Preparation method for N, O-disubstituted ketimine derivative

A technology of ketimine and derivatives, applied in the field of preparation of ketimine derivatives, to achieve the effect of increasing yield and ee value and wide application range

Active Publication Date: 2015-10-07
杭州乐敦科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The purpose behind this new method was improving the efficiency or effectiveness of an enzymatic process called asymmetry-addition reactions (AARs). By adding certain chemical compounds like sulfur donors onto other molecules containing atoms at different positions on their own structure instead of directly mixing them together they can create more complex structures than before. This results in better yields and increased activity compared to previous methods where all reactants were mixed up separately.

Problems solved by technology

The technical problem addressed by this patented method relates to how to make certain types of chemical structures that contain both nitrogen atoms at one location (N) within their own framework or other parts of these same chemistry. This can be done through direct reaction between specific substances called enzyme substrate(s).

Method used

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  • Preparation method for N, O-disubstituted ketimine derivative
  • Preparation method for N, O-disubstituted ketimine derivative
  • Preparation method for N, O-disubstituted ketimine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add N-substituted ketimine (R 1 = Me,R 2 =H, 0.1mmol), catalyst (Ⅲ-1, 10%mmol) and solvent (diethyl ether, 1mL), magnetically stirred at 0°C, added the corresponding alcohol (benzyl alcohol, 0.11mmol) once and stirred for 17 hours, and The reaction solution was concentrated and purified by column to obtain 36.4 mg of the corresponding N,O-disubstituted ketimine derivative with a yield of 94%. The ee value of the product detected by HPLC chiral column was 92%. The characterization data of the product are as follows:

[0031] [α] D 20 =+22 (c=1.0, CHCl 3 ); 1 H NMR (300MHz, CDCl 3 )δ7.80(d, J=7.2Hz, 1H), 7.37(td, J=7.8, 1.2Hz, 1H), 7.29-7.23(m, 5H), 7.13(td, J=11.0, 0.6Hz, 1H ),6.84(d,J=7.5Hz,1H),5.63(s,1H),4.51(dd,J=17.4,11.1Hz,2H),3.20(s,1H),1.34(s,9H) 13 C NMR (75MHz, CDCl 3 )δ172.1, 153.2, 143.7, 137.1, 130.6, 128.3, 127.9, 127.8, 126.3, 126.0, 123.3, 108.5, 84.3, 80.6, 66.1, 28.1, 26.3. HRMS (ESI) m / z calcd for C 21 h 24 N 2 NaO 4 [M+Na] + :391.1628, fou

Embodiment 2

[0033] Add N-substituted ketimine (R 1 =Et,R 2 =H, 0.1mmol), catalyst (Ⅲ-1, 10%mmol) and solvent (diethyl ether, 1mL), magnetically stirred at 0°C, added the corresponding alcohol (benzyl alcohol, 0.11mmol) once and stirred for 17 hours, and The reaction solution was concentrated and purified by column to obtain 35.1 mg of the corresponding N,O-disubstituted ketimine derivative with a yield of 92%. The ee value of the product detected by HPLC chiral column was 91%. The characterization data of the product are as follows:

[0034] [α] D 20 =+10 (c=1.0, CHCl 3 ); 1 H NMR (300MHz, CDCl 3 )δ7.85(d,J=7.2Hz,1H),7.39-7.36(m,1H),7.34-7.23(m,5H),7.12(t,J=7.5Hz,1H),6.87(d,J =7.8Hz,1H),5.64(s,1H),4.51(dd,J=16.8,11.1Hz,2H),3.87-3.64(m,2H),1.35(s,9H),1.28(t,J= 7.2Hz, 3H) 13 C NMR (75MHz, CDCl 3 )δ171.7, 153.3, 142.7, 137.2, 130.5, 128.3, 127.9, 127.8, 126.8, 126.2, 123.1, 108.6, 84.2, 80.6, 66.0, 34.9, 28.1, 12.6. HRMS (ESI) m / z calcd for C 22 h 27 N 2 o 4 [M+H] + :383.1965,f

Embodiment 3

[0036] Add N-substituted ketimine (R 1 = MOM,R 2 =H, 0.1mmol), catalyst (Ⅲ-1, 10%mmol) and solvent (diethyl ether, 1mL), magnetically stirred at 0°C, added the corresponding alcohol (benzyl alcohol, 0.11mmol) once and stirred for 17 hours, and The reaction solution was concentrated and purified by column to obtain 35.8 mg of the corresponding N,O-disubstituted ketimine derivative with a yield of 90%. The ee value of the product detected by HPLC chiral column was 89%. The characterization data of the product are as follows:

[0037] [α] D 20 =+11 (c=1.0, CHCl 3 ). 1 H NMR (300MHz, CDCl 3 )δ7.73(d,J=7.2Hz,1H),7.41–7.35(m,2H),7.32–7.23(m,4H),7.18–7.13(m,1H),7.06(d,J=7.8Hz ,1H),5.66(s,1H),5.11(dd,J=13.5,11.1,Hz,2H),4.49(dd,J=18.0,10.8Hz,2H),3.36(s,3H),1.34(s ,9H) 13 C NMR (75MHz, CDCl 3)δ172.8, 153.1, 142.2, 136.9, 130.8, 128.6, 128.3, 127.9, 127.0, 126.0, 125.5, 123.7, 110.0, 84.8, 80.8, 71.7, 66.2, 56.5, 28.1. HRMS (ESI) m / z calcd for C 22 h 26 N 2 NaO 5 [M+Na] + :

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Abstract

The invention discloses a preparation method for an N, O-disubstituted ketimine derivative. The preparation method comprises the following steps: under the action of a chiral thiourea catalyst, enabling N-substituted ketimine and alcohol to generate an asymmetric addition reaction; and after the reaction is completed, carrying out post-treating to obtain the N, O-disubstituted ketimine derivative. According to the preparation method, the special chiral thiourea catalyst is adopted as a catalyst for the asymmetric addition reaction, so that the efficiency and the ee value of the reaction are improved, and the scope of application of a substrate is wide.

Description

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Claims

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Application Information

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Owner 杭州乐敦科技有限公司
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