2-fuloro fumarate (formula I), and preparation method and application thereof

The technology of dialkyl fluorofumarate and dialkyl fumarate is applied in the field of dialkyl 2-fluorofumarate and its preparation, and can solve the immunosuppressive effect of fluorofumarate Unmanned research and other problems, to achieve the effect of increasing the difficulty of purification, easy control, and reducing yield

Active Publication Date: 2014-01-01
深圳市博圣康生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Herman Gershon also reported dimethyl fluorofumarate in 1977, diethyl ester, dipropyl ester, and dibutyl ester for the inhibition of mold (Journal of Medicinal Chemistry, 606, 20 (4), 1977; Journal of Pharmaceutical Sciences, 578, 67(4), 1978). However, no one has studied the immunosuppressive effect of fluorofumaric acid

Method used

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  • 2-fuloro fumarate (formula I), and preparation method and application thereof
  • 2-fuloro fumarate (formula I), and preparation method and application thereof
  • 2-fuloro fumarate (formula I), and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Preparation and biological activity of diethyl 2-fluorofumarate (compound YYK-1)

[0045] 1. Add ethanol (1.2g, 26mmol), butynedioic acid (1g, 8.77mmol), p-toluenesulfonic acid (30mg, 0.17mmol) and 1,2-dichloroethane (50mL) into a 250mL round bottom in the flask. After refluxing for 12 hours, add 50 mL of toluene and continue refluxing to separate water (using a water separator) for 8 hours. Concentrate and purify by flash chromatography (eluent PE / EA=98 / 2) to obtain diethyl butynedioate (1.35 g, yield 91%).

[0046] 2. Add diethyl butynedioate (1.1g, 6.46mmol), potassium fluoride (0.73g, 12.6mmol), DMF (50mL), acetonitrile (50mL) into a round bottom flask, add water (0.48mL) under stirring mL, 26.7 mmol) and stirred at 80°C for 2 hours. Cool to room temperature, add ethyl acetate (100mL) and transfer the solution into a separatory funnel, wash with saturated brine (4×30mL), dry the organic layer over anhydrous sodium sulfate, concentrate to give a brown liquid, pass...

Embodiment 2

[0058] Preparation of Dimethyl 2-Fluorofumarate (Compound YYK-2)

[0059] Add methanol, butynedioic acid, p-toluenesulfonic acid and 1,2-dichloroethane into a 250 mL round bottom flask. After refluxing for 8-12 hours, add toluene and continue refluxing to separate water (using a water separator) for 6-8 hours. Concentrate, and purify by flash chromatography (eluent PE / EA) to obtain dimethyl butyndioate (93% yield).

[0060] Add dimethyl butyndioate, potassium fluoride, DMF, and acetonitrile into a round bottom flask, add water while stirring and stir at 80°C for 2-3 hours. Cool to room temperature, add ethyl acetate and transfer the solution into a separatory funnel, wash with saturated brine, dry the organic layer over anhydrous sodium sulfate, and concentrate to obtain a brown liquid, which is subjected to silica gel column chromatography (eluent: PE / EA) was purified to obtain dimethyl 2-fluorofumarate (HPLC purity 98.56%, yield 65%).

[0061] 1 H NMR (400M, CDCl 3 ) δ...

Embodiment 3

[0065] Preparation of bis-(2'-ethoxyethyl)-2-fluorofumarate (compound YYK-3)

[0066] Add 2-ethoxyethanol, butynedioic acid, p-toluenesulfonic acid and 1,2-dichloroethane into a 250 mL round bottom flask. After refluxing for 8-16 hours, add toluene and continue refluxing to separate water (using a water separator) for 6-10 hours. Concentrate and purify by flash chromatography (eluent PE / EA) to obtain bis-(2'-ethoxyethyl) butyndioate (yield 78%).

[0067] Add bis-(2'-ethoxyethyl)butyndioate, potassium fluoride, DMF, and acetonitrile into a round bottom flask, add water under stirring and stir at 80°C for 2-3 hours. Cool to room temperature, add ethyl acetate and transfer the solution into a separatory funnel, wash with saturated brine, dry the organic layer over anhydrous sodium sulfate, and concentrate to obtain a brown liquid, which is subjected to silica gel column chromatography (eluent: PE / EA) was purified to obtain bis-(2'-ethoxyethyl)-2-fluorofumarate (yield 47%).

...

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Abstract

The invention discloses 2-fuloro fumarate (formula I) and a preparation method thereof. Experiments show that: the kinds of compounds are capable of effectively inhibiting NF-kB transcriptional activity introduced by TNF-alpha, and further are capable of treating diseases introduced by NF-kB, such as psoriasis, multiple sclerosis, arthritis, eye inflammation or allergy, asthma and lupus erythematosus, and can be used as an immunosuppressant for organ transplantation.

Description

technical field [0001] The invention relates to the field of new drug research and development, in particular to a dialkyl 2-fluorofumarate (structural formula I), a preparation method thereof and an application as an immunosuppressant. Background technique [0002] Formula 1: [0003] [0004] Fumaric acid (fumaric acid, formula 1) is an active ingredient of a plant, which is used to treat skin disorders such as acne and psoriasis in the United States, New Zealand and Australia. Normally, human skin cells produce fumaric acid when exposed to sunlight. In psoriasis patients, due to biochemical defects, the synthesis of fumaric acid in skin cells is blocked. [0005] Founded in 1983, the German pharmaceutical company FUMAPHARMA was approved in 1994 to treat moderate to severe psoriasis with a salt mixture of monoethyl fumarate and dimethyl fumarate (trade name FUMADERM). In May 2006, the American biopharmaceutical company BIOGEN purchased the further development rights ...

Claims

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Application Information

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IPC IPC(8): C07C69/657C07C67/307A61K31/225A61P17/06A61P25/00A61P19/02A61P27/02A61P27/14A61P11/06A61P37/00A61P37/06A61P29/00
CPCC07C67/307C07C69/657
Inventor 杨寅柯
Owner 深圳市博圣康生物科技有限公司
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