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A synthesis method and carbonyl technology, applied in the field of pharmaceutical preparation, can solve the problems of high industrial cost, many steps and high production cost, and achieve the effects of reducing production cost, mild reaction conditions and short reaction route.
Active Publication Date: 2020-11-06
BEIJING YAOCHENG HUIREN TECH CO LTD
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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
Method used
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Embodiment 1
[0045] A synthetic method of olaparib, comprising the following steps:
[0046] (1) Weigh phthalic hydrazide (8.1g, 0.05mol) and add POCl 3 (50mL, 0.25mol), react at 110°C for 4h, after the reaction system is cooled, pour the reaction system into ice water, a white solid precipitates, stir overnight, filter with suction, dry the filter cake, wash with ethyl acetate and filter cake, and finally obtained 8.5 g of 1-chloro-4-carbonylphthalazine with a yield of 94.4%.
[0047](2) Weigh zinc powder (654mg, 0.01mol), add solvent anhydrous tetrahydrofuran 3mL, add 50μL of 1,2-dibromoethane, stir at 60°C for 15 minutes, cool to room temperature, add 50μL of trimethyl At 0°C, 2-fluoro-5-bromomethylbenzoic acid ethyl ester (1.305g, 5mmol) was added dropwise to 3mL tetrahydrofuran solution, and the reaction was continued at 0°C for 2h to obtain a zinc reagent solution. Weigh the product (0.38 g, 2 mmol) in step (1), add 3 mL of tetrahydrofuran, 38 mg of tetrakis(triphenylphosphine)pall...
Embodiment 2
[0051] The molar ratio of phthalic hydrazide and phosphorus oxychloride in step (1) is 1:4 (i.e. phthalic hydrazide 8.1g, phosphorus oxychloride 40mL), other steps are the same as embodiment 1, obtain 8.4 g of 1-chloro-4-carbonylphthalazine, the yield was 93.2%.
Embodiment 3
[0053] The molar ratio of phthalic hydrazide and phosphorus oxychloride in step (1) is 1:3 (i.e. phthalic hydrazide 8.1g, phosphorus oxychloride 30mL), other steps are the same as embodiment 1, obtain 7.9 g of 1-chloro-4-carbonylphthalazine, the yield was 87.8%.
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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...
Claims
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