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Preparation method for 4-[4-(trifluoromethoxy)phenoxyl]piperidine

A technology of trifluoromethoxy and phenoxy is applied in the field of preparation of 4-[4-phenoxy] piperidine, an important intermediate of Delamanid, and can solve the problem that 4-halogen pyridine is expensive, incomplete impurities and equipment requirements Advanced problems, to achieve the effect of low cost, low equipment requirements, and cheap raw materials

Inactive Publication Date: 2016-04-06
SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] In this method, the starting material 4-halopyridine is very expensive, and expensive PtO is needed in the subsequent reaction. 2 For catalysis, the equipment requirements are very high, and there are likely to be incompletely reduced impurities
The impurity is similar to the polarity of the product and is difficult to remove

Method used

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  • Preparation method for 4-[4-(trifluoromethoxy)phenoxyl]piperidine
  • Preparation method for 4-[4-(trifluoromethoxy)phenoxyl]piperidine
  • Preparation method for 4-[4-(trifluoromethoxy)phenoxyl]piperidine

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Embodiment 1

[0038] The preparation of embodiment 1N-benzyl-4-[4-(trifluoromethoxy) phenoxy] pyridinium salt (formula III compound)

[0039] Add 2500 g of the compound of formula II and 6 L of petroleum ether to the reaction kettle in sequence, start stirring, add 1676.0 g of benzyl bromide, heat up to reflux for 16 hours, TLC (dichloromethane:methanol=10:1) monitors the disappearance of raw materials, and stops heating. Cool down to 15-25°C with an ice-water bath, a large amount of viscous oil precipitates, let it stand still, pour the supernatant liquid, the remaining oil precipitates into a solid, and dry to obtain 3700.0g of solid with a yield of 90.0% and a purity of 98.4% .

[0040] 1 HNMR (500MHz, chloroform) δ: 8.89-8.9(d,2H), 7.65-7.66(d,2H), 7.49-7.51(m,2H), 7.38-7.41(m,3H), 7.18-7.21(d, 2H), 6.98-6.98(d, 2H), 6.15(s, 2H).

[0041] 13 CNMR (125MHz, CDCl 3 )δ: 165.13, 154.38, 150.02-149.64, 142.72, 138.31, 129.31, 129.02, 128.45, 123.80, 121.93, 118.77, 118.58, 62.80.

[004...

Embodiment 2

[0043] The preparation of embodiment 2N-benzyl-4-[4-(trifluoromethoxy) phenoxy] pyridinium salt (formula III compound)

[0044]Add 100 g of the compound of formula II and 300 ml of toluene to the reaction flask in sequence, start stirring, add 70.0 g of benzyl bromide, heat up to reflux for 4 hours, TLC (dichloromethane:methanol=10:1) monitors the disappearance of raw materials, and stops heating. After cooling down, a large amount of viscous oil was precipitated, left to stand, poured the supernatant liquid, the remaining oil was stirred and crystallized, filtered with suction, and dried to obtain 151.0 g of solid, with a yield of 95.0% and a purity of 99.2%.

[0045] ESI-LR:347.1[M+H] + .

Embodiment 3

[0046] The preparation of embodiment 3N-benzyl-4-[4-(trifluoromethoxy) phenoxy group] pyridinium salt (formula III compound)

[0047] Add 100 g of the compound of formula II and 300 mL of toluene to the reaction flask in sequence, start stirring, add 52.5 g of benzyl chloride, and raise the temperature to reflux. After reflux reaction for 4 hours, TLC (dichloromethane:methanol=10:1) monitored the complete reaction of raw materials, and stopped heating. When the temperature was lowered, a large amount of viscous oil was precipitated, the supernatant was poured, and the remaining oil was stirred and crystallized, filtered by suction, and dried to obtain 111.2 g of solid, with a yield of 70.0% and a purity of 96.6%.

[0048] ESI-LR:347.1[M+H] + .

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Abstract

The invention discloses a preparation method for 4-[4-(trifluoromethoxy)phenoxyl]piperidine. The preparation method comprises the following steps: 1) synthesizing N-benzyl (or substituted benzyl)-4-[4-(trifluoromethoxy)phenoxyl]pyridinium salt from 4-[4-(trifluoromethoxy)phenoxyl]pyridine and a benzyl group or substituted benzyl halide; 2) reducing the product of the step 1) into N-benzyl (or substituted benzyl)-1,2,3,6-tetrahydro-4-[4-(trifluoromethoxy)phenoxyl]pyridine; 3) reacting the product of the step 2) with acid and a hydrogen source so as to produce 4-[4-(trifluoromethoxy)phenoxyl]pyridin salt; and 4) reacting the product of the step 3) with alkali so as to produce 4-[4-(trifluoromethoxy)phenoxyl]piperidine. The method provided by the invention prepares 4-[4-(trifluoromethoxy)phenoxyl]piperidine from 4-[4-(trifluoromethoxy)phenoxyl]pyridine, is reduced in production cost and improves product yield and purity.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of 4-[4-(trifluoromethoxy)phenoxy]piperidine, an important intermediate of Delamanid. Background technique [0002] Deltyba TM (Delamanid) was developed by Otsuka Pharmaceutical Co., Ltd. and approved by the European Union in May 2014 for the treatment of adult patients with multidrug-resistant tuberculosis (MDR-TB). Delamanid is a bactericidal drug with a novel mechanism of action that interferes with the metabolism of the Mycobacterium tuberculosis (MTB) cell wall. The drug has strong bactericidal activity against various sensitive and drug-resistant tuberculosis in vitro and in vivo, especially against various multidrug-resistant Mycobacterium tuberculosis [PLoSMed, 2006, 3: 2131-2144; Drugs2010; 70(17) :2201-2214]. [0003] The structure of Delamanid is as follows: [0004] [0005] The main method of synthesizing Delamanid at present [WO2004035547...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/46
Inventor 陈义朗王天才樊后兴韩硕
Owner SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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