Ceritinic synthesis intermediate and preparation method thereof
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A technology of ceritinib and intermediates, which is applied in the field of drug synthesis and can solve problems affecting the yield and purity of the final product
Active Publication Date: 2016-07-20
SHANGHAI INST OF PHARMA IND +2
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[0009] And this impurity 3a influences t
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Embodiment 1
[0033] Embodiment 1. Synthesis of compound 7a
[0034]
[0035] Compound 1 (1.0g, 3.67mmol), benzyl chloride (0.56g, 4.40mmol), and 10ml of acetone were heated to reflux. After the reaction was completed, they were filtered to obtain 1.3g of compound 7a. MS: m / z=363; 1 HNMRδ(DMSO): 1.261-1.276 (6H, d), 2.187 (3H, s), 4.814-4.904 (1H, m), 6.002 (1H, s), 7.416 (1H, s), 7.454-.7513 (3H , m), 7.623-7.646 (2H, m), 7.893 (1H, s), 8.299-8.316 (2H, d), 9.332-9.349 (2H, d)
Embodiment 2
[0036] Embodiment 2. Synthesis of compound 7b
[0037]
[0038] Compound 1 (1.0g, 3.67mmol), benzyl bromide (0.75g, 4.40mmol), and 10ml of acetone were heated to reflux. After the reaction was completed, they were filtered to obtain 1.4g of compound 7b. MS: m / z=363; 1 HNMRδ(DMSO): 1.261-1.276 (6H, d), 2.187 (3H, s), 4.816-4.908 (1H, m), 6.005 (2H, s), 7.416 (1H, s), 7.454-.7512 (3H , m), 7.623-7.646 (2H, m), 7.898 (1H, s), 8.297-8.313 (2H, d), 9.331-9.347 (2H, d)
Embodiment 3
[0039] Embodiment 3. Synthesis of compound 7c
[0040]
[0041] Compound 1 (1.0g, 3.67mmol), 3-methoxybenzyl chloride (0.69g, 4.40mmol), and 10ml of acetonitrile were heated to reflux. After the reaction was completed, they were filtered to obtain 1.4g of compound 7c. MS: m / z=393; 1 HNMRδ(DMSO): 1.261-1.276 (6H, d), 2.188 (3H, s), 3.832 (1H, s), 6.005 (2H, s), 6.889 (1H, m), 7.008 (1H, s) 7.283 ( 1H, s), 7.454-.7508 (2H, m), 7.611-7.632 (2H, m), 7.993 (1H, s), 8.304-8.317 (2H, d), 9.344-9.358 (2H, d).
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Abstract
The invention provides a synthesis intermediate 7 of an anti-tumor drug ceritinib. The intermediate 7 has a structural general formula as the following image. In the formula, Ar is phenyl or phenyl substituted by C1-C4 alkyl, C1-C4 alkoxyl, cyano, nitro or halogen; and X is Cl or Br. A preparation method of the intermediate 7 comprises the following step: the intermediate 7 is produced through a reaction of a compound 1 and substituted or unsubstituted benzyl halide (or ArCH2X). The invention also provides a novel route for applying an intermediate 7b in synthesizing ceritinib. With the route, a problem of using expensive platinum oxide as a reduction catalyst in an existing route 1 can be avoided. In the synthesis route 2 for synthesizing ceritinib with the compound 7b, the obtained synthesis intermediate 7b is quaternary ammonium salt. The salt can be precipitated from a solvent, and can be obtained by filtration, such that impurities can be retained in filtrate. Also, the conditions for all steps of reactions in the synthesis route 2 are mild, and post-treatment is simple. All the obtained intermediates 8b-10b do not need column chromatography purification. Therefore, the route is suitable for industrialized production.
Description
technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthetic intermediate of an antitumor drug-ceritinib and a preparation method thereof. Background technique [0002] Ceritinib, the chemical name is 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-( Propane-2-sulfonyl)-phenyl)-pyrimidine-2,4-diamine, the chemical structure is as follows: [0003] [0004] Ceritinib is an oral anaplastic lymphoma kinase (ALK) receptor inhibitor developed by Novartis. On April 29, 2014, the drug was approved by the FDA for marketing in the United States for the treatment of ALK-positive advanced non-small cell lung tumors. [0005] Regarding the synthesis of ceritinib, the synthetic route proposed in the patent CN200780051064.2 is shown in route 1: [0006] [0007] In this preparation route, the preparation of compound 2 from compound 1 requires the use of expensive platinum oxide, which is not suitable for ...
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