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Avalopam intermediate as well as preparation method and application thereof

A technology for avacopam and uses, applied in the field of avacopam intermediates and their preparation, can solve the problems of long preparation steps, low yield of final products, etc., and achieves cheap and easy-to-obtain raw materials and high yield of final products , the effect of mild reaction conditions

Pending Publication Date: 2022-03-11
CHONGQING MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] CN106999481A discloses the preparation method of alvacopam, which not only has lengthy preparation steps, but also needs to use ditoluoyl-L-tartaric acid for resolution, and the yield of the final product is low

Method used

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  • Avalopam intermediate as well as preparation method and application thereof
  • Avalopam intermediate as well as preparation method and application thereof
  • Avalopam intermediate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] The synthesis of embodiment 1 compound I

[0047] Formula II compound (R 1 is fluorine; R 2 for COR 4 ; 3 is nitro; R 4 For methoxy) reduction preparation formula I compound (R 1 is fluorine; R 2 for COR 4 ; 4 For methoxy) reaction scheme is:

[0048]

[0049] In containing bis(1,5-cyclooctadiene) rhodium(I) tetrafluoroborate (Rh(COD) 2 BF 4, 81mg, 0.2mmol) and ligand (R)-Ligand 1 (174mg, 0.4mmol) in dichloromethane (20mL) reaction flask, was added compound II (4g, 10mmol) isopropanol solution (40mL). It was then stirred at room temperature under 1 atm of hydrogen for 18 hours, and TLC showed that the reaction was complete. The reaction solution was diluted with 200mL ethyl acetate, and then saturated NaHCO 3 aqueous solution (100mL X2), saturated NaCl aqueous solution (100mL X2), and the organic layer was washed with anhydrous NaCl 2 SO 4 After drying, it was concentrated under reduced pressure, and the residue was separated through a silica gel column...

Embodiment 2

[0050] The synthesis of embodiment 2 compound II

[0051] Formula II compound (R 1 is fluorine; R 2 for COR 4 ; 3 is nitro; R 4 is methoxy) by formula III compound (R 2 for COR 4 ; 3 is nitro; R 4 For methoxy) and formula IV compound (R 1 It is prepared by fluorine) coupling, and the reaction formula is as follows:

[0052]

[0053] Dissolve 4.9g (22mmol) of compound III in 100mL of anhydrous acetone, then add 4.2g (30mmol) of K 2 CO 3 , and 5.5g (20mmol) of compound IV in 10mL of DMF, stirred at room temperature for 36 hours, added 5g of anhydrous Na 2 SO 4 , and then continued to stir at 50° C. for 3 hours, TLC showed that the reaction was complete. The residue after the reaction solution was concentrated under reduced pressure was added to 200 mL ethyl acetate, washed with saturated NaCl (100 mL X2) aqueous solution, and the organic layer was washed with anhydrous NaCl 2 SO 4 After drying, the concentrated crude product was filtered and separated through a...

Embodiment 3

[0054] The synthesis of embodiment 3 compound IV

[0055] IV compound (R 1 is fluorine) by formula VI compound and formula V compound (R 1 It is prepared by fluorine) reaction, and the reaction formula is as follows:

[0056]

[0057] Add 50mL of anhydrous THF and 0.2mL of anhydrous DMF, and 3.1g (20mmol) of compound V (2-fluoro-6-methylbenzoic acid) into a 250mL dry three-necked flask with magnetic stirring, and cool down in a low-temperature reaction tank After reaching 0°C, a THF (15 mL) solution containing 1.7 mL (20 mmol) oxalyl chloride was added dropwise, and after the addition was completed, it was moved to room temperature and stirred for 2 hours. After the reaction system was cooled to 0°C, a THF (20 mL) solution containing 1.7 mL (40 mmol) of pyridine and 2.8 g (20 mmol) of compound VI was added dropwise, and after the addition was completed, it was moved to room temperature and continued to stir for 4 hours. TLC showed that the reaction was complete. Add 200m...

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Abstract

The invention provides an avalcopam intermediate (a compound shown in a formula I). The compound can be used as an avalcopam raw material or intermediate for synthesizing avalcopam. The invention further provides a preparation method of the atavapam intermediate compound shown in the formula I. The target product atavapam intermediate compound shown in the formula I is obtained through three-step reaction, the whole route design is novel, the chiral resolution process adopted in the prior art is avoided, practicability is high, the yield is high, the reaction speed is high, few by-products are generated, and the preparation method is very suitable for industrial application.

Description

technical field [0001] The invention relates to alvacopam, in particular to an alvacopam intermediate and a preparation method and use thereof. Background technique [0002] Alvacopam is a drug developed by Chemocentrix Co., Ltd. of the United States for the treatment of severe active anti-neutrophil cytoplasmic autoantibody-associated vasculitis. Severely active antineutrophil cytoplasmic autoantibody-associated vasculitis is a rare systemic autoimmune disease involving small vessels. In previous decades, glucocorticoids were used to treat severe active antineutrophil cytoplasmic autoantibody-associated vasculitis. Although the prognosis of patients has been improved with the continuous optimization of treatment methods, long-term use of glucocorticoids produces Organ damage and other toxic reactions threaten patient health. Alvacopam phase III clinical trial data show that the 26-week remission effect of alvacopam in the treatment of patients with severe active anti-neut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60
CPCC07D211/60C07B53/00B01J31/186C07B2200/07B01J2231/645B01J2531/822
Inventor 李雁武胡叶敏
Owner CHONGQING MEDICAL UNIVERSITY
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