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Synthesis method of 3, 4-dihydro-2H-pyrano [2, 3-b] pyridine

A synthetic method, 3-b technology, applied in the direction of organic chemistry, can solve the problems of unavailable raw materials, expensive reagents, cumbersome operation, etc., and achieve the effect of easy separation and purification, and short route

Pending Publication Date: 2021-05-25
KANGHUA SHANGHAI DRUG RES DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The purpose of the present invention is to overcome the disadvantages of the existing routes, such as the difficulty in obtaining raw materials, expensive reagents, cumbersome operation, high risk, and high energy consumption, and provide a 3,4-dihydro-2H-pyrano[2, A new method for the synthesis of 3-b]pyridine

Method used

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  • Synthesis method of 3, 4-dihydro-2H-pyrano [2, 3-b] pyridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] In the first step, 3-bromopyridine (50g, 0.32mol) was dissolved in 250 mL of tetrahydrofuran, lithium diisopropylamide (0.44mol) was added dropwise at -50°C, and reacted for 1 hour, then DMF (28g, 0.38mol) was added , continued the reaction for 1 hour, quenched the reaction by adding water at 0°C, extracted with methyl tert-butyl ether, washed the organic phase with water, concentrated to remove most of the solvent, added petroleum ether to form a solid, filtered and dried to obtain compound 1 (46g, yield 78 %);

[0014] In the second step, triethyl acetyl phosphate (59g, 0.26mol) was dissolved in THF (800 mL), and NaH (12g, 0.31mol) was slowly added under ice-cooling conditions, and reacted for 0.5h; compound 1 (41g, 0.22 mol), react for 1h. After the reaction is completed, add water to quench, extract the aqueous phase with ethyl acetate, wash the organic phase twice with saturated brine, dry over anhydrous sodium sulfate, concentrate to remove most of the solvent, a...

Embodiment 2

[0018] In the first step, 3-bromopyridine (50g, 0.32mol) was dissolved in 250 mL of tetrahydrofuran, lithium tetramethylpiperidine (0.44mol) was added dropwise at -80°C, and reacted for 2 hours, then ethyl formate (28g, 0.38 mol), continue to react for 1 hour, quench the reaction by adding water at 0°C, extract with methyl tert-butyl ether, wash the organic phase with water, concentrate to remove most of the solvent, add petroleum ether to form a solid, filter and dry to obtain compound 1 (44g, product rate 75%);

[0019] In the second step, triethyl acetyl phosphate (59 g, 0.26 mol) was dissolved in THF (800 mL), and potassium tert-butoxide (35 g, 0.31 mol) was slowly added under ice-cooling conditions, and reacted for 0.5 h; compound 1 ( 41g, 0.22mol), react for 1h. After the reaction is completed, add water to quench, extract the aqueous phase with ethyl acetate, wash the organic phase twice with saturated brine, dry over anhydrous sodium sulfate, concentrate to remove mos...

Embodiment 3

[0023] In the first step, 3-bromopyridine (50g, 0.32mol) was dissolved in 250 mL of tetrahydrofuran, lithium tetramethylpiperidine (0.44mol) was added dropwise at -30°C, and reacted for 2 hours, then ethyl formate (28g, 0.38 mol), continue to react for 1 hour, quench the reaction by adding water at 0°C, extract with methyl tert-butyl ether, wash the organic phase with water, concentrate to remove most of the solvent, add petroleum ether to form a solid, filter and dry to obtain compound 1 (43g, product rate 73%);

[0024] In the second step, triethyl acetyl phosphate (59 g, 0.26 mol) was dissolved in THF (800 mL), and potassium tert-butoxide (35 g, 0.31 mol) was slowly added under ice-cooling conditions, and reacted for 0.5 h; compound 1 ( 41g, 0.22mol), react for 1h. After the reaction is completed, add water to quench, extract the aqueous phase with ethyl acetate, wash the organic phase twice with saturated brine, dry over anhydrous sodium sulfate, concentrate to remove mos...

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Abstract

The invention relates to a synthesis method of 3, 4-dihydro-2H-pyrano [2, 3-b] pyridine. The problems of difficult availability of raw materials, expensive reagents, complicated operation, high risk, high energy consumption and the like in the existing route are mainly solved. The method is realized through the following technical scheme: (1) reacting 2-bromopyridine with a formylation reagent under the action of alkali to generate 2-bromo-3-formylpyridine; (2) reacting an aldehyde group of the 2-bromine-3-formylpyridine with triethyl phosphonoacetate to generate 2-bromine-3-pyridine ethyl acrylate; (3) simultaneously reducing double bonds and ester groups of 2-bromo-3-pyridine ethyl acrylate by lithium borohydride in one step while enabling bromine not to be influenced, so as to obtain 2-bromo-3-pyridine propanol; and (4) carrying out ring closing on the 2-bromo-3-pyridyl propanol under the action of alkali to obtain a target compound.

Description

technical field [0001] The invention relates to a method for synthesizing 3,4-dihydro-2H-pyrano[2,3-b]pyridine. Background technique [0002] 3,4-Dihydro-2H-pyrano[2,3-b]pyridine (CAS: 26267-89-0) is an expensive fine chemical product. There are two main synthetic routes at present, the first A route (Organic Chemistry Communications, 21, 2482-2487; 2019), [0003] The route raw material compound 1 is very difficult whether it is synthesized in the laboratory or obtained commercially, and the expensive heavy metal catalyst methanesulfonic acid (2-dicyclohexylphosphine-2', 6'-diisopropoxy -1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II); the second route (Tetrahedron, 43, 5145-58; 1987 and Tetrahedron Communications, 27, 431-2; 1986), which discloses route two, [0004] This route is cumbersome to operate, and uses explosive reagents (m-chloroperoxybenzoic acid) and involves high-temperature reactions above 200°C, requiring high mechanical equipment and ...

Claims

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Application Information

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IPC IPC(8): C07D491/052
CPCC07D491/052
Inventor 徐红岩李响
Owner KANGHUA SHANGHAI DRUG RES DEV CO LTD
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