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Preparation method and application of chiral ugi's amine and its derivatives and optical isomers

A technology of optical isomers and derivatives, applied in organic chemistry methods, chemical instruments and methods, organic chemistry, etc., can solve problems such as lack of synthesis processes

Active Publication Date: 2020-05-22
SHANGHAI MAOSHENG KAIHUI TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In view of the wide use of chiral ferrocene compounds, but the lack of efficient synthesis process to prepare chiral Ugi's amines in large quantities, researchers hope to find a way to synthesize chiral Ugi's amines efficiently and cheaply without using chiral resolution, and then find Method for synthesizing chiral Josiphos-like ferrocene bisphosphine ligands with high efficiency and low cost

Method used

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  • Preparation method and application of chiral ugi's amine and its derivatives and optical isomers
  • Preparation method and application of chiral ugi's amine and its derivatives and optical isomers
  • Preparation method and application of chiral ugi's amine and its derivatives and optical isomers

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0126]

[0127] Weigh Va (100.0g, 438.4mmol), tetraisopropyl titanate [Ti(OiPr) 4 ] (263.0 mL, 876.9 mmol) and R-(+)-α-methylbenzylamine (113.1 mL, 876.9 mmol) were placed in a 2000 mL round bottom flask, and 500.0 mL of EtOH was added to dissolve it. After stirring and reacting for 14h, weigh the NaBH 4 (24.9g, 657.7mmol) was added to the reaction flask in batches, then stirred for another 2h, and the solvent was removed by rotary evaporation. Add 2400.0 mL of methyl tert-butyl ether (MTBE) to the residue to dissolve, then add 1200.0 mL of 2 N hydrochloric acid, stir for 2 h, filter to obtain a yellow solid, and use alkali to obtain 86.0 g of target compound IVa, yield: 58.9% , yellow solid. Mass Spectrometry MALDI-TOF-MS m / z:333(M + ).

[0128] 1 H-NMR (CDCl 3 / TMS,400MHz):δ(ppm)7.26-7.33(m,4H),7.19-7.23(m,1H),4.09(br.s.,1H),4.05(d,J=6.8Hz,2H), 4.01(s,5H),3.95(s,1H),3.72-3.79(m,1H),3.26(q,J=6.4Hz,1H),1.33(d,J=6.3Hz,3H),1.16(d , J=6.3Hz, 3H).

[0129] Route 1:

...

Embodiment 2

[0132]

[0133] Weigh IVa (68.0g, 240.1mmol) and NaBH 3 CN (10.3g, 163.2mmol) was dissolved in a 1000mL round bottom flask by adding 340.0mL MeOH, and aqueous formaldehyde solution (58.0g, 714.2mmol, 37%) was weighed and added dropwise to the reaction flask while stirring. After 2 hours, the reaction was completed, quenched by adding 3400.0 mL of water, a large amount of yellow solid was precipitated, filtered to obtain 57.1 g of target compound IIIa, yield: 80.6%, yellow solid. Mass spectrometry MALDI-TOF-MS m / z: 347 (M + ).

[0134] 1 H-NMR (CDCl 3 / TMS,400MHz):δ(ppm)7.26-7.34(m,4H),7.18-7.22(m,1H),4.04(m,4H),3.95(s,5H),3.72(d,J=6.8Hz , 1H), 3.43(d, J=6.5Hz, 1H), 1.85(s, 3H), 1.31(d, J=6.8Hz, 3H), 1.17(d, J=6.5Hz, 3H).

Embodiment 3

[0136]

[0137] Weigh IIIa (25.0 g, 72.0 mmol) into a 250 mL round bottom flask, dissolve it with 125.0 mL of acetic anhydride, and heat to 65°C. After 16 hours of reaction, the acetic anhydride was removed by rotary evaporation, and the residue was dissolved in 140.0 mL of methanol, and an aqueous solution of dimethylamine (24.4 g, 216.0 mmol, 40%) was weighed and added dropwise to the reaction flask with stirring. After 16 hours, the reaction was completed. After removing MeOH by rotary evaporation, the residue was diluted with 400.0 mL of ethyl acetate, washed with water, dried, and ethyl acetate was removed by rotary evaporation to obtain 16.1 g of target compound Ia, yield: 87.0 %, yellow oil. Mass Spectrometry MALDI-TOF-MS m / z:257(M + ).

[0138] 1 H-NMR (CDCl3 / TMS, 400MHz): δ (ppm) 4.02-4.07 (m, 9H), 3.52 (d, J = 6.8Hz, 1H), 2.00 (s, 6H), 1.37 (d, J = 7.0 Hz, 3H).

[0139] Route 2:

[0140]

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Abstract

The invention discloses a synthesis method of Ugi's amine as shown in formula (I) as well as a derivative and an optical isomer thereof. Chiral amine as shown in formula (VI) and a ferrocene compound as shown in formula (V) are used as starting raw materials, and then are subjected to reductive amination, reductive amination or alkylation of amido, substitution reaction and amine substitution reaction, thus obtaining the chiral Ugi's amine as shown in formula (I) as well as the derivative and the optical isomer thereof, or then are subjected to reductive amination, hydrogenation debenzylation, reductive amination or amino-alkylation reaction, thus obtaining the chiral Ugi's amine as shown in formula (I) as well as the derivative and the optical isomer thereof. The chiral Ugi's amine as shown in formula (I) as well as the derivative and the optical isomer thereof can be used for synthesizing a Josiphos type ferrocene diphosphine ligand which is used as a chiral ligand for various metal complex catalysts and is an important chiral catalyst ligand for preparing a medicine intermediate and an agricultural chemical; and the ligand is widely applied to asymmetric reaction of metal catalysis, and is applicable to industrial large-scale production.

Description

technical field [0001] The invention belongs to the technical field of chiral chemical synthesis, and in particular relates to a synthesis method of chiral Ugi's amine and its derivatives and optical isomers and an application in synthesizing Josiphos-like ferrocene bisphosphine ligands. Background technique [0002] Chiral ferrocenes have been widely and deeply studied in the fields of asymmetric catalysis, materials science and biomedicine [(a) Hyashi, T.; Togni, A., Eds.In Ferrocenes; VCH: Weinheim, Germany, 1995.( b) Togni, A.; Haltermann, R.L., Eds.In Metallocenes; VCH: Weinheim, Germany, 1998. (c) Stepnicka, P., Ed.In Ferrocenes; Wiley: Chichester, 2008.], where the key intermediate hands The active Ugi's amine is initially obtained by the resolution of the racemate through (R)-(+)-tartaric acid [(a) Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I.K., J.Am.Chem.Soc.1970,92,5389-5393; (b) Battelle, L.F.; Bau, R.; Gokel, G.W.; Oyakawa, R.T.; 1972, 11, 13...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F17/02
CPCC07B2200/07C07F17/02
Inventor 姜雪峰应永铖滕海鸽陈佩
Owner SHANGHAI MAOSHENG KAIHUI TECH CO LTD
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