Silicon-based quinoline drug intermediate and preparation method thereof

Abstract

The invention relates to a silyl quinoline drug intermediate and a preparation method thereof, and the preparation method specifically comprises the following steps: dissolving a quinoline olefin compound I in methanol, adding the quinoline olefin compound I and (dimethylphenylsilyl) bis (pinacolato) diboron into a mixing chamber of a mobile phase reaction device together, and premixing; the method comprises the following steps: filling a microchannel reactor of a mobile phase reaction device with a polymer composite copper catalytic material PICB-Cu; starting an injection pump, introducing the premixed solution into the micro-channel reactor at a set flow rate, setting reaction temperature and pressure, collecting a solution produced by a mobile phase after the reaction is finished, and performing liquid chromatography separation to obtain the product silicon-based quinoline drug intermediate II. The invention relates to an innovative mobile phase synthesis method, and provides a feasible path for industrial production of silicon-containing quinoline drug intermediates by optimizing reaction conditions, improving reaction efficiency, ensuring product purity and reducing production cost.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a silicon-based quinoline drug intermediate and a preparation method thereof. Background Art

[0002] Silicon-based organic heterocyclic compounds are widely used in the fields of drug development, functional materials and agricultural chemicals due to their unique properties. They serve as important synthetic intermediates in the construction of various natural product molecules and bioactive molecules. For example, trimethylsilylnitrobenzene and 2-methoxy-3-formaldehydequinoline were used as substrates to synthesize the key intermediate alcohol, which can be used to obtain KDR inhibitor compounds in high yields during the subsequent transformation and reductive cyclization process. Such compounds are of great value in drug development. In addition, silicon groups are also used as protecting groups to protect other functional groups from being affected during the synthesis process. For example, in the synthesis of 2-methyl-8-hydroxyquinoline, silicon groups are used as protecting groups, and the target product is finally obtained through steps such as silicon protection, bromination and Suzuki coupling.

[0003] Traditional quinoline drug intermediate synthesis methods, such as the Skraup-Doebner-Von Miller synthesis method, can achieve the synthesis of target compounds to a certain extent, but there are problems such as harsh reaction conditions, unstable yields, low product purity, and environmental pollution. In particular, some synthetic routes need to be carried out under strict conditions of low temperature, anhydrous and oxygen-free, and a large amount of impurities are easily generated during the reaction, which not only increases production costs, but also limits the possibility of industrial production. Summary of the invention

[0004] The present invention provides a silicon-based quinoline drug intermediate and a preparation method thereof. The mobile phase synthesis method is used to optimize reaction conditions, improve reaction efficiency, ensure product purity and reduce production costs, thereby achieving safe and efficient synthesis of drug intermediates. At the same time, environmental pollution and waste emissions are greatly reduced, which meets my country's environmental protection requirements for chemical drug production enterprises.

[0005] The solution of the present invention to solve the above technical problems is as follows: a silicon-based quinoline drug intermediate, the silicon-based quinoline drug intermediate has the following structural formula:

[0006]

[0007] Among them, R 1 It is one of 3-pyridyl, phenyl, p-tolyl, p-tert-butylphenyl, p-methoxyphenyl, p-biphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, m-tolyl, m-chlorophenyl, o-tolyl and o-chlorophenyl.

[0008] R 1The chemical formula corresponding to the group is as follows:

[0009]

[0010] Preferably, R 1 It is one of phenyl and p-methoxyphenyl.

[0011] The method for preparing the silicon-based quinoline drug intermediate as described above is characterized in that the synthesis route is as follows:

[0012]

[0013] The specific steps include:

[0014] 1) quinoline olefin compound I is dissolved in a solvent, and added together with (dimethylphenylsilyl) biboric acid pinacol ester into a mixing chamber of a mobile phase reaction device for premixing to obtain a premixed solution;

[0015] 2) Filling the polymer composite copper catalytic material PICB-Cu into a microchannel reactor of a mobile phase reaction device;

[0016] 3) Start the syringe pump, pass the premixed solution into the microchannel reactor at a set flow rate, set the reaction temperature and pressure to start the reaction, collect the solution produced by the mobile phase, and obtain the product silicon-based quinoline drug intermediate II after liquid chromatography separation.

[0017] Among them, the copper content in the polymer composite copper catalytic material PICB-Cu is 0.10-1.10 mmol / g, and its preparation method has been disclosed in the invention application with publication number CN116903773A, entitled "A preparation method of a polymer composite copper catalytic material and its application in the synthesis of chiral geminal diaryl borate".

[0018] The preparation method is as follows:

[0019] 1.1 Styrene is used as monomer M1, (2-(2-(4-vinylbenzyloxy)ethoxy)ethanol ether is used as monomer M2, and 4-vinylbenzyl glycidyl ether is used as monomer M3;

[0020] 1.2 Under argon protection, monomers M1, M2, and M3 with a molar ratio of 1:1:1 are dissolved in anhydrous dichloromethane (DCM), and initiator azobisisobutyronitrile (AIBN) is added, and the reaction is carried out at 35°C in an argon atmosphere for 40 to 80 hours. After the reaction is completed, the product is post-treated to obtain a terpolymer PI; the molar ratio of monomer M1 to initiator AIBN is 1:0.3 to 0.7, and the amount ratio of monomer M1 to anhydrous dichloromethane DCM is monomer M1:DCM=21mmol:12.6 to 16mL.

[0021] 1.3 Dissolve the copolymer PI in diglyme, add carbon black material, stir at room temperature for 30-40 minutes to form a uniform suspension, add diglyme solution containing CuCl dropwise in an ice-water bath, stir for 30-40 minutes, and then add excess NaBH 4 diglyme solution, fully stirred for 12 to 16 hours, and after the reaction, the precursor powder was obtained by post-treatment of the product;

[0022] 1.4 Place the precursor powder in a nitrogen atmosphere, cross-link at 150-170°C for 5-8h, cool to room temperature, grind into powder, wash, vacuum dry, and ball mill to obtain a polymer composite copper catalytic material PI-CB-Cu. ​​The carbon black material is one or more of Ketjen black and acetylene black, the mass ratio of copolymer PI to carbon black material is 1:1-1.2, the amount ratio of copolymer PI to CuCl is PI:CuCl=500mg:0.28-0.40mmol, NaBH 4 The molar ratio to CuCl is 10-12:1.

[0023] Preferably, in step 1), the concentration of quinoline olefin compound I in the premixed solution is 0.10-0.15 mol / L.

[0024] Preferably, in step 1), the concentration of quinoline olefin compound I in the premixed solution is 0.12 mol / L.

[0025] Preferably, in step 1), the concentration of (dimethylphenylsilyl)diboric acid pinacol ester in the premixed solution is 0.10 mol / L.

[0026] Preferably, in step 1), the solvent is methanol.

[0027] Preferably, in step 2), the molar ratio of the quinoline olefin compound I, (dimethylphenylsilyl)boric acid pinacol ester and the copper contained in the polymer composite copper catalyst material PICB-Cu is 1:0.6 to 1:0.03 to 0.07.

[0028] Preferably, in step 3), the flow rate of the premixed solution is 10 to 15 mL / min.

[0029] Preferably, in step 3), the reaction temperature is 10-40° C. and the reaction pressure is 0.1-1.5 apm.

[0030] The beneficial effects of the present invention are: the raw materials used in the present invention are green biomass-based materials, which are green and environmentally friendly, low in cost, mild in reaction conditions, can be completed at room temperature, and are safe in production. The production process is automated and efficient using a mobile phase reactor, and 24-hour production can be achieved, saving labor and production time.

[0031] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the following is a detailed description of the preferred embodiments of the present invention in conjunction with the accompanying drawings. The specific implementation of the present invention is given in detail by the following embodiments and their accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The drawings described herein are used to provide a further understanding of the present invention and constitute a part of this application. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0033] Figure 1 is the H NMR spectrum of the product in Example 1;

[0034] Figure 2 is the NMR carbon spectrum of the product in Example 1;

[0035] Figure 3 is the H NMR spectrum of the product in Example 2;

[0036] Figure 4 is the NMR carbon spectrum of the product in Example 2;

[0037] Figure 5 is the H NMR spectrum of the product in Example 3;

[0038] Figure 6 is the NMR carbon spectrum of the product in Example 3;

[0039] Figure 7 is the H NMR spectrum of the product in Example 4;

[0040] Figure 8 is the NMR carbon spectrum of the product in Example 4;

[0041] Fig. 9 is the H NMR spectrum of the product in Example 5;

[0042] Fig.10 The NMR carbon spectrum of the product in Example 5

[0043] Fig.11 is the H NMR spectrum of the product in Example 6;

[0044] Fig.12 is the NMR carbon spectrum of the product in Example 6;

[0045] Fig.13 is the H NMR spectrum of the product in Example 7;

[0046] Fig.14 is the NMR carbon spectrum of the product in Example 7;

[0047] Fig.15 is the H NMR spectrum of the product in Example 8;

[0048] Fig.16 is the NMR carbon spectrum of the product in Example 8;

[0049] Fig.17 is the H NMR spectrum of the product in Example 9;

[0050] Fig.18 is the NMR carbon spectrum of the product in Example 9;

[0051] Fig.19 is the H NMR spectrum of the product in Example 10;

[0052] Fig. 20 The NMR carbon spectrum of the product in Example 10

[0053] Fig.21 is the H NMR spectrum of the product in Example 11;

[0054] Fig. 22 is the NMR carbon spectrum of the product in Example 11;

[0055] Fig.23 is the H NMR spectrum of the product in Example 12;

[0056] Fig.24 is the NMR carbon spectrum of the product in Example 12;

[0057] Fig.25 is the H NMR spectrum of the product in Example 13;

[0058] Fig.26 is the NMR carbon spectrum of the product in Example 13;

[0059] Fig. 27 is the H NMR spectrum of the product in Example 14;

[0060] Fig.28 This is the NMR carbon spectrum of the product in Example 14. DETAILED DESCRIPTION

[0061] The principles and features of the present invention are described below in conjunction with the accompanying drawings. The examples given are only used to explain the present invention and are not used to limit the scope of the present invention.

[0062] The polymer composite copper catalytic material PICB-Cu used in all embodiments of the present invention is prepared by the following method:

[0063] 1.1 Styrene is used as monomer M1, (2-(2-(4-vinylbenzyloxy)ethoxy)ethanol ether is used as monomer M2, and 4-vinylbenzyl glycidyl ether is used as monomer M3;

[0064] 1.2 Under argon protection, monomers M1, M2, and M3 with a molar ratio of 1:1:1 were dissolved in anhydrous dichloromethane (DCM), and initiator azobisisobutyronitrile (AIBN) was added. The reaction was carried out at 35°C in an argon atmosphere for 72 hours. After the reaction, the product was post-treated to obtain a terpolymer PI; the molar ratio of monomer M1 to initiator AIBN was 1:0.3, and the amount ratio of monomer M1 to anhydrous dichloromethane DCM was monomer M1:DCM=21mmol:12.6mL.

[0065] 1.3 Dissolve the copolymer PI in 15 mL of diglyme, add 500 mg of carbon black material (the carbon black material is one or more of Ketjen black and acetylene black), stir at room temperature for 30 to 40 minutes to form a uniform suspension, add 5 mL of diglyme solution containing CuCl (0.28 mmol) dropwise in an ice-water bath and stir for 30 to 40 minutes, then add 5 mL of diglyme solution containing sodium borohydride (2.8 mmol) and fully react for 12 hours. After the reaction is completed, the product is post-treated (add excess Et 2 O washing, pouring, removing the unreacted monomer, the same washing procedure was repeated three times in total, and then filtered and washed with Et 2 O washing and vacuum drying) to obtain a precursor powder solid.

[0066] 1.4 The precursor powder was placed in a nitrogen atmosphere, cross-linked at 150-170°C for 5-8h, cooled to room temperature, and initially ground into powder. After washing, vacuum drying, and ball milling, the polymer composite copper catalytic material PI-CB-Cu was obtained. The copper content in the catalyst was 0.18mmol / g as determined by ICP.

[0067] Example 1

[0068] This example is a silicon-based quinoline drug intermediate II-1, and the synthesis route is as follows:

[0069]

[0070] The synthesis steps are as follows:

[0071] 1) 2-(Pyridin-3-yl)quinoline (quinoline olefin compound I-1) was dissolved in methanol and added together with (dimethylphenylsilyl)diboric acid pinacol ester to a mixing chamber of a mobile phase reaction device for premixing to obtain a premixed solution; in the premixed solution, the concentration of quinoline olefin compound I was 0.12 mol / L, and the concentration of (dimethylphenylsilyl)diboric acid pinacol ester was 0.10 mol / L.

[0072] 2) Filling the polymer composite copper catalytic material PICB-Cu into a microchannel reactor of a mobile phase reaction device;

[0073] 3) Start the syringe pump and pass the premixed solution into the microchannel reactor at a flow rate of 10 mL / min, set the reaction temperature not exceeding 40° C. and the reaction pressure not exceeding 1.5 apm. After the reaction is completed, collect the solution produced by the mobile phase, and separate it by liquid chromatography to obtain the product silicon-based quinoline drug intermediate II-1.

[0074] The yield of the product was 94% (10 h), and its H NMR and C NMR spectra were as follows: Figures 1-2 As shown, the data looks like this:

[0075] 1 H NMR (400 MHz, CDCl 3 )δ7.82(d,J=8.6Hz,1H),7.66(d,J=8.6Hz,1H),7.51–7.40(m,2H),7.33–7.21(m,3H),7.20–7.10(m,3H),7.0 1–6.87(m,3H),6.85–6.77(m,3H),3.39–3.17(m,2H),2.89(dd,J=10.9,5.6Hz,1H),0.15(s,3H),0.11(s,3H).

[0076] 13 C NMR (100 MHz, CDCl 3 )δ162.1,141.9,137.0,136.0,134.3,129.3,129.1,128.5,128.2,128.0,127.6,127.4,126.7,125.7,124.7,121.1,38.6,36.1,-3.8,-5.0.

[0077] Example 2

[0078] This example is a silicon-based quinoline drug intermediate II-2, the synthesis route is as follows:

[0079]

[0080] The synthesis steps are basically the same as those in Example 1, except that in step 1), quinoline olefin compound Ⅰ-1 is replaced by quinoline olefin compound Ⅰ-2.

[0081] The yield of the product was 98% (10 h), and its H NMR and C NMR spectra were as follows: Figures 3-4 As shown, the data looks like this:

[0082] 1 H NMR (400 MHz, CDCl 3 )δ7.82(d,J=8.6Hz,1H),7.66(d,J=8.6Hz,1H),7.51–7.40(m,2H),7.33–7.21(m,3H),7.20–7.10(m,3H),7.0 1–6.87(m,3H),6.85–6.77(m,3H),3.39–3.17(m,2H),2.89(dd,J=10.9,5.6Hz,1H),0.15(s,3H),0.11(s,3H).

[0083] 13 C NMR (100 MHz, CDCl 3 )δ162.1,141.9,137.0,136.0,134.3,129.3,129.1,128.5,128.2,128.0,127.6,127.4,126.7,125.7,124.7,121.1,38.6,36.1,-3.8,-5.0.

[0084] Example 3

[0085] This example is a silicon-based quinoline drug intermediate II-3, the synthesis route is as follows:

[0086]

[0087] The synthesis steps are basically the same as those in Example 1, except that in step 1), quinoline olefin compound Ⅰ-1 is replaced by quinoline olefin compound Ⅰ-3.

[0088] The yield of the product was 95% (10 h), and its H NMR and C NMR spectra were as follows: Figures 5-6 As shown, the data looks like this:

[0089] 1 H NMR (400 MHz, CDCl 3)δ8.01(s,1H),7.88(s,1H),7.78–7.56(m,2H),7.52–7.42(m,3H),7.40–7.30(m,3H),7.12(d,J=8.5Hz,1 H), 6.91 (q, J = 8.2Hz, 4H), 3.47 (s, 2H), 3.03 (dd, J = 11.2, 5.5Hz, 1H), 2.23 (s, 3H), 0.31 (d, J = 18.2Hz, 6H).

[0090] 13 C NMR (100 MHz, CDCl 3 )δ162.3,147.5,138.5,137.2,136.0,134.3,133.9,129.2,129.1,128.7,12 8.5,128.0,127.7,127.4,126.7,125.6,121.1,38.6,35.4,21.0,-3.7,-5.1.

[0091] Example 4

[0092] This example is a silicon-based quinoline drug intermediate II-4, the synthesis route is as follows:

[0093]

[0094] The synthesis steps are basically the same as those in Example 1, except that in step 1), quinoline olefin compound Ⅰ-1 is replaced by quinoline olefin compound Ⅰ-4.

[0095] The yield of the product was 96% (10 h), and its H NMR and C NMR spectra were as follows: Figures 7-8 As shown, the data looks like this:

[0096] 1 H NMR (400 MHz, CDCl 3 )δ8.01(s,1H),7.87(s,1H),7.76–7.59(m,2H),7.53–7.39(m,3H),7.37–7.23(m,3H),7.19–7.09(m,3H),6. 93(d,J=8.4Hz,2H),3.67–3.32(m,2H),3.03(dd,J=11.0,5.4Hz,1H),1.25(s,9H),0.33(s,3H),0.26(s,3H).

[0097] 13 C NMR (100 MHz, CDCl 3)δ162.3,147.4,138.5,137.3,136.0,134.3,129.3,127.0,128.5,127.6,12 7.6,127.4,126.7,125.7,124.8,121.2,38.6,35.2,34.2,31.4,-3.7,-5.1.

[0098] Example 5

[0099] This example is a silylquinoline drug intermediate II-5, the synthesis route is as follows:

[0100]

[0101] The synthesis steps are basically the same as those in Example 1, except that in step 1), quinoline olefin compound Ⅰ-1 is replaced by quinoline olefin compound Ⅰ-5.

[0102] The yield of the product was 98% (10 h), and its H NMR and C NMR spectra were as follows: Figures 9-10 As shown, the data looks like this:

[0103] 1 H NMR (400 MHz, CDCl 3 )δ7.98(d,J=8.6Hz,1H),7.83(d,J=8.6Hz,1H),7.69–7.51(m,2H),7.49–7.38(m,3H),7.38–7.28(m,3H),7.07(d,J=8.6Hz,1H),6 .89(d,J=8.7Hz,2H),6.66(d,J=8.7Hz,2H),3.70(s,3H),3.41(d,J=8.3Hz,2H),2.98(t,J=8.4Hz,1H),0.31(s,3H),0.28(s,3H).

[0104] 13 C NMR (100 MHz, CDCl 3 )δ162.4,156.9,137.3,135.8,134.4,133.8,129.2,129.1,128.8,127.73 ,127.70,127.5,126.7,125.6,121.2,113.5,55.2,39.0,35.0,-3.7,-4.9.

[0105] Example 6

[0106] This example is a silylquinoline drug intermediate II-6, the synthesis route is as follows:

[0107]

[0108] The synthesis steps are basically the same as those in Example 1, except that in step 1), quinoline olefin compound Ⅰ-1 is replaced by quinoline olefin compound Ⅰ-6.

[0109] The yield of the obtained product was 97% (calculated after 10 h of injection). Its H-NMR and C-NMR spectra were as follows: Figures 11-12 As shown, the data looks like this:

[0110] 1 H NMR (400 MHz, CDCl 3 )δ7.98(d,J=8.4Hz,1H),7.85(d,J=8.4Hz,1H),7.70–7.57(m,2H),7.55–7.49(m,2H),7.48–7.44(m,2H),7.44–7.28(m,9H ),7.11(d,J=8.4Hz,1H),7.04(d,J=8.3Hz,2H),3.56–3.39(m,2H),3.10(dd,J=11.2,5.4Hz,1H),0.35(s,3H),0.30(s,3H).

[0111] 13 C NMR (100 MHz, CDCl 3 )δ162.2,141.3,141.0,137.3,137.1,136.0,134.4,129.3,128.8,128.6,127. 8,127.5,126.9,126.80,126.79,126.6,125.7,121.2,38.7,35.9,-3.7,-4.9.

[0112] Example 7

[0113] This example is a silylquinoline drug intermediate II-7, the synthesis route is as follows:

[0114]

[0115] The synthesis steps are basically the same as those in Example 1, except that in step 1), quinoline olefin compound Ⅰ-1 is replaced by quinoline olefin compound Ⅰ-7.

[0116] The yield of the product was 94% (10 h), and its H NMR and C NMR spectra were as follows: Figures 13-14 As shown, the data looks like this:

[0117] 1 H NMR (400 MHz, CDCl 3)δ7.99(s,1H),7.87(d,J=8.6Hz,1H),7.74–7.59(m,2H),7.50–7.38(m,3H),7.39–7.29(m,3H),7.06(d,J=8.6Hz,1H),6. 89(dd,J=8.6,5.5Hz,2H),6.77(t,J=8.6Hz,2H),3.70–3.27(m,2H),3.04(dd,J=10.8,5.9Hz,1H),0.30(d,J=8.3Hz,6H).

[0118] 13 C NMR (100 MHz, CDCl 3 )δ161.8,161.7,159.2,137.3,136.7,136.2,134.3,133.1,129.5,129.3,129.3,129.2, 128.4,127.9,127.7,127.5,126.6,125.8,121.1,114.8,114.6,38.6,35.4,-4.0,-5.0.

[0119] Example 8

[0120] This example is a silylquinoline drug intermediate II-8, the synthesis route is as follows:

[0121]

[0122] The synthesis steps are basically the same as those in Example 1, except that in step 1), quinoline olefin compound Ⅰ-1 is replaced by quinoline olefin compound Ⅰ-8.

[0123] The yield of the product was 92% (10 h), and its H NMR and C NMR spectra were as follows: Figures 15-16 As shown, the data looks like this:

[0124] 1 H NMR (400 MHz, CDCl 3 )δ7.80(s,1H),7.71(d,J=8.6Hz,1H),7.56–7.41(m,2H),7.33–7.24(m,3H),7.23–7.13(m,3H),6 .96–6.83(m,3H),6.72(d,J=8.6Hz,2H),3.26(s,2H),2.90(dd,J=10.2,6.4Hz,1H),0.15(s,6H).

[0125] 13 C NMR (100 MHz, CDCl 3)δ161.6,140.4,136.5,136.1,134.3,133.1,130.1,129.4,129.3,128.5,12 8.0,127.9,127.8,127.5,126.7,125.8,121.0,77.4,38.4,35.7,-4.1,-5.0.

[0126] Example 9

[0127] This example is a silylquinoline drug intermediate II-9, the synthesis route is as follows:

[0128]

[0129] The synthesis steps are basically the same as those in Example 1, except that in step 1), quinoline olefin compound Ⅰ-1 is replaced by quinoline olefin compound Ⅰ-9.

[0130] The yield of the product was 90% (10 h), and its H NMR and C NMR spectra were as follows: Figures 17-18 As shown, the data looks like this:

[0131] 1 H NMR (400 MHz, CDCl 3 )δ7.97(d,J=8.5Hz,1H),7.86(dd,J=8.6,0.6Hz,1H),7.71–7.57(m,2H),7.46–7.40(m,3H),7.38–7.30(m,3H),7.20(d,J=8.5H z,2H),7.05(d,J=8.5Hz,1H),6.83(d,J=8.5Hz,2H),3.50–3.27(m,2H),3.05(dd,J=10.4,6.4Hz,1H),0.31(s,3H),0.29(s,3H).

[0132] 13 C NMR (100 MHz, CDCl 3 )δ161.7,141.2,136.6,136.1,134.4,131.0,129.9,129.43,129.39,12 8.8,127.9,127.6,126.8,125.8,121.1,118.3,38.6,35.8,-3.9,-4.9.

[0133] Example 10

[0134] This example is a silylquinoline drug intermediate II-10, the synthesis route is as follows:

[0135]

[0136] The synthesis steps are basically the same as those in Example 1, except that in step 1), quinoline olefin compound Ⅰ-1 is replaced by quinoline olefin compound Ⅰ-10.

[0137] The yield of the product was 94% (10 h), and its H NMR and C NMR spectra were as follows: Figures 19-20 As shown, the data looks like this:

[0138] 1 H NMR (400 MHz, CDCl 3 )δ7.81(s,1H),7.71(d,J=8.6Hz,1H),7.54–7.40(m,2H),7.30–7.21(m,3H),7.22–7.11(m,5H) ,6.89(dd,J=8.6,3.5Hz,3H),3.40–3.15(m,2H),3.03(t,J=8.1Hz,1H),0.14(d,J=8.1Hz,6H).

[0139] 13 C NMR (100 MHz, CDCl 3 )δ161.3,147.4,146.5,136.2,134.2,133.1,129.5,129.4,128.5,128.2,127.9,127.8,127.6,127.5,127.3,127.0 ,126.7,126.7,126.3,125.9,125.8,124.88,124.85,124.81,124.77,123.1,121.0,120.4,38.2,36.5,-4.1,-5.0.

[0140] Embodiment 11

[0141] This example is a silylquinoline drug intermediate II-11, the synthesis route is as follows:

[0142]

[0143] The synthesis steps are basically the same as those in Example 1, except that in step 1), quinoline olefin compound Ⅰ-1 is replaced by quinoline olefin compound Ⅰ-11.

[0144] The yield of the product was 93% (10 h), and its H NMR and C NMR spectra were as follows: Figures 21-22 As shown, the data looks like this:

[0145] 1 H NMR (400 MHz, CDCl 3)δ8.02(s,1H),7.86(d,J=8.6Hz,1H),7.73–7.58(m,2H),7.49–7.38(m,3H),7.38–7.27(m,3H),7.10(d,J=8.5Hz,1H),7.00 (t,J=7.6Hz,1H),6.88–6.70(m,3H),3.57–3.34(m,2H),3.00(dd,J=11.0,5.6Hz,1H),2.18(s,3H),0.29(d,J=15.6Hz,6H).

[0146] 13 C NMR (100 MHz, CDCl 3 )δ162.2,141.6,137.3,137.1,136.2,134.4,129.4,129.12,129.06,128.4,127. 8,127.6,127.4,126.7,125.7,125.5,125.2,121.1,38.4,35.9,21.5,-3.8,-5.1.

[0147] Example 12

[0148] This example is a silylquinoline drug intermediate II-12, the synthesis route is as follows:

[0149]

[0150] The synthesis steps are basically the same as those in Example 1, except that in step 1), quinoline olefin compound Ⅰ-1 is replaced by quinoline olefin compound Ⅰ-12.

[0151] The yield of the product was 90% (10 h), and its H NMR and C NMR spectra were as follows: Figures 23-24 As shown, the data looks like this:

[0152] 1 H NMR (400 MHz, CDCl 3 )δ7.99(s,1H),7.89(d,J=8.6Hz,1H),7.72–7.60(m,2H),7.49–7.39(m,3H),7.39–7.28(m,3H),7.07(d,J=8.6Hz,1H),7.01(t, J=7.7Hz,1H),6.97–6.91(m,2H),6.87–6.83(m,1H),3.43(d,J=8.7Hz,2H),3.07(dd,J=9.6,6.8Hz,1H),0.31(d,J=8.6Hz,6H).

[0153] 13 C NMR (100 MHz, CDCl 3 )δ161.5,144.2,136.4,134.3,133.7,129.5,129.4,129.1,128.5,128.1, 127.7,127.5,126.7,126.3,125.8,124.8,121.1,38.3,36.1,-4.1,-5.1.

[0154] Example 13

[0155] This example is a silylquinoline drug intermediate II-13, the synthesis route is as follows:

[0156]

[0157] The synthesis steps are basically the same as those in Example 1, except that in step 1), quinoline olefin compound Ⅰ-1 is replaced by quinoline olefin compound Ⅰ-13.

[0158] The yield of the product was 92% (10 h), and its H NMR and C NMR spectra were as follows: Figures 25-26 As shown, the data looks like this:

[0159] 1 H NMR (400 MHz, CDCl 3 )δ8.02–7.95(m,1H),7.81(d,J=8.5Hz,1H),7.69–7.57(m,2H),7.46–7.38(m,3H),7.38–7.27(m,3H),7.10(d,J=7.7Hz,1H),7.07–7.01( m,1H),6.97(d,J=8.5Hz,1H),6.93–6.86(m,2H),3.57–3.39(m,2H),3.35(dd,J=10.3,5.6Hz,1H),2.05(s,3H),0.37(s,3H),0.28(s,3H).

[0160] 13 C NMR (100 MHz, CDCl 3 )δ162.2,147.6,140.7,137.4,135.8,134.3,130.1,129.20,129.15,128.7,127. 7,127.4,126.9,126.7,125.7,125.6,124.4,121.2,39.7,30.5,20.6,-3.7,-4.9.

[0161] Embodiment 14

[0162] This example is a silylquinoline drug intermediate II-14, the synthesis route is as follows:

[0163]

[0164] The synthesis steps are basically the same as those in Example 1, except that in step 1), quinoline olefin compound Ⅰ-1 is replaced by quinoline olefin compound Ⅰ-14.

[0165] The yield of the product was 92% (10 h), and its H NMR and C NMR spectra were as follows: Figures 27-28 As shown, the data looks like this:

[0166] 1 H NMR (400 MHz, CDCl 3 )δ8.04–7.93(m,1H),7.88(d,J=8.6Hz,1H),7.70–7.58(m,2H),7.49(dd,J=7. 7,1.7Hz,2H),7.44–7.39(m,1H),7.37–7.28(m,3H),7.21(dd,J=7.8,1.4Hz,1 H),7.15(d,J=8.6Hz,1H),7.11(d,J=7.8Hz,1H),7.08–7.00(m,1H),6.95–6.8 8(m,1H),3.90–3.57(m,1H),3.47(d,J=6.7Hz,2H),0.37(s,3H),0.30(s,3H).

[0167] 13 C NMR (100 MHz, CDCl 3 )δ161.5,147.4,140.0,136.7,136.2,134.3,133.7,129.3,128.6,128.3,127. 8,127.4,126.7,126.6,125.71,125.69,120.4,119.0,38.7,30.6,-3.7,-5.5.

[0168] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any ordinary technician in the industry can smoothly implement the present invention as shown in the drawings and described above. However, any equivalent changes, modifications and evolutions made by technicians familiar with the profession without departing from the scope of the technical solution of the present invention using the technical content disclosed above are all equivalent embodiments of the present invention. At the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the technical solution of the present invention.

Claims

1. A silicon-based quinoline drug intermediate, characterized in that: The structural formula of the silicon-based quinoline drug intermediate is as follows: Among them, R1 is one of 3-pyridyl, phenyl, p-tolyl, p-tert-butylphenyl, p-methoxyphenyl, p-biphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, m-tolyl, m-chlorophenyl, o-tolyl, and o-chlorophenyl.

2. A silicon-based quinoline drug intermediate according to claim 1, characterized in that: R1 is either phenyl or p-methoxyphenyl.

3. A method for preparing the silicon-based quinoline drug intermediate according to any one of claims 1-2, characterized in that: The synthesis route is as follows: The specific steps include: 1) quinoline olefin compound I is dissolved in a solvent, and added together with (dimethylphenylsilyl) biboric acid pinacol ester into a mixing chamber of a mobile phase reaction device for premixing to obtain a premixed solution; 2) Filling the polymer composite copper catalytic material PICB-Cu into a microchannel reactor of a mobile phase reaction device; 3) Start the syringe pump, pass the premixed solution into the microchannel reactor at a set flow rate, set the reaction temperature and pressure to start the reaction, collect the solution produced by the mobile phase, and obtain the product silicon-based quinoline drug intermediate II after liquid chromatography separation.

4. The method for preparing a silicon-based quinoline drug intermediate according to claim 3, characterized in that: In the step 1), the concentration of the quinoline olefin compound I in the premixed solution is 0.10-0.15 mol / L.

5. The method for preparing a silicon-based quinoline drug intermediate according to claim 4, characterized in that: In the step 1), the concentration of the quinoline olefin compound I in the premixed solution is 0.12 mol / L.

6. The method for preparing a silicon-based quinoline drug intermediate according to claim 3, characterized in that: In the step 1), the concentration of (dimethylphenylsilyl)diboric acid pinacol ester in the premixed solution is 0.10 mol / L.

7. The method for preparing a silicon-based quinoline drug intermediate according to claim 3, characterized in that: In the step 1), the solvent is methanol.

8. The method for preparing a silicon-based quinoline drug intermediate according to claim 3, characterized in that: In the step 2), the molar ratio of the quinoline olefin compound I, (dimethylphenylsilyl) boric acid pinacol ester and the copper contained in the polymer composite copper catalyst material PICB-Cu is 1:0.6 to 1:0.03 to 0.

07.

9. The method for preparing a silicon-based quinoline drug intermediate according to claim 3, characterized in that: In step 3), the flow rate of the premixed solution is 10-15 mL / min.

10. The method for preparing a silicon-based quinoline drug intermediate according to claim 3, characterized in that: In the step 3), the reaction temperature is 10-40° C. and the reaction pressure is 0.1-1.5 apm.

Images