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

A kind of preparation method of Idelalisib Download PDF

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Publication number
CN106146503A
CN106146503A CN201510181247.2A CN201510181247A CN106146503A CN 106146503 A CN106146503 A CN 106146503A CN 201510181247 A CN201510181247 A CN 201510181247A CN 106146503 A CN106146503 A CN 106146503A
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CN
China
Prior art keywords
idelalisib
purine
tetrahydrochysene
fluoro
phenyl
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Pending
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CN201510181247.2A
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Chinese (zh)
Inventor
徐浩
吴雪松
岑均达
张锴婷
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Priority to CN201510181247.2A priority Critical patent/CN106146503A/en
Publication of CN106146503A publication Critical patent/CN106146503A/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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 present invention relates to Idelalisib preparation method technical field.
Background technology
Idelalisib is PI3K inhibitor to be administered orally by the first selectivity of lucky Leadd B.V research and development, compared with α, β, γ subunit, its Can high selectivity act on δ subunit, retardance PI3K δ-Akt signal path also promotes apoptosis, obtains in July, 2014 U.S. FDA approval listing, for recurring controlling of chronic lymphocytic leukemia, follicular lymphoma and small lymphocytic lymphoma Treat.Chemistry entitled (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-base amino) propyl group]-3H-quinazoline-4-one.
Its synthetic route of synthetic method that international monopoly WO2005113556A1 discloses a kind of Idelalisib is as follows:
The method final step is with 6-bromine purine as raw material, and (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one Nucleophilic substitution is occurred to obtain Idelalisib.The defect of this step reaction is that 6-bromine purine is much more expensive, and final products Obtain needing column chromatography, and yield only has 50%.Experimenter has also attempted 6-chloropurine and has substituted 6-bromine purine directly and quinoline simultaneously Oxazoline reactive ketone, finds that quinazolinone raw material reaction is the completeest, and thin layer chromatography display product point is markedly less than raw material point.
It is thus desirable to a kind of raw material of exploitation is easy to get, safety, the method that what yield was high prepare Idelalisib.
Summary of the invention
The purpose of the present invention is that the above-mentioned prior art defect of solution, it is provided that a kind of brand-new raw material is easy to get, and yield is high, is suitable for The method of large-scale production Idelalisib.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
The preparation method of a kind of Idelalisib, the method includes 1) the chloro-9-of 6-(tetrahydrochysene-2-pyranose)-purine and (S)-2-(1-amino- Propyl group)-5-fluoro-3-phenyl-3H-quinazoline-4-one generation nucleophilic substitution obtains (S)-5-fluoro-3-phenyl-2-{1-[(9-tetrahydrochysene-2H-pyrrole Mutter-2-base)-9H-purine-6-base amino] propyl group }-3H-quinazoline-4-one；2) (S)-5-fluoro-3-phenyl-2-{1-[(9-tetrahydrochysene-2H-pyrans -2-base)-9H-purine-6-base amino] propyl group }-3H-quinazoline-4-one deprotection in acidic alcohol obtains (S)-2-(1-amino-the third Base)-5-fluoro-3-phenyl-3H-quinazoline-4-one (i.e. Idelalisib):
Further, the chloro-9-of described 6-(tetrahydrochysene-2-pyranose)-purine is with 6-chloropurine as raw material, with 2,3 in ethyl acetate Dihydropyran reaction obtains.Gained crude product recrystallization in normal hexane or petroleum ether equal solvent may separate out the chloro-9-of 6-(tetrahydrochysene-2-pyrrole Mutter base)-purine, preferably normal hexane.
Beneficial effect: the inventive method uses the chloro-9-of 6-(tetrahydrochysene-2-pyranose)-purine to replace 6-bromine purine and (S)-2-(1-amino-the third Base)-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, then in acidic alcohol, deprotection i.e. obtains Idelalisib, Yield is far above prior art, and post processing is simple, it is only necessary to i.e. can get pure by suitable solvent extraction and recrystallization Idelalisib, is suitable to industrialized production.
Detailed description of the invention
The preparation of the chloro-9-of embodiment 1-2:6-(tetrahydrochysene-2-pyranose)-purine
6-chloropurine (15.5g), p-methyl benzenesulfonic acid (0.26g) are dissolved in ethyl acetate (180ml), are heated to 50 DEG C, 2,3 dihydropyran (10.5ml) slowly drop in reactant liquor, drip and finish, and continue stirring 1 hour at this temperature, slowly cool to Room temperature, adds saturated ammonium chloride solution (10ml), then washes twice under stirring, Sal is washed once, is dried, is concentrated to give Crude oil, is recrystallized to give the chloro-9-of 6-(tetrahydrochysene-2-pyranose)-purine 19.6g, yield 82.1% with normal hexane (150ml).1H 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]+
6-chloropurine (15.5g), p-methyl benzenesulfonic acid (0.26g) are dissolved in ethyl acetate (180ml), are heated to 50 DEG C, 2,3 dihydropyran (10.5ml) slowly drop in reactant liquor, drip and finish, and continue stirring 1 hour at this temperature, slowly cool to Room temperature, adds saturated ammonium chloride solution (10ml), then washes twice under stirring, Sal is washed once, is dried, is concentrated to give Crude oil, is recrystallized to give the chloro-9-of 6-(tetrahydrochysene-2-pyranose)-purine 18.5g, yield 77.5% with petroleum ether (150ml).
Embodiment 3-4:(S)-5-fluoro-3-phenyl-2-{1-[(9-tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base amino] propyl group }-3H-quinoline The preparation of oxazoline-4-ketone
By chloro-for 6-9-(tetrahydrochysene-2-pyranose)-purine (14.31g), (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4- Ketone (8.91g), triethylamine (9.54g) are dissolved in isopropanol (40ml), 80 DEG C of back flow reaction 24 hours, and room temperature cools down, mistake Filter, isopropanol is washed, and washes, normal hexane washing filter cake, 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 12.8g, yield 85.3%.
1H NMR(400MHz,CDCl3)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]+
By chloro-for 6-9-(tetrahydrochysene-2-pyranose)-purine (14.31g), (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4- Ketone (8.91g), triethylamine (9.54g) are dissolved in n-butyl alcohol (40ml), 80 DEG C of back flow reaction 24 hours, and room temperature cools down, mistake Filter, isopropanol is washed, and washes, normal hexane washing filter cake, obtains crude product, the fluoro-3-of recrystallization (S)-5-in isopropanol (30ml) Phenyl-2-{1-[(9-tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base amino] propyl group }-3H-quinazoline-4-one 10.9g, yield 72.6%.
The preparation of embodiment 5-6:Idelalisib
(S)-5-fluoro-3-phenyl-2-{1-[(9-tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base amino] is processed with acidic alcohol (40ml) Propyl group }-3H-quinazoline-4-one (10g), it is stirred at room temperature 3 hours, adjusts about PH to 8-9 with ammonia, add crystal seed, filter Obtain (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one 7.3g, yield 87.9%.
1H NMR (400MHz, DMSO) δ 10.46 (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]+
By (S)-5-fluoro-3-phenyl-2-{1-[(9-tetrahydrochysene-2H-pyrans-2-base)-9H-purine-6-base amino] propyl group }-3H-quinazoline-4-one (10g) it is dissolved in acidic alcohol (40ml), is stirred at room temperature 3 hours, uses saturated NaHCO3Solution cancellation, and PH is adjusted To about 7-8, extract with dichloromethane (50*3), be dried, concentrate, crude product ethyl acetate: normal hexane (15ml:15ml) It is recrystallized to give (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-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.
CN201510181247.2A 2015-04-16 2015-04-16 A kind of preparation method of Idelalisib Pending CN106146503A (en)

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CN107573345A (en) * 2017-09-12 2018-01-12 浙江新东港药业股份有限公司 A kind of Ai Dailalisi and its intermediate preparation method

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CN103387576A (en) * 2013-08-09 2013-11-13 中国药科大学 Aramide Raf kinase inhibitor based on purine structure and preparation method and application thereof
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107573345A (en) * 2017-09-12 2018-01-12 浙江新东港药业股份有限公司 A kind of Ai Dailalisi and its intermediate preparation method
CN107573345B (en) * 2017-09-12 2020-01-10 浙江乐普药业股份有限公司 Preparation method of erigeron and intermediate thereof

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