Idelalisib intermediate and preparation method thereof

A reaction system and compound technology, applied in chemical instruments and methods, preparation of organic compounds, preparation of carbamic acid derivatives, etc., can solve the problems of unfavorable industrial production, poor purity, low yield, etc. Production, high yield, and mild reaction conditions

Inactive Publication Date: 2016-11-23
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the defect of the above method is that compound 6 is an important raw material for preparing Idelalisib, and there is no cheap industrial product available on the market at present, and in the prior art disclosed in international patent WO2005113556A1, the yield of this step of preparing compound 4 is low , and it needs to be obtained by column chromatography. At the same time, the step of preparing compound 5 also needs to be obtained by column chromatography, and the obtained is a foamy solid with poor purity, which is not conducive to subsequent operations and industrial production

Method used

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  • Idelalisib intermediate and preparation method thereof
  • Idelalisib intermediate and preparation method thereof
  • Idelalisib intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-2

[0024] Example 1-2: Preparation of 2-fluoro-6-nitro-N-phenyl-benzamide formula (II)

[0025] 2-Fluoro-6-nitrobenzoic acid (18.5g), DMF (1ml) and dichloromethane (100ml) were mixed and stirred, and a dichloromethane solution (60ml) containing oxalyl chloride (19g) was added dropwise, and the reaction was stirred at room temperature After 2 hours, concentrate to give an orange solid syrup. The above slurry was dissolved in anhydrous dioxane (16ml), and slowly added dropwise to aniline (9ml) and sodium bicarbonate (16.8g) in dioxane (40) and water (40) at 6°C. After the addition, stir at room temperature for half an hour, add water (250ml), a solid is produced, collect the solid by filtration, wash with water, and obtain the title compound 2-fluoro-6-nitro-N-phenyl-benzene Formamide 25.6g, yield 98.4%. 1 H NMR (400MHz, CDCl 3 )δ8.01(d,J=8.2Hz,1H),7.70-7.60(m,,4H),7.41(t,J=7.8Hz,2H),7.23(t,J=7.4Hz,1H).ESI -MS(m / z):261[M+H] +

[0026] 2-Fluoro-6-nitrobenzoic acid (18.5g), DMF...

Embodiment 3-4

[0027] Example 3-4: Preparation of 2-amino-6-fluoro-N-phenyl-benzamide formula (Ⅲ)

[0028] A mixture of 2-amino-6-fluoro-N-phenyl-benzamide (13g), Pd / C (1g) and ethyl acetate (100ml) was hydrogenated at 50°C for four hours, filtered and concentrated to dryness to obtain the title Compound 2-amino-6-fluoro-N-phenyl-benzamide 11.1 g, yield 96.5%. 1 H NMR (400MHz, CDCl 3 )δ8.33(d,J=15.5Hz,1H),7.61(d,J=7.6Hz,2H),7.43–7.35(m,2H),7.21–7.12(m,2H),6.51(d,J =8.3Hz,1H),6.43(ddd,J=13.0,8.1,1.0Hz,1H),5.97(s,2H).ESI-MS(m / z):231[M+H] +

[0029] 2-Amino-6-fluoro-N-phenyl-benzamide (13g), Pd / C (0.8g) and ethyl acetate (100ml) were mixed and hydrogenated at 50°C for six hours, filtered and concentrated to dryness to obtain 10.5 g of the title compound 2-amino-6-fluoro-N-phenyl-benzamide, yield 91.3%.

Embodiment 5-6

[0030] Example 5-6: Preparation of (S)-2-{[3-fluoro-2-[(phenylamino)carbonyl]phenyl]amino-1-ethyl}-carbamate isobutyl ester formula (V)

[0031] Dissolve BOC-L-2-aminobutyric acid (20.3g) and N-methylmorpholine (11.2g) in anhydrous THF (120ml), and add isobutyl chloroformate (13.7g ) solution in anhydrous THF (40ml), dropwise, stirred at -15°C for 1 hour, then added dropwise an anhydrous solution containing 2-amino-6-fluoro-N-phenyl-benzamide (11.5g) THF (40ml) solution, dropwise, react at this temperature for half an hour, slowly rise to room temperature, react for 1 hour, filter out the solid, and the filtrate is heated to reflux for 3.5 hours, concentrate the reaction solution, add ethyl acetate (150ml) and Water (200ml), separated, the aqueous layer was extracted with ethyl acetate (100ml×2), the organic layers were combined, washed with water, washed with saturated brine, dried, filtered, and concentrated to obtain 19.2g of crude product, which was recrystallized with iso...

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PUM

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Abstract

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.).

Description

technical field [0001] The invention relates to the technical field of Idelalisib intermediates and preparation methods thereof. Background technique [0002] Idelalisib is the first selective oral PI3K inhibitor developed by Gilead. Compared with α, β, and γ subunits, it can highly selectively act on the δ subunit, block the PI3Kδ-Akt signaling pathway and promote cell Apoptosis, which was approved by the US FDA in July 2014, is used for the treatment of relapsed chronic lymphocytic leukemia, follicular lymphoma and small lymphocytic lymphoma. The chemical name is (S)-5-fluoro-3-phenyl-2-[1-(9H-purin-6-ylamino)propyl]-3H-quinazolin-4-one. [0003] [0004] International patent WO2005113556A1 discloses a synthesis method of Idelalisib, the synthesis route of which is as follows: [0005] [0006] The method uses 2-fluoro-6-nitrobenzoic acid as a raw material, first condenses with aniline, then reacts with thionyl chloride to obtain an intermediate, and then reacts wi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/22C07C269/06
Inventor 徐浩吴雪松岑均达
Owner SHANGHAI INST OF PHARMA IND CO LTD
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