CN109970752B

CN109970752B - Synthesis method of chiral 4-spiro pyrazole compound

Info

Publication number: CN109970752B
Application number: CN201910284007.3A
Authority: CN
Inventors: 王益锋; 储明明; 许丹倩; 徐振元
Original assignee: Zhejiang University of Technology ZJUT
Current assignee: Zhejiang University of Technology ZJUT
Priority date: 2019-04-10
Filing date: 2019-04-10
Publication date: 2020-11-13
Anticipated expiration: 2039-04-10
Also published as: CN109970752A

Abstract

The invention discloses a synthetic method of a chiral 4-spiro pyrazole compound shown in a formula (3), which comprises the following steps: in a water-oil two-phase system, raw materials, namely a compound phenol shown as a formula (1) and a compound shown as a formula (2), react under the action of an acid-binding agent and a chiral catalystAnd tracking and monitoring by TLC (thin layer chromatography) until the reaction is complete, and carrying out aftertreatment on the obtained reaction liquid to obtain the chiral 4-spiro pyrazole compound chiral compound shown in the formula (3). The invention has the advantages that: the chiral 4-spirocyclic pyrazole structure is an important structural unit, widely exists in the fields of pesticides and medicines, and has wide application prospect. The synthesis method has the advantages of mild conditions, high yield, good asymmetric selectivity, wide range of reaction substrates, cheap and easily-obtained reaction reagents and strong operability.

Description

Synthesis method of chiral 4-spiro pyrazole compound

(I) technical field

The invention relates to a method for synthesizing a chiral 4-spirocyclic pyrazole compound, in particular to a method for synthesizing the chiral 4-spirocyclic pyrazole compound by asymmetric domino ring-closure of raw materials 2-naphthol and 2- (aryl (p-toluenesulfonyl) methyl) phenol under catalysis of chiral tertiary amine-azoic acid in a water-oil two-phase system.

(II) background of the invention

70% of the existing new small molecule drugs contain at least one chiral center, so the development of a method for efficiently constructing chiral molecules is one of the important missions of synthetic chemists. The asymmetric synthesis catalyzed by organic small molecules is still in the interest of asymmetric catalysis, which is a high-efficiency asymmetric catalysis method developed after organometallic catalysis and enzyme catalysis. Compared with organic metal catalysis, the organic small molecular catalyst is generally stable to water and air, simple and convenient in reaction operation and easy for industrial amplification, and more importantly, the organic small molecular catalyst does not contain toxic metal, which is particularly important in drug synthesis. Compared with enzyme catalysis, small molecule catalysis has no strong substrate and reaction specificity like enzyme catalysis, one catalyst can catalyze several kinds of reactions, and the reaction substrate adaptability is relatively good. Just because of their unique advantages over other catalytic approaches, small organic molecule catalysis based on different catalytic mechanisms has been under great development over the last decade. As one of the important branches of organic small molecule catalysis, asymmetric reaction based on hydrogen bond catalysis also meets the requirements of larger generationMeanwhile, catalysts containing hydrogen bond donors (such as urea, thiourea, azosquaric acid, guanidine, phosphonic acid and the like) in various structures have been designed, show excellent chiral induction effect in a plurality of asymmetric catalytic reactions, and become an important synthesis strategy for constructing carbon-carbon bonds and carbon-heteroatom bonds. (A. Berkessel and H.

Asymmetric Organocatalysis,Wiley VCH,Weinheim,2005.；P.I.Dalko,Enantioselective Organocatalysis,Wiley-VCH,Weinheim,2007.)。

In recent years, Water-Oil two-phase (Water-Oil phases) has become an important reaction system in organic synthesis, and has received much attention because it enables organic compounds and Water-soluble ionic compounds to be separated or combined efficiently and rapidly during the reaction process. The asymmetric catalytic reaction under the water-oil two-phase system has important research and practical values. In the present research, the organic reaction based on the water-oil two-phase system mainly promotes the reaction of the organic substrate and the ionic reactant by the quaternary ammonium salt and crown ether phase transfer catalyst. For asymmetric organic catalysis in two-phase systems, it is currently limited to ionic liquids. Therefore, the development of more asymmetric catalytic systems based on two phases has important practical significance.

Disclosure of the invention

The invention aims to provide a method for synthesizing chiral 4-spiro pyrazole compounds in water and oil phases.

In order to achieve the purpose, the invention adopts the following technical scheme:

a synthetic method of a chiral 4-spirocyclic pyrazole compound shown in formula (3) comprises the following steps:

in a water-oil two-phase system, taking a compound shown in a formula (1) and a compound shown in a formula (2) as raw materials, reacting at 20-30 ℃ under the action of an acid-binding agent and a chiral catalyst, tracking and monitoring by TLC (thin layer chromatography) until the reaction is complete, and carrying out aftertreatment on the obtained reaction liquid to obtain a chiral 4-spiro pyrazole compound shown in a formula (3); the ratio of the amount of the compound represented by the formula (1) to the amount of the compound represented by the formula (2) and the acid-binding agent is 0.2-5: 1: 0.5 to 20; the amount ratio of the chiral catalyst to the compound represented by the formula (1) is 0.01 to 100: 100, respectively; the chiral catalyst is a bifunctional tertiary amine-azodicarbonic acid catalyst, which comprises a tertiary amine group containing a hydrogen bond donor azodicarbonic acid group and Lewis base function; the acid-binding agent is inorganic alkali; the water-oil two-phase system is prepared by mixing water and an organic solvent in a volume ratio of 1: 0.05-10 parts by weight;

the reaction formula is as follows:

in the formula (1), Ts represents a p-toluenesulfonyl group;

in the formula (1) or (3),

R¹is H, methoxy, ethoxy or halogen;

R²is C_1-20Alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted with one or more substituents each independently being methyl, methoxy, trifluoromethyl or halogen;

in the formula (2) or the formula (3),

R³is C_1-20Alkyl, naphthyl, phenyl or phenyl substituted with one or more substituents each independently being methyl, ethyl or halogen.

R⁴Is C_1-20Alkyl or phenyl groups.

Still further, the chiral catalyst is preferably one of compounds represented by the following formulas (4) to (7):

in the formula (4) or (5), the carbon atom marked with x is a chiral carbon atom;

in the formula (4), (5), (6) or (7),

R⁵、R⁸、R¹¹or R¹⁴Each independently is C₁～C₂₀Or phenyl or benzyl substituted with one or more substituents each independently being trifluoromethyl, nitro or halogen;

R⁶、R⁷、R⁹or R¹⁰Each independently is C₁～C₁₀Alkyl groups of (a);

R¹²or R¹⁵Each independently is ethyl or vinyl;

R¹³or R¹⁶Each independently is H, hydroxy or methoxy.

Still further, more preferably, the chiral catalyst is selected from one of the following:

further, the ratio of the amount of the compound represented by the formula (1) to the amount of the compound represented by the formula (2) and the acid-binding agent is preferably 0.5 to 2: 1:1 to 10.

Further, in the water-oil two-phase system, the organic solvent is selected from dichloromethane, chloroform, 1, 2-dichloroethane, diethyl ether, toluene, ethyl acetate or isopropyl acetate.

Further, the acid-binding agent is sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide or disodium hydrogen phosphate.

Further, the post-treatment method of the reaction solution comprises the following steps: after the reaction is finished, separating the reaction liquid, taking the organic phase, concentrating under reduced pressure, and then performing silica gel column chromatography separation, wherein the volume ratio of petroleum ether to ethyl acetate is 1-30: the mixed solution of 1 is used as eluent to carry out gradient elution, eluent containing a target compound is collected, the solvent is evaporated and dried, and the chiral 4-spiro pyrazole compound shown in the formula (3) is obtained.

Compared with the prior art, the invention has the beneficial effects that:

according to the synthesis method, a chiral catalyst containing at least one tertiary amine and a nitrilic acid functional group is used as a catalytic system, the reaction is carried out in water and oil phases, the product chiral 4-spiropyrazole compound is obtained through post-treatment separation, the synthesis method is mild in condition, high in yield, good in asymmetric selectivity, wide in range of reaction substrates, cheap and easily available in reaction reagents, and the chiral 4-spiropyrazole structure is an important structural unit, widely exists in the fields of pesticides and medicines, and has a wide application prospect.

(IV) detailed description of the preferred embodiments

The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto.

Example 1:

the catalysts (7) -b (0.01mmol, 6.3mg), 6-methoxy-2- (phenyl (p-toluenesulfonyl) methyl) phenol (0.1mmol, 36.8mg), 4-bromopyrazolone (0.13mmol, 33.0mg), potassium carbonate (0.26mmol, 36mg), chloroform (1.5ml), water (0.15ml) were added in this order to a dry 10ml reaction tube, the reaction tube was closed, stirred at room temperature for 24h with a magnetic stirrer, TLC showed complete consumption of 6-methoxy-2- (phenyl (p-toluenesulfonyl) methyl) phenol, and the reaction solution was CH₂Cl₂Extracting and separating liquid, taking organic phase, concentrating under reduced pressure, separating by using a silica gel chromatographic column, and mixing petroleum ether and ethyl acetate in a volume ratio of 1-20: 1 as eluent, collecting the eluent containing the target compound, evaporating the solvent and drying to obtain 37.0mg (yield 95%) of a white solid product,¹H NMR(500MHz,CDCl₃)7.34(q,J＝1.8Hz,1H),7.33(dd,J＝2.1,1.1Hz,1H),7.32-7.27(m,3H),7.27-7.23(m,4H),7.12-7.07(m,1H),7.02(dd,J＝8.1,7.5Hz,1H),6.94(dt,J＝8.2,1.0Hz,1H),6.79(dt,J＝7.5,1.1Hz,1H),5.16(s,1H),3.96(s,3H),2.40(s,3H).¹³C NMR(126MHz,CDCl₃)168.04,158.08,148.25,144.83,136.98,133.76,129.10,128.58,128.48,128.47,127.84,125.18,123.00,119.11,117.47,112.66,92.32,56.19,55.34,13.11, by chiral HPLC analysis, with the specific conditions (IA-H, 15% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 9.2min, t_R8.4min, 90:10, 98% ee.

The same reactants were taken according to example 1 and reacted under the same operating procedures with the following catalysts (7) -b in place of 0.01mmol, respectively, to obtain the results shown in Table 1 below:

in Table 1, the superscripts^aThe results show the yield of the separation,^bshows that the diastereoselectivity is obtained by chiral high performance liquid chromatography^cIndicating that the corresponding selectivity is obtained by chiral high performance liquid chromatography analysis.

TABLE 1

Numbering	Catalyst and process for preparing same	Reaction time (h)	Yield (%)^a	dr value^b	ee value (%)^c
						1	(4)-a	24	92	66:34	-60
2	(5)-a	24	95	70:30	-67
						3	(6)-a	24	92	85:15	96
4	(6)-b	24	90	82:18	90
						5	(7)-a	24	93	84:14	96
6	(7)-b	24	95	90:10	96
						7	(7)-c	24	93	80:20	92
8	(7)-d	24	60	79:21	94
						9	(7)-e	24	95	88:12	92
10	(7)-f	24	92	75:25	80
						11	(7)-g	24	87	75:25	81

The same reactants were taken according to example 1 and reacted under the same procedure with 0.26mol of the following inorganic bases, respectively, instead of potassium carbonate, with the results shown in Table 2 below:

TABLE 2

In Table 2, superscript^aThe results show the yield of the separation,^bshows that the diastereoselectivity is obtained by chiral high performance liquid chromatography^cShows that the corresponding selectivity is obtained by chiral high performance liquid chromatography analysis

The same reaction mixture was taken out according to example 1 and subjected to the same operation in the presence of 1.5ml of the following organic solvent in place of chloroform, respectively, to obtain the results shown in Table 3 below:

TABLE 3

Upper label^aThe results show the yield of the separation,^bshows that the diastereoselectivity is obtained by chiral high performance liquid chromatography^cShows that the corresponding selectivity is obtained by chiral high performance liquid chromatography analysis,^erepresents 1.5ml chloroform as the sole solvent^fRepresenting 1.5ml of water as the sole solvent.

Example 2:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-ethoxy-2-phenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 37.0mg (yield 93%) of a white solid product,¹H NMR(500MHz,CDCl₃)7.35–7.32(m,1H),7.32(dd,J＝2.1,1.1Hz,1H),7.31–7.29(m,1H),7.29–7.25(m,3H),7.25–7.23(m,3H),7.13–7.06(m,1H),6.99(dd,J＝8.2,7.4Hz,1H),6.97–6.90(m,1H),6.77(dt,J＝7.4,1.2Hz,1H),5.14(s,1H),4.21(q,J＝7.0Hz,2H),2.40(s,3H),1.49(t,J＝7.0Hz,3H).¹³C NMR(126MHz,CDCl₃)168.18,158.29,148.52,144.14,137.01,133.92,129.13,128.59,128.47,128.45,127.94,125.18,122.93,119.12,117.44,114.13,92.30,64.80,55.41,14.93,13.17. analysis by chiral HPLC, with the specific conditions (ID, 15% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 10.5min, t_R9.9min, 86:14dr, 92% ee.

Example 3:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 5-methoxy-2- (phenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 36.5mg (yield 95%) of a white solid product,¹H NMR(500MHz,CDCl₃)7.37–7.30(m,4H),7.30–7.24(m,4H),7.23(dd,J＝6.1,1.8Hz,2H),7.12–7.08(m,1H),7.07–7.03(m,1H),6.92(dd,J＝1.8,1.1Hz,1H),,5.13(s,1H),3.94(s,3H),2.40(s,3H).¹³C NMR(126MHz,CDCl₃)167.63,157.43,147.55,145.20,136.81,132.82,129.50,129.00,128.71,128.62,128.58,125.29,120.26,119.07,116.12,114.42,92.50,56.44,55.05,13.06, by chiral HPLC, with specific conditions (IC, 15% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 10.5min, t_R9.9min, 97:3dr, 93% ee.

Example 4:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-4-bromo-2- (4-methylphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 44mg (yield 95%) of the product as a white solid,¹H NMR(500MHz,CDCl₃)7.37–7.28(m,5H),7.28–7.24(m,2H),7.24–7.21(m,2H),7.12–7.04(m,2H),6.95–6.88(m,1H),,5.13(s,1H),3.94(s,3H),2.39(s,3H).¹³C NMR(126MHz,CDCl₃)167.67,157.47,147.59,145.24,136.84,132.85,129.03,128.75,128.66,128.62,128.15,125.32,120.30,119.11,116.15,114.45,92.54,56.47,55.08,13.10 by chiral HPLC analysis, with the specific conditions (OD-H, 4% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 17.0min, t_R(times) 20min, 80:20dr, 98% ee.

Example 5:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (4-fluorophenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operation were the same as in example 1 to give 38.1mg (yield 95%) of a white solid product,¹H NMR(500MHz,CDCl₃)7.41–7.36(m,2H),7.27(dd,J＝8.7,7.3Hz,2H),7.21(dd,J＝8.5,5.4Hz,2H),7.11(t,J＝7.4Hz,1H),7.04–6.92(m,4H),6.74(d,J＝7.5Hz,1H),5.13(s,1H),3.95(s,3H),2.38(s,3H).¹³C NMR(126MHz,CDCl₃)167.96,162.70(d, J-247.6 Hz),158.13,148.13,144.87,136.96,130.86(d, J-8.3 Hz),129.68(d, J-3.1 Hz),128.68,127.79,125.30,123.14,118.97,117.27,115.47(d, J-21.6 Hz),112.78,92.13,56.20,54.61,13.07. analysis by chiral HPLC, with the specific conditions (IA, 15% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 9.4min, t_R8.5min, 82:18dr, 98% ee.

Example 6:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (4-chlorophenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 38.9mg (yield 93%) of a solid product,¹H NMR(500MHz,CDCl₃)¹H NMR(500MHz,CDCl3)7.41–7.37(m,2H),7.30–7.27(m,2H),7.27–7.24(m,2H),7.19–7.16(m,2H),7.14–7.10(m,1H),7.04–6.99(m,1H),6.94(d,J＝8.2Hz,1H),6.73(dt,J＝7.6,1.1Hz,1H),5.11(s,1H),3.96(s,3H),2.37(s,3H).¹³C NMR(126MHz,CDCl₃)167.83,158.09,148.15,144.89,136.93,134.41,132.54,130.50,128.68,127.55,125.34,123.18,119.00,117.24,112.85,91.96,56.19,54.65,13.03, by chiral HPLC, with the specific conditions (IA, 15% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 10.1min, t_R9.1min, 82:18dr, 98% ee.

Example 7:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (4-trifluoromethylphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operation were the same as in example 1 to give 37.5mg (yield 83%) of a solid product,¹H NMR(500MHz,CDCl₃)7.55(d,J＝8.1Hz,2H),7.36(d,J＝8.1Hz,2H),7.32–7.29(m,2H),7.28–7.23(m,2H),7.14–7.09(m,1H),7.06–7.01(m,1H),6.96(d,J＝8.2Hz,1H),6.74(dt,J＝7.5,1.1Hz,1H),5.19(s,1H),3.96(s,3H),2.39(s,3H).¹³C NMR(126MHz,CDCl₃)167.68,158.05,148.26,144.98,138.25,136.75,130.68(q, J ═ 32.6Hz),129.64,128.69,127.09,125.49,125.41(q, J ═ 3.6Hz),123.86(q, J ═ 272.8Hz),123.32,119.07,117.21,112.97,91.95,56.21,54.98,13.07. analysis by chiral HPLC was carried out with the specific conditions (IC, 4% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 24.8min, t_R21.8min, 88:12dr, 96% ee.

Example 8:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (3-trifluoromethylphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and the operation were the same as in example 1 to obtain a solid product 43.0mg (yield 95%),¹H7.54–7.49(m,2H),7.44–7.40(m,2H),7.38–7.33(m,2H),7.28–7.23(m,2H),7.12–7.09(m,1H),7.04(dd,J＝8.2,7.5Hz,1H),6.96(dt,J＝8.2,1.0Hz,1H),6.74(dt,J＝7.4,1.1Hz,1H),5.19(s,1H),3.96(s,3H),2.39(s,3H).¹³C NMR(126MHz,CDCl₃)167.72,158.06,148.27,144.98,136.83,135.26,132.64,130.90(q, J ═ 32.6Hz),128.65,127.02,125.81(q, J ═ 3.7Hz),125.37(q, J ═ 3.5),125.35,123.79(q, J ═ 271),123.38,118.91,117.16,113.01,92.02,56.21,55.05,13.07. analysis by chiral HPLC was carried out with the specific conditions (IC, 5% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 14min, t_R(times) 11.5min, 81:19dr, 96% ee.

Example 9:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (2-trifluoromethylphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operation were the same as in example 1 to give 38mg (yield 84%) of the product, 7.62(d, J ═ 7.8Hz,1H), 7.59-7.48 (m,3H),7.38(t, J ═ 7.6Hz,1H), 7.33-7.24 (m,3H), 7.16-7.11 (m,1H), 7.04-6.91 (m,2H),6.64(d, J ═ 7.5Hz,1H),5.39(s,1H),4.12(s,3H),3.98(s,3H),2.21(s,3H).¹³C NMR(126MHz,CDCl₃)166.98,158.36,147.54,144.86,137.30,134.10,133.63,131.52,129.37,128.67,128.39(q, J ═ 29.2Hz),128.19,125.43(q, J ═ 5.7Hz),125.24,124.23(q, J ═ 272.08),123.60,119.15,117.30,112.69,90.12,56.19,49.81,12.71. analysis by chiral HPLC, specific conditions were (ID, 15% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 12.3min, t_R(times) 8.1min, 96:4dr, 99% ee.

Example 10:

the difference from the embodiment 1 is that: the substrate used is substituted benzeneThe phenol was 6-methoxy-2- (4-methylphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 38.7mg (yield 97%),¹H NMR(500MHz,CDCl₃)7.38(ddd,J＝8.7,2.0,1.1Hz,2H),7.29–7.24(m,2H),7.15–7.08(m,5H),7.04–6.98(m,1H),6.93(dt,J＝8.3,1.0Hz,1H),6.78(dt,J＝7.6,1.1Hz,1H),5.13(s,1H),3.96(s,3H),2.39(s,3H),2.29(s,3H).¹³C NMR(126MHz,CDCl₃)168.12,158.15,148.16,144.79,138.19,137.09,130.66,129.17,128.98,128.55,128.15,125.12,122.94,119.13,117.46,112.59,92.31,56.18,55.02,21.07,13.09. analysis by chiral HPLC was carried out with the specific conditions (IA, 15% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 9.9min, t_R8.8min, 85:15dr, 94% ee.

Example 11:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (3-methylphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 38.2mg (yield 96%),¹H NMR(500MHz,CDCl₃)7.39–7.34(m,2H),7.28–7.24(m,2H),7.20–7.15(m,1H),7.11–7.00(m,5H),6.93(d,J＝7.9Hz,1H),6.79(dd,J＝7.3,0.9Hz,1H),5.13(s,1H),3.96(s,3H),2.40(s,3H),2.27(s,3H).¹³C NMR(126MHz,CDCl₃)168.11,158.16,148.21,144.80,138.12,137.05,133.71,129.62,129.20,128.56,128.35,127.91,126.16,125.13,122.96,119.08,117.55,112.61,92.34,56.18,55.29,21.26,13.09. analysis by chiral HPLC was carried out with the specific conditions (IA, 5% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 12.2min, t_R13.8min, 85:15dr, 96% ee.

Example 12:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (2-methylphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 36.6mg (yield 92%) of the product,¹H NMR(500MHz,CDCl3)7.40(d,J＝7.8Hz,2H),7.30–7.26(m,2H),7.19–7.10(m,5H),7.01(t,J＝7.8Hz,1H),6.92(d,J＝8.1Hz,1H),6.70(d,J＝7.5Hz,1H),5.44(s,1H),3.97(s,3H),2.36(s,3H),2.30(s,3H).¹³C NMR(126MHz,CDCl₃)168.00,159.14,148.09,144.77,137.16,136.34,133.25,130.77,130.05,129.09,128.67,128.05,125.98,125.20,123.05,119.13,117.58,112.39,91.09,56.18,51.38,19.45,13.14. analysis by chiral HPLC, with the specific conditions (IA, 5% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 13.5min, t_R(times) 11.9min, 95:5dr, 96% ee.

Example 13:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (3-methoxyphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 40.3mg (yield 97%) of the product,¹H NMR(500MHz,CDCl₃)7.52(dd,J＝8.7,1.2Hz,2H),7.31–7.27(m,2H),7.23(ddd,J＝7.7,6.1,1.7Hz,2H),7.11(ddt,J＝8.6,7.2,1.2Hz,1H),7.03(t,J＝7.8Hz,1H),6.96–6.91(m,2H),6.84–6.74(m,2H),5.53(s,1H),3.95(s,3H),3.65(s,3H),2.33(s,3H).¹³C NMR(126MHz,CDCl₃)167.78,158.88,157.26,148.13,144.84,137.51,130.00,129.18,128.60,127.64,124.79,123.43,122.68,120.52,118.71,117.82,112.35,109.53,91.15,56.13,55.08,48.11,12.95 by chiral HPLC analysis, with the specific conditions (IA, 7% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 15.5min, t_R(times) 17.5min, 87:13dr, 97% ee.

Example 14:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (2-methoxyphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 39.8mg (yield 96%),¹H NMR(500MHz,CDCl₃)7.52–7.44(m,2H),7.28–7.18(m,4H),7.10–7.06(m,1H),7.00(dd,J＝8.1,7.5Hz,1H),6.93–6.88(m,2H),6.79(dt,J＝7.6,1.1Hz,1H),6.74(dd,J＝8.2,1.1Hz,1H),5.50(s,1H),3.92(s,3H),3.62(s,3H),2.30(s,3H).¹³C NMR(126MHz,CDCl₃)167.81,158.92,157.29,148.17,144.87,137.54,130.05,129.22,128.64,127.67,124.83,123.46,122.71,120.56,118.75,117.86,112.37,109.56,91.19,56.16,55.11,48.14,12.99. analysis by chiral HPLC, with the specific conditions (IC, 15% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 26min, t_R(times) ═ 20.2min, 95:15dr, 98% ee.

Example 15:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (3, 4-methyleneoxyphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operation were the same as in example 1 to give 41.1mg (yield 96%),¹H NMR(500MHz,CDCl3)7.47(dt,J＝8.7,1.6Hz,2H),7.31–7.27(m,2H),7.14–7.10(m,1H),7.01(t,J＝7.8Hz,1H),6.92(d,J＝8.1Hz,1H),6.79–6.68(m,4H),5.89(dd,J＝9.9,1.4Hz,2H),5.07(s,1H),3.95(s,3H),2.36(s,3H).¹³C NMR(126MHz,CDCl₃)168.07,158.13,148.04,147.75,147.66,144.80,137.18,128.63,128.03,127.42,125.14,123.02,122.68,118.97,117.42,112.69,109.49,108.13,101.11,92.18,56.16,55.10,13.05 by chiral HPLC analysis, with the specific conditions (IA, 4% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 37.0min, t_R(times) 39.8min, 80:20dr, 94% ee.

Example 16:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (1-naphthyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operation were the same as in example 1 to give 41.7mg (yield 96%),¹H NMR(500MHz,CDCl₃)7.83–7.73(m,3H),7.43–7.35(m,3H),7.26–7.22(m,1H),7.14–7.08(m,2H),7.06–6.97(m,4H),6.93(d,J＝8.1Hz,1H),6.78(d,J＝7.5Hz,1H),5.89(s,1H),3.95(s,3H),2.41(s,3H).¹³C NMR(125MHz,CDCl₃)167.46,158.71,148.16,144.95,136.81,133.54,131.88,131.62,129.12,128.72,128.49,128.38,128.18,126.48,125.63,125.25,125.13,123.16,121.40,119.25,118.06,112.51,90.88,56.14,50.36,13.13, by chiral HPLC, with the specific conditions (IA, 15% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 15.8min, t_R10.6min, 96:4dr, 99% ee.

Example 17:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (2-naphthyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operation were the same as in example 1 to give 32.6mg (yield 75%),¹H NMR(500MHz,CDCl₃)7.83–7.73(m,3H),7.43–7.35(m,3H),7.26–7.22(m,1H),7.14–7.08(m,2H),7.06–6.97(m,4H),6.93(d,J＝8.1Hz,1H),6.78(d,J＝7.5Hz,1H),5.89(s,1H),3.95(s,3H),2.41(s,3H).¹³C NMR(125MHz,CDCl₃)171.04,158.41,147.67,145.05,137.65,133.20,132.46,128.95,127.93,127.75,127.39,127.19,126.65,126.55,125.99,125.50,123.19,119.06,117.91,91.82,56.87,56.20,14.57 analysis by chiral HPLC, with the specific conditions (OD-H, 50% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 9.5min, t_R35.5min, 68:32dr, 99% ee.

Example 18:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (2-furyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 34.4mg (yield 92%) of the product,¹H NMR(500MHz,CDCl3)7.63(dt,J＝8.8,1.6Hz,2H),7.36–7.29(m,3H),7.19–7.13(m,1H),7.05–7.00(m,1H),6.92(t,J＝7.4Hz,2H),6.34–6.28(m,2H),5.34(s,0H),5.23(s,1H),3.94(s,3H),2.33(s,3H).¹³C NMR(126MHz,CDCl₃)167.53,157.88,148.91,144.85,142.92,137.40,128.87,128.70,125.74,125.16,123.10,118.94,117.30,113.05,110.74,109.58,90.42,56.19,48.56,12.97, by chiral HPLC, with the specific conditions (IC, 15% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 26min, t_R17.6min, 83:17dr, 85% ee.

Example 19:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (2-thienyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 35.5mg (yield 91%),¹H NMR(500MHz,CDCl3)7.50(dt,J＝8.8,1.6Hz,2H),7.32–7.27(m,2H),7.21(dd,J＝5.1,1.2Hz,1H),7.15–7.11(m,1H),7.04–7.00(m,2H),6.98–6.89(m,3H),5.42(s,1H),3.95(s,3H),2.37(s,3H).¹³C NMR(126MHz,CDCl₃)167.62,157.72,147.70,144.77,137.11,135.90,128.64,127.79,127.61,127.16,125.83,125.20,123.09,119.03,117.32,113.05,91.90,56.19,50.14,13.05. analysis by chiral HPLC, with the specific conditions (IC, 15% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 25.2min, t_R19.2min, 87:13dr, 92% ee.

Example 20:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (methyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 18.0mg (yield 56%),¹H NMR(500MHz,CDCl3)7.92–7.82(m,2H),7.45–7.36(m,2H),7.24–7.16(m,1H),6.96(td,J＝7.8,5.9Hz,1H),6.87–6.75(m,2H),3.90(s,3H),3.87(q,J＝7.5Hz,1H),2.20(s,3H),1.43(d,J＝7.1Hz,3H).¹³C NMR(126MHz,CDCl₃)168.52,158.98,146.64,144.57,137.64,130.66,128.87,125.22,122.94,118.73,115.83,112.26,91.35,56.12,43.15,14.09,12.94, by chiral HPLC analysis, with the specific conditions (IC, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 12.5min, t_R49.5min, 66:34dr, 60% ee.

Example 21:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (ethyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 21.8mg (yield 65%) of the product,¹H NMR(500MHz,CDCl₃)7.86–7.83(m,2H),7.42–7.37(m,2H),7.21–7.17(m,1H),6.94(dd,J＝8.6,7.1Hz,1H),6.83(d,J＝8.1Hz,2H),3.89(s,3H),3.75–3.66(m,1H),2.20(s,3H),2.04–1.96(m,2H),0.99(t,J＝7.5Hz,3H).¹³C NMR(125MHz,CDCl₃)168.37,159.41,146.54,144.65,137.63,130.17,128.90,125.27,122.72,118.82,116.30,112.18,90.55,56.09,50.37,23.37,12.97,12.38 by chiral HPLC analysis, with specific conditions (IC, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main ═12.6min,t_R(times) 61.8min, 83:17dr, 60% ee.

Example 22:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 2- (phenyl (p-toluenesulfonyl) methyl) phenol, and other reaction conditions and operation were the same as in example 1,

33.2mg (yield 94%) of the product are obtained,¹H NMR(500MHz,CDCl₃)7.26–7.23(m,3H),7.20–7.11(m,8H),6.99–6.94(m,3H),5.01(s,1H),2.26(s,3H).¹³C NMR(125MHz,CDCl₃)168.44,160.01,158.56,136.99,134.06,129.46,129.07,128.60,128.51,128.48,128.15,126.62,125.62,125.19,122.21,119.01,110.51,92.02,55.15,13.05 by chiral HPLC analysis, with the specific conditions (IA, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 11.3min, t_R7.0min, 72:18dr, 50% ee.

Example 23:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 2- (2-methoxyphenyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operating procedures were the same as in example 1 to give 36.9mg (yield 96%),¹H NMR(500MHz,CDCl₃)7.48–7.42(m,2H),7.22–7.16(m,4H),7.12–7.06(m,2H),7.03–6.92(m,3H),6.84(td,J＝7.5,1.1Hz,1H),6.67(d,J＝8.2Hz,1H),5.38(s,1H),3.53(s,3H),2.20(s,3H).¹³C NMR(125MHz,CDCl₃)168.16,159.88,159.27,157.27,137.57,129.88,129.24,129.20,128.66,126.40,125.97,124.79,123.71,121.94,120.58,118.61,110.48,109.55,90.87,55.11,47.84,12.94, by chiral HPLC analysis, with the specific conditions (ID, 20% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) ═ 13.3min, t_R(times) 20.5min, 83:17dr,61％ee。

Example 24:

the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2- (4-fluorophenyl) -5-methylpyrazolone, and other reaction conditions and operation were the same as in example 1 to obtain 33.4mg (yield 83%),¹H NMR(500MHz,CDCl3)7.31–7.22(m,7H),7.05–6.99(m,1H),6.93(t,J＝8.7Hz,3H),6.78(d,J＝7.5Hz,1H),5.16(s,1H),3.96(s,3H),2.40(s,3H).¹³C NMR(126MHz,CDCl₃)168.00,160.01(d, J ═ 244.6Hz),158.29,148.25,144.86,133.72,133.07(d, J ═ 2.7Hz),129.10,128.53,128.51,127.73,123.09,120.96(d, J ═ 8.1Hz),117.49,115.36(d, J ═ 22.7Hz),112.71,92.35,56.21,55.42,13.10. analysis by chiral HPLC, specific conditions were (IA, 10% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 10.4min, t_R9.7min, 89:11dr, 98% ee.

Example 25:

the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2- (4-bromophenyl) -5-methylpyrazolone, and the other reaction conditions and operating procedures were the same as in example 1, whereby 36.5mg (yield 79%) of the product was obtained,¹H NMR(500MHz,CDCl3)7.39–7.33(m,2H),7.30–7.25(m,5H),7.22(dd,J＝7.5,1.9Hz,2H),7.02(t,J＝7.8Hz,1H),6.94(s,1H),6.78(d,J＝7.5Hz,1H),5.15(s,1H),3.96(s,3H),2.40(s,3H).¹³C NMR(126MHz,CDCl₃)168.01,158.50,148.17,144.83,136.05,133.60,131.61,129.02,128.55,128.50,127.64,123.12,120.25,117.99,117.46,112.70,92.34,56.18,55.43,13.11. analysis by chiral HPLC, with the specific conditions (AD-H, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 10.1min, t_R(times) 8.4min, 99:1dr, 98% ee.

Example 26:

the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2- (4-bromophenyl) -5-methylpyrazolone, and the other reaction conditions and operating procedures were the same as in example 1, to give 40.7mg (yield 88%) of the product,¹H NMR(500MHz,CDCl₃)7.55(t,J＝2.0Hz,1H),7.33(ddd,J＝8.2,2.1,1.0Hz,1H),7.28–7.24(m,3H),7.21–7.16(m,3H),7.07(t,J＝8.1Hz,1H),7.02–6.98(m,1H),6.92(d,J＝8.2Hz,1H),6.76(dt,J＝7.6,1.1Hz,1H),5.13(s,1H),3.94(s,3H),2.38(s,3H).¹³C NMR(125MHz,CDCl₃)168.09,158.58,148.15,144.84,138.12,133.52,129.94,129.04,128.61,128.56,127.99,127.67,123.15,122.26,121.59,117.47,117.11,112.71,92.40,56.21,55.47,13.14, by chiral HPLC, with specific conditions (IC, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) ═ 13.3min, t_R10.8min, 98:2dr, 98% ee.

Example 27:

the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2- (2, 3, 4,5, 6-pentafluorophenyl) -5-methylpyrazolone, other reaction conditions and operating procedures were the same as in example 1, giving 42.9mg (yield 91%),¹H NMR(500MHz,CDCl3)7.37–7.32(m,3H),7.26–7.21(m,2H),7.03(t,J＝7.8Hz,1H),6.94(d,J＝8.1Hz,1H),6.77(dt,J＝7.6,1.1Hz,1H),5.20(s,1H),3.98(s,3H),2.38(s,3H),1.30(d,J＝14.3Hz,1H).¹³C NMR(126MHz,CDCl₃)168.69,159.88,147.81,144.89,144.81-144.63(m),142.76-142.57(m),140.67-140.40(m),138.81-138.51(m),136.79-136.51(m),133.21,129.18,128.74,128.73,127.70,123.34,117.41,112.60,111.50-111.24(m),90.51,56.14,55.50,13.13. analysis by chiral HPLC, specific conditions are (IC, 10% iPrOH in hexane, flow rate 1.0ml/min):t_R(main) ═ 19.3min, t_R17.9min, 90:10dr, 99% ee.

Example 28:

the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2- (4-methylphenyl) -5-methylpyrazolone, and the other reaction conditions and operating procedures were the same as in example 1, giving 33.4mg (yield 84%),¹H NMR(500MHz,CDCl3)7.30–7.23(m,5H),7.19(d,J＝8.5Hz,2H),7.03(dd,J＝20.3,8.1Hz,3H),6.93(d,J＝8.1Hz,1H),6.79(d,J＝7.5Hz,1H),5.15(s,1H),3.96(s,3H),2.39(s,3H),2.28(s,3H).¹³C NMR(126MHz,CDCl₃)167.90,157.89,148.29,144.82,134.94,134.53,133.81,129.12,128.46,128.43,127.89,122.95,119.26,117.48,112.66,92.31,56.19,55.30,20.88,13.08. analysis by chiral HPLC, with the specific conditions (IC, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 22.3min, t_R(times) 20.3min, 92:8dr, 98% ee.

Example 29:

the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2- (2-ethylphenyl) -5-methylpyrazolone, and the other reaction conditions and operating procedures were the same as in example 1, giving 33.6mg (yield 81%),¹H NMR(500MHz,CDCl₃)7.33–7.30(m,2H),7.26–7.19(m,7H),7.08–7.04(m,1H),7.00–6.95(m,1H),6.90(d,J＝8.1Hz,1H),6.75(dt,J＝7.5,1.1Hz,1H),5.22(s,1H),3.93(s,3H),3.08(hept,J＝7.0Hz,1H),1.49(d,J＝6.8Hz,3H),1.41(d,J＝7.0Hz,3H).¹³C NMR(125MHz,CDCl₃)168.26,164.80,148.36,144.91,137.13,134.01,129.12,128.53,128.43,128.40,127.93,125.07,122.85,119.12,117.55,112.94,93.13,56.31,55.53,28.18,21.30,20.06 analysis by chiral HPLC, with the specific conditions (ID, 7% iPrOH in h)exane,flow rate 1.0ml/min):t_R(main) 21.2min, t_R24.9min, 85:815dr, 95% ee.

Example 30:

the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2- (2-naphthyl) -5-methylpyrazolone, and other reaction conditions and operation procedures were the same as in example 1 to give 41.7mg (yield 96%),¹H NMR(500MHz,CDCl3)8.38(d,J＝1.9Hz,1H),8.11(dd,J＝8.9,2.2Hz,1H),7.94–7.84(m,3H),7.50(dddd,J＝20.9,8.1,6.9,1.3Hz,2H),7.38–7.33(m,3H),7.24–7.20(m,2H),7.10–7.06(m,1H),6.99–6.89(m,2H),5.40(t,J＝0.9Hz,1H),3.97(s,3H),1.65(s,3H).¹³C NMR(126MHz,CDCl₃)171.12,158.61,147.58,144.95,135.19,134.99,133.42,131.16,128.99,128.79,128.47,128.21,127.98,127.60,127.28,126.53,125.50,123.10,118.23,117.80,116.15,112.61,91.83,56.71,56.13,14.43, by chiral HPLC analysis, with the specific conditions (ID, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 20.9min, t_R16.3min, 80:20dr, 94% ee.

Example 31:

the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2-cyclohexyl-5-methylpyrazolone, and the other reaction conditions and operating procedures were the same as in example 1, giving 35.1mg (yield 90%) of the product,¹H NMR(500MHz,CDCl₃)7.30–7.27(m,3H),7.18(dd,J＝6.6,2.9Hz,2H),6.96(dd,J＝8.1,7.5Hz,1H),6.88(d,J＝8.1Hz,1H),6.73(dt,J＝7.5,1.1Hz,1H),,5.03(s,1H),3.93(s,3H),3.52–3.44(m,1H),2.27(s,3H),1.75–1.65(m,2H),1.62–1.51(m,3H),1.27–1.00(m,5H),0.88–0.81(m,1H).¹³C NMR(125MHz,CDCl₃)168.59,156.35,148.35,144.75,133.82,129.20,128.35,128.23,128.12,122.69,117.34,112.33,92.45,56.06,54.88,51.98,30.32,29.73,25.21,25.19,25.09,12.97, analysis by chiral HPLC, with specific conditions (ID, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 11.2min, t_R9.4min, 82:18dr, 98% ee.

Example 32:

the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2-phenyl-5-ethylpyrazolone, and the other reaction conditions and operating procedures were the same as in example 1, giving 36.6mg (yield 92%),¹H NMR(500MHz,CDCl3)7.39–7.34(m,2H),7.30–7.21(m,7H),7.09(t,J＝7.4Hz,1H),7.01(t,J＝7.8Hz,1H),6.93(d,J＝8.1Hz,1H),6.78(d,J＝7.5Hz,1H),5.17(s,1H),3.96(s,3H),2.77(dd,J＝7.4,3.7Hz,2H),1.44(t,J＝7.4Hz,3H).¹³C NMR(126MHz,CDCl₃)168.29,161.96,148.29,144.85,137.16,133.96,129.11,128.56,128.47,128.43,127.93,125.11,122.94,119.12,117.51,112.74,92.51,56.24,55.55,20.74,9.41. analysis by chiral HPLC, with the specific conditions (IA, 7% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 9.8min, t_R9.4min, 94:6dr, 97% ee.

Example 33:

the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2-phenyl-5-n-propylpyrazolone, and other reaction conditions and operation were the same as in example 1, whereby 37.5mg (yield 91%) of the product was obtained,¹H NMR(500MHz,CDCl₃)7.35(dt,J＝8.9,1.8Hz,2H),7.29–7.23(m,7H),7.12–7.07(m,1H),7.01(t,J＝7.8Hz,1H),6.93(dt,J＝8.1,1.0Hz,1H),6.78(dt,J＝7.6,1.1Hz,1H),5.18(s,1H),3.96(s,3H),2.76–2.64(m,2H),1.95(h,J＝7.4Hz,2H),1.14(t,J＝7.4Hz,3H).¹³C NMR(126MHz,CDCl₃)168.23,160.95,148.30,144.83,137.11,133.93,129.11,128.54,128.45,128.41,127.91,125.09,123.10,119.09,117.49,112.75,92.60,56.19,55.48,29.29,18.64,14.05. analysis by chiral HPLC, with the specific conditions (IA, 7% iPrOH in hexane, flow rate 0.7ml/min): t_R(main) 9.0min, t_R8.5min, 91:9dr, 87% ee.

Example 34:

the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2-phenyl-5-isopropyl pyrazolone, and other reaction conditions and operation procedures were the same as in example 1 to give 37.0mg (yield 90%),¹H NMR(500MHz,CDCl₃)7.33–7.30(m,2H),7.26–7.19(m,7H),7.08–7.04(m,1H),7.00–6.95(m,1H),6.90(d,J＝8.1Hz,1H),6.75(dt,J＝7.5,1.1Hz,1H),5.22(s,1H),3.93(s,3H),3.08(hept,J＝7.0Hz,1H),1.49(d,J＝6.8Hz,3H),1.41(d,J＝7.0Hz,3H).¹³C NMR(125MHz,CDCl₃)168.26,164.80,148.36,144.91,137.13,134.01,129.12,128.53,128.43,128.40,127.93,125.07,122.85,119.12,117.55,112.94,93.13,56.31,55.53,28.18,21.30,20.06. analysis by chiral HPLC, with the specific conditions (ID, 5% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 9.1min, t_R10.9min, 93:7dr, 95% ee.

Example 35:

the difference from the embodiment 1 is that: the substrate pyrazolone used was 4-bromo-2-phenyl-5-phenylpyrazolone, and other reaction conditions and operation were the same as in example 1 to give 38.4mg (yield 86%),¹H NMR(500MHz,CDCl₃)¹H NMR(500MHz,CDCl3)8.10–8.04(m,2H),7.54–7.47(m,3H),7.41–7.36(m,2H),7.30–7.25(m,5H),7.22(dd,J＝7.5,2.0Hz,2H),7.16–7.11(m,1H),7.09–7.03(m,1H),7.00(d,J＝8.1Hz,1H),6.80(dt,J＝7.4,1.2Hz,1H),5.42(s,1H),4.00(s,3H).¹³C NMR(125MHz,CDCl₃)168.53,155.48,148.20,145.16,136.91,133.68,130.97,129.19,129.17,129.15,128.61,128.48,127.85,126.81,125.52,123.12,119.50,117.69,113.12,92.89,57.12,56.40 by chiral HPLC analysis, with the specific conditions (ID, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 11.4min, t_R12.7min, 93:7dr, 95% ee.

Claims

1. A synthetic method of a chiral 4-spiro pyrazole compound shown in a formula (3) is characterized by comprising the following steps: the synthesis method comprises the following steps:

in a water-oil two-phase system, taking a compound shown in a formula (1) and a compound shown in a formula (2) as raw materials, reacting at 20-30 ℃ under the action of an acid-binding agent and a chiral catalyst to obtain a reaction solution, and performing post-treatment to obtain a chiral 4-spiro pyrazole compound shown in a formula (3); the ratio of the amount of the compound represented by the formula (1) to the amount of the compound represented by the formula (2) and the acid-binding agent is 0.2-5: 1: 0.5 to 20; the amount ratio of the chiral catalyst to the compound represented by the formula (1) is 0.01 to 100: 100, respectively; the chiral catalyst is a bifunctional tertiary amine-azodicarbonic acid catalyst, which comprises a tertiary amine group containing a hydrogen bond donor azodicarbonic acid group and Lewis base function; the acid-binding agent is inorganic alkali; the water-oil two-phase system is prepared by mixing water and an organic solvent in a volume ratio of 1: 0.05-10 parts by weight;

in the formula (1), Ts represents a p-toluenesulfonyl group;

in the formula (1) or (3),

R¹is H, methoxy, ethoxy or halogen;

R²is C_1-20Alkyl, furyl, thienyl, naphthyl, phenyl or phenyl substituted by one or more substituents each independently being methyl, methoxy, tri-nFluoromethyl or halogen;

in the formula (2) or the formula (3),

R³is C_1-20Alkyl, naphthyl, phenyl or phenyl substituted with one or more substituents each independently being methyl, ethyl or halogen,

R⁴is C_1-20Alkyl or phenyl of (a);

the chiral catalyst is one of the following compounds:

in the formulae (4), (5) and (6),

R⁵、R⁸、R¹¹each independently is C₁～C₂₀Or phenyl or benzyl substituted with one or more substituents each independently being trifluoromethyl, nitro or halogen;

R¹²is ethyl or vinyl;

R¹³is H, hydroxyl or methoxyl.

2. The method of claim 1, wherein: the chiral catalyst is selected from one of the following:

3. the method of claim 1, wherein: the ratio of the amount of the compound represented by the formula (1) to the amount of the compound represented by the formula (2) and the acid-binding agent is 0.5-2: 1:1 to 10.

4. The method of claim 1, wherein: in the water-oil two-phase system, the organic solvent is selected from dichloromethane, chloroform, 1, 2-dichloroethane, diethyl ether, toluene, ethyl acetate or isopropyl acetate.

5. The method of claim 1, wherein: the acid-binding agent is sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide or disodium hydrogen phosphate.

6. The method of claim 1, wherein: the post-treatment method of the reaction solution comprises the following steps: after the reaction is finished, separating the reaction liquid, taking the organic phase, concentrating under reduced pressure, and then performing silica gel column chromatography separation, wherein the volume ratio of petroleum ether to ethyl acetate is 1-30: the mixed solution of 1 is used as eluent to carry out gradient elution, eluent containing a target compound is collected, the solvent is evaporated and dried, and the chiral 4-spiro pyrazole compound shown in the formula (3) is obtained.