Synthesizing method for N, N-double substitution-3-amino isoxazole-5-methanol compound

A technology for the synthesis of aminoisoxazoles and methods, which is applied in the field of synthesizing N,N-disubstituted-3-aminoisoxazole-5-methanol compounds, can solve the problems of long steps and harsh reaction conditions, and achieve mild reaction conditions , the reaction steps are simple, avoid the effect of catalyst

Active Publication Date: 2012-07-11
WUXI BIOLOGICS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves technical problems such as long steps, harsh reaction conditions, and use of highly toxic reagents in existing synthetic methods

Method used

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  • Synthesizing method for N, N-double substitution-3-amino isoxazole-5-methanol compound
  • Synthesizing method for N, N-double substitution-3-amino isoxazole-5-methanol compound
  • Synthesizing method for N, N-double substitution-3-amino isoxazole-5-methanol compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014]

[0015] 3a Preparation of : Add 3-bromo-isoxazole-5-methanol (25 g, 140 mmol), cesium fluoride (42 g, 280 mmol) and pyrrolidine (20 mL ), when the addition is complete, seal the PTFE tank, and at 100 o C for 18 hours. After the reaction was completed, the jar was cooled to room temperature, the product was transferred to a 100 mL round-bottomed flask and spin-dried, then 100 mL of water was added to the flask to dissolve, extracted with dichloromethane (three times, 50 mL each), and combined The organic phase was dried with anhydrous sodium sulfate for one hour, filtered, concentrated, and separated by column chromatography (the volume ratio of developing solvent: petroleum ether to ethyl acetate was 2:1) to obtain the product 3-pyrrolidinyl-isoxazole-5- Methanol ( 3a ) 16.4 g, the yield was 70%. The product is a white solid.

[0016] 1 H NMR (400 MHz, d -DMSO) δ 5.90 (s, 1 H), 5.48 (t, J = 6.0 Hz, 1 H), 4.38 (d, J = 6.0 Hz, 2 H), 3.19-3.16 (m, 4 H), 1.8...

Embodiment 2

[0018]

[0019] 3b Preparation: In a dry 100 mL tetrafluoro tank, add 3-bromo-isoxazole-5-methanol (15 g, 84 mmol), cesium fluoride (32 g, 210 mmol) and 4-methylpiperone in sequence Pyridine (15 mL), after the addition is complete, seal the tetrafluoro stuffy jar, at 100 o C for 36 hours. After the reaction was completed, the jar was cooled to room temperature, the product was transferred to a 100 mL round-bottomed flask and spin-dried, then 100 mL of water was added to the flask to dissolve, extracted with dichloromethane (three times, 50 mL each), and combined The organic phase. Dry with anhydrous sodium sulfate for one hour, filter, concentrate, and separate by column chromatography (developing solvent: petroleum ether to ethyl acetate volume ratio is 2:1) to obtain the product 3-(4-methylpiperidinyl)-isoxazole -5-methanol ( 3b ) 9.8 g, the yield was 60%. The product is a white solid.

[0020] 1 H NMR (400 MHz, d -DMSO) δ 6.11 (s,1 H), 5.50-5.47 (t, J = 6.0 Hz...

Embodiment 3

[0022]

[0023] 3c Preparation of : Add 3-bromo-isoxazole-5-methanol (20 g, 112 mmol), cesium fluoride (17 g, 112 mmol) and piperidine (30 mL ), after the addition is complete, seal the PTFE tank, and at 120 o C for 72 hours. After the reaction was completed, the jar was cooled to room temperature, the product was transferred to a 100 mL round-bottomed flask and spin-dried, then 100 mL of water was added to the flask to dissolve, extracted with dichloromethane (three times, 50 mL each), and combined The organic phase. Dry with anhydrous sodium sulfate for one hour, filter, concentrate, and separate by column chromatography (developing solvent: sherwood oil to ethyl acetate volume ratio is 1:1) to obtain the product 3-piperidinyl-isoxazole-5-methanol ( 3c ) 16 g, the yield was 77 %. The product is a white solid.

[0024] 1 H NMR (400 MHz, d -DMSO) δ 6.14 (s, 1 H), 5.53-5.52 (t, J = 5.6 Hz, 1 H), 4.39-4.38 (d, J = 6.0 Hz, 2 H), 3.15-3.14 (m, 4 H), 1.54-1.53 ​​(m,...

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Abstract

The invention relates to a synthesizing method for an N, N-double substitution-3-amino isoxazole-5-methanol compound, and mainly solves the technical problems of long procedure, rigorous reaction conditions, toxic reagent using and the like in the conventional synthesis method. The synthesizing method for N, N-double substitution-3-amino isoxazole-5-methanol compound in the invention comprises the steps as follows: under the action of cesium fluoride, 3-bromine isoxazole-5-methenol 1 and an amine compound 2 are directly subjected to substitution reaction on a solvent-free condition to generate the N, N-double substitution-3-amino isoxazole-5-methanol compound 3. The reaction formula is as follows: the amine compound in one of pyrrolidine, piperidine and 4-methylpiperidine.

Description

technical field [0001] The invention relates to a synthetic N,N - Process for disubstituted-3-aminoisoxazole-5-methanol compounds. Background technique [0002] Isoxazole derivatives are a class of compounds with medicinal value, and their derivatives have been used clinically as anti-arthritis drugs ( J. A. Clzn. Rheum. Dis. 1984 , 10, 385 . ), can also be used as a diuretic ( J. Indian Chem. Soc. 1946, 23 , 189.; Jpn. Kokai. Tokkyo Koho. JP79 14, 968 etc.) and precursors of pesticides ( Jpn. Kokai Tokkyo Koho JP 79 09,278), which has great development and utilization value in medicine and pesticides. As an important isoxazole derivative, 3-aminoisoxazole-5-methanol has attracted much attention in recent years due to its potential medicinal value ( PCT Int. Appl. , 2008036653). Unfortunately, only a small number of documents have reported its synthetic methods, and these methods have long synthetic steps, harsh reaction conditions, and use reagents such as hi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/14C07D413/04
Inventor 周超马子倩柏祝段亚洲王智勇刘培元刘斯斯贺海鹰陈曙辉
Owner WUXI BIOLOGICS CO LTD
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