Catalytic synthesis method of chiral pyrazolo hydrogenated pyran compound

Abstract

The invention discloses a catalytic synthesis method of a chiral pyrazolo hydrogenated pyran compound, and belongs to the field of organic synthesis. The method comprises the following steps: taking pyrazolone and cyclodienone as reactants, adding a chiral primary amine catalyst and an acid additive, and reacting in a substituted benzene solvent at 25-40 DEG C for 12-48 hours to obtain the chiral pyrazolo hydrogenated pyran compound shown in the formula (I). According to the method, pyrazolone and cyclohexanedione are taken as reactants, the chiral pyrazolo hydrogenated pyran compound with the quaternary carbon spiro unit is synthesized under the catalysis of chiral primary amine, and the method is simple to operate and high in yield and has excellent yield and enantioselectivity; in the method provided by the invention, no non-ring-closed intermediate is generated, and a cyclization product can be obtained in one step. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a method for synthesizing a pyrazolohydrogenated pyran compound, in particular to a method for catalytically synthesizing a chiral pyrazolohydrogenated pyran compound, and belongs to the field of organic synthesis. Background Art

[0002] The pyrazolohydropyran structure is an important heterocyclic structural unit, which is widely present in biologically active molecules and natural products. Many active molecules containing this structure show a variety of biological activities such as antifungal, antituberculosis, and antibacterial. Therefore, the synthesis method of pyrazolohydropyran has attracted the interest of many scientific researchers.

[0003] With the development of organic asymmetric catalytic methods, the study of organocatalytic asymmetric Michael addition reactions using pyrazolone as a nucleophile has become a continuously developing field. Since pyrazolone provides an activated methylene group, continuous functionalization reactions are possible, and complex heterocyclic skeleton molecules can be constructed. Pyrazolohydrogenated pyran structures are one of the most important skeleton structures. However, in existing reports, examples of constructing pyrazolohydrogenated pyran compounds with quaternary carbon spiro skeletons are still scarce.

[0004] In 2015, Biju's research group reported the asymmetric [3+3] cyclization reaction of pyrazolone and cinnamaldehyde (Yetra, SR; Mondal, S.; Suresh, E.; Biju, A.E. Antioselective synthesis of functionalized pyrazoles by NHC-catalyzed reaction of pyrazolones with α, β-unsaturated aldehydes. Org. Lett. 2015, 17, 1417-1420). This method uses pyrazolone and cinnamaldehyde to construct pyrazole and hydrogenated pyran compounds in one step through chiral NHC asymmetric catalytic cyclization reaction. The reaction has the characteristics of moderate to excellent yield (40%-82%), excellent enantioselectivity (74%-96%), wide substrate range, mild conditions, etc. However, due to the limitation of substrates, this methodology can only generate pyrazole-hydrogenated pyran compounds containing a single chiral center, and the substituent on the nitrogen atom of pyrazolone can only be tert-butyl, and cannot be expanded to other more complex substituent groups.

[0005]

[0006] In 2016, Zhou's group reported a chiral amide-catalyzed cyclization reaction of pyrazolone and nitro-substituted MBH acetate to obtain a pyrazole-hydrogenated pyran compound with two consecutive chiral centers (Zheng, Y.; Cui, L.; Wang, Y.; Zhou, Z. Stereocontrolled construction of tetrahydropyrano[2,3-c]pyrazolescaffold via an organocatalyzed formal[3+3]annulation. J. Org. Chem. 2016, 81, 4340-4346). The reaction has moderate to excellent yields (52%-81%), excellent enantioselectivity (84%-99%), and moderate to excellent diastereoselectivity (9:1-20:1). Unfortunately, in this report, the expansion of pyrazolone substrates is very limited, and only R was tested. 1 The universality of the location.

[0007]

[0008] In 2016, Tong's research group used a new catalyst, which was obtained by linking cinchona alkaloids and amino acids, to successfully synthesize chiral pyrazolohydropyran compounds (Ni, C.; Tong, X. Amine-catalyze a symmetric [3+3] annulations of β′-acetoxy allenoates: enantioselective synthesis of 4H-pyrans. J. Am. Chem. Soc. 2016, 138, 7872-7875). The reaction uses pyrazolone and allenic ester as raw materials. Under the catalysis of this new catalyst, optically pure pyrazolohydropyran compounds are obtained with moderate to excellent yields (60%-96%) and high enantioselectivity (87%-98%). The final product can be further derivatized to obtain pyrazolohydropyran compounds with fungicidal activity. However, due to substrate limitations, the pyrazol-hydrogenated pyran compound generated in this report contains only one chiral center, and the pyrazolone nitrogen atom can only be tert-butyl, phenyl and p-bromophenyl, and the universality of other substituents has not been tested.

[0009]

[0010] Although the above literature has reported the construction of pyrazolohydropyran skeletons, these reports all face the problem of poor universality of pyrazolone substrates. In addition, examples of constructing more complex pyrazolohydropyran compounds containing quaternary carbon multichiral centers, especially quaternary carbon spirocyclic skeletons, are still under development. Summary of the invention

[0011] In view of the above problems, the purpose of the present invention is to provide a method for synthesizing chiral pyrazolohydrogenated pyran compounds by using a chiral primary amine to catalyze a [3+3] cyclization reaction. The method has a wide substrate universality, and can be well expanded to pyrazolone and cyclodienone substrates. The operation is simple, the yield is high, and the method has excellent enantioselectivity. More importantly, the method can obtain a quaternary carbon spiro ring-containing pyrazolohydrogenated pyran compound.

[0012] In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is:

[0013] A catalytic synthesis method of a chiral pyrazolohydrogenated pyran compound comprises the following steps: using pyrazolone and cyclodienone as reactants, adding a chiral primary amine catalyst and an acid additive, reacting in a substituted benzene solvent at 25-40° C. for 12-48 hours to obtain a chiral pyrazolohydrogenated pyran compound represented by formula (I):

[0014]

[0015] The chiral primary amine catalyst includes, but is not limited to, cinchona alkaloid-derived primary amines, chiral amino alcohols, diphenylethylenediamine and its derivatives, aliphatic hydrocarbon-substituted ethylenediamine and its derivatives, cyclohexanediamine and its derivatives, square amide primary amines, and the like.

[0016] The acid additives include, but are not limited to, 2-nitrobenzoic acid, 3-nitrobenzoic acid, 4-nitrobenzoic acid, benzoic acid, acetic acid, trifluoroacetic acid, (S)-N-Boc-2-piperidinic acid, and the like.

[0017] In terms of molar amount, the amount of the chiral primary amine catalyst is 10-20% of the cyclodienone; the amount of pyrazolone is 1-2 times of the cyclodienone; and the amount of the acid additive is 20-40% of the cyclodienone.

[0018] The substituted benzene solvent includes but is not limited to toluene, o-xylene, m-xylene or p-xylene.

[0019] The chemical structural formula of the pyrazolone is Where R 1 Selected from: one of methyl and ethyl; R 2One selected from phenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-chlorophenyl, 3-bromophenyl and 2-naphthyl.

[0020] The chemical structural formula of the cyclodienone is Where R 3 One selected from phenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 3-methylphenyl, 3-chlorophenyl, 3-bromophenyl, 2-methylphenyl, 2-chlorophenyl and 1-naphthyl.

[0021] In a preferred technical solution, the amount of the chiral primary amine catalyst used is 10% of the cyclodienone on a molar basis.

[0022] In a preferred technical solution, the amount of the pyrazolone used is twice that of the cyclodienonone in terms of molar amount.

[0023] In the preferred technical solution, the chemical structure of the chiral primary amine catalyst includes but is not limited to:

[0024]

[0025] In the above technical solution, after the reaction is completed, the product can be separated by simple column chromatography (the eluent is preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product.

[0026] The above reaction process is as follows:

[0027]

[0028] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0029] 1. The present invention realizes the synthesis of chiral pyrazole and hydrogenated pyran compounds having a quaternary carbon spirocyclic unit by using pyrazolone and cyclohexanedione as reactants through the catalysis of chiral primary amines. The method is simple to operate, has a high yield, and has excellent yield and enantioselectivity.

[0030] 2. In the method of the present invention, no unclosed ring intermediates are generated, and the cyclized product can be obtained in one step.

[0031] 3. The compounds synthesized in the present invention have potential pharmaceutical activity and are expected to obtain known biologically active molecules through further derivatization. DETAILED DESCRIPTION

[0032] The present invention will be further described below in conjunction with specific embodiments.

[0033] Embodiment 1:

[0034]

[0035] Pyrazolone 1a (34.8 mg, 0.2 mmol) and cyclodienone 2a (19.8 mg, 0.1 mmol), acid additive (S)-N-Boc-2-piperidinic acid (4.6 mg, 0.02 mmol) and toluene (4 ml) were added to the reaction flask in sequence. The above solution was stirred for 5 minutes, and then a chiral primary amine catalyst (3.3 mg, 0.01 mmol) was added. The reaction was carried out at 25°C for 24 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product 3a (27.9 mg), with a yield of 75%, dr = 6:1, and ee = 98%. The product 3a was analyzed, and the results were as follows: Daicel chiral IA column; i PrOH / Hexane=10 / 90; flow rate=1.0mL / min; t R1 =8.92min,1.1%;t R2 =12.44min,98.9%;[α] D 20 =+16.0 (c=0.1, CH2Cl2); 1 H NMR (400MHz, CDCl3): δ7.75 (d, J=7.7Hz, 2H), 7.42 (t, J=7.3Hz, 2H), 7.35-7 .32(m,2H),7.24-7.22(m,2H),7.20-7.14(m,2H),4.01(dd,J=11.2,5.3Hz,1 H),2.78(d,J=14.7Hz,1H),2.56(d,J=14.8Hz,1H),2.50-2.46(m,1H),2.34 -2.28(m,2H),2.22(dd,J=14.1,5.4Hz,1H),1.94-1.83(m,4H),1.76(s,3H); 13 C NMR (101MHz, CDCl3): δ207.4,149.1,146.7,141.0,137.1,130.5,129.18,129.16,128.7,124.7,118.3,98.0,8 4.6,50.1,42.8,40.3,34.9,31.1,20.6,13.4;IR(neat):ν3440,2923,1740,1659,1594,1460,1101,802,704cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 24 H 25N2O2:373.1911; found:373.1916.

[0036] Embodiment 2:

[0037]

[0038] Pyrazolone 1b (46.0 mg, 0.2 mmol) and cyclodienone 2a (19.8 mg, 0.1 mmol), acid additive (S)-N-Boc-2-piperidinic acid (4.6 mg, 0.02 mmol) and toluene (4 ml) were added to the reaction flask in sequence. The above solution was stirred for 5 minutes, and then a chiral primary amine catalyst (3.3 mg, 0.01 mmol) was added. The reaction was carried out at 25°C for 24 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product 3b (27.0 mg), with a yield of 63%, dr = 5:1, and ee = 91%. The product 3b was analyzed, and the results were as follows: Daicel chiral IA column; i PrOH / Hexane=20 / 80; flow rate=1.0mL / min; t R1 =5.38min,4.1%;t R2 =7.79min,95.9%;[α] D 20 =+54.2 (c=0.1, CH2Cl2); 1 H NMR (400MHz, CDCl3): δ7.65-7.62(m,2H),7.41-7.39(m,2H),7.35-7.31(m,2H),7.27-7.24(m,3H),4.01(dd,J=10.9,6.0Hz,1H),2.77(d,J=14.6 Hz,1H),2.55(d,J=14.5Hz,1H),2.49-2.47(m,1H),2.40-2.31(m,2H),2. 19(dd,J=14.1,6.0Hz,1H),1.97-1.79(m,4H),1.73(s,3H),1.33(s,9H); 13C NMR (101MHz, CDCl3): δ207.8,149.0,148.1,146.6,142.6,136.2,128.7,127.7,126.9,125.9,119.1,97.6,85.3,52.4, 43.2,40.6,34.8,34.4,31.3,30.6,20.7,13.6;IR(neat):ν3421,2934,1739,1605,1560,1499,1452,1265,1011,749cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 28 H 33 N2O2:429.2537; found:429.2533.

[0039] Embodiment 3:

[0040]

[0041] Pyrazolone 1c (50.4 mg, 0.2 mmol) and cyclodienone 2a (19.8 mg, 0.1 mmol), acid additive 2-nitrobenzoic acid (3.3 mg, 0.02 mmol) and toluene (4 ml) were added to the reaction flask in sequence. The above solution was stirred for 5 minutes, and then a chiral primary amine catalyst (3.3 mg, 0.01 mmol) was added. The reaction was carried out at 25°C for 24 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product 3c (32.0 mg), with a yield of 71%, dr = 4:1, and ee = 90%. The product 3c was analyzed, and the results were as follows: Daicel chiral IA column; i PrOH / Hexane=10 / 90; flow rate=1.0mL / min; t R1 =6.67min,5.1%;t R2 =9.40min,94.9%;[α] D 20 =+44.9 (c=0.1, CH2Cl2); 1H NMR (400MHz, CDCl3): δ7.72(d,J=7.7Hz,2H),7.47(d,J=8.4Hz,2H),7.41(t,J =8.0Hz,2H),7.21(t,J=7.4Hz,1H),7.15(d,J=8.4Hz,2H),3.98(dd,J=10.9,6. 0Hz,1H),2.76(d,J=14.6Hz,1H),2.55(d,J=14.6Hz,1H),2.49-2.46(m,1H),2. 39-3.28(m,2H),2.19(dd,J=14.1,6.0Hz,1H),1.91-1.79(m,4H),1.75(s,3H); 13 CNMR (101MHz, CDCl3): δ207.4,149.1,146.7,141.6,138.5,131.9,129.4,129.0,125.3,120.7,119.6,97.3,85.4 ,52.3,43.0,40.5,34.4,30.5,20.6,13.7;IR(neat):ν3460,2929,1744,1659,1605,1549,1506,1264,1005,755cm –1 ; HRMS (ESI): m / z [M+H] + calcd.forC 24 H 24 BrN2O2:451.1016; found:451.1014.

[0042] Embodiment 4:

[0043]

[0044] Pyrazolone 1d (40.8 mg, 0.2 mmol) and cyclodienone 2a (19.8 mg, 0.1 mmol), acid additive (S)-N-Boc-2-piperidinic acid (4.6 mg, 0.02 mmol) and toluene (4 ml) were added to the reaction flask in sequence. The above solution was stirred for 5 minutes, and then a chiral primary amine catalyst (3.3 mg, 0.01 mmol) was added. The reaction was carried out at 40°C for 36 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product 3d (26.1 mg), with a yield of 65%, dr = 5:1, and ee = 90%. The product 3d was analyzed, and the results were as follows: Daicel chiral IA column; i PrOH / Hexane=20 / 80; flow rate=1.0mL / min; t R1= 7.29 min, 4.9%; t R2 = 8.67 min, 95.1%; [α] D 20 = +43.0 (c = 0.1, CH2Cl2); 1 H NMR (400 MHz, CDCl3): δ 7.35 - 7.30 (m, 2H), 7.25 - 7.20 (m, 6H), 6.77 - 6.75 (m, 1H), 3.94 (dd, J = 11.0, 5.9 Hz, 1H), 3.84 (s, 3H), 2.94 (d, J = 14.6 Hz, 1H), 2.53 (d, J = 14.6 Hz, 2H), 2.43 - 2.35 (m, 1H), 2.23 - 2.15 (m, 3H), 2.02 - 1.91 (d, J = 25.2 Hz, 3H), 1.72 (s, 3H); 13 C NMR (101 MHz, CDCl3): δ 207.8, 160.0, 148.8, 146.9, 142.6, 139.6, 129.6, 128.7, 127.8, 126.9, 112.8, 112.0, 105.7, 98.0, 84.9, 55.4, 47.8, 43.6, 40.7, 35.7, 34.4, 20.6, 13.6; IR (neat): ν 3460, 2932, 1745, 1650, 1599, 1560, 1501, 1462, 1267, 1025, 749 cm –1 ; HRMS (ESI): m / z [M + H] + calcd. for C 25 H 27 N2O3: 403.2016; found: 403.2020.

[0045] Example 5:

[0046]

[0047] Pyrazolone 1e (41.6 mg, 0.2 mmol) and cyclodienone 2a (19.8 mg, 0.1 mmol), acid additive (S)-N-Boc-2-piperidinic acid (4.6 mg, 0.02 mmol) and toluene (4 ml) were added to the reaction flask in sequence. The above solution was stirred for 5 minutes, and then a chiral primary amine catalyst (3.3 mg, 0.01 mmol) was added. The reaction was carried out at 40°C for 24 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product 3e (26.4 mg), with a yield of 65%, dr = 4:1, and ee = 84%. The product 3e was analyzed, and the results were as follows: Daicel chiral IA column; i PrOH / Hexane=10 / 90; flow rate=1.0mL / min; t R1 =6.69min,8.1%;t R2 =7.74min,91.9%;[α] D 20 =+21.3 (c=0.1, CH2Cl2); 1 H NMR (400MHz, CDCl3): δ7.83 (t, J=2.0Hz, 1H), 7.63 (dd, J=8.3, 2.0Hz, 1H), 7. 35-7.29(m,3H),7.25-7.23(m,3H),7.17(dd,J=8.0,2.7Hz,1H),4.00(dd,J=1 0.9,6.0Hz,1H),2.78(d,J=14.6Hz,1H),2.57(d,J=14.6Hz,1H),2.52-2.47( m,1H),2.41-2.28(m,2H),2.22-2.17(m,1H),1.93-1.82(m,4H),1.73(s,3H); 13 C NMR (101MHz, CDCl3): δ207.4,149.3,147.6,142.2,139.6,134.8,130.1,128.8,127.7,127.1,125.1,119.6,117.0,98. 3,85.9,52.4,43.0,40.5,34.7,30.6,20.8,13.6;IR(neat):ν3450,2932,1734,1650,1601,1410,1259,1050,871,750cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 24 H 24ClN2O2:407.1521; found:407.1527.

[0048] Embodiment 6:

[0049]

[0050] Pyrazolone 1f (50.4 mg, 0.2 mmol) and cyclodienone 2a (19.8 mg, 0.1 mmol), acid additive 3-nitrobenzoic acid (3.3 mg, 0.02 mmol) and toluene (4 ml) were added to the reaction flask in sequence. The above solution was stirred for 5 minutes, and then a chiral primary amine catalyst (3.3 mg, 0.01 mmol) was added. The reaction was carried out at 40°C for 24 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product 3f (30.6 mg), with a yield of 68%, dr = 5:1, and ee = 94%. The product 3f was analyzed, and the results were as follows: Daicel chiral IC column; i PrOH / Hexane=10 / 90; flow rate=1.0mL / min; t R1 =19.06min,3.0%;t R2 =31.02min,97.0%;[α] D 20 =-34.3 (c = 0.1, CH2Cl2); 1 H NMR (400MHz, CDCl3): δ7.99(t,J=1.9Hz,1H),7.68(dt,J=8.0,1.6Hz,1H),7.35-7.27(m,4H),7.25-7.23(m,3H),4.00(dd,J=10.9,6.0Hz,1H),2 .77(d,J=14.6Hz,1H),2.52-2.47(m,1H),2.49(s,1H),2.41-2.35(m,1H ),2.33-2.29(m,1H),2.22-2.17(m,1H),1.93-1.84(m,4H),1.73(s,3H); 13C NMR (101MHz, CDCl3): δ207.4,149.3,147.7,142.2,139.7,130.3,128.8,128.0,127.7,127.1,122.8,122.5,117.5,98. 3,85.9,52.3,43.0,40.5,34.7,30.6,20.8,13.6;IR(neat):ν3451,2923,1749,1651,1605,1405,1250,1050,866,749cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 24 H 24 BrN2O2:451.1016; found:451.1011.

[0051] Embodiment 7:

[0052]

[0053] Pyrazolone 1g (44.8mg, 0.2mmol) and cyclodienone 2a (19.8mg, 0.1mmol), acid additive (S)-N-Boc-2-piperidinic acid (4.6mg, 0.02mmol) and toluene (4ml) were added to the reaction flask in sequence. The above solution was stirred for 5 minutes, and then a chiral primary amine catalyst (3.3mg, 0.01mmol) was added. The reaction was carried out at 25°C for 12 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product 3g (31.7mg), with a yield of 75%, dr = 5:1, and ee = 86%. The product 3g was analyzed, and the results were as follows: Daicel chiral IA column; i PrOH / Hexane=10 / 90; flow rate=1.0mL / min; t R1 =12.84min,7.0%;t R2 =21.52min,93.0%;[α] D 20 =+77.1 (c=0.1, CH2Cl2); 1H NMR (400MHz, CDCl3): δ8.18(d,J=2.0Hz,1H),8.01(dd,J=9.0,2.2Hz,1H),7.89-7.85(m,2 H),7.83(d,J=8.1Hz,1H),7.51-7.42(m,2H),7.37-7.33(m,2H),7.29-7.26(d,J=7.2Hz,3H ),4.05(dd,J=11.0,6.1Hz,1H),2.83(d,J=14.4Hz,1H),2.61(d,J=14.4Hz,1H),2.51-2.4 7(m,1H),2.41-2.33(m,2H),2.25(dd,J=14.1,6.0Hz,1H),1.98-1.81(m,4H),1.78(s,3H); 13 C NMR (101MHz, CDCl3): δ207.7,149.4,147.2,142.5,136.2,133.7,131.0,128.9,128.8,128.2,127.7,127.5,127.0,126.5,125.4,119 .0,116.4,98.1,85.8,52.5,43.2,40.6,34.9,30.5,20.8,13.7;IR(neat):ν3441,2929,1742,1507,1407,1261,1057,871,802,760cm –1 ;HRMS(ESI):m / z[M+H]+calcd.for C 28 H 27 N2O2:423.2067; found:423.2066.

[0054] Embodiment 8:

[0055]

[0056] Pyrazolone 1a (34.8 mg, 0.2 mmol) and cyclodienone 2b (21.2 mg, 0.1 mmol), acid additive 2-nitrobenzoic acid (3.3 mg, 0.02 mmol) and toluene (4 ml) were added to the reaction flask in sequence. The above solution was stirred for 5 minutes, and then a chiral primary amine catalyst (3.3 mg, 0.01 mmol) was added. The reaction was carried out at 25°C for 12 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product 3h (23.9 mg), with a yield of 62%, dr = 4:1, and ee = 95%. The product 3h was analyzed, and the results were as follows: Daicel chiral IA column; iPrOH / Hexane = 10 / 90; flow rate = 1.0 mL / min; t R1 = 9.45 min, 2.5%; t R2 = 11.23 min, 97.5%; [α] D 20 = +21.0 (c = 0.1, CH2Cl2); 1 1H NMR (400 MHz, CDCl3): δ 7.74 (d, J = 8.4 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.20 (t, J = 6.4 Hz, 1H), 7.14 (s, 4H), 3.97 (dd, J = 11.0, 6.0 Hz, 1H), 2.76 (d, J = 14.6 Hz, 1H), 2.55 (d, J = 14.6 Hz, 1H), 2.48 - 2.46 (m, 1H), 2.39 - 2.29 (m, 5H), 2.18 (dd, J = 14.1, 6.1 Hz, 1H), 1.91 - 1.80 (m, 4H), 1.75 (s, 3H); 13 13C NMR (101 MHz, CDCl3): δ 207.7, 149.1, 147.0, 139.4, 138.7, 136.5, 129.4, 129.0, 127.6, 125.2, 119.5, 98.0, 85.4, 52.4, 43.3, 40.6, 34.4, 30.6, 21.0, 20.7, 13.7; IR (neat): ν 3765, 2928, 2895, 1743, 1655, 1543, 1370, 1265, 1017, 858, 767 cm –1 ; HRMS (ESI): m / z [M + H]+ calcd. for C 25 H 27 N2O2: 387.2067; found: 387.2069.

[0057] Example 9:

[0058]

[0059] Pyrazolone 1a (34.8 mg, 0.2 mmol) and cyclodienone 2c (25.4 mg, 0.1 mmol), acid additive (S)-N-Boc-2-piperidinic acid (4.6 mg, 0.02 mmol) and toluene (4 ml) were added to the reaction flask in sequence. The above solution was stirred for 5 minutes, and then a chiral primary amine catalyst (3.3 mg, 0.01 mmol) was added. The reaction was carried out at 25°C for 12 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product 3i (26.5 mg), with a yield of 62%, dr = 4:1, and ee = 95%. The product 3i was analyzed, and the results were as follows: Daicel chiral IA column; i PrOH / Hexane=30 / 70; flow rate=1.0mL / min; t R1 =8.77min,2.4%;t R2 =10.67min,97.6%;[α] D 20 =+30.5 (c=0.1, CH2Cl2); 1 H NMR (400MHz, CDCl3): δ7.74(d,J=7.7Hz,2H),7.39(t,J=7.6Hz,2H),7.33(d,J=8.3Hz,2H),7.20-7.15(m,3H),3.98(dd,J=10.9,6.0Hz,1H),2.76(d,J= 14.6Hz,1H),2.55(d,J=14.6Hz,1H),2.50-2.46(m,1H),2.39-2.30(m,2H), 2.19(dd,J=14.1,6.1Hz,1H),1.93-1.82(m,4H),1.75(s,3H),1.32(s,9H); 13 C NMR (101MHz, CDCl3): δ207.7,149.9,149.1,147.1,139.2,138.6,129.0,127.3,125.6,125.2,119.6,98.1,85.4,52.4,43 .2,40.6,34.4,34.2,31.4,30.6,20.7,13.7;IR(neat):ν3641,2923,2894,1707,1661,1644,1567,1548,1527,1464,673cm –1 ;HRMS(ESI):m / z[M+H]+calcd.for C 28 H 33 N2O2:429.2537; found:429.2533.

[0060] Embodiment 10:

[0061]

[0062] Pyrazolone 1a (34.8 mg, 0.2 mmol) and cyclodienone 2d (21.6 mg, 0.1 mmol), acid additive (S)-N-Boc-2-piperidinic acid (4.6 mg, 0.02 mmol) and toluene (4 ml) were added to the reaction flask in sequence. The above solution was stirred for 5 minutes, and then a chiral primary amine catalyst (3.3 mg, 0.01 mmol) was added. The reaction was carried out at 40°C for 48 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product 3j (22.6 mg), with a yield of 58%, dr = 5:1, and ee = 91%. The product 3j was analyzed, and the results were as follows: Daicel chiral IA column; i PrOH / Hexane=10 / 90; flow rate=1.0mL / min; t R1 =15.47min,4.5%;t R2 =19.80min,95.5%;[α] D 20 =+16.6 (c=0.1, CH2Cl2); 1 H NMR (400MHz, CDCl3): δ7.73(d,J=7.9Hz,2H),7.41(t,J=7.7Hz,2H),7.24-7.17(m,3H),7.04(t,J=8.6Hz,2H),4.00(dd,J=10.8,5.9Hz,1H),2.7 6(d,J=14.6Hz,1H),2.56(d,J=14.6Hz,1H),2.49-2.46(m,1H),2.39-2. 29(m,2H),2.19(dd,J=14.2,5.8Hz,1H),1.90-1.80(m,4H),1.74(s,3H). 13 C NMR (101MHz, CDCl3): δ207.6,163.0(d,J C-F =246.2Hz),149.1,146.8,138.5,138.2(d,J C-F =3.1Hz),129.2(d,J C-F =7.9Hz),129.1,125.4,119.7,115.8(d,J C-F=21.4Hz),97.8,85.5,52.4,43.2,40.6,34.2,30.6,20.7,13.7; IR(neat):ν3452,2930,2856,1743,1662,1548,1404,1276,1086,1020cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 24 H 24 FN2O2:391.1816; found:391.1818.

[0063] Embodiment 11:

[0064]

[0065] Pyrazolone 1a (34.8 mg, 0.2 mmol) and cyclodiene ketone 2e (23.2 mg, 0.1 mmol), acid additive benzoic acid (2.4 mg, 0.02 mmol) and o-xylene (4 ml) were added to the reaction flask in sequence. The above solution was stirred for 5 minutes, and then a chiral primary amine catalyst (3.3 mg, 0.01 mmol) was added. The reaction was carried out at 25°C for 24 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product 3k (21.1 mg), with a yield of 52%, dr = 5:1, and ee = 91%. The product 3k was analyzed, and the results were as follows: Daicel chiral IA column; i PrOH / Hexane=10 / 90; flow rate=1.0mL / min; t R1 =12.19min,4.6%;t R2 =15.08min,95.4%;[α] D 20 =+37.0 (c=0.1, CH2Cl2); 1 H NMR (400MHz, CDCl3): δ7.73(d,J=7.6Hz,2H),7.41-7.37(m,2H),7.32(d,J=8.5Hz,2H),7.21-7.17(m,3H),4.00(dd,J=10.8,5.9Hz,1H),2.76( d,J=14.6Hz,1H),2.55(d,J=14.6Hz,1H),2.52-2.44(m,1H),2.39-2.28(m,2H),2.19(dd,J=14.1,6.1Hz,1H),1.91-1.81(m,4H),1.75(s,3H); 13C NMR (101MHz, CDCl3): δ207.4,149.1,146.7,141.1,138.5,132.7,129.1,129.0,128.9,125.3,119.6,97.4,85.4, 52.3,43.1,40.5,34.3,30.6,20.6,13.7;IR(neat):ν3452,2930,2856,1743,1662,1548,1404,1276,1086,1020cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 24 H 24 ClN2O2:407.1521; found:407.1520.

[0066] Embodiment 12:

[0067]

[0068] Pyrazolone 1a (34.8 mg, 0.2 mmol) and cyclodienone 2f (21.2 mg, 0.1 mmol), acid additive (S)-N-Boc-2-piperidinic acid (4.6 mg, 0.02 mmol) and toluene (4 ml) were added to the reaction flask in sequence. The above solution was stirred for 5 minutes, and then a chiral primary amine catalyst (3.3 mg, 0.01 mmol) was added. The reaction was carried out at 25°C for 24 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product 3l (23.6 mg), with a yield of 61%, dr = 4:1, and ee = 91%. The product 3l was analyzed, and the results were as follows: Daicel chiral IA column; i PrOH / Hexane=10 / 90; flow rate=1.0mL / min; t R1 =8.76min,4.6%;t R2 =11.23min,95.4%;[α] D 20 =+15.0 (c=0.1, CH2Cl2); 1H NMR (400MHz, CDCl3): δ7.75-7.73(m,2H),7.41(t,J=7.5Hz,2H),7.24-7.17(m,2H),7.08-7.04(m,3H),3.97(dd,J=11.0,6.0Hz,1H),2.78(d ,J=14.6Hz,1H),2.56(d,J=14.6Hz,1H),2.50-2.46(m,1H),2.39-2.30(m,5H),2.19(dd,J=14.1,6.0Hz,1H),1.92-1.80(m,4H),1.75(s,3H). 13 C NMR (101MHz, CDCl3): δ207.7,149.1,147.1,142.4,138.7,138.4,129.0,128.6,128.3,127.7,125.2,124.8,119.5,98.0,85.4 ,52.4,43.2,40.6,34.7,30.5,21.4,20.7,13.7.IR(neat):ν3450,2971,2928,1743,1662,1626,1549,1406,1273,1025,877cm –1 ; HRMS (ESI): m / z [M+H] + calcd.forC 25 H 27 N2O2:387.2067; found:387.2070.

[0069] Embodiment 13:

[0070]

[0071] Pyrazolone 1a (34.8 mg, 0.2 mmol) and cyclodienone 2g (27.6 mg, 0.1 mmol), acid additive (S)-N-Boc-2-piperidinic acid (4.6 mg, 0.02 mmol) and toluene (4 ml) were added to the reaction flask in sequence. The above solution was stirred for 5 minutes, and then a chiral primary amine catalyst (3.3 mg, 0.01 mmol) was added. The reaction was carried out at 40°C for 24 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product 3m (27.9 mg), with a yield of 62%, dr = 5:1, and ee = 92%. The product 3m was analyzed, and the results were as follows: Daicel chiral IA column; i PrOH / Hexane=10 / 90; flow rate=1.0mL / min; t R1=11.53min,3.8%;t R2 =14.26min,96.2%;[α] D 20 =+26.0 (c=0.1, CH2Cl2); 1 H NMR (400MHz, CDCl3): δ7.74-7.71(m,2H),7.41-7.38(m,4H),7.23-7.17(m,3H),3.98(dd,J=11.0,6.0Hz,1H),2.77(d,J=14.6Hz, 1H),2.56(d,J=14.6Hz,1H),2.49-2.45(m,1H),2.39-2.28(m,2H),2.20(dd,J=14.1,6.1Hz,1H),1.92-1.81(m,4H),1.77(s,3H); 13 C NMR (101MHz, CDCl3): δ207.4,149.1,146.7,145.0,138.5,130.8,130.4,130.2,129.0,126.3,125.3,122.8,119.6,97.2 ,85.4,52.3,43.0,40.5,34.6,30.5,20.6,13.7;IR(neat):ν3865,3660,2926,2895,1742,1707,1661,1404,1265,1023cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 24 H 24 BrN2O2:451.1016; found:451.1012.

[0072] Embodiment 14:

[0073]

[0074] Pyrazolone 1a (34.8 mg, 0.2 mmol) and cyclodiene ketone 2h (21.2 mg, 0.1 mmol), acid additive trifluoroacetic acid (2.3 mg, 0.02 mmol) and m-xylene (4 ml) were added to the reaction flask in sequence. The above solution was stirred for 5 minutes, and then a chiral primary amine catalyst (3.3 mg, 0.01 mmol) was added. The reaction was carried out at 40°C for 24 hours. After the reaction, the product was subjected to simple column chromatography (the eluent is preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product 3n (21.2 mg), with a yield of 55%, dr = 5:1, and ee = 88%. The product 3n was analyzed, and the results were as follows: Daicel chiral IA column;i PrOH / Hexane = 10 / 90; flow rate = 1.0 mL / min; t R1 = 6.37 min, 6.2%; t R2 = 8.44 min, 93.8%; [α] D 20 = +55.0 (c = 0.1, CH2Cl2); 1 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 7.8 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.21 - 7.14 (m, 5H), 4.29 (dd, J = 10.6, 5.5 Hz, 1H), 2.79 (d, J = 14.6 Hz, 1H), 2.59 (d, J = 14.6 Hz, 1H), 2.50 - 2.40 (m, 4H), 2.35 - 2.32 (m, 2H), 2.20 (dd, J = 14.0, 5.6 Hz, 1H), 1.91 - 1.82 (m, 4H), 1.73 (s, 3H); 13 13C NMR (101 MHz, CDCl3): δ 207.4, 149.1, 146.7, 145.0, 138.5, 130.8, 130.4, 130.2, 129.0, 126.3, 125.3, 122.8, 119.6, 97.2, 85.4, 52.3, 43.0, 40.5, 34.6, 30.5, 31.3, 20.6, 13.7; IR (neat): ν 2932, 1747, 1662, 1550, 1481, 1371, 1331, 1260, 1149, 1090, 870 cm –1 ; HRMS (ESI): m / z [M + H] + calcd. for C 25 H 27 N2O2: 387.2067; found: 387.2064.

[0075] Example 15:

[0076]

[0077] Pyrazolone 1a (34.8 mg, 0.2 mmol) and cyclodiene ketone 2i (23.2 mg, 0.1 mmol), acid additive trifluoroacetic acid (2.3 mg, 0.02 mmol) and m-xylene (4 ml) were added to the reaction flask in sequence. The above solution was stirred for 5 minutes, and then a chiral primary amine catalyst (3.3 mg, 0.01 mmol) was added. The reaction was carried out at 40°C for 48 hours. After the reaction, the product was subjected to simple column chromatography (the eluent was preferably petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain the target product 3o (21.1 mg), with a yield of 52%, dr = 5:1, and ee = 90%. The product 3o was analyzed, and the results were as follows: Daicel chiral IA column; i PrOH / Hexane=10 / 90; flow rate=1.0mL / min; t R1 =8.22min,5.2%;t R2 =12.78min,94.8%;[α] D 20 =+34.0 (c=0.1, CH2Cl2); 1 H NMR (400MHz, CDCl3): δ7.74-7.71(m,2H),7.41-7.38(m,4H),7.23-7.17(m,3H),3.98(dd,J=11.0,6.0Hz,1H),2.77(d,J=14.6Hz, 1H),2.56(d,J=14.6Hz,1H),2.49-2.45(m,1H),2.39-2.28(m,2H),2.20(dd,J=14.1,6.1Hz,1H),1.92-1.81(m,4H),1.77(s,3H); 13 CNMR (101MHz, CDCl3): δ207.2,149.1,146.7,146.2,144.3,143.7,140.5,137.7,130.2,129.4,128.9,127.5,118.4,95.2,8 4.4,57.4,42.1,41.2,36.3,32.6,21.6,15.7;IR(neat):ν2932,2830,1744,1655,1547,1387,1275,1158,1084,1043,749cm –1 ; HRMS (ESI): m / z [M+H] + calcd.for C 24 H 24 ClN2O2:407.1521; found:407.1529.

[0078] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A catalytic synthesis method of a chiral pyrazolohydropyran compound, characterized in that: The following steps are involved: Pyrazolone and cyclodione are used as reactants, a chiral primary amine catalyst and an acid additive are added, and the reaction is carried out in a substituted benzene solvent at 25-40° C. for 12-48 hours to obtain a chiral pyrazolohydropyran compound represented by formula (I): The chiral primary amine catalyst is one or more of cinchona alkaloid-derived primary amine, chiral amino alcohol, diphenylethylenediamine and its derivatives, aliphatic hydrocarbon-substituted ethylenediamine and its derivatives, cyclohexanediamine and its derivatives, and square amide primary amine.

2. The catalytic synthesis method of a chiral pyrazolohydropyran compound according to claim 1, characterized in that: The acid additive is one or more of 2-nitrobenzoic acid, 3-nitrobenzoic acid, 4-nitrobenzoic acid, benzoic acid, acetic acid, trifluoroacetic acid, and (S)-N-Boc-2-piperidinic acid.

3. The catalytic synthesis method of a chiral pyrazolohydropyran compound according to claim 1, characterized in that: In terms of molar amount, the amount of the chiral primary amine catalyst is 10-20% of the cyclodienone; the amount of pyrazolone is 1-2 times of the cyclodienone; and the amount of the acid additive is 20-40% of the cyclodienone.

4. The catalytic synthesis method of a chiral pyrazolohydropyran compound according to claim 1, characterized in that: The chemical structural formula of the pyrazolone is Where R 1 Selected from: one of methyl and ethyl; R 2 One selected from phenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-chlorophenyl, 3-bromophenyl and 2-naphthyl.

5. The catalytic synthesis method of a chiral pyrazolohydropyran compound according to claim 1, characterized in that: The chemical structural formula of the cyclodienone is Where R 3 One selected from phenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 3-methylphenyl, 3-chlorophenyl, 3-bromophenyl, 2-methylphenyl, 2-chlorophenyl and 1-naphthyl.

6. The catalytic synthesis method of a chiral pyrazolohydropyran compound according to claim 1, characterized in that: The substituted benzene solvent is toluene, o-xylene, m-xylene or p-xylene.

7. The catalytic synthesis method of a chiral pyrazolohydropyran compound according to claim 1, characterized in that: After the reaction is completed, the method further includes a step of separation and purification by column chromatography.

8. The catalytic synthesis method of a chiral pyrazolohydropyran compound according to claim 7, characterized in that: The eluent of the column chromatography is petroleum ether:ethyl acetate=10:1-5:1.

Images