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Preparation method of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one

A quinazoline, phenyl technology, applied in the field of preparation of -2--5-fluoro-3-phenyl-3H-quinazolin-4-one, can solve the problem of low yield, low overall yield, Purity is not good and other problems, to achieve the effect of mild reaction conditions, high yield and stable reaction

Inactive Publication Date: 2016-11-23
SHANGHAI INST OF PHARMA IND +1
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  • 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
Low overall yield and low atom utilization

Method used

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  • Preparation method of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one
  • Preparation method of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-2

[0023] Example 1-2: Preparation of 2-fluoro-6-nitro-N-phenyl-benzamide formula (II)

[0024] 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] +

[0025] 2-Fluoro-6-nitrobenzoic acid (18.5g), DMF...

Embodiment 3-4

[0026] Example 3-4: Preparation of 2-amino-6-fluoro-N-phenyl-benzamide formula (Ⅲ)

[0027] 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] +

[0028] 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

[0029] Example 5-6: Preparation of (S)-2-{[3-fluoro-2-[(phenylamino)carbonyl]phenyl]amino-1-ethyl}-carbamate isobutyl ester formula (V)

[0030] 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, 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 isoprop...

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Abstract

The invention discloses a preparation method of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one. According to the method, a compound represented as a formula (V) is subjected to cyclization under the action of trimethylchlorosilane, (S)-[1-(5-fluoro-4-oxo-3-phenyl-3,4-dihydro-quinazoline-2-yl) propyl]-isobutyl carbamate is obtained and subjected to BOC (t-butyloxycarboryl) de-protection through acid, and a product is obtained. A synthetic route provided by the invention overcomes defects in the prior art, has the advantages of being mild in reaction condition of each step, stable in reaction and high in yield, and is particularly applicable to industrial large-scale production of a key intermediate 6 of Idelalisib.

Description

technical field [0001] The present invention relates to the technical field of preparation methods of (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazolin-4-one. 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 ...

Claims

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Application Information

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IPC IPC(8): C07D239/91
Inventor 徐浩吴雪松岑均达
Owner SHANGHAI INST OF PHARMA IND
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