CN103467362A - S-diphenyl prolinol chiral small organic molecular compound with cyclopropane structure and synthetic method thereof - Google Patents

Abstract

The present invention provides a kind of synthetic method that has cyclopropane structure S-diphenylprolinol, and its step comprises: the first step, with (S)-1-N-tert-butoxycarbonyl-2,3-dihydro -Ethyl 2-pyrrolecarboxylate is subjected to Simmons-Smith cyclopropane reaction; in the second step, the enantiomers obtained in the first step are subjected to the Grignard reaction respectively; in the third step, the reaction products obtained in the second step are respectively carried out The reaction of removing the protection of the amino group gives S-diphenylprolinol with a cyclopropane structure. The method has reasonable process, simple operation and low cost, and does not need further chiral preparation and resolution to obtain optically pure enantiomer products, and is an ideal method for synthesizing R-diphenylprolinol with a cyclopropane structure.

Description

S-diphenylprolinol chiral organic small molecular compound with cyclopropane structure and its synthesis method

technical field

The invention relates to the technical field of compound preparation, in particular to a novel S-diphenylprolinol with a cyclopropane structure and a preparation method thereof.

Background technique

The asymmetric reaction catalyzed by organic small molecule compounds has developed rapidly in the past ten years, and has become the third type of potential asymmetric synthesis method that has the same status as organometallic catalysis and enzyme catalysis. However, most of the existing organic small molecular compounds use cheap and easy-to-obtain natural products as chiral sources, and their structural types are limited. On the premise of not changing its catalytic activity, there are certain limitations in the modification of its structure and the realization of structural diversity, which leads to problems such as fewer types of catalytic reactions and limited universality of catalytic reactions.

In 1987, Corey et al. first applied S-diphenylprolinol (hay-a) as a chiral-catalyst in the asymmetric reduction of prochiral ketones, with high efficiency, high yield and high enantioselectivity Chiral secondary alcohols (J.Am.Chem.Soc.1987, 109, 5551; Angew.Chem.Int.Ed.1998, 37, 1986), Hayashi research group on a series of prolin alcohols and their silicon ethers Catalysts Hay-b-d were attempted (Angew. Chem., Int. Ed., 2005, 44, 4212-4215.). Compared with the catalyst Hay-a, the catalytic effect of these catalysts is significantly improved: the products all reach 99% ee value. However, as the steric hindrance of the silyl ether group increases, the rate of the catalytic reaction decreases. In 2008, Hayashi et al. also used acetaldehyde as the aldehyde donor for the first time to catalyze. Although the aldehyde donor has changed, excellent enantioselectivity can still be obtained when using 1,4-dioxane as the solvent. (92%-98%).

Although prolinol and its silyl ether catalysts have been used in a variety of asymmetric reactions, for many catalytic substrates, in terms of catalytic activity and enantioselectivity, due to the small steric hindrance and the small rigidity of the catalyst, the asymmetric catalytic Diastereoselectivity and enantioselectivity are poor.

Based on the above research results, we imagined that a rigid chiral cyclopropane group was introduced into the ortho position of the pyrrole ring by means of merging rings, hoping to increase the rigidity and steric hindrance of the diphenylprolinol chiral catalyst to solve the problem of catalysis. The problem of poor enantioselectivity and diastereoselectivity in the reaction is expected to obtain a new catalyst with high catalytic activity and broad-spectrum efficient stereoselectivity.

In 1997, H.Stephen's group successfully synthesized S-proline with cyclopropane structure for the first time to study its angiotensin-converting enzyme inhibitory performance (Angew.Chem.Int.Ed.Engl.1997, 36, 1881), Because the cyclization reagent Me ₃ SnCH ₂ is expensive, highly toxic, and has a low ratio of enantiomeric products, it subsequently developed a Simmons-Smith cyclopropane reaction based on this compound (Bioorganic & Medicinal Chemistry Letters 8 (1998) 2123 -2128), its synthetic route is as follows:

In this synthetic route, the yield of products reduced to olefins is low, the cost of reagents is high, and the requirements for process conditions are harsh. During the cyclization process, the enantiomeric selectivity is low (structure A: structure B = 1:4) Further chiral preparation and resolution are required, and it is not suitable for large-scale industrial production.

Drawing lessons from the preparation method of S-proline with the above-mentioned chiral cyclopropane structure, while overcoming the above-mentioned problems existing in the method for synthesizing S-proline with the cyclopropane structure, we provide a new type of S-proline with the cyclopropane structure. -The synthetic method of diphenylprolinol has reasonable process, simple operation and low cost, does not need further chiral preparation and resolution to obtain enantiomeric products of optical purity, and has strong structural selectivity of corresponding bodies, which is ideal A method for synthesizing S-diphenylprolinol having a cyclopropane structure.

Contents of the invention

The purpose of the present invention is to address the deficiencies in the prior art, to provide a novel chiral organic small molecular compound with cyclopropane structure S-diphenylprolinol, which has reasonable technology, simple operation and low cost, and does not need further Perform chiral preparation and resolution to obtain optically pure enantiomeric products, which are ideal for the synthesis of chiral organic small molecule compounds of S-diphenylprolinol with cyclopropane structure. The S-diphenylprolinol with cyclopropane structure As a chiral catalyst, phenylprolinol has rigidity and steric hindrance, which can solve the problem of poor enantioselectivity and diastereoselectivity in non-pair catalytic reactions, and has high catalytic activity and broad-spectrum high-efficiency stereoselectivity.

In order to solve the above-mentioned technical problems, the invention provides a kind of S-diphenylprolinol chiral organic small molecular compound with cyclopropane structure, its structural formula is as shown in chemical formula I:

In chemical formula I, the chiral configuration of carbon marked with * can be one of R or S;

The chirality of C-1 and C-5 must be one of R or S at the same time.

In order to solve the problems of the technologies described above, the invention provides the synthetic method of the S-diphenylprolinol with cyclopropane structure represented by the above chemical formula, the steps comprising:

In the first step, carry out Simmons-Smith cyclopropane reaction with (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid ethyl ester to obtain enantiomers;

In the second step, the enantiomers obtained in the first step are subjected to a Grignard reaction respectively;

In the third step, the reaction products obtained in the second step are respectively subjected to the deprotection reaction of the amino group to obtain the S-diphenylprolinol chiral small organic molecule compound having the cyclopropane structure.

Wherein, the first step is specifically mixing ethyl (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylate with diethylzinc (ZnEt ₂ ) and chloroiodomethane ( CH ₂ ClI) mixed reaction to obtain enantiomers (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester and ( 1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester, the obtained mixture of enantiomers using ethylenediaminetetraacetic acid in water Treat with amine aqueous solution to improve the enantioselectivity of the two, enantiomer (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane -The molar ratio of ethyl 3-carboxylate to (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethylcarboxylate>20:1, Subsequently, the mixed eluent with a volume ratio of ethyl acetate/n-heptane=1/20 was used for chromatographic column separation to obtain the products (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo Ethyl [3,1,0]hexane-3-carboxylate and ethyl (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate ester.

Wherein, in the first step, ethyl (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylate and diethylzinc (ZnEt ₂ ) and chloroiodomethane (CH _2ClI ) mixed according to the molar ratio of 1:0.5～2:1～2, more preferably 1/0.5/1 or 1/1/1 or 1/1/2 or 1/2/2, maintained at the reaction temperature -20 Under the condition of ℃～-15℃, react for 22～24h.

Wherein, in the first step, the amine aqueous solution is any one of ethylamine, diethylamine, triethylamine, propylamine, isopropylamine and tert-butylamine aqueous solution.

Wherein, the second step is specifically the ethyl (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate obtained in the first step and (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate were mixed with magnesium and bromobenzene respectively, and carried out Grignard reaction to obtain ( 1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol and (1R,3S,5R)-N-tert-butoxycarbonyl -2-Azabicyclo[3,1,0]hexane-3-diphenylmethanol.

Wherein, in the second step, ethyl (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate and (1R, 3S, The molar ratio of 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate to magnesium and bromobenzene is 1:2.1～2.5:4.2～5 , the reaction condition is to react for 2-4 hours under the condition of maintaining the temperature at 65-75°C.

Wherein, the third step is specifically the product (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenyl obtained in the second step Amide under acidic conditions of methyl methanol and (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol with trifluoroacetic acid Hydrolysis reaction to obtain (1S, 3S, 5S)-2-azabicyclo[3,1,0]hexane-3-diphenylcarbinol and (1R,3S,5R)-2-azabicyclo[3, 1,0] hexane-3-diphenylmethanol.

Wherein, in the third step, (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenylcarbinol and (1R,3S , 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol and the reaction molar ratio of trifluoroacetic acid is 1:1.0～1.5, the reaction conditions In order to maintain the temperature of 5 ℃ reaction 2 ~ 4h.

The present invention also provides the use of S-diphenylprolinol with cyclopropane structure prepared by the above synthesis method of S-diphenylprolinol with cyclopropane structure as a catalyst.

Beneficial effects of the present invention:

The novel synthesis method of S-diphenylprolinol with cyclopropane structure provided by the present invention has reasonable process, simple operation and low cost, and does not need further chiral preparation and resolution to obtain enantiomers of optical purity The product has strong selectivity for the corresponding body structure, and is an ideal method for synthesizing R-diphenylprolinol with cyclopropane structure. The S-diphenylprolinol with cyclopropane structure has rigidity as a chiral catalyst. And steric hindrance, which can solve the problem of poor enantioselectivity and diastereoselectivity in non-catalytic reactions, and has high catalytic activity and broad-spectrum high-efficiency stereoselectivity.

Description of drawings

Fig. 1 is the high performance liquid chromatography (HPLC) of compound 1 and compound 2.

Detailed ways

The present invention provides a kind of S-diphenylprolinol chiral organic small molecule compound with cyclopropane structure, its structural formula is as shown in chemical formula I:

In chemical formula I, the chiral configuration of carbon marked with * can be one of R or S;

The chirality of C-1 and C-5 must be one of R or S at the same time.

The synthetic route of the S-diphenylprolinol with cyclopropane structure provided by the present invention is as follows:

Its synthetic steps include:

In the first step, carry out Simmons-Smith cyclopropane reaction with (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid ethyl ester to obtain enantiomers;

In the second step, the enantiomers obtained in the first step are subjected to a Grignard reaction respectively;

In the third step, the reaction products obtained in the second step are respectively subjected to the deprotection reaction of the amino group to obtain S-diphenylprolinol having a cyclopropane structure.

The first step is specifically mixing ethyl (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylate with diethylzinc (ZnEt ₂ ) and chloroiodomethane (CH ₂ ClI) is mixed according to the molar ratio of 1:0.5～2:1～2, more preferably 1/0.5/1 or 1/1/1 or 1/1/2 or 1/2/2, maintained at the reaction temperature -20～ Under the condition of -15°C, react for 22-24 hours to obtain the enantiomer (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3- Ethyl formate and (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate, the obtained enantiomeric mixture was The aqueous solution of amine tetraacetic acid and the aqueous solution of amines are treated to improve the enantioselectivity of the two. The aqueous amine solution is any one of ethylamine, diethylamine, triethylamine, propylamine, isopropylamine and tert-butylamine aqueous solution. Isomer (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate ethyl ester: (1R, 3S, 5R)-N-tert The molar ratio of butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate is >20:1, which is much higher than that in the literature (Bioorganic & MedicinalChemistry Letters 8 (1998) 2123-2128 ) reported a ratio of 4:1, then ethyl acetate/n-heptane was used to form a mixed solution at a volume ratio of 1/20, and the mixed eluent was subjected to chromatographic column separation to obtain the products (1S, 3S, 5S)-N -tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3, 1,0] Ethyl hexane-3-carboxylate.

The first step is further preferably under _N protection, adding (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid ethyl ester in a dry reaction flask, and then adding Dissolve the solvent dichloromethane (DCM), cool to -20°C ~ -15°C, add diethylzinc (ZnEt ₂ ) dropwise, stir for 0.5h after the dropwise addition, then add dropwise the solvent dissolved in dichloromethane (DCM) Chloroiodomethane (CH ₂ ClI) in the solution, maintained at a temperature of -20 to -15°C and stirred for 22h to 24h, and quenched with an aqueous solution of ethylenediaminetetraacetic acid (EDTA) with a concentration of 13% by mass after completion of the reaction reaction, warming up to 20-25°C, stirring for 2-3 hours, standing still for 20 minutes, extracting, combining the organic phases to obtain a yellow oil, adding a 30% aqueous solution of diethylamine and stirring for 12 hours, concentrating under reduced pressure, organic The layer was dried with an appropriate amount of anhydrous sodium sulfate, and eluted with a mixed eluent of ethyl acetate (EA)/n-heptane (h-heptane)=1/20. After the elution was complete, the products were collected and the products (1S , 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and (1R,3S,5R)-N-tert-butoxycarbonyl-2 -Azabicyclo[3,1,0]hexane-3-ethyl carboxylate, (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane- The molar ratio of ethyl 3-carboxylate:(1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate>20:1.

The second step is specifically the ethyl (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester and magnesium and bromobenzene according to the molar ratio of 1:2.1～2.5:4.2～ 5. Carry out Grignard reaction, keep the temperature at 65-75°C for 2-4 hours to obtain (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0] Hexane-3-diphenylcarbinol and (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenylcarbinol.

Described second step is further preferably in two different two-necked flasks, respectively adds the iodine of magnesium (0.3g, 12mmol) and catalytic amount, under _N Protection slowly drips the diethyl ether solution of bromobenzene (24mmol), When the reaction is initiated, keep the reaction system slightly boiling, and reflux for 2-4 hours after the dropwise addition to obtain the Grignard reagent. ]Hexane-3-ethyl carboxylate (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate ethyl ester (5.5mmol) was dissolved separately Add the prepared Grignard reagent to the ether solution (20 mL) in ether, reflux, and after TLC confirms that the raw materials have completely reacted, add saturated NH ₄ Cl aqueous solution to quench the reaction, and extract with ether (50 mL×3) , combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter with suction, remove the solvent by rotary evaporation under reduced pressure, and obtain a white solid by column chromatography, which is (1S, 3S, 5S)-N-tert-butoxycarbonyl- 2-Azabicyclo[3,1,0]hexane-3-diphenylmethanol and (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane Alkane-3-diphenylmethanol.

The third step is specifically to use the product (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol obtained in the second step and (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol and trifluoroacetic acid in a molar ratio of 1:1.0～1.5 Mixing for amide hydrolysis reaction under acidic conditions, followed by keeping the temperature at 5°C for 2 to 4 hours to obtain (1S, 3S, 5S)-2-azabicyclo[3,1,0]hexane-3-methanol and ( 1R, 3S, 5R)-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol.

The third step is further specifically under _N protection, adding the second step to obtain (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[ 3,1,0]hexane-3-diphenylmethanol and (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenyl Then dichloromethane (DCM) was added to dissolve, and trifluoroacetic acid (TFA) was added dropwise at 5°C. After the dropwise addition was completed, the reaction was stirred for 3 h, saturated ammonium chloride solution was added, and concentrated under reduced pressure to obtain a light yellow solid. That is (1S, 3S, 5S)-2-azabicyclo[3,1,0]hexane-3-methanol and (1R,3S,5R)-2-azabicyclo[3,1,0]hexane Alkane-3-diphenylmethanol.

The present invention also provides the use of S-diphenylprolinol with cyclopropane structure prepared by the above synthesis method of S-diphenylprolinol with cyclopropane structure as a catalyst.

Preferably, the S-diphenylprolinol is used as a catalyst to catalyze the asymmetric Michael addition reaction.

The following examples are used to describe the implementation of the present invention in detail, so as to fully understand and implement the process of how to apply technical means to solve technical problems and achieve technical effects in the present invention.

Example 1

(1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate 1 and (1R, 3S, 5R)-N-tert-butoxy Preparation of ethyl carbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate 2

Under _N2 protection, (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrole carboxylic acid ethyl ester (Shanghai Tongchang Biomedical Technology Co., Ltd. , CAS No.: 178172-26-4) (24.1g, 0.1mol) was dissolved in 200ml of dichloromethane (DCM), cooled to -15°C, diethylzinc (Et ₂ Zn) (1.2eq, 0.12 mol), stirred and reacted for 0.5h after the dropwise addition, added dropwise a dichloromethane (DCM) solution of chloroiodomethane (CH ₂ ClI) (1.1eq, 0.11mol), kept the temperature at -15°C and stirred for 24h, after the reaction was completed Quench the reaction by adding an aqueous solution of ethylenediaminetetraacetic acid (EDTA) with a concentration of 13% by mass, raise the temperature to 25°C, stir for 2 hours, let stand for 20 minutes, extract, and combine the organic phases to obtain a yellow oil, add mass percent 30% aqueous solution of diethylamine was stirred for 12 hours, concentrated under reduced pressure, the organic layer was dried with an appropriate amount of anhydrous sodium sulfate, and ethyl acetate (EA)/n-heptane (h-heptane) = 1/20 (volume ratio) The eluent is eluted, and the elution is completed, and the collection is until the product point is basically completed. Pale yellow oil 1, namely ethyl (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate, 19.4g, light yellow oil 2, namely (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate, 1.03g, the total yield of compound 1 and compound 2 80%, the molar ratio of Compound 1/Compound 2>20/1, which is much higher than the ratio 4:1 reported in the literature (Bioorganic & Medicinal Chemistry Letters 8 (1998) 2123-2128), proves that the preparation of The method is more selective for the enantiomer.

(1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate ethyl ester 1 NMR data are:

¹ HNMR (400MHz, CDCl ₃ ): δ=1.19-1.35 (3H, m), 1.40-1.54 (9H, m), 2.53-2.75 (2H, m), 2.95-3.18 (2H, m), 4.10-4.33 (2H, m), 4.50-4.70 (1H, m), 4.85-4.99 (1H, m), 6.46-6.71 (1H, m).

¹³ CNMR (400MHz, CDCl ₃ ): δ=173.31, 171.30, 83.54, 61.64, 58.93, 31.14, 27.86, 25.62, 21.53, 14.16.

The NMR spectrum data of (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate 2 is:

¹ HNMR (400MHz, CDCl ₃ ): δ=1.19-1.35 (3H, m), 1.40-1.54 (9H, m), 2.53-2.75 (2H, m), 2.95-3.18 (2H, m), 4.10-4.33 (2H, m), 4.50-4.70 (1H, m), 4.85-4.99 (1H, m), 6.46-6.71 (1H, m).

¹³ CNMR (400MHz, CDCl ₃ ): δ=173.31, 171.30, 83.54, 61.64, 58.93, 31.14, 27.86, 25.62, 21.53, 14.16.

Figure 1 shows compound 1: (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and compound 2: (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate high performance liquid chromatogram, in the figure, the substance reflected by peak 18.49 is compound 1, 23.08 The peak reacted substance was compound 2.

Example 2

Preparation of (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol 3

Magnesium (3g, 120mmol) and catalytic amount of iodine were added to a 100mL two-necked flask, and an ether solution of bromobenzene (240mmol) was slowly added dropwise under _N2 protection. After the reaction was triggered, the reaction temperature was kept at 75°C, and the system After boiling, reflux for 2 hours after the dropwise addition, add the newly prepared Grignard reagent dropwise to (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid Ethyl ester 1 (14.02g, 55mmol) in diethyl ether solution (200mL), reflux, after TLC confirms that the raw materials have completely reacted, add saturated NH ₄ Cl aqueous solution to quench the reaction, extract with diethyl ether (50mL×3), combine the organic phases, and saturate Wash with salt water, dry over anhydrous sodium sulfate, filter with suction, remove the solvent by rotary evaporation under reduced pressure, column chromatography with ethyl acetate/petroleum ether 3/5, and obtain a white solid 3, which is (1S, 3S, 5S)-N - tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol, yield 16.45 g, yield 82%.

The NMR data of (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol are:

¹ H NMR (500MHz, CDCl ₃ ): δ=0.81-0.95(m, 2H) 1.21-1.31(m, 1H), 1.44(s, 9H), 1.89-1.95(m, 1H), 2.05-2.13(m , 1H), 2.87(m, 1H), 3.35(m, 1H), 6.47(bs, 1H), 7.24-7.41(m, 10H);

¹³ C NMR (125MHz, CDCl ₃ ): δ=19.8, 23.1, 28.6, 29.9, 48.1, 65.9, 80.8, 81.9, 127.2, 127.3, 127.6, 127.9, 128.1, 128.5, 144.0, 146.7.

Example 3

Preparation of (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol 3

Add magnesium (1.5g, 60mmol) and catalytic amount of iodine in a 100mL two-necked flask, and slowly add the ether solution of bromobenzene (120mmol) dropwise under _N2 protection. After the reaction is initiated, keep the reaction temperature at 75°C, and Slightly boil, reflux for 2 hours after the dropwise addition, add the newly prepared Grignard reagent dropwise to (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3- Ethyl formate 2 (7.01g, 27.5mmol) in diethyl ether solution (100mL), reflux, after TLC confirms that the raw materials have completely reacted, add saturated NH ₄ Cl aqueous solution to quench the reaction, extract with diethyl ether (50mL×3), and combine the organic phases , washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the solvent was removed by rotary evaporation under reduced pressure. Column chromatography with ethyl acetate/petroleum ether was 3/5 to obtain a white solid 5, namely (1R, 3S, 5R) -N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol, yield 8.27g, yield 81%.

The NMR data of (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol are:

¹ H NMR (500MHz, CDCl ₃ ): δ=0.81-0.95(m, 2H) 1.21-1.31(m, 1H), 1.44(s, 9H), 1.89-1.95(m, 1H), 2.05-2.13(m , 1H), 2.87(m, 1H), 3.35(m, 1H), 6.47(bs, 1H), 7.24-7.41(m, 10H);

¹³ C NMR (125, CDCl ₃ ) δ=19.8, 23.1, 28.6, 29.9, 48.1, 65.9, 80.8, 81.9, 127.2, 127.3, 127.6, 127.9, 128.1, 128.5, 144.0, 146.7.

Example 4

Preparation of (1S, 3S, 5S)-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol 4

Under the protection of _N2 , add (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenyl in a dry 250ml two-necked reaction flask Methanol 3 (3.65g, 0.001mol) was dissolved in 200ml of dichloromethane (DCM), kept at 5°C, trifluoroacetic acid (TFA) (1.2eq, 0.0012mol) was added dropwise, and the reaction was stirred for 3h after the dropwise addition was completed. Add saturated ammonium chloride solution, extract with dichloromethane (DCM), and concentrate under reduced pressure to obtain white solid 4, which is (1S, 3S, 5S)-2-azabicyclo[3,1,0]hexane-3 - Diphenylmethanol, yield 2.25 g, yield 85%.

The nuclear magnetic spectrum data of (1S, 3S, 5S)-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol are:

¹ H NMR (400MHz, CDCl ₃ ): δ7.67-7.42(m, 2H), 7.44-7.07(m, 8), 4.55(dd, J=10.6, 5.6Hz, 1H), 3.73(dt, J= 11.4, 8.0Hz, 1H), 3.25(m, 1H), 2.10-1.79(m, 2H), 1.72(m, 1H), 1.12(m, 1H), 0.82-0.93(m, 2H);

¹³ C NMR (100 MHz, CDCl ₃ ): δ140.5, 128.8, 128.5, 127.9, 126.2, 125.7, 69.5, 46.3, 29.3, 25.1, 17.3.

Example 5

Preparation of (1R,3S,5R)-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol 6

Under the protection of _N2 , add (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenyl in a dry 250ml two-necked reaction flask Methanol 5 (1.85g, 0.0005mol) was dissolved in 100ml of dichloromethane (DCM), kept at 5°C, trifluoroacetic acid (TFA) (0.6eq, 0.0006mol, 5ml) was added dropwise, and the reaction was stirred after the addition was complete 3h, add saturated ammonium chloride solution, extract with dichloromethane (DCM), and concentrate under reduced pressure to obtain a white solid 6, which is (1S, 3S, 5S)-2-azabicyclo[3,1,0]hexane -3-Diphenylmethanol, yield 1.11g, yield 87%.

The NMR data of (1R, 3S, 5R)-2-azabicyclo[3,1,0]hexane-3-methanol are:

¹ H NMR (400MHz, CDCl ₃ ): δ7.67-7.42(m, 2H), 7.44-7.07(m, 8), 4.55(dd, J=10.6, 5.6Hz, 1H), 3.73(dt, J= 11.4, 8.0Hz, 1H), 3.25(m, 1H), 2.10-1.79(m, 2H), 1.72(m, 1H), 1.12(m, 1H), 0.82-0.93(m, 2H);

¹³ C NMR (100 MHz, CDCl ₃ ): δ140.5, 128.8, 128.5, 127.9, 126.2, 125.7, 69.5, 46.3, 29.3, 25.1, 17.3.

Example 6

The compound (1S, 3S, 5S)-2-azabicyclo[3,1,0]hexane-3-diphenylcarbinol 4 prepared in Example 4 was used as a catalyst to catalyze the asymmetric Michael addition reaction, which The reaction formula and condition screening are as follows:

Dichloromethane (1 mL), catalyst (0.01 mmol), N,N-diisopropylethylamine DIPEA (1.75 μL, 0.01 mmol) and n-butyraldehyde (0.2 mmol) were successively added into a 3 mL reaction flask at 0°C. After the system was stirred for 5 min, nitrovinylbenzene substrate (0.2 mmol) was added. Subsequently, the reaction was kept at 0° C., and the reaction was monitored by TLC until the reaction was completed. After the reaction, the solvent was evaporated under reduced pressure by a rotary evaporator. The crude product was separated by silica gel column chromatography (petroleum ether PE:ethyl acetate EA=8:1) to obtain 35.36 mg of the catalytic product with a yield of 80% and an ee value of 91%. The diastereoselectivity of the product was determined by crude NMR 1H NMR analysis obtained. The ee value of the product is obtained by HPLC analysis of the product passed through the column. (Chiralcel OD-H), Hexane/i-PrOH=91:9, UV230nm, 0.9mL/min, syn: t _R1 =32.96min(major) and t _R2 =24.73min(minor).

The NMR spectrum data of the product are as follows:

¹ HNMR (400MHz, CDCl ₃ ): δ9.71(d, J=2.5Hz, 1H), 7.72-7.04(m, 5H), 4.67(ddd, J=22.3, 12.7, 7.4Hz, 2H), 3.79( td, J=9.8, 5.0Hz, 1H), 2.68(dddd, J=10.0, 7.5, 5.0, 2.6Hz, 1H), 1.58-1.44(m, 2H), 0.83(t, J=7.5Hz, 3H) .

Example 7

Divided by the compound (1R, 3S, 5R)-2-azabicyclo[3,1,0]hexane-3-diphenylcarbinol 6 prepared by example 5 to replace compound (1S, 3S, 5S)- Except for 2-azabicyclo[3,1,0]hexane-3-diphenylcarbinol 4, the other steps are the same as in Example 5, using dichloromethane with the best effect at 20°C to catalyze the asymmetric Michael addition After the reaction, 37.57 mg of the catalytic product was obtained with a yield of 85% and an ee value of 83%.

Example 8

Except that -20°C is used as the reaction condition of Example 8 instead of 20°C in Example 7, the other steps are the same as in Example 7, which is used to catalyze the asymmetric Michael addition reaction to obtain 41.28 mg of the product, with a yield of 89%, ee The value is 93%.

Comparative example 1

Except that S-proline is used as the reaction condition of Comparative Example 1 to replace the catalyst in Example 8, other steps are the same as in Example 6, which is used to catalyze the asymmetric Michael addition reaction to obtain 35.73 mg of product, with a yield of 83%. , ee value is 75%.

Catalytic experimental data are shown in Table 1.

Table 1

group temperature(℃) Yield (%) ee(%) ^a Example 10 0 80% 91% Example 11 20 85% 83% Example 12 -20 89% 93% Comparative example 1 -20 83% 75%

^a Determined by chiral HPLC using a chiralpak AD-H column

All of the foregoing are primary implementations of this intellectual property and are not intended to limit other forms of implementation of this new product and/or new method. Those skilled in the art will, with this important information, modify the above to achieve a similar implementation. However, all modifications or alterations to the new product based on the present invention belong to reserved rights.

The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention to other forms. Any skilled person who is familiar with this profession may use the technical content disclosed above to change or modify the equivalent of equivalent changes. Example. However, any simple modifications, equivalent changes and modifications made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still belong to the protection scope of the technical solution of the present invention.

Claims (10)

1. the S-diphenylprolinol chiral organic micromolecule compound with cyclopropane structure is characterized in that:

Described organic micromolecule compound structural formula is as shown in Formula I:

In Formula I, the chiral configuration of mark * carbon can be a kind of in R or S;

The chirality of C-1 and C-5 must be a kind of in R or S simultaneously.

2. the preparation method with S-diphenylprolinol chiral organic micromolecule compound of cyclopropane structure claimed in claim 1, is characterized in that, comprising:

The first step, with (S)-1-N-tertbutyloxycarbonyl-2,3-dihydro-2-minaline ethyl ester carries out the reaction of Simmons-Smith cyclopropane, obtains enantiomer;

Second step, the enantiomer that the first step is obtained is carried out respectively grignard reaction;

The 3rd step, the reaction product that second step is obtained is removed respectively the reaction of amido protecting, obtains and has cyclopropane structure R-diphenylprolinol chiral organic micromolecule compound.

3. preparation method as claimed in claim 1, it is characterized in that: the described the first step is specially the tertbutyloxycarbonyl-2 by (S)-1-N-, 3-dihydro-2-minaline ethyl ester and zinc ethyl (ZnEt ₂) and chloroiodomethane (CH ₂clI) hybrid reaction, obtain enantiomer (1S, 3S, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate and (1R, 3S, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate, the corresponding isomer mixture obtained adopts the aqueous solution of ethylenediamine tetraacetic acid (EDTA) and the amine aqueous solution to process, improve both enantioselectivity, enantiomer (1S, 3S, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate and (1R, 3S, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] mol ratio>20:1 of hexane-3-ethyl formate, adopt subsequently the mixing leacheate of volume ratio ethyl acetate/normal heptane=1/20 to carry out the separation of chromatography post, obtain respectively product (1S, 3S, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate and (1R, 3S, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate.

4. preparation method as claimed in claim 2 is characterized in that: in the described the first step, and (S)-1-N-tertbutyloxycarbonyl-2,3-dihydro-2-minaline ethyl ester and zinc ethyl (ZnEt ₂) and chloroiodomethane (CH ₂clI) according to mol ratio 1:0.5～2:1～2, mix, further preferably 1/0.5/1 or 1/1/1 or 1/1/2 or 1/2/2, maintain under the condition of temperature of reaction-20 ℃～-15 ℃, react 22～24h.

5. preparation method as described as claim 2 to 4, it is characterized in that: in the described the first step, the amine aqueous solution is that the amine aqueous solution is any one in ethamine, diethylamine, triethylamine, propylamine, Isopropylamine and the TERTIARY BUTYL AMINE aqueous solution.

6. preparation method as described as claim 2 to 5, it is characterized in that: described second step is specially the (1S that the first step is obtained, 3S, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate and (1R, 3S, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-ethyl formate separately with magnesium, bromobenzene mixes, carry out grignard reaction, obtain (1S, 3S, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-diphenyl-carbinol and (1R, 3S, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-diphenyl-carbinol.

7. preparation method as described as claim 2 to 6, it is characterized in that: in described second step, (1S, 3S, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-ethyl formate and (1R, 3S, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-ethyl formate is 1:2.1～2.5:4.2～5 with the mol ratio of reacting of magnesium, bromobenzene separately, and reaction conditions is to react 2～4h under the holding temperature condition that is 65～75 ℃.

8. preparation method as described as claim 2 to 7, it is characterized in that: described the 3rd step is specially the product (1S that second step is obtained, 3S, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-diphenyl-carbinol and (1R, 3S, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3, 1, 0] hexane-3-diphenyl-carbinol carries out the amide hydrolysis under acidic conditions with trifluoroacetic acid separately, obtain (1S, 3S, 5S)-2-azabicyclo [3, 1, 0] hexane-3-diphenyl-carbinol and (1R, 3S, 5R)-2-azabicyclo [3, 1, 0] hexane-3-diphenyl-carbinol.

9. preparation method as described as claim 2 to 8, it is characterized in that: in described the 3rd step, (1S, 3S, 5S)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-diphenyl-carbinol and (1R, 3S, 5R)-N-tertbutyloxycarbonyl-2-azabicyclo [3,1,0] hexane-3-diphenyl-carbinol is 1: 1.0～1.5 with the mol ratio of reacting of trifluoroacetic acid separately, and reaction conditions is for keeping 5 ℃ of reaction 2～4h of temperature.

10. the S-diphenylprolinol with cyclopropane structure that adopts the described preparation method of claim 2 to 9 to prepare is as the application of catalyzer.

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