CN114736193A - Bedaquinoline derivative and preparation method thereof - Google Patents
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Abstract
The invention belongs to the technical field of synthetic pharmaceutical chemistry, and particularly relates to a bedaquiline derivative and a preparation method thereof. The invention provides a bedaquiline-coumarin hybrid molecule with an optically active amino acid-based structure by hybridizing pharmacodynamic structural fragments of bedaquiline and coumarin by a chemical synthesis method. The preparation method comprises the step of carrying out condensation reaction on a compound I containing a quinoline parent nucleus segment and an amino-substituted coumarin II containing a chiral amino acid segment in the presence of a proper catalyst under the conditions of alkalinity and heating to directly obtain target products III and III#. The method is suitable for various substrates, is simple to operate and environment-friendly, can synthesize various substituted and structurally diverse bedaquinoline-coumarin hybrid molecules by optimizing and adjusting reaction substrates, and the compounds are applied to pharmaceutical chemistry and biomedicineAnd the like, and are widely applied in the fields.
Description
Technical Field
The invention belongs to the technical field of synthetic pharmaceutical chemistry, and particularly relates to a bedaquiline derivative and a preparation method thereof.
Background
The bedaquiline on the market by the hadamard corporation in 12 months 2012 is the first antitubercular drug with a completely new action mechanism in nearly 40 years. The bedaquiline can act on ATP synthetase of mycobacterium tuberculosis uniquely, so that energy metabolism of bacteria is disordered to achieve bacteriostatic and bactericidal effects. It has the advantages of high selectivity, good activity, durable drug effect, almost no toxic or side effect and the like, and has better activity on multi-drug resistant tubercle bacillus and pan-drug resistant tubercle bacillus. The unique chiral structure of the bedaquiline is a key factor of the activity of the bedaquiline.
Coumarin is a common structural fragment in active natural products, and has wide physiological functions. Coumarin and its derivatives have antitumor, antiviral, antiinflammatory, antioxidant, and antituberculosis (TB) biological activities. In recent years, with the continuous and deep research on coumarin components and the gradual deepening of people's understanding on the relevant pharmacodynamic action mechanism of coumarin, a plurality of novel coumarin derivatives are developed and applied and are commonly used as intermediates and medicaments in the pharmaceutical industry.
Disclosure of Invention
In view of the above, the present invention aims to solve the problems in the prior art, a chemical synthesis method is applied to perform hybridization on pharmacodynamic structural fragments of bedaquiline and coumarin to provide a bedaquiline-coumarin hybrid molecule with an optically active amino acid-based structure, and based on the design concept of molecular hybridization, a designed target compound has excellent activities of two pharmacodynamic structural fragments of bedaquiline and coumarin, so as to discover a new lead compound with more biological activities and development prospects, provide a new concept for developing new antituberculosis clinical drugs, and provide a new structural model for novel antituberculosis clinical drugs. Also provides a corresponding asymmetric synthesis preparation method.
In order to achieve the purpose, the invention adopts the following technical scheme:
a Bedaquinoline derivative has a structural general formula III:
wherein:
R1is hydrogen, halogen, cyano, hydroxyHaloalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, aryl, arylalkyl or diarylalkyl;
R2is hydrogen, hydroxy, mercapto, alkoxy, alkylthio or
Wherein Y is S, O, NH or N-alkyl;
R3is independently chlorine;
R4is alkoxy, alkylthio, halogen, hydrogen, haloalkyl, alkylthioalkyl, alkoxyalkyl, arylalkyl or diarylalkyl;
R5is hydrogen, alkyl or aryl;
R6is arylalkyl of the S or R type or benzylalkyl of the S or R type;
R7independently hydrogen, benzyl or alkyl; or, R7With N attached to it form: imidazolidinyl, 2-imidazolidinyl, 3-imidazolidinyl, pyrrolyl, 2H-pyrrolyl, 2-pyrrolinyl, pyrrolidinyl, triazolyl, pyrazolyl, piperazinyl, pyridazinyl, pyrazinyl, triazinyl, morpholinyl or thiomorpholinyl, and R7The aforementioned groups formed with the N to which they are attached may be optionally substituted with hydroxy, halogen, alkyl, amino, haloalkyl, alkylthioalkyl, alkoxyalkyl or pyrimidinyl;
R8is a substituent on the aminocoumarin nucleus, independently hydrogen, benzyl or alkyl; or, an N heterocyclic group: imidazolidinyl, 2-imidazolidinyl, 3-imidazolidinyl, pyrrolyl, 2H-pyrrolyl, 2-pyrrolinyl, pyrrolidinyl, triazolyl, pyrazolyl, piperazinyl, pyridazinyl, pyrazinyl, triazinyl, morpholinyl, thiomorpholinyl, and said groups may be optionally substituted by hydroxy, halogen, alkyl, amino, haloalkyl, alkylthioalkyl, alkoxyalkyl or pyrimidinyl;
halogen is a substituent of fluorine, chlorine, bromine or iodine;
the halogenated alkyl is selected from cyclic saturated hydrocarbon formed by 3-6 saturated carbon atoms or straight chain or branched chain saturated hydrocarbon group formed by 1-6 saturated carbon atoms.
The compound designed by the invention has two pharmacophores of bedaquiline and coumarin, and according to the analysis of the structure-activity relationship of bedaquiline and coumarin, 6-bromo-3- (phenyl chloromethyl) -2-methoxyquinoline is a mother nucleus skeleton which is crucial for bedaquiline to exert the antitubercular activity, 7-amino-4-methylcoumarin also retains a structural skeleton which is crucial for coumarin to exert the antitubercular activity, and the application range of the single structure of bedaquiline and coumarin is expanded by utilizing the design idea of molecular hybridization to carry out hybridization on the pharmacophores of bedaquiline and coumarin and design a hybridized molecule of bedaquiline-coumarin, so that reference is provided for developing novel antitubercular drugs.
Further, the derivatives are: (S) -N- [ (6-bromo-2-methoxyquinolin-3-yl) phenylmethyl) amino ] - (S) -N- (4-methyl-2-oxo-2H-chromen-7-amino) -3-phenylacrylamide, (R) -N- [ (6-bromo-2-methoxyquinolin-3-yl) phenylmethyl) amino ] - (S) -N- (4-methyl-2-oxo-2H-chromen-7-amino) -3-phenylacrylamide, (S) -N- [ (6-bromo-2-methoxyquinolin-3-yl) phenylmethyl) amino ] - (S) -N- (4-hydroxyphenyl) (4-methyl- 2-oxo-2H-chromen-7-amino) -3-propionamide or (R) -N- [ (6-bromo-2-methoxyquinolin-3-yl) phenylmethyl) amino ] - (S) -N- (4-hydroxyphenyl) (4-methyl-2-oxo-2H-chromen-7-amino) -3-hydrocinnamamide.
It is worth noting that the present invention also includes optical isomers and tautomers of the compounds of the above formula.
A second object of the present invention is to provide a method for preparing the bedaquiline derivative.
In order to achieve the above purpose, the invention provides the following technical scheme:
a method for preparing bedaquiline derivative comprises dissolving compound I containing quinoline parent nucleus segment and amino-substituted coumarin II containing chiral amino acid segment in organic solvent, and performing condensation reaction under the presence of catalyst, alkali and heating condition to obtain target compounds III and III#：
Wherein:
R1is hydrogen, halogen, cyano, hydroxy, haloalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, aryl, arylalkyl or diarylalkyl;
R2is hydrogen, hydroxy, mercapto, alkoxy, alkylthio or
Wherein Y is S, O, NH or N-alkyl;
R3is independently chlorine;
R4is alkoxy, alkylthio, halogen, hydrogen, haloalkyl, alkylthioalkyl, alkoxyalkyl, arylalkyl or diarylalkyl;
R5is hydrogen, alkyl or aryl;
R6is arylalkyl of the S or R type or benzylalkyl of the S or R type;
R7independently hydrogen, benzyl or alkyl; or, R7With the N to which it is attached to form: imidazolidinyl, 2-imidazolidinyl, 3-imidazolidinyl, pyrrolyl, 2H-pyrrolyl, 2-pyrrolinyl, pyrrolidinyl, triazolyl, pyrazolyl, piperazinyl, pyridazinyl, pyrazinyl, triazinyl, morpholinyl or thiomorpholinyl, and, R7The aforementioned groups formed with the N to which they are attached may be optionally substituted with hydroxy, halogen, alkyl, amino, haloalkyl, alkylthioalkyl, alkoxyalkyl or pyrimidinyl;
R8is a substituent on the aminocoumarin nucleus, independently hydrogen, benzyl or alkyl; or, an N heterocyclic group: imidazolidinyl, 2-imidazolidinyl, 3-imidazolidinyl, pyrrolyl, 2H-pyrrolyl, 2-pyrrolinyl, pyrrolidinyl, triazolyl, pyrazolyl, piperazinyl, pyridazinyl, pyrazinyl, triazinyl, morpholinyl, thiomorpholinyl, and said groups may be optionally substituted by hydroxy, halogen, alkyl, amino, haloalkyl, alkylthioalkyl, alkoxyalkyl or pyrimidinyl;
halogen is a substituent of fluorine, chlorine, bromine or iodine;
the halogenated alkyl is selected from cyclic saturated hydrocarbon formed by 3-6 saturated carbon atoms or straight chain or branched chain saturated hydrocarbon group formed by 1-6 saturated carbon atoms.
It is worth to say that the invention provides an asymmetric synthesis preparation method of the bedaquiline-coumarin hybrid molecule. The method has few synthesis steps, simple related chemical reactions, environmental protection and suitability for various substrates, and can synthesize various substituted and structurally diverse bedaquinoline-coumarin hybrid molecules by optimizing and adjusting the reaction substrates, and the compounds are widely applied to the fields of medicinal chemistry, biomedicine and the like.
Further, the organic solvent is one of acetonitrile, tetrahydrofuran, diethyl ether, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, chloroform and acetone, and a mixed solvent of any combination of the solvents.
Further, the base is potassium carbonate, sodium bicarbonate, triethylamine, sodium hydroxide, potassium hydroxide or pyridine.
Further, the catalyst is potassium halide, sodium halide or tetra-n-butylammonium halide.
Further, the reaction temperature is-20 ℃ to the solvent reflux temperature.
Further, the reaction time is 0.5-30 h.
Further, the molar ratio of the reaction raw materials I and II is 1: 1-1: 10.
Further, the preparation method also comprises the steps of extracting, crystallizing and purifying the target product III by column chromatography.
Compared with the prior art, the invention has the advantages that: the synthesis method is simple, green and environment-friendly, is suitable for various substrates, can synthesize various substituted and structurally diverse bedaquiline-coumarin hybrid molecules by optimizing and adjusting reaction substrates, and the compounds are widely applied to the fields of medicinal chemistry, biomedicine and the like.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts
FIG. 1 is an infrared spectrum of Compound I1 of example 1.
FIG. 2 shows the NMR spectrum of Compound I1 in example 1.
FIG. 3 is a NMR carbon spectrum of Compound I1 of example 1.
FIG. 4 shows Compound I1 of example 1#Infrared spectrum of (2).
FIG. 5 shows Compound I1 of example 1#Hydrogen spectrum of Nuclear Magnetic Resonance (NMR).
FIG. 6 shows Compound I1 of example 1#Nuclear magnetic resonance carbon spectrum of (1).
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The present invention will be further specifically illustrated by the following examples for better understanding, but the present invention is not to be construed as being limited thereto, and certain insubstantial modifications and adaptations of the invention by those skilled in the art based on the foregoing disclosure are intended to be included within the scope of the invention.
Example 1
Bedaquinoline derivative (S) -N- [ (6-bromo-2-methoxyquinolin-3-yl) phenylmethyl) amino]- (S) -N- (4-methyl-2-oxo-2H-chromen-7-amino) -3-phenylalanmide I1 and (R) -N- [ (6-bromo-2-methoxyquinolin-3-yl) phenylmethyl) amino]- (S) -N- (4-methyl-2-oxo-2H-chromen-7-amino) -3-hydrocinnamamide I1#And the preparation method comprises the following steps:
the synthetic route is as follows:
a NaCO3,THF,0℃b NMM,THF,-15℃c HCl d K2CO3,TBAI,ACN,82℃
i3 at 0 deg.C, placing L-phenylalanine (i.e. S-phenylalanine) and Boc anhydride (molar ratio 1: 1.5) in 150mL eggplant-shaped bottle, dissolving with mixed solvent of water and tetrahydrofuran (volume ratio 10: 1), Na2CO3As an acid-binding agent, the mixture was stirred at room temperature for 12 hours, and the reaction was completed. Adding 10% hydrochloric acid solution into a reaction bottle at low temperature, adjusting the system ph to 2, extracting with (100mL × 3) ethyl acetate, combining organic phases, repeatedly washing the organic phases with saturated saline solution, drying with sodium sulfate, and concentrating ethyl acetate under vacuum to obtain the compound I3. Yield 86.3%, melting point: 87-89 ℃ and MS (ESI (+)): M/z 264.3(M + H)+),m/z 265(M+2+H+)。
I4, placing the compound I3 and an acid-binding agent 4-methylmorpholine (the molar ratio is 1: 1) in a 150mL eggplant-shaped bottle, dissolving the compound in dried tetrahydrofuran, stirring the solution at the temperature of minus 15 ℃ for 10min, dropwise adding isobutyl chloroformate diluted by the tetrahydrofuran, maintaining the temperature of minus 10 ℃ for reaction for 30min, then adding 4-methyl-7-aminocoumarin, stirring the solution at room temperature for 2h, and finishing the reaction. Concentrating the tetrahydrofuran under vacuum, dissolving the residue with ethyl acetate, and sequentially adding 10% Na to the organic phase2CO3The solution, 0.1mol/L hydrochloric acid solution, and saturated saline solution were washed twice each. Drying with magnesium sulfate, concentrating the organic phase under vacuum, crystallizing with mixed solvent of petroleum ether and ethyl acetate to obtain compound I4 with 91% yield, melting point of 112-114 deg.C, MS (ESI (+): M/z408.16(M + H)+)，m/z 410.2(M+2+H+)。
And I5, dissolving the compound I4 in a methanol solution containing saturated hydrogen chloride gas, and stirring at room temperature for 2 hours until the reaction is finished. Concentration of methanol under vacuum gave compound I5 in 91% yield, mp 125 ℃ -126 ℃, MS (ESI (+): m/z308.1(M+H+),m/z 309.1(M+2+H+)。
I1 Compound I2 and Compound I5 (molar ratio in the range of 1: 10) are added to an eggplant-shaped bottle, dissolved with acetonitrile, K2CO3And as an acid-binding agent, tetra-n-butyl ammonium iodide is used as a catalyst, stirring is carried out at 70 ℃ for 6 hours, TLC shows that the raw material I2 is completely reacted, two round thick spots are close to each other to form a new generation point, and the reaction is finished. Extracting with appropriate amount of ethyl acetate, combining organic phases, washing the organic phases with saturated saline solution, concentrating ethyl acetate in vacuum, and extracting with petroleum ether: ethyl acetate 10: 1, purifying by silica gel column chromatography to obtain optically active I1 and I1 respectively#。
The I1 yield was 22.93%, and the characterization data were as follows:
[α]D＝+55.6°(c＝1,CH2Cl2)
IR(KBr pellets)/cm-1:3378.93(N-H)；3238.73(NH-C＝O)；3059.34,3026.43(Ar-H)；2920.51,2848.55(OCH3)；1729.48(O-C＝O)；1664.81NH-C＝O)；1602.85(ArC＝C)；1464.76(CH2)；1399.11,1349.13(OCH3)；1017.14(O-C＝O)；924.47(Ar-H)；696.29(C-Br)；
1H NMR(600MHz,CDCl3)δ7.99(s,1H),7.93-7.84(m,3H),7.80–7.75(m,3H),7.73(s,,1H),7.75–7.36(m,2H),7.39(m,2H),7.26(t,J＝5.1Hz,3H),7.27–6.60(m,4H),5.59(s,1H),5.30(s,1H),4.08-3.98(m,3H),3.79(s,1H),3.54(s,1H),3.20(s,1H),2.76(s,1H)；
13C NMR(125MHz,CDCl3)δ162.50(s),162.36(m),139.81(s),138.51(s),136.22(s),135.96(s),135.13(s),134.76(s),134.26(s),132.35(d,J＝4.3Hz),130.19(s),129.46(s),129.20–129.13(m),128.91-128.57(m),128.25-127.78(m,),127.39(s),126.94(d,J＝6.3Hz),126.51(s),121.50(s),120.85(s),117.04(s),114.95(s),65.51(s),56.91(s),36.05(s),18.94(s)；
MS(ESI(+)):m/z 646.1(M+H+),m/z 648(M+2+H+)。
I 1#the yield was 16.22%, and the characterization data were as follows:
[α]D＝-54.1°(c＝1,CH2Cl2)
IR(KBr pellets)/cm-1:3382.94(N-H)；3241.33(NH-C＝O)；3058.53,3038.32(Ar-H)；2921.41,2845.53(OCH3)；17298.44(O-C＝O)；1664.31NH-C＝O)；1604.55(ArC＝C)；1466.46(CH2)；1395.11,1349.13(OCH3)；1016.14(O-C＝O)；924.49(Ar-H)；696.28(C-Br)；
1H NMR(600MHz,CDCl3)δ7.92(s,1H),7.87(s,1H),7.75(s,2H),7.83–7.62(m,4H),7.32–7.28(m,4H),7.28–7.08(m,3H),7.13(s,1H),6.12(s,1H),5.19(s,4H),4.19(s,1H),4.08-3.97(m,3H),2.98(s,1H),2.81(s,1H),2.40–2.39(m,3H),1.58(S,1H)；
13C NMR(125MHz,CDCl3)δ174.65(s),168.05(s),152.74(s),150.16(s),130.83(s),129.77(s),129.73–128.64(m),128.43(d,J＝8.9Hz),127.19(s),126.94(s),111.57(s),110.23(s),101.08(s),60.21(s),53.34(s),38.78–38.64(m),35.96–35.83(m),21.07(s)；
MS(ESI(+)):m/z 646.1(M+H+),m/z 648(M+2+H+)。
example 2
Bedaquin derivative (S) -N- [ (6-bromo-2-methoxyquinolin-3-yl) phenylmethyl) amino]- (S) -N- (4-hydroxyphenyl) (4-methyl-2-oxo-2H-chromen-7-amino) -3-propanamide II 1 and (R) -N- [ (6-bromo-2-methoxyquinolin-3-yl) phenylmethyl) amino]- (S) -N- (4-hydroxyphenyl) (4-methyl-2-oxo-2H-chromen-7-amino) -3-phenylpropanamide II 1#And the preparation method, the synthesis method and the conditions thereof were the same as in example 1 except that L-phenylalanine, which is one of the reaction raw materials, was changed to L-tyrosine.
IR(KBr pellets)/cm-1:3378.67(N-H)；3242.22(NH-C＝O)；3061.34,3028.93(Ar-H)；2921.23,2843.65(OCH3)；1729.68(O-C＝O)；1666.61NH-C＝O)；1604.65(ArC＝C)；1462.24(CH2)；1397.14,1348.12(OCH3)；1014.17(O-C＝O)；926.47(Ar-H)；696.29(C-Br)；
1H NMR(600MHz,CDCl3)δ8.40(s,14H),8.21–7.90(m,7H),7.85(t,J＝18.8Hz,4H),7.80–7.63(m,8H),7.62(s,2H),7.43(s,3H),7.34(d,2H),6.72(d,2H),6.11(s,2H),,4.03–3.70(m,8H),3.72(s,2H),3.72(s,2H),2.43–2.27(m,6H),2.09(s,2H)；
13C NMR(125MHz,CDCl3)δ171.20(s),162.43(s),156.19(s),154.15(s),153.28(s),152.59(s),146.46(s),145.59(s),142.06(s),134.53(s),131.82(s),130.91(s),129.67(s),129.10(s),128.75(d,J＝2.2Hz),128.32(s),127.79(d,J＝9.9Hz),124.11(s),122.60(s),120.29(s),117.51(s),115.62(s),113.96(s),111.63(s),105.27(s),59.02(s),56.69(s),54.00(s),39.01(s),21.53(s)；
MS(ESI(+)):m/z 662.1(M+H+),m/z 663(M+2+H+)。
IR(KBr pellets)/cm-1:3382.93(N-H)；3235.43(NH-C＝O)；3054.54,3029.43(Ar-H)；2921.51,2847.25(OCH3)；1728.48(O-C＝O)；1667.81NH-C＝O)；1605.24(ArC＝C)；1458.79(CH2)；1389.19,1347.45(OCH3)；1013.32(O-C＝O)；924.23(Ar-H)；696.29(C-Br)；
1H NMR(600MHz,CDCl3)δ7.99(d,J＝7.6Hz,2H),7.94(s,1H),7.76(s,1H),7.55(s,1H),7.37–7.29(m,4H),7.26(d,J＝7.2Hz,2H),7.08–6.95(m,2H),6.89(s,1H),6.79–6.65(m,2H),6.16(d,J＝1.6Hz,2H),5.19(s,1H),4.20(s,1H),3.99–3.95(m,3H),3.57(s,1H),3.29(s,1H),2.85(s,1H),2.54–2.49(m,3H),1.53(s,1H)；
13C NMR(125MHz,CDCl3)δ173.20(s),165.23(s),158.25(s),154.15(s),153.28(s),152.59(s),146.46(s),145.59(s),142.06(s),134.53(s),131.82(s),130.91(s),129.67(s),129.10(s),128.75(d,J＝2.2Hz),128.32(s),127.79(d,J＝9.9Hz),124.11(s),122.60(s),120.29(s),117.51(s),115.62(s),113.96(s),111.63(s),105.27(s),59.02(s),56.69(s),54.00(s),39.01(s),21.53(s)；
MS(ESI(+)):m/z 662.1(M+H+),m/z 663(M+2+H+)。
the previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. A bedaquiline derivative is characterized in that the structural general formula III is as follows:
wherein:
R1is hydrogen, halogen, cyano, hydroxy, haloalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, aryl, arylalkyl or diarylalkyl;
R2is hydrogen, hydroxy, mercapto, alkoxy, alkylthio or
Wherein Y is S, O, NH or N-alkyl;
R3is independently chlorine;
R4is alkoxy, alkylthio, halogen, hydrogen, haloalkyl, alkylthioalkyl, alkoxyalkyl, arylalkyl or diarylalkyl;
R5is hydrogen, alkyl or aryl;
R6is arylalkyl of the S or R type or benzylalkyl of the S or R type;
R7independently hydrogen, benzyl or alkyl; or, R7With the N to which it is attached to form: imidazolidinyl, 2-imidazolidinyl, 3-imidazolidinyl, pyrrolyl, 2H-pyrrolyl, 2-pyrrolinyl, pyrrolidinyl, triazolyl, pyrazolyl, piperazinyl, pyridazinyl, pyrazinyl, triazinyl, morpholinyl or thiomorpholinyl, and R7The aforementioned groups formed with the N to which they are attached may be optionally substituted with hydroxy, halogen, alkyl, amino, haloalkyl, alkylthioalkyl, alkoxyalkyl or pyrimidinyl;
R8is a substituent on the aminocoumarin nucleus, independently hydrogen, benzyl or alkyl; or, an N heterocyclic group: imidazolidinyl, 2-imidazolidinyl, 3-imidazolidinyl, pyrrolyl, 2H-pyrrolyl, 2-pyrrolinyl, pyrrolidinyl, triazolyl, pyrazolyl, piperazinyl, pyridazinyl, pyrazinyl, triazinyl, morpholinyl, thiomorpholinyl, and said groups may be optionally substituted by hydroxy, halogen, alkyl, amino, haloalkyl, alkylthioalkyl, alkoxyalkyl or pyrimidinyl;
halogen is a substituent of fluorine, chlorine, bromine or iodine;
the halogenated alkyl is selected from cyclic saturated hydrocarbon formed by 3-6 saturated carbon atoms or straight chain or branched chain saturated hydrocarbon group formed by 1-6 saturated carbon atoms.
2. The bedaquiline derivative according to claim 1, wherein the derivative is: (S) -N- [ (6-bromo-2-methoxyquinolin-3-yl) phenylmethyl) amino ] - (S) -N- (4-methyl-2-oxo-2H-chromen-7-amino) -3-phenylacrylamide, (R) -N- [ (6-bromo-2-methoxyquinolin-3-yl) phenylmethyl) amino ] - (S) -N- (4-methyl-2-oxo-2H-chromen-7-amino) -3-phenylacrylamide, (S) -N- [ (6-bromo-2-methoxyquinolin-3-yl) phenylmethyl) amino ] - (S) -N- (4-hydroxyphenyl) (4-methyl- 2-oxo-2H-chromen-7-amino) -3-propionamide or (R) -N- [ (6-bromo-2-methoxyquinolin-3-yl) phenylmethyl) phenylamino ] - (S) -N- (4-hydroxyphenyl) (4-methyl-2-oxo-2H-chromen-7-amino) -3-phenylacrylamide.
3. A process for the preparation of the bedaquiline derivatives according to any of claims 1 or 2, characterised in that the compound I containing the quinoline nucleus fragment and the amino-substituted coumarin II containing the chiral amino acid fragment are used as reactants, oneDissolving in organic solvent, and performing condensation reaction under the presence of catalyst, alkali and heating to obtain target compounds III and III#：
Wherein:
R1is hydrogen, halogen, cyano, hydroxy, haloalkyl, alkoxy, alkoxyalkyl, alkylthio, alkylthioalkyl, aryl, arylalkyl or diarylalkyl;
R2is hydrogen, hydroxy, mercapto, alkoxy, alkylthio or
Wherein Y is S, O, NH or N-alkyl;
R3is independently chlorine;
R4is alkoxy, alkylthio, halogen, hydrogen, haloalkyl, alkylthioalkyl, alkoxyalkyl, arylalkyl or diarylalkyl;
R5is hydrogen, alkyl or aryl;
R6is arylalkyl of the S or R type or benzylalkyl of the S or R type;
R7independently hydrogen, benzyl or alkyl; or, R7With the N to which it is attached to form: imidazolidinyl, 2-imidazolidinyl, 3-imidazolidinyl, pyrrolyl, 2H-pyrrolyl, 2-pyrrolinyl, pyrrolidinyl, triazolyl, pyrazolyl, piperazinyl, pyridazinyl, pyrazinyl, triazinyl, morpholinyl or thiomorpholinyl, and R7The aforementioned groups formed with the N to which they are attached may be optionally substituted with hydroxy, halogen, alkyl, amino, haloalkyl, alkylthioalkyl, alkoxyalkyl or pyrimidinyl;
R8is a substituent on the aminocoumarin parent nucleus, independently hydrogen, benzyl or alkyl; or, an N heterocyclic group: imidazolidinyl, 2-imidazolidinyl, 3-imidazolidinyl, pyrrolyl, 2H-pyrrolyl, 2-pyrrolinyl, pyrrolidinyl, triimidazolidinyl(ii) azolyl, pyrazolyl, piperazinyl, pyridazinyl, pyrazinyl, triazinyl, morpholinyl, thiomorpholinyl, and said groups may be optionally substituted by hydroxy, halogen, alkyl, amino, haloalkyl, alkylthioalkyl, alkoxyalkyl or pyrimidinyl;
halogen is a substituent of fluorine, chlorine, bromine or iodine;
the halogenated alkyl is selected from cyclic saturated hydrocarbon formed by 3-6 saturated carbon atoms or straight chain or branched chain saturated hydrocarbon group formed by 1-6 saturated carbon atoms.
4. The method for preparing a bedaquiline derivative according to claim 3, wherein the organic solvent is a mixed solvent of one or any combination of acetonitrile, tetrahydrofuran, diethyl ether, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, chloroform and acetone.
5. The method for producing a bedaquiline derivative according to claim 3, wherein the base is potassium carbonate, sodium hydrogen carbonate, triethylamine, sodium hydroxide, potassium hydroxide or pyridine.
6. The process for preparing a bedaquiline derivative according to claim 3, wherein the catalyst is a potassium halide, a sodium halide or a tetra-n-butylammonium halide.
7. The process for preparing a bedaquiline derivative according to claim 3, wherein the reaction temperature is from-20 ℃ to the solvent reflux temperature.
8. The method for preparing a bedaquiline derivative according to claim 3, wherein the reaction time is 0.5 to 30 hours.
9. The preparation method of the bedaquiline derivative according to claim 3, wherein the molar ratio of the reaction raw materials I and II is 1: 1-1: 10.
10. The preparation method of the bedaquiline derivative as claimed in claim 3, further comprising the steps of extracting, crystallizing and purifying by column chromatography the target product III.
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