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R-diphenyl prolinol chiral organic small molecule compound with cyclopropane structure and synthesis method of R-diphenyl prolinol chiral organic small molecule compound

A technology for diphenylprolinol and small molecular compounds, applied in the field of compound preparation, can solve problems such as poor enantioselectivity and diastereoselectivity, and achieve the effects of simple operation, high catalytic activity and strong structural selectivity

Inactive Publication Date: 2013-12-18
JIAXING UNIV
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  • Claims
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Problems solved by technology

[0011] The object of the present invention is to aim at the deficiencies in the prior art, provide a kind of novel chiral organic small molecular compound with cyclopropane structure R-diphenylprolinol, its process is reasonable, easy to operate, low in cost, 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 with cyclopropane structure R-diphenylprolinol, which has cyclopropane structure R-diphenylprolinol 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

Method used

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  • R-diphenyl prolinol chiral organic small molecule compound with cyclopropane structure and synthesis method of R-diphenyl prolinol chiral organic small molecule compound
  • R-diphenyl prolinol chiral organic small molecule compound with cyclopropane structure and synthesis method of R-diphenyl prolinol chiral organic small molecule compound
  • R-diphenyl prolinol chiral organic small molecule compound with cyclopropane structure and synthesis method of R-diphenyl prolinol chiral organic small molecule compound

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Experimental program
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Effect test

Embodiment 1

[0051] (1S, 3R, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-ethyl carboxylate 1 and (1R, 3R, 5R)-N-tert-butoxy Preparation of ethyl carbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate 2

[0052] in N 2 Under protection, add ethyl (R)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrolecarboxylate (manufactured by Shanghai Aladdin Reagent Co., Ltd., CAS No.: 72925-16-7) (24.1g, 0.1mol) was dissolved in 200ml of dichloromethane (DCM), cooled to -15°C, diethylzinc (Et 2 Zn) (1.2eq, 0.12mol), stirred for 0.5h after the dropwise addition, added dropwise chloroiodomethane (CH 2 ClI) (1.1eq, 0.11mol) in dichloromethane (DCM) solution, maintain the temperature at -15 ° C and stir for 24h, after the reaction is completed, it is 13% ethylenediaminetetraacetic acid (EDTA) aqueous solution to quench Extinguish the reaction, heat up to 25°C, stir for 2 hours, let stand for 20 minutes, extract, combine the organic phases to obtain a yellow oil, add a 30% aqueous solution of diethylamine ...

Embodiment 2

[0061] Preparation of (1S, 3R, 5S)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol 3

[0062] In a 100mL two-necked flask, magnesium (3g, 120mmol) and a catalytic amount of iodine were added, under N 2 Slowly add the ether solution of bromobenzene (240mmol) dropwise under protection. When the reaction is initiated, keep the reaction temperature at 75°C, and the system will boil slightly. )-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylic acid ethyl ester 1 (14.02g, 55mmol) in ether solution (200mL), reflux, TLC confirmed that the raw material was completely After the reaction, add saturated NH 4 Quench the reaction with aqueous Cl solution, extract with diethyl ether (50mL×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, column chromatography ethyl acetate / petroleum ether is 3 / 5, the white solid 3 was obtained, name...

Embodiment 3

[0067] Preparation of (1R, 3R, 5R)-N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-diphenylmethanol 3

[0068] Add magnesium (1.5g, 60mmol) and catalytic amount of iodine in a 100mL two-necked flask, 2 Slowly add the ether solution of bromobenzene (120mmol) dropwise under protection. When the reaction is initiated, keep the reaction temperature at 75°C, and the system will boil slightly. After the dropwise addition, reflux for 2h, and add the newly prepared Grignard reagent dropwise to (1R3R, 5R)- Ethyl N-tert-butoxycarbonyl-2-azabicyclo[3,1,0]hexane-3-carboxylate 1 (7.01g, 25.75mmol) in ether solution (100mL), reflux, TLC confirmed the complete reaction of raw materials After adding saturated NH 4 Quench the reaction with aqueous Cl solution, extract with diethyl ether (50mL×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, column chromatography...

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Abstract

The invention provides a synthesis method of R-diphenyl prolinol with a cyclopropane structure. The method comprises the following steps of: step 1, performing a Simmons-Smith cyclopropane reaction on (R)-1-N-tert-butoxycarbonyl-2,3-dihydro-2-pyrrole ethyl formate; step 2, respectively performing grignard reactions on enantiomers obtained by the step 1; and step 3, respectively performing amino-protection removing actions on reaction products obtained by the step 2, thereby obtaining the R-diphenyl prolinol with the cyclopropane structure. The method is reasonable in process, simple to operate and low in cost, and can be used for obtaining the enantiomer products with optical purity while chiral preparation and separation are not required further. Thus, the method is ideal for synthesis of the R-diphenyl prolinol with the cyclopropane structure.

Description

technical field [0001] The invention relates to the technical field of compound preparation, in particular to a novel R-diphenylprolinol with a cyclopropane structure and a preparation method thereof. Background technique [0002] 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. [0003] In 1987, Corey et al. first applied...

Claims

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Application Information

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IPC IPC(8): C07D209/52B01J31/02C07B37/02C07B53/00C07C201/12C07C205/44
Inventor 谢景力余焓张俊勇
Owner JIAXING UNIV
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