CN109896999B

CN109896999B - Synthesis method of pyrazolone compound containing adjacent tertiary carbon-quaternary carbon chiral center

Info

Publication number: CN109896999B
Application number: CN201910102602.0A
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: 2019-01-31
Filing date: 2019-01-31
Publication date: 2020-10-23
Anticipated expiration: 2039-01-31
Also published as: CN109896999A

Abstract

The invention provides a synthesis method of pyrazolone compounds containing adjacent tertiary carbon-quaternary carbon chiral centers, which is shown in a formula (3). in a water-oil two-phase system, 2- (aryl (p-toluenesulfonyl) methyl) phenol shown in a raw material formula (1) and 4-benzyl pyrazolone shown in a formula (2) react under the action of an acid binding agent and a chiral catalyst, TLC (thin layer chromatography) tracking monitoring is carried out until the reaction is complete, and then reaction liquid is subjected to post-treatment to obtain the product pyrazolone compounds containing adjacent tertiary carbon-quaternary carbon chiral centers, which is shown in the formula (3); the invention is widely applied to the fields of pesticides and medicines, and has the advantages of wide application prospect, mild synthesis conditions, high yield, good asymmetric selectivity, wide range of reaction substrates, cheap and easily-obtained reaction reagents and strong operability.

Description

Synthesis method of pyrazolone compound containing adjacent tertiary carbon-quaternary carbon chiral center

Technical Field

The invention relates to a method for synthesizing pyrazolone compounds containing adjacent tertiary carbon-quaternary carbon chiral centers, in particular to a method for synthesizing pyrazolone compounds containing adjacent tertiary carbon-quaternary carbon chiral centers by asymmetric conjugate addition of raw materials of 4-benzyl pyrazolone and 2- (aryl (p-toluenesulfonyl) methyl) phenol under catalysis of chiral tertiary amine-azosquaric acid in an aqueous-oil two-phase system.

Background

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 reactions based on hydrogen bond catalysis have been greatly developed, and catalysts comprising 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 effects in many asymmetric catalytic reactions, and have 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 Invention

The invention aims to provide a method for synthesizing pyrazolones containing adjacent tertiary carbon-quaternary carbon chiral centers in two phases of water and oil.

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

a synthetic method of pyrazolone compounds containing adjacent tertiary carbon-quaternary carbon chiral centers shown in formula (3) comprises the following steps:

in a water-oil two-phase system, 2- (aryl (p-toluenesulfonyl) methyl) phenol shown in a formula (1) and 4-benzyl pyrazole shown in a formula (2) are reacted under the action of an acid binding agent and a chiral catalyst, TLC (thin layer chromatography) tracking monitoring is carried out until the reaction is completed, and then reaction liquid is subjected to post-treatment to obtain the pyrazolone compound containing the adjacent tertiary carbon-quaternary carbon chiral center shown in the formula (1).

The reaction formula is as follows:

in the formula (1), Ts is p-toluenesulfonyl;

in the formulae (1), (2) and (3),

R¹is H, methoxy, ethoxy or halogen;

R²is alkyl, 1-naphthyl, 2-naphthyl, phenyl or phenyl substituted with one or more substituents each independently being methyl, hexyl, methoxy, trifluoromethyl, trifluoromethoxy, phenyl or halogen;

R³is 2-naphthyl or phenyl substituted by one or more substituents, each of which is independently methyl, ethyl, methoxy or halogen.

R⁴Is methyl, ethyl, isopropyl, phenyl or substituted by oneOr phenyl substituted with a plurality of substituents, wherein each substituent is independently methyl, hexyl, methoxy, trifluoromethyl, trifluoromethoxy, phenyl or halogen.

The synthesis method comprises the following steps: the reaction is usually carried out at normal temperature (20 to 30 ℃).

Preferably, the ratio of the amount of the 2- (aryl (p-toluenesulfonyl) methyl) phenol represented by the formula (1) to the amount of the 4-benzylpyrazole represented by the formula (2) is 0.2 to 5: 1, preferably 0.5 to 2: 1.

preferably, the ratio of the amount of the chiral catalyst to the amount of the 2- (aryl (p-toluenesulfonyl) methyl) phenol represented by the formula (1) is 0.01 to 100: 100, preferably 0.1 to 20: 1.

preferably, the amount ratio of the acid scavenger to the 2- (aryl (p-toluenesulfonyl) methyl) phenol represented by the formula (2) is 0.5 to 20: 1, preferably 1 to 10: 1.

preferably, the volume ratio of the water to the organic solvent in the water-oil two-phase system is 1: 0.05-10, wherein the organic solvent is selected from dichloromethane, chloroform, 1, 2-dichloroethane, diethyl ether, toluene, ethyl acetate or isopropyl acetate.

Preferably, the acid scavenger is a commonly used inorganic base, such as: sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, or disodium hydrogen phosphate.

Preferably, the post-treatment method of the reaction solution is as follows: 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 pyrazolone compound containing the adjacent tertiary carbon-quaternary carbon chiral center shown in the formula (1) is obtained.

Preferably, the chiral catalyst contains at least one of tertiary amine and nitrogen squaric acid functional groups.

Preferably, the chiral catalyst is selected from one of the following compounds represented by the formulas (4) to (7):

in the formulae (4) and (5), the carbon atom denoted by x is a chiral carbon atom.

In the formulae (4), (5), (6), (7),

R⁵、R⁸、R¹¹、R¹⁴each independently is C1-C20 alkyl, or phenyl or benzyl substituted by one or more substituents, each independently is trifluoromethyl, nitro or halogen;

R⁶、R⁷、R⁹、R¹⁰each independently is a C1-C10 alkyl group;

R¹²、R¹⁵each independently is ethyl or vinyl;

R¹³、R¹⁶each independently is H, hydroxy or methoxy.

More preferably, the chiral catalyst is selected from one of the following:

the invention has the beneficial effects that: according to the synthesis method, a chiral catalyst containing at least one tertiary amine and a azosquaric acid functional group is used as a catalytic system, reaction is carried out in water and oil phases, and the product pyrazolone compound containing adjacent tertiary carbon-quaternary carbon chiral centers is obtained through post-treatment separation. The synthesis method has the advantages of mild conditions, high yield, good asymmetric selectivity, wide range of reaction substrates and cheap and easily-obtained reaction reagents.

Detailed Description

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

Example 1:

after the completion of the addition of catalyst IVb (0.005mmol, 3.15mg), 6-methoxy-2- (phenyl (p-toluenesulfonyl) methyl) phenol (0.1mmol, 36.8mg), 4-benzylpyrazolone (0.13mmol, 33.0mg), potassium carbonate (0.12mmol, 16.6mg), 1.2-dichloroethane (1.5ml), and water (0.5ml) were added in this order to a dry 10ml reaction tube, the reaction tube was closed, stirred at room temperature for 12 hours using a magnetic stirrer, and TLC showed the completion of the consumption of 6-methoxy-2- (phenyl (p-toluenesulfonyl) methyl) phenol and the reaction solution was CH-substituted₂Cl₂Extracting 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 a white solid product (yield 93%),¹H NMR(500MHz,CDCl₃)7.70(d,J＝8.1Hz,1H),7.44(dd,J＝26.6,7.8Hz,4H),7.31(t,J＝7.9Hz,2H),7.23(t,J＝7.4Hz,2H),7.15(dq,J＝23.1,7.6Hz,7H),6.92(t,J＝8.1Hz,1H),6.81(d,J＝8.0Hz,1H),6.15(s,1H),5.19(s,1H),3.88(s,3H),3.41(d,J＝13.6Hz,1H),3.14(d,J＝13.6Hz,1H),2.22(s,3H).¹³C NMR(126MHz,CDCl₃)174.47,161.62,146.27,143.71,139.26,137.50,134.94,129.24,128.85,128.56,128.48,128.15,127.23,127.09,125.29,124.49,123.94,120.14,119.21,109.33,63.78,56.00,46.78,40.82,15.16 by chiral HPLC analysis, with the specific conditions (IA-H, 30% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 7.56min, t_R(times) 11.13min, 97:3, 99% ee.

The same reactants were taken and reacted under the same operation procedures with the following catalysts (7) -b replaced with 0.01mmol, respectively, of the following catalysts, and the results are shown in the following Table 1:

TABLE 1

Numbering	Catalyst and process for preparing same	Reaction time (h)	Yield (%)^a	dr value^b	ee value (%)^c
						1	(4)-a	12	85	95:5	90
2	(5)-a	12	80	95:5	89
						3	(6)-a	12	91	94:6	-90
4	(6)-b	12	89	95:5	-98
						5	(7)-a	12	90	96:4	99
6	(7)-b	12	92	96:4	99
						7	(7)-c	12	93	91:9	99
8	(7)-d	12	85	94:6	99
						9	(7)-e	12	87	90:10	98
10	(7)-f	12	92	62:38	97
						12	(7)-g	12	87	39:61	84

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^cShows that the corresponding selectivity is obtained by chiral high performance liquid chromatography analysis

The same reactants were taken and reacted under the same operation procedures with 0.12mol of the following inorganic bases instead of potassium carbonate, respectively, and the results are shown in the following Table 2:

TABLE 2

Numbering	Acid-binding agent	Reaction time (h)	Yield (%)^a	dr value^b	ee value (%)^c
						1	Na₂CO₃	12	91	96:4	99
2	CsCO₃	12	90	96:4	99
						3	NaOH	12	90	86:14	91
4	Et₃N	24	78	85:15	94

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 and subjected to the same operation procedure in which 1.5ml of the following organic solvents were used instead of chloroform, respectively, and the results are shown in the following Table 3:

TABLE 3

Numbering	Organic solvent	Reaction time (h)	Yield (%)^a	dr value^b	ee value (%)^c
						1	DCM	12	85	95:5	99
2	DCE	12	93	97:3	99
						3	PhCH₃	12	93	95:5	99
4	THF	12	46	62:38	56
						5^d	DCE	12	85	70:30	74
6^e	no	12	25	65:35	44

In Table 3, 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,^drepresents 1.5ml of 1.2-dichloroethane as the sole solvent^eRepresenting 1.5ml of water as the sole solvent.

The same reactants were used and the reaction was carried out under the same operation steps and with different catalytic amounts of (7) -b, and the results are shown in the following table 4:

TABLE 4

Numbering	Amount of catalyst (mol%)	Reaction time (h)	Yield (%)^a	dr value^b	ee value (%)^c
						1	10	12	93	97:3	99
2	5	12	93	97:3	99
						3	2.5	12	90	95:5	99
4	1	12	90	92:8	98

In Table 4, superscript^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.

Example 2:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-ethoxy-2-phenyl (p-toluenesulfonyl) methyl) phenol, the other reaction conditions and the operation were the same as in example 1, and the yield was 93%,¹H NMR(500MHz,CDCl₃)7.70(d,J＝8.1Hz,1H),7.44(dd,J＝26.6,7.8Hz,4H),7.31(t,J＝7.9Hz,2H),7.23(t,J＝7.4Hz,2H),7.15(dq,J＝23.1,7.6Hz,7H),6.92(t,J＝8.1Hz,1H),6.81(d,J＝8.0Hz,1H),6.15(s,1H),5.19(s,1H),3.88(s,3H),3.41(d,J＝13.6Hz,1H),3.14(d,J＝13.6Hz,1H),2.22(s,3H).¹³C NMR(126MHz,CDCl₃)174.47,161.62,146.27,143.71,139.26,137.50,134.94,129.24,128.85,128.56,128.48,128.15,127.23,127.09,125.29,124.49,123.94,120.14,119.21,109.33,63.78,56.00,46.78,40.82,15.16 by chiral HPLC analysis, with the specific conditions (ID, 30% iPrOH in hexane, flow rate0.7ml/min): t_R(main) 10.68min, t_R43.44min, 88:12dr, 99% ee.

Example 3:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-5-bromo-2- (phenyl (p-toluenesulfonyl) methyl) phenol, the other reaction conditions and the operation were the same as in example 1, the yield was 96%,¹H NMR(500MHz,CDCl₃)7.94(d,J＝2.0Hz,1H),7.44(d,J＝7.7Hz,2H),7.38(d,J＝7.3Hz,2H),7.32(t,J＝7.9Hz,2H),7.24(t,J＝7.3Hz,2H),7.17(dt,J＝23.2,7.8Hz,7H),6.92(d,J＝2.2Hz,1H),6.16(s,1H),5.11(s,1H),3.85(s,3H),3.41(d,J＝13.5Hz,1H),3.07(d,J＝13.5Hz,1H),2.20(s,3H).¹³C NMR(126MHz,CDCl₃)174.32,161.22,146.92,142.94,138.52,137.33,134.67,129.22,128.76,128.63,128.60,128.21,127.50,127.21,126.47,126.19,125.50,120.36,113.00,111.33,63.64,56.27,46.64,40.73,15.09. analysis by chiral HPLC was carried out with the specific conditions (IA, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 18.6min, t_R(times) 34.63min, 98:2dr, 97% ee.

Example 4:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-fluoro- (4-methylphenyl (p-toluenesulfonyl) methyl) phenol, the other reaction conditions and the operation procedure were the same as in example 1, and the yield was 92%,¹H NMR(500MHz,CDCl₃)7.73(dd,J＝8.1,1.3Hz,1H),7.45(dd,J＝8.7,1.2Hz,2H),7.41–7.36(m,2H),7.35–7.28(m,2H),7.20–7.08(m,6H),6.91(dd,J＝9.6,8.2Hz,3H),6.82(dd,J＝8.1,1.3Hz,1H),5.17(s,1H),3.89(s,3H),3.41(d,J＝13.6Hz,1H),3.09(d,J＝13.6Hz,1H),2.23(s,3H).¹³C NMR(126MHz,CDCl₃)174.77,161.84,151.59(d, J-237.5 Hz),142.30(d, J-13.9 Hz),138.44,137.06,134.37,129.13,128.61,128.59(d, J-5.3 Hz),128.57,128.23,127.50,127.49(d, J-2.4), 127.28,127.09,125.69,120.36,119.67(d, J-7.4 Hz),114.39(d, J-18.3 Hz),64.13,47.99,40.80,15.07. analysis by chiral HPLC is carried out with the specific conditions (IA, 410% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 15.28min, t_R32.80min, 95:5dr, 88% ee.

Example 5:

the difference from the embodiment 1 is that: the substrate substituted phenol is 6-methoxy-2- (4-fluorophenyl (p-toluenesulfonyl) methyl) phenol, and other reactionsThe conditions and the operation procedures were the same as those in example 1, the yield was 95%,¹H NMR(500MHz,CDCl₃)7.73(dd,J＝8.1,1.3Hz,1H),7.45(dd,J＝8.7,1.2Hz,2H),7.41–7.36(m,2H),7.35–7.28(m,2H),7.20–7.08(m,6H),6.91(dd,J＝9.6,8.2Hz,3H),6.82(dd,J＝8.1,1.3Hz,1H),5.17(s,1H),3.89(s,3H),3.41(d,J＝13.6Hz,1H),3.09(d,J＝13.6Hz,1H),2.23(s,3H).¹³C NMR(126MHz,CDCl₃)174.34,161.84(d, J ═ 246.2Hz),161.45,146.27,143.61,137.34,135.01(d, J ═ 3.4Hz),134.80,130.40(d, J ═ 8.0Hz),129.14,128.59,128.17,127.12,125.38,124.30,123.64,120.03,119.31,115.27(d, J ═ 21.2Hz),109.37,63.87,55.96,45.79,40.63,15.09, analysis by chiral HPLC, specific conditions being (ID, 30% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 12.82min, t_R50.63min, 93:7dr, 99% 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, the other reaction conditions and the operation were the same as in example 1, the yield was 93%,¹H NMR(500MHz,CDCl₃)7.68(dd,J＝8.2,1.4Hz,1H),7.46(dd,J＝8.6,1.2Hz,2H),7.36–7.30(m,4H),7.22–7.16(m,3H),7.16–7.12(m,3H),7.10(dd,J＝7.4,2.1Hz,2H),6.92(t,J＝8.1Hz,1H),6.81(dd,J＝8.1,1.4Hz,1H),6.13(s,1H),5.16(s,1H),3.89(s,3H),3.40(d,J＝13.6Hz,1H),3.10(d,J＝13.6Hz,1H),2.22(s,3H).¹³C NMR(126MHz,CDCl₃)174.24,161.36,146.26,143.62,137.81,137.32,134.68,133.09,130.15,129.15,128.60,128.17,127.15,125.41,123.98,123.60,120.03,119.34,109.44,63.65,55.97,45.95,40.69,15.10 by chiral HPLC analysis, with the specific conditions (IA, 70% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 20.00min, t_R(times) 24.35min, 95:5dr, 99% 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, the other reaction conditions and the operation procedure were the same as in example 1, the yield was 90%,¹H NMR(500MHz,CDCl₃)7.72(dd,J＝8.1,1.4Hz,1H),7.50(q,J＝8.4Hz,4H),7.46–7.40(m,2H),7.36–7.29(m,2H),7.19–7.13(m,4H),7.11(dd,J＝7.4,2.0Hz,2H),6.94(t,J＝8.1Hz,1H),6.83(dd,J＝8.1,1.4Hz,1H),6.14(s,1H),5.25(s,1H),3.89(s,3H),3.43(d,J＝13.5Hz,1H),3.10(d,J＝13.6Hz,1H),2.23(s,3H).¹³C NMR(126MHz,CDCl₃)174.14,161.19,146.31,143.73,143.36,137.25,134.57,129.17,129.41(q, J ═ 32.6Hz),128.63,128.22,127.23,125.41(q, J ═ 3.7Hz),123.98(q, J ═ 272.7Hz),123.69,123.54,120.07,119.44,109.60,63.52,55.99,46.32,40.66,15.09, analysis by chiral HPLC, specifically with the conditions (IA, 5% iPrOHin hexane, flow rate 1.0ml/min): t_R(Main) 28.4min, t_R(times) 30.18min, 97:3dr, 98% 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, the other reaction conditions and the operation procedure were the same as in example 1, the yield was 92%,¹H NMR(500MHz,CDCl₃)7.75(dd,J＝8.2,1.3Hz,1H),7.68(s,1H),7.62(d,J＝8.3Hz,1H),7.48–7.41(m,3H),7.36–7.29(m,3H),7.16(q,J＝6.4,5.1Hz,4H),7.11(dd,J＝7.4,2.0Hz,2H),6.95(t,J＝8.1Hz,1H),6.83(dd,J＝8.1,1.4Hz,1H),6.15(s,1H),5.25(s,1H),3.89(s,3H),3.43(d,J＝13.6Hz,1H),3.10(d,J＝13.6Hz,1H),2.22(s,3H).¹³C NMR(126MHz,CDCl₃)174.11,161.15,146.29,143.72,140.30,137.23,134.63,132.04,130.73(q,J＝32.0Hz),129.16,128.97,128.56,128.22,127.20,125.70(q,J＝3.8Hz),125.45,124.12(q,J＝3.7Hz),123.90(q,J＝272.5Hz),123.58,123.55,120.04,119.47,109.58,63.63,55.97,46.32,40.54,15.03, by chiral HPLC, with the specific conditions (IA, 10% iPrOH in hexane, flowrate 1.0ml/min): t_R(main) 13.37min, t_R18.64min, 97:3dr, 99% 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, the other reaction conditions and the operation procedure were the same as in example 1, the yield was 89%,¹H NMR(500MHz,CDCl₃)7.67(d,J＝7.7Hz,1H),7.56(dd,J＝11.2,7.6Hz,3H),7.41(t,J＝7.7Hz,1H),7.37–7.31(m,3H),7.17(t,J＝7.3Hz,1H),7.09(q,J＝5.8,5.2Hz,5H),6.84(h,J＝7.3Hz,3H),6.17(s,1H),5.72(s,1H),3.93(s,3H),3.55(d,J＝13.4Hz,1H),3.34(d,J＝13.3Hz,1H),2.07(s,3H).¹³C NMR(126MHz,CDCl₃)173.89,161.48,146.16,143.80,138.81,137.54,134.28,132.16,129.47,128.69,128.63,128.27(q, J ═ 29.5Hz),127.95,127.33,127.14,126.83(q, J ═ 6.3Hz),125.20,124.88,121.42,124.21(q, J ═ 274.8Hz),119.65,118.21,109.43,63.17,56.05,41.96,41.84,14.45, analysis by chiral HPLC, with the specific conditions (IA, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 8.55min, t_R10.94min, 99:1dr, 99% ee.

Example 10:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (3, 5-trifluoromethylphenyl (p-toluenesulfonyl) methyl) phenol, the other reaction conditions and the operation procedure were the same as in example 1, the yield was 95%,¹H NMR(500MHz,CDCl₃)7.88(s,2H),7.83(d,J＝8.1Hz,1H),7.71(s,1H),7.43(d,J＝7.7Hz,2H),7.32(t,J＝7.9Hz,2H),7.19–7.14(m,4H),7.10(dd,J＝7.1,2.3Hz,2H),6.99(t,J＝8.1Hz,1H),6.86(dd,J＝8.2,1.3Hz,1H),6.14(s,1H),5.30(s,1H),3.91(s,3H),3.46(d,J＝13.6Hz,1H),3.05(d,J＝13.7Hz,1H),2.23(s,3H).¹³C NMR(126MHz,CDCl₃)173.81,160.71,146.38,143.78,141.94,137.00,134.39,131.71(q, J ═ 33.4Hz)129.14,129.01(q, J ═ 2.65Hz),128.58,128.34,127.35,125.64,123.26,123.08(q, J ═ 273.42Hz),122.72,121.23-121.41(m),119.96,119.86,109.93,63.54,56.02,46.06,40.33,14.97, analysis by chiral HPLC, with the specific conditions (IA, 5% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 12.09min, t_R15.96min, 97:3dr, 99% ee.

Example 11:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (4-phenylphenyl (p-toluenesulfonyl) methyl) phenol, the other reaction conditions and the operation procedure were the same as in example 1, the yield was 90%,¹H NMR(500MHz,CDCl₃)7.73(d,J＝7.9Hz,1H),7.52(d,J＝7.4Hz,2H),7.48(dd,J＝7.5,4.3Hz,6H),7.41(t,J＝7.6Hz,2H),7.32(t,J＝7.9Hz,3H),7.15(p,J＝7.0,6.3Hz,6H),6.95(t,J＝8.1Hz,1H),6.82(d,J＝7.7Hz,1H),6.17(s,1H),5.24(s,1H),3.90(s,3H),3.43(d,J＝13.5Hz,1H),3.17(d,J＝13.6Hz,1H),2.27(s,3H).¹³C NMR(126MHz,CDCl₃)174.44,161.63,146.26,143.67,140.52,139.98,138.26,137.45,134.88,129.21,128.65,128.57,128.15,127.19,127.13,127.09,126.94,125.32,124.38,123.87,120.15,119.26,109.34,63.76,55.98,46.39,40.78,15.20. analysis by chiral HPLC, specific conditions are (IA, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 25.44min, t_R24.17min, 95:5dr, 99% ee.

Example 12:

the difference from the embodiment 1 is that: the substrate substituted phenol is 6-methoxy-2- (4-methoxyphenyl (p-methoxyphenyl)Tosyl) methyl) phenol, the other reaction conditions and the operation procedure were the same as in example 1, yield 93%,¹H NMR(500MHz,CDCl₃)7.64(d,J＝8.0Hz,1H),7.48(dd,J＝8.5,1.2Hz,2H),7.34–7.28(m,4H),7.17–7.09(m,6H),7.04(d,J＝7.9Hz,2H),6.91(t,J＝8.1Hz,1H),6.80(dd,J＝8.1,1.4Hz,1H),6.14(s,1H),5.16(s,1H),3.88(s,3H),3.39(d,J＝13.6Hz,1H),3.16(d,J＝13.6Hz,1H),2.26(s,3H),2.22(s,3H).¹³C NMR(126MHz,CDCl₃)174.51,161.74,158.57,146.22,143.52,137.47,134.96,131.30,129.87,129.16,128.52,128.10,127.02,125.22,124.83,123.69,120.05,119.16,113.80,109.18,63.94,55.94,55.09,45.93,40.76,15.16. analysis by chiral HPLC, with the specific conditions (AD-H, 20% iPrOH in hexane, flow rate0.7ml/min): t_R(main) 30.42min, t_R(times) 11.01min, 87:13dr, 99% 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, the other reaction conditions and the operation were the same as in example 1, and the yield was 93%,¹H NMR(500MHz,CDCl₃)7.65(d,J＝7.8Hz,1H),7.50(d,J＝7.7Hz,2H),7.31(t,J＝7.9Hz,2H),7.17–7.08(m,7H),7.01–6.95(m,2H),6.91(t,J＝8.1Hz,1H),6.80(d,J＝7.3Hz,1H),6.72(dd,J＝8.1,2.1Hz,1H),6.14(s,1H),5.16(s,1H),3.88(s,3H),3.64(s,3H),3.37(d,J＝13.5Hz,1H),3.15(d,J＝13.5Hz,1H),2.22(s,3H).¹³C NMR(126MHz,CDCl₃)174.44,161.67,159.51,146.19,143.64,140.81,137.52,134.84,129.41,129.20,128.52,128.10,127.06,125.18,124.27,123.87,121.15,119.92,119.17,114.33,112.85,109.29,63.61,55.97,55.00,46.69,40.83,15.13 by chiral HPLC analysis, with specific conditions (IA, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(Main) 20.28min, t_R36.74min, 95:5dr, 99% 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, the other reaction conditions and the operation procedure were the same as in example 1, and the yield was 91%,¹H NMR(500MHz,CDCl₃)7.64(d,J＝8.0Hz,1H),7.48(dd,J＝8.5,1.2Hz,2H),7.34–7.28(m,4H),7.17–7.09(m,6H),7.04(d,J＝7.9Hz,2H),6.91(t,J＝8.1Hz,1H),6.80(dd,J＝8.1,1.4Hz,1H),6.14(s,1H),5.16(s,1H),3.88(s,3H),3.39(d,J＝13.6Hz,1H),3.16(d,J＝13.6Hz,1H),2.26(s,3H),2.22(s,3H).¹³C NMR(126MHz,CDCl₃)174.49,161.73,146.20,143.57,137.50,136.77,136.22,134.94,129.19,129.16,128.65,128.52,128.09,127.02,125.21,124.66,123.81,120.08,119.15,109.19,63.75,55.95,46.40,40.83,20.91,15.16 by chiral HPLC analysis, with the specific conditions (IA, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(Main) 29.36min, t_R32.49min, 93:7dr, 99% ee.

Example 15:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (4-trifluoromethoxyphenyl (p-toluenesulfonyl) methyl) phenol, the other reaction conditions and the operation steps were the same as in example 1, the yield was 89%,¹H NMR(500MHz,CDCl₃)7.78(dd,J＝8.2,1.4Hz,1H),7.42(t,J＝9.1Hz,4H),7.31(t,J＝8.0Hz,2H),7.18–7.13(m,4H),7.13–7.10(m,2H),7.07(d,J＝8.2Hz,2H),6.95(t,J＝8.1Hz,1H),6.83(dd,J＝8.1,1.4Hz,1H),6.14(s,1H),5.19(s,1H),3.90(s,3H),3.43(d,J＝13.6Hz,1H),3.06(d,J＝13.6Hz,1H),2.24(s,3H).¹³C NMR(126MHz,CDCl₃)174.26,161.29,148.24,146.32,143.70,137.85,137.26,134.75,130.23,129.15,128.60,128.22,127.18,125.50,123.97,123.69,120.73,120.36(q, J ═ 257.3Hz),120.14,119.40,109.50,63.80,55.98,45.79,40.52,15.08, analysis by chiral HPLC, havingThe volume conditions were (IA, 10% iPrOH in hexane, flow rate0.7ml/min): t_R(main) 22.70min, t_R(times) 25.78min, 96:4dr, 99% ee.

Example 16:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (3-trifluoromethoxyphenyl (p-toluenesulfonyl) methyl) phenol, the other reaction conditions and the operation procedure were the same as in example 1, the yield was 81%,¹H NMR(500MHz,CDCl₃)7.74(dd,J＝8.2,1.4Hz,1H),7.48–7.40(m,2H),7.36(d,J＝7.9Hz,1H),7.31(t,J＝8.0Hz,2H),7.25(dd,J＝17.4,9.4Hz,2H),7.15(q,J＝6.4,4.7Hz,4H),7.10(dd,J＝7.3,2.0Hz,2H),7.05(d,J＝8.2Hz,1H),6.94(t,J＝8.1Hz,1H),6.83(dd,J＝8.1,1.3Hz,1H),6.13(s,1H),5.19(s,1H),3.89(s,3H),3.41(d,J＝13.6Hz,1H),3.08(d,J＝13.6Hz,1H),2.22(s,3H).¹³C NMR(126MHz,CDCl₃)174.12,161.16,149.10,146.30,143.72,141.54,137.29,134.62,129.74,129.17,128.53,128.20,127.19,127.09,125.39,123.67,123.54,121.73,120.37(q, J-257.3 Hz),120.02,119.53,119.43,109.56,63.68,55.97,46.18,40.69,15.06 by chiral HPLC analysis, with the specific conditions (IA, 15% iPrOH in hexane, flow rate0.7ml/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- (4-methylphenyl (p-toluenesulfonyl) methyl) phenol, the other reaction conditions and the operation were the same as in example 1, and the yield was 94%,¹H NMR(500MHz,CDCl₃)7.53–7.45(m,4H),7.34–7.30(m,2H),7.18–7.13(m,3H),7.12(d,J＝2.7Hz,4H),6.91–6.78(m,4H),6.21(s,1H),5.87(s,1H),3.89(s,3H),3.82(s,3H),3.40(d,J＝13.6Hz,1H),3.26(d,J＝13.6Hz,1H),2.17(s,3H).¹³C NMR(126MHz,CDCl₃)174.72,162.30,156.59,146.14,144.08,137.59,135.06,129.26,129.04,128.50,128.25,128.16,128.00,126.93,125.06,124.61,124.02,120.69,119.94,118.74,111.13,109.14,63.48,55.94,55.80,40.85,37.94,14.77 by chiral HPLC analysis, with the specific conditions (IA, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 21.0min, t_R25.16min, 96:4dr, 99% ee.

Example 18:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (2-methylphenyl (p-toluenesulfonyl) methyl) phenol, the other reaction conditions and the operation were the same as in example 1, and the yield was 94%,¹H NMR(500MHz,CDCl₃)7.50(dd,J＝8.2,1.4Hz,1H),7.35(d,J＝7.6Hz,2H),7.19(t,J＝7.9Hz,2H),7.07(d,J＝8.4Hz,2H),7.03–6.96(m,7H),6.86(d,J＝7.4Hz,1H),6.78(t,J＝8.1Hz,1H),6.67(dd,J＝8.1,1.3Hz,1H),6.01(s,1H),5.02(s,1H),3.76(s,3H),3.25(d,J＝13.6Hz,1H),3.03(d,J＝13.5Hz,1H),2.10(s,3H),2.08(s,3H).¹³C NMR(126MHz,CDCl₃)174.49,161.70,146.17,143.60,139.18,137.98,137.50,134.97,129.42,129.21,128.53,128.34,128.11,127.98,127.03,125.80,125.23,124.41,123.97,120.09,119.14,109.23,63.62,55.96,46.73,40.69,21.42,15.11. analysis by chiral HPLC, with the specific conditions (AD-H, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(Main) 20.67min, t_R(times) 49.9min, 96:4dr, 99% ee.

Example 19:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (2, 3-methyleneoxyphenyl (p-toluenesulfonyl) methyl) phenol, the other reaction conditions and the operation were the same as in example 1, giving a product yield of 83%,¹H NMR(500MHz,CDCl₃)7.70(dd,J＝8.1,1.3Hz,1H),7.50–7.43(m,2H),7.34–7.30(m,2H),7.14(dt,J＝7.6,4.8Hz,4H),7.09(dd,J＝7.4,2.1Hz,2H),6.95–6.86(m,3H),6.80(dd,J＝8.1,1.2Hz,1H),6.66(d,J＝8.1Hz,1H),6.14(s,1H),5.85(dd,J＝11.3,1.5Hz,2H),5.10(s,1H),3.88(s,3H),3.37(d,J＝13.5Hz,1H),3.09(d,J＝13.6Hz,1H),2.24(s,3H).¹³C NMR(126MHz,CDCl₃)174.43,161.65,147.58,146.59,146.22,143.51,137.43,134.86,132.97,129.16,128.56,128.54,128.11,127.05,125.29,124.65,123.56,122.04,120.11,119.25,109.33,109.28,108.08,100.92,63.88,55.95,46.27,40.78,15.18 by chiral HPLC analysis, with the specific conditions (IA, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(Main) 31.82min, t_R52.97min, 88:12dr, 97% ee.

Example 20:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (1-naphthyl (p-toluenesulfonyl) methyl) phenol, the other reaction conditions and the operation procedure were the same as in example 1, the yield was 91%,¹H NMR(500MHz,CDCl₃)8.42(d,J＝8.6Hz,1H),7.82(d,J＝7.8Hz,1H),7.73(d,J＝8.2Hz,1H),7.66–7.60(m,2H),7.57–7.52(m,2H),7.47(d,J＝7.2Hz,1H),7.37(t,J＝7.2Hz,2H),7.35–7.31(m,1H),7.22–7.11(m,7H),6.86–6.75(m,2H),6.37(s,1H),6.08(s,1H),3.91(s,3H),3.54(d,J＝13.2Hz,1H),3.38(d,J＝13.2Hz,1H),1.96(s,3H).¹³C NMR(126MHz,CDCl₃)174.34,161.93,145.88,143.26,137.67,136.43,134.42,134.04,131.77,129.42,128.93,128.61,127.96,127.95,127.11,126.64,125.54,125.37,125.23,125.15,123.88,123.01,122.70,119.83,118.82,109.31,62.75,55.98,41.80,41.47,14.60 by chiral HPLC analysis, with the specific conditions (IA, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(Main) 20.70min, t_R27.63min, 98:2dr, 99% ee.

Example 21:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 6-methoxy-2- (2-naphthyl (p-toluenesulfonyl) methyl) phenol, the other reaction conditions and the operation procedure were the same as in example 1, the yield was 91%,¹H NMR(500MHz,CDCl₃)8.42(d,J＝8.6Hz,1H),7.82(d,J＝7.8Hz,1H),7.73(d,J＝8.2Hz,1H),7.66–7.60(m,2H),7.57–7.52(m,2H),7.47(d,J＝7.2Hz,1H),7.37(t,J＝7.2Hz,2H),7.35–7.31(m,1H),7.22–7.11(m,7H),6.86–6.75(m,2H),6.37(s,1H),6.08(s,1H),3.91(s,3H),3.54(d,J＝13.2Hz,1H),3.38(d,J＝13.2Hz,1H),1.96(s,3H).¹³C NMR(126MHz,CDCl₃)174.34,161.93,145.88,143.26,137.67,136.43,134.42,134.04,131.77,129.42,128.93,128.61,127.96,127.95,127.11,126.64,125.54,125.37,125.23,125.15,123.88,123.01,122.70,119.83,118.82,109.31,62.75,55.98,41.80,41.47,14.60 by chiral HPLC analysis, with the specific conditions (IA, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(Main) ═ 29.37min, t_R32.88min, 94:6dr, 99% ee.

Example 22:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 2- (phenylethynyl (p-toluenesulfonyl) methyl) phenol, and the other reaction conditions and operation were the same as in example 1, with a yield of 78%,¹H NMR(500MHz,CDCl₃)7.50(d,J＝7.7Hz,2H),7.40–7.37(m,2H),7.30–7.27(m,5H),7.23–7.16(m,7H),6.89(t,J＝8.0Hz,1H),6.80(dd,J＝8.0,1.4Hz,1H),6.17(s,1H),5.03(s,1H),3.86(s,3H),3.52(d,J＝13.7Hz,1H),3.35(d,J＝13.7Hz,1H),2.51(s,3H).¹³C NMR(126MHz,CDCl₃)173.21,160.71,146.69,143.35,137.42,134.90,131.63,129.20,128.51,128.28,128.24,128.21,127.15,125.11,122.82,122.75,121.53,119.77,119.53,110.35,86.75,84.53,63.96,56.06,39.20,35.43,15.88 by chiral HPLC analysis, with specific conditions (ID, 40% iPrOH in) hexane,flow rate 0.7ml/min):t_R(Main) 14.92min, t_R42.04min,80:20dr, 86% ee.

Example 23:

the difference from the embodiment 1 is that: the substrate-substituted phenol used was 2- (2-methyl (p-toluenesulfonyl) methyl) phenol, the other reaction conditions and the operation were the same as in example 1, and the yield was 40%,¹H NMR(500MHz,CDCl₃)7.64(d,J＝8.6Hz,2H),7.35–7.32(m,3H),7.17–7.13(m,5H),7.06–7.02(m,2H),6.95(t,J＝8.0Hz,1H),6.13(s,1H),3.92(s,3H),3.91(q,J＝8.0Hz 1H),3.12(d,J＝13.7Hz,1H),2.98(d,J＝13.7Hz,1H),2.30(s,3H),1.25(d,J＝7.3Hz,3H).¹³C NMR(126MHz,CDCl₃)174.36,162.29,146.19,143.73,137.65,135.52,128.99,128.60,128.14,127.04,126.90,125.02,122.74,119.56,119.34,109.27,64.19,56.02,38.99,16.07,14.87,14.65 by chiral HPLC analysis, with specific conditions (ID, 20% iPrOH in hexane, flow rate 1.0ml/min): t_R(Main) 20.56min, t_R13.3min, 60:40dr, 90% ee.

Example 24:

the difference from the embodiment 1 is that: the substrate pyrazolone is 5-methyl-4-benzyl-2- (4-bromophenyl) pyrazolone, other reaction conditions and operation steps are the same as those of the example 1, the yield is 85 percent,¹H NMR(500MHz,CDCl₃)7.61(d,J＝8.1Hz,1H),7.41(s,4H),7.37–7.34(m,2H),7.24–7.16(m,3H),7.12(dd,J＝5.2,1.9Hz,3H),7.07–7.04(m,2H),6.90(t,J＝8.1Hz,1H),6.80(dd,J＝8.1,1.4Hz,1H),6.08(s,1H),5.16(s,1H),3.89(s,3H),3.37(d,J＝13.5Hz,1H),3.13(d,J＝13.6Hz,1H),2.20(s,3H).¹³CNMR(126MHz,CDCl₃)174.44,162.05,146.23,143.64,139.09,136.54,134.73,131.57,129.14,128.76,128.52,128.16,127.30,127.16,124.23,123.73,121.08,119.20,118.03,109.31,63.92,56.00,46.66,40.82,15.19 by chiral HPLC, with the specific conditions (IA, 10% iPrOpin hexane, flow rate0.7ml/min): t_R(main) 10.36min, t_R9.7min, 89:11dr, 98% ee.

Example 25:

the difference from the embodiment 1 is that: the substrate pyrazolone is 5-methyl-4-benzyl-2- (3-bromophenyl) pyrazolone, other reaction conditions and operation steps are the same as those of example 1, the yield is 78%,¹H NMR(500MHz,CDCl₃)7.70(t,J＝1.9Hz,1H),7.60(d,J＝8.1Hz,1H),7.52(ddd,J＝8.2,2.1,1.0Hz,1H),7.38–7.34(m,2H),7.27–7.15(m,5H),7.14–7.11(m,3H),7.06(dd,J＝7.2,2.3Hz,2H),6.91(t,J＝8.1Hz,1H),6.81(dd,J＝8.1,1.3Hz,1H),6.08(s,1H),5.17(s,1H),3.89(s,3H),3.37(d,J＝13.6Hz,1H),3.14(d,J＝13.6Hz,1H),2.21(s,3H).¹³C NMR(126MHz,CDCl₃)174.53,162.10,146.21,143.61,139.06,138.60,134.65,129.86,129.12,128.72,128.53,128.17,127.95,127.30,127.18,124.18,123.72,122.30,122.20,119.19,117.85,109.30,63.94,55.99,46.64,40.86,15.17, by chiral HPLC analysis, with the specific conditions (ID, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 21.93min, t_R75.67min, 96:4dr, 99% ee.

Example 26:

the difference from the embodiment 1 is that: the substrate pyrazolone used was 5-methyl-4-benzyl-2- (2,3, 4,5, 6-pentafluorophenyl) pyrazolone, other reaction conditions and operating procedures were the same as in example 1, yield was 95%,¹H NMR(500MHz,CDCl₃)7.68(dd,J＝8.2,1.3Hz,1H),7.42–7.38(m,2H),7.30(d,J＝8.4Hz,2H),7.22(t,J＝7.4Hz,2H),7.19–7.16(m,1H),7.15–7.08(m,7H),6.90(t,J＝8.1Hz,1H),6.80(dd,J＝8.1,1.3Hz,1H),5.16(s,1H),3.89(s,3H),3.39(d,J＝13.5Hz,1H),3.11(d,J＝13.6Hz,1H),2.32(s,3H),2.20(s,3H).¹³C NMR(126MHz,CDCl₃)174.74,163.37,146.23,144.64-144.43 (m),143.63,142.54-142.34 (m), 140.27-140.00 (m), 138.80-138.56 (m),138.59,136.88-136.45 (m),134.13,129.36,128.84,128.62,128.38,124.08,123.54,119.39,111.91-111.53 (m),109.37,62.74,55.97,46.66,40.78,15.35. analysis by chiral HPLC, specific conditions are (ID, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 10.46min, t_R37.30min,99:1dr, 99% ee.

Example 27:

the difference from the embodiment 1 is that: the used substrate pyrazolone is 5-methyl-4-benzyl-2- (4-methylphenyl) pyrazolone, other reaction conditions and operation steps are the same as those of the example 1, the yield of the product is 85 percent,¹H NMR(500MHz,CDCl₃)7.68(dd,J＝8.2,1.3Hz,1H),7.42–7.38(m,2H),7.30(d,J＝8.4Hz,2H),7.22(t,J＝7.4Hz,2H),7.19–7.16(m,1H),7.15–7.08(m,7H),6.90(t,J＝8.1Hz,1H),6.80(dd,J＝8.1,1.3Hz,1H),5.16(s,1H),3.89(s,3H),3.39(d,J＝13.5Hz,1H),3.11(d,J＝13.6Hz,1H),2.32(s,3H),2.20(s,3H).¹³C NMR(126MHz,CDCl₃)174.29,161.45,146.24,143.66,139.26,135.04,135.00,134.97,129.24,129.12,128.84,128.47,128.13,127.20,127.06,124.48,123.96,120.25,119.18,109.27,63.65,55.99,46.75,40.76,20.98,15.15. analysis by chiral HPLC, specific conditions are (IC, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 26.31min, t_R(times) 52.49, 97:3dr, 97% ee.

Example 28:

the difference from the embodiment 1 is that: the substrate pyrazolone is 5-methyl-4-benzyl-2- (4-methoxyphenyl) pyrazolone, other reaction conditions and operation steps are the same as those in example 1, and the yield is high93％，¹H NMR(500MHz,CDCl₃)7.71(d,J＝8.1Hz,1H),7.44–7.39(m,2H),7.28–7.21(m,4H),7.21–7.10(m,6H),6.91(t,J＝8.1Hz,1H),6.85–6.82(m,2H),6.80(dd,J＝8.1,1.2Hz,1H),5.17(s,1H),3.88(s,3H),3.78(s,3H),3.11(d,J＝13.5Hz,1H),2.21(s,3H).¹³C NMR(126MHz,CDCl₃)174.22,161.41,157.36,146.28,143.69,139.27,135.01,130.71,129.29,128.88,128.46,128.14,127.22,127.08,124.51,123.94,122.28,119.19,113.84,109.29,63.59,55.99,55.43,46.71,40.69,15.15. analysis by chiral HPLC, with the specific conditions (IC, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 25.55min, t_R(times) 41.21min, 97:3dr, 99% ee.

Example 29:

the difference from the embodiment 1 is that: the substrate pyrazolone is 5-methyl-4-benzyl-2- (2-ethylphenyl) pyrazolone, other reaction conditions and operation steps are the same as those in example 1, the yield is 77 percent,¹H NMR(500MHz,CDCl₃)7.95(d,J＝8.1Hz,1H),7.54–7.48(m,2H),7.29(t,J＝7.4Hz,2H),7.26–7.22(m,4H),7.21–7.16(m,4H),7.03(td,J＝7.5,1.9Hz,1H),6.94(t,J＝8.1Hz,1H),6.82(dd,J＝8.1,1.3Hz,1H),6.29(dd,J＝7.9,1.2Hz,1H),6.26(s,1H),5.18(s,1H),3.89(s,3H),3.44(d,J＝13.5Hz,1H),3.03(d,J＝13.5Hz,1H),2.38(s,3H),1.87(qd,J＝7.6,4.4Hz,2H),0.94(t,J＝7.6Hz,3H).¹³C NMR(126MHz,CDCl₃)174.82,160.90,146.50,143.85,141.09,138.87,135.13,135.08,129.85,129.49,128.46,128.37,128.35,128.34,127.24,127.14,126.55,125.92,124.90,123.89,119.35,109.36,63.58,56.00,46.75,40.40,23.27,15.51,14.07. analysis by chiral HPLC, specific conditions were (IC, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 16.39min, t_R21.40min, 97:3dr, 99% ee.

Example 30:

the difference from the embodiment 1 is that: the substrate pyrazolone is 5-methyl-4-benzyl-2- (2-naphthyl) pyrazolone, other reaction conditions and operation steps are the same as those in example 1, the yield is 94%,¹H NMR(500MHz,CDCl₃)8.05(d,J＝2.0Hz,1H),7.84–7.78(m,3H),7.73–7.67(m,2H),7.45(dd,J＝7.9,1.5Hz,4H),7.26–7.21(m,2H),7.20–7.16(m,1H),7.16–7.11(m,5H),6.95(t,J＝8.1Hz,1H),6.82(dd,J＝8.0,1.3Hz,1H),6.17(s,1H),5.24(s,1H),3.89(s,3H),3.46(d,J＝13.5Hz,1H),3.19(d,J＝13.6Hz,1H),2.27(s,3H).¹³C NMR(126MHz,CDCl₃)174.69,161.92,146.27,143.70,139.27,135.14,134.91,133.41,131.15,129.24,128.85,128.56,128.38,128.21,127.99,127.55,127.29,127.15,126.25,125.31,124.42,123.92,119.25,117.02,109.33,63.93,56.01,46.81,40.94,15.25, by chiral HPLC, with the specific conditions (IC, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 9.75min, t_R(times) 17.67min.95:5dr, 99% ee.

Example 31:

the difference from the embodiment 1 is that: the substrate pyrazolone is 5-ethyl-4-benzyl-2-phenyl pyrazolone, other reaction conditions and operation steps are the same as those in example 1, the yield is 89%,¹H NMR(500MHz,CDCl₃)7.64(dd,J＝8.2,1.3Hz,1H),7.56–7.49(m,2H),7.41–7.36(m,2H),7.35–7.30(m,2H),7.24–7.19(m,2H),7.19–7.11(m,5H),7.08(dd,J＝7.4,2.1Hz,2H),6.91(t,J＝8.1Hz,1H),6.80(dd,J＝8.0,1.4Hz,1H),6.15(s,1H),5.20(s,1H),3.89(s,3H),3.38(d,J＝13.6Hz,1H),3.16(d,J＝13.6Hz,1H),2.60(q,J＝7.3Hz,2H),1.10(t,J＝7.3Hz,3H).¹³C NMR(126MHz,CDCl₃)174.77,165.33,146.19,143.64,139.48,137.70,135.00,129.20,128.74,128.51,128.43,128.06,127.11,127.01,125.15,124.55,124.05,120.09,119.13,109.22,63.70,55.96,46.78,41.12,22.04,8.60 by chiral HPLC analysis, with specific conditions (IC, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 9.16min,t_R(times) ═ 15.1min.98:2dr, 99% ee.

Example 32:

the difference from the embodiment 1 is that: the substrate pyrazolone is 5-isopropyl-4-benzyl-2-phenyl-pyrazolone, other reaction conditions and operation steps are the same as those in example 1, the yield is 85 percent,¹H NMR(500MHz,CDCl₃)7.65(d,J＝7.8Hz,2H),7.40–7.34(m,3H),7.28(d,J＝7.2Hz,2H),7.22–7.14(m,4H),7.13–7.07(m,5H),6.88(t,J＝8.0Hz,1H),6.80(dd,J＝8.0,1.4Hz,1H),6.29(s,1H),5.38(s,1H),3.34(d,J＝14.0Hz,1H),3.30(d,J＝14.0Hz,1H),2.93(hept,J＝6.9Hz,1H),1.15(d,J＝6.8Hz,3H),1.06(d,J＝6.8Hz,3H).¹³C NMR(126MHz,CDCl₃)174.77,169.16,146.09,143.59,140.61,137.83,135.17,129.37,128.61,128.46,128.28,127.95,126.95,126.82,125.34,125.13,124.99,119.92,119.07,109.11,62.94,56.00,46.36,41.33,28.43,21.90,21.26. analysis by chiral HPLC, with the specific conditions (IA, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 25.58min, t_R(times) 54.29min.97:3dr, 99% ee.

Example 33:

the difference from the embodiment 1 is that: the substrate pyrazolone is 4-benzyl-2, 5-diphenyl pyrazolone, other reaction conditions and operation steps are the same as those in example 1, the yield is 82%,¹H NMR(500MHz,CDCl₃)8.13(dd,J＝6.6,3.2Hz,2H),7.92(d,J＝8.0Hz,1H),7.52(dd,J＝5.0,1.9Hz,3H),7.49(dt,J＝8.6,1.6Hz,2H),7.36–7.32(m,2H),7.22–7.18(m,3H),7.07(dd,J＝5.1,1.9Hz,3H),7.03–6.97(m,6H),6.86(dd,J＝8.1,1.2Hz,1H),6.33(s,1H),5.79(s,1H),3.92(s,3H),3.69(d,J＝13.7Hz,1H),3.53(d,J＝13.7Hz,1H).¹³C NMR(126MHz,CDCl₃)175.11,159.13,146.32,144.04,138.72,137.36,134.94,131.69,129.98,129.42,129.06,12867,128.54,128.05,127.88,127.04,127.03,126.88,125.59,124.59,124.30,120.49,119.20,109.40,64.06,56.03,46.58,41.29 analysis by chiral HPLC, with the specific conditions (IA, 7% iPrOH in hexane, flow rate0.7ml/min): t_R(main) 12.82min, t_R(times) 50.62min.93:7dr, 99% ee.

Example 34:

the difference from the embodiment 1 is that: the substrate pyrazolone is 4-benzyl-2-phenyl-5- (4-methoxyphenyl) pyrazolone, other reaction conditions and operation steps are the same as those in example 1, the yield is 82%,¹H NMR(500MHz,CDCl₃)8.10–8.07(m,2H),7.97–7.91(m,1H),7.51–7.46(m,2H),7.35–7.31(m,2H),7.23–7.20(m,2H),7.19–7.15(m,1H),7.08(dt,J＝4.8,1.7Hz,3H),7.06–7.03(m,3H),7.03–6.96(m,6H),6.85(dd,J＝8.1,1.3Hz,1H),6.37(s,1H),5.76(s,1H),3.93(s,3H),3.91(s,3H),3.63(d,J＝13.7Hz,1H),3.51(d,J＝13.7Hz,1H).¹³C NMR(126MHz,CDCl₃)174.96,160.91,158.93,146.33,144.04,138.76,137.43,135.04,129.43,129.10,128.69,128.62,128.50,128.03,127.85,127.00,126.83,125.45,124.63,124.39,124.36,120.44,114.08,109.39,64.01,56.02,55.32,46.72,41.21. analysis by chiral HPLC, with the specific conditions (IA, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) ═ 19.96min, t_R(times) 35.47min.95:5dr, 99% ee.

Example 35:

the difference from the embodiment 1 is that: the substrate pyrazolone is 4-benzyl-2-phenyl-5- (4-fluorophenyl) pyrazolone, other reaction conditions and operation steps are the same as those in example 1, the yield is 86 percent,¹H NMR(500MHz,CDCl₃)8.10–8.07(m,2H),7.97–7.91(m,1H),7.51–7.46(m,2H),7.35–7.31(m,2H),7.23–7.20(m,2H),7.19–7.15(m,1H),7.08(dt,J＝4.8,1.7Hz,3H),7.06–7.03(m,3H),7.03–6.96(m,6H),6.85(dd,J＝8.1,1.3Hz,1H),6.37(s,1H),5.76(s,1H),3.93(s,3H),3.91(s,3H),3.63(d,J＝13.7Hz,1H),3.51(d,J＝13.7Hz,1H).¹³C NMR(126MHz,CDCl₃)174.96,160.91,158.93,146.33,144.04,138.76,137.43,135.04,129.43,129.10,128.69,128.62,128.50,128.03,127.85,127.00,126.83,125.45,124.63,124.39,124.36,120.44,114.08,109.39,64.01,56.02,55.32,46.72,41.21. analysis by chiral HPLC, with the specific conditions (IA, 10% iPrOH in hexane, flow rate 1.0ml/min): t_R(main) 22.50min, t_R(times) 29.53min.97:3dr, 99% ee.

Example 36:

the difference from the embodiment 1 is that: the substrate pyrazolone is 5-methyl-4- (2-fluorobenzyl) -2-phenyl pyrazolone, other reaction conditions and operation steps are the same as those in example 1, the yield is 94%,¹H NMR(500MHz,CDCl₃)7.64(dd,J＝8.2,1.4Hz,1H),7.50(dd,J＝8.6,1.2Hz,2H),7.42–7.37(m,2H),7.35–7.30(m,2H),7.22(t,J＝7.3Hz,2H),7.20–7.14(m,3H),7.12–7.05(m,1H),6.99–6.84(m,3H),6.80(dd,J＝8.1,1.4Hz,1H),6.17(s,1H),5.22(s,1H),3.89(s,3H),3.54(d,J＝13.8Hz,1H),3.21–3.14(m,1H),2.21(s,3H).¹³C NMR(126MHz,CDCl₃)174.34,160.78(d, J ═ 244.7Hz),162.27,146.17,143.63,139.18,137.38,131.64(d, J ═ 3.9Hz),128.83(d, J ═ 8.6Hz),128.66,128.57,128.51,127.22,124.02,124.00(d, J ═ 36.1Hz),123.83,121.92(d, J ═ 15.4Hz),119.95,119.11,115.09(d, J ═ 23.1Hz),109.22,63.17,55.94,46.56,32.70,14.47_R(main) 18.42min, t_R(times) 45.23min.98:2dr, 99% ee.

Example 37:

the difference from the embodiment 1 is that: used ofThe substrate pyrazolone is 5-methyl-4- (2-methylbenzyl) -2-phenyl pyrazolone, other reaction conditions and operation steps are the same as those of the example 1, the yield is 84 percent,¹H NMR(500MHz,CDCl₃)7.83(d,J＝8.0Hz,1H),7.46–7.40(m,4H),7.34–7.29(m,2H),7.21(dd,J＝8.2,6.4Hz,2H),7.18–7.13(m,2H),7.07(d,J＝7.5Hz,1H),7.03(td,J＝7.5,6.8,2.5Hz,1H),6.98–6.90(m,3H),6.81(dd,J＝8.0,1.4Hz,1H),6.13(s,1H),5.18(s,1H),3.89(s,3H),3.45(d,J＝14.5Hz,1H),3.21(d,J＝14.5Hz,1H),2.29(s,3H),2.19(s,3H).¹³C NMR(126MHz,CDCl₃)174.78,161.84,146.11,143.66,139.00,137.45,136.52,133.75,130.48,128.79,128.58,128.56,128.39,127.20,126.88,125.68,125.27,124.58,123.88,120.13,119.19,109.22,63.26,55.96,46.86,35.66,20.04,15.08. analysis by chiral HPLC, with the specific conditions (AD-H, 10% iPrOH in hexane, flow rate0.7ml/min): t_R(main) 19.70min, t_R(times) 43.00min.90:10dr, 99% ee.

Example 38:

the difference from the embodiment 1 is that: the substrate pyrazolone is 5-methyl-4- (4-methylbenzyl) -2-phenyl pyrazolone, other reaction conditions and operation steps are the same as those in example 1, the yield is 95%,¹H NMR(500MHz,CDCl₃)7.67(dd,J＝8.1,1.4Hz,1H),7.47(dd,J＝8.6,1.2Hz,2H),7.43–7.38(m,2H),7.35–7.30(m,2H),7.25–7.20(m,2H),7.19–7.14(m,2H),6.99(d,J＝8.1Hz,2H),7.00–6.89(m,3H),6.80(dd,J＝8.0,1.4Hz,1H),6.15(s,1H),5.17(s,1H),3.88(s,3H),3.37(d,J＝13.6Hz,1H),3.10(d,J＝13.6Hz,1H),2.21(s,3H),2.21(s,3H).¹³C NMR(126MHz,CDCl₃)174.54,161.78,146.17,143.59,139.20,137.44,136.53,131.72,128.99,128.82,128.77,128.52,128.43,127.16,125.23,124.38,123.82,120.10,119.12,109.19,63.75,55.92,46.71,40.36,20.93,15.15. analysis by chiral HPLC with the specific conditions (IC, 10% iPrOH in hexane, flow rate0.7ml/min): t_R(main) 19.16min, t_R(times) 37.45min.98:2dr, 99% ee.

Example 39:

the difference from the embodiment 1 is that: the substrate pyrazolone is 4, 5-dimethyl-2-phenyl pyrazolone, other reaction conditions and operation steps are the same as those of the example 1, the yield is 81 percent,¹H NMR(500MHz,CDCl₃)7.76(dd,J＝8.7,1.2Hz,2H),7.54(dd,J＝8.0,1.4Hz,1H),7.40–7.36(m,2H),7.34–7.31(m,2H),7.23–7.15(m,4H),6.86(t,J＝8.0Hz,1H),6.77(dd,J＝8.1,1.4Hz,1H),6.03(s,1H),4.99(s,1H),3.87(s,3H),2.17(s,3H),1.44(s,3H).¹³C NMR(126MHz,CDCl₃)175.57,164.04,146.18,143.58,139.08,137.91,128.70,128.35,127.14,125.01,124.50,123.27,119.37,119.05,109.17,57.40,55.92,46.73,20.81,14.23. analysis by chiral HPLC, with the specific conditions (IA, 10% iPrOpin hexane, flow rate0.7ml/min): t_R(main) 21.43min, t_R23.25min.92:8dr, 97% ee.

Example 40:

the difference from the embodiment 1 is that: the substrate pyrazolone is 4-bromo-2-phenyl-5- (4-fluorophenyl) pyrazolone, other reaction conditions and operation steps are the same as those in example 1, the yield is 85%,¹H NMR(500MHz,CDCl₃)7.79–7.72(m,2H),7.58(dd,J＝8.1,1.3Hz,1H),7.41–7.36(m,2H),7.36–7.32(m,2H),7.21–7.17(m,3H),7.15(dd,J＝8.4,6.0Hz,1H),6.86(t,J＝8.1Hz,1H),6.76(dd,J＝8.0,1.4Hz,1H),6.03(s,1H),5.00(s,1H),3.87(s,3H),2.15(s,3H),2.09–2.04(dd,J＝14.0,7.3Hz,1H),1.87(dd,J＝14.0,7.3Hz,1H),0.70(t,J＝7.5Hz,3H).¹³C NMR(126MHz,CDCl₃)174.85,162.46,146.13,143.56,139.24,137.74,128.71,128.69,128.37,127.12,125.09,124.58,123.50,119.50,119.02,109.10,63.08,55.92,46.70,27.51,14.41,8.44. analysis by chiral HPLC, with the specific conditions (IE, 10% iPrOH in hexane, flow rate0.7ml/min): t_R(main) 29.62min, t_R(times) 72.78min.95:5dr, 99% ee.

The above embodiments are only intended to describe preferred embodiments of the present invention, and do not limit the scope of the present invention. Any simple modifications, equivalent modifications and substitutions made in accordance with the technical spirit of the present invention are also included in the scope of the present invention.

Claims

1. A synthetic method of pyrazolone compounds containing adjacent tertiary carbon-quaternary carbon chiral centers, which is shown in formula (3), is characterized by comprising the following steps: in a water-oil two-phase system, reacting a compound shown in a formula (1) and a compound shown in a formula (2) as raw materials 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 then carrying out post-treatment on a reaction liquid to obtain a pyrazolone compound shown in a formula (3);

the reaction formula is as follows:

in the formula (1), Ts is p-toluenesulfonyl;

in the formulae (1), (2) and (3),

R¹is H, methoxy, ethoxy or halogen;

R²is methyl, 1-naphthyl, 2-naphthyl, phenyl or phenyl substituted by one or more substituents each independently being methyl, hexyl, methoxy, trifluoromethyl, trifluoromethoxy, phenyl or halogen;

R³is 2-naphthyl or phenyl substituted with one or more substituents each independently being methyl, ethyl, methoxy or halogen;

R⁴is methyl, ethyl, isopropyl, phenyl or phenyl substituted with one or more substituents each independently being methyl, hexyl, methoxy, trifluoromethyl, trifluoromethoxy, phenyl or halogen;

the chiral catalyst is selected from one of the following:

in the formula (7), R¹⁵Is ethyl or vinyl.

2. The method for synthesizing pyrazolones with adjacent tertiary carbon-quaternary carbon chiral centers according to claim 1, wherein the ratio of the amount of the compound of formula (1) to the amount of the compound of formula (2) is 0.2-5: 1.

3. the method for synthesizing pyrazolones with adjacent tertiary carbon-quaternary carbon chiral centers according to claim 2, characterized in that the ratio of the amount of the compound of formula (1) to the amount of the compound of formula (2) is 0.5-2: 1.

4. the method for synthesizing pyrazolones with adjacent tertiary carbon-quaternary carbon chiral centers as shown in formula (3) according to claim 1, wherein the ratio of the amount of the chiral catalyst to the amount of the compound shown in formula (1) is 0.01-100: 100.

5. the method for synthesizing pyrazolones with adjacent tertiary carbon-quaternary carbon chiral centers as shown in claim 4, wherein the ratio of the amount of the chiral catalyst to the amount of the compound shown in formula (1) is 0.01-20: 1.

6. the method for synthesizing pyrazolones with adjacent tertiary carbon-quaternary carbon chiral centers as shown in formula (3) according to claim 1, wherein the ratio of the acid-binding agent to the compound of formula (2) is 0.5-20: 1.

7. the method for synthesizing pyrazolone compounds containing adjacent tertiary carbon-quaternary carbon chiral centers as shown in formula (3) according to claim 6, wherein the ratio of the acid-binding agent to the compound shown in formula (2) is 1-10: 1.

8. the method for synthesizing pyrazolones with adjacent tertiary carbon-quaternary carbon chiral centers according to claim 1, characterized in that the water-oil two-phase system comprises water and organic solvent in a volume ratio of 1: 0.05-10, wherein the organic solvent is selected from dichloromethane, chloroform, 1, 2-dichloroethane, diethyl ether, toluene, ethyl acetate or isopropyl acetate, and tetrahydrofuran.

9. The method for synthesizing pyrazolone compounds containing adjacent tertiary carbon-quaternary carbon chiral centers as shown in formula (3) according to 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.

10. The method for synthesizing pyrazolone compounds containing adjacent tertiary carbon-quaternary carbon chiral centers as shown in formula (3) according to claim 1, wherein the post-treatment method of the reaction solution comprises: 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 1-20: 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 pyrazolone compound containing the adjacent tertiary carbon-quaternary carbon chiral center shown in the formula (3) is obtained.