CN106146503A - A kind of preparation method of Idelalisib - Google Patents

Abstract

The invention discloses a kind of new Idelalisib preparation method, the method includes 1) the chloro-9-of 6-(tetrahydrochysene-2-pyranose)-purine and (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one generation nucleophilic substitution obtain (S)-5-fluoro-3-phenyl-2-{1-[(9-tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base amino] propyl group }-3H-quinazoline-4-one；2) first step product deprotection in acidic alcohol is obtained Idelalisib.The inventive method yield is far above prior art, and post processing is simple, it is only necessary to extraction and recrystallization i.e. can get pure Idelalisib, are suitable to industrialized production.

Description

A kind of preparation method of Idelalisib

technical field

The invention relates to the technical field of preparation methods of Idelalisib.

Background technique

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.

International patent WO2005113556A1 discloses a synthesis method of Idelalisib, the synthesis route of which is as follows:

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 Idelalisib. 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%. At the same time, the experimenters also tried 6-chloropurine instead of 6-bromopurine to directly react with quinazolinone, and found that the raw material of quinazolinone could not be reacted completely, and the TLC showed that the product point was significantly weaker than the raw material point.

Therefore need to develop a kind of raw material easy to get, safe, the method for preparing Idelalisib with high yield.

Contents of the invention

The purpose of the present invention is to solve the above-mentioned defects in the prior art, and provide a new method with easy access to raw materials, high yield, and suitable for large-scale production of Idelalisib.

For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:

A preparation method of Idelalisib comprising 1) 6-chloro-9-(tetrahydro-2-pyranyl)-purine and (S)-2-(1-amino-propyl)-5-fluoro- 3-Phenyl-3H-quinazolin-4-one undergoes a nucleophilic substitution reaction to obtain (S)-5-fluoro-3-phenyl-2-{1-[(9-tetrahydro-2H-pyran- 2-yl)-9H-purin-6-ylamino]propyl}-3H-quinazolin-4-one; 2)(S)-5-fluoro-3-phenyl-2-{1-[( 9-tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino]propyl}-3H-quinazolin-4-one is deprotected in hydrochloric acid ethanol to obtain (S)-2- (1-Amino-propyl)-5-fluoro-3-phenyl-3H-quinazolin-4-one (i.e. Idelalisib):

Further, the 6-chloro-9-(tetrahydro-2-pyranyl)-purine is obtained by reacting 6-chloropurine with 2,3-dihydropyran in ethyl acetate. The obtained crude product can be recrystallized in a solvent such as n-hexane or petroleum ether to separate 6-chloro-9-(tetrahydro-2-pyranyl)-purine, preferably n-hexane.

Beneficial effects: the method of the present invention uses 6-chloro-9-(tetrahydro-2-pyranyl)-purine to replace 6-bromopurine and (S)-2-(1-amino-propyl)-5-fluoro- 3-Phenyl-3H-quinazolin-4-one undergoes a nucleophilic substitution reaction to obtain (S)-5-fluoro-3-phenyl-2-{1-[(9-tetrahydro-2H-pyran- 2-yl)-9H-purin-6-ylamino]propyl}-3H-quinazolin-4-one, and then deprotection in hydrochloric acid ethanol to obtain Idelalisib, the yield is much higher than that of the prior art, and the subsequent The treatment is simple, and pure Idelalisib can be obtained only through appropriate solvent extraction and recrystallization, which is suitable for industrial production.

detailed description

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

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] ⁺

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) while stirring, then wash twice with water and once with salt water, dry, and concentrate to obtain an oily crude product. Ether (150ml) was recrystallized to obtain 18.5g of 6-chloro-9-(tetrahydro-2-pyranyl)-purine with a yield of 77.5%.

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

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%.

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] ⁺

6-Chloro-9-(tetrahydro-2-pyranyl)-purine (14.31g), (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H- Dissolve quinazolin-4-one (8.91g) and triethylamine (9.54g) in n-butanol (40ml), reflux at 80°C for 24 hours, cool at room temperature, filter, wash with isopropanol, wash with water, and wash with n-hexane The filter cake was washed to give a crude product which was recrystallized from isopropanol (30ml) to (S)-5-fluoro-3-phenyl-2-{1-[(9-tetrahydro-2H-pyran-2-yl )-9H-purin-6-ylamino]propyl}-3H-quinazolin-4-one 10.9g, yield 72.6%.

Embodiment 5-6: Preparation of Idelalisib

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%.

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] ⁺

(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, quenched with saturated NaHCO ₃ solution, and the pH was adjusted to about 7-8, and dichloromethane (50* 3) Extraction, drying, concentration, and recrystallization of the crude product from ethyl acetate:n-hexane (15ml:15ml) to obtain (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H- Quinazolin-4-one 6.9g, yield 83.1%.

Claims (5)

1. a preparation method of Idelalisib, the method comprising the steps of 1) the chloro-9-of 6-(tetrahydrochysene-2-pyranose)-purine and (S)-2-(1- Amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one generation nucleophilic substitution obtains (S)-5-fluoro-3-phenyl-2-{1-[(9- Tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base amino] propyl group }-3H-quinazoline-4-one；Step 2) (S)-5-fluoro-3-phenyl -2-{1-[(9-tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base amino] propyl group } remove-insurance in acidic alcohol of-3H-quinazoline-4-one Protect and obtain (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one:

2. the preparation method of Idelalisib as claimed in claim 1, it is characterised in that: the chloro-9-of 6-(tetrahydrochysene-2-pyranose)-purine be with 6-chloropurine is raw material, obtains with the reaction of 2,3 dihydropyran in ethyl acetate.

3. the preparation method of Idelalisib as claimed in claim 1, it is characterised in that: reaction terminates gained crude product in organic solvent Extraction and recrystallization isolate sterling.

4. the preparation method of Idelalisib as claimed in claim 3, it is characterised in that: the solvent used by extraction is normal hexane or oil Ether.

5. the preparation method of Idelalisib as claimed in claim 3, it is characterised in that: the solvent used by recrystallization is normal hexane.