A class of chiral amine compounds derived from tertiary leucine and its preparation method and application

Abstract

The invention discloses a chiral amine compound derived from tert-leucine and its preparation method and application. The chiral amine compound contains a tert-butyl group, a primary amine, a secondary amine or a tertiary amine functional group, Its structural formula is:; the chiral amine and its salt use widely existing chiral tertiary leucine as a raw material, and the chiral amine compound is obtained through simple preparation steps; the chiral amine or salt of the present invention can be used for α, β -Asymmetric Michael addition reaction of unsaturated ketones with nitromethane, malonate, substituted oxazolone and other nucleophiles, which can be used for α, β-unsaturated ketones and 5-unsaturated rhodanine, 5-unsaturated Asymmetric tandem reaction of saturated hydantoin and α, β-unsaturated ketones; it has high catalytic activity and stereoselectivity, with anisotropic selectivity up to 30 / 1 and enantioselectivity up to 99%. The reaction substrate wide range.

Description

Technical field

[0001] The present invention involves a new type of handamine compound derived from Uncle Liangine, and involves the preparation method and new application of the handicide compounds. Background technique

[0002] The simple synthetic method, high catalytic efficiency, and the ability to achieve asymmetric catalysis capabilities in large scale are the goals that organic chemical researchers are always pursuing, and apply organic catalysts to the structural unit of drug molecules, biological active molecules or natural products.It is an important content in the field of organic catalytic research.

[0003] In the past ten years, the main content of the success of organic catalytic research is the general model of discovering and confirming the activation of catalyst activation substrates.The general activation model describes the type of reaction and can selectively participate in a variety of types of chemical reactions with stable high -screening.Such a chemical ...

Examples

preparation Embodiment 1

[0047] The preparation of a chiral amine compound derived from tert-leucine comprises the following steps:

[0048] (1) Dissolve 0.68g (8.0 mmol) of piperidine in 40 mL of anhydrous acetonitrile, and add 2.27 g (8.0 mmol) of ( S )-N-p-nitrobenzenesulfonyl-1-tert-butyl-cycloethyleneimine in 40ml of acetonitrile solution, stirred at 20°C for 36 hours, TLC detected that the reaction was complete; the mixture was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum Ether and ethyl acetate, their volume ratio = 3:1) were separated to obtain 2.80 g of white solid, and the yield was 95%.

[0049] (2) Dissolve 1.85g (5.0mmol) of the white solid obtained in step (1) in 30mL DMF, add potassium carbonate (2.07g, 15.0mmol molar concentration), thioglycolic acid (0.92g, 10.0mmol), and mix at 50°C The mixture was stirred for 12 hours, and TLC detected that the reaction was complete; the mixture was added with 100 mL of ethyl acetate, wa...

preparation Embodiment 2

[0055] The difference between Preparation Example 2 and Preparation Example 1 is that the amine used in step (1) is N-Ts protected 1,2-diphenylethylenediamine, the temperature used is 100°C, and the amine used in step (2) The temperature is 80°C, other preparations and conditions are the same as in Example 1, the final product is a white solid chiral primary amine product, and the product configuration is R , R , S ; 1 for hydrogen, R 2 It is 1,2-diphenylethylamine protected by N-Ts, and its structural formula is as follows:

[0056] .

[0057] Melting point 120-121°C; 1 HNMR (400MHz, CDCl 3 ):d7.41-7.39(m,2H),7.16-7.15(m,3H),7.06-7.03(m,5H),6.96-6.94(m,4H),4.33(d, J =8.0Hz,1H),3.64(d, J =8.8Hz,1H),2.66(dd, J =11.0,2.5Hz,1H),2.52(d, J =12.3Hz,4H),2.35(s,3H),2.28(dd, J =12.3,2.8Hz,3H),0.94(9H,s). 13 CNMR (100MHz, CDCl 3 ):d142.7, 139.6, 138.4, 137.3, 129.1, 128.3, 127.9, 127.6, 127.5, 127.4, 127.2, 127.1, 68.5, 63.3, 54.5, 49.1, 45.1, 24.6, 23.4, 22.0, 21.4. HRM...

preparation Embodiment 3

[0059] The difference between Preparation Example 3 and Preparation Example 1 is that the amine used in step (1) is cyclohexylamino alcohol, the temperature used is 20°C, the temperature used in step (2) is 20°C, and other preparation steps and conditions are the same Preparation Example 1. The final product is a colorless oily chiral primary amine product, and the product configuration is R , R , S ; 1 for hydrogen, R 2 For o-hydroxycyclohexane, its structural formula is as follows:

[0060] .

[0061] 1 HNMR (400MHz, CDCl 3 ):δ3.40(m,1H),2.82(dd, J =2.4,8.8Hz,1H),2.40(dd, J =2.4,8.4Hz,1H),2.35(td, J =3.6,10.4Hz,1H),2.16(t, J =11.2Hz,1H),1.85(d, J =12.0Hz, 2H), 1.67-1.71(m, 2H), 1.55-1.59(m, 1H), 1.08-1.24(m, 4H), 0.85(s, 9H). 13 CNMR (100MHz, CDCl 3 ): δ60.4, 57.0, 48.5, 33.9, 33.6, 33.5, 26.2, 26.2, 25.1, 25.0. HRMS (ESI): Theory (M+H) + C 12 h 27 N 2 O215.2123, yielding m / z 215.2125.

Technical field

[0001] The present invention involves a new type of handamine compound derived from Uncle Liangine, and involves the preparation method and new application of the handicide compounds. Background technique

[0002] The simple synthetic method, high catalytic efficiency, and the ability to achieve asymmetric catalysis capabilities in large scale are the goals that organic chemical researchers are always pursuing, and apply organic catalysts to the structural unit of drug molecules, biological active molecules or natural products.It is an important content in the field of organic catalytic research.

[0003] In the past ten years, the main content of the success of organic catalytic research is the general model of discovering and confirming the activation of catalyst activation substrates.The general activation model describes the type of reaction and can selectively participate in a variety of types of chemical reactions with stable high -screening.Such a chemical ...

Examples

preparation Embodiment 1

[0047] The preparation of a chiral amine compound derived from tert-leucine comprises the following steps:

[0048] (1) Dissolve 0.68g (8.0 mmol) of piperidine in 40 mL of anhydrous acetonitrile, and add 2.27 g (8.0 mmol) of ( S )-N-p-nitrobenzenesulfonyl-1-tert-butyl-cycloethyleneimine in 40ml of acetonitrile solution, stirred at 20°C for 36 hours, TLC detected that the reaction was complete; the mixture was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column (petroleum Ether and ethyl acetate, their volume ratio = 3:1) were separated to obtain 2.80 g of white solid, and the yield was 95%.

[0049] (2) Dissolve 1.85g (5.0mmol) of the white solid obtained in step (1) in 30mL DMF, add potassium carbonate (2.07g, 15.0mmol molar concentration), thioglycolic acid (0.92g, 10.0mmol), and mix at 50°C The mixture was stirred for 12 hours, and TLC detected that the reaction was complete; the mixture was added with 100 mL of ethyl acetate, wa...

preparation Embodiment 2

[0055] The difference between Preparation Example 2 and Preparation Example 1 is that the amine used in step (1) is N-Ts protected 1,2-diphenylethylenediamine, the temperature used is 100°C, and the amine used in step (2) The temperature is 80°C, other preparations and conditions are the same as in Example 1, the final product is a white solid chiral primary amine product, and the product configuration is R , R , S ; 1 for hydrogen, R 2 It is 1,2-diphenylethylamine protected by N-Ts, and its structural formula is as follows:

[0056] .

[0057] Melting point 120-121°C; 1 HNMR (400MHz, CDCl 3 ):d7.41-7.39(m,2H),7.16-7.15(m,3H),7.06-7.03(m,5H),6.96-6.94(m,4H),4.33(d, J =8.0Hz,1H),3.64(d, J =8.8Hz,1H),2.66(dd, J =11.0,2.5Hz,1H),2.52(d, J =12.3Hz,4H),2.35(s,3H),2.28(dd, J =12.3,2.8Hz,3H),0.94(9H,s). 13 CNMR (100MHz, CDCl 3 ):d142.7, 139.6, 138.4, 137.3, 129.1, 128.3, 127.9, 127.6, 127.5, 127.4, 127.2, 127.1, 68.5, 63.3, 54.5, 49.1, 45.1, 24.6, 23.4, 22.0, 21.4. HRM...

preparation Embodiment 3

[0059] The difference between Preparation Example 3 and Preparation Example 1 is that the amine used in step (1) is cyclohexylamino alcohol, the temperature used is 20°C, the temperature used in step (2) is 20°C, and other preparation steps and conditions are the same Preparation Example 1. The final product is a colorless oily chiral primary amine product, and the product configuration is R , R , S ; 1 for hydrogen, R 2 For o-hydroxycyclohexane, its structural formula is as follows:

[0060] .

[0061] 1 HNMR (400MHz, CDCl 3 ):δ3.40(m,1H),2.82(dd, J =2.4,8.8Hz,1H),2.40(dd, J =2.4,8.4Hz,1H),2.35(td, J =3.6,10.4Hz,1H),2.16(t, J =11.2Hz,1H),1.85(d, J =12.0Hz, 2H), 1.67-1.71(m, 2H), 1.55-1.59(m, 1H), 1.08-1.24(m, 4H), 0.85(s, 9H). 13 CNMR (100MHz, CDCl 3 ): δ60.4, 57.0, 48.5, 33.9, 33.6, 33.5, 26.2, 26.2, 25.1, 25.0. HRMS (ESI): Theory (M+H) + C 12 h 27 N 2 O215.2123, yielding m / z 215.2125.

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