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Preparation method of ceritinib and intermediate

A technology of ceritinib and intermediates, which is applied in the field of preparation of ceritinib and its intermediates, can solve the problems of increased side reactions, cumbersome operations, and reduced total yield, and achieves mild conditions, simple processes, and side effects. Response reduction effect

Active Publication Date: 2014-08-20
SCI GENERAL MATERIAL & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Investigate this method, because the three chlorine atoms in the starting material 2,4,5-trichloropyrimidine (IX) have limited selectivity differences when nucleophilic substitution reactions occur, there are multiple competitive reactions, which increase side reactions
In the actual operation process, in order to reduce side reactions, the piperidine ring in the raw material (XII) has to be protected by Boc of secondary amines, thereby increasing the reaction steps; at the same time, due to the existence of side reactions, the post-treatment of most reactions has to Purification and separation by column chromatography, the operation is cumbersome, the total yield is reduced, and it is not suitable for the requirements of industrial scale-up

Method used

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  • Preparation method of ceritinib and intermediate
  • Preparation method of ceritinib and intermediate
  • Preparation method of ceritinib and intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Add 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine (II) (2.72g, 10mmol) and 10% palladium carbon (0.27g, 10%w / w), 25mL saturated hydrogen chloride isopropanol solution and 100mL isopropanol, according to the hydrogenation reaction operation procedure, feed hydrogen, keep at 50-60°C, 8-10Kg / em 2 The reaction was stirred for 16 hours until hydrogen was no longer consumed. Cool, filter and recover palladium carbon, concentrate under reduced pressure to recover the solvent, dissolve the residue with dichloromethane and wash with saturated sodium bicarbonate, separate the organic phase, concentrate under reduced pressure, and the obtained crude product is washed with ethyl acetate and n-hexane (1:1) Recrystallization gave 2.27 g of off-white solid 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (III), with a yield of 91.5%.

Embodiment 2

[0032] Add 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine (II) (2.72g, 10mmol), Raney nickel (0.54g), 0.1mL concentrated Sulfuric acid and 120mL isopropanol, according to the hydrogenation reaction operating procedure, pass in hydrogen, keep at 40-50°C, 5-8Kg / cm 2 The reaction was stirred for 22 hours until hydrogen was no longer consumed. Cool, filter to recover the catalyst, concentrate under reduced pressure to recover the solvent, dissolve the residue with dichloromethane and wash with saturated sodium bicarbonate, separate the organic phase, concentrate under reduced pressure, and weigh the obtained crude product with ethyl acetate and n-hexane (1:1). Crystallized to obtain 2.21 g of off-white solid 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (III), with a yield of 89.1%.

Embodiment 3

[0034]Add 2-isopropoxy-5-methyl-4-(piperidin-4-yl)aniline (III) (2.48g, 10mmol), 5mL of 40% hydrobromic acid solution and 20mL of water into the three-necked flask, keep At 0-5°C, a 20 mL aqueous solution of sodium nitrite (1.38 g, 20 mmol) was added dropwise, and the reaction was continued for 2 hours after the drop was completed. Add cuprous bromide (1.57g, 11mmol), heat up to 50-60°C, react for 2 hours, cool, filter to remove solids, extract the mother liquor 3 times with dichloromethane, combine the organic phases, and successively wash with saturated sodium bicarbonate solution Wash with saturated brine, dry over anhydrous sodium sulfate, recover the solvent under reduced pressure, and the resulting oil is 2-isopropoxy-5-methyl-4-(piperidin-4-yl)bromobenzene (I) 2.58g , yield 83.0%.

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Abstract

The invention discloses an intermediate 2-isopropoxy-5-methyl-4-(piperidyl-4-yl)halogeno-benzene (I) for preparing ceritinib and a preparation method thereof. The preparation method comprises the following steps: carrying out catalytic hydrogenation on the raw material 4-(5-isopropoxy-2-methyl-4-nitrophenyl)pyridine (II) to obtain 2-isopropoxy-5-methyl-4-(piperidyl-4-yl)aniline (III); and carrying out Sandmeyer reaction on the compound (III) to obtain the 2-isopropoxy-5-methyl-4-(piperidyl-4-yl)halogeno-benzene (I). The invention also discloses a preparation method of ceritinib. The 2-isopropoxy-5-methyl-4-(piperidyl-4-yl)halogeno-benzene (I) used as the raw material is sequentially subjected to substitution, reduction and substitution reaction to obtain the ceritinib (VIII). The preparation method has the advantages of simple technique, mild conditions and fewer side reactions, and is suitable for industrial amplification.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of Ceritinib and intermediates thereof. Background technique [0002] Ceritinib (formerly known as LDK378) is an anaplastic lymphoma enzyme (ALK) tyrosine kinase inhibitor developed by Novartis. The treatment of patients with metastatic NSCLC whose disease has progressed or cannot be tolerated after Crizotinib treatment, the trade name is Zykadia. Since the drug has not been officially marketed in my country and does not have a standard Chinese translation, the applicant hereby transliterates it as "ceritinib". Ceritinib is the second ALK inhibitor approved by the FDA after Crizotinib, and also the second drug to be marketed through the quadruple special approval channel after Ibrutinib. [0003] Ceritinib (Ceritinib, VIII), the chemical name is 5-chloro-N 2 -[2-Isopropox...

Claims

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Application Information

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IPC IPC(8): C07D211/22C07D401/12
CPCC07D211/22C07D401/12
Inventor 许学农
Owner SCI GENERAL MATERIAL & CHEM
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