo-2-phenylacetic acid 3- (2-benzoylamino-5-chlorophenyl) prop-2-yn-1-yl ester, i.e. R of Compound 1 1 R of hydrogen to Compound 5 1 Chlorine gives compound 5 in a product isolation yield of 51%, a dr value of 91:9 and an ee value of 91%. Mass spectrum information of the compound is as follows:
1 H NMR(400MHz,CDCl3)δ7.92(d,J＝7.4Hz,1H),7.56–7.53(m,1H),7.46–7.37(m,3H),7.26(dd,J＝14.8,9.1Hz,2H),7.08(t,J＝7.4Hz,1H),6.77(d,J＝6.3Hz,1H),6.71(t,J＝7.1Hz,1H),6.44(d,J＝6.6Hz,1H),5.13(d,J＝7.6Hz,1H),4.47(dd,J＝26.2,12.7Hz,1H),3.82(d,J＝17.8Hz,1H). 13 C NMR(101MHz,CDCl3)δ159.75,155.00,144.90,138.34,135.32,135.12,132.53,132.24,130.40,130.25,130.08,129.43,129.13,128.83,128.55,128.22,127.78,126.74,125.29,123.33,119.04,113.76,83.42,72.17,61.25.HRMS(ESI)Calcd.for C 37 H 26 N 2 O 3 C l2 (M+H)+617.1393,found:617.1395.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝94:6,flow rate＝1.0mL/min),t major ＝21.77min,t minor ＝16.46min。
6. preparation of Compound 6
Compound 6 is R 1 Is hydrogen, R 2 Is p-methylphenyl, R 3 Is phenyl, ar 1 Is p-chlorophenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, the structure of the compound 6 is shown as (6):
the procedure for the preparation of this compound is as in example 1, except thatIn the following steps: substitution of 3-diazo-2-phenylacetic acid-3- (2-benzoylaminophenyl) prop-2-yn-1-yl ester in step (2) with 3- (2-benzoylaminophenyl) prop-2-yn-1-yl-2-diazo-2- (p-tolyl) acetate, i.e. R of Compound 1 2 Conversion of phenyl into R of Compound 6 2 Para-methylphenyl can be prepared to give compound 6 in 57% isolated yield, a dr of 91:9 and an ee of 93%. Mass spectrum information of the compound is as follows:
1 H NMR(400MHz,Chloroform-d)δ7.85(d,J＝7.7Hz,2H),7.52–7.38(m,7H),7.30–7.28(m,2H),7.07(t,J＝7.6Hz,2H),6.90(d,J＝7.7Hz,2H),6.83–6.79(m,1H),6.69(t,J＝7.4Hz,1H),6.61(d,J＝7.7Hz,1H),6.52(d,J＝7.6Hz,2H),6.42(d,J＝8.0Hz,2H),5.17(d,J＝7.1Hz,1H),4.60(d,J＝17.8Hz,1H),4.46(d,J＝7.1Hz,1H),3.95(d,J＝17.8Hz,1H),2.22(s,3H). 13 C NMR(101MHz,Chloroform-d)δ172.7,159.5,154.9,145.3,139.7,138.5,135.8,134.9,132.0,131.8,130.7,130.2,130.0,129.4,129.0,128.5,128.4,127.7,127.0,126.3,125.7,124.5,121.9,118.7,113.4,83.8,72.0,61.3,21.2.HRMS(ESI)Calcd.for C 38 H 29 N 2 O 3 Cl(M+H)+597.1939,found:597.1941.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝97:3,flow rate＝1.0mL/min),t major ＝31.87min,t minor ＝29.24min。
7. preparation of Compound 7
Compound 7 is R 1 Is hydrogen, R 2 Is p-fluorophenyl, R 3 Is phenyl, ar 1 Is p-chlorophenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, the structure of the compound 7 is shown as (7):
the procedure for the preparation of this compound was as in example 1, except that: replacing 3-diazo-2-phenylacetic acid-3- (2-benzoylaminophenyl) prop-2-yn-1-yl ester in step (2) with 3- (2-benzoylaminophenyl) prop-2-yn-1-yl-2-diazo-2- (4-fluorophenyl) acetate, i.e.R of Compound 1 2 Conversion of phenyl into R of Compound 7 2 Para-fluorophenyl can be prepared to give compound 7 in a product isolation yield of 60%, the compound having a dr of 95:5 and an ee of 89%. Mass spectrum information of the compound is as follows:
1 H NMR(400MHz,Chloroform-d)δ7.86(d,J＝7.8Hz,2H),7.54(t,J＝7.4Hz,1H),7.45–7.34(m,8H),7.11(t,J＝7.7Hz,2H),6.97–6.94(m,1H),6.80–6.73(m,4H),6.62–6.59(m,2H),6.46(d,J＝7.9Hz,2H),5.16(d,J＝7.4Hz,1H),4.73(d,J＝18.0Hz,1H),4.48(d,J＝7.4Hz,1H),4.11(d,J＝17.8Hz,1H). 13 C NMR(101MHz,CDCl3)δ172.57,160.59,154.14,145.40,137.36,137.05,135.86,134.90,132.04,131.56,130.85,130.79,130.17,129.49,129.31,129.02,128.72,128.69,128.54,128.24,127.58,125.50,125.45,121.53,118.67,113.62,83.70,72.38,61.48,21.33. 19 F NMR(376MHz,Chloroform-d)δ-112.41(tt,J＝9.0,5.2Hz).HRMS(ESI)Calcd.for C 37 H 26 N 2 O 3 FCl(M+H)+601.1689,found:601.1688.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝94:6,flow rate＝1.0mL/min),t major ＝18.49min,t minor ＝17.19min。
8. preparation of Compound 8
Compound 8 is R 1 Is hydrogen, R 2 Is p-chlorophenyl, R 3 Is phenyl, ar 1 Is p-chlorophenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, the structure of compound 8 is shown as (8):
the procedure for the preparation of this compound was as in example 1, except that: substitution of 3-diazo-2-phenylacetic acid-3- (2-benzoylaminophenyl) prop-2-yn-1-yl ester in step (2) with 3- (2-benzoylaminophenyl) prop-2-yn-1-yl 2- (4-chlorophenyl) -2-diazoacetic acid ester, i.e. R of Compound 1 2 Conversion of phenyl into R of Compound 8 2 P-chlorophenyl can be prepared to give compound 8 in 55% isolated yield, which isThe dr value of the compound was 91:9 and the ee value was 92%. Mass spectrum information of the compound is as follows:
1 H NMR(500MHz,CDCl3)δ7.86(d,J＝6.7Hz,1H),7.49(d,J＝6.3Hz,1H),7.33(dd,J＝60.4,18.9Hz,4H),7.07(s,1H),6.87(s,1H),6.74–6.64(m,1H),6.64–6.50(m,2H),6.42(d,J＝7.0Hz,1H),5.16(d,J＝6.1Hz,1H),4.62(d,J＝17.7Hz,1H),4.46(d,J＝5.8Hz,1H),3.98(d,J＝17.7Hz,1H). 13 C NMR(101MHz,CDCl3)δ172.57,160.59,154.14,145.40,137.36,137.05,135.86,134.90,132.04,131.56,130.85,130.79,130.17,129.49,129.31,129.02,128.72,128.69,128.54,128.24,127.58,125.50,125.45,121.53,118.67,113.62,83.70,72.38,61.48,21.33.HRMS(ESI)Calcd.for C 37 H 26 N 2 O 3 C l2 (M+H)+617.1393,found:617.1393.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝9:1,flow rate＝1.0mL/min),t major ＝12.96min,t minor ＝8.79min。
9. preparation of Compound 9
Compound 9 is R 1 Is hydrogen, R 2 Is phenyl, R 3 Is p-tolyl, ar 1 Is p-chlorophenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, the structure of the compound 9 is shown as (9):
the procedure for the preparation of this compound was as in example 1, except that: replacing 3-diazo-2-phenylacetic acid-3- (2-benzoylaminophenyl) prop-2-yn-1-yl ester in step (2) with 3-diazo-2-phenylacetic acid 3- (2- (4- (methylbenzamide) phenyl) prop-2-yn-1-yl ester, i.e. R of Compound 1 3 Conversion of phenyl into R of Compound 9 3 Para-methylphenyl can be prepared to give compound 9 in 63% isolated yield, with a dr of 94:6 and an ee of 94%. Mass spectrum information of the compound is as follows:
1 H NMR(500MHz,Chloroform-d)δ7.81(d,J＝7.9Hz,2H),7.47(d,J＝8.0Hz,2H),7.39(d,J＝8.0Hz,2H),7.28–7.19(m,5H),7.14(t,J＝7.5Hz,2H),7.07(t,J＝7.7Hz,2H),6.71–6.67(m,4H),6.48(d,J＝7.8Hz,1H),6.41(d,J＝7.9Hz,2H),5.16(d,J＝7.0Hz,1H),4.60–4.43(m,2H),3.82(d,J＝17.9Hz,1H),2.42(s,3H). 13 C NMR(126MHz,Chloroform-d)δ172.6,160.5,155.1,145.3,142.9,139.8,135.9,134.9,131.8,130.2,129.9,129.5,129.4,129.4,129.0,128.6,128.5,128.4,127.9,127.8,126.7,125.5,124.5,121.9,118.7,113.4,83.6,72.3,61.4,21.7.HRMS(ESI)Calcd.for C 38 H 29 N 2 O 3 Cl(M+H)+597.1939,found:597.1941.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝9:1,flow rate＝1.0mL/min),t major ＝14.84min,t minor ＝8.43min。
10. preparation of Compound 10
Compound 10 is R 1 Is hydrogen, R 2 Is phenyl, R 3 Is p-chlorophenyl, ar 1 Is p-chlorophenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, the structure of the compound 10 is shown as (10):
the procedure for the preparation of this compound was as in example 1, except that: replacing 3-diazo-2-phenylacetic acid-3- (2-benzoylaminophenyl) prop-2-yn-1-yl ester in step (2) with 3-diazo-2-phenylacetic acid 3- (2- (4-chlorobenzoylamino) phenyl) -2-propynyl-2-prop-1-yl ester, i.e. R of Compound 1 3 Conversion of phenyl into R of Compound 10 3 P-chlorophenyl can be prepared to give compound 10 in 53% isolated yield with a dr of 89:11 and an ee of 97%. Mass spectrum information of the compound is as follows:
1 H NMR(400MHz,Chloroform-d)δ7.76(d,J＝8.6Hz,2H),7.40–7.30(m,8H),7.19–7.09(m,5H),6.90(td,J＝7.4,1.8Hz,1H),6.75–6.67(m,4H),6.46(d,J＝7.9Hz,2H),5.17(d,J＝7.5Hz,1H),4.69(d,J＝17.8Hz,1H),4.42(d,J＝7.6Hz,1H),4.14(d,J＝17.8Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ172.4,159.5,153.9,145.1,139.4,138.3,135.5,135.0,132.0,130.2,130.0,129.4,129.4,129.3,129.0,128.8,128.6,128.5,128.3,127.2,125.9,124.4,121.5,119.0,113.6,83.7,71.9,61.5.HRMS(ESI)Calcd.for C 37 H 26 N 2 O 3 Cl 2 (M+H)+617.1393,found:617.1393.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝9:1,flow rate＝1.0mL/min),t major ＝17.47min,t minor ＝9.65min。
11. preparation of Compound 11
Compound 11 is R 1 Is hydrogen, R 2 Is phenyl, R 3 Is naphthyl, ar 1 Is p-chlorophenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, the structure of compound 11 is shown below:
the procedure for the preparation of this compound was as in example 1, except that: substitution of 3-diazo-2-phenylacetic acid-3- (2-benzoylaminophenyl) prop-2-yn-1-yl ester in step (2) with 3-diazo-2-phenylacetic acid 3- (2- (2- (naphthyl) phenyl) prop-2-yn-1-yl ester, i.e. R of Compound 1 3 Conversion of phenyl into R of Compound 11 3 Naphthyl, compound 11 was prepared in 43% isolated yield with a dr of 86:14 and an ee of 98%. Mass spectrum information of the compound is as follows:
1 H NMR(400MHz,Chloroform-d)δ8.26(s,1H),8.06(dd,J＝8.7,1.7Hz,1H),7.92–7.87(m,3H),7.65–7.59(m,2H),7.53(d,J＝8.4Hz,2H),7.45(d,J＝8.4Hz,2H),7.39–7.31(m,2H),7.13–7.08(m,5H),6.85(td,J＝7.5,1.5Hz,1H),6.75–6.71(m,3H),6.65(d,J＝7.4Hz,1H),6.48(d,J＝7.9Hz,2H),5.24(d,J＝7.4Hz,1H),4.70(d,J＝17.9Hz,1H),4.52(d,J＝7.4Hz,1H),4.07(d,J＝17.9Hz,1H). 13 C NMR(126MHz,Chloroform-d)δ172.5,160.0,154.9,145.2,139.8,135.8,135.1,132.6,131.9,130.2,130.1,129.4,129.4,129.1,129.0,128.6,128.5,128.4,128.4,128.3,128.1,128.1,127.9,127.0,126.9,125.8,124.5,124.0,121.8,118.8,113.5,83.7,72.1,61.5.HRMS(ESI)Calcd.for C 41 H 29 N 2 O 3 Cl(M+H)+633.1939,found:633.1942.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝94:6,flow rate＝1.0mL/min),t major ＝25.68min,t minor ＝28.53min。
12. preparation of Compound 12
Compound 12 is R 1 Is hydrogen, R 2 Is phenyl, R 3 Is 2-thienyl, ar 1 Is p-chlorophenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, compound 12 has the structure shown below:
the preparation process is described with reference to example 1, with the difference that: r of Compound 1 can be obtained by substituting 3-diazo-2-phenylacetic acid-3- (2-benzoylaminophenyl) prop-2-yn-1-yl ester in step (2) with 3- (2- (thiophene-2-carboxamide) phenyl) 2-diazo-2-phenylacetic acid ester 3 Conversion of phenyl into R of Compound 12 3 2-thienyl, compound 12 can be prepared with a product isolation yield of 64%. The dr value of this compound was 95:5 and the ee value was 95%. Mass spectrum information of the compound is as follows:
1 H NMR(400MHz,Chloroform-d)δ7.53(d,J＝5.0Hz,1H),7.49–7.47(m,3H),7.41(d,J＝8.2Hz,2H),7.28–7.05(m,8H),6.73–6.67(m,4H),6.49(d,J＝7.7Hz,1H),6.42(d,J＝7.9Hz,2H),5.15(d,J＝7.0Hz,1H),4.63(d,J＝17.9Hz,1H),4.46(d,J＝7.1Hz,1H),3.81(d,J＝17.9Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ172.4,160.0,151.5,145.3,139.7,135.7,135.0,134.9,131.8,131.6,130.4,130.2,130.0,129.4,129.3,129.1,128.6,128.5,128.4,128.2,126.8,125.4,124.5,121.7,118.7,113.4,84.0,72.1,61.3.HRMS(ESI)Calcd.for C 35 H 25 N 2 O 3 SCl(M+H)+589.1347,found:589.1347.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝97:3,flow rate＝1.0mL/min),t major ＝46.38min,t minor ＝42.64min。
13. preparation of Compound 13
Compound 13 is R 1 Is hydrogen, R 2 Is phenyl, R 3 Is phenyl, ar 1 Is phenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, compound 13 has the structure shown below:
the procedure for the preparation of this compound was as in example 1, except that: substitution of 1- (4-chlorophenyl) -N-phenylazomethine in step (1) to 1-phenyl-N-phenylazomethine, ar of Compound 1 1 Ar of conversion of p-chlorophenyl to Compound 13 1 Phenyl can be prepared to give compound 13 in 64% isolated yield with a dr of 95:5 and an ee of 95%. Mass spectrum information of the compound is as follows:
1 H NMR(400MHz,Chloroform-d)δ7.53(d,J＝5.0Hz,1H),7.49–7.47(m,3H),7.41(d,J＝8.2Hz,2H),7.28–7.05(m,8H),6.73–6.67(m,4H),6.49(d,J＝7.7Hz,1H),6.42(d,J＝7.9Hz,2H),5.15(d,J＝7.0Hz,1H),4.63(d,J＝17.9Hz,1H),4.46(d,J＝7.1Hz,1H),3.81(d,J＝17.9Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ172.4,160.0,151.5,145.3,139.7,135.7,135.0,134.9,131.8,131.6,130.4,130.2,130.0,129.4,129.3,129.1,128.6,128.5,128.4,128.2,126.8,125.4,124.5,121.7,118.7,113.4,84.0,72.1,61.3.HRMS(ESI)Calcd.for C 35 H 25 N 2 O 3 SCl(M+H)+589.1347,found:589.1347.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝97:3,flow rate＝1.0mL/min),t major ＝46.38min,t minor ＝42.64min。
14. preparation of Compound 14
Compound 14 is R 1 Is hydrogen, R 2 Is phenyl, R 3 Is phenyl, ar 1 Is p-fluorophenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, compound 14 has the structure shown below:
the procedure for the preparation of this compound was as in example 1, except that: substitution of 1- (4-chlorophenyl) -N-phenylazomethine in step (1) to 1- (4-fluorophenyl) -N-phenylazomethine, ar of Compound 1 1 Ar for conversion of p-chlorophenyl into Compound 14 1 Para-fluorophenyl can be prepared to give compound 14 in 74% isolated yield with a dr of 84:16 and an ee of 74%. Mass spectrum information of the compound is as follows:
1 H NMR(500MHz,Chloroform-d)δ7.90(d,J＝7.7Hz,2H),7.53–7.46(m,3H),7.42(t,J＝7.6Hz,2H),7.29–7.24(m,2H),7.19–7.06(m,7H),6.77–6.67(m,4H),6.55(d,J＝7.7Hz,1H),6.43(d,J＝7.9Hz,2H),5.17(d,J＝6.9Hz,1H),4.57(d,J＝17.9Hz,1H),4.47(d,J＝7.1Hz,1H),3.90(d,J＝17.8Hz,1H). 13 C NMR(126MHz,Chloroform-d)δ172.6,163.0(d,J＝248.9Hz),160.3,154.8,145.3,139.7,132.8(d,J＝3.2Hz),132.2,131.8,130.8,130.4(d,J＝8.1Hz),129.9,129.4,129.4,128.6,128.6,128.5,128.4,127.7,126.9,125.6,124.5,121.8,118.7,116.0,115.8,113.5,83.7,72.2,61.3. 19 F NMR(471MHz,Chloroform-d)δ-112.09.HRMS(ESI)Calcd.for C37H28N2O3F(M+H)+567.2078,found:567.2079.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝90:10,flow rate＝1.0mL/min),t major ＝10.67min,t minor ＝12.02min。
15. preparation of Compound 15
Compound 15 is R 1 Is hydrogen, R 2 Is phenyl, R 3 Is phenyl, ar 1 Is m-fluorophenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, compound 15 has the structure shown below:
the preparation process of the compoundThe difference from example 1 is that: substitution of 1- (4-chlorophenyl) -N-phenylazomethine in step (1) to 1- (3-fluorophenyl) -N-phenylazomethine, ar of Compound 1 1 Ar for conversion of p-chlorophenyl into Compound 15 1 M-fluorophenyl may be prepared as compound 15 in 63% isolated yield with a dr of 91:9 and an ee of 63%. Mass spectrum information of the compound is as follows:
1 H NMR(500MHz,Chloroform-d)δ7.92(d,J＝7.8Hz,2H),7.51(t,J＝7.4Hz,1H),7.42(t,J＝7.6Hz,2H),7.37(q,J＝7.5Hz,1H),7.32–7.25(m,4H),7.19–7.07(m,6H),6.76(t,J＝7.5Hz,1H),6.71–6.68(m,3H),6.54(d,J＝7.7Hz,1H),6.45(d,J＝8.0Hz,2H),5.19(d,J＝7.1Hz,1H),4.57(d,J＝17.8Hz,1H),4.48(d,J＝7.2Hz,1H),3.86(d,J＝17.8Hz,1H). 13 C NMR(126MHz,Chloroform-d)δ172.5,163.1(d,J＝248.0Hz),160.1,154.8,145.3,140.1(d,J＝6.4Hz),139.7,132.2,131.8,130.7,130.3(d,J＝8.1Hz),130.0,129.4,129.4,128.7,128.6,128.5,128.4,127.7,127.0,125.7,124.5(d,J＝2.8Hz),124.5,121.8,118.8,116.2,116.1(d,J＝4.3Hz),115.9,113.4,83.7,72.2,61.5. 19 F NMR(471MHz,Chloroform-d)δ-111.60.HRMS(ESI)Calcd.for C37H28N2O3F(M+H)+567.2078,found:567.2080.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝94:6,flow rate＝1.0mL/min),t major ＝15.55min,t minor ＝17.16min。
16. preparation of Compound 16
Compound 16 is R 1 Is hydrogen, R 2 Is phenyl, R 3 Is phenyl, ar 1 Is p-bromophenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, compound 16 has the structure shown below:
the procedure for the preparation of this compound was as in example 1, except that: substitution of 1- (4-chlorophenyl) -N-phenylazomethine in step (1) to 1- (4-bromophenyl) -N-phenylazomethine, ar of Compound 1 1 Conversion of p-chlorophenyl into Ar of Compound 16 1 Para-bromophenyl can be prepared to give compound 16 in 58% isolated yield with a dr of 89:11 and an ee of 98%. Mass spectrum information of the compound is as follows:
1 H NMR(500MHz,Chloroform-d)δ7.92(d,J＝7.7Hz,2H),7.58–7.53(m,3H),7.47–7.41(m,4H),7.34–7.28(m,2H),7.22–7.09(m,5H),6.79(t,J＝7.4Hz,1H),6.73–6.71(m,3H),6.59(d,J＝7.7Hz,1H),6.45(d,J＝7.9Hz,2H),5.18(d,J＝7.1Hz,1H),4.62(d,J＝17.8Hz,1H),4.50(d,J＝7.1Hz,1H),3.96(d,J＝17.9Hz,1H). 13 C NMR(126MHz,Chloroform-d)δ172.5,160.1,154.8,145.2,139.7,136.3,132.2,132.0,131.9,130.7,130.5,130.0,129.4,129.4,128.7,128.6,128.5,128.4,127.7,127.0,125.7,124.5,123.1,121.8,118.8,113.5,83.6,72.2,61.5.HRMS(ESI)Calcd.for C37H28N2O3Br(M+H)+627.1278,found:627.1282.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝94:6,flow rate＝1.0mL/min),t major ＝19.04min,t minor ＝23.06min。
17. preparation of Compound 17
Compound 17 is R 1 Is hydrogen, R 2 Is phenyl, R 3 Is phenyl, ar 1 Is p-methylphenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, compound 17 has the structure shown below:
the procedure for the preparation of this compound was as in example 1, except that: replacing 1- (4-chlorophenyl) -N-phenylazomethine in step (1) with 1- (4-methylphenyl) -N-phenylazomethine, which is Ar of Compound 1 1 Ar for conversion of p-chlorophenyl into Compound 17 1 Para-methylphenyl can be prepared to give compound 17 in 59% isolated yield, 95:5 dr and 96% ee. Mass spectrum information of the compound is as follows:
1 HNMR(400MHz,Chloroform-d)δ7.98(d,J＝7.8Hz,2H),7.54–7.41(m,5H),7.30–7.11(m,7H),7.06(t,J＝7.8Hz,2H),6.70–6.63(m,4H),6.51(d,J＝7.7Hz,1H),6.45(d,J＝8.0Hz,2H),5.18(s,1H),4.51–4.43(m,2H),3.66(d,J＝17.8Hz,1H),2.40(s,3H). 13 C NMR(101MHz,Chloroform-d)δ172.7,160.8,155.1,145.7,139.8,138.9,134.0,132.1,131.5,130.9,129.6,129.6,129.3,128.7,128.6,128.6,128.5,128.3,127.8,126.8,125.4,124.6,122.4,118.3,113.4,84.0,72.4,61.4,21.3.HRMS(ESI)Calcd.for C38H31N2O3(M+H)+563.2329,found:563.2329.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝90:10,flow rate＝1.0mL/min),t major ＝9.24min,t minor ＝10.86min。
18. preparation of Compound 18
Compound 18 is R 1 Is hydrogen, R 2 Is phenyl, R 3 Is phenyl, ar 1 Is 2, 3-dimethylphenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, compound 18 has the structure shown below:
the procedure for the preparation of this compound was as in example 1, except that: substitution of 1- (4-chlorophenyl) -N-phenylazomethine in step (1) to 1- (3, 4-dimethylphenyl) -N-phenylazomethine, i.e., ar of Compound 1 1 Ar for conversion of p-chlorophenyl into Compound 18 1 3, 4-dimethylphenyl, compound 18 was prepared in 57% isolated yield with a dr value of 81:19 and an ee value of 92%. Mass spectrum information of the compound is as follows:
1 H NMR(400MHz,Chloroform-d)δ7.98(d,J＝7.7Hz,2H),7.54–7.38(m,4H),7.30–7.05(m,9H),6.72–6.64(m,4H),6.53–6.47(m,3H),5.13(d,J＝7.2Hz,1H),4.51–4.44(m,2H),3.65(d,J＝17.7Hz,1H),2.29(s,6H). 13 C NMR(101MHz,Chloroform-d)δ172.7,160.8,155.1,145.8,139.8,137.5,137.1,134.3,132.1,131.3,130.9,130.3,129.9,129.6,129.6,129.3,128.6,128.6,128.4,128.3,127.9,126.8,126.1,125.4,124.6,122.4,118.2,113.4,84.0,72.4,61.4,19.9,19.7.HRMS(ESI)Calcd.for C39H33N2O3(M+H)+577.2486,found:577.2487.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝94:6,flow rate＝1.0mL/min),t major ＝12.72min,t minor ＝13.53min。
19. preparation of Compound 19
Compound 19 is R 1 Is hydrogen, R 2 Is phenyl, R 3 Is phenyl, ar 1 Is phenyl, ar 2 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] as phenyl group]Oxazine derivative, compound 19 has the structure shown below:
the procedure for the preparation of this compound was as in example 1, except that: replacing 1- (4-chlorophenyl) -N-phenylazomethine in step (1) with 1- (4-chlorophenyl) -N- (4-methylphenyl) azomethine, which is Ar of Compound 1 2 Ar of conversion of phenyl into Compound 19 2 Para-methylphenyl can be prepared to give compound 19 in 52% isolated yield, the compound having a dr of 80:20 and an ee of 95%. Mass spectrum information of the compound is as follows:
1 H NMR(500MHz,Chloroform-d)δ7.90(d,J＝7.7Hz,2H),7.54(t,J＝7.4Hz,1H),7.44–7.38(m,6H),7.32–7.28(m,2H),7.21–7.13(m,3H),6.92(d,J＝7.9Hz,2H),6.81(t,J＝6.3Hz,1H),6.74(d,J＝7.4Hz,2H),6.62(d,J＝7.7Hz,1H),6.38(d,J＝7.9Hz,2H),5.16(d,J＝6.6Hz,1H),4.64(d,J＝17.9Hz,1H),4.37(d,J＝6.9Hz,1H),4.02(d,J＝17.9Hz,1H),2.20(s,3H). 13 C NMR(126MHz,Chloroform-d)δ172.6,160.3,154.8,142.9,139.7,135.8,134.9,132.1,131.8,130.8,130.1,123.0,129.9,129.5,129.0,128.6,128.6,128.5,128.3,128.1,127.7,126.9,125.7,124.5,121.8,113.6,83.6,72.2,61.7,20.4.HRMS(ESI)Calcd.for C38H30N2O3Cl(M+H)+597.1939,found:597.1939.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝94:6,flow rate＝1.0mL/min),t major ＝15.71min,t minor ＝17.71min。
20. preparation of Compound 20
Compound 20 is R 1 Is hydrogen, R 2 Is phenyl, R 3 Is phenyl, ar 1 Is p-bromophenyl, ar 2 3-phenyl-furan-containing 2-phenyl-4H-benzo [1,3] as p-methylphenyl]Oxazine derivative, compound 20 has the structure shown below:
the procedure for the preparation of this compound was as in example 1, except that: replacing 1- (4-chlorophenyl) -N-phenylazomethine in step (1) with 1- (4-bromophenyl) -N- (4-methylphenyl) azomethine, i.e., ar of Compound 1 1 Ar for conversion of p-chlorophenyl into Compound 20 1 P-bromophenyl group, ar of Compound 1 2 Ar of conversion of phenyl into Compound 20 2 Para-methylphenyl can be prepared to give compound 20 in 62% isolated yield with a dr of 86:14 and an ee of 98%. Mass spectrum information of the compound is as follows:
1 H NMR(400MHz,Chloroform-d)δ7.86(d,J＝7.7Hz,2H),7.51(d,J＝8.0Hz,3H),7.41(t,J＝7.6Hz,2H),7.35(d,J＝8.1Hz,2H),7.27–7.25(m,2H),7.18–7.09(m,3H),6.88(d,J＝7.9Hz,2H),6.78(t,J＝5.9Hz,1H),6.69(d,J＝7.2Hz,2H),6.58(d,J＝7.7Hz,1H),6.34(d,J＝7.9Hz,2H),5.11(d,J＝6.6Hz,1H),4.61(d,J＝17.9Hz,1H),4.34(d,J＝6.9Hz,1H),3.99(d,J＝17.9Hz,1H),2.16(s,3H). 13 C NMR(101MHz,Chloroform-d)δ172.6,160.2,154.8,142.9,139.7,136.4,132.1,131.9,131.8,130.8,130.4,130.0,129.9,129.4,128.6,128.6,128.5,128.3,128.1,127.7,126.9,125.7,124.5,123.0,121.8,113.6,83.6,72.2,61.8,20.4.HRMS(ESI)Calcd.for C38H30N2O3Br(M+H)+641.1434,found:641.1437.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝94:6,flow rate＝1.0mL/min),t major ＝17.77min,t minor ＝20.22min。
21. preparation of Compound 21
Compound 21 is R 1 Is hydrogen, R 2 Is phenyl, R 3 Is phenyl, ar 1 Is phenyl, ar 2 3-phenyl-containing groups as phenyl groups2-phenyl-4H-benzo [1,3] furans]Oxazine derivative, compound 21 has the structure shown below:
the procedure for the preparation of this compound was as in example 1, except that: replacing 1- (4-chlorophenyl) -N-phenylazomethine in step (1) with 1- (4-fluorophenyl) -N- (4-chlorophenyl) azomethine, i.e. Ar of Compound 1 1 Ar for conversion of p-chlorophenyl into Compound 21 1 Para-fluorophenyl group, ar of Compound 1 2 Ar of conversion of phenyl into Compound 21 2 P-chlorophenyl can be prepared to give compound 21 in 71% isolated yield with a dr of 83:17 and an ee of 98%.
Mass spectrum information of the compound is as follows:
1 H NMR(400MHz,Chloroform-d)δ7.91(d,J＝7.7Hz,2H),7.54–7.41(m,5H),7.31–7.26(m,2H),7.22–7.11(m,5H),7.02(d,J＝8.5Hz,2H),6.77–6.69(m,3H),6.48(d,J＝7.8Hz,1H),6.35(d,J＝8.4Hz,2H),5.12(d,J＝6.9Hz,1H),4.56–4.48(m,2H),3.82(d,J＝17.8Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ172.4,163.0(d,J＝249.3Hz),160.0,154.8,143.9,139.7,132.4(d,J＝3.2Hz),132.3,131.9,130.7,130.4(d,J＝8.2Hz),130.0,129.3,129.3,128.7,128.7,128.5,128.4,127.7,126.9,125.7,124.3,123.4,121.8,116.1,115.9,114.5,83.7,72.2,61.4. 19 F NMR(376MHz,Chloroform-d)δ-111.64.HRMS(ESI)Calcd.for C37H27N2O3FCl(M+H)+601.1689,found:601.1690.HPLC(Chrial IA,λ＝254nm,hexane/2-propanol＝90:10,flow rate＝1.0mL/min),t major ＝12.78min,t minor ＝16.06min。
EXAMPLE 2 inhibitory Activity of 3-phenyl-furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivatives on tumor cells
1. Tumor cells used for the test were: human osteosarcoma cells (Sjsa-1) (purchased from Guangzhou Sakuku Biotechnology Co., ltd.), human colon cancer cells (HCT 116) (purchased from Guangzhou Saku Biotechnology Co., ltd.), human non-small cell lung cancer cells (A549) (purchased from Guangzhou Saku Biotechnology Co., ltd.), human breast cancer cells (MCF-7) (purchased from Wuhan Punuo Seisaku Life technologies Co., ltd.).
2. The testing method comprises the following steps: the proliferation inhibition effect of the 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivatives (compounds 1 to 21) on human osteosarcoma cells, human colon cancer cells, human non-small cell lung cancer cells and human breast cancer cells is measured by adopting a CCK-8 method, and the specific test process is as follows:
(1) Preparing the tumor cells into single cell suspension with corresponding complete culture medium, wherein the concentration of single cell suspension is 50000 cells/mL, inoculating 100uL of cell suspension into 96-well culture plate, and placing in CO 2 Incubator (37 ℃,5% CO) 2 95% air) for 24 hours; wherein, human osteosarcoma cells (Sjsa-1), human colon cancer cells (HCT 116) and human non-small cell lung cancer cells (A549) adopt a 1640 culture medium (containing 10 percent of newborn calf serum and 1 percent of double antibody); human breast cancer cells (MCF-7) were cultured in MEM medium (containing 10% neonatal calf serum, 1% diabody, 0.01mg/mL insulin).
(2) Compounds 1 to 21 were dissolved in DMSO, respectively, and prepared as 10mM stock solutions, and then diluted to a concentration of 2mM, respectively. Adding 1.0uL diluted compounds 1-21 into each well cell, arranging two parallel wells for each compound, adding 1.0uL DMSO into negative control group and blank control group, and placing into CO 2 Culturing in an incubator for 48 hours.
(3) After 48h of culture, the medium was removed and replaced with fresh medium, then 10uL of CCK-8 (Cell Counting Kits-8) reagent was added to each well of cells, and after incubation for 2 hours at 37 ℃, absorbance a at 450nm was measured using a Biotek multifunctional microplate reader, and the inhibition rates of compounds 1 to 21 on tumor cell growth were calculated; the method for calculating the inhibition rate comprises the following steps: [1- (A) Drug treatment group -A Blank control )/(A Negative control group -A Blank control )]X 100%, A is absorbance.
3. Test results: as shown in Table 1, the 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivatives have certain inhibitory activity on four tumor cells (human osteosarcoma cells, human colon cancer cells, human non-small cell lung cancer cells and human breast cancer cells). Wherein, the inhibition rate of the compounds 3,4, 5, 6, 7, 8, 11, 17 and 20 to the non-small cell lung cancer A549 cells at the concentration of 20 mu M is more than 60%, and the compounds have good anti-tumor effect. Therefore, the 2-phenyl-4H-benzo [1,3] oxazine derivatives containing 3-phenyl furan are expected to be prepared into medicaments for inhibiting tumor cells (human osteosarcoma cells, human colon cancer cells, human non-small cell lung cancer cells and human breast cancer cells), and particularly are prepared into medicaments for resisting the non-small cell lung cancer cells for application.
TABLE 1 inhibition of 3-phenyl-furan containing 2-phenyl-4H-benzo [1,3] oxazine derivatives on various cancer cell lines
[ Note ] the following: ND: not detected.
The embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, and yet fall within the scope of the invention.

Claims (9)

1. 2-phenyl-4H-benzo [1,3] oxazine derivatives containing 3-phenyl furan, characterized in that said derivatives are selected from at least one of the compounds 1-21:
2. the 3-phenylfuran-containing 2-phenyl-4H-benzo [1,3] of claim 1]OxazinesA process for producing a derivative, which comprises starting from compound 1a and compound 1b, chiral PA and Rh according to the following reaction scheme 2 (OAc) 4 As a catalyst and a molecular sieve as a water absorbent, firstly, the compound 1b and Rh are mixed 2 (OAc) 4 Mixing PA and a molecular sieve in an organic solvent to prepare a solution A, using argon to protect the solution A, dissolving a compound 1a in the organic solvent to prepare a solution B, then dripping the solution B into the solution A at the temperature of minus 30 ℃ to 30 ℃, and continuing to react for 0.5 to 3 hours after dripping, thus obtaining the target product of claim 1;
in the formula (I), R 1 Selected from hydrogen, methyl, isopropyl, fluorine, chlorine, R 2 Selected from phenyl, p-methylphenyl, p-fluorophenyl, p-chlorophenyl, R 3 Selected from phenyl, p-tolyl, p-chlorophenyl, naphthyl, 2-thienyl, ar 1 Selected from p-chlorophenyl, phenyl, p-fluorophenyl, m-fluorophenyl, p-bromophenyl, p-methylphenyl, 2, 3-dimethylphenyl, ar 2 Selected from phenyl, p-methylphenyl, p-chlorophenyl.
3. 3-phenyl-furan-containing 2-phenyl-4H-benzo [1,3] according to claim 2]The preparation method of oxazine derivatives is characterized in that the oxazine derivatives are prepared from a compound 1a, a compound 1b, chiral PA and Rh 2 (OAc) 4 The reaction molar ratio of (1.0-1.5:0.5-1.2:0.05-0.1:0.01-0.05).
4. The method for preparing the 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivatives according to claim 2, wherein the dosage of the molecular sieve is 10.0mg/mmol based on the dosage of the compound 1 a; the dosage of the organic solvent is 5 mL-10 mL/mmol.
5. 3-phenyl-furan-containing 2-phenyl-4H-benzo [1,3] according to claim 2]Oxazine derivativesThe preparation method of the material is characterized in that the organic solvent is dichloromethane or trichloromethane, and the molecular sieve isMolecular sieves.
6. Use of a 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivative according to claim 1 for the preparation of a medicament for inhibiting the activity of a tumor cell, wherein the tumor cell is a colon cancer cell, and the derivative is at least one selected from the group consisting of compounds 2-9, 11-12, 14-18, and 20-21:
7. use of a 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivative according to claim 1 for the preparation of a medicament for inhibiting the activity of a tumor cell, wherein the tumor cell is a breast cancer cell, and the derivative is at least one selected from the group consisting of compound 3, compound 5, compound 9, and compounds 20-21:
8. the use of a 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivative according to claim 1 for the preparation of a medicament for inhibiting tumor cell activity, wherein the tumor cell is a non-small cell lung cancer cell, and the derivative is at least one selected from the group consisting of compounds 2-9, 11-12, 15-16, and 20-21:
9. use of a 3-phenyl furan-containing 2-phenyl-4H-benzo [1,3] oxazine derivative according to claim 1 for the preparation of a medicament for inhibiting tumor cell activity, wherein the tumor cell is a osteosarcoma cell, and the derivative is at least one selected from the group consisting of compounds 5-8, 14, 16 and 20-21:
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0840908A (en) * 1994-07-28 1996-02-13 Yamanouchi Pharmaceut Co Ltd Cancerous cell proliferation inhibitor
CN106565713A (en) * 2016-10-10 2017-04-19 浙江工业大学 2'-pyrazol-1H-imidazole [4,5-f][1,10] phenanthroline derivate and preparing method and application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0840908A (en) * 1994-07-28 1996-02-13 Yamanouchi Pharmaceut Co Ltd Cancerous cell proliferation inhibitor
CN106565713A (en) * 2016-10-10 2017-04-19 浙江工业大学 2'-pyrazol-1H-imidazole [4,5-f][1,10] phenanthroline derivate and preparing method and application thereof

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* Cited by examiner, † Cited by third party
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