CN103435533A - Chiral organic small molecular compound of S-prolinol having cyclopropane structure and synthetic method of chiral organic small molecular compound - Google Patents

Abstract

The invention provides a kind of S-prolinol chiral organic small molecular compound with cyclopropane structure and its synthesis method, the steps comprising: the first step, with (S)-1-N-tert-butoxycarbonyl-2 , 3-dihydro-2-pyrrolecarboxylic acid ethyl ester carries out Simmons-Smith cyclopropane reaction; The second step, the reaction product obtained in the first step is subjected to ester reduction reaction; The third step, the reaction product obtained in the second step is carried out The reaction of removing the protection of the amino group obtains the S-prolinol chiral organic small molecular compound 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 enantiomeric products of optical purity. It is an ideal method for synthesizing S-prolinol chiral organic small molecule compounds with cyclopropane structure. , S-prolinol with cyclopropane structure can be used as a chiral catalyst in a variety of asymmetric catalytic reactions.

Description

S-prolinol 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-prolinol chiral organic small molecule compound with a cyclopropane structure and a synthesis 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.

Carrillo et al. used 3,3-dimethoxynitropropene as the electrophile for the addition reaction with aldehydes for the first time, and used proline derivatives as catalysts to screen the catalytic performance of proline derivatives and prolinol (Org. Lett., 2006, 8, 6135-6138). The results showed that prolinol had good catalytic activity and enantioselectivity, but its diastereoselectivity was poor due to its small steric hindrance.

Based on the above research results, we imagined that a rigid chiral cyclopropane group would be introduced into the ortho position of the pyrrole ring of prolinol by merging rings, hoping to increase the rigidity and steric hindrance of the prolinol chiral catalyst to solve the problem. The problem of poor enantioselectivity and diastereoselectivity in catalytic reactions is expected to obtain new catalysts with high catalytic activity and broad-spectrum high-efficiency 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) , and 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 the above-mentioned chiral cyclopropane structure S-proline, 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 synthesis method of prolinol has reasonable process, simple operation and low cost, and does not need further chiral preparation and resolution to obtain enantiomeric products of optical purity. Methods for the structure of S-prolinol.

Contents of the invention

The purpose of the present invention is to address the deficiencies in the prior art, to provide a novel S-prolinol chiral organic small molecule compound with a cyclopropane structure, which has reasonable technology, simple operation and low cost, and does not need further chiralization. The enantiomeric products of optical purity are obtained by preparation and resolution, which is ideal for the synthesis of S-prolinol chiral organic small molecular compounds with cyclopropane structure.

The present invention is achieved through the following technical solutions. The present invention provides a S-prolinol chiral organic small molecule compound having a chiral cyclopropane structure, and 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 present invention also provides the preparation method of the S-prolinol chiral organic small molecule compound of the cyclopropane structure represented by the above chemical formula I, specifically as follows:

In the first step, (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid ethyl ester is subjected to Simmons-Smith cyclopropane reaction;

In the second step, the reaction product obtained in the first step is subjected to an ester reduction reaction;

In the third step, the reaction product obtained in the second step is subjected to a deprotection reaction of the amino group to obtain an S-prolinol chiral small organic molecule compound 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) mixed reaction to obtain enantiomer (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 enantiomeric mixture obtained using ethylenediaminetetraacetic acid solution and amines Aqueous solution treatment, improve the enantioselectivity of both, enantiomer (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3- The molar ratio of ethyl formate to ethyl (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate >20:1, followed by acetic acid The eluent of ethyl ester/n-heptane=1/20 was subjected to chromatographic column separation to obtain the products (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0 ]hexane-3-carboxylic acid ethyl ester and (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester.

In the first step, ethyl (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylate was mixed with diethylzinc (ZnEt ₂ ) and chloroiodomethane (CH ₂ ClI ) with a mixing molar ratio of 1:0.5~2:1~2, more preferably 1/0.5/11/1/1 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.

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

The second step is specifically the (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester obtained in the first step and ( 1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate were mixed with lithium aluminum tetrahydrogen (LiAlH ₄ ) and subjected to alkaline conditions The following hydrolysis reaction, obtain (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol or (1S,3S,5S)-N- tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol.

In the second step, (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate, (1S,3S,5S) The molar reaction ratio of -N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate to lithium aluminum tetrahydrogen (LiAlH ₄ ) is 1:1.0～2.0, the reaction The condition is to react at a temperature of 15-25° C. for 2-4 hours.

The third step is specifically to combine the product (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol and (1S , 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol was mixed with trifluoroacetic acid at a molar ratio of 1:1.0~1.5 for acidic conditions For the amide hydrolysis reaction, keep the temperature at 5°C for 2-4 hours to obtain (1R, 3S, 5R)-2-azabicyclo[3,1,0]hexane-3-methanol and (1S,3S,5S)-2 - Azabicyclo[3,1,0]hexane-3-methanol.

In the third step, (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol, (1S,3S,5S)-N The reaction molar ratio of -tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexan-3-ol to trifluoroacetic acid is 1:1.0~1.5, and the reaction conditions are to keep the temperature at 5°C for 2~ 4h.

The present invention provides a kind of S-prolinol chiral organic small molecular compound with cyclopropane structure, and its preparation method comprises:

In the first step, ethyl (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylate was mixed with diethylzinc (ZnEt ₂ ) and chloroiodomethane (CH ₂ ClI) according to The molar ratio is 1:0.5～2:1～2, more preferably 1/0.5/1 or 1/1/1 or 1/1/2 or 1/2/2, and the reaction temperature is maintained at -20～-15°C Under certain conditions, react for 22 to 24 hours to obtain enantiomer (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate, the enantiomeric mixture obtained using ethylenediaminetetraacetic acid Solution and amine aqueous solution process, improve the enantioselectivity of both, amine solvent is any one in ethylamine, diethylamine, triethylamine, propylamine, isopropylamine and tert-butylamine aqueous solution, enantiomer ( 1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and (1R,3S,5R)-N-tert-butoxycarbonyl- The molar ratio of ethyl 2-azabicyclo[3,1,0]hexane-3-carboxylate>20:1, followed by the eluent of ethyl acetate/n-heptane=1/20 for chromatographic column Separated to obtain the product (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate ethyl ester and (1S,3S,5S)-N - ethyl tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate;

In the second step, the (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester obtained in the first step and (1S, 3S , 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and lithium aluminum tetrahydrogen (LiAlH ₄ ) according to the molar ratio of 1:1.0～2.0 Mix, carry out the hydrolysis reaction under basic conditions, and keep the temperature at 15-25°C for 2-4 hours to obtain (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3, 1,0]hexane-3-methanol and (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol;

In the third step, the product (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol and (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol was mixed with trifluoroacetic acid at a molar ratio of 1:1.0~1.5 for amide hydrolysis under acidic conditions , followed by keeping the temperature at 5°C for 2 to 4 hours to obtain (1R, 3S, 5R)-2-azabicyclo[3,1,0]hexane-3-methanol and (1S,3S,5S)-2-nitrogen Heterobicyclo[3,1,0]hexane-3-methanol.

The present invention also provides the application of the above-mentioned S-prolinol chiral organic small molecular compound having a cyclopropane structure as a chiral catalyst.

Beneficial effects of the present invention:

The novel synthesis method of S-proline with chiral 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 enantiomeric products of optical purity , is an ideal method for synthesizing S-prolinol with a chiral cyclopropane structure, and the S-prolinol with a chiral cyclopropane structure can be used as a chiral catalyst in various asymmetric catalytic reactions.

Description of drawings

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

Detailed ways

The invention provides a compound of S-prolinol having a chiral cyclopropane structure, and its chemical structural formula I is as follows:

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 compound of S-prolinol with chiral cyclopropane structure provided by the present invention, its synthetic route is as follows:

Its synthetic steps include:

In the first step, (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid ethyl ester is subjected to Simmons-Smith cyclopropane reaction;

In the second step, the reaction product obtained in the first step is subjected to an ester reduction reaction;

In the third step, the reaction product obtained in the second step is subjected to a deprotection reaction of the amino group to obtain an S-prolinol chiral small organic molecule compound 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 1/0.5/11/1/1 or 1/1/2 or 1/2/2, and maintained at the reaction temperature of -20～-15 Under the condition of ℃, react for 22~24h to obtain the enantiomer (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl Ethyl ester and (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate, the enantiomeric mixture obtained using ethylenediaminetetra Treat with acetic acid solution and amine aqueous solution to improve the enantioselectivity of the two. The amine solvent is any one of ethylamine, diethylamine, triethylamine, propylamine, isopropylamine and tert-butylamine, and the enantiomer (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate: (1R,3S,5R)-N-tert-butoxycarbonyl - The molar ratio of ethyl 2-azabicyclo[3,1,0]hexane-3-carboxylate is >20:1, which is much higher than the ratio 4 reported in the literature (Bioorganic & Medicinal Chemistry Letters 8 (1998) 2123-2128): 1, followed by chromatographic column separation using the eluent of ethyl acetate/n-heptane=1/20 (volume ratio), to obtain the products (1R, 3S, 5R)-N-tert-butoxycarbonyl-2- Ethyl azabicyclo[3,1,0]hexane-3-carboxylate and (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3 - ethyl formate.

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 Solvent dichloromethane (DCM), cooled to -20 ° C ~ -15 ° C, dropwise added diethyl zinc (ZnEt ₂ ), stirred for 0.5 h after the dropwise addition, and then added dropwise chloroiodomethane ( CH ₂ ClI), maintained at a temperature of -20 to -15°C and stirred for 24 hours, after the reaction was completed, the reaction was quenched by adding an aqueous solution of ethylenediaminetetraacetic acid (EDTA) with a concentration of 13% by mass, and the temperature was raised to 20 to 25°C , stirred for 2 to 3 hours, stood still for 20 minutes, extracted, combined the organic phases to obtain a yellow oil, added a 30% aqueous solution of diethylamine and stirred for 12 hours, concentrated under reduced pressure, and dried the organic layer with an appropriate amount of anhydrous sodium sulfate , eluted with ethyl acetate (EA)/n-heptane (h-heptane)=1/20 eluent, after the elution was completed, the products were collected to obtain the products (1S, 3S, 5S)-N-tert-butyl Oxycarbonyl-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, molar ratio >20:1.

The second step is specifically the (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester obtained in the first step and ( 1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and lithium aluminum tetrahydrogen (LiAlH ₄ ) in a molar ratio of 1: Mix 1.0 to 2.0, carry out hydrolysis reaction under alkaline conditions, keep the temperature at 15-25°C for 2-4 hours, and obtain (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo [3,1,0]hexane-3-methanol and (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol.

The second step is further preferably adding the product obtained in the first step (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1, 0] hexane-3-ethyl carboxylate or (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate, added without Dissolve tetrahydrofuran in water, control the temperature at 15-25°C, add lithium aluminum tetrahydrogen (LiAlH ₄ ) in small amounts gradually under stirring, then keep stirring at 15-25°C for 4 hours, concentrate THF under reduced pressure, and add mass The percentage concentration is 1% dilute hydrochloric acid, remove the upper organic layer, add dichloromethane (DCM) to the water layer, then stir for 10-20 minutes, remove the lower organic layer, and add dichloromethane to the water layer (DCM), the lower organic layer was separated, the organic layers were combined, and dried with an appropriate amount of anhydrous sodium sulfate, and then concentrated to dryness, the white solid was (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-nitrogen Heterobicyclo[3,1,0]hexane-3-methanol or (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol.

The third step is specifically to use the product (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol or (1S , 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol was mixed with trifluoroacetic acid at a molar ratio of 1:1.0~1.5 for acidic conditions Amide hydrolysis reaction, followed by reaction at 5°C for 2 to 4 hours to obtain (1R,3S,5R)-2-azabicyclo[3,1,0]hexane-3-methanol and (1S,3S,5S)- 2-Azabicyclo[3,1,0]hexane-3-methanol.

The third step is further specifically under _N protection, adding the second step to two dry reaction flasks respectively to obtain (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[ 3,1,0]hexane-3-carboxylic acid or (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexan-3-ol followed by addition of each Dichloromethane (DCM) was dissolved, and trifluoroacetic acid (TFA) was added dropwise at 5°C. After the dropwise addition was completed, the reaction was stirred for 3 hours, saturated ammonium chloride solution was added, and concentrated under reduced pressure to obtain a light yellow solid, namely (1R, 3S,5R)-2-azabicyclo[3,1,0]hexane-3-methanol or (1S,3S,5S)-2-azabicyclo[3,1,0]hexane-3-methanol .

The present invention also provides the application of the above-mentioned S-prolinol chiral organic small molecular compound having a cyclopropane structure as a chiral catalyst.

More specifically, the S-prolinol chiral organic small molecular compound with a cyclopropane structure provided by the present invention is used as a chiral catalyst for catalyzing asymmetric Michael addition reactions.

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. Provided, CAS number: 178172-26-4) (34.0g, 0.13mol) was dissolved in 200ml of dichloromethane (DCM), cooled to -15°C, diethylzinc (Et ₂ Zn) (1.2eq, 0.17mol), stirring and reacting for 0.5h after completion of the dropwise addition, dichloromethane (DCM) solution of chloroiodomethane (CH ₂ ClI) (1.1eq, 0.15mol) was added dropwise, kept at -15°C and stirred for 24h, after the reaction was completed, use Add ethylenediaminetetraacetic acid (EDTA) aqueous solution with a concentration of 13% by mass to quench the reaction, raise the temperature to 25°C, stir for 2 hours, let stand for 20 minutes, extract, combine the organic phases to obtain a yellow oil, add mass percent The concentration was 30% diethylamine aqueous solution, stirred for 12 hours, concentrated under reduced pressure, the organic layer was dried with an appropriate amount of anhydrous sodium sulfate, and the eluent was eluted with ethyl acetate (EA)/n-heptane (h-heptane)=1/20 volume ratio Carry out elution, after elution is completed, collect 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, this ratio is far higher than the ratio 4:1 reported in literature (Bioorganic & Medicinal Chemistty Letters8 (1998) 2123-2128), proves that adopting the preparation method of the present invention to Enantiomers are more selective.

(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-carboxylate ethyl ester 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-methanol 3

The three-necked reaction flask was added with (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate ethyl ester prepared in Example 1, namely compound 1 ( 25.5g, 0.10mol), add anhydrous tetrahydrofuran to dissolve, control the temperature at 20°C, add lithium aluminum tetrahydrogen (LiAlH ₄ ) in small amounts under stirring, add 3.8g (0.10mol) lithium aluminum tetrahydrogen in total, and then keep Stir at 20°C for 4 hours, concentrate THF under reduced pressure, add 1% dilute hydrochloric acid dropwise after concentration, remove the upper organic layer, add dichloromethane (DCM) to the water layer, then stir for 10-20 minutes, remove For the lower organic layer, add dichloromethane (DCM) to the water layer, separate the lower organic layer, combine the organic layers, and dry with an appropriate amount of anhydrous sodium sulfate, continue to concentrate to dryness, and the white solid 3 is (1S, 3S , 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol, 20.4g, yield 80%.

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

¹ HNMR (400MHz, CDCl ₃ ): δ=3.81-4.16(m, 2H), 3.28-3.58(m, 3H), 1.71-2.14(m, 4H), 1.46(br s, 9H),

¹³ CNMR (400MHz, CDCl ₃ ): δ=156.56, 79.79, 66.54, 59.67, 47.18, 28.23, 23.68.

Example 3

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

The three-necked reaction flask was added with (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate prepared in Example 1, namely compound 2 ( 2.55g, 0.01mol), add anhydrous tetrahydrofuran to dissolve, control the temperature at 20°C, add lithium aluminum tetrahydrogen (LiAlH ₄ ) in small amounts under stirring, add a total of 0.38g (0.01mol) of lithium aluminum tetrahydrogen, and then keep Stir at 20°C for 4 hours, concentrate THF under reduced pressure, add 1% dilute hydrochloric acid dropwise after concentration, remove the upper organic layer, add dichloromethane (DCM) to the water layer, then stir for 10-20 minutes, remove For the lower organic layer, dichloromethane (DCM) was added to the water layer, the lower organic layer was separated, the organic layers were combined, dried with an appropriate amount of anhydrous sodium sulfate, and concentrated to dryness to obtain a white solid 5, namely (1R, 3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol, 1.98g, yield 78%.

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

¹ HNMR (400MHz, CDCl ₃ ): δ=3.81-4.16(m, 2H), 3.28-3.58(m, 3H), 1.71-2.14(m, 4H), 1.46(br s, 9H),

¹³ CNMR (400MHz, CDCl ₃ ): δ=156.56, 79.79, 66.54, 59.67, 47.18, 28.23, 23.68.

Example 4

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

Under _N protection, (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol was added to a dry 250ml two-necked reaction flask, namely Compound 3 (2.13g, 0.01mol) was dissolved in 200ml of dichloromethane (DCM), kept at 5°C, trifluoroacetic acid (TFA) (1.2eq, 0.012mol) was added dropwise, and the reaction was stirred for 3h after the dropwise addition was completed. Saturated ammonium chloride solution was added, followed by extraction with dichloromethane (DCM), and concentration to dryness under reduced pressure to obtain a white solid 4, namely (1S,3S,5S)-2-azabicyclo[3,1,0]hexyl Alkane-3-methanol, 0.8 g, 79% yield.

The NMR data of (1S, 3S, 5S)-2-azabicyclo[3,1,0]hexane-3-methanol 4 are:

¹ H NMR (400MHz, CD ₃ OD): δ=3.98(t, J=8.8Hz, 1H), 3.52-3.41(m, 2H) 2.78(m, 2H) 3.30(dt, J=3.2, 1.6Hz, 1H), 2.78(m, 1H), 2.53(m, 1H), 2.29-2.16(m, 1H), 2.07-1.97(m, 1H), 1.91(m, 1H);

¹³ C NMR (100 MHz, CD ₃ OD): δ=73.2, 64.2, 59.7, 42.1, 34.5, 29.0.

Example 5

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

Under _N protection, (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol was added to a dry 250ml two-necked reaction flask, namely Compound 5 (2.13g, 0.01mol) was dissolved in 200ml of dichloromethane (DCM), kept at 5°C, trifluoroacetic acid (TFA) (1.2eq, 0.012mol) was added dropwise, and the reaction was stirred for 3h after the dropwise addition was completed. Saturated ammonium chloride solution was added, followed by extraction with dichloromethane (DCM), and concentration to dryness under reduced pressure to obtain a white solid 6, namely (1R,3S,5R)-2-azabicyclo[3,1,0]hexyl Alkane-3-methanol, 0.8 g, 79% yield.

The NMR spectrum data of (1R, 3S, 5R)-2-azabicyclo[3,1,0]hexane-3-methanol 6 is:

¹ H NMR (400MHz, CD ₃ OD): δ=3.96(t, J=8.8Hz, 1H), 3.49-3.41(m, 2H) 2.73(m, 2H) 3.29(dt, J=3.2, 1.6Hz, 1H), 2.76(m, 1H), 2.51(m, 1H), 2.29-2.16(m, 1H), 2.03-1.95(m, 1H), 1.89(m, 1H);

¹³ C NMR (100 MHz, CD ₃ OD): δ = 73.1, 64.0, 59.6, 41.9, 34.3, 29.2.

Example 6

The compound (1S, 3S, 5S)-2-azabicyclo[3,1,0]hexane-3-methanol 4 prepared by Example 4 is used as a catalyst to catalyze the asymmetric Michael addition reaction, and its reaction formula and Conditional filter see below:

Add dichloromethane (1 mL), catalyst (0.01 mmol), N, N-diisopropylethylamine DIPEA (1.75 μL, 0.01 mmol) and n-butyraldehyde (0.2 mmol) in 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 35.32 mg of the catalytic product, the yield was 80%, and the ee value was 88%. The diastereoselectivity of the product was determined by the crude product 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

Compound (1R, 3R, 5R)-2-azabicyclo[3,1,0]hexane-3-carbinol 6, which is divided by example 5, replaces compound (1S, 3R, 5S)-2-nitrogen in example 6 Except for heterobicyclo[3,1,0]hexane-3-methanol 4, the other steps were the same as in Example 6, and dichloromethane with the best effect was used to catalyze the asymmetric Michael addition reaction at 20°C to obtain 39.71 mg of the product , the yield was 90%, and the ee value was 75%.

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 6, which is used to catalyze the asymmetric Michael addition reaction to obtain 39.80 mg of the product, with a yield of 91%, ee The value is 92%.

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 6 0 80% 88% Example 7 20 90% 75% Example 8 -20 91% 92%

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. a kind of S-prolinol chiral organic small molecule compound with cyclopropane structure, it is characterized in that: described compound 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. 2. the preparation method of the S-prolinol chiral organic small molecular compound with cyclopropane structure as claimed in claim 1, is characterized in that, comprises: In the first step, (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid ethyl ester is subjected to Simmons-Smith cyclopropane reaction; In the second step, the reaction product obtained in the first step is subjected to an ester reduction reaction; In the third step, the reaction product obtained in the second step is subjected to a deprotection reaction of the amino group to obtain an S-prolinol chiral small organic molecule compound having a cyclopropane structure. 3. the preparation method of the S-prolinol chiral organic small molecule compound with cyclopropane structure as claimed in claim 2, it is characterized in that: described first step is specifically the (S)-1-N-tert Butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid ethyl ester mixed with diethylzinc (ZnEt ₂ ) and chloroiodomethane (CH ₂ ClI) to obtain enantiomers (1R, 3S, 5R )-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo [3,1,0]Hexane-3-ethyl carboxylate, the enantiomeric mixture obtained is treated with ethylenediaminetetraacetic acid solution and amine aqueous solution to improve the enantioselectivity of the two, enantiomeric (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and (1R,3S,5R)-N-tert-butoxy The molar ratio of ethyl carbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate>20:1, followed by eluent with volume ratio of ethyl acetate/n-heptane=1/20 Chromatographic column separation to obtain the product (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and (1S, 3S, 5S)-Ethyl N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate. 4. the preparation method of the S-prolinol chiral organic small molecular compound with cyclopropane structure as claimed in claim 2 or 3, is characterized in that: in the first step, (S)-1-N- The molar ratio of ethyl tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylate to diethyl zinc (ZnEt ₂ ) and chloroiodomethane (CH ₂ ClI) is 1:0.5～2:1～2 Mixing, more preferably 1/0.5/1 or 1/1/1 or 1/1/2 or 1/2/2, maintained at the reaction temperature of -20 to -15°C, and reacted for 22 to 24 hours. 5. the preparation method of the S-prolinol chiral organic small molecular compound with cyclopropane structure as claimed in claim 2 to 4, it is characterized in that: the amine solvent in the described first step is ethylamine, two Any one of ethylamine, triethylamine, propylamine, isopropylamine and t-butylamine. 6. the preparation method of the S-prolinol chiral organic small molecular compound with cyclopropane structure as claimed in claim 2 to 5, it is characterized in that: described second step is specifically the (1R ,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and (1S,3S,5S)-N-tert-butoxycarbonyl-2 -Ethyl azabicyclo[3,1,0]hexane-3-carboxylate was mixed with lithium aluminum tetrahydrogen (LiAlH ₄ ) and hydrolyzed under alkaline conditions to obtain (1R,3S,5R)-N -tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol or (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1, 0] hexane-3-methanol. 7. the preparation method of the S-prolinol chiral organic small molecular compound with cyclopropane structure as claimed in claim 2 to 6, it is characterized in that: in the second step, (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] The molar reaction ratios of ethyl hexane-3-carboxylate and lithium aluminum tetrahydrogen (LiAlH ₄ ) were both 1:1.0-2.0, and the reaction conditions were 2-4 hours at a temperature of 15-25°C. 8. the preparation method of the S-prolinol chiral organic small molecular compound with cyclopropane structure as claimed in claim 2 to 7, it is characterized in that: described the 3rd step is specially the product ( 1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol and (1S,3S,5S)-N-tert-butoxycarbonyl-2- Azabicyclo[3,1,0]hexane-3-methanol was mixed with trifluoroacetic acid at a molar ratio of 1:1.0~1.5 to carry out amide hydrolysis under acidic conditions, and the temperature was maintained at 5°C for 2~4 hours to obtain ( 1R,3S,5R)-2-Azabicyclo[3,1,0]hexane-3-methanol and (1S,3S,5S)-2-Azabicyclo[3,1,0]hexane-3 - Methanol. 9. a kind of S-prolinol chiral organic small molecular compound with cyclopropane structure, it is characterized in that, the preparation method of described compound comprises: In the first step, ethyl (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylate was mixed with diethylzinc (ZnEt ₂ ) and chloroiodomethane (CH ₂ ClI) according to The molar ratio is 1:0.5～2:1～2, more preferably 1/0.5/1 or 1/1/1 or 1/1/2 or 1/2/2, and the reaction temperature is maintained at -20～-15°C Under certain conditions, react for 22 to 24 hours to obtain enantiomer (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester and (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate, the enantiomeric mixture obtained using ethylenediaminetetraacetic acid solution and amine aqueous solution to improve the enantioselectivity of the two, the amine solvent is any one of ethylamine, diethylamine, triethylamine, propylamine, isopropylamine and tert-butylamine aqueous solution, enantiomer (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and (1R,3S,5R)-N-tert-butoxycarbonyl - The molar ratio of ethyl 2-azabicyclo[3,1,0]hexane-3-carboxylate>20:1, followed by chromatography with ethyl acetate/n-heptane=1/20 eluent Column separation, product (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and (1S, 3S, 5S)- Ethyl N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate; In the second step, the (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester obtained in the first step and (1S, 3S , 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and lithium aluminum tetrahydrogen (LiAlH ₄ ) according to the molar ratio of 1:1.0～2.0 Mix, carry out the hydrolysis reaction under basic conditions, and keep the temperature at 15-25 °C for 2-4 hours to obtain (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3, 1,0]hexane-3-methanol and (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol; In the third step, the product (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol and (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-methanol is mixed with trifluoroacetic acid at a molar ratio of 1:1.0~1.5 for amide hydrolysis under acidic conditions , followed by keeping the temperature at 5°C for 2 to 4 hours to obtain (1R, 3S, 5R)-2-azabicyclo[3,1,0]hexane-3-methanol and (1S,3S,5S)-2-nitrogen Heterobicyclo[3,1,0]hexane-3-methanol. 10. The application of the S-prolinol chiral organic small molecular compound with cyclopropane structure described in claims 1 to 8 as a chiral catalyst.

Images