A heterogeneous catalytic axial chiral click synthesis method of alkynes and azides

Abstract

The present invention relates to a method for synthesizing axial chiral Click of alkyne and azide by heterogeneous catalysis. The alkyne and the azide undergo axial chiral Click reaction under the catalytic action of an asymmetric catalyst loaded with metal rhodium in a polymer. The structural formula of the asymmetric catalyst loaded with metal rhodium in a polymer is: wherein n1 is an integer of 10-100, n2 is an integer of 1-10, and n3 is 1. The method utilizes the asymmetric catalyst loaded with metal rhodium in a polymer to cause the alkyne and the azide to undergo axial chiral Click reaction. The asymmetric catalyst loaded with metal rhodium in a polymer not only has excellent reaction activity and enantioselectivity, but also has the advantages of catalyst recyclability, no metal leaching, simple separation, and the like.

Description

Technical Field

[0001] The invention relates to the field of Click reactions, and in particular to an axial chiral Click synthesis method of heterogeneous catalysis of alkynes and azides. Background Art

[0002] The main purpose of click reaction is to quickly and reliably complete the chemical synthesis of various molecules by splicing small units, especially emphasizing the development of new combinatorial chemistry methods based on carbon-heteroatom bond (CXC) synthesis, and using these reactions to obtain molecular diversity simply and efficiently. In many fields such as drug development and biomedical materials, it has become one of the most useful and attractive synthetic concepts.

[0003] However, there are still some problems in the Click reaction, such as the expensive catalysts used in the reaction process, the difficulty in recycling, the metal residues, the difficulty in separation and the resulting decrease in yield, etc., which limit the application of Click-related reactions. Therefore, it is particularly important to find an axial chiral Click reaction method. Summary of the invention

[0004] In view of the prior art, the present invention has developed a heterogeneously catalyzed axial chiral Click synthesis method of alkynes and azides. The method utilizes a polymer-loaded metal rhodium asymmetric catalyst to cause an axial chiral Click reaction between alkynes and azides. The polymer-loaded metal rhodium asymmetric catalyst not only has excellent reaction activity and enantioselectivity, but also has the advantages of catalyst recycling, no metal leaching, and simple separation.

[0005] Based on this, the present invention provides a method for synthesizing axial chiral Click of alkynes and azides by heterogeneous catalysis, wherein the alkynes and the azides undergo axial chiral Click reaction under the catalytic action of an asymmetric catalyst supported by a polymer metal rhodium, and the structural formula of the asymmetric catalyst supported by a polymer metal rhodium is: Wherein, n1 is an integer from 10 to 100, n2 is an integer from 1 to 10, and n3 is 1.

[0006] More specifically, the preparation method of the polymer-supported rhodium asymmetric catalyst is as follows:

[0007] Step 1, (S)-binaphthol and pivaloyl chloride undergo a monoesterification reaction under the action of an alkaline catalyst to obtain an intermediate (S)-1; Step 2, the intermediate (S)-1 undergoes a bromine substitution reaction with liquid bromine at the 6' position of another naphthol ring of the (S)-binaphthol, and then a NaHSO3 aqueous solution is added to quench, and after the quenching is completed, the organic phase is extracted and concentrated, and the concentrate is subjected to an ester hydrolysis reaction to obtain an intermediate (S)-2; Step 3, the intermediate (S)-2 undergoes a 4-vinylphenyl coupling reaction with (4-vinylphenyl)boric acid at the 6' bromine substituent position reaction to obtain intermediate (S)-3; step 4, intermediate (S)-3, iminostilbene, and phosphorus trichloride undergo a phosphoramidation reaction under the action of an alkaline catalyst to obtain monomer 1; step 5, monomer 1 and (1,5-cyclooctadiene)chlororhodium (I) dimer undergo a complexation reaction, and the reaction liquid after the reaction is filtered to obtain a monomer 2 solution; step 6, the monomer 2 solution undergoes a copolymerization reaction with styrene and divinylbenzene under the action of a copolymerization catalyst and an initiator, and after the reaction is completed, the reaction product is filtered, washed, and dried to obtain the polymer-loaded metal rhodium asymmetric catalyst.

[0008] The process control of the monoesterification reaction is as follows: (S)-binaphthol and an alkaline catalyst are dissolved in a solvent, pivaloyl chloride is added dropwise at -5 to 5°C, and the temperature is raised to 20 to 30°C for reaction for 4 to 6 hours after the addition is completed; wherein the molar ratio of (S)-binaphthol to pivaloyl chloride is 1:(1.0 to 1.01).

[0009] The process control of the bromine substitution reaction is as follows: dissolving the intermediate (S)-1 in a solvent, adding liquid bromine at -5 to 5°C, and keeping the reaction warm for 3 to 4 hours after the addition; wherein the molar ratio of the intermediate (S)-1 to the liquid bromine is 1:(1.8 to 2.2).

[0010] The process control of the ester hydrolysis reaction is as follows: adding a solvent and a strong alkaline solution to the concentrate and mixing them evenly, reacting at 20-30° C. for 2-3 hours, and then acidifying with a strong acid to a pH of 1-2.

[0011] The strong alkali solution is at least one of potassium hydroxide, sodium hydroxide, sodium acetate, potassium acetate, sodium carbonate, sodium bicarbonate, and lithium hydroxide solution; the concentration of the strong alkali solution is 5-6 mol / L.

[0012] The strong acid solution is at least one of hydrochloric acid, sulfuric acid and nitric acid; the concentration of the strong acid solution is 3 mol / L.

[0013] The process control of the coupling reaction is: the intermediate (S)-2, (4-vinylphenyl)boric acid, Pd(PPh3)4, K2CO3 and the solvent are mixed evenly, and heated to reflux for reaction for 10 to 14 hours under nitrogen protection; wherein the molar ratio of the intermediate (S)-2, (4-vinylphenyl)boric acid, K2CO3, and Pd(PPh3)4 is 1:(1.2 to 1.3):(2.5 to 3.5):0.03.

[0014] The process control of the phosphoramidation reaction is as follows: dissolving the alkaline catalyst and PCl3 in a solvent, adding iminostilbene dropwise at -5 to 5°C, reacting at 20 to 30°C for 3 to 4 hours, then adding the intermediate (S)-3 at -5 to 5°C, reacting at 20 to 30°C for 18 to 20 hours; wherein the molar ratio of the intermediate (S)-3, iminostilbene, PCl3, and the alkaline catalyst is 1:1:(1 to 1.05):(5 to 7).

[0015] The process control of the complex reaction is as follows: the solvent, monomer 1 and (1,5-cyclooctadiene)chlororhodium (I) dimer are uniformly mixed under nitrogen protection, and reacted at 20-30° C. for 2-3 hours to obtain a monomer 2 solution; wherein the molar ratio of monomer 1 to (1,5-cyclooctadiene)chlororhodium (I) dimer is 1:(0.5-0.52).

[0016] The process control of the copolymerization reaction is as follows: after uniformly mixing the monomer 2 solution, divinylbenzene, azobisisobutyronitrile, styrene and solvent, the temperature is raised to 55-65° C., and the mixture is reacted for 36 hours under stirring at 500-700 rpm; wherein the molar ratio of monomer 2, divinylbenzene and styrene is 1:(1-10):(10-100), and the molar amount of azobisisobutyronitrile is 1-5% of the molar amount of monomer 2.

[0017] The alkaline catalyst is at least one of Et3N, N,N-diisopropylethylamine, pyridine and piperidine.

[0018] The solvent is at least one of acetonitrile, toluene, dichloromethane, tetrahydrofuran, acetone, ethyl acetate, methanol, ethanol and petroleum ether.

[0019] Furthermore, the axial chiral Click synthesis method comprises the following steps: under the protection of an inert gas, the polymer-loaded metal rhodium asymmetric catalyst is uniformly mixed in a solvent, the alkyne and the azide are added at room temperature, and the reaction is completed for 10 to 24 hours; after the reaction is completed, the product is filtered and concentrated to obtain the product.

[0020] Furthermore, the reaction equation of the axial chiral Click reaction is:

[0021]

[0022] Among them, R 1 is any one of aryl, heteroaryl, and heteroatom alkyl; R 2 is an aryl group or an alkyl group.

[0023] Furthermore, the alkyne is any one of 1a to 1j, and the molecular structures of 1a to 1j are as follows:

[0024]

[0025] Furthermore, the azide is any one of 2a to 2e, and the molecular structures of 2a to 2e are as follows:

[0026]

[0027] Furthermore, the molar amount of the polymer-supported asymmetric catalyst of metal rhodium is 0.001 to 0.2 times the molar amount of the alkyne.

[0028] Furthermore, the molar amount of the azide is 0.5 to 3.0 times the molar amount of the alkyne.

[0029] Furthermore, the solvent is at least one of toluene, dichloromethane, ethyl ether, tetrahydrofuran, p-xylene, acetonitrile, and methyl tert-ether.

[0030] Preferably, the solvent is acetonitrile.

[0031] Furthermore, the axial chiral Click synthesis method can also adopt a continuous flow method, and the specific steps include:

[0032] S1, filling the asymmetric catalyst of the polymer-supported metal rhodium into a solid support bed, connecting the solid support bed to a continuous flow device, and purging the pipeline of the continuous flow device with nitrogen;

[0033] S2. Add the alkyne and the azide solvent, and inject the mixed solution into a continuous flow device at a constant flow rate using a syringe pump to react. After the reaction is completed, collect the effluent, concentrate under reduced pressure, and then use column chromatography to obtain the product.

[0034] In summary, the present invention has the following beneficial effects:

[0035] The present invention utilizes a polymer-loaded metal rhodium asymmetric catalyst to cause an axial chiral Click reaction between alkynes and azide. The polymer-loaded metal rhodium asymmetric catalyst not only has excellent reaction activity and enantioselectivity, but also has the advantages of catalyst recycling, no metal leaching, and simple separation. DETAILED DESCRIPTION

[0036] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0037] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials and reagents used in the following examples are all commercially available unless otherwise specified. The quantitative tests in the following examples were performed in triplicate, and the data are the average or average ± standard deviation of the triplicate experiments.

[0038] In addition, the "and / or" in the full text includes three solutions. Taking A and / or B as an example, it includes technical solution A, technical solution B, and a technical solution that satisfies both A and B. In addition, the technical solutions between the various embodiments can be combined with each other, but it must be based on the fact that ordinary technicians in the field can implement it. When the combination of technical solutions is contradictory or cannot be implemented, it should be deemed that such a combination of technical solutions does not exist and is not within the protection scope required by the present invention.

[0039] The invention provides a method for synthesizing axial chiral Click of alkynes and azides by heterogeneous catalysis. The alkynes and the azides undergo axial chiral Click reaction under the catalytic action of an asymmetric catalyst loaded with metal rhodium in a polymer.

[0040] Among them, the structural formula of the asymmetric catalyst of polymer-supported metal rhodium is: n1 is an integer from 10 to 100, n2 is an integer from 1 to 10, and n3 is 1.

[0041] Meanwhile, the alkyne used in the embodiments of the present invention is any one of 1a to 1j, and the molecular structural formulas of 1a to 1j are as follows:

[0042]

[0043] Furthermore, the azide used in the embodiments of the present invention is any one of 2a to 2e, and the molecular structures of 2a to 2e are as follows:

[0044]

[0045] Example 1

[0046] In this embodiment, the alkyne is 1a, the azide is 2a,

[0047] Asymmetric catalyst of polymer-supported metal rhodium, n1=50, n2=5, n3=1.

[0048] The specific reaction steps are as follows:

[0049] Asymmetric catalyst (40 mg, 2 mol%) of macromolecular supported metal rhodium was added to a dry schlenk tube equipped with a stirring rod, and Ar was replaced three times with a vacuum pump. Under Ar protection, acetonitrile (2.0 mL) was added, and alkyne 1a (0.2 mmol) and azide 2a (0.4 mmol) were added, stirred at room temperature for 24 h, filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography, recorded as C1, with a yield of 98% and an ee value of 91%.

[0050] The analytical test of product C1 is as follows:

[0051] Yellow oil, 83.7 mg, 98% yield, 91% ee [Daicel Chiralpak ID (0.46cm x25cm), n-hexane / 2-propanol=80 / 20, v=1.0mL·min -1 ,λ=254nm, t(minor)=13.127min, t(major)=14.470min]. (c=0.5,CHCl3).

[0052] 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.03(d,J=9.0Hz,1H),7.85(d,J=8.1Hz,1H), 7.83–7.76(m,1H),7.70(d,J=8.5Hz,1H),7.64–7.57(m,1H),7.52–7.46(m,2H),7.46 –7.41(m,2H),7.39(d,J=9.0Hz,1H),7.30(d,J=1.7Hz,1H),7.25–7.17(m,4H),7.16 –7.09(m,2H),6.87(d,J=8.3Hz,1H),5.47(d,J=15.3Hz,1H),5.39(d,J=15.2Hz,1H). 13C NMR(101MHz,DMSO-d6)δ155.10,144.83,133.27,133.21,132.94,132.72,131.82,129.68,129.07,128.86,128.41,128 .30,128.10,128.03,127.92,127.84,127.26,126.73,126.64,126.11,125.77,123.68,122.98,118.69,106.22,52.02.

[0053] HRMS(ESI)calcd for C 29 H 22 N3O[M+H] + :428.1757.Found:428.1757.

[0054] The difference between Example 2 and Example 1 is that the alkyne is 1b and the product is denoted as C2.

[0055] The analytical test of product C2 is as follows:

[0056] Yellow soild, 245-247℃, 85.7mg, 93% yield, 95%ee [Daicel Chiralpak ID (0.46cm x 25cm), n-hexane / 2-propanol=80 / 20, v=1.0mL·min -1 ,λ=254nm, t(minor)=9.497min, t(major)=10.437min]. (c=0.5,CHCl3).

[0057] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.06(d,J=8.9Hz,1H),7.87(d,J=8.0Hz,1H),7.79(d,J=5.5Hz,1H),7.70(d,J=8.5Hz,1H),7.61(s,1H),7. 54(s,1H),7.42(dt,J=15.3,5.1Hz,4H),7.32(s,1H),7.22(dd,J=13.1, 6.2Hz,3H),7.18–7.09(m,2H),6.88(d,J=8.3Hz,1H),5.57–5.34(m,2H). 13C NMR(101MHz,DMSO-d6)δ155.17,143.46,133.84,133.11,133.06,132.98,132.94,132.75,131.08,130.38,128.95,128.45,128 .29,128.12,128.04,127.93,127.88,127.30,126.76,126.68,126.09,125.37,124.16,123.80,122.81,118.67,105.62,52.12.

[0058] HRMS(ESI)calcd for C 29 H 21 ClN3O[M+H] + :462.1368.Found:462.1371.

[0059] The difference between Example 3 and Example 1 is that the alkyne is 1c and the product is recorded as C3.

[0060] The analytical test of product C3 is as follows:

[0061] Yellow oil, 87.2 mg, 98% yield, 92% ee [Daicel Chiralpak ID (0.46cm x25cm), n-hexane / 2-propanol=80 / 20, v=1.0mL·min -1 ,λ=254nm, t(minor)=9.313min, t(major)=10.173min]. (c=0.5,CHCl3).

[0062] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.06(d,J=8.8Hz,1H),7.87(d,J=8.0 Hz,1H),7.82–7.75(m,1H),7.70(d,J=8.5Hz,1H),7.64–7.59(m,1H),7.43(d d,J=12.9,7.0Hz,3H),7.31(d,J=6.3Hz,2H),7.28–7.18(m,3H),7.14(t,J= 7.5Hz,2H),7.03(t,J=8.3Hz,1H),6.88(d,J=8.2Hz,1H),5.53–5.38(m,2H). 13C NMR(101MHz,DMSO-d6)δ163.91,161.49,155.16,143.64,134.11(d,J=8.7Hz),1 33.13,133.06,132.95,132.74,131.24(d,J=8.3Hz),130.32,128.94,128.44,1 28.30,128.11,128.01,127.92,127.30,126.75,126.67,126.09,123.79,122.8 3,121.73,118.70,114.81(d,J=21.1Hz),112.16(d,J=22.9Hz),105.71,52.11.

[0063] HRMS(ESI)calcd for C 29 H 21 FN3O[M+H] + :446.1663.Found:446.1663.

[0064] The difference between Example 4 and Example 1 is that the alkyne is 1d and the product is recorded as C4.

[0065] The analytical test of product C4 is as follows:

[0066] Yellow oil, 90.2 mg, 93% yield, 91% ee [Daicel Chiralpak ID (0.46cm x25cm), n-hexane / 2-propanol=80 / 20, v=1.0mL·min -1 ,λ=254nm, t(minor)=26.973, t(major)=23.163min]. (c=0.5,CHCl3).

[0067] 1H NMR (400MHz, DMSO-d6) δ10.51(s,1H),8.06(d,J=8.9Hz,1H),7.87(dd,J=8.2,1.3Hz,1H),7.80( dd,J=8.7,1.7Hz,3H),7.70(d,J=8.5Hz,1H),7.65–7.57(m,3H),7.50–7.41(m,2H),7.38(d,J=9 .0Hz,1H),7.30(d,J=1.7Hz,1H),7.21(ddd,J=8.0,6.8,1.2Hz,1H),7.13(dtd,J=8.3,3.2,1.3H z,2H),6.86(dd,J=8.3,1.2Hz,1H),5.49(d,J=15.3Hz,1H),5.42(d,J=15.3Hz,1H),3.78(s,3H). 13 C NMR(101MHz,DMSO-d6)δ166.31,155.10,143.83,136.30,133.05,132.96,132.73,130.91,130.06,128.93,128.45 ,128.32,128.11,127.92,127.26,126.76,126.68,126.06,125.73,123.77,122.79,118.70,105.65,52.56,52.12.

[0068] HRMS(ESI)calcd for C 31 H 24 N3O3[M+H] + :486.1812.Found:486.1816.

[0069] The difference between Example 5 and Example 1 is that the alkyne is 1e and the product is recorded as C5.

[0070] The analytical test of product C5 is as follows:

[0071] Yellow oil, 79.6 mg, 88% yield, 90% ee [Daicel Chiralpak ID (0.46cm x25cm), n-hexane / 2-propanol=80 / 20, v=1.0mL·min -1 ,λ=254nm, t(minor)=17.217, t(major)=15.763min]. (c=0.5,CHCl3).

[0072] 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.06(d,J=9.0Hz,1H),7.88(dd,J=8.2,1.3Hz, 1H),7.84–7.76(m,1H),7.74–7.67(m,3H),7.66–7.57(m,3H),7.48–7.41(m,2H),7.38 (d,J=9.0Hz,1H),7.30(d,J=1.7Hz,1H),7.22(ddd,J=8.1,6.8,1.2Hz,1H),7.18–7.0 9(m,2H),6.85(dd,J=8.5,1.1Hz,1H),5.48(d,J=15.3Hz,1H),5.42(d,J=15.3Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ155.12,143.25,136.22,133.25,133.12,132.95,132.92,132.74,131.27,129.01,128.46, 128.32,128.12,127.92,127.32,126.77,126.70,126.07,123.86,122.68,119.19,118.71,110.44,105.35,52.17.

[0073] HRMS(ESI)calcd for C 30 H 21 N4O[M+H] + :453.1710.Found:453.1706.

[0074] The difference between Example 6 and Example 1 is that the alkyne is 1f and the product is recorded as C6.

[0075] The analytical test of product C6 is as follows:

[0076] Yellow soild, 276-278℃, 89.5mg, 89% yield, 99%ee [Daicel Chiralpak IC (0.46cm x 25cm), n-hexane / 2-propanol=80 / 20, v=1.0mL·min -1 ,λ=254nm, t(minor)=14.553, t(major)=27.823min]. (c=0.5,CHCl3).

[0077] 1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),8.06(d,J=8.9Hz,1H),7.91–7.84(m,1 H),7.84–7.77(m,1H),7.71(d,J=8.5Hz,1H),7.65–7.51(m,7H),7.50–7.44(m ,2H),7.41(t,J=7.7Hz,3H),7.36–7.28(m,2H),7.21(ddd,J=8.1,6.8,1.3Hz ,1H),7.18–7.12(m,2H),6.90(dd,J=8.4,1.2Hz,1H),5.44(q,J=15.2Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ155.13,144.48,139.90,139.58,133.30,133.18,132.94,132.74,130.89,129.76,129.38,128.90,128 .42,128.33,128.11,127.97,127.93,127.30,126.93,126.75,126.66,126.22,126.13,123.73,122.99,118.72,106.18,52.04.

[0078] HRMS(ESI)calcd for C 35 H 26 N3O[M+H] + :504.2070.Found:504.2075.

[0079] The difference between Example 7 and Example 1 is that the amount of alkyne is 1 g and the product is recorded as C7.

[0080] The analytical test of product C7 is as follows:

[0081] Yellow soild, 254-259℃, 94.2mg, 88% yield, 91%ee [Daicel Chiralpak IA (0.46cm x 25cm), n-hexane / 2-propanol=80 / 20, v=1.0mL·min -1 ,λ=254nm, t(minor)=17.443, t(major)=14.607min]. (c=0.5,CHCl3).

[0082] 1H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.04(d,J=8.9Hz,1H),7.88(d,J=7.6Hz,1H),7.83–7.7 7(m,1H),7.70(d,J=8.5Hz,1H),7.65–7.57(m,1H),7.43(p,J=4.7,4.1Hz,3H),7.32(s,1H),7 .21(dt,J=13.7,6.8Hz,2H),7.18–7.12(m,1H),6.99(d,J=7.9Hz,1H),5.51(d,J=15.3Hz,1H) ,5.36(d,J=15.3Hz,1H),4.33(d,J=2.4Hz,1H),4.11–4.07(m,1H),4.04(s,2H),3.88(s,5H). 13 C NMR (101MHz, DMSO-d6) δ154.87,144.49,133.76,133.51,132.97,132.69,132.48,128.82,128.38,128.22(d,J=3.6Hz),128.07,127 .91,127.47,127.05,126.73,126.58,126.02,123.67,118.55,106.52,76.71,69.54,68.43(d,J=4.1Hz),66.34(d,J=5.2Hz),51.88.

[0083] HRMS(ESI)calcd for C 33 H 26 FeN3O[M+H] + :536.1420.Found:536.1423.

[0084] The difference between Example 8 and Example 1 is that the alkyne is 1h and the product is recorded as C8.

[0085] The analytical test of product C8 is as follows:

[0086] Yellow soild, 176-179℃, 76.1mg, 90% yield, 94%ee [Daicel Chiralpak ID (0.46cm x 25cm), n-hexane / 2-propanol=95 / 5, v=1.0mL·min -1 ,λ=254nm, t(minor)=24.863, t(major)=26.973min]. (c=0.5,CHCl3).

[0087] 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),7.97(d,J=8.9Hz,1H),7.89–7.76(m,2H),7.71(d,J=8.5Hz,1H),7.65–7.59(m,1H),7.47–7.41(m,2H),7.3 6–7.29(m,2H),7.25–7.16(m,2H),7.14(dd,J=8.5,1.8Hz,1H),6.91–6. 71(m,1H),5.43(d,J=15.2Hz,1H),5.33(d,J=15.2Hz,1H),-0.06(s,9H). 13 C NMR(101MHz,DMSO-d6)δ154.70,145.01,139.12,134.23,133.56,132.95,132.70,132.10,128.57,128.36,128 .08,127.98,127.93,127.30,127.26,126.73,126.61,126.26,123.64,123.47,118.34,107.16,51.34,-0.94.

[0088] HRMS(ESI)calcd for C 26 H 26 SiN3O[M+H] + :424.1840.Found:424.1841.

[0089] The difference between Example 9 and Example 1 is that the azide is 2b and the product is recorded as C9.

[0090] The analysis and test of product C9 are as follows:

[0091] Yellow soild, 220-223℃, 77.7mg, 91% yield, 90%ee [Daicel Chiralpak IC (0.46cm x 25cm), n-hexane / 2-propanol=80 / 20, v=1.0mL·min -1 ,λ=254nm, t(minor)=9.603, t(major)=14.537min]. (c=0.5,CHCl3).

[0092] 1H NMR (400MHz, DMSO-d6) δ10.43 (s, 1H), 8.00 (dd, J=8.8, 3.0Hz, 2H), 7.84 (dd, J=8.1,3.2Hz,2H),7.69(d,J=8.2Hz,1H),7.58–7.41(m,4H),7.41–7.33(m,1H ),7.27–7.16(m,4H),7.09(td,J=7.8,1.9Hz,2H),6.78(d,J=7.2Hz,1H),6.72 (dd,J=9.4,4.1Hz,1H),5.86(d,J=15.2Hz,1H),5.69(dd,J=15.3,2.4Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ155.06,144.82,133.58,133.06,132.61,131.76,131.08,130.71,129.84,129.03,128.97, 128.82,128.29,128.01,127.82,127.70,126.85,126.27,125.75,125.29,123.69,122.85,118.63,106.39,50.37.

[0093] HRMS(ESI)calcd for C 29 H 22 N3O[M+H] + :428.1757.Found:428.1760.

[0094] The difference between Example 10 and Example 1 is that the alkyne is 1i, the azide is 2b, and the product is recorded as C10.

[0095] The analysis and test of product C10 are as follows:

[0096] Yellow soild, 254-258℃, 83.1mg, 86% yield, 95%ee [Daicel Chiralpak ID (0.46cm x 25cm), n-hexane / 2-propanol=90 / 10, v=1.0mL·min -1 ,λ=254nm, t(minor)=34.607, t(major)=28.143min]. (c=0.5,CHCl3).

[0097] 1H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.04(d,J=8.9Hz,1H),7.86(d,J=8.1Hz,1H),7.84–7.76(m,1H),7.70(d,J=8.5Hz,1H),7.67–7.56(m,1H),7.4 2(dd,J=19.3,8.6Hz,5H),7.30(s,1H),7.21(dd,J=15.2,7.9Hz,3H),7.17 –7.08(m,2H),6.87(d,J=8.4Hz,1H),5.41(q,J=15.2Hz,2H),1.18(s,9H). 13 C NMR (101MHz, DMSO-d6) δ155.12,150.48,144.76,133.45,133.21,132.94,132.63,129.31,129.02,128.86,128.35(d,J=9.6Hz),12 8.11,127.88(d,J=8.1Hz),127.32,126.72,126.63,126.16,125.86,125.45,123.68,123.05,118.71,106.39,51.97,34.72,31.44.

[0098] HRMS(ESI)calcd for C 33 H 30 N3O[M+H] + :484.2383.Found:484.2385.

[0099] The difference between Example 11 and Example 1 is that the alkyne is 1j, the azide is 2b, and the product is recorded as C11.

[0100] The analysis and test of product C11 are as follows:

[0101] Yellow soild, 256-259℃, 77.9mg, 90% yield, 99%ee [Daicel Chiralpak IC (0.46cm x 25cm), n-hexane / 2-propanol=80 / 20, v=1.0mL·min -1 ,λ=254nm, t(minor)=9.987, t(major)=13.443min]. (c=0.5,CHCl3).

[0102] 1H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.03(d,J=9.0Hz,1H),7.86(dd,J=8.1,1.4Hz,1H), 7.83–7.77(m,1H),7.71(d,J=8.5Hz,1H),7.65–7.58(m,1H),7.50–7.40(m,3H),7.38(d,J= 9.0Hz,1H),7.32(d,J=1.7Hz,1H),7.27–7.20(m,2H),7.16(td,J=8.4,1.6Hz,2H),7.03(dd ,J=5.1,1.2Hz,1H),6.89(d,J=8.3Hz,1H),5.50(d,J=15.3Hz,1H),5.41(d,J=15.3Hz,1H). 13 CNMR(101MHz,DMSO-d6)δ155.10,142.12,133.31,132.95,132.71,132.68,129.10,128.88,128.41,128.27,128.09 ,127.92,127.85,127.14,127.12,126.75,126.63,126.03,125.79,123.71,123.09,121.09,118.68,105.90,52.02.

[0103] HRMS(ESI)calcd for C 27 H 20 SN3O[M+H] + :434.1322.Found:434.1322.

[0104] The difference between Example 12 and Example 1 is that the azide is 2c and the product is recorded as C12.

[0105] The analysis and test of product C12 are as follows:

[0106] Yellow soild, 203-207℃, 86.8mg, 95% yield, 90%ee [Daicel Chiralpak IC (0.46cm x 25cm), n-hexane / 2-propanol=80 / 20, v=1.0mL·min -1 ,λ=254nm, t(minor)=12.920, t(major)=21.997min]. (c=0.5,CHCl3).

[0107] 1H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.11–8.05(m,1H),8.02(d,J=8.9Hz,1H), 7.99–7.91(m,1H),7.85(d,J=8.1Hz,1H),7.52–7.36(m,5H),7.27–7.09(m,4H),7 .02(ddd,J=8.3,6.9,1.3Hz,1H),6.63(d,J=8.0Hz,1H),6.58(d,J=8.4Hz,1H),6. 42(d,J=8.0Hz,1H),5.80(d,J=15.1Hz,1H),5.53(d,J=15.0Hz,1H),3.81(s,3H). 13 C NMR(101MHz,DMSO-d6)δ155.41,155.00,144.79,133.16,132.55,132.05,131.81,129.62,129.01,128.72,128.32,127.95 ,127.57,127.22,125.72,125.52,125.35,123.73,123.56,122.81,122.43,122.32,118.63,106.62,103.55,55.95,50.50.

[0108] HRMS(ESI)calcd for C 30 H 24 N3O2[M+H] + :458.1863.Found:458.1860.

[0109] The difference between Example 13 and Example 1 is that the azide is 2d and the product is recorded as C13.

[0110] The analysis and test of product C13 are as follows:

[0111] Yellow soild, 216-218℃, 37.6mg, 51% yield, 91%ee [Daicel Chiralpak IC (0.46cm x 25cm), n-hexane / 2-propanol=80 / 20, v=1.0mL·min -1 ,λ=254nm, t(minor)=6.573, t(major)=7.357min]. (c=0.5,CHCl3).

[0112] 1H NMR(400MHz, DMSO-d6)δ10.39(s,1H),8.04(d,J=8.9Hz,1H),7.96–7.84(m,1H),7.45 –7.37(m,3H),7.38–7.30(m,2H),7.24–7.11(m,3H),7.01–6.94(m,1H),3.71(tt,J=1 1.7,3.9Hz,1H),2.14–2.02(m,1H),1.94(qt,J=12.0,2.2Hz,2H),1.82–1.60(m,3H), 1.54(d,J=11.3Hz,1H),1.30–1.08(m,2H),0.97(dddd,J=16.4,12.9,8.3,3.4Hz,1H). 13 CNMR(101MHz,DMSO-d6)δ155.14,144.09,133.66,132.57,132.00,129.06,129.00,128.60,128.35, 128.21,127.84,125.78,123.89,122.89,118.81,106.56,57.96,33.37,33.17,25.33,25.23,25.15.

[0113] HRMS(ESI)calcd for C 24 H 24 N3O[M+H] + :370.1914.Found:370.1914.

[0114] The difference between Example 14 and Example 1 is that the azide is 2e and the product is recorded as C14.

[0115] The analytical test of product C14 is as follows:

[0116] Yellow soild,272-276℃,126.3mg,87% yield,90%ee,>20:1d.r.[DaicelChiralpak IC(0.46cm x 25cm),n-hexane / 2-propanol=80 / 20,v=1.0mL·min -1 ,λ=254nm, t(minor)=12.737, t(major)=20.227min]. (c=0.5,CHCl3).

[0117] 1H NMR (400MHz, DMSO-d6) δ10.45(s,2H),7.88(d,J=9.0Hz,2H),7.83(dd,J=6.5,3.3Hz,2H),7.76–7.64(m,2H),7.49–7.35(m,4H),7.35(s,4H),7.18( qd,J=6.6,2.2Hz,8H),7.02(ddd,J=8.3,6.8,1.3Hz,2H),6.62(dd,J=8.5 ,1.1Hz,2H),6.44(s,2H),5.73(d,J=15.4Hz,2H),5.44(d,J=15.4Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ155.00,144.69,132.93,132.59,131.68,131.16,130.97,129.79,129.04,128 .76,128.23,128.02,127.67,126.57,125.72,124.19,123.52,122.75,118.55,106.26,79.71,50.13.

[0118] HRMS(ESI)calcd for C 48 H 35 N6O2[M+H] + :727.2816.Found:727.2819.

[0119] Specifically, the structural formulas of products C1 to C14 are shown below:

[0120]

[0121] Embodiment 15

[0122] Experimental study on the recovery and application of asymmetric catalysts supported by polymers with metal rhodium

[0123] The filter cake after filtration in Example 1 was collected, washed with ethanol, acetone and petroleum ether in sequence, and dried under vacuum at 40° C. for 1 h to recover the asymmetric catalyst loaded with metal rhodium in a polymer.

[0124] The recovered polymer-loaded rhodium asymmetric catalyst is reused, and the synthesis steps of Example 1 are repeated, the product mixture is filtered, and the above operation is repeated to obtain the product and recover the polymer-loaded rhodium asymmetric catalyst.

[0125] The cycle was repeated ten times, and the yield and ee value of each cycle are shown in Table 1.

[0126] Table 1 Yield and ee value of four cycles

[0127]

[0128] It can be seen from Table 1 that the asymmetric catalyst of polymer-supported metal rhodium can stably maintain the reaction activity and enantioselectivity.

[0129] Example 16

[0130] This embodiment provides another method for synthesizing product C1, that is, using a continuous flow device, the specific process is as follows:

[0131] First, fill 300 mg of asymmetric catalyst (n1=50, n2=5, n3=1) of polymer-loaded metal rhodium into the solid support bed, connect the solid support bed to the continuous flow device, and purge the continuous flow device pipeline with nitrogen, and then use anhydrous acetonitrile (or ether, tetrahydrofuran, ethylene glycol dimethyl ether, dichloromethane, etc.) to discharge the gas in the continuous flow device pipeline.

[0132] Prepare 81 mL of acetonitrile / DMSO (10 / 1) mixed solution (0.3 mol / L) of alkyne 1a (24.3 mmol) and azide 2a (48.6 mmol), and inject the mixed solution into the continuous flow system at a flow rate of 0.010 mL / min using a syringe pump. After all the solutions have been injected, use anhydrous acetonitrile at the same flow rate to clean the pipeline. Collect the effluent, and concentrate the filtrate under reduced pressure. Column chromatography on silica gel is performed to obtain 10.09 g of product C1, with a yield of 97% and an ee value of 91%.

[0133] In summary, the present invention utilizes a polymer-loaded metal rhodium asymmetric catalyst to cause an axial chiral Click reaction between alkynes and azides. The polymer-loaded metal rhodium asymmetric catalyst not only has excellent reaction activity and enantioselectivity, but also has the advantages of catalyst recycling, no metal leaching, and simple separation.

[0134] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0135] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A heterogeneous catalytic axial chiral Click synthesis method of alkynes and azides, characterized in that: The alkyne and the azide undergo an axial chiral Click reaction under the catalytic action of a polymer-supported metal rhodium asymmetric catalyst, and the structural formula of the polymer-supported metal rhodium asymmetric catalyst is: Wherein, n1 is an integer of 10-100, n2 is an integer of 1-10, and n3 is 1; the reaction equation of the axial chiral Click reaction is: The alkyne is any one of 1a to 1j, and the molecular structural formulas of 1a to 1j are as follows: The azide is any one of 2a to 2e, and the molecular structures of 2a to 2e are as follows:

2. The method for the heterogeneous catalytic axial chiral Click synthesis of alkynes and azides according to claim 1, characterized in that: The following steps are involved: Under the protection of inert gas, the polymer-loaded metal rhodium asymmetric catalyst is uniformly mixed in a solvent, and the alkyne and the azide are added at room temperature, and the reaction is completed for 10 to 24 hours; after the reaction is completed, the product is filtered and concentrated to obtain the product.

3. The method for the heterogeneous catalytic axial chiral Click synthesis of alkynes and azides according to claim 2, characterized in that: The molar amount of the polymer-supported metal rhodium asymmetric catalyst is 0.001 to 0.2 times the molar amount of the alkyne.

4. The method for the heterogeneous catalytic axial chiral Click synthesis of alkynes and azides according to claim 2, characterized in that: The molar amount of the azide is 0.5 to 3.0 times the molar amount of the alkyne.

5. The method for the heterogeneous catalytic axial chiral Click synthesis of alkynes and azides according to claim 2, characterized in that: The solvent is at least one of toluene, dichloromethane, ether, tetrahydrofuran, p-xylene, acetonitrile and tert-methyl ether.

6. The method for the heterogeneous catalytic axial chiral Click synthesis of alkynes and azides according to claim 1, characterized in that: The axial chiral Click synthesis method adopts a continuous flow method, and the specific steps include: S1, filling the asymmetric catalyst of the polymer-supported metal rhodium into a solid support bed, connecting the solid support bed to a continuous flow device, and purging the pipeline of the continuous flow device with nitrogen; S2. Add the alkyne and the azide solvent, and inject the mixed solution into a continuous flow device at a constant flow rate using a syringe pump to react. After the reaction is completed, collect the effluent, concentrate under reduced pressure, and then use column chromatography to obtain the product.

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