CN103435534A - Preparation method of S-proline having cyclopropane structure - Google Patents

Abstract

The invention provides a method for synthesizing S-proline with a cyclopropane structure, the steps comprising: the first step, carrying out esterification reaction of S-pyroglutamic acid; the second step, converting the reaction obtained in the first step The product is subjected to an amino protection reaction; in the third step, the reaction product obtained in the second step is subjected to a reduction reaction; in the fourth step, the reaction product obtained in the third step is subjected to a hydroxyl elimination reaction; in the fifth step, the reaction product obtained in the fourth step is The product is subjected to Simmons-Smith cyclopropane reaction; in the sixth step, the enantiomers obtained in the fifth step are subjected to ester hydrolysis respectively; in the seventh step, the reaction products obtained in the sixth step are respectively subjected to the reaction of removing amino protection , to obtain S-proline with cyclopropane structure. The method has reasonable process, simple operation and low cost, does not need further chiral preparation and resolution to obtain optically pure enantiomer products, and is an ideal method for synthesizing S-proline with a cyclopropane structure.

Description

Preparation method of S-proline with cyclopropane structure

technical field

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

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 1997, H.Stephen's group successfully synthesized S-proline with a 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, and subsequently developed the Simmons-Smith cyclopropane reaction based on the 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.

In view of the problems existing in the method for synthesizing S-proline with a cyclopropane structure, we provide a novel synthesis method for S-proline with a cyclopropane structure, which has a reasonable process, simple operation and low cost , no need for further chiral preparation and resolution to obtain enantiomeric products of optical purity, with strong enantiomeric structure selectivity, and is an ideal method for synthesizing S-proline with cyclopropane structure.

Contents of the invention

The technical problem to be solved by the present invention is to provide a novel synthesis method of S-proline with cyclopropane structure, which has reasonable process, simple operation and low cost, and does not need further chiral preparation and resolution to obtain optical purity The enantiomeric product has strong enantiomeric structure selectivity, and is an ideal method for synthesizing S-proline with cyclopropane structure.

For solving the problems of the technologies described above, the invention provides a kind of synthetic method with the S-proline of cyclopropane structure, and its step comprises:

In the first step, S-pyroglutamic acid undergoes an esterification reaction;

In the second step, the reaction product obtained in the first step is subjected to an amino protection reaction;

In the third step, the reaction product obtained in the second step is subjected to a reduction reaction;

In the fourth step, the reaction product obtained in the third step is subjected to a hydroxyl elimination reaction;

In the fifth step, the reaction product obtained in the fourth step is subjected to a Simmons-Smith cyclopropane reaction to obtain enantiomers;

In the sixth step, the enantiomers obtained in the fifth step are subjected to ester hydrolysis respectively;

In the seventh step, the reaction products obtained in the sixth step are respectively subjected to a deprotection reaction to obtain S-proline having a cyclopropane structure.

The first step is specifically to mix S-pyroglutamic acid and thionyl chloride at a molar ratio of 1:1.1~2, and react for 2h~3h at a reaction temperature of -10°C~-5°C, S-pyroglutamate ethyl ester is obtained.

The second step is specifically to mix the S-pyroglutamic acid ethyl ester obtained in the first step with the N-protecting reagent di-tert-butyl dicarbonate in a molar ratio of 1:1.5-2, and maintain the reaction temperature at 10 ℃～15℃ for 3～4 hours to obtain Boc-S-pyroglutamic acid ethyl ester.

The third step is specifically reducing the Boc-S-pyroglutamic acid ethyl ester obtained in the second step using diisobutylaluminum hydride (DIBAL-H), and the Boc-S-pyroglutamic acid ethyl The reaction molar ratio of the ester to the diisobutylaluminum hydride is 1:1.1~1.5, and when the reaction temperature is maintained at -65~-60°C, the reaction is carried out for 1~2h to obtain (S)-1-N-tert-butyl Oxycarbonyl-2-hydroxy-2-pyrrolecarboxylic acid ethyl ester.

The fourth step is specifically to use trifluoroacetic anhydride (TFAA) to carry out the hydroxyl elimination reaction of (S)-1-N-tert-butoxycarbonyl-2-hydroxy-2-pyrrolecarboxylic acid ethyl ester obtained in the third step, ( The molar ratio of S)-1-N-tert-butoxycarbonyl-2-hydroxyl-2-pyrrolecarboxylic acid ethyl ester and trifluoroacetic anhydride is 1:1.0～1.3, and the reaction temperature is maintained at -15～-10°C for 1 ~2h, ethyl (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylate was obtained.

The fifth step is specifically to combine (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid ethyl ester obtained in the fourth step with diethylzinc (ZnEt ₂ ) and chlorine Iodomethane (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 Under the condition of reaction temperature -20～-15℃, react for 22～24h to obtain enantiomer (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0] Ethyl hexane-3-carboxylate and ethyl (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate, obtained enantioiso The mixture of conformers is treated with an aqueous solution of ethylenediaminetetraacetic acid and an aqueous solution of amines to improve the enantioselectivity of the two. The amine solvents are ethylamine, diethylamine, triethylamine, propylamine, isopropylamine and tert-butylamine aqueous solution Any of the enantiomers (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate and (1R,3S ,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate in a molar ratio >20:1, followed by ethyl acetate/n-heptane=1 /20 (volume ratio) of the eluent of the mixed solution is subjected to chromatographic column separation to obtain the product (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0] Ethyl hexane-3-carboxylate and ethyl (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate.

The sixth step is specifically the (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester obtained in the fifth step and ( 1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and lithium hydroxide (LiOH) in a molar ratio of 1:1.0～ 1.5 mixed, carry out the hydrolysis reaction under alkaline conditions, and keep the temperature at 15-25 °C for 14-18 hours to obtain (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[ 3,1,0]hexane-3-carboxylic acid and (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid.

The seventh step is specifically to combine the product (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid and (1S , 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid is mixed with trifluoroacetic acid according to the molar ratio of 1:1.0～1.5 and carried out under 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-carboxylic acid and (1S, 3S, 5S) -2-Azabicyclo[3,1,0]hexane-3-carboxylic acid.

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

Beneficial effects of the present invention:

The novel synthetic method of S-proline 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 enantiomeric products of optical purity. The enantiomeric structure has strong selectivity, and is an ideal method for synthesizing S-proline with cyclopropane structure.

Description of drawings

Fig. 1 is the high performance liquid chromatography (HPLC) of compound 6 and compound 7.

Detailed ways

The present invention provides a kind of synthetic method that has cyclopropane structure S-proline, and its step comprises:

In the first step, S-pyroglutamic acid undergoes an esterification reaction;

In the second step, the reaction product obtained in the first step is subjected to an amino protection reaction;

In the third step, the reaction product obtained in the second step is subjected to a reduction reaction;

In the fourth step, the reaction product obtained in the third step is subjected to a hydroxyl elimination reaction;

In the fifth step, the reaction product obtained in the fourth step is subjected to a Simmons-Smith cyclopropane reaction to obtain enantiomers;

In the sixth step, the enantiomers obtained in the fifth step are subjected to ester hydrolysis respectively;

In the seventh step, the reaction products obtained in the sixth step are respectively subjected to a deprotection reaction to obtain S-proline with a cyclopropane structure.

The following reaction equation has specifically reflected the method for the synthesis of chiral cyclopropane structure S-proline of the present invention:

The first step is specifically to mix S-pyroglutamic acid and thionyl chloride at a molar ratio of 1:1.1~2, and react for 2h~3h at a reaction temperature of -10°C~-5°C, S-pyroglutamate ethyl ester is obtained.

Furthermore, the first step is specifically to add S-pyroglutamic acid in a dry reaction flask under _N2 protection, then add absolute ethanol to dissolve S-pyroglutamic acid in ethanol, and then maintain the temperature At -10°C to -5°C, add thionyl chloride (SOCl ₂ ) dropwise while maintaining stirring for 2 hours. After the dropwise addition, stir for 0.5 hours. Concentrate under reduced pressure to remove the solvent to obtain a colorless oil. Concentrate toluene under reduced pressure to remove the remaining thionyl chloride, then add triethylamine to adjust the pH of the system to 8-9, concentrate under reduced pressure, and recrystallize with n-heptane to obtain white solid S-pyroglutamic acid ethyl ester.

The second step is specifically to mix the S-pyroglutamic acid ethyl ester obtained in the first step with the N-protecting reagent di-tert-butyl dicarbonate ((Boc) ₂ O) in a molar ratio of 1:1.5-2 , maintained at a reaction temperature of 10° C. to 15° C. for 3 to 4 hours to obtain Boc-S-ethyl pyroglutamate.

The second step is further specifically described as under _N protection, adding the ethyl S-pyroglutamate obtained in the first step in a dry reaction flask, and then adding toluene to dissolve the ethyl S-pyroglutamate in In toluene, add dipropylene glycol methyl ether acetate (DMAP) and stir, then maintain the temperature at 10°C to 15°C, add di-tert-butyl dicarbonate ((Boc) ₂ O) toluene solution dropwise while maintaining stirring, drop Add 1h, stir for 3h after the dropwise addition, concentrate under reduced pressure to remove the solvent to obtain a colorless oil, then add triethylamine to adjust the pH of the system to 8-9, concentrate under reduced pressure, and recrystallize with n-heptane to obtain a white solid Boc -S-Ethyl pyroglutamate.

The third step is specifically reducing the Boc-S-pyroglutamic acid ethyl ester obtained in the second step using diisobutylaluminum hydride (DIBAL-H), and the Boc-S-pyroglutamic acid ethyl The reaction molar ratio of the ester to the diisobutylaluminum hydride is 1:1.1~1.5, and when the reaction temperature is maintained at -65~-60°C, the reaction is carried out for 1~2h to obtain (S)-1-N-tert-butyl Oxycarbonyl-2-hydroxy-2-pyrrolecarboxylic acid ethyl ester.

The third step is further specifically described as under the protection of N ₂ , adding the Boc-S-pyroglutamic acid ethyl ester obtained in the second step to the dry reaction flask, and then adding tetrahydrofuran (THF) to dissolve it, and maintaining it at -65 ℃～-60℃, add dropwise the tetrahydrofuran solution obtained by dissolving diisobutylaluminum hydride in tetrahydrofuran, stir for 1.5h after the dropwise addition, concentrate under reduced pressure to remove the solvent, and obtain a colorless oil, then add toluene to dissolve, then add Adjust the pH of the system to 8-9 with triethylamine, concentrate under reduced pressure, and recrystallize from n-heptane to obtain ethyl (S)-1-N-tert-butoxycarbonyl-2-hydroxy-2-pyrrolecarboxylate as a white solid.

The fourth step is specifically to use trifluoroacetic anhydride (TFAA) to carry out the hydroxyl elimination reaction of (S)-1-N-tert-butoxycarbonyl-2-hydroxy-2-pyrrolecarboxylic acid ethyl ester obtained in the third step, ( The molar ratio of S)-1-N-tert-butoxycarbonyl-2-hydroxyl-2-pyrrolecarboxylic acid ethyl ester and trifluoroacetic anhydride is 1:1.0～1.3, and the reaction temperature is maintained at -15～-10°C for 1 ~2h, ethyl (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylate was obtained.

The fourth step is further specifically adding (S)-1-N-tert-butoxycarbonyl-2-hydroxyl-2-pyrrolecarboxylic acid ethyl ester obtained in the third step into a dry reaction flask under the protection of _N2 , followed by adding tetrahydrofuran to dissolve, maintaining at -65 ° C ~ -60 ° C dropwise adding N, N-diisopropylethylamine (DIPEA), N, N-diisopropylethylamine and (S)-1-N- The molar ratio of tert-butoxycarbonyl-2-hydroxy-2-pyrrole carboxylic acid ethyl ester is 1～2:1. After the dropwise addition is completed, keep warm for 1h, keep it at -65℃～-60℃, add trifluoroacetic anhydride dropwise, dropwise After completion, keep warm for 1 hour, then raise the temperature to -15°C to -10°C, stir for 2 hours, then add potassium sodium tartrate aqueous solution with a concentration of 50% by mass for extraction, dry the organic layer with an appropriate amount of anhydrous sodium sulfate, and concentrate under reduced pressure to obtain The light yellow oily substance is (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid ethyl ester.

The fifth step is specifically to combine (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid ethyl ester obtained in the fourth step with diethylzinc (ZnEt ₂ ), chlorine Iodomethane (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 Under the condition of reaction temperature -20℃～-15℃, react for 22～24h to obtain enantiomer (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0 ]hexane-3-carboxylate ethyl ester and (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate ethyl ester, the obtained enantio The isomer mixture is treated with ethylenediamine tetraacetic acid aqueous solution and amine aqueous solution to improve the enantioselectivity of the two. The amine is any of ethylamine, diethylamine, triethylamine, propylamine, isopropylamine and tert-butylamine aqueous solution. One, enantiomer (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester obtained after treatment: (1R ,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate molar ratio>20:1, the ratio is much higher than the literature (Bioorganic & Medicinal Chemistry Letters8 (1998) 2123-2128) reported a ratio of 4:1, then ethyl acetate/n-heptane was used to form a mixed solution according to a volume ratio of 1/20, and the mixed eluent was subjected to chromatographic column separation to obtain the product (1S , 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and (1R,3S,5R)-N-tert-butoxycarbonyl-2 - Ethyl azabicyclo[3,1,0]hexane-3-carboxylate.

The fifth step is further preferably under the protection of _N2 , adding (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid obtained in the fourth step to the dry reaction flask Ethyl ester, then add the solvent dichloromethane (DCM) to dissolve, cool to -20°C ~ -15°C, add diethyl zinc (ZnEt ₂ ) dropwise, stir for 0.5h after the dropwise addition, then dropwise add the solvent dissolved in DCM Chloroiodomethane (CH ₂ ClI) in the solution was maintained at a temperature of -20°C 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. , heated to 20-25°C, stirred for 2-3 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 the organic layer was Dry with an appropriate amount of anhydrous sodium sulfate, and elute with a mixed eluent of ethyl acetate (EA)/n-heptane (h-heptane)=1/20 (volume ratio). After the elution is complete, collect the products and obtain The products (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate ethyl ester and (1R,3S,5R)-N-tert-butoxy Ethyl carbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate, molar ratio >20:1.

The sixth step is specifically the (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester obtained in the fifth step and ( 1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and lithium hydroxide (LiOH) in a molar ratio of 1:1.0～ 1.5 Mix, carry out the hydrolysis reaction under alkaline conditions, keep the temperature at 15-25 °C for 14-18 hours, and obtain the products (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo [3,1,0]hexane-3-carboxylic acid and (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid.

The sixth step is further preferably adding the product obtained in the fifth step (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1, 0] Ethyl hexane-3-carboxylate and (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]ethyl hexane-3-carboxylate, add anhydrous Dissolve ethanol, control the temperature at 15-25°C, add LiOH aqueous solution dropwise under stirring, then keep stirring at 15-25°C for 16 hours, concentrate ethanol under reduced pressure, add methyl tert-butyl ether (MTBE) after concentration , remove the upper organic layer, add dichloromethane (DCM) to the water layer, use 1N hydrochloric acid HCl to adjust the pH value of the solution to 1-2, then stir for 10-20 minutes, remove the lower organic layer, and add to the water layer Dichloromethane (DCM) was added to the mixture, the lower organic layer was separated, the organic layers were combined, and dried with an appropriate amount of anhydrous sodium sulfate, then concentrated to dryness, and n-heptane was added for recrystallization to obtain yellow solids, namely (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid and (1S,3S,5S)-N-tert-butoxycarbonyl-2-aza Bicyclo[3,1,0]hexane-3-carboxylic acid.

The seventh step is specifically to combine the product (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid and (1S , 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid is mixed with trifluoroacetic acid according to the molar ratio of 1:1.0～1.5 and carried out under 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-carboxylic acid and (1S, 3S, 5S) -2-Azabicyclo[3,1,0]hexane-3-carboxylic acid.

The seventh step is further specifically to add the sixth step to obtain (1R, 3S, 5R)-N _- tert-butoxycarbonyl-2-azabicyclo[ 3,1,0]hexane-3-carboxylic acid and (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid, followed by adding di Chloromethane (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 h, saturated ammonium chloride solution was added, and concentrated under reduced pressure to obtain light yellow solids, namely (1R, 3S,5R)-2-Azabicyclo[3,1,0]hexane-3-carboxylic acid and (1S,3S,5S)-2-Azabicyclo[3,1,0]hexane-3-carboxylic acid .

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

Preferably, the S-proline is used as 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

Preparation of S-pyroglutamic acid ethyl ester

Under the protection of _N2 , add S-pyroglutamic acid (31g, 0.024mol) in a dry 500ml two-necked reaction flask and dissolve it in 250ml of absolute ethanol. Sulfoxide (SOCl ₂ ) (32.0 g, 0.0265 mol) was added dropwise for 2 h, stirred for 0.5 h after the dropwise addition, and the solvent was concentrated under reduced pressure to obtain a colorless oil. Add 100ml of toluene to concentrate under reduced pressure to remove the residual SOCl ₂ , then add 200ml of triethylamine to adjust the pH of the system to 8, concentrate under reduced pressure, and recrystallize with n-heptane to obtain a white solid 2, which is S-pyroglutamic acid ethyl ester , 35.1g, yield 98.1%.

The nuclear magnetic spectrum data of S-pyroglutamic acid ethyl ester is:

¹ H NMR (400MHz, CDCl ₃ ): δ=7.04(br, 1H), 4.10-4.22(m, 3H), 2.22-2.48(m, 3H), 2.07-2.22(m, 1H), 1.22(t, 3H, J=7.1Hz);

¹³ C NMR (400 MHz, CDCl ₃ ): δ=178.4, 172.1, 61.6, 55.6, 29.3, 24.8, 14.1.

Example 2

Preparation of Boc-S-pyroglutamic acid ethyl ester

_N Under protection, add S-pyroglutamic acid ethyl ester (34.6g, 0.22mol) in dry 500ml two-necked reaction flask and be dissolved in 250ml toluene, add dipropylene glycol methyl ether acetate DMAP (13.45g) and stir, maintain Add a toluene solution system of di-tert-butyl dicarbonate ((Boc) ₂ O) (72.6g, 0.33mol) dropwise at 15°C for 1 hour, stir for 3 hours after the dropwise addition, and concentrate the solvent under reduced pressure to obtain a colorless oil Add 100ml of toluene, adjust PH=8 with 200ml of triethylamine, concentrate under reduced pressure, and recrystallize with n-heptane to obtain white solid 3, namely 49.1g of Boc-S-ethyl pyroglutamate, with a yield of 86.5%. ee%99.9%.

Example 3

Preparation of (S)-1-N-tert-butoxycarbonyl-2-hydroxy-2-pyrrolecarboxylic acid ethyl ester

Under the protection of _N2 , in a dry 250ml two-necked reaction flask, add Boc-S-ethyl pyroglutamate (45.0g, 0.175mol) dissolved in 260ml tetrahydrofuran (THF), and add dropwise at a temperature of -65°C The THF solution (185ml, 1.4M) obtained by dissolving diisobutylaluminum hydride DIBAL-H in THF was stirred for 1.5h after the dropwise addition, and the solvent was concentrated under reduced pressure to obtain a colorless oil, then 100ml of toluene was added, and three Adjust PH=8 with 200ml of ethylamine, concentrate under reduced pressure, and recrystallize from n-heptane to obtain white solid 4, namely (S)-1-N-tert-butoxycarbonyl-2-hydroxy-2-pyrrolecarboxylic acid ethyl ester 40.5g, Yield 89.5%, ee% 99.3%.

(S)-1-N-tert-butoxycarbonyl-2-hydroxyl-2-pyrrolecarboxylate ethyl NMR data are as follows:

¹ H NMR (400MHz, CDCl ₃ ): δ6.73-6.44(m, 1H), 4.93(d, J=19.1Hz, 1H), 4.73-4.49(m, 1H), 4.36-4.09(m, 2H) , 3.19-2.94(m, 2H), 2.77-2.54(m, 2H), 1.57-1.37(m, 9H), 1.37-1.18(m, 3H).

¹³ C NMR (400 MHz, CDCl ₃ ): δ 14.0, 26.9, 27.8, 32.2, 59.0, 60.9, 80.6, 82.1, 153.1, 172.8.

Example 4

Preparation of (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid ethyl ester

Under _N2 protection, (S)-1-N-tert-butoxycarbonyl-2-hydroxy-2-pyrrolecarboxylic acid ethyl ester (40.5g, 0.157mol) was added to a dry 250ml two-necked reaction flask and dissolved in 540ml THF, -60°C, dropwise add N,N-diisopropylethylamine (0.157mol), then keep stirring for 1 hour, at -60°C, add dropwise trifluoroacetic anhydride (TFAA) (12ml0.204mol), then keep stirring for 1 hour hour, warmed up to -10°C, stirred for 2 hours, added 35% potassium sodium tartrate aqueous solution, dried the organic layer with an appropriate amount of anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light yellow oil 5, namely (S)-1-N- 34.1 g of ethyl tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylate, yield 90%, ee% 98.7%.

The nuclear magnetic spectrum data of (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid ethyl ester is:

¹ H NMR (400MHz, CDCl ₃ ): δ6.53-6.65(m, 1H), 4.96-4.91(m, 1H), 4.67-4.55(m, 1H), 4.24-4.17(m, 2H), 3.13- 3.01(m, 1H), 2.71-2.61(m, 1H), 1.74-1.49(m, 9H), 1.31-1.26(m, 3H);

¹³ C NMR (400 MHz, CDCl ₃ ): δ 13.9, 27.9, 33.4, 58.2, 60.9, 80.6, 104.8, 129.8, 151.2, 171.4.

Example 5

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

Under the protection of _N2 , in a dry 250ml two-necked reaction flask, add (S)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylic acid ethyl ester (34.0g, 0.13mol) in In 200ml of dichloromethane (DCM), cooled to -15°C, diethylzinc (Et ₂ Zn) (1.2eq, 0.17mol) was added dropwise, stirred for 0.5h after the addition was completed, and chloroiodomethane (CH ₂ ClI) (1.1eq, 0.15mol) in DCM, kept at -15°C and stirred for 24h, after the reaction was completed, the reaction was quenched by adding an aqueous solution of ethylenediaminetetraacetic acid (EDTA) with a mass percent concentration of 13%, and the temperature was raised to 25 ℃, stirred for 2 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. Elute with ethyl acetate (EA)/n-heptane (h-heptane) = 1/20 eluent. After elution is complete, collect until the product point is basically completed. Pale yellow oil 6, namely (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester 19.4g, light yellow oil 7 , namely (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate 1.03g, the total yield of compound 6 and compound 7 was 80 %, the molar ratio of Compound 6/Compound 7>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 method of the present invention is used to enantiomerically Constructive selectivity is stronger.

(1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate ethyl 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.

(1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate ethyl 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.

Figure 1 shows compound 6: (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and compound 7: (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 6, 23.08 The peak reacted substance was compound 7.

Example 6

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

Add (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester (26.2g, 0.10mol) and no Water ethanol, control the temperature at 20°C, add anhydrous (1.5eq0.15mol) lithium hydroxide (LiOH) aqueous solution dropwise under stirring, then keep stirring at 20°C for about 16 hours, concentrate the ethanol under reduced pressure, and add methyl tert-butyl ether (MTBE), divide the upper organic layer, add dichloromethane (DCM) to the water layer, adjust the pH value of the solution to 1.5 with 1N HCl, then stir for 20 minutes, divide the lower organic layer, and add to the water layer Then add DCM, 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 add n-heptane to obtain a yellow solid 8, namely (1S, 3S, 5S)-N-tert Butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid 18.6g, yield 87%.

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

¹ H NMR (300 MHz, CDCl ₃ ): δ=4.37-4.22 (m, 1H), 3.57-3.39 (m, 2H), 2.70-1.89 (m, 4H), 1.48-1.40 (m, 9H).

Example 7

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

Add (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester (0.13g, 0.0005mol) and no Water ethanol, control the temperature at 20°C, add anhydrous (1.5eq0.00075mol) lithium hydroxide (LiOH) aqueous solution dropwise under stirring, then keep stirring at 20°C for about 16 hours, concentrate ethanol under reduced pressure, add methyl tert-butyl ether (MTBE), divide the upper organic layer, add dichloromethane (DCM) to the water layer, adjust the pH value of the solution to 1.5 with 1N HCl, then stir for 20 minutes, divide the lower organic layer, and add to the water layer Then add DCM, 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 add n-heptane to obtain a yellow solid 10, namely (1R, 3S, 5R)-N-tert Butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid 0.09g, yield 86%.

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

¹ H NMR (300 MHz, CDCl ₃ ): δ=4.37-4.22 (m, 1H), 3.57-3.39 (m, 2H), 2.70-1.89 (m, 4H), 1.48-1.40 (m, 9H).

Example 8

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

Under the protection of _N2 , (1S, 3S, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid (10g , 0.044mol) was dissolved in 200ml DCM, at 5°C, trifluoroacetic acid (TFA) (1.2eq, 0.088mol) was added dropwise, stirred and reacted for 3h after the dropwise addition, saturated ammonium chloride solution was added, concentrated under reduced pressure, light yellow Solid 9, namely (1S,3S,5S)-2-azabicyclo[3,1,0]hexane-3-carboxylic acid 5.06g, yield 79%.

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

¹ H NMR (400MHz, D ₂ O): δ=3.96(t, J=8.8Hz, 1H), 3.33(dt, J=3.2, 1.6Hz, 1H), 2.73(m, 1H), 2.50(m, 1H), 2.30-2.10(m, 1H), 2.10-1.90(m, 1H), 0.4-1.2(m, 2H);

¹³ C NMR (100MHz, D ₂ O): δ=173.5, 64.4, 59.3, 42.5, 34.3, 29.2.

Example 9

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

Under the protection of _N2 , (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid (0.1 g, 0.00044mol) was dissolved in 200ml of DCM, at 5°C, trifluoroacetic acid (TFA) (1.2eq, 0.00088mol) was added dropwise, stirred and reacted for 3h after the dropwise addition, saturated ammonium chloride solution was added, concentrated under reduced pressure, light Yellow solid 11, namely (1R,3S,5R)-2-azabicyclo[3,1,0]hexane-3-carboxylic acid 0.08g, yield 81%.

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

¹ H NMR (400MHz, D ₂ O): δ=3.96(t, J=8.8Hz, 1H), 3.33(dt, J=3.2, 1.6Hz, 1H), 2.73(m, 1H), 2.50(m, 1H), 2.30-2.10(m, 1H), 2.10-1.90(m, 1H), 0.4-1.2(m, 2H);

¹³ C NMR (100MHz, D ₂ O): δ=173.5, 64.4, 59.3, 42.5, 34.3, 29.2.

Example 10

The compound (1S, 3S, 5S)-2-azabicyclo[3,1,0]hexane-3-carboxylic acid prepared by Example 8 is used as a catalyst to catalyze the asymmetric Michael addition reaction, its reaction formula and conditions Filter see below:

Add dichloromethane (1ml), catalyst (1S, 3S, 5S)-2-azabicyclo[3,1,0]hexane-3-carboxylic acid (0.01mmol) successively in a 3ml reaction flask at 0°C, N,N-Diisopropylethylamine DIPEA (1.75 μL, 0.01 mmol) and n-butyraldehyde (0.2 mmol). 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 42.43 mg of the catalytic product, the yield was 96%, and the ee value was 91%. ¹ H 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 11

Divided by the compound (1R, 3S, 5R)-2-azabicyclo[3,1,0]hexane-3-carboxylic acid prepared in Example 9 to replace the compound (1S, 3S, 5S)-2-nitrogen in Example 10 Except for heterobicyclo[3,1,0]hexane-3-carboxylic acid, the other steps were the same as in Example 10, and dichloromethane with the best effect was used to catalyze the asymmetric Michael addition reaction at 20°C to obtain 41.99 mg of the product, Yield 95%, ee 73%.

Example 12

Except that -20°C is used as the reaction condition of Example 12 instead of 20°C in Example 11, the other steps are the same as in Example 10, which is used to catalyze the asymmetric Michael addition reaction to obtain 41.90 mg of the product, with a yield of 96%, ee The value is 95%.

Comparative example 1

Except that S-proline is used as the reaction condition of Comparative Example 1 to replace the catalyst in Example 12, the other steps are the same as in Example 10, and are 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 11 0 96% 91% Example 12 20 95% 73% Example 13 -20 96% 95% 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 (9)

1. a kind of synthetic method with the S-proline of cyclopropane structure, is characterized in that, step comprises: In the first step, S-pyroglutamic acid undergoes an esterification reaction; In the second step, the reaction product obtained in the first step is subjected to an amino protection reaction; In the third step, the reaction product obtained in the second step is subjected to a reduction reaction; In the fourth step, the reaction product obtained in the third step is subjected to a hydroxyl elimination reaction; In the fifth step, the reaction product obtained in the fourth step is subjected to a Simmons-Smith cyclopropane reaction to obtain enantiomers; In the sixth step, the enantiomers obtained in the fifth step are subjected to ester hydrolysis respectively; In the seventh step, the reaction products obtained in the sixth step are respectively subjected to a deprotection reaction to obtain S-proline with a cyclopropane structure. 2. the synthetic method of the S-proline with cyclopropane structure as claimed in claim 1, is characterized in that: described the first step is specially with S-pyroglutamic acid and thionyl chloride according to molar ratio: Mix at a ratio of 1:1.1~2, and react for 2h~3h under the condition of keeping the reaction temperature at -10°C~-5°C to obtain ethyl S-pyroglutamate. 3. the synthetic method of the S-proline with cyclopropane structure as claimed in claim 1 or 2, is characterized in that: described second step is specially the S-pyroglutamic acid ethyl ester that the first step obtains Mix with the N-protecting reagent di-tert-butyl dicarbonate at a molar ratio of 1:1.5~2, maintain the reaction temperature at 10°C~15°C, and react for 3~4 hours to obtain Boc-S-ethyl pyroglutamate . 4. the synthetic method of the S-proline with cyclopropane structure as claimed in claim 1 to 3, is characterized in that: described the 3rd step is specifically the Boc-S- pyroglutamic acid that the 2nd step obtains The ethyl ester is reduced by diisobutylaluminum hydride (DIBAL-H), and the reaction molar ratio of the Boc-S-pyroglutamate ethyl ester to the diisobutylaluminum hydride is 1: 1.1～1.5, When the reaction temperature is maintained at -65～-60°C, react for 1～2 hours to obtain ethyl (S)-1-N-tert-butoxycarbonyl-2-hydroxy-2-pyrrolecarboxylate. 5. the synthetic method that has cyclopropane structure S-proline as claimed in claim 1 to 4, is characterized in that: described 4th step is specifically the (S)-1-N-tertiary that the 3rd step obtains Butoxycarbonyl-2-hydroxy-2-pyrrolecarboxylate ethyl ester Hydroxyl elimination reaction with trifluoroacetic anhydride (TFAA), (S)-1-N-tert-butoxycarbonyl-2-hydroxy-2-pyrrolecarboxylate ethyl ester The molar ratio of the reaction with trifluoroacetic anhydride is 1:1.0~1.3, and the reaction temperature is maintained at -15~-10°C for 1~2h to obtain (S)-1-N-tert-butoxycarbonyl-2,3-di Hydrogen-2-pyrrolecarboxylate ethyl ester. 6. as claimed in claim 1 to 5, have cyclopropane structure S---the synthetic method of proline, it is characterized in that: described the 5th step is specially (S)-1-N- that the 4th step obtains tert-butoxycarbonyl-2,3-dihydro-2-pyrrole carboxylic acid ethyl ester is mixed with diethyl zinc (ZnEt ₂ ) and chloroiodomethane (CH ₂ ClI) 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 a reaction temperature of -20 to -15°C, reacted for 22 to 24 hours to obtain enantiomeric Constructs (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate and (1S,3S,5S)-N-tert-butyl Oxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate, the obtained enantiomeric mixture is treated with ethylenediaminetetraacetic acid aqueous solution and amine aqueous solution to improve the ratio of the two Enantioselectivity, the amine is any one of ethylamine, diethylamine, triethylamine, propylamine, isopropylamine and tert-butylamine aqueous solution, the product (1S, 3S, 5S)-N-tert-butoxycarbonyl-2- Ethyl azabicyclo[3,1,0]hexane-3-carboxylate and (1R,3S,5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3 - The molar ratio of ethyl formate> 20:1, followed by chromatographic column separation using a mixed eluent with a volume ratio of ethyl acetate/n-heptane=1/20 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. 7. the synthetic method with cyclopropane structure S-proline as claimed in claim 1 to 6, is characterized in that: described the 6th step is specially the product (1R, 3S, 5R) that the 5th step obtains- 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 is mixed with lithium hydroxide (LiOH) according to the molar ratio of 1:1.0~1.5, and the hydrolysis reaction is carried out under alkaline conditions, and the temperature is maintained at 15~25°C After 14-18 hours of reaction, (1R, 3S, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid and (1S,3S,5S)- N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid. 8. The synthetic method with cyclopropane structure S-proline as claimed in claims 1 to 7, characterized in that: the seventh step is specifically the product (1R, 3S, 5R) obtained in the sixth step- N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid and (1S,3S,5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1 , 0] Hexane-3-carboxylic acid is mixed with trifluoroacetic acid according to the molar ratio of 1: 1.0～1.5 to carry out the amide hydrolysis reaction under acidic conditions, and then keep the temperature at 5°C for 2～4h to obtain respectively (1R, 3S, 5R )-2-azabicyclo[3,1,0]hexane-3-carboxylic acid and (1S,3S,5S)-2-azabicyclo[3,1,0]hexane-3-carboxylic acid. 9. the application of the S-proline of the cyclopropane structure prepared by the synthetic method of the S-proline with the cyclopropane structure described in claims 1 to 8 as a catalyst.