A quinazolinone catalyst with both NN and CC axis chirality and its synthesis method and application

Abstract

A quinazolinone catalyst with both N-N and C-C axis chirality and its synthesis method and application, its chemical structural formula is shown in Formula 4; Synthesis method: using indole-derived o-aminobenzamide and 1-naphthaldehyde derivative as raw materials, using molecular sieve as dehydrating agent, bromobenzene as reaction solvent, stirring for 4h under the catalysis of chiral phosphoric acid and 10°C, then adding ethyl acetate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, stirring for 10h under room temperature, TLC tracking reaction to complete formula 3 compound; using formula 3 compound, phenylsilane, trifluoromethanesulfonic acid as raw materials, adding toluene, stirring reaction under 100°C, TLC tracking reaction to end to obtain formula 4 compound. The catalyst prepared by the present invention can be used as a chiral ligand in transition metal-catalyzed asymmetric allylation reaction, with excellent stereoselectivity control effect; the method has mild reaction conditions, low cost and high enantioselectivity.

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and specifically relates to a quinazolinone catalyst having both NN and CC axial chirality and a synthesis method and application thereof. Background Art

[0002] Axial chiral catalysts are a class of chiral catalysts with a wide range of applications. They can not only participate in asymmetric reactions as organic catalysts, but also play an important role as ligands in transition metal-catalyzed asymmetric reactions. However, current axial chiral catalysts focus on catalysts derived from CC axial chiral skeletons, and research on multiple axial chiral catalysts, especially catalysts with both CC and NN axial chirality, is very limited. There are currently no literature reports on quinazolinone catalysts with both NN and CC axial chirality, and quinazolinone catalysts with both NN and CC axial chirality have more chiral regulation sites than CC axial chiral catalysts. Therefore, quinazolinone catalysts with both NN and CC axial chirality are expected to have better enantioselectivity control capabilities than existing CC axial chiral catalysts. Summary of the invention

[0003] One of the purposes of the present invention is to provide a quinazolinone catalyst having both NN and CC axis chirality, which has an excellent stereoselective control effect as a chiral ligand.

[0004] The second object of the present invention is to provide a method for synthesizing a quinazolinone catalyst having both NN and CC axial chirality, which has mild reaction conditions, low cost and high enantioselectivity.

[0005] The third object of the present invention is to provide an application of a quinazolinone catalyst having both NN and CC axial chirality, which can be used as a ligand in a transition metal-catalyzed asymmetric allylation reaction.

[0006] To achieve the above object, the technical solution adopted by the present invention is: a quinazolinone catalyst having both NN and CC axis chirality, whose chemical structure is shown in Formula 4:

[0007]

[0008] The present invention also provides a method for synthesizing the above-mentioned quinazolinone catalyst having both NN and CC axial chirality, comprising the following steps:

[0009] (1) Using the indole-derived o-aminobenzamide of Formula 1 and the 1-naphthaldehyde derivative of Formula 2 as reaction raw materials, Molecular sieves are used as a dehydrating agent and bromobenzene is used as a reaction solvent. The reaction is stirred at -10°C for 4 hours under the catalysis of chiral phosphoric acid, and then ethyl acetate and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) are added. The reaction is stirred at room temperature for 10 hours. The reaction is followed by TLC until it is complete. The compound of formula 3 having both NN and CC chiral quinazolinone derivatives is obtained by filtration, concentration and purification.

[0010] The molar ratio of the indole-derived o-aminobenzamide of the compound of formula 1, the 1-naphthaldehyde derivative of the compound of formula 2, the chiral phosphoric acid catalyst, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is 1:2:0.3:10; the indole-derived o-aminobenzamide of the compound of formula 1, bromobenzene, ethyl acetate, The usage ratio of molecular sieves is 1mmol:10mL:30mL:1g;

[0011] The structural formula of the indole-derived anthranilamide of the compound of formula 1 is

[0012] The structural formula of the 1-naphthaldehyde derivative of the compound of formula 2 is

[0013] The compound of formula 3 is a quinazolinone derivative having both NN and CC axis chirality.

[0014] (2) using phenylsilane, trifluoromethanesulfonic acid and the compound of formula 3 prepared in step (1) as raw materials, adding toluene, stirring and reacting at 100° C. for 1 hour, and tracking the reaction by TLC until the end to obtain the compound of formula 4, which is a quinazolinone catalyst having both NN and CC axial chirality;

[0015] The molar ratio of the compound of formula 3 having both NN and CC axial chiral quinazolinone derivative, phenylsilane, and trifluoromethanesulfonic acid is 1:5:0.4; the dosage ratio of the compound of formula 3 having both NN and CC axial chiral quinazolinone derivative and toluene is 1 mmol:10 mL;

[0016] The structural formula of the compound of formula 4 is

[0017] Preferably, the chiral phosphoric acid catalyst is a compound of formula 5, and the structural formula of the compound of formula 5 is

[0018] Preferably, in step (1), the purification method is silica gel column chromatography, and the eluent is a mixture of petroleum ether / ethyl acetate in a volume ratio of 3:1.

[0019] Preferably, in step (2), after the reaction is completed, the reaction is quenched with a saturated sodium bicarbonate solution, extracted with ethyl acetate, concentrated, and purified to obtain a compound of formula 4 having both NN and CC axial chiral quinazolinone catalysts.

[0020] Preferably, in step (2), the purification method is silica gel column chromatography, and the eluent is a mixture of petroleum ether / ethyl acetate in a volume ratio of 5:1.

[0021] The present invention also provides the use of the above-mentioned quinazolinone catalyst having both NN and CC axial chirality in a transition metal-catalyzed asymmetric allylation reaction, wherein the reaction formula of the asymmetric allylation reaction is:

[0022]

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] (1) The quinazolinone catalyst synthesized by the present invention has both NN and CC axis chirality and can be used as a chiral ligand in transition metal-catalyzed asymmetric allylation reactions;

[0025] (2) The present invention uses chiral phosphoric acid as a catalyst in the process of synthesizing a quinazolinone catalyst having both NN and CC axes chirality, thereby obtaining extremely high enantioselectivity; the reaction conditions are relatively conventional, and the reaction process is mild, simple, easy to operate, and low in cost, and is suitable for industrial large-scale production. DETAILED DESCRIPTION

[0026] The present invention is further described in detail below in conjunction with embodiments.

[0027] In the following examples, unless otherwise specified, indole-derived o-aminobenzamide, 1-naphthaldehyde derivatives, chiral phosphoric acid catalysts and other reagents can be purchased from the market or obtained according to known literature reports; the experimental methods are usually carried out under conventional conditions or conditions recommended by the manufacturer.

[0028] Example

[0029] (1) The synthetic route of the compound of formula 3 having both NN and CC axis chiral quinazolinone derivatives is as follows:

[0030]

[0031] 0.1 mmol of the indole-derived o-aminobenzamide of the compound of formula 1 and 0.2 mmol of the 1-naphthaldehyde derivative of the compound of formula 2 were added as reactants in 1 mL of bromobenzene solvent. Under the action of 0.03 mmol (30 mol% of the indole-derived o-aminobenzamide) of chiral phosphoric acid of formula 5, 100 mg of In the presence of molecular sieves, the reaction was stirred at -10°C for 4 hours; then 1.0 mmol of DDQ and 3 mL of ethyl acetate were added, the reaction was stirred at room temperature for 10 hours, and the reaction was followed by TLC until completion. After filtration and concentration, the reaction was purified and separated by silica gel column chromatography (the eluent was a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 3:1), thereby obtaining a compound of formula 3 having both NN and CC axis chiral quinazolinone derivatives, and the yield, stereoselectivity and structural characterization data were as follows: 82% yield (59.1 mg) as a white solid; >95:5 dr; mp 115.9-116.8°C; [α] D 20 = +47.9 (c = 0.73, acetone); 1 H NMR(400MHz, CDCl3)δ8.43(d,J=7.6Hz,1H),8.27(d,J=8.4Hz,1H),7.91–7.76(m,3H) ,7.73(d,J=8.8Hz,1H),7.64–7.53(m,1H),7.50–7.44(m,1H),7.36–7.28(m,2H),7.1 9(s,1H),7.12–7.03(m,3H),7.01–6.85(m,10H),6.84–6.76(m,2H),6.69–6.61(m,1H ),6.54–6.47(m,2H),4.61–4.51(m,1H),1.30(d,J=6.0Hz,3H),1.25(d,J=6.0Hz,3H); 13 C NMR (100MHz, CDCl3) δ161.7,154.8,154.0,147.0,142.0,134.6,134.1,133.0, 132.8,132.6,132.5,132.2,132.1,131.9,131.8,131.6,131.4,131.0,130.2,1 29.0,128.1,127.9,127.8,127.6,127.5,127.4,127.3,127.2,126.8,126.7,126.6,125.1,124.5,122.2,122.1,120.2,119.1,115.7,113.2,74.3,22.7,22.6; 31 PNMR(162MHz, CDCl3)δ24.91; IR(KBr):3420,2815,1593,1384,1351,1119,765,617cm -1 ;ESI FTMS exactmass calcd for(C 47 H36 N3O3P+H) + requires m / z 722.2567, found m / z 722.2549; Theenantiomeric excess: 85%, determined by HPLC (Daicel Chiralpak IA, hexane / isopropanol=85 / 15, flow rate 1.0mL / min, T=30℃, 254nm): t R =6.883(major),t R =10.630(minor).

[0032] (2) The synthesis route of the compound of formula 4 having both NN and CC chiral quinazolinone catalysts is as follows:

[0033]

[0034] 0.1mmol of the compound of formula 3 (recrystallized to >95:5dr, 99%ee) having both NN and CC axis chiral quinazolinone derivatives was dissolved in 1mL of toluene, 0.5mmol of phenylsilane and 0.04mmol of trifluoromethanesulfonic acid were added, and then the reaction was carried out at 100°C for 1h. After the reaction was completed, the reaction was quenched with a saturated sodium bicarbonate solution, extracted with ethyl acetate, concentrated, and purified and separated by silica gel column chromatography (the eluent was a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 5:1), thereby obtaining the compound of formula 4 having both NN and CC axis chiral quinazolinone catalyst. The yield, stereoselectivity and structural characterization data are as follows: 61% yield (43.0mg) as a white solid.91:9dr; mp116.8-117.6°C; [α] D 20 = +95.2 (c = 0.29, acetone); 1H NMR(400MHz,CDCl3)δ8.41(d,J=8.0Hz,1H),8.01–7.87(m,3H),7.68(d,J=9.2Hz,1H),7.65–7.59(m,1H),7.53(d,J=8.0Hz,1H),7.42–7.35(m,1H),7.29–7.26(m,2H),7.26–7.22(m,1H),7.14(d,J=7.6Hz,1H),7.11–7.04(m,2H),6.99–6.84(m,9H),6.80–6.70(m,4H),6.61–6.52(m,2H),6.35–6.27(m,2H),4.60–4.50(m,1H),1.27(d,J=6.0Hz,3H),1.06(d,J=6.2Hz,3H); 13 C NMR(100MHz,CDCl3)δ160.5,154.6,154.6,147.0,140.8,135.4,135.3,135.1,134.2,133.6,133.4,132.8,132.5,132.3,132.0,131.5,131.3,130.5,129.5,129.4,128.9,128.2,127.6,127.5,127.5,127.4,127.2,127.2,127.1,126.9,126.8,126.1,124.9,124.8,124.2,124.0,121.8,119.9,117.7,114.9,112.9,73.3,22.6,21.8; 31 PNMR(162MHz,CDCl3)δ-29.72;IR(KBr):3521,2924,2760,1704,1568,1472,1279,1200,745,528;ESI FTMS exact mass calcd for(C 47 H 38 N3O2P+H) + requires m / z 706.2618,found m / z 706.2607;The enantiomeric excess:97%,determined by HPLC(DaicelChiralpak IA,hexane / isopropanol=97 / 3,flow rate 0.5mL / min,T=30℃,254nm):t R =13.422(minor),t R =16.868(major).

[0035] Example 2

[0036] The synthetic route of the quinazolinone catalyst with both NN and CC axial chirality in the transition metal-catalyzed asymmetric allylation reaction is as follows:

[0037]

[0038] 0.1mmol of allyl acetate of compound 6, 0.005mmol (5mol% of compound 6) of [Pd(C3H5)Cl]2, and 0.02mmol (20mol% of compound 6) of compound 4 having both NN and CC axial chirality of quinazolinone catalyst were dissolved in 1mL of dichloromethane, and 0.04mmol of potassium acetate was added, and stirred at room temperature for 30 minutes; then the temperature was lowered to 0°C, and 0.3mmol of N,O-bistrimethylsilylacetamide (BAS) and 0.3mmol of dimethyl malonate of compound 7 were added in sequence, and the reaction was continued at 0°C. The reaction was followed by TLC until completion, and after filtration and concentration, the mixture was purified and separated by silica gel column chromatography (the eluent was a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 4:1), to obtain quinazolinone compound 8 having both NN and CC axial chirality of quinazolinone, and the yield, stereoselectivity and structural characterization data were as follows:

[0039] 85%yield(27.5mg)as a colorless oil.[α] D 20 = -13.3 (c = 0.51, acetone); 1 HNMR(400MHz, CDCl3)δ7.34–7.27(m,7H),7.26–7.17(m,3H),6.48(d,J=15.6Hz,1H),6 .38–6.27(m,1H),4.35–4.22(m,1H),3.95(d,J=10.8Hz,1H),3.71(s,3H),3.52(s,3H); 13 C NMR (100MHz, CDCl3) δ168.3,167.8,140.2,136.9,131.9,129.1,128.8,128.5,127.9,127.6,1 27.2,126.4,57.7,52.7,52.5,49.2;IR(KBr):3451,2106,1651,1578,1385,1260,748,696;ESI FTMS exact mass calcd for(C 20 H 20 O4+Na) +requires m / z 347.1254, found m / z347.1254; The enantiomeric excess: 52%, determined by HPLC (Daicel Chiralpak ID, hexane / isopropanol=70 / 30, flowrate 1mL / min, T=30℃, 254nm): t R =8.792(major),t R =18.468(minor).

[0040] It can be seen from Example 2 that the compound of formula 4 has both NN and CC axial chiral quinazolinone catalysts and has an excellent stereoselective control effect in the transition metal-catalyzed asymmetric allylation reaction.

Claims

1. A quinazolinone catalyst having both NN and CC axis chirality, characterized in that: Its chemical structure is shown in Formula 4: 。 2. A method for synthesizing the quinazolinone catalyst having both NN and CC axial chirality according to claim 1, characterized in that: The following steps are involved: (1) using the indole-derived o-aminobenzamide of the compound of formula 1 and the 1-naphthaldehyde derivative of the compound of formula 2 as the reaction raw materials, using 4Å molecular sieve as the dehydrating agent and bromobenzene as the reaction solvent, stirring and reacting for 4 hours at -10°C under the catalysis of chiral phosphoric acid, then adding ethyl acetate and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, stirring and reacting for 10 hours at room temperature, tracking the reaction by TLC until completion, filtering, concentrating and purifying to obtain the compound of formula 3 having both NN and CC axis chiral quinazolinone derivatives; The molar ratio of the indole-derived o-aminobenzamide of the compound of formula 1, the 1-naphthaldehyde derivative of the compound of formula 2, the chiral phosphoric acid catalyst, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is 1:2:0.3:10; the amount ratio of the indole-derived o-aminobenzamide of the compound of formula 1 to bromobenzene, ethyl acetate, and 4Å molecular sieve is 1 mmol:10 mL:30 mL:1 g; The structural formula of the indole-derived anthranilamide of the compound of formula 1 is ; The structural formula of the 1-naphthaldehyde derivative of the compound of formula 2 is ; The compound of formula 3 is a quinazolinone derivative having both NN and CC axis chirality. ; The chiral phosphoric acid catalyst is a compound of formula 5, and the structural formula of the compound of formula 5 is ; (2) using phenylsilane, trifluoromethanesulfonic acid and the compound of formula 3 prepared in step (1) which is a quinazolinone derivative having both NN and CC axial chirality as raw materials, adding toluene, stirring and reacting at 100° C. for 1 hour, and tracking the reaction by TLC until completion to obtain the compound of formula 4 which is a quinazolinone catalyst having both NN and CC axial chirality; The molar ratio of the compound of formula 3 having both NN and CC axial chiral quinazolinone derivatives, phenylsilane, and trifluoromethanesulfonic acid is 1:5:0.4; the dosage ratio of the compound of formula 3 having both NN and CC axial chiral quinazolinone derivatives and toluene is 1 mmol:10 mL; The structural formula of the compound of formula 4 is .

3. The method for synthesizing a quinazolinone catalyst having both NN and CC axial chirality according to claim 2, characterized in that: In step (1), the purification method is silica gel column chromatography, and the eluent is a mixture of petroleum ether / ethyl acetate in a volume ratio of 3:

1.

4. The method for synthesizing a quinazolinone catalyst having both NN and CC axial chirality according to claim 2, characterized in that: In step (2), after the reaction is completed, the reaction is quenched with a saturated sodium bicarbonate solution, extracted with ethyl acetate, concentrated, and purified to obtain a compound of formula 4 having both NN and CC axial chiral quinazolinone catalysts.

5. The method for synthesizing a quinazolinone catalyst having both NN and CC axial chirality according to claim 2, characterized in that: In step (2), the purification method is silica gel column chromatography, and the eluent is a mixture of petroleum ether / ethyl acetate in a volume ratio of 5:

1.

6. Use of a quinazolinone catalyst having both NN and CC axial chirality as claimed in claim 1 in a transition metal-catalyzed asymmetric allylation reaction, wherein the reaction formula of the asymmetric allylation reaction is: 。

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