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A kind of asymmetric allylation reaction to synthesize chiral n 1 - Allylpyrimidine method

An allylpyrimidine and allylation technology, which is applied in the field of asymmetric synthesis in organic chemistry, can solve the problems of difficult preparation of chiral substrates and high cost, and achieves abundant product structures, efficient synthesis methods, and product stereoselectivity. high sex effect

Active Publication Date: 2020-07-10
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Typically, chiral substrates are relatively difficult and expensive to prepare
Relatively speaking, low-cost, cheap and easy-to-obtain achiral allyl reagents are used to prepare chiral N 1 -Allylpyrimidine method, not yet reported

Method used

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  • A kind of asymmetric allylation reaction to synthesize chiral n <sup>1</sup> - Allylpyrimidine method
  • A kind of asymmetric allylation reaction to synthesize chiral n <sup>1</sup> - Allylpyrimidine method
  • A kind of asymmetric allylation reaction to synthesize chiral n <sup>1</sup> - Allylpyrimidine method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018]

[0019]

[0020]

[0021]

[0022] a Entry 1, Conditions A: 1a(0.2mmol, 1.0equiv), cinnamyl carbonate 2b(0.2mmol) [Ir(COD)Cl] 2 (2mol%) and L1 (4mol%), tetrahydrofuran (THF) (0.2mL), K 3 PO 4 (1.0equiv.) 50℃,N 2 ,12h. b Entries 2-10, Conditions B: 1a (0.2mmol, 1.0equiv), cinnamyl carbonate 2b (0.2mmol)[Rh(COD)Cl] 2 (3mol%) and Ligand(6mol%), DCE(0.2M), 80℃, N 2 ,12h. c The ratio determined form crude 1 H NMR. d Yields of isolated product. e The ee values ​​were determined by chrial-phase HPLC analysis.

[0023] In the screening process of reaction conditions, the effects of metal Ir and metal Rh on the reaction were first investigated (entries1-2). At the same time, by comparing the effects of different ligands on the reaction, the ligands L9 and L10 were determined to be the best ligands.

[0024] Investigation of reaction conditions: In a 10mL vacuum tube, add N 3 -Bz protected thymine (46.1mg, 0.2mmol), [Rh(COD)Cl 2 ] (2.9 mg, 0.006 mmo...

Embodiment 2

[0039] In a 10 mL vacuum tube, add N 3 -Bz protected thymine (46.1mg, 0.2mmol), [Rh(COD)Cl 2 ] (2.9 mg, 0.006 mmol) and (R)-DTBM-Segphos (14.2 mg, 0.012 mmol). The reaction tube was filled with nitrogen by nitrogen replacement 3 times, and then, under nitrogen flow, carbonate 2b (82.4 mg, 0.4 mmol) was added, and 1 mL of 1,2-dichloroethane was added. The reaction tube was sealed, and the reaction tube was placed in an oil bath at 80° C. for 12 hours to react. Track the reaction with TLC. After the reaction is terminated, add ethyl acetate / water for extraction, dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase in vacuo, and then obtain the target compound 3ab by column chromatography with a yield of 84% and an ee value of 98%. . The preparation of products 3aa-3ib refers to the synthesis and post-processing methods of compound 3ab.

Embodiment 3

[0041] In a 10mL vacuum tube, add 5-I-N 3-Bz protected thymine (68.4mg, 0.2mmol), [Rh(COD)Cl 2 ] (2.9 mg, 0.006 mmol) and (R)-DTBM-Segphos (14.2 mg, 0.012 mmol). The reaction tube was filled with argon by replacing it with argon three times, and then, under nitrogen flow, carbonate 2b (82.4 mg, 0.4 mmol) was added, and 1 mL of 1,2-dichloroethane was added. The reaction tube was sealed, and the reaction tube was placed in an oil bath at 80° C. for 12 hours to react. Track the reaction with TLC. After the reaction is terminated, add ethyl acetate / water for extraction, dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase in vacuo, and then obtain the target compound 3cb through column chromatography with a yield of 83% and an ee value of 95%. .

[0042] Representative compound characterization data are as follows:

[0043] 3cb Light yellow oil.[α] D 27 =-115.4° (c=0.92, CH 2 Cl 2 ).HPLC CHIRALCEL IA, n-hexane / 2-propanol=70 / 30, flow rate=0.8mL...

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Abstract

The invention discloses a method for synthesizing chiral N1-allyl pyrimidine by asymmetric allyl reaction, and belongs to the field of asymmetric synthesizing. The method is characterized in that N3-protected pyrimidine and allyl carbonate are used as the raw materials, [Rh(COD)Cl]2 is used as a catalyst, DTBM-Segphos or DTBM-MeOBIPHEP is used as a chiral ligand, and the chiral N1-allyl pyrimidine is obtained after reaction, so that the yield rate is medium to excellent.

Description

technical field [0001] The present invention relates to the synthesis method of chiral acyclic pyrimidine, in particular to a kind of asymmetric allylation reaction to synthesize chiral N 1 - Method for allylpyrimidines, belonging to the field of asymmetric synthesis in organic chemistry. Background technique [0002] Chiral acyclic pyrimidine compounds have a wide range of physiological activities, such as (S)-cidofovir has a strong inhibitory effect on cytomegalovirus (CMV), herpes simplex virus (HSV) and herpes zoster virus (VZV), etc. active. Other chiral acyclic nucleosides such as: (S)-FPMPT, (S)-willardiine, (S)-HPMPA and (R)-Tenofovir have different pharmaceutical activities. Meanwhile, the absolute configuration of acyclic nucleosides has a great influence on their activity. For example: the activity of the S configuration of cidofovir is higher than that of the R configuration; the IC of the anti-HIV virus activity of the S configuration of FMPPA 50 The value i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/54C07B53/00B01J31/24
CPCB01J31/2409B01J2531/0266B01J2531/822C07B53/00C07B2200/07C07D239/54
Inventor 郭海明梁磊谢明胜王东超王海霞牛红英张齐英渠桂荣
Owner HENAN NORMAL UNIV
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