Synthesis of ponatinib

A synthetic method, 2-b technology, applied in the direction of organic chemistry, etc., can solve the problems of high pollution, acid chlorination, low yield of condensation reaction, unsuitable for industrial production, etc., achieve high product purity, increase reaction yield, and cost low effect

Active Publication Date: 2015-12-16
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

[0015] Although this route avoids the use of metal coupling agents in the last step, the yield of acid chloride and condensation reactions is still low, and it is highly polluting, so it is not suitable for industrial production

Method used

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  • Synthesis of ponatinib
  • Synthesis of ponatinib
  • Synthesis of ponatinib

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Experimental program
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Embodiment Construction

[0039] 1. Synthetic method and route:

[0040] 1. The synthesis method is as follows:

[0041] Using imidazo[1,2-b]pyridazine (1) as raw material to react with N-halogenated succinimide to obtain 3-halogenated imidazo[1,2-b]pyridazine (2), 3- Iodo-4-methylbenzoate (3) reacts to generate 4-methyl-3-trimethylsilylethynyl benzoate (4), and (4) removes trimethyl under the action of deprotecting reagent Silyl group to obtain 3-ethynyl-4-methylbenzoate (5), intermediate (2) and intermediate (5) reaction to obtain intermediate 3-(imidazol[1,2-b]pyridazine- 3-ylethynyl)-4-methylbenzoate (6), final intermediate (6) and intermediate 4-((4-methylpiperazin-1-yl)methylene)-3- Trifluoromethylaniline (7) was reacted under alkaline conditions to obtain ponatinib.

[0042] 2. The synthetic route is as follows:

[0043]

[0044] 2. Synthesis steps:

[0045] A kind of method for synthesizing ponatinib, operates as follows:

[0046] A. Preparation of 3-imidazo[1,2-b]pyridazine (2)

[00...

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Abstract

The invention discloses a synthesis method of ponatinib. The method comprises the following steps: taking imidazo[1,2-b]pyridazine as a raw material, then subjecting the imidazo[1,2-b]pyridazine to react with N-halogenated succinimide so as to obtain 3-halogenated imidazo[1,2-b]pyridazine; making 3-iodo-4-R-benzoate carry out reactions to generate 4-R-3-trimethylsilylethynyl benzoate, then removing the trimethysilyl group so as to obtain 3-ethynyl-Rbenzonate, then carrying out reactions between 3-halogenated imidazo[1,2-b]pyridazine and 3-ethynyl-R-benzonate so as to obtain the reaction product 3-(imidazole[1,2-b]pyridazine-3-yl-ethynyl)-4-R-benzonate, then making the product react with 4-((4-methylpiperazine-1-yl) methylene)-3-trifluoromethyl phenylamine so as to obtain ponatinib, wherein the R represents one component selected from methyl, ethyl, propyl, isopropyl, n-butyl, and tertiary butyl. The synthesis process has the advantages of simple technology, mild reaction conditions, high product purity, high yield, low cost, and benefit for industrial production.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals, and in particular relates to a synthesis method of ponatinib, an anti-chronic myeloid leukemia drug wild-type or T315I mutant Bcr-abl fusion protein inhibitor. Background technique [0002] Chronic myeloid (myelocytic) leukemia (chronicmyelocyticleukemia, CML) is a hematopoietic stem cell clonal proliferative disease, the bone marrow is characterized by myeloid hyperplasia, peripheral blood leukocytosis and splenomegaly. [0003] Molecular Pathology of CML In 1960, Nowell and Hungerfor described the Ph chromosome associated with CML, which was the first nonrandom chromosomal abnormality found to be associated with a specific human tumor. In 1973, Rowley used quinine and Giemsa staining techniques to confirm for the first time that the Ph chromosome (22q-abnormality) found in CML was caused by t(9;22)(q34;q11) chromosome translocation. In 1982, the ABL gene was cloned in the break region of 9q34...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 丁克冯玉冰陆小云李伟华李宇鹏沈梦婕
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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