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Preparation method of 2-isopropoxy-5-methyl-4-(piperidine-4-yl) aniline dihydrochloride

A technology of aniline dihydrochloride and propyloxy, which is applied in the field of medicine, can solve the problems of long reaction time of the preparation method, harsh conditions of the preparation method, and low safety, and achieve short synthesis time, easy operation and control, and economical energy effect

Active Publication Date: 2017-05-17
山东轩德医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The Chinese invention patent application CN201410625539.6 introduces the preparation method of ceritinib and its intermediates. However, a hydrogenation kettle is used in this method, and a pressurized reaction is required. The preparation method has harsh conditions and low safety, and the preparation method Long reaction time, waste of energy, not conducive to environmental protection

Method used

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  • Preparation method of 2-isopropoxy-5-methyl-4-(piperidine-4-yl) aniline dihydrochloride
  • Preparation method of 2-isopropoxy-5-methyl-4-(piperidine-4-yl) aniline dihydrochloride
  • Preparation method of 2-isopropoxy-5-methyl-4-(piperidine-4-yl) aniline dihydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1: Preparation of 1-chloro-5-isopropyloxy-2-methyl-4-nitrobenzene

[0031]

[0032] Add 1.5L of isopropanol, 1-chloro-5-fluoro-2-methyl-4-nitrobenzene (260g) and add solid potassium hydroxide (116g) in batches at a temperature of 15-25°C, and keep warm for 20 ℃ reaction, monitor the disappearance of raw materials, stop stirring, add the reaction solution to 5L water, filter, and dry the filter cake to obtain the product 1-chloro-5-isopropyloxy-2-methyl-4-nitrobenzene, 271g , Yield: 86.3%.

Embodiment 2

[0033] Example 2: Preparation of 4-(5-isopropyloxy-2-methyl-4-nitrophenyl)pyridine

[0034]

[0035] 4-pyridineboronic acid (51.5g), 1-chloro-5-isopropyloxy-2-methyl-4-nitrobenzene (96.2g), 2-dicyclohexylphosphine-2',6'- Dimethoxy-biphenyl (6.87g), catalyst Pd2 (dba) 3 (7.68g), potassium phosphate (245.7g), 1.4-dioxane (840ml), water (240ml) add in the reaction flask, nitrogen Substitute three times, keep the internal temperature 60-70°C under the protection of nitrogen, monitor the disappearance of raw materials, and stop the reaction. When the temperature of the reaction liquid is lowered to below 30°C, add activated carbon, stir, spread and filter with diatomaceous earth, separate the filtrate, distill out the dioxane from the organic phase under reduced pressure, add 500ml of n-heptane, stir and crystallize at 40°C. Cool to 10°C, filter and dry to obtain the product 4-(5-isopropyloxy-2-methyl-4-nitrophenyl)pyridine, 89g, yield 77.9%.

Embodiment 3

[0036] Example 3: Preparation of 1-benzyl-4-(5-isopropyloxy-2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine

[0037]

[0038] 4-(5-isopropyloxy-2-methyl-4-nitrophenyl)pyridine (13.7g), benzyl bromide (11.4g) and toluene (150ml) were reacted under heating for 12 hours. Monitor the disappearance of raw materials, cool to 20-25°C, filter with suction, add the filter cake to 100ml of methanol, add lithium chloride (0.57g), control the temperature at 20-30°C, add sodium borohydride (5.1g) while stirring. After the addition, slowly rise to 20-30°C for 8 hours of reaction. After monitoring the completion of the reaction, 10 ml of saturated ammonium chloride aqueous solution was added dropwise to the reaction solution, and the methanol was distilled off under reduced pressure. Add 50ml ethyl acetate, 50ml water solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1-benzyl-4-(5-isopropyloxy-2-methyl-4-nitrophenyl)...

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Abstract

The invention relates to a preparation method of 2-isopropoxy-5-methyl-4-(piperidine-4-yl) aniline dihydrochloride. The preparation method comprises the following steps: carrying out a nucleophilic substitution reaction, a coupling reaction and a reduction reaction by taking 1-chloro-5-fluoro-2-methyl-4-nitrobenzene as a starting material so as to obtain 1-benzyl-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine; carrying out a reduction reaction on the 1-benzyl-4-(5-isopropoxy-2-methyl-4-nitrophenyl)-1,2,3,6-tetrahydropyridine again to obtain the 2-isopropoxy-5-methyl-4-(piperidine-4-yl) aniline dihydrochloride. The method does not use catalysts such as platinum and rhodium, is simple and convenient in reaction technology and high in yield, avoids the high pressure reaction condition of the existing process, improves the safety, and shortens the reaction time, thus being suitable for mass production.

Description

[0001] 1. Technical field [0002] The invention belongs to the technical field of medicine and relates to a method for preparing 2-isopropyloxy-5-methyl-4-(piperidin-4-yl)aniline dihydrochloride. [0003] 2. Background technology [0004] Ceritinib is an ALT(+)-targeted inhibitor of base drugs, suitable for anaplastic lymphoma kinase (ALK)-positive patients who have progressed or cannot tolerate crizotinib treatment The treatment of patients with metastatic non-small cell lung cancer (NSCLC) was first approved by the US Food and Drug Administration in April 2015. [0005] The Chinese invention patent application CN201410625539.6 introduces the preparation method of ceritinib and its intermediates. However, a hydrogenation kettle is used in this method, and a pressurized reaction is required. The preparation method has harsh conditions and low safety, and the preparation method The reaction time is long, wastes energy, and is not conducive to environmental protection. [0006...

Claims

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Application Information

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IPC IPC(8): C07D211/26
CPCC07D211/26
Inventor 董岩岩
Owner 山东轩德医药科技有限公司
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