Synthesis method of ibrutinib

Abstract

The invention discloses a synthesis method of ibrutinib. The method uses Suzuki coupling reaction and Kumada coupling reaction, does not need to separate the intermediate, obtains the intermediate (9) at high yield by a one-pot process, and uses mixed anhydrides instead of acryloyl chloride. The technique utilizes cheap 4-halodianisole as the initial raw material, adopts Suzuki coupling reaction and Kumada coupling reaction, and uses the one-pot process. The whole route is disclosed in the specification. The method can obtain the intermediate (9) (the chemical purity and optical purity are greater than or equal to 99%) at high yield without separating and purifying the intermediate, and avoids microwave, high temperature / high pressure and other specific reaction conditions; and the acrylic acid and mixed anhydrides generated by acyl chloride and sulfonyl chloride are used instead of the acryloyl chloride in the last step to avoid the amidation reaction of the intermediate (10) in multiple sites and reduce the generation of the byproduct, thereby obtaining the high-purity ibrutinib at high yield. The method has the advantages of short process route and lower cost, and is beneficial to the environment and suitable for industrialized scale-up production.

Description

technical field [0001] The invention relates to the field of chemical drug synthesis, in particular to ibrutinib. Background technique [0002] Pharmacyclics and Johnson & Johnson jointly developed a new drug, Ibrutinib, which was approved by the US Food and Drug Administration (FDA) on November 13, 2013. The chemical name of Ibrutinib: 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1- yl]prop-2-en-1-one, CAS number: 936563-96-1), for the treatment of a rare and aggressive blood cancer - mantle cell lymphoma (MCL) and leukemia (CLL). Ibrutinib is an oral first-in-class Bruton's tyrosine kinase (BTK) inhibitor, which selectively binds to the cysteine ​​residue (Cys-481) in the active site of the target protein BTK. It covalently binds to and irreversibly inhibits BTK, thereby effectively preventing tumor migration from B cells to lymphoid tissues adapted to the tumor growth environment. Mantle cell lymphoma (MCL) is a rare but rapidly pro...

AI Technical Summary

Problems solved by technology

Among them, when synthesizing intermediate 7 in step 6, the ring closure reaction needs to be carried out under high temperature conditions of 180 ° C, the reaction conditions are harsh, the yield is low, and it is difficult to carry out industrial scale-up production

[0013] 2. When the second step of the Suzuki coupling reaction is carried out in route-3, since the amino group on the six-membered ring is not protected, it can be complexed with Pd(0), which affects the effective progress of the Suzuki coupling reaction, resulting in a low reaction yield in this step

In addition, route-3 requires microwave irradiation and high temperature of 180°C, which makes industrial scale-up production more difficult

[0014] 3. The last step of routes 1, 2 and 3 requires the use of acryloyl chloride to produce amides, the reaction conditions are severe, the yield is low, there are many by-products, and the product is difficult to purify

Possible reason: due to the high reactivity of acryloyl chloride, the intermediate (10) has two reaction sites for amino groups, and acryloyl chloride can react with the amino group on the piperidine ring and the amino group on the six-membered heterocycle at the same time, resulting in a complex reaction system and side effects. There are many products, the products are difficult to purify, and are not suitable for industrial production

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