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Method for preparing N-substituted-1,2,3,6-tetrahydropyridine

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

Active Publication Date: 2018-03-23
SHANGHAI HOBOR CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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  • Method for preparing N-substituted-1,2,3,6-tetrahydropyridine

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Experimental program
Comparison scheme
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Embodiment 1

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

[0017]

[0018] In a 500mL three-neck flask, dissolve N-benzyl-4-piperidinol (38.3g, 0.2mol) and triphenylphosphine (78.7g, 0.3mol) in 400mL dichloromethane at -5~0℃ Add diisopropyl azodicarboxylate (60.7g, 0.3mol) dropwise, after dropping, stir at room temperature for 4 hours, after the reaction is over, cool to below -20°C, stir to precipitate solid, filter, filter out PPh3O / (NHCO2i- Pr)2 complex 89.7g, the filtrate was distilled to remove the solvent, n-heptane was added, and the mixture was stirred at 0°C for 1 hour to filter out 4.8g of solid complex. The filtrate was concentrated to remove the solvent and then distilled under reduced pressure to obtain a colorless oil 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-neck flask, dissolve N-benzyl-4-piperidinol (38.3g, 0.2mol) and triphenylphosphine (63.0g, 0.24mol) in 400mL tetrahydrofuran, and add dropwise at -5~0℃ Diethyl azodicarboxylate (41.8g, 0.24mol), after dripping, stir at room temperature for 4 hours, after the reaction, cool to below -20℃, stir to precipitate solid, filter, filter out PPh3O / (NHCO2Et)2 complex The solvent was distilled from the filtrate, n-hexane was added, and the mixture was stirred at 0°C for 1 hour to filter out 6.1g of solid complex. The filtrate was concentrated to remove the solvent and distilled under reduced pressure to obtain a colorless oil 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 the coupling dropwise at -5~0℃. Diisopropyl azodicarboxylate (80.9g, 0.4mol), after dripping, stir at room temperature for 4 hours, after the reaction, cool to below -20°C, stir to precipitate solid, filter, filter out PPh3O / (NHCO2i-Pr)2 Complex 80.0g, the solvent was distilled from the filtrate, n-heptane was added, and the mixture was stirred at 0°C for 1 hour to filter out 6.9g of solid complex. The filtrate was concentrated to remove the solvent and then 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 and belongs to the technical field of organic chemistry. N-substituted-4-piperidinol as a raw material reacts with triphenylphosphine and azodicarbonic acid diester, alcoholic hydroxyl groups are converted into alkenyl groups, and N-substituted-1,2,3,6-tetrahydropyridine is prepared. The method has the advantages that the raw materials are easily available, the operation is simple and convenient, the product purity is high, demands of the conventional method for high-temperature condition and highly toxic chemicals are avoided, and the method has potential route advantage.

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, anti-tumor, treatment of Alzheimer's disease 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. It is widely used in the synthesis of pharmaceutical intermediates such as kinase inhibitors, and has developed a synthetic method suitable for industrial production. important meaning. [0003] At present, the synthetic methods of this compound mainly include the following two: 1) 1,2,3,6-tetrahydropyridine reacts directly with the protecting group to obtain N-substituted-1,2,3,6-tetrahydropyridine (Tetrahedron, 2014 ,70,3893...

Claims

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Application Information

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