Chiral barbital spiro tetrahydroquinoline compound and preparation method thereof

A barbiturate and tetrahydroquinoline technology, which is applied in the field of compound preparation, can solve the problems of narrow applicable substrate range, high equipment and technical requirements, and achieves wide substrate range, enantioselectivity and diastereomeric effects. Excellent selectivity and mild reaction conditions

Active Publication Date: 2018-08-24
BEIJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It has high requirements on instruments and techniques, and has a narrow range of applicable substrates

Method used

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  • Chiral barbital spiro tetrahydroquinoline compound and preparation method thereof
  • Chiral barbital spiro tetrahydroquinoline compound and preparation method thereof
  • Chiral barbital spiro tetrahydroquinoline compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032]

[0033] Weigh 1a (32.9mg, 0.1mmol), 2a (24.4mg, 0.1mmol), palladium catalyst (5.2mg, 0.005mmol) and chiral ligand L1 (7.2mg, 0.02mmol) dissolved in 1mL of dichloromethane, Stir at room temperature for 3 hours (use TLC to detect the reaction). After the reaction is complete, the crude product can be subjected to column chromatography (eluent is ethyl acetate / petroleum ether=1 / 5~1 / 6) to obtain the target product 3aa (40mg), the yield was 76%.

[0034] Characterization and analysis of the target object: white solid, dr>99:1; ee=96%; [α] 1 D 8 :160 (c=0.10, CHCl 3 ), 1 H NMR (400MHz, CDCl 3 ):δ8.01(d,J=7.6Hz,1H),7.52–7.47(m,3H),7.29–7.24(m,5H),7.21–7.18(m,3H),6.89(d,J=7.6 Hz,1H),6.31(s,1H),5.46–5.36(m,1H),5.22(dd,J=10.0,1.2Hz,1H),4.80(d,J=16.4Hz,1H),3.32(s ,3H),2.80(d,J=10.0Hz,1H),2.64(s,3H),2.42(s,3H)ppm; HRMS(ESI)m / z: C 29 h 28 N 3 o 5 S[M+H] + The theoretically calculated value is 530.1744, and the measured value is 530.1751.

Embodiment 2

[0036]

[0037] Weigh 1b (40.8mg, 0.1mmol), 2a (24.4mg, 0.1mmol), palladium catalyst (5.2mg, 0.005mmol) and chiral ligand L1 (7.2mg, 0.02mmol) dissolved in 1mL of dichloromethane, Stir at room temperature for 3 hours (use TLC to detect the reaction), after the reaction is complete, the crude product can be obtained through column chromatography (eluent is ethyl acetate / petroleum ether=1 / 5~1 / 6) to obtain the target product 3ba (40mg), the yield was 66%.

[0038] Characterization and analysis of the target object: white solid, dr>99:1; ee=58%; [α] 1 D 8 :94 (c=0.10, CHCl 3 ), 1 H NMR (400MHz, CDCl 3 ): δ7.87(d, J=8.8Hz, 1H), 7.60(dd, J=8.4, 1.6Hz, 1H), 7.54(d, J=8.0Hz, 2H), 7.30–7.21(m, 5H) ,7.14(d,J=6.8Hz,2H),7.02(s,1H),6.22(s,1H),5.40–5.31(m,1H),5.26(dd,J=10.0,1.2Hz1H),4.85– 4.80(m,1H),3.32(s,3H),2.81(d,J=9.6Hz,1H),2.64(s,3H),2.44(s,3H)ppm; HRMS(ESI)m / z: C 29 h 27 BrN 3 o 5 S[M+H] + The theoretical calculation value is 608.0849, and the measured value is 608.083...

Embodiment 3

[0040]

[0041]Weigh 1c (36.3mg, 0.1mmol), 2a (24.4mg, 0.1mmol), palladium catalyst (5.2mg, 0.005mmol) and chiral ligand L1 (7.2mg, 0.02mmol) dissolved in 1mL of dichloromethane, Stir at room temperature for 5 hours (use TLC to detect the reaction). After the reaction is complete, the crude product can be obtained by column chromatography (eluent is ethyl acetate / petroleum ether=1 / 5~1 / 6) to obtain the target product 3ca (37mg), the yield was 66%.

[0042] Characterization and analysis of the target object: white solid, dr>99:1; ee=66%; [α] 1 D 8 :84 (c=0.10, CHCl 3 ), 1 H NMR (400MHz, CDCl 3 ): δ7.93(d, J=8.4Hz, 1H), 7.53(d, J=8.0Hz, 2H), 7.45(d, J=7.2Hz, 1H), 7.30–7.21(m, 5H), 7.14 (d, J=6.8Hz, 2H), 6.87(s, 1H), 6.23(s, 1H), 5.40–5.31(m, 1H), 5.26(d, J=9.6Hz, 1H), 4.82(d, J =16.4Hz1H),3.32(s,3H),2.78(d,J=9.6Hz,1H),2.64(s,3H),2.44(s,3H)ppm; HRMS(ESI)m / z: C 29 h 27 ClN 3 o 5 S[M+H] + The theoretical calculation value is 564.1354, and the measured value is 564.134...

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Abstract

Belonging to the technical field of compound preparation, the invention relates to a chiral barbital spiro tetrahydroquinoline compound and a preparation method thereof. The method specifically includes: taking a vinyl benzoxazinone compound and a barbital olefin compound as the reactants, also adding a metal palladium catalyst and a phosphorus-containing chiral ligand, and carrying out reaction at room temperature to obtain the product. The preparation method has the advantages of mild reaction conditions, fast reaction speed, simple post-treatment, and wide range of applicable substrates, and also most of the synthesized target compounds have high yield, excellent enantioselectivity and non-enantioselectivity. The method is a brand new method for efficient synthesis of chiral barbital spiro tetrahydroquinoline compound with potential medicinal value.

Description

technical field [0001] The invention relates to a chiral barbiturate spirotetrahydroquinoline compound and a preparation method, belonging to the technical field of compound preparation. Background technique [0002] Barbiturate spirotetrahydroquinoline compounds are a class of nitrogen-containing heterocycles with complex structures. According to literature reports, many medicinal compounds contain their structural fragments, which have antibacterial and antitumor activities, and play important roles in biology and medicine. . Tetrahydroquinoline compounds can be used to treat and prevent various diseases. Many biologically active natural products and drug molecules contain tetrahydroquinoline skeleton structures. Barbiturates are general CNS depressants. The barbiturate spirotetrahydroquinoline compound contains barbiturate and tetrahydroquinoline structural units, and is of great significance as a fragment of a medicinal compound. [0003] In the past few years, most ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/10A61P31/00A61P35/00
CPCA61P31/00A61P35/00C07B2200/07C07D471/10
Inventor 赵洪武冯宁宁杜娟郭家明丁晚秋王立茹
Owner BEIJING UNIV OF TECH
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