CN101676288A - Iminazole chiral organic micromolecule compound with bicyclo-structure and synthesizing method thereof - Google Patents

Abstract

The invention relates to an iminazole chiral organic micromolecule compound with a bicyclo-structure, as shown in chemical formula (I), and a synthesizing method thereof. The compound can be applied in various asymmetric reactions as a chiral catalyst, such as asymmetric acylation, asymmetric phosphorylation, asymmetric sulfonylation, asymmetric halogenate, asymmetric Micheal addition, asymmetricSteglich rearrangement reaction, asymmetric Morita-Baylis-Hillman reaction and the like. In addition, the compound also has potential bioactivities, such as anti-ulcer, anti-depression, antibiosis andenzyme inhibitory activities and the like.

Description

A class of imidazole chiral organic small molecule compounds with bicyclic structure and synthesis method thereof

technical field

The invention relates to a class of imidazole chiral organic small molecule compounds with a bicyclic structure and a synthesis method thereof.

Background technique

The rapid rise of the chiral drug industry is mainly due to the great development of asymmetric synthesis methodology research, and in turn, the chiral drug industry has promoted the research of asymmetric synthesis methodology. Asymmetric catalytic organic synthesis is one of the most effective and beneficial methods to obtain chiral compounds. In asymmetric catalytic organic synthesis reactions, the key to achieving high reactivity and high enantioselectivity lies in the structure of chiral catalysts, and chiral organic small molecule catalysts have attracted widespread attention due to their green and stable performance. Therefore, the development of chiral organic small molecule catalysts has always been a key research area of concern in academia and industry.

In 1996, the E.Vedejs group first synthesized a chiral small molecule catalyst derived from pyridine (J.Am.Chem.Soc.1996, 118, 1809), and successfully applied it to the kinetic resolution of secondary alcohols. A high enantioselectivity ratio of 53-fold was obtained. At the same time, it was also found in the research that there is a problem of mutual restriction between catalytic activity and stereoselectivity of this type of catalyst. Then T.Kawabata and K.Fuji (J.Am.Chem.Soc.1997,119,3169), A.C.Spivey (J.Org.Chem.2000,65,3154), G.C.Fu (J.Am.Chem. Soc.1997, 119, 1492) and other research groups have carried out related research, although they have achieved certain results, but the above-mentioned contradictions have not been completely resolved, and the catalysts developed by them generally have the problem of difficult synthesis. On the other hand, in 1998, S.J. Miller's research group used polypeptide molecules containing imidazole groups as small molecule catalysts, and achieved good results in various asymmetric reactions (J.Am.Chem.Soc.1999, 121, 11638) , but from the perspective of industrial application, the polypeptide catalyst also has the disadvantages of complex structure and difficult synthesis.

On the other hand, studies have also shown that imidazole compounds with a bicyclic structure have certain biological activities, such as: anti-ulcer, anti-depressant, antibacterial and enzyme inhibitory activities. The synthesis of this type of compound has also been reported in the literature (J.Hetercyclic Chem.1987, 24, 561), but no literature report on the application of this type of compound to asymmetric catalytic research has been found so far.

Based on the above research results, we envisioned introducing a chiral group at the 2-position of the imidazole ring by merging rings, hoping to use the difference between the imidazole ring and the pyridine ring to solve the problem between catalytic activity and stereoselectivity in chiral pyridine catalysts. Contradictory, while the rigid design of the bicyclic structure can further improve the difference between the upper and lower spaces of the imidazole ring. Under the guidance of this concept, the present invention designed and synthesized an imidazole chiral organic small molecule catalyst with a bicyclic structure. By investigating the influence of different angles on the asymmetric catalytic effect, in order to obtain a catalyst with high catalytic activity and broad-spectrum high-efficiency stereoselectivity new catalysts.

Contents of the invention

The object of the present invention is to provide a chiral imidazole organic small molecule compound with a bicyclic structure in view of the deficiencies in the prior art.

The present invention is achieved through the following technical solutions, the imidazole chiral organic small molecular compound with bicyclic structure described in the present invention has a structural formula as shown in chemical formula (XI):

where n=0, 1, 2, 3;

The chirality of the carbon marked * can be R or S;

R ¹ is a hydroxyl group, a mercapto group, an amino group, and various substituted hydroxyl groups, substituted mercapto groups, substituted amino groups, alkyl groups or aryl groups of C1 to C10.

Substituted hydroxy is methoxy, ethoxy, isopropoxy, tert-butoxy, benzyloxy, phenoxy, acetoxy, propionyloxy, dimethylacetoxy, trimethylacetoxy base, trimethylsiloxy, triethylsiloxy, tert-butyldimethylsiloxy, diphenylphosphineoxy, etc.;

Substituted mercapto groups are methylthio, ethylthio, isopropylthio, tert-butylthio, benzylthio, etc.;

The substituted amino group is methylamino, ethylamino, isopropylamino, tert-butylamino, benzylamino, methylethylamino, methylphenylamino, dimethylamino, diethylamino, diisopropylamino, dibenzylamino, 1-piperidine Base, 1-morpholine group, 1-pyrrolidinyl group, N-formylmethylamino group, N-acetylmethylamino group, N-acetylethylamino group, N-valerolactam group, etc.;

Alkyl is methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, cyclopentyl, benzyl, etc.;

Aryl is phenyl, substituted phenyl, 2-furyl, 2-thienyl, 2-pyrrolyl and the like.

R ² is halogen, hydroxyl, mercapto, amino, and various substituted hydroxyl, substituted mercapto, substituted amino (including substituted amido), alkyl or aryl of C1-C10.

Halogen is fluorine, chlorine, bromine, iodine;

Substituted hydroxy is methoxy, ethoxy, isopropoxy, tert-butoxy, benzyloxy, phenoxy, acetoxy, propionyloxy, dimethylacetoxy, trimethylacetoxy base, trimethylsiloxy, triethylsiloxy, tert-butyldimethylsiloxy, diphenylphosphineoxy, etc.;

Substituted mercapto groups are methylthio, ethylthio, isopropylthio, tert-butylthio, benzylthio, etc.;

The substituted amino group is methylamino, ethylamino, isopropylamino, tert-butylamino, benzylamino, methylethylamino, methylphenylamino, dimethylamino, diethylamino, diisopropylamino, dibenzylamino, 1-piperidine Base, 1-morpholine group, 1-pyrrolidinyl group, N-formylmethylamino group, N-acetylmethylamino group, N-acetylethylamino group, N-valerolactam group, etc.;

Alkyl is methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, cyclopentyl, benzyl, etc.;

Aryl is phenyl, substituted phenyl, 2-furyl, 2-thienyl, 2-pyrrolyl and the like.

The imidazole chiral organic small molecule compound with a bicyclic structure of the present invention is prepared by the following method: using imidazole as a raw material, adding acrolein and cyclizing to obtain (XII), and then obtaining the target compound through the following three steps:

(1): For the case where R is ^hydroxyl and substituted hydroxyl, first use optically pure chiral acid or use CSP-HPLC method to optically resolve (XII) to obtain optically pure (XIII), and then further derivatize to obtain (XIV) (R ¹ is various substituted hydroxyl groups described in claim 1). The synthetic route is shown in Scheme 4:

The details of the above further derivatization are as follows:

The optically pure (XIII) is treated with sodium hydride and then reacted with an alkyl halide under reflux to obtain (XIV) (R ¹ is various substituted alkoxy groups of C1 to C10 described in claim 1);

Alternatively, the optically pure (XIII) is treated with reagents such as acid anhydrides, acid chlorides, chlorosilanes, and phosphine chlorides in an organic solvent to obtain (XIV) (R ¹ is various substituted acyloxygens of C1 to C10 described in claim 1 base, siloxyl group or phosphinyl group), need to add alkali as acid-binding agent in this method;

Alternatively, optically pure (XIII) and halogenated aromatic hydrocarbons are coupled in an organic solvent by a CO bond catalyzed by a metal complex to obtain (XIV) (R ¹ is any of C1 to C10 described in claim 1 substituted aryloxy), this reaction requires the addition of a base.

(2): For the case where R ¹ is mercapto and substituted mercapto, amino and substituted amino, alkyl or aryl, the racemic (XV) is first treated with a halogenating reagent to obtain (XVI) (R ¹ =C1, Br orI) , then the halide is further reacted with nucleophiles such as mercaptans, amines or Grignard reagents to obtain (XVI) (R ¹ is various substituted mercapto groups, amino groups and C1～C10 described in claim 1, Amino, alkyl or aryl), then the compound is resolved with optically pure chiral acid or resolved with CSP-HPLC method to obtain optically pure (XVII) (R ¹ is the mercapto, amino group described in claim 1 and C1～C10 various substituted mercapto, substituted amino, alkyl or aryl). The synthetic route is shown in Scheme 5:

(3): compound (XVIII) obtained in the above two steps (R ¹ is the hydroxyl group, mercapto group, amino group and various substituted hydroxyl groups, substituted mercapto groups, substituted amino groups, alkyl groups or aryl groups of C1 to C10 described in claim 1) Further modification to obtain (XIX) (R ¹ is the hydroxyl group, mercapto group, amino group and various substituted hydroxyl groups, substituted mercapto groups, substituted amino groups, alkyl or aryl groups of C1 to C10 described in claim 1, and R ² is the substituted group in claim 1 The halogen, hydroxyl, mercapto, amino and various substituted mercapto, substituted amino, alkyl or aryl of C1-C10). The synthetic route is shown in Scheme 6:

The details of the above further modifications are as follows:

First, the optically pure (XVII) (R ¹ is the hydroxyl group, mercapto group, amino group and various substituted hydroxyl groups, substituted mercapto groups, substituted amino groups, alkyl groups or aryl groups of C1 to C10 described in claim 1) is treated with a halogenating reagent, Obtain (XIX) (R ¹ is the hydroxyl group, mercapto group, amino group and C1～C10 various substituted hydroxyl groups, substituted mercapto groups, substituted amino groups, alkyl or aryl groups described in claim 1, R ² is halogen);

Then in an organic solvent, utilize CO, CS, CN bond coupling reaction under metal complex catalysis to obtain (XIX) (R ¹ is the various substituted hydroxyl groups of hydroxyl, mercapto, amino and C1～C10 described in claim 1, Substituted mercapto, substituted amino, alkyl or aryl, ^R2 is hydroxyl, mercapto, amino and C1～C10 various substituted hydroxyls, substituted mercapto, substituted amido, alkyl or aryl described in claim 1), The reaction requires the addition of a base;

Finally, hydrolysis of the amide bond method or the reduction of the amide bond method by lithium aluminum hydride to obtain (XIX) (R ¹ is the various substituted hydroxyl groups, sulfhydryl groups, amino groups, sulfhydryl groups, and amino groups of C1 to C10 described in claim 1. Alkyl or aryl, R ² is the various substituted amino groups of amino and C1～C10 described in claim 1).

The imidazole chiral compound with bicyclic structure synthesized by the present invention can be used as a chiral catalyst in various asymmetric reactions, such as asymmetric acylation, asymmetric phosphorylation, asymmetric sulfonylation, asymmetric halogenation, Asymmetric Micheal addition, asymmetric Steglich rearrangement reaction and asymmetric Morita-Baylis-Hillman reaction, etc. have high catalytic activity and stereoselectivity, and have good application prospects.

Detailed ways

Example 1:

Preparation of 7-Hydroxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

Add imidazole (50.0g, 0.734mol), glacial acetic acid (3.0ml, 0.051mol, 0.07eq) and solvent 1,4-dioxane (750ml) into a 1L three-necked flask, and stir to dissolve at room temperature. Then pour freshly steamed acrolein (63.0ml, 0.943mol, 1.3eq) in one go, and reflux for 48h. Then the volatile solvent was evaporated under reduced pressure, and the obtained solid crude product was separated by column chromatography (EtOAc/MeOH=3/1) to obtain 73.8 g of light yellow solid with a yield of 81%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.07 (d, J=1.2Hz, 1H), 6.85 (d, J=1.2Hz, 1H), 5.23 (dd, J=3.2Hz, 7.2Hz, 1H) , 4.24-4.16(m, 1H), 3.98-3.98(m, 1H), 3.00-2.88(m, 1H), 2.64-2.54(m, 1H).

¹³ C NMR (100MHz, CDCl ₃ ): δ156.4, 132.5, 114.3, 63.6, 43.2, 36.3.

Example 2:

(+)-7-hydroxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole and (-)-7-hydroxy-6,7-dihydro-5H-pyrrole[1,2- Preparation of α]imidazole

CSP-HPLC method: (+)-7-hydroxyl-6,7-dihydro-5H-pyrrole[1,2-α]imidazole and (-)-7-hydroxyl- 6,7-Dihydro-5H-pyrrole[1,2-α]imidazole, ee>99%, yield 95%.

Optical resolution method: Dissolve 7-hydroxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole (14.5g, 0.11mol) in 100ml methanol in a dry 250ml two-necked bottle, stir and reflux Add (+)-tartaric acid (17.5g, 0.11mol, 1.0eq) in methanol solution 100ml, and reflux for 2h. After cooling to room temperature, a pale yellow solid was precipitated (the solid was alkalized with an appropriate amount of NaOH to liberate 7-hydroxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole, the ee value was about 30%). The above-mentioned pale yellow solid was recrystallized several times with 200 ml of methanol and a small amount of water to obtain a solid that was basified with NaOH, extracted with dichloromethane, and evaporated to remove the solvent to obtain 0.6 g of a white powdery solid with a yield of 4%, ee> 99% (Daicel CHIRALCEL ODH, 4.6μm×25cm, 0.5ml/min, Hexane/i-PrOH=90/10, Rt=32.7min). After the above mother liquor was recrystallized multiple times by the same method, 1.6 g of white powdery solid was obtained, with a yield of 11%, ee>99% (Daicel CHIRALCEL ODH, 4.6 μm × 25cm, 0.5ml/min, Hexane/i- PrOH = 90/10, Rt = 19.2 min).

Example 3:

Preparation of (+)-7-methoxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

Add (+)-7-hydroxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole (128.0mg, 1.0mmol) into a dry 25ml two-necked bottle, add dry 1,4-bis Oxycycline (10ml), stirred and dissolved, put NaH (56.0mg, 1.4mmol, 1.4eq) under nitrogen atmosphere, stirred at room temperature for 2h, then slowly added MeI (0.09ml, 1.4mmol, 1.4eq), refluxed for 12h . After the volatile solvent was evaporated, it was extracted with dichloromethane (15ml×3), dried over sodium sulfate, dichloromethane was evaporated under reduced pressure, and separated by column chromatography (EtOAc/MeOH=10/1) to obtain 55.9 mg of a yellow oily liquid, yielding The rate is 67%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.13(s, 1H), 6.92(d, J=1.2Hz, 1H), 4.63(dd, J=7.2Hz, 2.0Hz, 1H), 4.18-4.10( m, 1H), 3.96-3.89(m, 1H), 3.52(s, 3H), 2.86-2.80(m, 1H), 2.60-2.46(m, 1H).

¹³ C NMR (100MHz, CDCl ₃ ): δ153.0, 133.3, 114.7, 73.0, 56.4, 42.8, 34.7.

Example 4

Preparation of (+)-7-ethoxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

The experimental operation process is the same as in Example 3, and the productive rate is 54%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.07(s, 1H), 6.86(d, J=1.6Hz, 1H), 4.69(dd, J=7.2Hz, 2.4Hz, 1H), 4.16-4.06( m, 1H), 3.92-3.82(m, 2H), 3.66-3.56(m, 1H), 2.88-2.76(m, 1H), 2.56-2.48(m, 1H), 1.17(t, J=7.2Hz, 3H).

¹³ C NMR (100MHz, CDCl ₃ ): δ153.2, 133.2, 114.5, 71.3, 64.1, 42.6, 34.7, 14.8.

Example 5:

Preparation of (+)-7-isopropoxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

The experimental operation process is the same as in Example 3, and the yield is 11%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.11(s, 1H), 6.89(s, 1H), 4.85(dd, J=6.4Hz, 1.6Hz, 1H), 4.20-4.06(m, 2H), 3.93-3.85(m, 1H), 2.91-2.80(m, 1H), 2.56-2.46(m, 1H), 1.25(d, J=6.0Hz, 3H), 1.16(d, J=6.0Hz, 3H) .

Embodiment 6:

Preparation of (+)-7-benzyloxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

The experimental operation process is the same as in Example 3, and the productive rate is 73%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.41-7.27(m, 5H), 7.16(d, J=1.2Hz, 1H), 6.93(d, J=1.2Hz, 1H), 4.92-4.70(dd , J=67.6Hz, 11.6Hz, 2H), 4.83(dd, J=7.2Hz, 1H), 4.21-4.13(m, 1H), 3.96-3.89(m, 1H), 2.92-2.82(m, 1H) , 2.67-2.59(m, 1H).

¹³ C NMR (100MHz, CDCl ₃ ): δ153.5, 137.9, 133.8, 128.4, 128.1, 127.7, 115.0, 71.1, 70.8, 43.1, 35.3.

Embodiment 7:

Preparation of (+)-7-Acetoxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

(+)-7-Hydroxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole (316.5mg, 2.6mmol) was added to a dry 50ml two-necked flask, and dry dichloromethane (10ml ), Et ₃ N (0.53ml, 3.8mmol, 1.5eq), CH ₃ COCl (0.22ml, 3.1mmol, 1.2eq) was added dropwise under ice-cooling, stirred for 0.5h, then raised to room temperature and stirred for 4h. Dichloromethane (15ml×3) was extracted, dried over sodium sulfate, dichloromethane was distilled off under reduced pressure, and separated by column chromatography (EtOAc/MeOH=50:1) to obtain 289.6 mg of a yellow oily liquid with a yield of 68%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.17(s, 1H), 6.95(s, 1H), 5.97(dd, J=7.2Hz, 2.4Hz, 1H), 4.20-4.09(m, 1H), 4.03-3.93(m, 1H), 3.12-2.99(m, 1H), 2.59-2.47(m, 1H), 2.07(s, 3H).

¹³ C NMR (100MHz, CDCl ₃ ): 169.8, 150.5, 134.0, 115.2, 66.6, 42.4, 34.3, 20.5.

Embodiment 8:

Preparation of (+)-7-phenoxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

In a 20ml dry reaction tube, (+)-7-Hydroxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole (124mg, 1.00mmol), CuI (28mg, 0.15mmol, 0.15eq) , 2,2'-bipyridine (31mg, 0.20mmol), _K2CO3 (166mg, 1.20mmol, 1.2eq) and PhBr (0.12ml, 1.15mmol, 1.15eq) were refluxed in toluene _for 24h. The reaction mixture was diluted with toluene, washed with water, dried over sodium sulfate, evaporated under reduced pressure to remove the volatile solvent, and separated by column chromatography (Pure EtOAc) to obtain 104 mg of a white solid with a yield of 56%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.32(td, J=7.6Hz, 0.8Hz, 2H), 7.18(s, 1H), 7.15(dd, J=7.6Hz, 0.8Hz, 2H), 6.98 (td, J=8.0Hz, 1.2Hz, 1H), 6.95(d, J=1.2Hz, 1H), 5.53(dd, J=6.8Hz, 1.6Hz, 1H), 4.28-4.16(m, 1H), 4.04-3.94(m, 1H), 3.10-2.96(m, 1H), 2.84-2.72(m, 1H).

¹³ C NMR (100MHz, CDCl ₃ ): δ157.3, 129.3, 121.2, 115.6, 70.4, 42.7, 35.0.

Embodiment 9:

Preparation of 7-(1-morpholinyl)-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

7-Hydroxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole (2.0g, 16.1mmol) was added into a 50ml dry two-necked flask, and SOCl ₂ (10.0ml, 137.8mmol, 8.6eq), and then warmed to reflux until the solution turned black. Then the _SOCl2 was removed. The solid material obtained was treated with a dichloromethane solution (20ml) of morpholine (7.0ml, 80.3mmol, 5.0eq), and after reflux for 18h, the reaction solution was diluted with dichloromethane and washed with water, dried over sodium sulfate, and evaporated to remove the solvent. The product was separated by column chromatography (EtOAc/MeOH=3/1) to obtain 0.8 g of a yellow oily liquid with a yield of 48%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.03(s, 1H), 6.81(d, J=1.6Hz, 1H), 4.03-3.95(m, 1H), 3.89-3.81(m, 2H), 3.66 (t, J=4.8, 4H), 2.87-2.78(m, 2H), 2.76-2.65(m, 1H), 2.55-2.38(m, 3H).

¹³ C NMR (100MHz, CDCl ₃ ): δ152.8, 133.6, 114.5, 66.9, 60.2, 50.5, 43.1, 30.8.

Example 10:

(+)-7-(1-morpholinyl)-6,7-dihydro-5H-pyrrole[1,2-α]imidazole and (-)-7-(1-morpholinyl)-6,7 - Preparation of dihydro-5H-pyrrole [1,2-α] imidazole

CSP-HPLC method: (+)-7-(1-morpholinyl)-6,7-dihydro-5H-pyrrole[1,2-α]imidazole and (- )-7-(1-morpholinyl)-6,7-dihydro-5H-pyrrole[1,2-α]imidazole, ee>99%, yield 90%.

Optical resolution method: slowly add (+)-DBTA (3.2g, 8.9mmol) in acetone solution (20ml) to 7-(1-morpholinyl)-6,7-dihydro- In a solution of 5H-pyrrole[1,2-α]imidazole (2.2g, 0.04mol, 1.0eq) in acetone (40ml), reflux for 2h and slowly cool down to room temperature. The obtained solid was filtered, washed with cold acetone, and then recrystallized several times with acetone. The finally obtained solid was treated with 2M sodium hydroxide saturated saline solution and extracted with dichloromethane to obtain 0.1 g of a yellow oily liquid with a yield of 5%. , ee>99% (Daicel CHIRALCEL OJ-H, 25cm×4.6μm, 0.5ml/min, Hexane/i-Propanol=95/5, 230nm, _tR =44.5min(minor), 48.6min(major)).

Example 11:

Preparation of 7-(1-pyrrolidinyl)-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

The experimental operation process was the same as in Example 9, and the yield was 53%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.12(s, 1H), 6.93(s, 1H), 4.25-4.17(m, 2H), 4.00-3.92(m, 1H), 3.22-3.12(m, 2H), 3.00-2.75(m, 4H), 1.95-1.87(m, 4H).

Example 12:

Preparation of 7-cyclohexyl-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

Add 7-hydroxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole (10.0g, 0.08mol) into a 500ml dry two-necked flask, and drop SOCl ₂ (80.0ml, 1.10mol, 13.8eq), and then warmed to reflux until the solution turned black. Then the _SOCl2 was removed. Utilize EtBr (39.0ml, 0.32mol, 4.0eq) and Mg (8.5g, 0.35mol, 4.4eq) to prepare the tetrahydrofuran solution 200ml of CyMgBr in another 500ml two-necked flask, then add the tetrahydrofuran solution of the above-mentioned CyMgBr to the first In the reaction flask, stir at room temperature for 26 h, and then quench with water under the protection of an ice bath. The resulting suspension was filtered, washed with tetrahydrofuran and then spin-dried, then extracted with ethyl acetate (150ml×3), dried over sodium sulfate and spin-dried. The obtained crude product was separated by Al ₂ O ₃ column chromatography (PE/EtOAc=1/1) to obtain 0.7 g of yellow oily liquid with a yield of 5%.

¹ H NMR (400MHz, CDCl ₃ ): 7.05(d, J=0.8Hz, 1H), 6.82(d, J=1.2Hz, 1H), 3.98-3.80(m, 2H), 2.96-2.86(m, 1H ), 2.70-2.58(m, 1H), 2.40-2.28(m, 1H), 2.14-2.02(m, 1H), 1.80-1.46(m, 5H), 1.34-0.98(m, 5H).

¹³ C NMR (100MHz, CDCl ₃ ): 156.7, 132.9, 114.0, 44.1, 41.6, 41.5, 30.8, 30.6, 30.1, 26.5.

Example 13:

(+)-7-cyclohexyl-6,7-dihydro-5H-pyrrole[1,2-α]imidazole and (-)-7-cyclohexyl-6,7-dihydro-5H-pyrrole[1, Preparation of 2-α]imidazole

CSP-HPLC method: (+)-7-cyclohexyl-6,7-dihydro-5H-pyrrole[1,2-α]imidazole and (-)-7-cyclo Hexyl-6,7-dihydro-5H-pyrrole[1,2-α]imidazole, ee>99%, yield 95%.

Example 14:

Preparation of 7-ethyl-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

The experimental operation process was the same as in Example 13, and the yield was 6%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.03(d, J=0.8Hz, 1H), 6.81(d, J=1.2Hz, 1H), 4.00-3.82(m, 2H), 3.03-2.94(m , 1H), 2.78-2.68(m, 1H), 2.26-2.15(m, 1H), 1.95-1.83(m, 1H), 1.64-1.51(m, 1H), 1.04(t, J=7.2Hz, 3H ).

Example 15:

Preparation of 7-isopropyl-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

The experimental operation process is the same as in Example 13, and the yield is 10%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.05(s, 1H), 6.81(s, 1H), 3.98-3.80(m, 2H), 2.96-2.88(m, 1H), 2.69-2.58(m, 1H), 2.36-2.24(m, 1H), 2.08-1.97(m, 1H), 1.07(dd, J=6.4Hz, 2.4Hz, 3H), 0.93(dd, J=7.2Hz, 1.6Hz, 3H) .

Example 16:

Preparation of 7-cyclopentyl-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

The experimental operation process was the same as in Example 13, and the yield was 11%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.03(d, J=0.8Hz, 1H), 6.81(d, J=1.2Hz, 1H), 3.99-3.81(m, 2H), 3.04-2.95(m , 1H), 2.74-2.64(m, 1H), 2.34-2.23(m, 1H), 2.21-1.30(m, 9H).

Example 17:

Preparation of 7-phenyl-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

The experimental operation process was the same as in Example 13, and the yield was 7%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.35-7.20(m, 5H), 4.35(dd, J=8.4Hz, 6.8Hz, 1H), 4.15-4.07(m, 1H), 4.03-3.95(m , 1H), 3.15-3.05(m, 1H), 2.63-2.52(m, 1H).

Example 18:

Preparation of 7-(2-pyrrolyl)-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

The experimental operation process was the same as in Example 9, and the yield was 43%.

¹ H NMR (400MHz, CDCl ₃ ): δ9.56(b, 1H), 7.07(d, J=1.2Hz, 1H), 6.87(d, J=1.6Hz, 1H), 6.73-6.70(m, 1H ), 6.14(q, J=2.8Hz, 1H), 6.04-6.01(m, 1H), 4.39(t, J=3.2Hz, 1H), 4.10-3.96(m, 2H), 3.13-3.03(m, 1H), 2.86-2.75(m, 1H).

Example 19:

Preparation of (+)-3-bromo-7-ethoxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

Into a solution of (+)-7-ethoxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole (600.0mg, 3.9mmol) in carbon tetrachloride (20ml) at room temperature Add NBS (702.0 mg, 3.9 mmol, 1.0 eq) slowly, and then reflux for about 4.5 h. Then the insoluble solid was removed by filtration, and the obtained solution was spin-dried to dry the volatile solvent, and separated by Al ₂ O ₃ column chromatography (PE/EtOAc=2/1) to obtain 513.6 mg of the product with a yield of 57%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.01(s, 1H), 6.76(dd, J=6.8Hz, 2.0Hz, 1H), 4.12-4.02(m, 1H), 3.92-3.82(m, 2H ), 3.68-3.58(m, 1H), 2.92-2.82(m, 1H), 2.62-2.52(m, 1H), 1.20(t, J=6.8Hz, 3H).

¹³ C NMR (100MHz, CDCl ₃ ): δ154.0, 133.0, 98.4, 72.8, 64.7, 42.7, 34.7, 15.1.

Example 20:

Preparation of (+)-3-bromo-7-benzyloxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

The experimental operation process was the same as in Example 19, and the yield was 35%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.40-7.27(m, 5H), 7.05(s, 1H), 4.77(dd, J=68.8Hz, 12.0Hz, 2H), 4.85(dd, J=7.2 Hz, 1.6Hz, 1H), 4.15-4.05(m, 1H), 3.92-3.85(m, 1H), 2.93-2.82(m, 1H), 2.68-2.59(m, 1H).

¹³ C NMR (100MHz, CDCl ₃ ): δ153.7, 137.5, 133.0, 128.3, 128.0, 127.7, 98.5, 72.1, 70.7, 42.6, 34.7.

Example 19:

Preparation of (+)-3-bromo-7-cyclohexyl-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

The experimental operation process was the same as in Example 19, and the yield was 63%.

¹ H NMR (400MHz, CDCl ₃ ): δ6.95(s, 1H), 3.88-3.67(m, 2H), 3.07-2.94(m, 1H), 2.71-260(m, 1H), 2.41-2.30( m, 1H), 2.08-2.00(m, 1H), 1.79-1.55(m, 5H), 1.32-0.98(m, 5H).

¹³ C NMR (100MHz, CDCl ₃ ): δ156.5, 131.1, 97.4, 43.9, 43.0, 41.2, 30.4, 30.0, 29.9, 26.3, 26.2, 26.1, 26.1.

Example 20:

Preparation of (+)-3-(N-valerolactamyl)-7-ethoxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

Add (+)-3-bromo-7-ethoxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole (75.0 mg, 0.32 mmol), pyrrolidone ( 37μl, 0.48mmol, 1.5eq), CuI (12.2mg, 0.064mmol, 0.2eq), 2,2'-Bipyridine (12.5mg, 0.08mmol, 0.25eq), K ₂ CO ₃ (66.3mg, 0.48mmol, 1.5 eq) and 2ml of toluene, then the reaction mixture was refluxed for 20h, then diluted with toluene and filtered to remove insoluble solids, and the obtained filtrate was evaporated to remove volatile solvents Al ₂ O ₃ column chromatography (Pure EtOAc) to obtain product 58.2mg , the yield was 77%.

¹ H NMR (400MHz, CDCl ₃ ): δ6.86(s, 1H), 4.73-4.67(dd, J=7.2Hz, 2.4Hz, 1H), 4.22-4.13(m, 1H), 4.07-3.99(m , H), 3.93-3.83(m, 1H), 3.75(t, J=7.2Hz, 2H), 3.68-3.57(m, 1H), 2.91-2.79(m, 1H), 2.53(t, J=8.0 Hz, 2H), 2.57-2.47(m, 1H), 2.56-2.15(m, 1H), 1.21(t, J=7.2Hz, 3H).

¹³ C NMR (100MHz, CDCl ₃ ): δ174.2, 150.9, 126.4, 123.7, 72.3, 64.8, 50.3, 44.6, 35.2, 31.0, 19.0, 15.3.

Example 21:

Preparation of (+)-3-(N-valerolactamyl)-7-benzyloxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

The experimental operation process was the same as in Example 20, and the yield was 58%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.42-7.22 (m, 5H), 6.87 (s, 1H), 4.77 (dd, J=112.0Hz, 12.0Hz, 2H), 4.77 (dd, J=7.2 Hz, 1.6Hz, 1H), 4.23-4.13(m, 1H), 4.07-3.97(m, 1H), 3.73(t, J=7.2Hz, 2H), 2.88-2.76(m, 1H), 2.60-2.53 (m, 1H), 2.51(t, J=8.0Hz, 2H), 2.24-2.12(m, 2H).

¹³ C NMR (100MHz, CDCl ₃ ): δ174.0, 137.9, 128.4, 128.0, 127.6, 123.8, 71.5, 70.8, 50.0, 44.3, 35.0, 30.9, 18.8.

Example 22:

Preparation of (+)-3-(N-valerolactamyl)-7-cyclohexyl-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

The experimental operation process was the same as in Example 20, and the yield was 84%.

¹ H NMR (400MHz, CDCl ₃ ): δ6.76(s, 1H), 4.01-3.85(m, 2H), 3.71(t, J=3.2Hz, 2H), 2.92-2.83(m, 1H), 2.64 -2.53(m, 1H), 2.50(t, J=8.0Hz, 2H), 2.35-2.23(m, 1H), 2.23-2.13(m, 2H), 2.13-2.07(m, 1H), 1.78-1.69 (m, 2H), 1.69-1.57 (m, 3H), 1.31-0.98 (m, 5H).

¹³ C NMR (100MHz, CDCl ₃ ): δ174.2, 154.1, 125.5, 123.2, 50.5, 45.1, 42.1, 41.4, 31.1, 30.8, 30.3, 26.5, 26.4, 26.4, 19.0.

Example 23:

Preparation of (+)-3-(N-pyrrolidinyl)-7-ethoxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

In a 50ml two-necked bottle, (+)-3-(N-valerolactamyl)-7-ethoxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole (531mg, 2.3 mmol) in tetrahydrofuran (15ml) was slowly dropped into a suspension of LAH (258mg, 6.8mmol, 2.0eq) in tetrahydrofuran (3ml), then refluxed for 4h, quenched with saturated aqueous sodium sulfate solution after cooling, and then filtered , washed with methanol, and the obtained filtrate was spin-dried to dry the solvent and separated by Al ₂ O ₃ column chromatography (EtOAc/MeOH=20/1) to obtain 325 mg of the product with a yield of 43%.

¹ H NMR (400MHz, CDCl ₃ ): δ6.25(s, 1H), 4.57(dd, J=6.4Hz, 1.6Hz, 1H), 4.11-4.02(m, 1H), 3.91-3.81(m, 2H ), 3.63-3.53(m, 1H), 3.17-3.03(m, 4H), 2.84-2.73(m, 1H), 2.54-2.45(m, 1H), 1.96-1.88(m, 4H), 1.17(t , J=7.2Hz, 3H).

¹³ C NMR (100MHz, CDCl ₃ ): δ148.3, 139.7, 113.8, 71.9, 64.4, 50.8, 42.8, 35.7, 24.8, 15.4.

Example 24:

Preparation of (+)-3-(N-pyrrolidinyl)-7-benzyloxy-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

The experimental operation process was the same as in Example 23, and the yield was 40%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.42-7.27 (m, 5H), 6.31 (s, 1H), 4.77 (dd, J=69.6Hz, 11.6Hz, 2H), 4.72 (dd, J=6.4 Hz, 0.4Hz, 1H), 4.16-4.07(m, 1H), 3.96-3.87(m, 1H), 3.20-3.07(m, 4H), 2.87-2.76(m, 1H), 2.63-2.54(m, 1H), 1.99-1.91(m, 4H).

Example 25:

Preparation of (+)-3-(N-pyrrolidinyl)-7-cyclohexyl-6,7-dihydro-5H-pyrrole[1,2-α]imidazole

The experimental operation process was the same as in Example 23, and the yield was 66%.

¹ H NMR (400MHz, CDCl ₃ ): δ6.22(s, 1H), 3.93-3.84(m, 1H), 3.84-3.76(m, 1H), 3.13.3.01(m, 4H), 2.87-2.77( m, 1H), 2.64-2.53(m, 1H), 2.34-2.23(m, 1H), 2.15-2.06(m, 1H), 1.96-1.88(m, 4H), 1.78-1.55(m, 5H), 1.35-1.00(m, 5H).

Claims (9)

1. A class of imidazole chiral organic small molecule compounds with a bicyclic structure, characterized in that it is a compound of the following chemical formula (II):

Its first n=0, 1, 2, 3; The chirality of the carbon marked * can be R or S; R ¹ is a hydroxyl group, a mercapto group, an amino group, and various substituted hydroxyl groups, substituted mercapto groups, substituted amino groups, alkyl groups or aryl groups of C1 to C10. R ² is halogen, hydroxyl, mercapto, amino, and various substituted hydroxyl, substituted mercapto, substituted amino, alkyl or aryl of C1-C10. 2. the imidazole chiral organic small molecule compound (II) with bicyclic structure according to claim 1, is characterized in that, ^R is hydroxyl, mercapto, amino, and various C1～C10 substituted hydroxyl, substituted mercapto , substituted amino, alkyl or aryl: Substituted hydroxy is methoxy, ethoxy, isopropoxy, tert-butoxy, benzyloxy, phenoxy, acetoxy, propionyloxy, dimethylacetoxy, trimethylacetoxy base, trimethylsiloxy, triethylsiloxy, tert-butyldimethylsiloxy, diphenylphosphineoxy, etc.; Substituted mercapto groups are methylthio, ethylthio, isopropylthio, tert-butylthio, benzylthio, etc.; The substituted amino group is methylamino, ethylamino, isopropylamino, tert-butylamino, benzylamino, methylethylamino, methylphenylamino, dimethylamino, diethylamino, diisopropylamino, dibenzylamino, 1-piperidine Base, 1-morpholine group, 1-pyrrolidinyl group, N-formylmethylamino group, N-acetylmethylamino group, N-acetylethylamino group, N-valerolactam group, etc.; Alkyl is methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, cyclopentyl, benzyl, etc.; Aryl is phenyl, substituted phenyl, 2-furyl, 2-thienyl, 2-pyrrolyl and the like. 3. the imidazole chiral organic small molecular compound (II) with bicyclic structure according to claim 1, is characterized in that, ^R Be halogen, hydroxyl, mercapto, amino, and the substituted hydroxyl of various C1～C10, Substituted mercapto, substituted amino, alkyl or aryl: Halogen is fluorine, chlorine, bromine, iodine; Substituted hydroxy is methoxy, ethoxy, isopropoxy, tert-butoxy, benzyloxy, phenoxy, acetoxy, propionyloxy, dimethylacetoxy, trimethylacetoxy base, trimethylsiloxy, triethylsiloxy, tert-butyldimethylsiloxy, diphenylphosphineoxy, etc.; Substituted mercapto groups are methylthio, ethylthio, isopropylthio, tert-butylthio, benzylthio, etc.; The substituted amino group is methylamino, ethylamino, isopropylamino, tert-butylamino, benzylamino, methylethylamino, methylphenylamino, dimethylamino, diethylamino, diisopropylamino, dibenzylamino, 1-piperidine Base, 1-morpholine group, 1-pyrrolidinyl group, N-formylmethylamino group, N-acetylmethylamino group, N-acetylethylamino group, N-valerolactam group, etc.; Alkyl is methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, cyclopentyl, benzyl, etc.; Aryl is phenyl, substituted phenyl, 2-furyl, 2-thienyl, 2-pyrrolyl and the like. 4. the synthetic method of a class of imidazoles chiral organic small molecular compound (II) with bicyclic structure according to claim 1, is characterized in that, comprises following three-step reaction: ( ¹ ): For the case of R being a hydroxyl group and a substituted hydroxyl group, at first utilize an optically pure chiral acid to optically resolve (III) or obtain optically pure (IV) by CSP-HPLC method resolution, and then further derivatize to obtain ( V) (R ¹ is various substituted hydroxyl groups described in claim 1). The synthetic route is shown in Scheme 1: (2): For the case where R ¹ is mercapto and substituted mercapto, amino and substituted amino, alkyl or aryl, the racemic (VI) is first treated with a halogenating reagent to obtain (VII) (R ¹ =Cl, Br orI) , and then the halide is further reacted with nucleophiles such as mercaptans, amines or Grignard reagents to obtain (VII) (R ¹ is various substituted mercapto groups, amino groups and C1～C10 described in claim 1, substituted Amino, alkyl or aryl), then the compound is resolved with optically pure chiral acid or resolved with CSP-HPLC method to obtain optically pure (VIII) (R ¹ is the mercapto, amino group described in claim 1 and C1～C10 various substituted mercapto, substituted amino, alkyl or aryl). The synthetic route is shown in Scheme 2:

(3): compound (IX) obtained in the above two steps (R ¹ is the hydroxyl group, mercapto group, amino group and various substituted hydroxyl groups, substituted mercapto groups, substituted amino groups, alkyl groups or aryl groups of C1 to C10 described in claim 1) Further modification to obtain (X) (R ¹ is the hydroxyl group, mercapto group, amino group and various substituted hydroxyl groups, substituted mercapto groups, substituted amino groups, alkyl or aryl groups of C1～C10 described in claim 1, R ² is in claim 1 The halogen, hydroxyl, mercapto, amino and various substituted mercapto, substituted amino, alkyl or aryl of C1-C10). The synthetic route is shown in Scheme 3:

5. the synthetic method of a class of imidazoles chiral organic small molecular compound (II) with bicyclic structure according to claim 4, is characterized in that, the reaction of step (1) is: Optically pure (IV) is obtained by resolving (III) with optically pure chiral acid or by CSP-HPLC. 6. the synthetic method of a class of imidazoles chiral organic small molecular compound (II) with bicyclic structure according to claim 4, is characterized in that, the reaction of step (1) is: The optically pure (IV) is treated with sodium hydride and then reacted with haloalkane under reflux to obtain (V) ( ^R1 is various substituted alkoxy groups of C1-C10 described in claim 1); Alternatively, the optically pure (IV) is treated with an acid anhydride, acid chloride, chlorosilane, phosphine chloride and other reagents in an organic solvent to obtain (V) (R ¹ is various substituted acyloxygens of C1 to C10 described in claim 1 base, siloxyl group or phosphinyl group), need to add alkali as acid-binding agent in this method; Alternatively, optically pure (IV) and halogenated aromatic hydrocarbons are coupled in an organic solvent using a metal complex to catalyze a CO bond coupling reaction to obtain (V) (R ¹ is any of C1 to C10 described in claim 1. substituted aryloxy), this reaction requires the addition of a base. 7. the synthetic method of a class of imidazole chiral organic small molecular compound (II) with bicyclic structure according to claim 4, is characterized in that, the reaction of step (2) is: First, the racemic (VI) is treated with a halogenating reagent to obtain (VII) (R ¹ =Cl, Br or I), and then the halogenated product is further reacted with a nucleophile such as a thiol, an amine or a Grignard reagent to obtain ( VII) (R ¹ is the various substituted mercapto, substituted amino, alkyl or aryl groups of mercapto, amino and C1-C10 described in claim 1). 8. the synthetic method of a class of imidazoles chiral organic small molecular compound (II) with bicyclic structure according to claim 2, is characterized in that, the reaction of step (2) is: (VII) (R ¹ is the mercapto group, amino group and various substituted mercapto groups, substituted amino groups, alkyl groups or aryl groups of C1 to C10 described in claim 1) is resolved with optically pure chiral acid or by CSP-HPLC method The optically pure (VIII) (R ¹ is the mercapto group, amino group and C1-C10 various substituted mercapto groups, substituted amino groups, alkyl groups or aryl groups described in claim 1) was obtained by resolution. 9. the synthetic method of a class of imidazoles chiral organic small molecular compound (II) with bicyclic structure according to claim 2, is characterized in that, the reaction of step (3) is: First, optically pure (IX) (R ¹ is hydroxyl, mercapto, amino and various substituted hydroxyl, substituted mercapto, substituted amino, alkyl or aryl of C1～C10 described in claim 1) is treated with a halogenating reagent, Obtain (X) (R ¹ is various substituted hydroxyl groups, mercapto groups, substituted amino groups, alkyl groups or aryl groups of C1-C10 described in claim 1, R ² is halogen); Then in an organic solvent, utilize metal complexes to catalyze CO, CS, and CN bond coupling reactions to obtain (X) (R ¹ is various substituted hydroxyl groups of hydroxyl, mercapto, amino and C1～C10 described in claim 1, Substituted mercapto, substituted amino, alkyl or aryl, ^R2 is hydroxyl, mercapto, amino and C1～C10 various substituted hydroxyls, substituted mercapto, substituted amido, alkyl or aryl described in claim 1), The reaction requires the addition of a base; Finally, hydrolysis of the amide bond method or the reduction of the amide bond method by lithium aluminum hydride to obtain (X) (R ¹ is various substituted hydroxyl groups, sulfhydryl groups, amino groups and C1～C10 described in claim 1, substituted mercapto groups, substituted amino groups, Alkyl or aryl, R ² is the various substituted amino groups of amino and C1～C10 described in claim 1).