Idelalisib synthesis method and preparation of intermediate
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A synthesis method and intermediate technology are applied in the field of pharmaceutical synthesis and can solve problems such as waste, drug metal residues, and difficult recovery of acetic acid.
Active Publication Date: 2016-11-23
SHANGHAI INST OF PHARMA IND CO LTD +2
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Problems solved by technology
[0009] 1) The step of preparing compound 5 from compound 3 involves the preparation of key intermediate 4. Intermediate 4 is extremely unstable and will be hydrolyzed when it meets water. Therefore, the reaction needs to be strictly controlled under anhydrous and oxygen-free conditions. There are defects that the raw materials are difficult to react completely, the entire reaction system has many impurities, and it is not easy to purify, resulting in extremely low yield and cumbersome operation in this step, which is not suitable for industrial production;
[0010] 2) Zn / HOAc reagent was used during the preparation of compound 6, the by-product zinc acetate obtained after the reaction was completed was difficult to handle, the product was difficult to extract, a large amount of acetic acid was difficult to recycle, and the waste was serious, while the use of zinc powder easily caused the metal residue of the drug, Caused Idelalisib to be ineligible;
[0011] 3) Expensive 6-bromopurine is used in the step of preparing Idelaris from compound 7, and its substitution reaction will produce bromine-containing wastewater, which will pollute the environment;
[0012] 4) This route uses compound 1 as the starting material, and obtains Idelaris through 7 steps of reaction, the total yield is only 20%, and the synthesis efficiency is not high
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Embodiment 1
[0054] Embodiment 1. Synthesis of Compound II
[0055]
[0056] Compound 3 (19g, 73.1mmol) was dissolved in methanol (100ml), 10%Pd / C (1.9g) was added and washed with H 2 Replacement reaction system four times, in H 2 Stir overnight at room temperature under ambient (0.5 MPa), TLC analysis shows that the reaction is complete, the reaction liquid is filtered through diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain 16.5 g of compound II as a white solid, with a yield of 98.2% (HPLC: 98.5%).
[0059] Compound 3 (10g, 38.5mmol) was dissolved in methanol (50ml), added Raney Ni (1.0g), and washed with H 2 Replacement reaction system four times, in H 2 Stir overnight at room temperature under ambient (1.0 MPa), TLC analysis shows that the reaction is complete, the reaction liquid is filtered through diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain 8.7 g of compound II as a white solid, with a yield of 99.2%. Instrument analysis data is consistent with the compound of embodiment 1.
Embodiment 3
[0060] Embodiment 3. Synthesis of compound II
[0061] Dissolve 3 (26g, 100mmol) in ethanol (200ml), add 10% Pd / C (2.6g), wash with H 2 Replacement reaction system four times, in H 2 Stirring at room temperature overnight under ambient conditions, TLC analysis showed that the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 22.5 g of compound II as a white solid, with a yield of 97.8%. The instrumental analysis data is consistent with the compound of Example 1.
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Abstract
The invention provides an Idelalisib synthesis method. The method comprises steps as follows: a compound 3 is processed with hydrogen in the presence of a hydrogenation catalyst and a solvent, nitro is enabled to be reduced, and an amino compound II is obtained; the compound II and N-Boc protected L-2-aminobutyric acid are subjected to condensation in the presence of alkali and a carboxylic acid activator or in the presence of alkali and a condensation agent, and an intermediate I is obtained; the intermediate I is subjected to a ring closing reaction in an appropriate solvent under the action of a hexamethyldisilazane / lewis acid catalytic system, and a compound 7 is obtained; the compound 7 reacts with 6-chloro-9-(2-tetrahydropyran) purine in an appropriate solvent in the presence of an acid-binding agent, and a compound III is obtained; the compound III is subjected to protecting group removal with an appropriate reagent, and Idelalisib is obtained. A reaction path is shown in the specification. The preparation method has the advantages that the reaction conditions of each step are mild, the post-processing is simple and easy to implement and the total yield is high, and the preparation method is environment-friendly and is very suitable for industrial production.
Description
technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to an intermediate of Idelalisib, a drug for treating chronic lymphocytic leukemia, a preparation method and application thereof. Background technique [0002] Phosphatidylinositol 3-kinase / protein kinase B (PI3K / Akt) signaling pathway plays an important role in the occurrence, development, treatment and metastasis of malignant tumors. Phosphoinositide 3-kinase (PI3K ) as a bridge molecule connecting extracellular signals and cell response effects, under the influence of a series of upstream or bypass signal molecules, it acts on downstream signal molecules and plays a very important role in regulating cell apoptosis. The anti-apoptosis of PI3K and Akt has been confirmed in many studies, the expression level of Akt is increased and promotes the growth of cancer cells by protecting cells from apoptosis. Studies have found that PI3K is related to the products of oncogenes su...
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