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Method for synthesizing Piragliatin and analogues thereof

A technology of analogs and complexes, applied in the direction of organic chemistry, bulk chemical production, etc., can solve the problems of lengthy steps, environmental pollution, increase production cost, etc., and achieve the effect of cheap synthesis and low price

Pending Publication Date: 2022-05-27
WUHAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] However, the current method for synthesizing Piragliatin is lengthy, the complex structure on the substrate needs to be constructed and protected in advance, the use of a large number of metal reagents and harsh conditions not only pollute the environment but also increase the production cost

Method used

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  • Method for synthesizing Piragliatin and analogues thereof
  • Method for synthesizing Piragliatin and analogues thereof
  • Method for synthesizing Piragliatin and analogues thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The synthesis path is as follows:

[0032]

[0033] The preparation method is as follows:

[0034] Under an inert atmosphere, tetrabutylammonium decatungstate (13.3 mg, 0.004 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine) nickel dibromide (9.8 mg) were added to the reaction tube. , 0.02mmol), potassium phosphate (84.8mg, 0.4mmol), benzyl acrylate (97.2mg, 0.6mmol), cyclopentanone (168.2mg, 2mmol), 4-bromo-2-chloro-1-(methylsulfonic acid) acyl)benzene (53.9 mg, 0.2 mmol) and acetone (0.5 mL). Under the irradiation of a violet lamp (10w, 390nm), the reaction was carried out at room temperature for 18 hours, concentrated, and subjected to flash column chromatography to obtain the product 2-(3-chloro-4-(methylsulfonyl)phenyl)-3-(3-oxocycle) Benzyl pentyl)propionate 41.8 mg (yield 48%, d.r.=1:1, colorless transparent liquid.

[0035] 1 H NMR (600MHz, CDCl 3 )δ8.11-8.08(m,1H),7.54-7.51(m,1H),7.42-7.38(m,1H),7.37-7.31(m,4H),7.28-7.26(m,1H),5.19- 5.15(m, 1H), 5.11-5.07(m,...

Embodiment 2

[0043] The synthesis path is as follows:

[0044]

[0045] The preparation method is as follows:

[0046] Under an inert atmosphere, tetrabutylammonium decatungstate (13.3 mg, 0.004 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine) nickel dibromide (9.8 mg) were added to the reaction tube. , 0.02 mmol), potassium phosphate (84.8 mg, 0.4 mmol), methyl acrylate (51.7 mg, 0.6 mmol), cyclopentane (140.2 mg, 2 mmol), 4-bromo-2-chloro-1-(methylsulfonic acid) acyl)benzene (53.9 mg, 0.2 mmol) and acetone (0.5 mL). Under the irradiation of a violet lamp (10w, 390nm), the reaction was carried out at room temperature for 18 hours, concentrated, and subjected to flash column chromatography to obtain the product, methyl 2-(3-chloro-4-(methylsulfonyl)phenyl)-3-cyclopentylpropanoate Ester 31.0 mg (yield 45%, colorless transparent liquid).

[0047] 1 H NMR (600MHz, CDCl 3 )δ8.08(d,J=8.2Hz,1H),7.53(d,J=1.7Hz,1H),7.44-7.37(m,1H),3.68(s,3H),3.66(t,J=7.8 Hz, 1H), 3.26(s, 3H), 2.12-2.05(m, 1H),...

Embodiment 3

[0055] The synthetic route is as follows:

[0056]

[0057] The preparation method is as follows:

[0058] Under an inert atmosphere, tetrabutylammonium decatungstate (13.3 mg, 0.004 mmol), (4,4'-di-tert-butyl-2,2'-bipyridine) nickel dibromide (9.8 mg) were added to the reaction tube. , 0.02mmol), potassium phosphate (84.8mg, 0.4mmol), methyl acrylate (51.7mg, 0.6mmol), cyclopentane (140.2mg, 2mmol), 4-bromo-2-chloro-1-fluorobenzene (41.8 mg, 0.2 mmol) and acetone (0.5 mL). Under the irradiation of a violet lamp (10w, 390nm), the reaction was performed at room temperature for 18 hours, concentrated, and subjected to flash column chromatography to obtain 30.6 mg of the product, methyl 2-(3-chloro-4-fluorophenyl)-3-cyclopentylpropionate (yield 30.6 mg). The rate is 54%, colorless and transparent liquid).

[0059] 1 H NMR(600MHz, CDCl3)δ7.37(dd,J=7.0,2.3Hz,1H),7.20-7.16(m,1H),7.08(t,J=8.7Hz,1H),3.67(s,3H) ,3.56(t,J=7.8Hz,1H),2.07-2.01(m,1H),1.80-1.70(m,3H),1.65-1.60(m,2H)...

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Abstract

The invention discloses a method for synthesizing Piragliatin and an analogue of the Piragliatin. Specifically, an aryl halide, an acrylic acid derivative and alkane are used as raw materials, and the Piragliatin and the analogues thereof are efficiently constructed through concerted catalysis of decatungstate and a metal nickel complex. The method comprises the following steps: firstly realizing aryl alkylation of olefin under illumination, then hydrolyzing ester into acid to prepare acyl chloride, and finally condensing the acyl chloride with 2-aminopyrazine to obtain Piragliatin. A novel methodology for alkene alkylarylation is used, and compared with a previous synthesis method, the method has the advantages that the raw materials are commercially available, the steps are simple and efficient, further derivatization is easy, the operation is simple, and the method is suitable for synthesis of a large amount of Piraglidin and analogues thereof.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a synthetic method for synthesizing Piragliatin and its analogs. Background technique [0002] Piragliatin can treat type II diabetes by activating glucokinase (GK). Experiments by Sarabu et al. demonstrated that Piragliatin reduces fasting and post-oral glucose tolerance test blood glucose levels, improves insulin secretion, increases beta cell sensitivity to glucose, and reduces hepatic glucose output (Science 2003, 301, 370; J. Med Chem. 2010, 53, 3618; J. Med. Chem. 2012, 55, 7021). The drug is currently in Phase II clinical development. [0003] However, the current method for synthesizing Piragliatin is lengthy, the complex structure on the substrate needs to be constructed and protected in advance, the use of a large number of metal reagents and harsh conditions not only pollute the environment but also increase the production cost. Based on the long-term rese...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/20
CPCC07D241/20Y02P20/55
Inventor 孔望清许盛陈荷蓉
Owner WUHAN UNIV
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