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Preparation method of 1-morpholinyl-4-(2,4,5-trifluorophenyl)butane-1,3-dione

An alkyl and methyl technology is applied in the field of preparation of 1-morpholine-4-butane-1,3-dione, which can solve the problems of using dangerous diazomethane, not using industrialized large-scale production, and complicated post-processing. , to achieve the effect of mild reaction conditions, simple post-processing and high yield

Pending Publication Date: 2020-04-21
ABIOCHEM BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this design route is that it needs to use dangerous diazomethane and heavy metal Ag, the post-processing is cumbersome, and it does not use industrialized large-scale production.

Method used

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  • Preparation method of 1-morpholinyl-4-(2,4,5-trifluorophenyl)butane-1,3-dione
  • Preparation method of 1-morpholinyl-4-(2,4,5-trifluorophenyl)butane-1,3-dione
  • Preparation method of 1-morpholinyl-4-(2,4,5-trifluorophenyl)butane-1,3-dione

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1 prepares morpholine monopotassium malonate

[0058]

[0059] Morpholine (357g, 4.1mol) was dissolved in xylene (3.5L); while stirring, dimethyl malonate (720g, 5.45mol) was added. The temperature was raised to 130° C., and the stirring was continued for 24 h; TLC showed that the starting material disappeared. Concentrate under reduced pressure to obtain 1100 g of crude product, which is purified by column chromatography to obtain 620 g of colorless oily product 2-(4-morpholinecarbonyl) methyl acetate, with a yield of 81%. HNMR (400MHz, CDCl 3 )δ3.73(s, 3H), 3.68-3.65(m, 4H), 3.63(s, 2H), 3.62-3.42(m, 4H)

[0060]

[0061] At 20°C, methyl 2-(4-morpholinecarbonyl)acetate (20 g, 0.11 mol) was dissolved in MeOH (200 mL); KOH (1.0 eq, 6.2 g) and H 2 O (2.0eq, 4g); Stir at this temperature for 16h; Concentrate and remove the solvent under reduced pressure; Add MTBE (40mL*2) for beating twice; After drying, 20.3 g of monopotassium morpholine malonate was...

Embodiment 2

[0062] Embodiment 2 prepares 2,4,5-trifluorophenylacetyl imidazoles

[0063]

[0064] At 30°C, 2,4,5-trifluorophenylacetic acid (1g, 5.26mmol) was added to acetonitrile (10mL), and then N,N'-carbonyldiimidazole (CDI) (0.94g, 5.79mmol) was added; Stirred at 25°C for 3h, TLC showed disappearance of starting material. The obtained reaction solution was directly used in the next step without purification.

Embodiment 3

[0065] Example 3 Preparation of morphine 2,4,5-trifluorophenylacetoacetate

[0066]

[0067] Add morpholine monopotassium malonate (1.33g, 6.31mmol) in acetonitrile (6mL), nitrogen protection, then add triethylamine (1.28g, 12.62mmol) and magnesium chloride (0.6g, 6.31mmol); At ℃, stir for 2h; cool down to 0℃; slowly add dropwise the solution of 2,4,5-trifluorophenylacetylimidazole (1.26g, 5.26mmol) prepared in Example 2 in acetonitrile (10mL); at 25℃, stir for 16h ; Cool down to 5°C; add saturated brine (10mL) to quench the reaction, adjust the pH value to 3-4 with 1N HCl; extract the product with ethyl acetate (15mL×3); combine and dry the organic phase; concentrate; column Chromatography (PE:EA=1:1) gave a pale yellow solid (1.1 g, 69.4% overall yield over two steps).

[0068] HNMR (400MHz, DMSO-D6) δ7.52-7.45(m, 1H), 7.40-7.33(m, 1H), 3.91(s, 2H), 3.76(s, 2H), 3.53-3.51(m, 4H) , 3.44-3.42 (m, 2H), 3.41-3.32 (m, 2H).

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Abstract

The invention discloses a preparation method of 1-morpholinyl-4-(2,4,5-trifluorophenyl)butane-1,3-dione, and belongs to the technical field of organic synthesis. The preparation method comprises the following step: under the action of a metal chelating agent and an alkali, carrying out a reaction of the following formula on a compound 2 and a compound 3 in an organic solvent to obtain a compound 1. The preparation method disclosed by the invention is high in yield, simple in post-treatment, simple, feasible, mild in reaction condition and suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of 1-morpholine-4-(2,4,5-trifluorophenyl)butane-1,3-dione. Background technique [0002] Diabetes mellitus is a metabolic disease that occurs due to changes in insulin secretion, resulting in insulin deficiency, or decreased insulin activity, or under the combined influence of the two. The disease is characterized by hyperglycemia, accompanied by metabolic disorders of protein, sugar and fat. Diabetes and its complications are the third most harmful to human health after cardiovascular diseases and tumors, becoming an important disease that endangers human health. The International Diabetes Federation predicts that by 2030, the total number of people suffering from diabetes will exceed 435 million. And my country has become one of the countries with the fastest growing rate of diabetes prevalence in the world. At present, there are about 40 million diabetic patients, second only to India, ranking second i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/185C07C69/96C07C68/00C07C57/58C07C51/56C07C67/14C07C69/65C07D233/60
CPCC07D295/185C07C69/96C07C68/00C07C57/58C07C51/56
Inventor 秦丽军田振华
Owner ABIOCHEM BIOTECH CO LTD