CN104876931A - (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl]-3H-quinazolin-4-one preparation method - Google Patents
(S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl]-3H-quinazolin-4-one preparation method Download PDFInfo
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Abstract
The present invention relates to a (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl]-3H-quinazolin-4-one preparation method, wherein a three-step reaction is used to prepare the finished product, and the preparation method has characteristics of simple reaction step simple, high yield, high product optical purity, and mass production.
Description
1, technical field
The present invention relates to the novel method that one prepares the fluoro-3-phenyl of (S)-5--2-[1-(9H-purine-6-is amino)-propyl group]-3H-quinazoline-4-one.
2, background technology
Its chemistry of the Idelalisib fluoro-3-phenyl of (S)-5--2-by name [1-(9H-purine-6-is amino)-propyl group]-3H-quinazoline-4-one, by Gilead Sciences(Gilid Science Co.) the highly selective oral PI3K δ inhibitor researched and developed, can be used for treating chronic lymphocytic leukemia, non-Hodgkin lymphoma.
The white blood of chronic lymphocytic (CLL) is sick as a kind of progress cancer comparatively slowly, and be the most common leukemia of U.S.'s Equations of The Second Kind, the accumulation of too much eukocyte may cause the mortality complication comprising severe infections.At present, a roentgenism x of this disease is the scheme of the one or more chemotherapeutics of rituximab combination.Can recur after the immunotherapy of most patient's original chemical, the patient of about 20% is intractable.Idelalisib is very good to the curative effect of CLL, see statistically significant effect in advance, be expected to become the new chronic leukemia therapy not comprising chemotherapy regimen, this methods for the treatment of is not only effectively simple, and be oral administration due to it, therefore can improve the overall quality of life of patient.As the PI3K inhibitor of highly selective, the security of Idelalisib is good compared with other other PI3K inhibitor.
In current prior art, the existing preparation example to Idelalisib is as just described the preparation method about Idelalisib in WO2005/113554, but the step comparison step of preparation is long, and preparation method is more loaded down with trivial details, yield is lower, and optical purity is lower.
3, summary of the invention
The object of this invention is to provide a kind of method of the fluoro-3-phenyl of preparation (S)-5--2-[1-(9H-purine-6-is amino)-propyl group]-3H-quinazoline-4-one newly, concrete technical scheme is as follows:
The preparation method of the fluoro-3-phenyl of a kind of (S)-5--2-[1-(9H-purine-6-is amino)-propyl group]-3H-quinazoline-4-one, is characterized in that, comprise the following steps:
A 2-amino-6-fluorobenzoic acid and N-tertbutyloxycarbonyl-C4H9NO2 join in pyridine by (), add triphenyl phosphite, stirring reaction 8-15 hour in 40-70 DEG C of oil bath, add aniline, stirring reaction 5-10 hour in 80-140 DEG C of oil bath, concentrating under reduced pressure, filtrate adds acetic acid ethyl dissolution, respectively with water and saturated sodium-chloride washing, dry, obtain 1-(the fluoro-4-carbonyl of 5--3-phenyl-3,4-dihydroquinazoline-2-base) propyl group-(S)-t-butylcarbamate crude product;
B step a products therefrom adds in methylene dichloride by (), add trifluoroacetic acid, stirring at room temperature 6-10 hour under ice bath, thin-layer chromatography is monitored, under ice bath, drip ammoniacal liquor and adjust pH to be 8-12, dichloromethane extraction 1-5 time, dry, concentrated, add re-crystallizing in ethyl acetate, filter, dry, obtain (S)-2-(1-aminophenyl)-5-fluoro-3-phenylquinazoline-4 (3H)-one;
C step b products therefrom adds in the trimethyl carbinol by (); add triethylamine and 6-chloropurine; nitrogen protection; reflux in 80-120 DEG C of oil bath 8-15 hour, after completion of the reaction, concentrated; add methylene chloride dissolving; washing, is spin-dried for, and adds ethyl alcohol recrystallization and obtains the fluoro-3-phenyl of (S)-5--2-[1-(9H-purine-6-is amino)-propyl group]-3H-quinazoline-4-one.
The oil bath temperature adding triphenyl phosphite reaction in described step a is 55 DEG C, and churning time is 12 hours.
The oil bath temperature adding the reaction of aniline in described step a is 110 DEG C, and churning time is 7 hours.
Wash 3 times in described step a with water, wash 1 time with saturated sodium-chloride.
Stirring at room temperature in described step b 8 hours.
Dripping ammoniacal liquor in described step b adjusts pH to be 10.
Dichloromethane extraction 3 times in described step b.
In described step c, oil bath temperature is 100 DEG C, and return time is 12 hours.
The present invention has the following advantages:
1) the present invention's reaction is obtained by three-step reaction, and reactions steps is few;
2) reaction conditions of the present invention is gentle, is easy to operate and control;
3) yield of reactions steps of the present invention is higher;
4) reaction products obtained therefrom optical purity of the present invention is high, and not easily racemization occurs, EE value is more than 99%;
5) production technique of the present invention can realize industrialization, can carry out hundred feather weight productions.
4, embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following examples.
the preparation of the fluoro-3-phenyl of embodiment 1 (S)-5--2-[1-(9H-purine-6-is amino)-propyl group]-3H-quinazoline-4-one
The synthesis of 1.1-(the fluoro-4-carbonyl of 5--3-phenyl-3,4-dihydroquinazoline-2-base) propyl group-(S)-t-butylcarbamate
By 2-amino-6-fluorobenzoic acid and SM1(310g, 2mol) with N-tertbutyloxycarbonyl-C4H9NO2 (446.6g, 2.2mol) join in 15L pyridine, finally add triphenyl phosphite (744g, 2.4mol), stir 12 hours in 55 DEG C of oil baths, after completion of the reaction, in reaction solution, add aniline (223.2g, 2.4mol), stir 7 hours in 110 DEG C of oil baths, HPLC monitoring is without after raw material, and concentrating under reduced pressure, adds acetic acid ethyl dissolution, wash 3 times with water, saturated sodium-chloride is washed once, and dry, evaporate to dryness obtains 0.9kg crude product.
2. the synthesis of (S)-2-(1-aminophenyl)-5-fluoro-3-phenylquinazoline-4 (3H)-one
By upper step gained 1-(the fluoro-4-carbonyl of 5--3-phenyl-3,4-dihydroquinazoline-2-base) propyl group-(S)-t-butylcarbamate (0.9kg) joins in 1L methylene dichloride, trifluoroacetic acid (TFA) (1.1kg is added under ice bath, 1.02mol), stirring at room temperature 8 hours, thin-layer chromatography monitoring is without after raw material, concentrating under reduced pressure, under ice bath, drip ammoniacal liquor and adjust pH to 10, dichloromethane extraction 3 times, dry, concentrated, obtain oily matter, add 1 liter of re-crystallizing in ethyl acetate, obtain white solid, filter, 417 grams of oven dry, two step yields amount to: 70.2%
3. the synthesis of the fluoro-3-phenyl of (S)-5--2-[1-(9H-purine-6-is amino)-propyl group]-3H-quinazoline-4-one
By the fluoro-3-phenyl of upper step gained (S)-5--2-[1-(9H-purine-6-is amino)-propyl group]-3H-quinazoline-4-one (297g, 1.0mol) join in the 4.0L trimethyl carbinol, then triethylamine (202g is added, 2.0mol) with 6-chloropurine (SM4) (309g, 2mol).Nitrogen protection, refluxes 12 hours in 100 DEG C of oil baths, and HPLC monitors, and after completion of the reaction, concentrated, add methylene chloride dissolving, and washing, be spin-dried for, ethyl alcohol recrystallization obtains white solid 285g, productive rate 68.7%.
1H NMR(400MHz,25℃,DMSO-d6)：
12.94(broad s,1H)，8.12-8.17(m,2H)，7.75-7.80(m,2H)，7.43-7.62(m,6H)，7.24-7.28(m,1H)，4.65(broad s,1H)，1.88-1.89(m,2H)，0.73(t,J=7.3Hz,3H)。
Claims (8)
1. a preparation method for the fluoro-3-phenyl of (S)-5--2-[1-(9H-purine-6-is amino)-propyl group]-3H-quinazoline-4-one, is characterized in that, comprise the following steps:
A 2-amino-6-fluorobenzoic acid and N-tertbutyloxycarbonyl-C4H9NO2 join in pyridine by (), add triphenyl phosphite, stirring reaction 8-15 hour in 40-70 DEG C of oil bath, add aniline, stirring reaction 5-10 hour in 80-140 DEG C of oil bath, concentrating under reduced pressure, filtrate adds acetic acid ethyl dissolution, respectively with water and saturated sodium-chloride washing, dry, obtain 1-(the fluoro-4-carbonyl of 5--3-phenyl-3,4-dihydroquinazoline-2-base) propyl group-(S)-t-butylcarbamate crude product;
B step a products therefrom adds in methylene dichloride by (), add trifluoroacetic acid, stirring at room temperature 6-10 hour under ice bath, thin-layer chromatography is monitored, under ice bath, drip ammoniacal liquor and adjust pH to be 8-12, dichloromethane extraction 1-5 time, dry, concentrated, add re-crystallizing in ethyl acetate, filter, dry, obtain (S)-2-(1-aminophenyl)-5-fluoro-3-phenylquinazoline-4 (3H)-one;
C step b products therefrom adds in the trimethyl carbinol by (); add triethylamine and 6-chloropurine; nitrogen protection; reflux in 80-120 DEG C of oil bath 8-15 hour, after completion of the reaction, concentrated; add methylene chloride dissolving; washing, is spin-dried for, and adds ethyl alcohol recrystallization and obtains the fluoro-3-phenyl of (S)-5--2-[1-(9H-purine-6-is amino)-propyl group]-3H-quinazoline-4-one.
2. preparation method according to claim 1, is characterized in that, the oil bath temperature adding triphenyl phosphite reaction in described step a is 55 DEG C, and churning time is 12 hours.
3. preparation method according to claim 1, is characterized in that, the oil bath temperature adding the reaction of aniline in described step a is 110 DEG C, and churning time is 7 hours.
4. preparation method according to claim 1, is characterized in that, washes 3 times in described step a with water, washes 1 time with saturated sodium-chloride.
5. preparation method according to claim 1, is characterized in that, the stirring at room temperature in described step b 8 hours.
6. preparation method according to claim 1, is characterized in that, drips ammoniacal liquor and adjust pH to be 10 in described step b.
7. preparation method according to claim 1, is characterized in that, dichloromethane extraction 3 times in described step b.
8. preparation method according to claim 1, is characterized in that, in described step c, oil bath temperature is 100 DEG C, and return time is 12 hours.
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| CN201410070320.4A CN104876931B (en) | 2014-02-28 | A kind of preparation method of (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl group]-3H-quinazoline-4-one |
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| CN201410070320.4A CN104876931B (en) | 2014-02-28 | A kind of preparation method of (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl group]-3H-quinazoline-4-one |
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| CN104876931A true CN104876931A (en) | 2015-09-02 |
| CN104876931B CN104876931B (en) | 2016-11-30 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016188506A1 (en) * | 2015-05-22 | 2016-12-01 | Zentiva, K.S. | Solid forms of 5-fluoro-3-phenyl-2-[(1s)-1-(9h-purin-6-ylamino)propyl]quinazolin-4-one and preparation thereof |
| CN106854183A (en) * | 2016-12-22 | 2017-06-16 | 山东轩德医药科技有限公司 | The preparation method of Ai Dailalisi intermediates |
| CN108409674A (en) * | 2018-02-09 | 2018-08-17 | 南京法恩化学有限公司 | A kind of preparation method of Ai Dailalisi intermediates |
| WO2018198131A1 (en) * | 2017-04-24 | 2018-11-01 | Natco Pharma Limited | Process for the preparation of amorphous idelalisib |
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|---|---|---|---|---|
| WO2006023381A1 (en) * | 2004-08-16 | 2006-03-02 | Taigen Biotechnology | Pyrimidinone compounds |
| CN101006088A (en) * | 2004-06-28 | 2007-07-25 | 安进Sf公司 | Fused pyrimidine derivatives and compositions thereof as CXCR3 receptor modulators, useful in prevention and treatment of inflammatory and immunoregulatory disorders and diseases |
| CN101031569A (en) * | 2004-05-13 | 2007-09-05 | 艾科斯有限公司 | Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta |
| WO2013082540A1 (en) * | 2011-12-02 | 2013-06-06 | Gilead Calistoga Llc | Compositions and methods of treating a proliferative disease with a quinazolinone derivative |
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101031569A (en) * | 2004-05-13 | 2007-09-05 | 艾科斯有限公司 | Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta |
| CN101006088A (en) * | 2004-06-28 | 2007-07-25 | 安进Sf公司 | Fused pyrimidine derivatives and compositions thereof as CXCR3 receptor modulators, useful in prevention and treatment of inflammatory and immunoregulatory disorders and diseases |
| WO2006023381A1 (en) * | 2004-08-16 | 2006-03-02 | Taigen Biotechnology | Pyrimidinone compounds |
| WO2013082540A1 (en) * | 2011-12-02 | 2013-06-06 | Gilead Calistoga Llc | Compositions and methods of treating a proliferative disease with a quinazolinone derivative |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016188506A1 (en) * | 2015-05-22 | 2016-12-01 | Zentiva, K.S. | Solid forms of 5-fluoro-3-phenyl-2-[(1s)-1-(9h-purin-6-ylamino)propyl]quinazolin-4-one and preparation thereof |
| CN106854183A (en) * | 2016-12-22 | 2017-06-16 | 山东轩德医药科技有限公司 | The preparation method of Ai Dailalisi intermediates |
| WO2018198131A1 (en) * | 2017-04-24 | 2018-11-01 | Natco Pharma Limited | Process for the preparation of amorphous idelalisib |
| US10870650B2 (en) | 2017-04-24 | 2020-12-22 | Natco Pharma Limited | Process for the preparation of amorphous idelalisib |
| CN108409674A (en) * | 2018-02-09 | 2018-08-17 | 南京法恩化学有限公司 | A kind of preparation method of Ai Dailalisi intermediates |
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