A kind of synthetic method of olaparib

Abstract

The invention discloses a synthetic method of olaparib. The synthetic method comprises the following steps: with phthalhydrazide as a starting material, reacting with phosphorus oxychloride to generate 1-chloro-4-carbonylpyridazine, and further reacting with ethyl 2-fluoro-5-bromomethylbenzoate, so as to generate ethyl 2-fluoro-5-[(4-carbonyl-3,4-dihydropyridazin-1-yl)methyl]benzoate; and carryingout hydrolysis and acylation, and carrying out condensation reaction by virtue of ethyl 2-fluoro-5-[(4-carbonyl-3,4-dihydropyridazin-1-yl)methyl]benzoate and 1-(cyclopropylcarbonyl)-piperazine, so asto generate olaparib. The synthetic method has the beneficial effects that phthalhydrazide is taken as the starting material for the first time, is easily available and is environmentally friendly; by utilizing Neigishi coupling, organic metal is utilized for reaction, catecholborane with a relatively high cost is not used, and zinc powder is used, so that the production cost is lowered, and thetotal yield of the route reaches 70.2%; and the reaction route is relatively short, reaction conditions are mild, and the synthetic method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a synthesis method of olaparib. Background technique [0002] Poly(ADP-ribose) polymerase (PARP) is a ribozyme involved in DNA repair, which plays an important role in DNA damage repair and provides a new target for tumor therapy. Therefore, PARP inhibitors have been a research hotspot in recent years. With the deepening of PARP research, the intervention of this target of PARP to treat tumors will open up a new path for tumor treatment. Among them, AstraZeneca's olaparib as a PARP inhibitor has made great progress in the treatment of ovarian cancer. It was approved by the European Commission on December 18, 2014 as a monotherapy for platinum-sensitive recurrent BRCA mutations. Maintenance treatment of adult patients with ovarian cancer, the drug also became the first PARP inhibitor for BRCA-mutated platinum-sensitive recurrent ovarian cancer. On Decemb...

AI Technical Summary

Problems solved by technology

[0007] (1) This route is longer, and there are many steps, it is not easy to improve the total yield of enlarged production;

[0008] (2) The cost of 3-fluoro-2-cyanobenzaldehyde in reaction b is too high, which will increase the production cost of the whole route

[0009] (3) O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU), N, N-diisopropylethylamine (DIPEA) are used in reaction e. The cost of raw materials is high, and the total yield of the route Only 26.7%

[0012] This route improves the first route, but the following problems still exist: Reaction A, B, C are the same as the above-mentioned patent reaction conditions, but the reaction D is directly connected to 1-cyclopropanylpiperazine instead, and the used condensing agent Same as the above-mentioned patent, so the production cost is higher, and the yield of this step reaction is only 62.2% at the same time

[0016] (1) When compound 3 was synthesized, compound 2 catechol borane was used. The price of this compound is relatively high, and it will increase the production cost of the route when it is scaled up.

[0017] (2) Carbonyldiimidazole (CDI) is used as a condensing agent in the method for obtaining compound 8 in this route. The industrial cost of this compound is high, which will increase the cost of enlarged production

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