CN108101852A - A kind of preparation method of olaparib - Google Patents
A kind of preparation method of olaparib Download PDFInfo
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- CN108101852A CN108101852A CN201711440860.7A CN201711440860A CN108101852A CN 108101852 A CN108101852 A CN 108101852A CN 201711440860 A CN201711440860 A CN 201711440860A CN 108101852 A CN108101852 A CN 108101852A
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- Prior art keywords
- olaparib
- reaction
- method described
- compound iii
- crude product
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
- C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
Abstract
The invention discloses a kind of preparation methods of olaparib.The present invention is using compound ii in AlMe3Under the conditions of carry out amidation process and be made compound III, reacted after compound III hydrolysis with 1 cyclopropane carbonyl piperazine, be refining to obtain finished product olaparib (I) fine work.The preparation method route is simple, easy to operate, and total yield of products is high, and by-product is few, is suitble to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to the preparation method of antitumor drug olaparib.
Background technology
Olaparib is researched and developed first by biotech company of Britain KuDOS (Ku Duosi) Pharm Pur GmbH, is oral poly-
Adenylate diphosphonic acid phosphoribosynltransferase (PARP) inhibitor.Major retardation DNA damage reparation, causes DNA damage to accumulate, finally kills
Dead tumour cell；In addition, moreover it is possible to increase sensibility of the cell to other interior exogenous DNA damage factors；Inhibit angiogenesis；
Enhance the immunity of normal cell, so as to resist the invasion of cancer cell.
Olaparib has obtained highly recognition to the therapeutic effect of oophoroma.EMEA and FDA successively authorizes olaparib and controls
Treat the Orphan drug certification of oophoroma.
The chemical name of olaparib is 4- [3- (4- cyclopropane carbonyls-piperazine -1- carbonyls) the fluoro- benzyls of -4-] -2H- phthaleins
Piperazine -1- ketone, structural formula are：
It is as follows on olaparib synthetic route and preparation method report situation at present：
1st, document J.Med.Chem., 2008,51：6581-6591 reports the synthetic method of olaparib：
Shortcoming：The route synthetic route is long, and final step is using needs in O- benzotriazole-tetramethylurea hexafluorophosphoric acid
Salt (HBTU), n,N-diisopropylethylamine (DIPEA) condition are reacted, and cost of material is higher, and product is through preparing liquid-phase pure
Change, be unfavorable for industrialized production.
2nd, patent CN201510651102.4 discloses a wherein synthetic route and is：
The reaction is although avoid document J.Med.Chem., and 2008,51：6581-6591 final step costliness raw materials HBTU
Use, but the reaction is there are the fluoro- 5- formylbenzoates of raw material 2- are expensive, compound VIa (VIb) and phthalide preparationization
The problem of object VIIIa yields are low (about 60%) is closed, causes product entirety yield not high, is still unfavorable for industrialized production.
For a series of problems existing in the prior art, seek that raw material is cheap and easy to get, and reaction step is few, product yield is high,
By-product is low, is suitble to industrialized production synthetic route, has great importance.
The content of the invention
The defects of it is an object of the invention to overcome the prior art, provides a kind of new olaparib preparation method, should
Preparation method starting material is cheap and easy to get, and process route is simple, and total recovery is high, and by-product is few, and purified product purity is high, is suitble to work
Industry metaplasia is produced.
The present invention provides a kind of preparation method of olaparib, includes the following steps：
A, compound ii and anhydrous hydrazine are in AlMe3Under the conditions of react be made compound III；
B, compound III first hydrolyzes under NaOH environment, is then reacted in organic solvent condition and 1- cyclopropane carbonyls piperazine
Generate final product olaparib (I)；
C, obtained olaparib (I) is refined；
Its reaction scheme is as follows：
Wherein, the reaction dissolvent described in step a is n-hexane, toluene or acetonitrile；Compound ii, anhydrous hydrazine and AlMe3It rubs
You are than being 1:1~1.1:1~2；Reaction temperature is 20~25 DEG C, and the reaction time is 5~10h.
Organic solvent used is methanol or ethyl alcohol in step b；Compound III is 1 with NaOH molar ratios:2, compound III
It is 1.5~1 with 1- cyclopropane carbonyl piperazines molar ratio:1.
Step c process for purification is：Olaparib crude product is taken, is placed in dissolving tank, adds in isopropanol and acetone mixed solvent,
Controlled at 45~50 DEG C, stirring and dissolving adds in activated carbon after crude product is completely dissolved, is filtered while hot after decoloring reaction, filter
Crystallization is stirred at room temperature in liquid, be then cooled to 0~10 DEG C of growing the grain 4 it is small when more than, filtering and is washed with acetone, is filtered, and is done
It is dry to get；The mass volume ratio of olaparib crude product and mixed solvent is 1 in process for purification:10~30g/ml, isopropanol and third
Ketone volume ratio is 1:1~10, the activated carbon decolorizing time is 30min.
The preparation method of olaparib of the present invention obtains following advantageous effect：
(1) compound ii and anhydrous hydrazine are in AlMe3Ring-opening reaction obtains compound III, with AlMe3It is high to carry out catalytic activity,
Easily make compound ii open loop and hydrazine reaction, improve product yield.
(2) reacted after compound III hydrolysis with 1- cyclopropane carbonyl piperazines under the conditions of alcoholic solvent, simplify process route,
Improve product yield.
(3) synthesis route is simple, easy to operate, and total yield of products is high, and by-product is few, is suitble to industrialized production.
(4) specific process for purification is used, the olaparib finished product purity of acquisition is high, and single miscellaneous and total miscellaneous content is low, symbol
Close medicinal requirements.
Specific embodiment
The content of the invention of the present invention is described in further detail below by specific embodiment, but is not therefore limited
Determine present disclosure.Wherein, in compound ii referenced patent CN105175370A prepared by two method of embodiment.
Embodiment 1
The preparation of compound III
Under nitrogen protection, n-hexane 500ml is sequentially added in reaction bulb, concentration is the trimethyl aluminium (0.1mol) of 2M
Hexane solution 50ml, compound ii 27.83g, under 20~25 DEG C of temperature conditionss, add anhydrous hydrazine (0.1mol), instead
It is 5h between seasonable, TLC is monitored after reaction, adds water quenching reaction, and filtering is extracted with ethyl acetate, and merges organic phase, with nothing
Water magnesium sulfate is dried, and is concentrated under reduced pressure, and obtains compound III 25.82g, yield 92.3%, and HPLC purity is 99.83%.
Embodiment 2
The preparation of compound III
Under nitrogen protection, toluene 500ml is sequentially added in reaction bulb, concentration is the trimethyl aluminium (0.1mol) of 2M
Toluene solution 50ml, compound ii 27.83g under 20~25 DEG C of temperature conditionss, add anhydrous hydrazine (0.11mol), during reaction
Between for 10h, TLC is monitored after reaction, adds water quenching reaction, and filtering is extracted with ethyl acetate, and merges organic phase, use is anhydrous
Magnesium sulfate is dried, and is concentrated under reduced pressure, and obtains compound III 26.59g, yield 95.1%, and HPLC purity is 99.87%.
Embodiment 3
The preparation of compound III
Under nitrogen protection, anhydrous acetonitrile 500ml is sequentially added in reaction bulb, concentration is the trimethyl aluminium of 2M
The toluene solution 100ml of (0.2mol), compound ii 27.83g under 20~25 DEG C of temperature conditionss, add anhydrous hydrazine
(0.11mol), reaction time 10h, TLC are monitored after reaction, add water quenching reaction, and filtering is extracted with ethyl acetate, closes
And organic phase, it is dried, is concentrated under reduced pressure with anhydrous magnesium sulfate, obtain compound III 27.03g, yield 96.7%, HPLC purity is
99.91%.
Embodiment 4
The preparation of olaparib (I) crude product
Compound III 25.82g, purified water 100ml are added in reaction bulb, stirs at normal temperatures, adds 2M hydroxides
Said mixture temperature is heated to 100 DEG C, stirs 12h, be cooled to room temperature, filtered by sodium 92.4ml, washing, by the filter of merging
Liquid carries out acidification 30min with 2M dilute hydrochloric acid 46.2ml, sequentially adds methanol 500ml, triethylamine 18.70g, 1- the third first of ring
Acyl piperazine 14.25g, in 20~25 DEG C of reaction temperature, be stirred to react 10 it is small when, after reaction, be cooled to 0 DEG C, filter
To solid 38.66g, yield 96.2%, purity 99.89%.
Olaparib (I) refines
Olaparib crude product 30g is taken to be placed in dissolving tank, adds in isopropanol 81.82ml and acetone 818.2ml, controls temperature
For 45~50 DEG C, stirring and dissolving adds in activated carbon decolorizing 30min after crude product is completely dissolved, is filtered while hot after decoloring reaction, filtered
Crystallization is stirred at room temperature in liquid, be then cooled to 0~10 DEG C of growing the grain 4 it is small when, filtering and is washed with acetone, is filtered, dry, i.e.,
Olaparib fine work 28.35g, yield 94.5%, purity 99.99%, single miscellaneous 0.05%, total miscellaneous 0.11%.
Embodiment 5
The preparation of olaparib (I) crude product
Compound III 26.59g, purified water 100ml are added in reaction bulb, stirs at normal temperatures, adds 2M hydroxides
Said mixture temperature is heated to 100 DEG C, stirs 12h, be cooled to room temperature, filtered by sodium 95.2ml, washing, by the filter of merging
Liquid carries out acidification 30min with 2M dilute hydrochloric acid 47.6ml, sequentially adds ethyl alcohol 500ml, triethylamine 18.70g, 1- the third first of ring
Acyl piperazine 13.26g, in 20~25 DEG C of reaction temperature, be stirred to react 10 it is small when, after reaction, be cooled to 0 DEG C, filter
To solid 38.73g, yield 93.5%, purity 99.85%.
Olaparib (I) refines
Olaparib crude product 30g is taken to be placed in dissolving tank, isopropanol 150ml and acetone 150ml is added in, controlled at 45
~50 DEG C, stirring and dissolving adds in activated carbon decolorizing 30min after crude product is completely dissolved, is filtered while hot after decoloring reaction, filtrate exists
Stirring and crystallizing at room temperature, be then cooled to 0~10 DEG C of growing the grain 4 it is small when, filtering and is washed with acetone, is filtered, dry to get Austria
La Pani fine work 27.19g, yield 90.6%, purity 99.96%, single miscellaneous 0.09%, total miscellaneous 0.18%.
Embodiment 6
The preparation of olaparib (I) crude product
Compound III 27.03g, purified water 100ml are added in reaction bulb, stirs at normal temperatures, adds 2M hydroxides
Said mixture temperature is heated to 100 DEG C, stirs 12h, be cooled to room temperature, filtered by sodium 96.8ml, washing, by the filter of merging
Liquid carries out acidification 30min with 2M dilute hydrochloric acid (48.4ml, 0.0968mol), sequentially adds methanol 500ml, triethylamine
19.59g, 1- cyclopropane carbonyl piperazine 13.42g, in 20~25 DEG C of reaction temperature, be stirred to react 10 it is small when, it is after reaction, cold
But to 0 DEG C, it is obtained by filtration solid 38.91g, yield 92.3%, 99.77%.
Olaparib (I) refines
Olaparib crude product 30g is taken to be placed in dissolving tank, adds in isopropanol 27.27ml and acetone 272.7ml, controls temperature
For 45~50 DEG C, stirring and dissolving adds in activated carbon decolorizing 30min after crude product is completely dissolved, is filtered while hot after decoloring reaction, filtered
Crystallization is stirred at room temperature in liquid, be then cooled to 0~10 DEG C of growing the grain 4 it is small when, filtering and is washed with acetone, is filtered, dry, i.e.,
Olaparib fine work 27.88g, yield 92.9%, purity 99.97%, single miscellaneous 0.07%, total miscellaneous 0.16%.
Claims (9)
1. a kind of preparation method of olaparib, it is characterised in that the preparation method includes the following steps：
A, compound ii and anhydrous hydrazine are in AlMe3Under the conditions of react be made compound III；
B, compound III first hydrolyzes under NaOH environment, is then generated in organic solvent condition and the reaction of 1- cyclopropane carbonyls piperazine
Olaparib (I) crude product；
C, obtained olaparib (I) crude product is refined；
Its reaction scheme is as follows：
。
2. according to the method described in claim 1, which is characterized in that reaction dissolvent described in step a is n-hexane, toluene or
Acetonitrile.
3. according to the method described in claim 1, which is characterized in that in step a, compound ii, anhydrous hydrazine and AlMe3Mole
Than for 1:1~1.1:1~2.
4. according to the method described in claim 1, which is characterized in that step a reaction temperatures are 20~25 DEG C, and the reaction time is
5~10h.
5. according to the method described in claim 1, which is characterized in that the organic solvent described in step b is methanol or ethyl alcohol.
6. according to the method described in claim 1, which is characterized in that compound III and NaOH molar ratios are 1 in step b:2,
Compound III is 1.5~1 with 1- cyclopropane carbonyl piperazines molar ratio:1.
7. according to the method described in claim 1, which is characterized in that the process for purification described in step c is：Take olaparib thick
Product are placed in dissolving tank, add in isopropanol and acetone mixed solvent, controlled at 45~50 DEG C, stirring and dissolving treats that crude product is complete
Activated carbon is added in after fully dissolved, is filtered while hot after decoloring reaction, crystallization is stirred at room temperature in filtrate, is then cooled to 0~10 DEG C
More than when growing the grain 4 is small, filtering and is washed with acetone, is filtered, it is dry to get.
8. according to the method described in claim 8, which is characterized in that the mass volume ratio of olaparib crude product and mixed solvent
For 1:10~30g/ml, isopropanol are 1 with acetone volume ratio:1~10.
9. according to the method described in claim 8, which is characterized in that the activated carbon decolorizing time is 30min in process for purification.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101528714A (en) * | 2006-10-17 | 2009-09-09 | 库多斯药物有限公司 | Polymorphic form of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2h-phthalazin-1-one |
| CN102485721A (en) * | 2010-12-03 | 2012-06-06 | 苏州科瑞戈医药科技有限公司 | Substituted 2,3-phthalazinone compounds and application thereof |
| CN104003940A (en) * | 2014-06-16 | 2014-08-27 | 华东理工大学 | 2,4-difluoro-5-( phthalazone-1-methyl)-benzoyl piperazine compound and application thereof |
| CN105175370A (en) * | 2015-07-27 | 2015-12-23 | 安徽万邦医药科技有限公司 | Synthetic method for 2-fluoro-5-[(3-oxo-1(3H)-isobenzofurylidene)methyl] benzonitrile |
-
2017
- 2017-12-27 CN CN201711440860.7A patent/CN108101852A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101528714A (en) * | 2006-10-17 | 2009-09-09 | 库多斯药物有限公司 | Polymorphic form of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2h-phthalazin-1-one |
| CN102485721A (en) * | 2010-12-03 | 2012-06-06 | 苏州科瑞戈医药科技有限公司 | Substituted 2,3-phthalazinone compounds and application thereof |
| CN104003940A (en) * | 2014-06-16 | 2014-08-27 | 华东理工大学 | 2,4-difluoro-5-( phthalazone-1-methyl)-benzoyl piperazine compound and application thereof |
| CN105175370A (en) * | 2015-07-27 | 2015-12-23 | 安徽万邦医药科技有限公司 | Synthetic method for 2-fluoro-5-[(3-oxo-1(3H)-isobenzofurylidene)methyl] benzonitrile |
Non-Patent Citations (1)
| Title |
|---|
| KEITH A. MENEAR,ET AL.: ""4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1"", 《J. MED. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10662178B2 (en) | 2018-01-31 | 2020-05-26 | Apotex Inc. | Crystalline form of Olaparib |
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Application publication date: 20180601 |