A method for preparing n-substituted-1,2,3,6-tetrahydropyridine

A technology of tetrahydropyridine and piperidinol, applied in organic chemistry and other directions, can solve problems such as restricting amplification synthesis, unfriendly environment, irritating odor, etc., and achieve the effect of improving market competitiveness, environmental friendliness, and avoiding high temperature reactions

Active Publication Date: 2021-01-29
SHANGHAI HOBOR CHEM CO LTD
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  • Abstract
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  • Claims
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AI Technical Summary

Problems solved by technology

[0003] At present, the synthesis methods of this compound mainly include the following two types: 1) direct reaction of 1,2,3,6-tetrahydropyridine with a protecting group to obtain N-substituted-1,2,3,6-tetrahydropyridine (Tetrahedron, 2014 , 70, 3893–3900; J.Org.Chem., 1991, 56, 3133–3137; Synth.Commun., 2015, 45, 2259–2265), although this method is simple to operate and only has one-step reaction, the raw materials The source of 1,2,3,6-tetrahydropyridine is limited and difficult to obtain
[0004] The second one, N-substituted-4-piperidine sulfonate and strong base DUB or potassium tert-butoxide in a high boiling point solvent, heated to about 75-150 ° C to eliminate N-substituted-1,2,3, 6-tetrahydropyridine (WO201371697, WO2010 / 16005; Tetrahedron Lett., 2010, 51, 5191-5194), the reaction temperature of this method is close to 150°C, and the energy consumption is serious; the raw material used is N-substituted-4-piperidine sulfonate It needs to be prepared by reacting N-substituted-4-piperidinol with methanesulfonyl chloride or p-toluenesulfonyl chloride. Methanesulfonyl chloride or p-toluenesulfonyl chloride has a pungent smell and strong corrosion, and methanesulfonyl chloride is a highly toxic chemical , the purchase is subject to certain restrictions, and it is not friendly to the environment, which restricts the amplified synthesis of this type of compound

Method used

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  • A method for preparing n-substituted-1,2,3,6-tetrahydropyridine
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  • A method for preparing n-substituted-1,2,3,6-tetrahydropyridine

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Experimental program
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Effect test

Embodiment 1

[0016] Synthesis of N-Benzyl-1,2,3,6-tetrahydropyridine

[0017]

[0018] In a 500mL three-necked flask, dissolve N-benzyl-4-piperidinol (38.3g, 0.2mol) and triphenylphosphine (78.7g, 0.3mol) in 400mL of dichloromethane, and Add diisopropyl azodicarboxylate (60.7 g, 0.3 mol) dropwise, and stir at room temperature for 4 hours. After the reaction, cool down to below -20°C, stir to precipitate a solid, filter, and filter out PPh3O / (NHCO2i- Pr)2 complex 89.7g, the filtrate distilled off the solvent, added n-heptane, stirred at 0°C for 1 hour, filtered out 4.8g of the solid complex, concentrated the filtrate to remove the solvent, and distilled under reduced pressure to obtain a colorless oily substance N- Benzyl-1,2,3,6-tetrahydropyridine 28.8g (95-98℃ / 5mmHg), yield 83.5%, GC: 98.7%, 1 HNMR (400MHz, CDCl3): δ2.15-2.22 (2H, m), 2.58 (t, J = 5.6, 2H), 2.97-3.01 (2H, m), 3.60 (2H, s), 5.65-5.71 (1H ,m), 5.74-5.81(1H,m), 7.24-7.40(5H,m).

Embodiment 2

[0020] Synthesis of N-Benzyl-1,2,3,6-tetrahydropyridine

[0021]

[0022] In a 500mL three-necked flask, dissolve N-benzyl-4-piperidinol (38.3g, 0.2mol) and triphenylphosphine (63.0g, 0.24mol) in 400mL tetrahydrofuran, and add dropwise Diethyl azodicarboxylate (41.8g, 0.24mol), after dropping, stir at room temperature for 4 hours, after the reaction, cool down to below -20°C, stir to precipitate a solid, filter, filter out PPh3O / (NHCO2Et)2 complex 80.5 g of compound, the filtrate distilled off the solvent, added n-hexane, stirred at 0°C for 1 hour, filtered out 6.1 g of the solid complex, concentrated the filtrate to remove the solvent, and distilled under reduced pressure to obtain a colorless oily substance N-benzyl-1,2 , 3,6-tetrahydropyridine 28.5g (95-98°C / 5mmHg), yield 82.3%, GC: 98.8%.

Embodiment 3

[0024] Synthesis of N-Boc-1,2,3,6-tetrahydropyridine

[0025]

[0026] In a 500mL three-necked flask, dissolve N-Boc-4-piperidinol (40.3g, 0.2mol) and triphenylphosphine (104.9g, 0.4mol) in 400mL tetrahydrofuran, and add Diisopropyl nitrogen dicarboxylate (80.9g, 0.4mol), after dropping, stir at room temperature for 4 hours, after the reaction, cool down to below -20°C, stir to precipitate a solid, filter, and filter out PPh3O / (NHCO2i-Pr)2 Complex 80.0g, the filtrate distilled off the solvent, added n-heptane, stirred at 0°C for 1 hour, filtered out 6.9g of the solid complex, concentrated the filtrate to remove the solvent, and distilled under reduced pressure to obtain a light yellow oil N-Boc-1 ,2,3,6-Tetrahydropyridine 31.2g (55-57℃ / 3mmHg), yield 85.1%, GC detection: purity 98.5%, 1 H-NMR (400MHz, CDCl3): δ5.83–5.74(m,1H),5.67–5.57(m,1H),3.84(2H),3.45(2H),2.09(m,2H),1.44(s, 9H).

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Abstract

The invention discloses a method for preparing N-substituted-1,2,3,6-tetrahydropyridine, which belongs to the technical field of organic chemistry. Using N-substituted-4-piperidinol as raw material, reacting with triphenylphosphine and azodicarboxylate to convert alcoholic hydroxyl group into alkenyl group to obtain N-substituted-1,2,3,6-tetrahydropyridine. The method is easy to obtain raw materials, easy to operate, and high in product purity, avoids the need for high temperature conditions and the use of highly toxic chemicals in previous methods, and has potential route advantages.

Description

Technical field: [0001] The invention relates to a method for preparing N-substituted-1,2,3,6-tetrahydropyridine, which belongs to the technical field of organic synthesis. Background technique: [0002] Many piperidine derivatives have various pharmacological activities such as antibacterial, antitumor, treatment of senile dementia and anesthesia, and are also one of the important drugs for the treatment of viral infections (including AIDS) and diabetes. N-substituted-1,2,3,6-tetrahydropyridine or its derivatives is one of the important intermediates, widely used in the synthesis of pharmaceutical intermediates such as kinase inhibitors, and the development of a synthetic method suitable for industrial production has important meaning. [0003] At present, the synthesis methods of this compound mainly include the following two types: 1) direct reaction of 1,2,3,6-tetrahydropyridine with a protecting group to obtain N-substituted-1,2,3,6-tetrahydropyridine (Tetrahedron, 201...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/70
CPCC07D211/70
Inventor 帅小华洪伟
Owner SHANGHAI HOBOR CHEM CO LTD
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