CN109535082A - A kind of preparation method of olaparib - Google Patents
A kind of preparation method of olaparib Download PDFInfo
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- CN109535082A CN109535082A CN201811580065.2A CN201811580065A CN109535082A CN 109535082 A CN109535082 A CN 109535082A CN 201811580065 A CN201811580065 A CN 201811580065A CN 109535082 A CN109535082 A CN 109535082A
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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; include the following steps: 2- fluoro- 5- [(4- oxo -3; 4- dihydro benzodiazine -1- base) methyl] benzoic acid, condensing agent, 1- cyclopropyl formyl piperazine hydrochloride, alkaline matter reacted in reaction dissolvent; then plus water quenching reaction, purifying obtain olaparib；Wherein, condensing agent is I-hydroxybenzotriazole, dicyclohexylcarbodiimide, N, N- diisopropylcarbodiimide, 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 2- (7- aoxidizes benzotriazole)-N, N, at least one of N', N'- tetramethylurea hexafluorophosphoric acid ester.Reaction speed of the present invention is fast, without cumbersome heating and cooling process, shortens the production cycle；Operation is succinct convenient, and purification procedures are simple, is convenient for industry's enlarging production；Reaction yield is high, the olaparib purity is high being prepared.
Description
Technical field
The present invention relates to chemical substance preparation technical field more particularly to a kind of preparation methods of olaparib.
Background technique
Olaparib (English name Olaparib, trade name Lynparza) is the U.S. by AstraZeneca wholly-owned subsidiary library
One Poly ADP-Ribose Polymerase (PARP) inhibitor of this more research and development.It is by inhibiting DNA of tumor cell damage
It repairs, apoptosis of tumor cells is promoted to be mainly used for controlling so as to enhance the curative effect of radiotherapy and alkylating agent and platinum-based chemotherapy
Mastocarcinoma gene No.1 (BRCA-1), mastocarcinoma gene two (BRCA-2) gene mutation cancers are treated, breast cancer is primarily present in,
Oophoroma and prostate cancer.The medicine obtains FDA approval listing in December, 2014.The chemical name of olaparib (Olaparib)
Are as follows: 1- (cyclopropane carbonyl) -4- [5- [(3,4- dihydro -4- oxo -1- phthalazinyl) methyl] -2- fluorobenzoyl] piperazine, knot
Structure formula is as follows:
The method of preparation olaparib mainly has at present:
Document J.Med.Chem.2008,51:6581-6591 report the synthetic method of olaparib, and synthetic route is such as
Under:
The route successively reacts with dimethylphosphite using 2-carboxybenzaldehyde as raw material and generates intermediate (II), then
Horner-Wadsworth-Emmon, which is carried out, with the fluoro- 5- formoxyl cyanophenyl of 2- reacts generation intermediate (III) 2- fluoro- 5- (3- oxygen
Generation -3H- isobenzofuran -1- methylene) cyanophenyl, the intermediate (III) under alkaline condition cyan-hydrolysis at carboxyl, and with
Hydrazine hydrate carries out cyclization and obtains the fluoro- 5- of intermediate (IV) 2- [(4- oxo -3,4- dihydro phenol piperazine -1- base) methyl] benzoic acid, most
Afterwards with 1- cyclopropane carbonyl piperazine in O- benzotriazole-tetramethylurea hexafluorophosphate (HBTU), n,N-diisopropylethylamine
(DIPEA) olaparib is obtained under acting on.The route final step uses O- benzotriazole-tetramethylurea hexafluorophosphate
(HBTU), n,N-diisopropylethylamine (DIPEA) carries out, and the route overall yield is lower, and cost of material is higher, and HBTU also can band
Carry out more serious waste water post processing cost, is not appropriate for the needs of industrialized production；
Chinese patent CN 10152871 reports an other synthetic route, and reaction route is as follows:
The route is with the fluoro- 5- of intermediate (IV) 2- [(4- oxo -3,4- dihydro phthalazines -1- base) methyl] benzoic acid and uncle 1-
Butoxy carbonyl piperazine is made in O- benzotriazole-tetramethylurea hexafluorophosphate (HBTU), n,N-diisopropylethylamine (DIPEA)
Intermediate (V) 4- [the fluoro- 5- of 2- (4- oxo -3.4- dihydro-phthalazin -1- ylmethyl)-benzoyl]-piperazine -1- first is obtained under
Then tert-butyl acrylate sloughs tertbutyloxycarbonyl in acid condition, then react to obtain olaparib with Cyclopropyl carbonyl chloride.The road
Line is long, and the acyl chlorides finally used can also generate certain corrosion to industrial equipment, and also adopt when preparing intermediate (V)
With O- benzotriazole-tetramethylurea hexafluorophosphate (HBTU), it is unfavorable for industrialized production；
Nanjing University of Technology's Master's thesis " olaparib and the like study on the synthesis " middle report in 2012, intermediate
(IV) acid chloride intermediate is obtained through oxalyl chloride acylation, then obtains target product under the catalysis of DMAP with 1- cyclopropane carbonyl piperazine
Olaparib, but its yield is relatively low (48%), and reaction route is as follows:
Patent CN 105820126B is using 5- (bromomethyl) -2- fluorophenyl carbamate as raw material, through boration reaction, coupling
Reaction, hydrolysis, aminolysis reaction obtain olaparib, and reaction route is as follows:
This route uses catechol borine, expensive, the palladium catalyst price in addition used in coupling reaction
Valuableness, palladium residual, which also compares, in post-processing is difficult to handle, and is unfavorable for industrialized production；
In general, the prior art produces olaparib, is all mainly by raw material 2- fluoro- 5- [(4- oxo -3,4- bis-
Hydrogen benzodiazine -1- base) methyl] benzoic acid (II) reacts to prepare with bridged piperazine derivatives, specifically has as follows:
One, patent CN1788000B uses the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzene first
Sour (II) the effect of coupling agent 2- (1H- benzotriazole -1- base) -1,1,3,3- tetramethylurea hexafluorophosphate (HBTU) it is lower and
1- (tertbutyloxycarbonyl) piperazine condensation obtains compound (III), and (III) sloughs Boc through trifluoroacetic acid hydrolysis and obtain compound (IV),
(IV) olaparib is obtained with Cyclopropyl carbonyl chloride acylation again, reaction route is as follows:
Two, patent WO2008047082 uses the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzene
Formic acid (II) obtains olaparib, reaction route with 1- cyclopropyl formyl piperazine direct polycondensation under coupling agent HBTU effect
It is as follows:
Toxic coupling agent HBTU is all used in this two lines, dosage is big, and it is at high cost, and wastewater treatment trouble, no
Conducive to industrial production；Acyl chlorides used in other first route can also generate certain corrosion to equipment, and step is more, yield
It can decline therewith, the last condensation yield of Article 2 route also only has 66% or so, and yield is undesirable.
With the fluoro- 5- of raw material 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzene in patent CN105503739B
Formic acid (II) is reacted with bridged piperazine derivatives to prepare, and route is as follows:
This route is using the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid (II) and occasionally
The Viability intermediate of mixture Mr. CDI is condensed to yield Aura with 1- cyclopropyl formyl piperazine again after certain post-processing
Pa Ni.
The reaction time that reactive intermediate is formed in this route is too long, needs 8-10h, and last handling process needs to be concentrated
Solvent has an impact to production efficiency, extends the process time, and in addition concentration need to be relatively complicated through cooling-heating-temperature-fall period,
And time-consuming.
Summary of the invention
Technical problems based on background technology, the invention proposes a kind of preparation method of olaparib, the present invention
Reaction speed is fast, without cumbersome heating and cooling process, shortens the production cycle；The separation of progress intermediate, one kettle way preparation are not needed
Product is convenient for worker operation, and it is succinct convenient to operate, and purification procedures are simple, are convenient for industry's enlarging production；Reaction yield is high,
The olaparib purity is high being prepared.
A kind of preparation method of olaparib proposed by the present invention includes the following steps: 2- fluoro- 5- [(4- oxo -3,4-
Dihydro benzodiazine -1- base) methyl] benzoic acid, condensing agent, 1- cyclopropyl formyl piperazine hydrochloride, alkaline matter reacting
It is reacted in solvent, then plus water quenching reaction, purifying obtain olaparib；Wherein, condensing agent be I-hydroxybenzotriazole,
Dicyclohexylcarbodiimide, N, N- diisopropylcarbodiimide, 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimine hydrochloric acid
Salt, 2- (7- aoxidizes benzotriazole)-N, N, N', at least one of N'- tetramethylurea hexafluorophosphoric acid ester.
Preferably, include the following steps: to adjust the temperature to 20-30 DEG C, by the fluoro- 5- of 2- [(4- oxo -3,4- dihydro phenodiazine
Miscellaneous naphthalene -1- base) methyl] benzoic acid is added in reaction dissolvent, condensing agent is added, insulated and stirred 0.5-1h obtains solution A；By 1- ring
Propyl formyl piperazine hydrochloride, alkaline matter are added in reaction dissolvent, and 15-30min is stirred at room temperature and obtains solution B；By solution A
It is added drop-wise in solution B and is reacted, then plus water quenching reaction, purifying obtain olaparib.
Preferably, purification step are as follows: concentration removes reaction dissolvent, and recrystallization solvent and active carbon is added, is warming up to reflux,
It filters while hot, filtrate is taken to recrystallize, wash, be dried to obtain olaparib.
Preferably, alkaline matter is n,N-diisopropylethylamine, triethylamine, pyridine, triethylenediamine, 4- dimethylamino
At least one of pyridine.
Preferably, alkaline matter is pyridine.
Preferably, reaction dissolvent is ethyl acetate, in methylene chloride, acetonitrile, tetrahydrofuran, n,N-Dimethylformamide
It is at least one.
Preferably, reaction dissolvent is tetrahydrofuran.
Preferably, reaction temperature is 0-50 DEG C.
Preferably, reaction temperature can be 0,5,10,15,20,25,30,35,40,45 or 50 DEG C.
Preferably, reaction temperature is 20-30 DEG C.
Preferably, reaction time 2-8h.
Preferably, the reaction time can be 2,2.5,3,3.5,4,4.5,5,5.5,6,6.5,7,7.5 or 8h.
Preferably, reaction time 5-6h.
Preferably, in purification step, recrystallization solvent be ethyl acetate, methylene chloride, acetonitrile, tetrahydrofuran, methanol,
At least one of ethyl alcohol, N,N-dimethylformamide.
Preferably, it in purification step, is successively washed with water, ethyl acetate.
Preferably, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, condensing agent, 1- ring
Propyl formyl piperazine hydrochloride, alkaline matter molar ratio be 1:1-2:1-2:1-3.
Preferably, mole of the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, condensing agent
Than that can be 1:1,1:1.1,1:1.2,1:1.3,1:1.4,1:1.5,1:1.6,1:1.7,1:1.8,1:1.9 or 1:2.
Preferably, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, 1- cyclopropyl formyl
The molar ratio of base piperazine hydrochloride can be 1:1,1:1.1,1:1.2,1:1.3,1:1.4,1:1.5,1:1.6,1:1.7,1:
1.8,1:1.9 or 1:2.
Preferably, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, alkaline matter rub
Your ratio can be 1:1,1:1.1,1:1.2,1:1.3,1:1.4,1:1.5,1:1.6,1:1.7,1:1.8,1:1.9,1:2,1:
2.1,1:2.2,1:2.3,1:2.4,1:2.5,1:2.6,1:2.7,1:2.8,1:2.9 or 1:3.
Preferably, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, condensing agent, 1- ring
Propyl formyl piperazine hydrochloride, alkaline matter molar ratio be 1:1.3-1.5:1.3-1.5:1.3-1.5.
Preferably, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid and quenching reaction are used
The bulking value (g/ml) of water is than being 1:1-20.
Preferably, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid and quenching reaction are used
The bulking value (g/ml) of water is than being 1:8-12.
Preferably, the weight of the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, reaction dissolvent
Volume (g/ml) is measured than being 1:1-20, wherein reaction dissolvent is the summation of reaction dissolvent in solution A and solution B.
Preferably, the weight of the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, reaction dissolvent
Volume (g/ml) is measured than being 1:5-6, wherein reaction dissolvent is the summation of reaction dissolvent in solution A and solution B.
Preferably, in purification step, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzene first
Sour, recrystallization solvent bulking value (g/ml) is than being 1:1-20.
Preferably, in purification step, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzene first
Sour, recrystallization solvent bulking value (g/ml) is than being 1:8-12.
Synthetic route of the invention is as follows:
The present invention uses the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, 1- cyclopropyl
Formyl piperazine hydrochloride is raw material, and reaction speed is fast, without cumbersome heating and cooling process, shortens the production cycle；It does not need to carry out
The separation of intermediate, one kettle way prepare product, are convenient for worker operation, and it is succinct convenient to operate, and purification procedures are simple, are convenient for work
Industry amplification production；Reaction yield can achieve 90% or more, the olaparib that is prepared purity is high, can achieve 99.1% with
On, it is single miscellaneous less than 0.1%.
Specific embodiment
In the following, technical solution of the present invention is described in detail by specific embodiment.
Embodiment 1
A kind of preparation method of olaparib includes the following steps: to adjust the temperature to 20 DEG C, by 2- fluoro- 5- [(4- oxo-
3,4- dihydro benzodiazine -1- bases) methyl] benzoic acid be added n,N-Dimethylformamide in, be added I-hydroxybenzotriazole, protect
Temperature stirring 0.5h obtains solution A；1- cyclopropyl formyl piperazine hydrochloride, triethylamine are added in n,N-Dimethylformamide,
15min is stirred at room temperature and obtains solution B；Solution A is added drop-wise in solution B, adjust temperature be 50 DEG C, insulation reaction 2h, then plus
Water quenching reaction, concentration remove n,N-Dimethylformamide, and methanol and active carbon is added, is warming up to reflux, filters while hot, take filter
Liquid recrystallization, is successively washed with water, ethyl acetate, is dried to obtain olaparib；
Wherein, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, 1- hydroxy benzo three
Azoles, 1- cyclopropyl formyl piperazine hydrochloride, triethylamine molar ratio be 1:2:1:3；
The fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, N,N-dimethylformamide
Bulking value (g/ml) is than being 1:1, wherein n,N-Dimethylformamide is n,N-Dimethylformamide in solution A and solution B
Summation；
The weight of the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid and quenching reaction water
Volume (g/ml) is than being 1:20；
In purification step, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, methanol
Bulking value (g/ml) is than being 1:1.
Embodiment 2
A kind of preparation method of olaparib includes the following steps: to adjust the temperature to 30 DEG C, by 2- fluoro- 5- [(4- oxo-
3,4- dihydro benzodiazine -1- bases) methyl] benzoic acid be added methylene chloride in, be added dicyclohexylcarbodiimide, insulated and stirred
0.6h obtains solution A；1- cyclopropyl formyl piperazine hydrochloride, triethylenediamine are added in methylene chloride, are stirred at room temperature
20min obtains solution B；Solution A is added drop-wise in solution B, adjusting temperature is 0 DEG C, insulation reaction 8h, and then plus water quenching is gone out instead
It answers, concentration removes methylene chloride, and acetonitrile and active carbon is added, is warming up to reflux, filters while hot, filtrate is taken to recrystallize, successively use
Water, ethyl acetate washing, are dried to obtain olaparib；
Wherein, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, dicyclohexyl carbon two are sub-
Amine, 1- cyclopropyl formyl piperazine hydrochloride, triethylenediamine molar ratio be 1:1:2:1；
The bulking value of the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, methylene chloride
(g/ml) than being 1:20, wherein methylene chloride is the summation of methylene chloride in solution A and solution B；
The weight of the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid and quenching reaction water
Volume (g/ml) is than being 1:1；
In purification step, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, acetonitrile
Bulking value (g/ml) is than being 1:20.
Embodiment 3
A kind of preparation method of olaparib includes the following steps: to adjust the temperature to 28 DEG C, by 2- fluoro- 5- [(4- oxo-
3,4- dihydro benzodiazine -1- bases) methyl] benzoic acid be added acetonitrile in, be added 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne
Diimmonium salt hydrochlorate, insulated and stirred 0.8h obtain solution A；By 1- cyclopropyl formyl piperazine hydrochloride, 4-dimethylaminopyridine
It is added in acetonitrile, 25min is stirred at room temperature and obtains solution B；Solution A is added drop-wise in solution B, adjusting temperature is 20 DEG C, and heat preservation is anti-
6h is answered, then plus water quenching reaction, concentration remove acetonitrile, and ethyl alcohol and active carbon is added, is warming up to reflux, filters while hot, take filter
Liquid recrystallization, is successively washed with water, ethyl acetate, is dried to obtain olaparib；
Wherein, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, 1- ethyl-(3- diformazan
Base aminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 1- cyclopropyl formyl piperazine hydrochloride, 4-dimethylaminopyridine molar ratio be
1:1.2:1.8:2.5；
Bulking value (the g/ of the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, acetonitrile
Ml) than being 1:6, wherein acetonitrile is the summation of acetonitrile in solution A and solution B；
The weight of the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid and quenching reaction water
Volume (g/ml) is than being 1:12；
In purification step, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, ethyl alcohol
Bulking value (g/ml) is than being 1:8.
Embodiment 4
A kind of preparation method of olaparib includes the following steps: to adjust the temperature to 25 DEG C, by 2- fluoro- 5- [(4- oxo-
3,4- dihydro benzodiazine -1- bases) methyl] benzoic acid be added tetrahydrofuran in, in batches be added 1- ethyl-(3- dimethylamino
Base propyl) phosphinylidyne diimmonium salt hydrochlorate, insulated and stirred 1h obtains solution A；1- cyclopropyl formyl piperazine hydrochloride, pyridine are added
Enter in tetrahydrofuran, 30min is stirred at room temperature and obtains solution B；Solution A is added drop-wise in solution B, adjusting temperature is 25 DEG C, heat preservation
5h is reacted, is cooled to 20 DEG C, then plus water quenching reaction, control temperature are lower than 25 DEG C, and concentration removes tetrahydrofuran, and addition is tied again
Brilliant solvent ethyl acetate and active carbon are warming up to reflux, filter while hot, filtrate is taken to recrystallize, and are successively washed with water, ethyl acetate
It washs, is dried to obtain olaparib；
Wherein, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, 1- ethyl-(3- diformazan
Base aminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 1- cyclopropyl formyl piperazine hydrochloride, pyridine molar ratio be 1:1.5:1.5:
1.5；
The bulking value of the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, tetrahydrofuran
(g/ml) than being 1:3.3, wherein tetrahydrofuran is the summation of tetrahydrofuran in solution A and solution B；
The volume ratio of tetrahydrofuran is 3:2 in solution A and solution B；
The weight of the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid and quenching reaction water
Volume (g/ml) is than being 1:3.3；
In purification step, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, recrystallization
The bulking value (g/ml) of solvent ethyl acetate is than being 1:3.3；
The volume weight (ml/g) of recrystallization solvent ethyl acetate and active carbon is than being 100:3；
Nucleus magnetic hydrogen spectrum detection, nucleus magnetic hydrogen spectrum testing result are carried out to gained olaparib are as follows:1HNMR (DMSO-d6): δ
ppm:12.588(s 1H)；8.257-8.276(dd 1H)；7.913-7.977(d1H)；7.850-7.898(m 2H)；7.813-
7.833(m 1H)；7.425-7.465(m 1H)；7.368-7.381(d1H)；7.218-7.264(t 1H)；4.336(s 2H)；
3.166-.3747(m 8H)；1.904-1.989(m 1H)；0.713-0.769 (m, 4H).
Embodiment 5
A kind of preparation method of olaparib includes the following steps: to adjust the temperature to 25 DEG C, by 2- fluoro- 5- [(4- oxo-
3,4- dihydro benzodiazine -1- bases) methyl] benzoic acid be added tetrahydrofuran in, in batches be added 1- ethyl-(3- dimethylamino
Base propyl) phosphinylidyne diimmonium salt hydrochlorate, insulated and stirred 1h obtains solution A；By 1- cyclopropyl formyl piperazine hydrochloride, N, N- bis-
Wopropyl ethyl amine is added in tetrahydrofuran, and 30min is stirred at room temperature and obtains solution B；Solution A is added drop-wise in solution B, temperature is adjusted
It is 25 DEG C, insulation reaction 5h is cooled to 20 DEG C, and then plus water quenching reaction, control temperature are lower than 25 DEG C, and concentration removes tetrahydro furan
Mutter, recrystallization solvent ethyl acetate and active carbon be added, is warming up to reflux, filters while hot, filtrate is taken to recrystallize, successively use water,
Ethyl acetate washing, is dried to obtain olaparib；
Wherein, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, 1- ethyl-(3- diformazan
Base aminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 1- cyclopropyl formyl piperazine hydrochloride, N, the molar ratio of N- diisopropylethylamine
For 1:1.5:1.5:1.5；
The bulking value of the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, tetrahydrofuran
(g/ml) than being 1:3.3, wherein tetrahydrofuran is the summation of tetrahydrofuran in solution A and solution B；
The volume ratio of tetrahydrofuran is 3:2 in solution A and solution B；
The weight of the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid and quenching reaction water
Volume (g/ml) is than being 1:3.3；
In purification step, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, recrystallization
The bulking value (g/ml) of solvent ethyl acetate is than being 1:3.3；
The volume weight (ml/g) of recrystallization solvent ethyl acetate and active carbon is than being 100:3.
The yield of Statistics Implementation example 1-5, and the purity of olaparib is detected, the result is as follows:
| Embodiment | Yield % | Purity % |
| 1 | 91.1 | 99.20 |
| 2 | 92.0 | 99.16 |
| 3 | 91.8 | 99.34 |
| 4 | 90.6 | 99.51 |
| 5 | 94.5 | 99.55 |
As can be seen from the above table, the purity of high income of the present invention, the olaparib being prepared is good.
The production cycle of patent CN105503739 and present invention preparation olaparib are counted, as a result as follows:
As can be seen from the above table, the present invention is with short production cycle.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Anyone skilled in the art in the technical scope disclosed by the present invention, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of olaparib, which comprises the steps of: the fluoro- 5- of 2- [(4- oxo -3,4- dihydro
Benzodiazine -1- base) methyl] benzoic acid, condensing agent, 1- cyclopropyl formyl piperazine hydrochloride, alkaline matter is in reaction dissolvent
In reacted, then plus water quenching reaction, purifying obtains olaparib；Wherein, condensing agent is I-hydroxybenzotriazole, two rings
Hexyl carbodiimide, N, N- diisopropylcarbodiimide, 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate,
2- (7- aoxidizes benzotriazole)-N, N, N', at least one of N'- tetramethylurea hexafluorophosphoric acid ester.
2. the preparation method of olaparib according to claim 1, which comprises the steps of: adjust the temperature to
20-30 DEG C, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid is added in reaction dissolvent, is added
Enter condensing agent, insulated and stirred 0.5-1h obtains solution A；Reaction is added in 1- cyclopropyl formyl piperazine hydrochloride, alkaline matter
In solvent, 15-30min is stirred at room temperature and obtains solution B；Solution A is added drop-wise in solution B and is reacted, then plus water quenching is gone out instead
It answers, purifying obtains olaparib.
3. the preparation method of olaparib according to claim 1 or claim 2, which is characterized in that purification step are as follows: concentration removes anti-
Solvent is answered, recrystallization solvent and active carbon is added, is warming up to reflux, filters while hot, filtrate is taken to recrystallize, washs, is dried to obtain
Olaparib.
4. the preparation method of any one of -3 olaparibs according to claim 1, which is characterized in that alkaline matter N, N- bis-
At least one of wopropyl ethyl amine, triethylamine, pyridine, triethylenediamine, 4-dimethylaminopyridine；Preferably, basic species
Matter is pyridine.
5. the preparation method of any one of -4 olaparibs according to claim 1, which is characterized in that reaction dissolvent is acetic acid second
At least one of ester, methylene chloride, acetonitrile, tetrahydrofuran, N,N-dimethylformamide；Preferably, reaction dissolvent is tetrahydro
Furans.
6. the preparation method of any one of -5 olaparibs according to claim 1, which is characterized in that reaction temperature 0-50
℃；Preferably, reaction temperature is 20-30 DEG C；Preferably, reaction time 2-8h；Preferably, reaction time 5-6h.
7. according to the preparation method of any one of the claim 3-6 olaparib, which is characterized in that in purification step, weight
Recrystallisation solvent be ethyl acetate, methylene chloride, acetonitrile, tetrahydrofuran, methanol, ethyl alcohol, in N,N-dimethylformamide at least
It is a kind of；Preferably, it in purification step, is successively washed with water, ethyl acetate.
8. the preparation method of any one of -7 olaparibs according to claim 1, which is characterized in that 2- fluoro- 5- [(4- oxo -
3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, condensing agent, 1- cyclopropyl formyl piperazine hydrochloride, alkaline matter
Molar ratio is 1:1-2:1-2:1-3；Preferably, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzene first
Acid, condensing agent, 1- cyclopropyl formyl piperazine hydrochloride, alkaline matter molar ratio be 1:1.3-1.5:1.3-1.5:1.3-
1.5；Preferably, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid and quenching reaction water
Bulking value (g/ml) is than being 1:1-20；Preferably, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzene
The bulking value (g/ml) of formic acid and quenching reaction water is than being 1:8-12.
9. according to the preparation method of any one of the claim 2-8 olaparib, which is characterized in that 2- fluoro- 5- [(4- oxo-
3,4- dihydro benzodiazine -1- bases) methyl] benzoic acid, reaction dissolvent bulking value (g/ml) than being 1:1-20, wherein it is anti-
Answering solvent is the summation of reaction dissolvent in solution A and solution B；Preferably, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -
1- yl) methyl] benzoic acid, reaction dissolvent bulking value (g/ml) than be 1:5-6, wherein reaction dissolvent be solution A and solution
The summation of reaction dissolvent in B.
10. according to the preparation method of any one of the claim 3-9 olaparib, which is characterized in that in purification step, 2-
Bulking value (g/ml) ratio of fluoro- 5- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzoic acid, recrystallization solvent
For 1:1-20；Preferably, in purification step, the fluoro- 5- of 2- [(4- oxo -3,4- dihydro benzodiazine -1- base) methyl] benzene first
Sour, recrystallization solvent bulking value (g/ml) is than being 1:8-12.
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| CN111732547A (en) * | 2020-07-31 | 2020-10-02 | 北京鑫开元医药科技有限公司 | Refining method and application of olapari |
| CN112047890A (en) * | 2020-10-20 | 2020-12-08 | 连云港杰瑞药业有限公司 | Preparation method of olaparib |
| CN112500379A (en) * | 2020-12-23 | 2021-03-16 | 南京方生和医药科技有限公司 | Olapari intermediate and preparation method of Olapari |
| CN112979557A (en) * | 2019-12-13 | 2021-06-18 | 南京亿华药业有限公司 | Novel synthesis method of Olaparib bulk drug |
| CN113234024A (en) * | 2021-05-20 | 2021-08-10 | 北京迈索化学技术有限公司 | Novel preparation method of olapari |
| CN113264887A (en) * | 2021-05-27 | 2021-08-17 | 神隆医药（常熟）有限公司 | Novel crystal form X of olaparib and preparation method thereof |
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| CN113264887A (en) * | 2021-05-27 | 2021-08-17 | 神隆医药（常熟）有限公司 | Novel crystal form X of olaparib and preparation method thereof |
| CN113264887B (en) * | 2021-05-27 | 2022-03-25 | 神隆医药（常熟）有限公司 | Novel crystal form X of olaparib and preparation method thereof |
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