New synthetic route of Tucatinib, a new anti-breast cancer drug

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Introduction

Tucatinib (Tukysa) Tucatinib/Tucatinib (ONT-380) is a small molecule oral tyrosine kinase (TKI) inhibitor It has highly specific targeting selectivity for HER2.

On April 17, 2020, the US FDA approved the HER2 specific inhibitor Tukysa (tucatinib) developed by Seattle Genetics to be combined with trastuzumab and capecitabine It is used for the treatment of locally advanced, unresectable or metastatic (including with brain metastasis) HER2-positive breast cancer in adult patients.

The median progression-free survival (PFS) of patients receiving the combination therapy of Tukysa, trastuzumab and capecitabine was 7.8 months, and the overall survival (OS) was 21.9 months; while receiving comfort The patients treated with the drug, trastuzumab and capecitabine were 5.6 months, and the overall survival (OS) was 17.4 months. Among patients with brain metastases, the 1-year progression-free survival rate was 24.9% in the Tucatinib combination group and 0% in the placebo combination group. The research results can be found at: 10.1056/NEJMoa1914609

Recently, the Mao team reported a new route for the efficient synthesis of Tucatinib.

The results were published on Synthesis (DOI: 10.1055/s-0037-1610706).

Previously, the synthesis report route of Tucatinib was published by Array BioPharma in a patent document (WO 2007059257, 2007). The synthetic route reported in the patent is shown in the figure below:

Using 4-nitro-2-cyanoaniline as the raw material, the first step is to condense with DMF-DMA to prepare imine 3 (yield 87%); subsequent catalytic hydrogenation of palladium on carbon to reduce the nitro group to obtain the amine 4 (90% yield); followed by 1,1&39;-thiocarbonyldiimidazole (TCDI) and The amino alcohol undergoes condensation to prepare the thiourea derivative 5 (yield is only 34%); further with the intermediate 6 to undergo ring-closure reaction to obtain the key intermediate 7 (yield 62%) ; Finally, under the action of p-toluenesulfonic acid, intramolecular dehydration and ring closure to form oxazoline, complete the synthesis of the target compound tucatinib.

Reverse synthesis analysis

The author broke the bond of Tucatinib from two points a and b and split them into three fragments. : Thioether oxazoline 17, nitrobenzene 3 and the key fragment of the original research route 6.

Preparation of key fragment 6

4-nitro-3-methylphenol 8 as a starting point The material, with pyridine derivative 9, undergoes aromatic affinity substitution reaction to prepare aryl ether 10 (yield 64%); then it is condensed with DMF-DMA, and then treated with hydroxylamine hydrochloride. The step yield was 81% to obtain the oxime derivative 12; subsequently, the ring was closed under the treatment of trifluoroacetic anhydride, the mostAfter palladium-catalyzed hydrogenation to reduce the nitro group, the key aniline triazole 6 was successfully prepared, with a total yield of 32.8%.

aromatic ring skeleton construction

fragment 3 was synthesized according to the method reported in the literature. The estimated aromatic ring fragment was then constructed with the aniline triazole 6 prepared above:

Compound 6 and fragment 3 were cyclized in acetic acid , 14 was successfully prepared, and finally the nitro group was reduced by palladium-catalyzed hydrogenation to obtain the key arylamine 15 with a two-step yield of 76.4%.

Fragment 17 and Tucatinib synthesis

amino alcohol and 1,1&39;-thiocarbonyl diimidazole (TCDI) The ring is closed to obtain 16, which is then treated with methyl trifluoromethanesulfonate to obtain oxazoline 17, with a total yield of 67.23% in the two steps.

oxazoline17 and arylamine 15 in the presence of cesium carbonate, heated in DMF for 20 hours, and finally completed the synthesis of Tucatinib with a yield of 76%.

Comparison of the new route and the patent route

The yield of the last step of the patent is unknown, starting with key intermediates 3 and 6, total income The rate is less than 19%.

The overview of the new route is as follows:

Correspondingly, starting from the intermediate 3 and 6, the total yield of the new route There is a significant improvement to 39%. Moreover, the purity of the product and other aspects also meet the requirements of API.

Comment

Tucatinib (Tukysa) Tucatinib/Tucatinib as a small-molecule oral tyrosine kinase (TKI) inhibitor for HER2 Positive breast cancer has highly specific targeting selectivity. The study of the new synthetic route

effectively improves the production efficiency in terms of ensuring the purity of the compound, and the raw materials used are relatively simple and easy to obtain.

Medicinal chemists have completed the research and development and synthesis of compounds (from 0 to 1), while process chemists have optimized the synthetic routes and processes, so that the compounds can be prepared more simply, efficiently, economically and environmentally.