31 results about "Idelalisib" patented technology

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.

The present invention discloses an Idelalisib crystal form A and a preparation method thereof. According to the present invention, the Idelalisib crystal form A is a single molecule hydrate, and has the characteristic peak having a relative intensity of more than 50% at a 2[theta] angle of 8.5+ / -0.2 DEG, 10.7+ / -0.2 DEG, 13.6+ / -0.2 DEG, 15.8+ / -0.2 DEG, 20.2+ / -0.2 DEG, 23.7+ / -0.2 DEG and 24.3+ / -0.2 DEG under powder X-ray diffraction; the preparation method comprises: dissolving an Idelalisib raw material in a suitable solvent to obtain a clarified solution, adding an antisolvent to the obtained solution in a dropwise manner until the turbidity initially appears, carrying out thermal insulation stirring to crystallize, cooling to a room temperature, filtering, and drying to prepare the Idelalisib crystal form A; and the Idelalisib crystal form A has advantages of excellent solubility, excellent thermal stability, excellent high-humidity stability and excellent pressure stability, and can be used as the pharmaceutically active ingredient of the preparation.

The invention discloses a novel Idelalisib preparation method. The method includes the steps that firstly, 6-chloro-9-(tetrahydro-2-pyranyl)-purine and (S)-2-(1-aMinopropyl)-5-fluoro-3-phenylquinazolin-3H-quinazoline-4-ketone have a nucleophilic substitution reaction to obtain (S)-5-fluoro-3-phenylquinazolin-2-{1-[(9-tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino]propyl}-3H-4-hydroxyquinazoline; secondly, the product in the first step is subjected to deprotection by means of hydrochloric acid and ethyl alcohol to obtain Idelalisib. The yield of the method is much higher than that of the prior art, post-treatment is easy, pure Idelalisib can be obtained only through extraction and re-crystallization, and the method is suitable for industrial production. Please see the molecular formula in the description.

The invention discloses an Idelalisib new intermediate compound (V)(S)-2-{[3-fluoro-2-[(phenyl amino) carbonyl] phenyl] amino-1-ethyl}-amino acid butyl ester. According to the Idelalisib prepared by the intermediate, compared with the existing disclosed methods, the reaction is stable, the yield is high, the reaction condition is mild, the defects in the prior art are overcome, the Idelalisib intermediate is very suitable for industry large scale production, and the yield is higher than that of the existing method. (Please see the formula of the compound in the description.).

The present invention relates to an amorphous form of Idelalisib and its methods of preparation. Using a Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern does not contain sharp diffraction peaks at a diffraction angle expressed in degrees 2θ, and the X-ray powder diffraction pattern is shown in FIG. 1. The present invention also provides a preparation method for the amorphous form of Idelalisib. The amorphous form of Idelalisib of the present invention increases the solubility of Idelalisib and improves bioavailability of the drug product. As compared to the existing crystalline forms of Idelalisib, its solubility increases significantly, which improves body's absorption of the drug and makes it more efficacious in the clinical therapeutic treatment of diseases. Under the stress test conditions, the amorphous material can maintain good physical and chemical stabilities. The preparation method of amorphous Idelalisib according to the present invention is simple to operate and easy to implement.

A preparing method of Idelalisib (I) is disclosed. The preparing method includes following steps of: subjecting R-2-hydroxybutyrate (II) and 6-amino-9H-purine to nucleophilic substitution under actions of a leaving agent and an acid-binding agent to produce an intermediate S-2-(N-9H-purin-6-yl)aminobutyrate (III); subjecting the intermediate (III) and 2-amino-6-fluorobenzoic acid to amidation under actions of a catalyst to produce S-2-(N-9H-purin-6-yl)amino-N-(2-carboxyl-3-fluorophenyl)butyramide (IV); subjecting the intermediate (IV) to a cyclization reaction in acetic anhydride; and performing a substitution reaction with phenylamine to obtain the Idelalisib (I). The preparing method has characteristics of easily available raw materials, simple and concise process, capability of being economical and environmental friendly, and suitability for industrial production.

The present invention relates to an amorphous form of Idelalisib and its methods of preparation. Using a Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern does not contain sharp diffraction peaks at a diffraction angle expressed in degrees 2θ, and the X-ray powder diffraction pattern is shown in FIG. 1. The present invention also provides a preparation method for the amorphous form of Idelalisib. The amorphous form of Idelalisib of the present invention increases the solubility of Idelalisib and improves bioavailability of the drug product. As compared to the existing crystalline forms of Idelalisib, its solubility increases significantly, which improves body's absorption of the drug and makes it more efficacious in the clinical therapeutic treatment of diseases. Under the stress test conditions, the amorphous material can maintain good physical and chemical stabilities. The preparation method of amorphous Idelalisib according to the present invention is simple to operate and easy to implement.

The invention discloses a preparation method of Idelalisib and an intermediate thereof. The method comprises the following steps: using 2-halogeno-6-fluorine-N-phenyl benzamide as a raw material, performing a reaction on the 2-halogeno-6-fluorine-N-phenyl benzamide and N-(9'-tetrahydropyrane-6'-purinyl)-L-2-aminobutyric acid, performing a reaction on a reaction product and ammonium carbonate or liquid ammonia to replace 2-halogeno with ammonia by cuprous oxide, copper and potassium carbonate or cesium carbonate, performing a ring-closure reaction under the existence of hexamethyl disilazane and iodine, and performing a reaction on a reaction product and hydrochloric acid solution to remove pyran finally, so as to generate an Idelalisib finished product. According to the process, the novelmethod is provided for synthesizing the Idelalisib; in the process, the easily available 2-halogeno-6-fluorobenzoic acid is used as a starting material, and zinc acetate pollution and the like can beprevented from being generated through reduction of nitro and the like with zinc powder in a synthesis process.

The invention relates to idelalisib crystal, a pharmaceutical composition comprising the idelalisib crystal, and a preparation method and application of the idelalisib crystal, and belongs to the technical field of pharmaceutical composition crystals. The invention particularly provides crystal R; under Cu-KAlpha irradiation, the crystal R has X-ray powder diffraction spectrum substantially shown as in figure 1, 2 or 9. The preparation method of the crystal R is simple, the form of the crystal is easy to control, production efficiency is significantly increased, and the crystal R is more suitable for industrial production. The crystal has improved hygroscopicity, chemical stability and preparation adaptability, as well as improved efficacy and safety.

The invention discloses an Idelalisib crystal form A and a preparation method thereof. The Idelalisib crystal form A is a molecular hydrate of Idelalisib, and under powder X-ray diffraction, the 2θ is 8.5±0.2°, 10.7±0.2°, 13.6±0.2°, 15.8±0.2°, 20.2±0.2°, 23.7±0.2°, 24.3±0.2° have characteristic peaks with relative intensities greater than 50%, and a clear solution can be obtained by dissolving the Idelalisib raw material in a suitable solvent , and then add the anti-solvent dropwise to the obtained solution until the initial turbidity, and then heat and stir to crystallize, cool down to room temperature, filter, and dry to prepare. The Idelalisib crystal form A provided by the present invention has excellent solubility, thermal stability, high humidity stability and pressure stability, and is more suitable as a pharmaceutically active component of a preparation.

The invention belongs to the field of medicine synthesis and provides a novel idelalisib preparation method. The novel idelalisib preparation method includes steps: in an appropriate solvent, subjecting a compound A to nucleophilic substitution reaction with B in existence of an acid-binding agent to obtain an intermediate C; hydrolyzing the compound C into an intermediate D under appropriate alkali action; subjecting the intermediate D and a compound E to condensation to obtain an intermediate F; in an appropriate solvent, subjecting the intermediate F to ring closing reaction under a catalytic system of HMDS (hexamethyl disilazane) / lewis acid to obtain a final product namely idelalisib.

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.

The invention relates to an o-fluoro-o-iminobenzoic acid intermediate compound and a preparation method and application thereof, belonging to the technical field of pharmaceutical intermediate synthesis. In order to solve the existing problems of difficult separation and poor activity, an intermediate compound of o-fluoro-o-iminobenzoic acid and its preparation method and application are provided. The method comprises dissolving the compound of formula II in an organic solvent, and then adding pyridine Stir with triphenyl phosphite to activate the carboxyl group, add 2-amino-6-fluorobenzoic acid for condensation reaction, and obtain the corresponding intermediate compound of o-fluoro-o-iminobenzoic acid. The intermediate compound of the present invention has high reactivity and is easy to be active, can be effectively applied to the key intermediate raw material for synthesizing Idelalisib, and has high reaction stability, and the obtained corresponding intermediate product also has the effect of high quality and purity.

The invention discloses a preparation method of Idelalisib and an intermediate thereof. The method comprises the following steps: using 2-halogeno-6-fluorine-N-phenyl benzamide as a raw material, performing a reaction on the 2-halogeno-6-fluorine-N-phenyl benzamide and N-(9'-tetrahydropyrane-6'-purinyl)-L-2-aminobutyric acid, performing a reaction on a reaction product and ammonium carbonate or liquid ammonia to replace 2-halogeno with ammonia by cuprous oxide, copper and potassium carbonate or cesium carbonate, performing a ring-closure reaction under the existence of hexamethyl disilazane and iodine, and performing a reaction on a reaction product and hydrochloric acid solution to remove pyran finally, so as to generate an Idelalisib finished product. According to the process, the novelmethod is provided for synthesizing the Idelalisib; in the process, the easily available 2-halogeno-6-fluorobenzoic acid is used as a starting material, and zinc acetate pollution and the like can beprevented from being generated through reduction of nitro and the like with zinc powder in a synthesis process.

The present invention relates to a process for the preparation of stable and 5 pure amorphous form of Idelalisib. Further, the present process is simple, more economical, cost effective and efficient method of manufacturing that is suitable for industrial scale-up having a high degree of chromatographic purity.