General chiral catalyst with (hydrogenated) cinchona alkaloid (thio) urea and o-pyridine oxazoline structural unit and preparation method of general chiral catalyst with (hydrogenated) cinchona alkaloid (thio) urea and o-pyridine oxazoline structural unit

Abstract

The invention discloses a general chiral catalyst with (hydrogenated) cinchona alkali (thio) urea and o-pyridine oxazoline structural units and a preparation method thereof, and belongs to the field of catalysts, the structure of the catalyst is characterized in that additional nitrogen ligand (pyridine and oxazoline) groups capable of being coordinated are introduced at proper positions of (hydrogenated) cinchona alkali, therefore, the novel compound with a specific function forms an asymmetric metal catalyst through coordination of a bidentate ligand and metal; the catalyst disclosed by the invention not only can be independently used as a chiral small molecule catalyst, but also can be independently used for realizing asymmetric metal catalysis through metal coordination, or can be used for realizing common catalysis of chiral small molecules and metal through different combinations, and is expected to become a transboundary'universal 'chiral catalyst and chiral ligand to realize more and richer asymmetric catalytic reactions; in addition, the preparation method disclosed by the invention has the advantages of wide raw material source, mild reaction conditions, short route, low cost and the like, and has a very good application prospect.

Description

Technical Field

[0001] The invention relates to the field of asymmetric catalysis and organic synthesis, and in particular to a general chiral catalyst having (hydrogenated) cinchona alkaloid (thio)urea and orthopyridine oxazoline structural units and a preparation method thereof. Background Art

[0002] Chiral synthesis and asymmetric catalysis are the main methods for synthesizing chiral substances. Asymmetric catalysis can achieve chirality amplification and chirality value-added, and is the most efficient method for obtaining chiral compounds. Asymmetric catalysis includes biocatalysis, asymmetric metal catalysis and organic small molecule catalysis, each with its own advantages and disadvantages. Although enzyme catalysis is efficient and specific, it has strict requirements on the reaction environment; metal catalysis has a wide range of activation of chemical bonds and can activate inert chemical bonds, but its tolerance for functional groups is relatively poor and it is very sensitive to the structure of ligands and reaction substrates; while organic small molecule catalysis has better tolerance for functional groups, but its activation and catalytic modes are relatively limited.

[0003] In recent years, the combination of transition metals and organic small molecules has greatly promoted the development of asymmetric catalysis. According to different catalytic modes, organic small molecules and metal combined catalysis is mainly divided into three types: synergistic catalysis, relay catalysis and continuous catalysis. With the rapid development of organic small molecule catalysis and people's in-depth understanding of metal catalysis, organic small molecules and metal combined catalysis has gradually become a hot topic.

[0004] In the asymmetric catalytic process, the first is the regulation of reaction activity, and the second is the control of stereoselectivity. On the one hand, chiral ligands can affect the activation ability of the metal center to the substrate through activation or deactivation, and make the complex dissolve in the organic solvent. On the other hand, they can control or affect the stereoselectivity of the reaction through their own chiral environment. Due to the wide variety of metals and their diverse activities, they are easily regulated by ligands and can catalyze chemical transformations with different requirements. In the more than half a century since the 1960s, asymmetric metal catalysis has developed rapidly, and transition metal catalysis has long occupied a major position and has become a frontier research direction in organic synthesis methodology and an important branch of homogeneous catalysis.

[0005] The selectivity and efficiency of metal-catalyzed asymmetric reactions depend on the chiral ligands and the central metal. The development of new and efficient chiral ligands has always been the key to the study of metal-catalyzed asymmetric reactions. Chemists have developed a series of chiral ligands that are easy to synthesize and modify, which are used in cross-coupling, asymmetric catalytic hydrogenation, asymmetric allylation, asymmetric cyclization and other reactions, and have obtained excellent enantioselectivity. (Heng Wang, Xumu Zhang, et al. Chem. Rev. 2021, 121, 13, 7530–7567; Qiang Cheng, Shu-Li You, et al. Chem. Rev. 2019, 119, 3, 1855–1969;). Among them, pyridine oxazoline ligands play an important role, and oxazoline ligands appear frequently in metal-catalyzed asymmetric catalysis research. (Connon, R.; Guiry, PJ, et al. Chem. Rev. 2021, 121 (11), 6373-6521.). Due to its high efficiency and economy, pyridine oxazoline has quickly become one of the most commonly used ligands and a symbol of metal-catalyzed asymmetric reactions. Since the development of the first oxazoline-containing ligand, the pyridine-oxazoline type ligand Pyox, this chiral coordination group has been widely used to develop a variety of very effective chiral ligands, such as PyBox, Box, Phox, Tox, etc., and has achieved excellent catalytic effects. It is considered to be a "dominant chiral ligand" in the field of transition metal asymmetric catalysis, but only a few chiral pyridine oxazoline ligands have been widely used (Wanbin Zhang, Guoqiang Yang, et al. Chem. Rev. 2018, 47, 1783;). At the same time, chemists are not limited to simple pyridine-oxazoline ligands. Based on existing research, they have developed various heteroatom-containing oxazoline ligands such as monopyridine-bis-oxazoline and its derivative compounds. Heteroatom-containing oxazoline ligands have played an important role in tandem cyclization, asymmetric conjugate addition, free radical chemistry, and hydrosilylation (Han Yuhong, Application of pyridine-oxazoline ligands in asymmetric catalysis, Liaoning Chemical Industry, 2020, 4.396-397.).

[0006] (Hydrogenated) cinchona alkaloids were first used as antimalarial drugs in the production and life of humans. As early as 2003, Jacobson wrote in Science that this type of alkaloid has a broad application prospect in the field of asymmetric catalytic synthesis (Yoon TP, Jacobsen EN Piloted Chiral Catalysts [J]. Science, 2003, 299 (5613): 1691-1693.). Because (hydrogenated) cinchona alkaloids have unique rigid chemical structure, multiple chiral centers, and functional groups that are easily modified or transformed, they are widely used in various asymmetric catalytic reactions and have achieved good reaction results. Therefore, they are also known as "dominant skeletons" in the field of chiral catalysis.

[0007] The above catalytic modes all require that the reaction substrates are functionalized molecules, so it is difficult to activate inert chemical bonds or molecular systems using organic small molecule catalysis. Transition metals can activate a variety of chemical bonds. With the assistance of chiral ligands, they are combined with small molecule catalysts to achieve a variety of asymmetric catalytic reactions.

[0008] However, there are currently no reports on catalysts that can meet the above requirements. Summary of the invention

[0009] One of the purposes of the present invention is to provide a general chiral catalyst having (hydrogenated) cinchona alkaloid (thio)urea and orthopyridine oxazoline structural units to solve the above problems.

[0010] In order to achieve the above object, the technical solution adopted by the present invention is as follows: a general chiral catalyst having (hydrogenated) cinchona alkali (thio) urea and orthopyridine oxazoline structural units, wherein the catalyst simultaneously has cinchona primaamine urea structural unit or hydrogenated cinchona primaamine urea structural unit or cinchona primaamine thiourea structural unit or hydrogenated cinchona primaamine thiourea structural unit and orthopyridine oxazoline structural unit, and its structural formula is shown in the following formula I, II, Ia or IIa:

[0011]

[0012] Among them, R 1 , R 2 , R3, R 4 Each is independently selected from: a hydrogen atom, a C1-C30 substituted or unsubstituted alkyl and cyclic alkyl group, a C5-C50 substituted or unsubstituted aryl group, a C5-C50 substituted or unsubstituted para-aryl group, a C5-C50 substituted or unsubstituted fused aryl group; and a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted para-heterocyclic group or a substituted or unsubstituted fused heterocyclic group.

[0013] As a preferred technical solution, the cinchona primamide urea structural unit or hydrogenated cinchona primamide urea structural unit or cinchona primamide thiourea structural unit or hydrogenated cinchona primamide thiourea structural unit is connected to the 3rd, 4th, 5th or 6th position of the ortho-pyridine oxazoline structural unit, as shown below:

[0014]

[0015]

[0016] As a preferred technical solution, the compound shown in the following structure is included:

[0017]

[0018]

[0019]

[0020] Compared with the existing (hydrogenated) cinchona alkali catalyst, the present invention introduces additional coordinating nitrogen ligands (pyridine and oxazoline) groups at appropriate positions, thereby forming a new compound with specific functions, and forms an asymmetric metal catalyst through the coordination of bidentate ligands and metals. At the same time, (hydrogenated) cinchona alkali can also be used as a separate small molecule chiral catalyst to achieve an asymmetric reaction catalyzed by tertiary amine (thio) urea, which is a molecular structure and catalytic function that the existing common (hydrogenated) cinchona alkali chiral small molecule catalyst does not have. The new compound of the present invention retains all the characteristics of the orthopyridine oxazoline ligand and the (hydrogenated) cinchona alkali (thio) urea chiral small molecule catalyst, so that it can be used as a chiral small molecule catalyst alone, and can also achieve asymmetric metal catalysis alone through metal coordination, or achieve co-catalysis of chiral small molecules and metals through different combinations. The principle is as follows Figure 1 shown.

[0021] The catalyst of the present invention is a multifunctional universal chiral catalyst containing both (hydrogenated) cinchona alkali (thio)urea and chiral orthopyridine oxazoline structural units. Its structural characteristics determine its functional characteristics, including but not limited to:

[0022] (1) Its structure contains a (hydrogenated) cinchona alkali (thio)urea structural unit, which is a typical chiral tertiary amine (thio)urea small molecule catalyst. Therefore, the new compound can be used alone as a chiral tertiary amine (thio)urea catalyst and catalyze asymmetric reactions. By regulating the steric hindrance and electronic properties of the connected ortho-pyridine oxazoline structural unit, the steric hindrance and electronic properties of the chiral tertiary amine (thio)urea catalyst can be regulated, thereby regulating the activity and stereoselectivity of its (thio)urea catalytic center, and further catalyzing more, wider, and richer asymmetric reactions;

[0023] (2) Its structure contains an o-pyridine oxazoline structural unit, which is a typical commonly used chiral ligand. Therefore, the new compound can be used alone as a chiral ligand to catalyze different types of asymmetric metal-catalyzed reactions by coordinating with the central metal. By regulating the steric hindrance and electronic properties of the connected (hydrogenated) cinchona (thio) urea structural unit, it is possible to regulate the steric hindrance and electronic properties of the o-pyridine oxazoline chiral ligand, thereby regulating its coordination properties, and regulating its catalytic activity and stereoselectivity by coordinating with the central metal, thereby catalyzing more, wider and richer asymmetric metal-catalyzed reactions.

[0024] The second object of the present invention is to provide a method for preparing the above-mentioned universal chiral catalyst having (hydrogenated) cinchona alkali (thio) urea and orthopyridine oxazoline structural units, the technical scheme adopted is, comprising the following steps:

[0025] (1) using an orthopyridine oxazoline compound (1) substituted with amino groups at different positions as a raw material, in a solvent S 1 In, T 1 At a temperature, phosgene / thiophosgene is added to react to generate a compound iso(thio)cyanate-2-pyridine oxazoline (2);

[0026] (2) using iso(thio)cyanate-2-pyridine oxazoline compounds (2) substituted at different positions as raw materials, in a solvent S 2 In, T 2 At a temperature, adding (hydrogenated) cinchona alkaloid primary amine (3) to react and generate compound Ⅰ or Ⅱ;

[0027] The reaction formula of the reaction is as follows:

[0028]

[0029] As a preferred technical solution,

[0030] In step (1), the feed ratio is: the compound (1) is one molar equivalent, the phosgene or thiophosgene is 2 to 3 molar equivalents, and the solvent S is 1 The amount used is 1 to 20 ml of solvent per mmol of compound (1);

[0031] The solvent S 1 A mixed solvent selected from: one or more of a C4-C20 alkane solvent, an aromatic solvent, and an ether solvent;

[0032] The temperature T 1 0℃~Solvent S 1 reflux temperature.

[0033] As a further preferred technical solution,

[0034] The C4-C20 alkane solvent is selected from at least one of n-hexane, cyclohexane, heptane and petroleum ether;

[0035] The aromatic hydrocarbon solvent is selected from at least one of benzene, toluene, xylene, mesitylene, chlorobenzene and bromobenzene;

[0036] The ether solvent is selected from at least one of methyl tert-butyl ether, tetrahydrofuran and dioxane.

[0037] As a further preferred technical solution, the solvent S 1 It is an aromatic solvent.

[0038] As a preferred technical solution,

[0039] In step (2), the feed ratio is: the compound (2) is one molar equivalent, the (hydrogenated) cinchona alkaloid primary amine (3) is 1 to 2 molar equivalents, and the solvent S is 1 to 2 molar equivalents. 2 The dosage is 1-20 ml of solvent per millimole of compound (2);

[0040] The solvent S 2 Selected from: aprotic solvents;

[0041] The temperature T 2 0℃~Solvent S 2 reflux temperature.

[0042] As a further preferred technical solution,

[0043] The aprotic solvent is selected from at least one of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, toluene, chlorobenzene and xylene.

[0044] As for the application of the catalyst of the present invention, as mentioned above, it can be used alone as a chiral small molecule catalyst, and can also be used alone to achieve asymmetric metal catalysis through metal coordination, or can be used to achieve co-catalysis of chiral small molecules and metals through different combinations. Specific application examples are as follows:

[0045]

[0046] Compared with the prior art, the advantages of the present invention are: the catalyst of the present invention can be used alone as a chiral small molecule catalyst, and can also achieve asymmetric metal catalysis alone through metal coordination, or achieve co-catalysis of chiral small molecules and metals through different combinations. It is expected to become a cross-border "universal" chiral catalyst and chiral ligand, realizing more and richer asymmetric catalytic reactions; in addition, the preparation method of the catalyst of the present invention has the advantages of a wide source of raw materials, mild reaction conditions, short route and low cost, and has a good application prospect. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 It is a schematic diagram of the catalytic function principle of the catalyst of the present invention. DETAILED DESCRIPTION

[0048] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the present invention is further described below in conjunction with specific examples. In the embodiments, if the specific conditions are not indicated, the conditions are carried out according to normal conditions or manufacturer recommendations. If the manufacturer is not indicated in the reagents or instruments used, they are all conventional products that can be purchased commercially. All features disclosed in this specification, except mutually exclusive features and / or steps, can be combined in any way.

[0049] The following examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way.

[0050] In the following examples, the starting materials amino-o-pyridine oxazoline 1 and (hydrogenated) cinchona alkaloid primary amine 3 can be prepared by referring to relevant literature reports, such as: Yoon TP, Jacobsen EN Piloted Chiral Catalysts [J]. Science, 2003, 299 (5613): 1691-1693.; Preston, AJ; Gallucci, JC; Parquette, JR The influence of sterics on the formation of polar 1-D hydrogen bonded networks. Chem. Commun. 2005, (26).

[0051] Example 1

[0052] The general chiral catalyst I-62, the reaction formula for its preparation is:

[0053]

[0054] The specific preparation process is as follows:

[0055] Step 1: Add compound S-5-isopropyl-2-(6-aminopyridine)oxazoline 1 (2.1 g, 10 mmol) into a reactor, add 1.5 g (10.5 mmol) of thiophosgene to 10 mL of dichloromethane solvent at room temperature to react to generate compound S-5-isopropyl-2-(6-isothiocyanate pyridine)oxazoline 2; after the reaction is completed, remove the solvent by distillation under reduced pressure, and purify by column chromatography [eluent: V (petroleum ether) / V (ethyl acetate) = 3:1] to obtain compound 2, 1.5 g (6.2 mmol);

[0056] Step 2: Using the above compound 2 (1.5 g, 6.2 mmol) as raw material, add quinine primary amine 3 (2.4 g, 6.5 mmol) in 10 mL of dichloromethane solvent at room temperature to react to generate compound Ⅰ-62; ​​after the reaction is completed, remove the solvent by distillation under reduced pressure, and purify by column chromatography [eluent: V (petroleum ether) / V (ethyl acetate) = 1:3] to obtain compound Ⅰ-62, 2.5 g (4.4 mmol).

[0057] Characterization data of Ⅰ-62 are: 1 H NMR (400 MHz, DMSO-d 6 )δ10.3(s,-1H),8.9(s,1H),8.8(d,J=4.4Hz,1H),8.4(d,J=5.6Hz,1H),8.3(s,1H),8.0(d,J=9.2Hz,1H),7.9(s,1H),7.8(d,J=5. 6Hz,1H),7.6(d,J=4.4Hz,1H),7.5(d,J=9.2Hz,1H),6.1–5.8(m,1H),5.8(d,J=9.2Hz,1H),5.0(d,J=17.2Hz,1H),4.9(d,J=10.0H z,1H),4.4(t,J=8.8Hz,1H),4.1(dt,J=1.2,8.0Hz,2H),4.0(s,3H),3.3–3.2(m,3H),2.7(dd,J=13.2,6.3Hz,2H),2.3(d,J=11.2H z,1H),1.8(h,J=6.0Hz,1H),1.6(s,2H),1.6(s,1H),1.2(d,J=11.2Hz,1H),1.1(s,1H),1.0(d,J=6.0Hz,3H),0.9(d,J=6.0Hz,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ179.8,162.5,157.6,150.3,148.2,147.9,147.5,144.6,142.4,131.8,128.5,121.8 ,116.2,114.8,103.5,72.5,70.6,56.2,55.6,41.5,32.8,27.9,27.5,25.9,19.1,18.7.

[0058] HRMS calculated for C 32 H 38 N 6 O 2 S[M+H] +:571.2850,measured:571.2852.

[0059] Example 2-11

[0060] The solvent S in step 1 of Example 1 is 1 The same compound Ⅰ-62 was obtained by column chromatography purification under the same conditions as chloroform (yield 55%), carbon tetrachloride (yield 51%), 1,2-dichloroethane (yield 54%), 1,1-dichloroethane (yield 50%), chlorobenzene (yield 47%), toluene (yield 49%), o-xylene (yield 47%), m-xylene (yield 46%), p-xylene (yield 46%) and mesitylene (yield 43%).

[0061] It should be noted that the yields in brackets when using various solvents in the above examples refer to the yields of the products of the steps corresponding to the changed conditions, and the same applies to the following examples.

[0062] Examples 12-17

[0063] In Example 1, the temperature T 1 The temperature was changed to -10°C (yield 43%), 0°C (yield 54%), 10°C (yield 55%), 20°C (yield 55%), 30°C (yield 49%), 40°C (yield 39%), and other conditions were the same, and column chromatography purification gave the same compound Ⅰ-62.

[0064] Examples 18-27

[0065] The solvent S in step 2 of Example 1 is 2 The same compound Ⅰ-62 was obtained by column chromatography purification under the same conditions as chloroform (yield 75%), carbon tetrachloride (yield 70%), 1,2-dichloroethane (yield 77%), 1,1-dichloroethane (yield 72%), chlorobenzene (yield 70%), toluene (yield 71%), o-xylene (yield 72%), m-xylene (yield 72%), p-xylene (yield 73%) and mesitylene (yield 70%).

[0066] Examples 28-33

[0067] In Example 1, the temperature T 2 The temperature was changed to -10°C (yield 64%), 0°C (yield 68%), 10°C (yield 71%), 20°C (yield 75%), 30°C (yield 77%), 40°C (yield 76%), and other conditions were the same, and column chromatography purification gave the same compound Ⅰ-62.

[0068] Embodiment 34

[0069] The general chiral catalyst I-44 is prepared by the following reaction formula:

[0070]

[0071] The specific preparation process is:

[0072] Step 1: Add compound 4-amino-2-pyridine oxazoline 1 (1.5 g, 10 mmol) into a reactor, add phosgene 1.2 g (10.5 mmol) to 10 mL of dichloromethane solvent at room temperature to react to generate compound 4-isocyanate-2-pyridine oxazoline 2; after the reaction is completed, remove the solvent by distillation under reduced pressure, and purify by column chromatography [eluent: V (petroleum ether) / V (ethyl acetate) = 3:1, to obtain compound 2, 1.3 g (6.5 mmol);

[0073] Step 2: Compound 2 (1.3 g, 6.5 mmol) was used as the raw material, and quinine primary amine 3 (2.2 g, 6.7 mmol) was added to 10 mL of dichloromethane at room temperature to generate compound I-41. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the mixture was purified by column chromatography [eluent: V (petroleum ether) / V (ethyl acetate) = 1:3] to obtain compound I-41, 2.3 g (4.3 mmol).

[0074] Characterization data of Ⅰ-41 are: 1 H NMR (400 MHz, DMSO-d 6 )δ9.1(s,1H),8.8(d,J=4.4Hz,1H),8.6(t,J=5.2Hz,1H),8.4(d,J=5.2Hz,1H),8.3(d,J=2.0Hz,1H),8.0(d ,J=9.2Hz,1H),7.9–7.9(m,2H),7.6(d,J=4.4Hz,1H),7.4(dd,J=9.2,2.6Hz,1H),5.8(ddd,J=13.2,10.0,7 .2Hz,1H),5.0(d,J=14.0Hz,1H),5.0(d,J=10.0Hz,1H),4.8(s,1H),4.0(s,3H),3.5(d,J=6.0Hz,2H),3.4( q,J=6.0Hz,4H),2.8(s,2H),2.4(s,1H),1.7–1.6(m,2H),1.3(s,1H),1.1(s,2H),0.9(q,J=6.0,6.4Hz,1H). 13C NMR (101MHz, DMSO) δ179.4,163.6,157.3,150.6,148.7,148.2,147.7,144.1,141.2,131.3,127.8,121.4,116.0,114. 7,112.4,103.0,59.7,55.8,54.6,48.7,41.6,41.3,40.2,39.9,39.7,39.5,39.3,39.1,38.9,38.4,26.8,26.8,25.0.

[0075] HRMS(ESI)m / z calcd for C 29 H 33 N 6 O2S + (M+H) + 512.2536, found 529.2537.

[0076] Examples 35-44

[0077] The solvent S in step 1 of Example 34 was 1 The same compound Ⅰ-41 was obtained by column chromatography purification under the same conditions as chloroform (yield 48%), carbon tetrachloride (yield 47%), 1,2-dichloroethane (yield 49%), 1,1-dichloroethane (yield 42%), chlorobenzene (yield 42%), toluene (yield 45%), o-xylene (yield 42%), m-xylene (yield 43%), p-xylene (yield 43%) and mesitylene (yield 44%).

[0078] Examples 45-50

[0079] In Example 34, the temperature T 1 The temperature was changed to -10℃ (yield 46%), 0℃ (yield 48%), 10℃ (yield 44%), 20℃ (yield 44%), 30℃ (yield 42%), 40℃ (yield 38%), and other conditions were the same, and column chromatography purification gave the same compound Ⅰ-41.

[0080] Examples 51-60

[0081] In Example 34, the solvent S in step 2 2 The same compound Ⅰ-41 was obtained by column chromatography purification under the same conditions as chloroform (yield 73%), carbon tetrachloride (yield 74%), 1,2-dichloroethane (yield 76%), 1,1-dichloroethane (yield 71%), chlorobenzene (yield 69%), toluene (yield 72%), o-xylene (yield 71%), m-xylene (yield 71%), p-xylene (yield 70%) and mesitylene (yield 72%).

[0082] Examples 61-66

[0083] In Example 34, the temperature T 2 The temperature was changed to -10°C (yield 67%), 0°C (yield 70%), 10°C (yield 72%), 20°C (yield 76%), 30°C (yield 78%), 40°C (yield 76%), and other conditions were the same, and column chromatography purification gave the same compound Ⅰ-41.

[0084] Embodiment 67

[0085] The general chiral catalyst I-54 is prepared by the following reaction formula:

[0086]

[0087] The preparation process is:

[0088] Step 1: Add compound R-5-phenyl-2-(5-aminopyridine)oxazoline 1 (2.4 g, 10 mmol) into a reactor, add 1.5 g (10.5 mmol) of thiophosgene to 10 mL of dichloromethane at room temperature to react to generate compound R-5-phenyl-2-(5-isothiocyanate pyridine)oxazoline 2; after the reaction is completed, remove the solvent by distillation under reduced pressure, and purify by column chromatography [eluent: V (petroleum ether) / V (ethyl acetate) = 3:1] to obtain compound 2, 1.7 g (6.0 mmol);

[0089] Step 2: Compound 2 (1.7 g, 6.5 mmol) was used as the raw material, and quinidine primary amine 3 (2.2 g, 6.7 mmol) was added to 10 mL of dichloromethane at room temperature to generate compound I-54. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the mixture was purified by column chromatography [eluent: V (petroleum ether) / V (ethyl acetate) = 1:3] to obtain compound I-54, 2.3 g (4.0 mmol).

[0090] Characterization data of Ⅰ-54 are: 1H NMR (400MHz, DMSO-d6) δ9.06(s,1H),8.71(d,J=4.4Hz,1H),8.47(d,J=5.6Hz,1H),8.39(d,J=2.0Hz,1H),7.96(d,J=9.2Hz,1H),7.87(d,J=2.4 Hz,1H),7.76(dd,J=5.6,2.0Hz,1H),7.62(d,J=4.4Hz,1H),7.44(dd,J=9.2,2.4Hz,1H),7.38(dd,J=8.0,6.4Hz,2H),7.31(d,J=7.2Hz,3H),6.1 0(s,1H),5.96(dd,J=10.4,6.0Hz,1H),5.44(dd,J=10.0,8.0Hz,1H),5.19(d,J=13.2Hz,1H),5.15(dt,J=10.4,1.6Hz,1H),4.86(dd,J=10.0,8. 4Hz,1H),4.22(t,J=8.4Hz,1H),3.01(s,1H),2.93(s,1H),2.31(s,1H), 1.60(s,1H),1.52(s,2H),1.26–1.16(m,1H),1.12(s,2H),0.91(s,1H). 13 CNMR(101MHz,DMSO)δ163.8,157.7,150.4,148.2,148.0,147.2,144.6,143.0,131.7,129.1,12 8.4,127.9,127.1,122.1,116.4,114.9,69.7,56.1,49.1,47.3,38.9,27.3,25.3.HRMS(ESI)m / z calcd for C 35 H 37 N 6 O 2 S + (M+H) + 574.2515, found 574.2519.

[0091] Examples 68-77

[0092] The solvent S in step 1 of Example 67 was 1Replaced with chloroform (yield 42%), carbon tetrachloride (yield 35%), 1,2-dichloroethane (yield 46%), 1,1-dichloroethane (yield 40%), chlorobenzene (yield 41%), toluene (yield 44%), o-xylene (yield 43%), m-xylene (yield 40%), p-xylene (yield 42%), and mesitylene (yield 42%), and other conditions were the same, and purified by column chromatography to obtain the same compound Ⅰ-54.

[0093] Examples 78-83

[0094] In Example 67, the temperature T 1 The temperature was changed to -10°C (yield 40%), 0°C (yield 46%), 10°C (yield 47%), 20°C (yield 44%), 30°C (yield 40%), and 40°C (yield 36%). Other conditions remained the same and column chromatography purification gave the same compound Ⅰ-54.

[0095] Examples 84-93

[0096] In Example 67, the solvent S in step 2 2 The same compound Ⅰ-54 was obtained by column chromatography purification under the same conditions as chloroform (yield 71%), carbon tetrachloride (yield 70%), 1,2-dichloroethane (yield 74%), 1,1-dichloroethane (yield 72%), chlorobenzene (yield 78%), toluene (yield 71%), o-xylene (yield 70%), m-xylene (yield 70%), p-xylene (yield 69%) and mesitylene (yield 70%).

[0097] Examples 94-99

[0098] In Example 67, the temperature T 2 The temperature was changed to -10°C (yield 68%), 0°C (yield 71%), 10°C (yield 83%), 20°C (yield 75%), 30°C (yield 74%), 40°C (yield 73%), and other conditions were the same, and column chromatography purification gave the same compound Ⅰ-54.

[0099] Embodiment 100

[0100] Universal chiral catalyst II-35, the reaction formula for its preparation is:

[0101]

[0102] The preparation process is:

[0103] Step 1: Add compound R-5-benzyl-2-(5-aminopyridine)oxazoline 1 (2.5 g, 10 mmol) into a reactor, add 1.5 g (10.5 mmol) of thiophosgene to 10 mL of dichloromethane at room temperature to react and generate compound R-5-phenyl-2-(5-isothiocyanate pyridine)oxazoline 2; after the reaction is completed, remove the solvent by distillation under reduced pressure, and purify by column chromatography [eluent: V (petroleum ether) / V (ethyl acetate) = 3:1] to obtain compound 2, 1.6 g (5.4 mmol);

[0104] Step 2: Compound 2 (1.6 g, 5.4 mmol) was used as the raw material, and quinidine primary amine 3 (1.9 g, 5.5 mmol) was added to 10 mL of dichloromethane at room temperature to react to generate compound II-35. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the mixture was purified by column chromatography [eluent: V (petroleum ether) / V (ethyl acetate) = 1:3] to obtain compound II-35, 2.4 g (4.1 mmol).

[0105] The characterization data of Ⅱ-35 are: 1 H NMR (400MHz, DMSO-d6) δ8.8(d,J=4.4Hz,2H),8.4(d,J=5.2Hz,1H),8.3(d,J=2.4Hz,1H),8.0(dd,J=9.2,1.9Hz,1H) ,7.9(s,1H),7.8(dd,J=5.6,2.2Hz,1H),7.6(d,J=4.4Hz,1H),7.3–7.3(m,5H),7.2–7.2(m,1H),5.9–5.8(m,1H),5. 0–4.9(m,3H),4.6(dq,J=9.2,7.2Hz,1H),4.4(dd,J=9.6,8.4Hz,1H),4.1(t,J=8.0Hz,1H),4.0(s,2H),3.2(s,2H), 3.1(s,1H),3.0–3.0(m,1H),2.8–2.8(m,1H),2.3(s,1H),1.6(s,3H),1.3(d,J=3.6Hz,2H),1.1(s,3H),0.9(s,1H). 13C NMR(101MHz,DMSO-d6)δ179.8,162.9,157.6,150.3,148.2,147.9,147.4,144.6,142.5,142.3,138.7,131.8,129.8,128.7,1 26.7,121.8,116.2,114.8,103.5,72.2,67.7,56.2,55.6,49.2,41.4,31.5,27.9,27.5,27.3,25.9,22.6,14.5.HRMS(ESI)m / z calcd for C36H39N6O2S+(M+H)+590.2828,found 590.2829.

[0106] Examples 101-110

[0107] In Example 100, the solvent S in step 1 1 The same compound Ⅱ-35 was obtained by column chromatography purification under the same conditions as chloroform (yield 47%), carbon tetrachloride (yield 42%), 1,2-dichloroethane (yield 49%), 1,1-dichloroethane (yield 45%), chlorobenzene (yield 43%), toluene (yield 45%), o-xylene (yield 43%), m-xylene (yield 44%), p-xylene (yield 43%) and iso-trimethylolbenzene (yield 43%).

[0108] Examples 111-116

[0109] In Example 100, the temperature T 1 The temperature was changed to -10℃ (yield 44%), 0℃ (yield 47%), 10℃ (yield 45%), 20℃ (yield 42%), 30℃ (yield 41%), 40℃ (yield 37%), and other conditions were the same, and column chromatography purification gave the same compound Ⅱ-35.

[0110] Examples 117-126

[0111] In Example 100, the solvent S in step 2 2 The same compound Ⅱ-35 was obtained by column chromatography purification under the same conditions as chloroform (yield 77%), carbon tetrachloride (yield 72%), 1,2-dichloroethane (yield 77%), 1,1-dichloroethane (yield 73%), chlorobenzene (yield 72%), toluene (yield 76%), o-xylene (yield 74%), m-xylene (yield 73%), p-xylene (yield 73%) and mesitylene (yield 71%).

[0112] Examples 127-132

[0113] In Example 100, the temperature T 2 The temperature was changed to -10°C (yield 72%), 0°C (yield 74%), 10°C (yield 75%), 20°C (yield 75%), 30°C (yield 74%), 40°C (yield 76%), and other conditions were the same, and column chromatography purification gave the same compound Ⅱ-35.

[0114] Embodiment 133

[0115] The general chiral catalyst Ⅱa-61, the reaction formula for its preparation is:

[0116]

[0117] The preparation process is:

[0118] Step 1: Add compound 6-amino-2-pyridinebenzoxazoline 1 (2.1 g, 10 mmol) into a reactor, add 1.5 g (10.5 mmol) of thiophosgene to 10 mL of dichloromethane at room temperature to react and generate compound 6-isothiocyanate-2-pyridinebenzoxazoline 2; after the reaction is completed, remove the solvent by distillation under reduced pressure, and purify by column chromatography [eluent: V (petroleum ether) / V (ethyl acetate) = 3:1] to obtain compound 2, 1.4 g (5.5 mmol);

[0119] Step 2: Compound 2 (1.4 g, 5.5 mmol) was used as the raw material, and hydroquinone primary amine 3 (2.0 g, 5.6 mmol) was added to 10 mL of dichloromethane at room temperature to generate compound IIa-61. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the mixture was purified by column chromatography [eluent: V (petroleum ether) / V (ethyl acetate) = 1:3] to obtain compound IIa-61, 2.1 g (3.8 mmol).

[0120] The characterization data of Ⅱa-61 are: 1H NMR (400MHz, DMSO-d6) δ9.1 (s, 1H), 8.7 (d, J = 4.0Hz, 1H), 8.5 (t, J = 3.2Hz, 1H), 8.3 (d, J = 3.2Hz, 1H), 8.1(d,J=2.0Hz,1H),8.0(d,J=7.2Hz,3H),7.9–7.9(m,3H),7.6(d,J=4.4Hz,3H),7.4(dd,J=9.2,2.6 Hz,2H),5.8(ddd,J=13.2,10.0,7.2Hz,1H),4.8(s,1H),4.0(s,3H),3.5(d,J=6.0Hz,1H),3.4(q,J=6 .0Hz,2H),2.8(s,2H),2.4(s,1H),1.7–1.6(m,1H),1.3(s,1H),1.1(s,2H),0.9(q,J=6.0,6.4Hz,1H). 13 CNMR(101MHz,DMSO)δ179.2,163.4,157.6,150.4,148.2,148.1,147.0,144.6,141.6,131.7,127.2,121.4,116.3,114 .3,112.3,103.2,59.3,55.2,54.2,48.2,41.3,41.2,40.5,39.6,39.3,39.7,39.8,39.8,38.4,38.2,26.5,26.8,25.2.

[0121] HRMS(ESI)m / z calcd for C36H39N6O2S+(M+H)+548.2358, found 548.2355.

[0122] Examples 134-143

[0123] In Example 133, the solvent S in step 1 1 The same compound Ⅱa-61 was obtained by column chromatography purification under the same conditions as chloroform (yield 42%), carbon tetrachloride (yield 42%), 1,2-dichloroethane (yield 43%), 1,1-dichloroethane (yield 40%), chlorobenzene (yield 43%), toluene (yield 44%), o-xylene (yield 42%), m-xylene (yield 41%), p-xylene (yield 43%) and mesitylene (yield 41%).

[0124] Examples 144-149

[0125] In Example 133, the temperature T 1The temperature was changed to -10℃ (yield 42%), 0℃ (yield 41%), 10℃ (yield 42%), 20℃ (yield 37%), 30℃ (yield 37%), 40℃ (yield 32%), and other conditions were the same, and column chromatography purification gave the same compound Ⅱa-61.

[0126] Examples 150-159

[0127] In Example 133, the solvent S in step 2 2 The same compound Ⅱa-61 was obtained by column chromatography purification under the same conditions as chloroform (yield 63%), carbon tetrachloride (yield 62%), 1,2-dichloroethane (yield 62%), 1,1-dichloroethane (yield 62%), chlorobenzene (yield 65%), toluene (yield 64%), o-xylene (yield 65%), m-xylene (yield 62%), p-xylene (yield 67%) and iso-trimethylolbenzene (yield 65%).

[0128] Examples 160-165

[0129] In Example 133, the temperature T 2 The temperature was changed to -10℃ (yield 62%), 0℃ (yield 75%), 10℃ (yield 67%), 20℃ (yield 68%), 30℃ (yield 66%), 40℃ (yield 64%), and other conditions were the same, and column chromatography purification gave the same compound Ⅱa-61.

[0130] The protection content of the present invention is not limited to the above examples. Within the spirit and principles of the present invention, for those skilled in the art, the present invention can have various changes and variations. Any modifications, equivalent substitutions, improvements, etc. made should be included in the protection scope of the present invention and the attached claims shall be the protection scope.

Claims

1. A general chiral catalyst having (hydrogenated) cinchona alkaloid (thio)urea and orthopyridine oxazoline structural units, characterized in that: The catalyst simultaneously has a cinchona primamide urea structural unit or a hydrogenated cinchona primamide urea structural unit or a cinchona primamide thiourea structural unit or a hydrogenated cinchona primamide thiourea structural unit and an orthopyridine oxazoline structural unit, and its structural formula is shown in the following formula I, II, Ia or IIa: Among them, R 1 , R 2 , R3, R 4 Each is independently selected from: a hydrogen atom, a C1-C30 substituted or unsubstituted alkyl and cyclic alkyl group, a C5-C50 substituted or unsubstituted aryl group, a C5-C50 substituted or unsubstituted para-aryl group, a C5-C50 substituted or unsubstituted fused aryl group; and a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted para-heterocyclic group or a substituted or unsubstituted fused heterocyclic group.

2. The universal chiral catalyst having (hydrogenated) cinchona alkali (thio)urea and orthopyridine oxazoline structural units according to claim 1, characterized in that: The cinchona primamide urea structural unit or hydrogenated cinchona primamide urea structural unit or cinchona primamide thiourea structural unit or hydrogenated cinchona primamide thiourea structural unit is connected to the 3rd position, 4th position, 5th position or 6th position of the ortho-pyridine oxazoline structural unit.

3. The universal chiral catalyst having (hydrogenated) cinchona alkali (thio)urea and orthopyridine oxazoline structural units according to claim 1, characterized in that: Including compounds shown in the following structures:

4. The method for preparing a universal chiral catalyst having (hydrogenated) cinchona alkali (thio)urea and orthopyridine oxazoline structural units according to any one of claims 1 to 3, characterized in that: The steps include: (1) using an orthopyridine oxazoline compound (1) substituted with amino groups at different positions as a raw material, adding phosgene / thiophosgene in a solvent S1 at a temperature T1 to react and generate a compound iso(thio)cyanate-2-pyridine oxazoline (2); (2) Using iso(thio)cyanate-2-pyridine oxazoline compounds (2) substituted at different positions as raw materials, (hydrogenated) cinchona alkaloid primary amine (3) is added in solvent S2 at temperature T2 to react and generate compound I or II.

5. The preparation method according to claim 4, characterized in that: In step (1), the feeding ratio is: the compound (1) is one molar equivalent, the phosgene or thiophosgene is 2 to 3 molar equivalents, and the amount of solvent S1 is 1 to 20 ml per mmol of compound (1); The solvent S1 is selected from: a mixed solvent of one or more of a C4-C20 alkane solvent, an aromatic solvent, and an ether solvent; The temperature T1 is from 0°C to the reflux temperature of the solvent S1.

6. The preparation method according to claim 5, characterized in that: The C4-C20 alkane solvent is selected from at least one of n-hexane, cyclohexane, heptane and petroleum ether; The aromatic hydrocarbon solvent is selected from at least one of benzene, toluene, xylene, mesitylene, chlorobenzene and bromobenzene; The ether solvent is selected from at least one of methyl tert-butyl ether, tetrahydrofuran and dioxane.

7. The preparation method according to claim 5 or 6, characterized in that: The solvent S1 is an aromatic hydrocarbon solvent.

8. The preparation method according to claim 4, characterized in that: In step (2), the feeding ratio is: the compound (2) is one molar equivalent, the (hydrogenated) cinchona alkaloid primary amine (3) is 1-2 molar equivalent, and the amount of solvent S2 is 1-20 ml per millimole of compound (2); The solvent S2 is selected from: aprotic solvents; The temperature T2 is from 0°C to the reflux temperature of the solvent S2.

9. The preparation method according to claim 8, characterized in that: The aprotic solvent is selected from at least one of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, toluene, chlorobenzene and xylene.

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