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Idelalisib preparation method

A phenyl and purine technology, applied in the field of Idelalisib preparation, can solve the problems of only 50% yield and expensive 6-bromopurine, etc., and achieve the effect of simple post-treatment

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

The defect of this step reaction is that 6-bromopurine is very expensive, and the obtaining of the final product requires column chromatography, and the yield is only 50%

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-2

[0015] Example 1-2: Preparation of 6-chloro-9-(tetrahydro-2-pyranyl)-purine

[0016] Dissolve 6-chloropurine (15.5g) and p-toluenesulfonic acid (0.26g) in ethyl acetate (180ml), heat to 50°C, and slowly drop 2,3 dihydropyran (10.5ml) into the reaction After dripping, continue to stir at this temperature for 1 hour, slowly cool to room temperature, add saturated ammonium chloride solution (10ml) under stirring, then wash twice with water and once with salt water, dry, concentrate to obtain an oily crude product, and use n-hexane Recrystallization of alkane (150ml) gave 19.6g of 6-chloro-9-(tetrahydro-2-pyranyl)-purine, yield 82.1%. 1 H NMR (400MHz,d6-DMSO)δ8.91(s,1H),8.82(s,1H),5.80(d,1H),4.04(m,1H),3.75(m,1H),2.35(m, 1H),2.01(m,2H),1.76(m,1H),1.62(m,2H).ESI-MS(m / z):239[M+H] +

[0017] Dissolve 6-chloropurine (15.5g) and p-toluenesulfonic acid (0.26g) in ethyl acetate (180ml), heat to 50°C, and slowly drop 2,3 dihydropyran (10.5ml) into the reaction After dripping, continue...

Embodiment 3-4

[0018] Example 3-4: (S)-5-fluoro-3-phenyl-2-{1-[(9-tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino] Preparation of propyl}-3H-quinazolin-4-one

[0019] 6-Chloro-9-(tetrahydro-2-pyranyl)-purine (14.31g), (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H- Quinazolin-4-one (8.91g) and triethylamine (9.54g) were dissolved in isopropanol (40ml), refluxed at 80°C for 24 hours, cooled at room temperature, filtered, washed with isopropanol, washed with water, n-hexane The filter cake was washed to give (S)-5-fluoro-3-phenyl-2-{1-[(9-tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino]propane Base}-3H-quinazolin-4-one 12.8g, yield 85.3%.

[0020] 1 H NMR (400MHz, CDCl 3 )δ12.01(s,1H),8.28(s,1H),8.02(s,1H),7.71–7.63(m,1H),7.63–7.45(m,5H),7.35(d,J=7.4Hz ,1H),7.15–7.05(m,1H),5.71(d,J=10.1Hz,1H),4.21–4.12(m,1H),3.78(t,J=11.3Hz,1H),3.12(qd, J=7.3,4.9Hz,6H), 2.07–1.79(m,2H),0.87(t,J=7.4Hz,3H).ESI-MS(m / z):500[M+H] +

[0021] 6-Chloro-9-(tetrahydro-2-pyranyl)-purine (14.31g), (S)-2-(1-amino-propyl)-5-...

Embodiment 5-6

[0022] Embodiment 5-6: Preparation of Idelalisib

[0023] Treat (S)-5-fluoro-3-phenyl-2-{1-[(9-tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino with hydrochloric acid ethanol (40ml) ]Propyl}-3H-quinazolin-4-one (10g), stirred at room temperature for 3 hours, adjusted the pH to about 8-9 with ammonia water, added seed crystals, and filtered to obtain (S)-2-(1-amino- Propyl)-5-fluoro-3-phenyl-3H-quinazolin-4-one 7.3 g, yield 87.9%.

[0024] 1 H NMR (400MHz, DMSO) δ10.46(s, 1H), 10.11(s, 1H), 8.14(d, J=17.4Hz, 2H), 7.87(d, J=8.1Hz, 1H), 7.77(s ,1H),7.54–7.39(m,3H),7.27(t,J=7.7Hz,2H),7.09(t,J=7.4Hz,2H),4.72(s,1H),2.07–1.79(m, 2H), 0.94(t, J=7.3Hz, 3H).ESI-MS(m / z): 416[M+H] +

[0025] (S)-5-fluoro-3-phenyl-2-{1-[(9-tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino]propyl}-3H -Quinazolin-4-one (10g) was dissolved in hydrochloric acid ethanol (40ml), stirred at room temperature for 3 hours, washed with saturated NaHCO 3 The solution was quenched, and the pH was adjusted to about 7-8, e...

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Abstract

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.

Description

technical field [0001] The invention relates to the technical field of preparation methods of Idelalisib. 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 last step of the method uses 6-bromopurine as a raw material, and (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazolin-4-one undergoes nucleophilic substitution The reaction yields Idelalis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/34
CPCC07D473/34
Inventor 徐浩吴雪松岑均达张锴婷
Owner SHANGHAI INST OF PHARMA IND CO LTD
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