CN104876931B - A kind of preparation method of (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl group]-3H-quinazoline-4-one - Google Patents
A kind of preparation method of (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl group]-3H-quinazoline-4-one Download PDFInfo
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- CN104876931B CN104876931B CN201410070320.4A CN201410070320A CN104876931B CN 104876931 B CN104876931 B CN 104876931B CN 201410070320 A CN201410070320 A CN 201410070320A CN 104876931 B CN104876931 B CN 104876931B
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- 238000002360 preparation method Methods 0.000 title claims description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 239000012141 concentrate Substances 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 5
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- HVLLSGMXQDNUAL-UHFFFAOYSA-N Triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000002027 dichloromethane extract Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- -1 (S)-2-(1-aminophenyl)-5-fluoro-3-phenylquinazoline-4 (3H)-one Chemical compound 0.000 claims description 3
- ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-chloro-7H-purine Chemical compound ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 229940091252 Sodium supplements Drugs 0.000 claims 1
- 238000004458 analytical method Methods 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 230000003287 optical Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- GZLYSDJGEXGQDO-UHFFFAOYSA-N C1=CC=CC2=NCNC=C21 Chemical compound C1=CC=CC2=NCNC=C21 GZLYSDJGEXGQDO-UHFFFAOYSA-N 0.000 abstract 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 abstract 1
- 229910052731 fluorine Inorganic materials 0.000 abstract 1
- 239000011737 fluorine Substances 0.000 abstract 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 abstract 1
- 150000002576 ketones Chemical class 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- YKLIKGKUANLGSB-HNNXBMFYSA-N Idelalisib Chemical compound C1([C@@H](NC=2[C]3N=CN=C3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 YKLIKGKUANLGSB-HNNXBMFYSA-N 0.000 description 5
- 229960003445 Idelalisib Drugs 0.000 description 5
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 3
- 108040005185 1-phosphatidylinositol-3-kinase activity proteins Proteins 0.000 description 3
- 206010008943 Chronic leukaemia Diseases 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 206010008958 Chronic lymphocytic leukaemia Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 230000001684 chronic Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- 210000003746 Feathers Anatomy 0.000 description 1
- 206010024324 Leukaemias Diseases 0.000 description 1
- 208000008456 Leukemia, Myelogenous, Chronic, BCR-ABL Positive Diseases 0.000 description 1
- 206010029592 Non-Hodgkin's lymphomas Diseases 0.000 description 1
- 108010001645 Rituximab Proteins 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N TFA trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000973 chemotherapeutic Effects 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 201000006934 chronic myeloid leukemia Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001926 lymphatic Effects 0.000 description 1
- 230000000527 lymphocytic Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- BHMCUDMQFKNMRX-UHFFFAOYSA-N phenyl phosphite Chemical compound [O-]P([O-])OC1=CC=CC=C1 BHMCUDMQFKNMRX-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Abstract
The formula of the present invention relates to relates to the method that one prepares (S) 5 fluorine 3 phenyl 2 [1 (9H purine 6 amino) propyl group] 3H quinazoline 4 ketone, the method prepares gained by three-step reaction, reactions steps is simple, yield is high, optical purity is high, can be with volume production.
Description
1, technical field
The present invention relates to one and prepare the new side of (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl group]-3H-quinazoline-4-one
Method.
2, background technology
Its chemistry of Idelalisib entitled (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl group]-3H-quinazoline-4-one, be by
Gilead Sciences(Gilid Science Co.) the high selectivity researched and developed is administered orally PI3K δ inhibitor, can be used for treating chronic lymphatic
Chronic myeloid leukemia, non-Hodgkin lymphoma.
The white blood of chronic lymphocytic (CLL) is sick as a kind of progress cancer the most slowly, is that U.S.'s Equations of The Second Kind is most commonly seen
Leukemia, the accumulation of too much eukocyte may cause the mortality complication including severe infections.At present, this disease
The sick scheme that a gamma therapy is the one or more chemotherapeutics of rituximab combination.Most patient's original chemical immunity are controlled
Can recur after treatment, the patient of about 20% is intractable.Idelalisib is the best to the curative effect of CLL, sees statistically significant in advance
Effect, is expected to become the new chronic leukemia therapy not comprising chemotherapy regimen, and this Therapeutic Method is not only simple effective, Er Qieyou
It is oral medication in it, therefore can improve the overall quality of life of patient.As height selective PI3K inhibitor, Idelalisib
Safety good compared with other other PI3K inhibitor.
In current prior art, to the preparation such as WO2005/113554 of Idelalisib just describes about
The preparation method of Idelalisib, but the step comparison step of preparation is long, and preparation method is comparatively laborious, and yield is relatively low, and
And optical purity is relatively low.
3, summary of the invention
It is an object of the invention to provide a kind of new preparation (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl group]-3H-quinoline azoles
The method of quinoline-4-ketone, concrete technical scheme is as follows:
The preparation method of a kind of (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl group]-3H-quinazoline-4-one, its feature exists
In, comprise the following steps:
A 2-amino-6-fluobenzoic acid and N-tertbutyloxycarbonyl-C4H9NO2 are joined in pyridine by (), add tricresyl phosphite
Phenyl ester, in 40-70 DEG C of oil bath, stirring reaction 8-15 hour, adds 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, is dried, obtains 1-(5-fluoro-4-carbonyl-3-
Phenyl-3,4-dihydroquinazoline-2-base) propyl group-(S)-t-butylcarbamate crude product；
B step a products therefrom is added in dichloromethane by (), add trifluoroacetic acid, be stirred at room temperature 6-10 hour under ice bath, thin
Analysing monitoring layer by layer, under ice bath, dropping ammonia adjusts pH to be 8-12, and dichloromethane extracts 1-5 time, is dried, and concentrates, and adds acetic acid
Ethyl ester recrystallization, filters, and dries, obtains (S)-2-(1-aminophenyl)-5-fluoro-3-phenylquinazoline-4 (3H)-one；
C step b products therefrom is added in the tert-butyl alcohol by (), add triethylamine and 6-chloropurine, and nitrogen is protected, 80-120 DEG C of oil
Refluxing 8-15 hour in bath, after completion of the reaction, concentrate, add methylene chloride dissolving, washing, is spin-dried for, and adds ethyl alcohol recrystallization and obtains
(S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl group]-3H-quinazoline-4-one.
The oil bath temperature adding triphenyl phosphite reaction in described step a is 55 DEG C, and mixing time is 12 hours.
The oil bath temperature of the reaction adding aniline in described step a is 110 DEG C, and mixing time is 7 hours.
Described step a washes with water 3 times, wash 1 time with saturated sodium-chloride.
It is stirred at room temperature 8 hours in described step b.
Dripping ammonia in described step b adjusts pH to be 10.
In described step b, dichloromethane extracts 3 times.
In described step c, oil bath temperature is 100 DEG C, and return time is 12 hours.
The invention have the advantages that
1) present invention reaction is prepared by three-step reaction, and reactions steps is few；
2) reaction condition of the present invention is gentle, it is easy to operates and controls；
3) yield of the reactions steps of the present invention is higher；
4) the reaction products obtained therefrom optical purity of the present invention is high, is not susceptible to racemization, and EE value is more than 99%；
5) production technology of the present invention can realize industrialization, can carry out hundred feather weight productions.
4, detailed description of the invention
The detailed description of the invention of form by the following examples, is described in further detail the foregoing of the present invention.But no
This should being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to following example.
The preparation of embodiment 1 (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl group]-3H-quinazoline-4-one
The synthesis of 1.1-(5-fluoro-4-carbonyl-3-phenyl-3,4-dihydroquinazoline-2-base) propyl group-(S)-t-butylcarbamate
By the 2-amino i.e. SM1(310g of-6-fluobenzoic acid, 2mol) and N-tertbutyloxycarbonyl-C4H9NO2 (446.6g,
2.2mol) join in 15L pyridine, be eventually adding triphenyl phosphite (744g, 2.4mol), stir in 55 DEG C of oil baths
12 hours, after completion of the reaction, in reactant liquor, add aniline (223.2g, 2.4mol), in 110 DEG C of oil baths, stir 7 little
Time, after HPLC monitoring is without raw material, concentrating under reduced pressure, add acetic acid ethyl dissolution, wash 3 times with water, saturated sodium-chloride is washed once,
It is dried, is evaporated to obtain 0.9kg crude product.
2. the synthesis of (S)-2-(1-aminophenyl)-5-fluoro-3-phenylquinazoline-4 (3H)-one
By upper step gained 1-(5-fluoro-4-carbonyl-3-phenyl-3,4-dihydroquinazoline-2-base) propyl group-(S)-t-butylcarbamate
(0.9kg) join in 1L dichloromethane, add trifluoroacetic acid (TFA) (1.1kg, 1.02mol) under ice bath, be stirred at room temperature
8 hours, after thin layer chromatography monitoring is without raw material, concentrating under reduced pressure, under ice bath, dropping ammonia adjusted pH to 10, dichloromethane extraction 3
Secondary, it is dried, concentrates, obtain grease, add 1 liter of re-crystallizing in ethyl acetate, obtain white solid, filter, 417 grams of drying,
Two step yields amount to: 70.2%
3. the synthesis of (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl group]-3H-quinazoline-4-one
By upper step gained (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl group]-3H-quinazoline-4-one (297g, 1.0mol)
Join in the 4.0L tert-butyl alcohol, be subsequently adding triethylamine (202g, 2.0mol) and 6-chloropurine (SM4) (309g, 2mol).
Nitrogen is protected, and refluxes 12 hours in 100 DEG C of oil baths, and HPLC monitors, and after completion of the reaction, concentrates, and add methylene chloride dissolving,
Washing, is spin-dried for, and ethyl alcohol recrystallization obtains white solid 285g, productivity 68.7%.
1H NMR (400MHz, 25 DEG C, 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 (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl group]-3H-quinazoline-4-one, its feature exists
In, comprise the following steps:
A 2-amino-6-fluobenzoic acid and N-tertbutyloxycarbonyl-C4H9NO2 are joined in pyridine by (), add triphenyl phosphite,
In 40-70 DEG C of oil bath, stirring reaction 8-15 hour, adds aniline, and in 80-140 DEG C of oil bath, stirring reaction 5-10 hour, reduces pressure dense
Contracting, filtrate adds acetic acid ethyl dissolution, respectively with water and saturated sodium-chloride washing, is dried, obtains 1-(5-fluoro-4-carbonyl-3-phenyl-3,4-
Dihydroquinazoline-2-base) propyl group-(S)-t-butylcarbamate crude product；
B step a products therefrom is added in dichloromethane by (), add trifluoroacetic acid, be stirred at room temperature 6-10 hour, thin layer under ice bath
Analysis monitoring, under ice bath, dropping ammonia adjusts pH to be 8-12, and dichloromethane extracts 1-5 time, is dried, and concentrates, and adds ethyl acetate
Recrystallization, filters, and dries, obtains (S)-2-(1-aminophenyl)-5-fluoro-3-phenylquinazoline-4 (3H)-one；
C step b products therefrom is added in the tert-butyl alcohol by (), add triethylamine and 6-chloropurine, and nitrogen is protected, in 80-120 DEG C of oil bath
Refluxing 8-15 hour, after completion of the reaction, concentrate, add methylene chloride dissolving, washing, is spin-dried for, and adds ethyl alcohol recrystallization and obtains (S)-5-
Fluoro-3-phenyl-2-[1-(9H-purine-6-amino)-propyl group]-3H-quinazoline-4-one.
Preparation method the most according to claim 1, it is characterised in that add triphenyl phosphite reaction in described step a
Oil bath temperature is 55 DEG C, and mixing time is 12 hours.
Preparation method the most according to claim 1, it is characterised in that add the oil bath temperature of the reaction of aniline in described step a
Degree is 110 DEG C, and mixing time is 7 hours.
Preparation method the most according to claim 1, it is characterised in that wash with water in described step a 3 times, use saturated chlorination
Sodium washes 1 time.
Preparation method the most according to claim 1, it is characterised in that be stirred at room temperature 8 hours in described step b.
Preparation method the most according to claim 1, it is characterised in that drip ammonia in described step b and adjust pH to be 10.
Preparation method the most according to claim 1, it is characterised in that in described step b, dichloromethane extracts 3 times.
Preparation method the most according to claim 1, it is characterised in that in described step c, oil bath temperature is 100 DEG C, during backflow
Between be 12 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104876931A CN104876931A (en) | 2015-09-02 |
| CN104876931B true CN104876931B (en) | 2016-11-30 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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