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Process for preparing (S)-1-ferrocene ethyl dimethylamine

A kind of ferrocene ethyl dimethylamine, the technology of preparation process, applied in the direction of metallocene, organic compound/hydride/coordination complex catalyst, organic chemistry, etc., can solve the problem of large amount of catalyst and poor enantioselectivity control. High problems, to achieve the effect of low catalyst dosage, easy availability of raw materials and mild reaction conditions

Active Publication Date: 2018-08-17
江苏信和生物医药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method has made a major breakthrough in the synthesis of (R)-1-ferroceneethyl dimethylamine (Org. Lett.2017,19,690-693; CN103755748), but for (S)-1-ferroceneethyl However, there are still deficiencies in the synthesis of dimethylamine, such as a large amount of catalyst and low enantioselectivity control (Adv.Synth.Catal.2006,348,370-374; Tetrahedron:Asymmetry 2009,20,584-587)
Therefore, how to prepare (S)-1-ferrocenylethyldimethylamine with high enantioselectivity easily and on a large scale is still a challenging task.

Method used

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  • Process for preparing (S)-1-ferrocene ethyl dimethylamine
  • Process for preparing (S)-1-ferrocene ethyl dimethylamine
  • Process for preparing (S)-1-ferrocene ethyl dimethylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Synthesis of Ligand L1

[0028]

[0029] Compound 4 (4.41 g, 10 mmol) was dissolved in 8.0 mL of acetic anhydride and reacted at 55° C. for 4 hours. After the reaction was completed, excess acetic anhydride was recovered under reduced pressure, and then impurities with low boiling points were removed under high vacuum to obtain crude product 5, which was directly used in the next step without purification.

[0030]

[0031] Crude products 5 (0.46g, 0.1mmol) and 6 (0.54g, 0.2mmol) were added to the reaction flask, and after nitrogen was replaced, 5mL of methanol was added and reacted at 50°C for 12 hours. Concentration and column chromatography gave yellow ligand L1 (0.41 g, 61%).

[0032]

[0033] 1 H NMR (600MHz, CDCl 3 )δ7.70(d, J=8.2Hz, 2H), 7.50–7.44(m, 2H), 7.39–7.34(m, 3H), 7.24(d, J=8.1Hz, 2H), 7.18–7.12(m ,1H),7.09–7.01(m,4H),5.89(s,1H),4.49(s,1H),4.34(t,J=2.4Hz,1H),4.05(s,5H),4.03–3.96( m,1H),3.68(s,1H),2.42(s,3H),2.10(s,2H),1.97–1.87(m...

Embodiment 2

[0034] Example 2: Synthesis of Ligand L2

[0035] The preparation method of crude product 5 is the same as that of Example 1.

[0036]

[0037] Crude products 5 (0.46 g, 0.1 mmol) and 7 (0.60 g, 0.2 mmol) were added to the reaction flask, and after replacing the nitrogen, 5 mL of methanol was added and reacted at 50° C. for 12 hours. Concentration and column chromatography gave yellow ligand L2 (0.37 g, 53%).

[0038]

[0039] 1 H NMR (600MHz, CDCl 3)δ7.52–7.46(m,2H),7.39–7.34(m,3H),7.14(m,1H),7.01(s,4H),6.91(s,2H),5.92(s,1H),4.48 (s,1H),4.35–4.31(s,1H),4.05(m,5H),4.03(s,1H),3.69(s,1H),2.59(s,6H),2.31(s,3H), 2.17–2.01(m,2H),1.92–1.84(m,1H),1.75(s,1H),1.43(m,5H),1.27(m,1H),0.96(m,2H),0.81–0.72( m,1H),-0.44(d,J=8.1Hz,1H). 13 CNMR (151MHz, CDCl 3 )δ141.45,140.03,139.95,138.98,136.43,136.36,135.03,134.86,134.19,132.59,132.44,131.68,129.14,128.31,128.26,128.12,128.06,74.05,74.00,71.03,71.00,69.62,69.31,69.28,69.14 ,57.66,56.89,46.18,31.93,29.70,24.78,23.87,23.03,20.86...

Embodiment 4

[0046] Embodiment 4: Preparation of (S)-1-ferroceneethyl dimethylamine

[0047] (1) Ligand L1 (0.32g, 0.48mmol), metal [Ir(COD)Cl] 2 (0.16g, 0.22mmol) was added to a reaction flask, methanol (20mL) was added under an argon atmosphere, and the reaction was stirred at 25°C for 0.5h to obtain a catalyst.

[0048] (2) Add acetylated ferrocene 1 (1.03kg, 4.52mol) in the autoclave, add the catalyst prepared by step (1), sodium methoxide (1.19g, 22mmol), methanol (1.50L), and fill with H 2 (3.0MPa), reacted at 40°C for 12h, concentrated under reduced pressure to recover the organic solvent, and obtained (S)-1-ferrocenyl ethanol 2 (1.03kg, 4.47mol), yield: 99%, purity: 98%, The ee value was 91%.

[0049] (3) Put (S)-1-ferrocenyl ethanol 2 (1.03kg, 4.47mol), dichloromethane (3.0L), and triethylamine (902.9g, 8.94mol) prepared above into the reactor in sequence Add acetic anhydride (683.4g, 6.70mol) dropwise at room temperature, continue to stir for 3 hours; then slowly add 4.31kg of...

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Abstract

The invention discloses a process for preparing (S)-1-ferrocene ethyl dimethylamine. In the preparation process, acetylferrocene is used as a raw material, and a complex obtained by reacting a metal Ir complex with a chiral ferrocene tridentate ligand L* is used as a catalyst, (S)-1-ferrocenyl ethanol is prepared by asymmetric catalytic hydrogenation, and the(S)-1-ferrocene ethyl dimethylamine isprepared by acetylation and dimethylamine substitution reaction. Compared with a traditional chiral separation method for preparing the (S)-1-ferrocene ethyl dimethylamine, the process has main beneficial effects of mild reaction conditions, simple operation, good stereoselectivity, high yield, short production cycle, small amount of "three wastes", easy industrialization, and large implementationvalue and social and economic benefits.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation process of (S)-1-ferrocenylethyldimethylamine. Background technique [0002] (S)-1-Ferrocenylethyldimethylamine is an important class of pharmaceutical and chemical intermediates, often used as chiral catalysts and key skeletons of chiral ligands. For example, a ferrocenephosphine catalyst derived from (S)-1-ferrocenylethyldimethylamine can catalyze the asymmetric Morita-Baylis-Hillman reaction (Org. Biomol. Chem., 2017, 15, 7523-7526; Org .Biomol.Chem.,2016,14,752-760), chiral compounds were obtained with higher yield and ee value. Ferrocene ligands derived from (S)-1-ferroceneethyldimethylamine can also coordinate with metals to achieve efficient asymmetric catalytic reactions (Angew.Chem.Int.Ed.2014,53,8467- 8470; Org. Lett. 2017, 19, 690-693; Org. Lett. 2016, 18, 2938-2941; CN105732725.). Therefore, chemists have been actively exploring ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F17/02B01J31/22
CPCB01J31/2295B01J2531/842C07F17/02
Inventor 钟为慧凌飞年三飞
Owner 江苏信和生物医药有限公司
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