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Oxa-spiro phosphine-oxazoline ligand as well as preparation method and application thereof

An oxaspiro and oxazoline technology is applied in the field of oxaspirophosphine-oxazoline ligands and their preparation, and can solve the problems of low total yield, long reaction steps, low product ee value and the like

Active Publication Date: 2020-11-20
SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This route has long reaction steps, low overall yield, long time consumption, and low ee value of the product

Method used

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  • Oxa-spiro phosphine-oxazoline ligand as well as preparation method and application thereof
  • Oxa-spiro phosphine-oxazoline ligand as well as preparation method and application thereof
  • Oxa-spiro phosphine-oxazoline ligand as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Embodiment 1 compound (S a )-2b preparation

[0085]

[0086] Under an argon atmosphere, the compounds (S a )-1b (3.90 g, 7.0 mmol), methanol (42 mL), palladium acetate (259 mg, 1.16 mmol), dppp (478 mg, 1.46 mmol), dimethylsulfoxide (60 mL) and triethylamine (11.6 mL). The reaction mixture was reacted in a carbon monoxide atmosphere at 70° C. until the reaction was complete. Cool to room temperature, extract three times with ethyl acetate, and then remove the solvent in the mixture under reduced pressure, and the crude product is directly hydrolyzed in the presence of potassium hydroxide. Finally, the compound (S a )-2b (2.02 g, yield 64%);

[0087] [α] 25 D = -32.00 (c = 0.5, acetone);

[0088] 1 H NMR (400MHz, Chloroform-d): δ7.36-7.17(m, 4H), 7.17-7.00(m, 2H), 6.94(d, J=6.5Hz, 1H), 6.76(t, J=8.5Hz , 4H), 6.54(s, 1H), 4.98(d, J=8.4Hz, 1H), 4.74(d, J=8.3Hz, 2H), 4.62(d, J=8.5Hz, 1H), 1.15(s , 18H), 1.13(s, 18H). 13C NMR (101MHz, Chloroform-d): δ162.2, ...

Embodiment 2

[0090] Embodiment 2 compound (R a )-2a preparation

[0091]

[0092] According to the method described in Example 1, the compound (R a )-1a prepared compound (R a )-2a, the detection data are as follows:

[0093] [α] 25 D =+23.40 (c=0.5, methanol);

[0094] 1 H NMR (400MHz, Chloroform-d): δ7.32-7.22 (m, 4H), 7.22-7.14 (m, 3H), 7.13-7.01 (m, 4H), 6.90-6.79 (m, 2H), 6.67 ( m, 1H), 6.29(dd, J=7.9, 0.8Hz, 1H), 5.73(dd, J=8.0, 0.8Hz, 1H), 5.01(dd, J=9.2, 2.6Hz, 1H), 4.67(d , J=9.3Hz, 1H), 4.62(dd, J=9.2, 1.3Hz, 1H), 4.53(d, J=9.4Hz, 1H). 13 C NMR (101MHz, Chloroform-d): δ161.29, 161.27, 160.25, 160.2, 143.5, 137.1, 137.0, 135.9, 135.7, 135.1, 135.0, 134.1, 133.9, 133.3, 133.1, 132.5, 1394.2, 139.0. 128.7, 128.29, 128.25, 128.2, 128.1, 128.0, 127.8, 127.7, 110.9, 108.8, 83.3, 80.7, 56.1. 31 P NMR (162MHz, Chloroform-d): δ-22.55;

[0095] HRMS(ESI)calcd.for C 28 h 20 o 4 P[M-H] - : 451.1105.Found: 451.1104.

Embodiment 3

[0096] Embodiment 3 compound (S a , Preparation of S)-3d

[0097] Under the protection of argon, add (S a )-2b (1000 mg, 1.48 mmol), (S)-(+)-2-phenylglycinol (637 mg, 4.65 mmol), HOBt (504 mg, 3.29 mmol), DCC (881 mg, 4.27 mmol) and 80 mL THF. The reaction mixture was reacted at 40° C. for 24 hours, and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure to remove the solvent, and separated and purified by column chromatography. Then the obtained product and 0.32 mL of triethylamine, 4-dimethylaminopyridine (5 mg, 0.04 mmol) were added into 65 mL of dichloromethane. Methanesulfonyl chloride (120 μL, 1.55 mmol) was added to the mixture at 0° C., stirred for 30 minutes, and then 1.35 mL of triethylamine was added, warmed to room temperature, and stirred until the reaction was completed. Carry out separation and purification by column chromatography, can obtain product (S a , S)-3d (678mg, yield 59%);

[0098] [α] 25 D =-154.40 ...

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Abstract

The invention discloses an oxa-spiro phosphine-oxazoline ligand as well as a preparation method and application thereof. The oxa-spiro phosphine-oxazoline ligand is a compound as shown in a formula (3) or a stereoisomer of the compound as shown in the formula (3), can form a catalyst complex with good catalytic performance after being complexed with a metal iridium catalyst, and can be used for asymmetric reduction reaction, particularly reduction reaction of a lorcaserin intermediate and an analogue thereof.

Description

technical field [0001] The invention relates to the technical field of catalytic reaction ligands, in particular to an oxaspirophosphine-oxazoline ligand, a preparation method thereof and an application in asymmetric synthesis of lorcaserin. Background technique [0002] The phosphine-oxazoline ligand is a dominant ligand with the characteristics of both phosphine and nitrogen ligands, which can be applied to a variety of asymmetric catalytic reactions (Li, M.-L.; Yang, S.; Su, X.-C.; Wu, H.-L.; Yang, L.-L.; Zhu, S.-F.; Zhou, Q.-L.J.Am.Chem.Soc.2017, 139, 541; A.; Diesen, J.S.; Chapman, C.J.; Andersson, P.G Org. Lett. 2004, 6, 3825). With the development of asymmetric science, more and more phosphine-oxazoline ligands have been developed, and their application in the synthesis of marketed drugs and / or their analogs can make the process route simpler and the cost of drugs lower . [0003] Lorcaserin hydrochloride (Lorcaserin), a kind of 5-HT developed by American Ainena (A...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561B01J31/24C07D223/16C07C233/11C07C231/12
CPCC07F9/6561B01J31/2404C07D223/16C07C231/12C07B2200/07B01J2531/827B01J2531/0238B01J2231/645C07C2531/24C07C233/11
Inventor 叶祥宇梁志钦郑龙生陈根强张绪穆
Owner SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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