CN108129397A - A kind of synthetic method of olaparib - Google Patents

A kind of synthetic method of olaparib Download PDF

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Publication number
CN108129397A
CN108129397A CN201810141920.3A CN201810141920A CN108129397A CN 108129397 A CN108129397 A CN 108129397A CN 201810141920 A CN201810141920 A CN 201810141920A CN 108129397 A CN108129397 A CN 108129397A
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fluoro
carbonyl
methyl
olaparib
bases
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CN108129397B (en
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乔红炜
卞伟光
李乔莹
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Beijing Yeh Shen Technology Co Ltd
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Beijing Yeh Shen Technology Co Ltd
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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 synthetic methods of olaparib, this method is using phthalylhydrazine as starting material, by generating 1 chlorine, 4 carbonyl phthalazines with phosphorus oxychloride reaction, and then 2 fluorine 5 [(4 3,4 dihydro phthalazines of carbonyl, 1 base) methyl] ethyl benzoates of generation are reacted with 2 fluorine, 5 bromomethyl-benzoic acid ethyl ester；Then it hydrolyzes, through acylation, generation olaparib is reacted with 1 (cyclopropyl carbonyl) piperazine condensation.For the first time using phthalylhydrazine as starting material, raw material is easy to get synthetic method of the present invention, environmentally protective；And Neigishi couplings are employed, it is reacted using organic metal, avoids youngster's naphthols borine that use cost is higher, use zinc powder instead, reduce production cost, route gross production rate reaches 70.2%.The reaction route of synthetic method of the present invention is shorter, and reaction condition is mild, suitable for industrialized production.

Description

A kind of synthetic method of olaparib
Technical field
The invention belongs to the technical fields of medicine preparation, and in particular to a kind of synthetic method of olaparib.
Background technology
Poly ADP-ribose polymerase (Poly (ADP-ribose) polymerase, PARP) is a kind of core for participating in DNA and repairing Enzyme plays an important role in DNA damage reparation, and the treatment for tumour provides a new target spot.Therefore, PARP inhibitor is always It is research hotspot in recent years, with going deep into for PARP researchs, tumour is treated by the intervention of this target spot to PARP, is A new road is opened up in oncotherapy.Wherein the olaparib of AstraZeneca is treating oophoroma side as the inhibitor of PARP Face achieves huge progress, in EU Committee's approval on December 18th, 2014 as a kind of single medication, for platinum sensitivity Recurrent BRCA is mutated the maintaining treatment of oophoroma adult patient, which also becomes is mutated platinum sensitivity recurrent ovarian for BRCA The first PARP inhibitor of cancer.The approval of U.S. Food and Drug Administration (FDA) is obtained December 19 the same year as previously The treatment of BRCA germline mutation Patients with Advanced Ovarian Carcinoma through at least 3 times chemotherapeutic treatment failures.The entitled 1- of chemistry of olaparib (cyclopropane carbonyl) -4- [5- [(3,4- dihydro -4- oxo -1- phthalazinyls) methyl] -2- fluorobenzoyls] piperazine, structural formula is such as Under：
Medicine patent WO2004080976A1 reports are ground according to original, the synthetic method of olaparib is as follows：
The patent route has the following disadvantages：
(1) route is longer, and step is more, is not easy to improve the total recovery of amplification production；
(2) the fluoro- 2- itrile groups benzaldehyde costs of 3- are excessively high in reaction b, can increase the production cost of entire route.
(3) it reacts in e and uses O- benzotriazole-tetramethylurea hexafluorophosphate (HBTU), n,N-diisopropylethylamine (DIPEA) cost of material is high and route total recovery only has 26.7%.
In addition, patent WO2008047082A2 provides the synthetic method of another olaparib, synthetic route is：
This route is improved first route, but there are still problems with：React A, B, C and above-mentioned patent Reaction condition is identical, only reacts D and is changed to directly connect 1- cyclopropane carbonyl piperazines, and condensing agent used is identical with above-mentioned patent, Therefore production cost is higher, while the yield of this step reaction only has 62.2%.So the total recovery of this route is also only 34.3%.
Existing newest Chinese patent CN105820126 also discloses that the synthetic method of olaparib；Route is as follows：
This method is to be different from WO2008047082A2 and WO2004080976A1, employs a kind of new method, although Yield is improved, but still remains problems with：
(1) when synthesizing compound 3,2 youngster's naphthols borine of compound has been used, this compound higher price is given birth in amplification During production, the production cost of route can be increased.
(2) this route is obtained in the method for compound 8 using carbonyl dimidazoles (CDI) as condensing agent, this compound work Industry is of high cost, can increase the cost of amplification production.
Invention content
In order to solve deficiency of the prior art, the present invention provides a kind of new synthetic method of olaparib, the synthesis Method is using phthalylhydrazine as starting material.
The present invention provides a kind of synthetic method of olaparib, the synthetic method includes the following steps：
(1) phthalylhydrazine is added in phosphorus oxychloride, the reaction generation chloro- 4- carbonyls phthalazines of 1-；
(2) the chloro- 4- carbonyls phthalazines of 1- under the effect of the catalyst, reacts generation with the fluoro- 5- bromomethyl-benzoic acid ethyl esters of 2- The fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] ethyl benzoate；
(3) the fluoro- 5- of the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] ethyl benzoate hydrolysis generation 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] benzoic acid；
(4) benzoic acid is through acylation by the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl], with 1- (cyclopropyl carbonyls Base)-piperazine condensation reaction generation olaparib.
The synthetic method of the present invention is for the first time using phthalylhydrazine as starting material, the reaction generation chloro- 4- carbonyls phthalazines of 1-. Phthalylhydrazine is by-product common in pharmaceutical synthesis, and phthalylhydrazine annual output is big, stable structure, and post processing is tired Difficulty annoyings many domestic and international pharmacy corporations always, long-term using filling out burning and burying method processing, and air and groundwater resources are made Into potential pollution.The present invention is easy to get using phthalylhydrazine as Material synthesis olaparib with raw material, technique green ring It protects, production cost is relatively low, is suitble to industrialized production.
Preferably, reaction temperature is 90~140 DEG C, and the reaction time is 1~6h.
Preferably, in step (1), the molar ratio of phthalylhydrazine and phosphorus oxychloride is 1:3~6.
Preferably, in step (2), 2- fluoro- 5- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] benzoic acid second is generated Ester the specific steps are：
1. zinc powder, glycol dibromide, trim,ethylchlorosilane, the fluoro- 5- bromomethyls benzene of 2- are added in tetrahydrofuran solvent Ethyl formate reacts 1~3h at 0~60 DEG C, obtains zincon solution；
2. and then the chloro- 4- carbonyls phthalazines of 1-, catalyst and the zincon solution in 1. walking are added in tetrahydrofuran solvent, 60~85 DEG C of 2~6h of reaction, obtain the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] ethyl benzoate.
Wherein, the molar ratio of the fluoro- 5- bromomethyl-benzoic acid ethyl esters of zinc powder, 2- and the chloro- 4- carbonyls phthalazines of 1- is 10：10~2： 2。
Wherein, catalyst is tetrakis triphenylphosphine palladium (Pd [(C6H5)3P]4), double (bis- Ya Benzyl benzylacetones) palladium (Pd (dba)2), three (dibenzalacetone) two palladium (Pd2(dba)3At least one of).
Preferably, in step (3), generation 2- fluoro- 5- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] benzoic acid The specific steps are：In the ethanol solution of the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] ethyl benzoate, add Enter lye, 2~6h of back flow reaction, hydrolysis obtains the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] benzoic acid.
Wherein, lye be potassium hydroxide solution or lithium hydroxide solution, the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- Base) methyl] molar ratio of ethyl benzoate and lye is 1：5~20.
Preferably, in step (4), generate olaparib the specific steps are：
1. in dichloromethane solvent, addition 2- fluoro- 5- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] benzoic acid, Trimethyl-aceyl chloride, triethylamine, 20~30 DEG C of 2~3h of reaction, obtain the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) Methyl] chlorobenzoyl chloride；
2. 1- (rings are added in the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] chlorobenzoyl chloride 1. walked Propyl carbonyl)-piperazine ethanol solution, 20~30 DEG C reaction 2~3h, obtain olaparib.
Wherein, the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] benzoic acid, trimethyl-aceyl chloride, three second The molar ratio of amine and 1- (cyclopropyl carbonyl)-piperazine is 1：1~1.5：1.5~2：2~2.5.
Beneficial effects of the present invention are：
(1) synthetic method of olaparib of the present invention is for the first time using phthalylhydrazine as starting material, phthalylhydrazine Common waste, raw material are easy to get when being produced for pharmacy and fine chemical industry, and recycling recycling has been carried out to solid waste, It is environmentally protective.
(2) synthetic method of the present invention employs Neigishi couplings, is reacted using organic metal, avoids use cost Higher youngster's naphthols borine, uses zinc powder instead, reduces production cost, and route gross production rate reaches 70.2%.
(3) reaction route of synthetic method of the present invention is shorter, and reaction condition is mild, suitable for industrialized production.
Description of the drawings
Fig. 1 is the Technology Roadmap of the synthetic method of olaparib of the present invention.
Specific embodiment
With reference to embodiment, the present invention is further explained.Embodiment is raw materials used and reagent is commercial product.
Embodiment 1
A kind of synthetic method of olaparib, includes the following steps：
(1) it weighs phthalylhydrazine (8.1g, 0.05mol) and adds in POCl3(50mL, 0.25mol), in 110 DEG C of reactions Reaction system after reaction system cooling, is then poured into ice water, has white solid precipitation, be stirred overnight, filtered by 4h, Filter cake is dried, filter cake is washed with ethyl acetate, finally obtains the chloro- 4- carbonyls phthalazines 8.5g of 1-, yield 94.4%.
(2) zinc powder (654mg, 0.01mol) is weighed, adds in solvent anhydrous tetrahydro furan 3mL, adds in 1, the 2- dibromos of 50 μ L Ethane is stirred 15 minutes at 60 DEG C, is cooled to room temperature, and adds in the trim,ethylchlorosilane of 50 μ L, and under the conditions of 0 DEG C, 2- is added dropwise The tetrahydrofuran solution 3mL of fluoro- 5- bromomethyl-benzoic acid ethyl esters (1.305g, 5mmol) continues to react 2h under the conditions of 0 DEG C, obtain To zincon solution.The product (0.38g, 2mmol) weighed in step (1) adds in 3mL tetrahydrofurans, tetrakis triphenylphosphine palladium 38mg, nitrogen protection, adds in zincon solution.2h is reacted at 80 DEG C.Solvent is spin-dried for, adds in methanol 10mL, filtering takes filter Cake is dried to obtain the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] ethyl benzoate 0.6g, yield 87.4%.
(3) product (652mg, 1mmol) of previous step is weighed, is added in the methanol of 10mL, is stirred, adds in potassium hydroxide Solution (10mL, 1mol/L), reacts 6h under conditions of reflux.System is cooled down, dichloro extraction (20mL × 3), phase of fetching water, pH It is 3, there is solid precipitation, filter, dries filter cake, obtain the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] benzene first Sour 0.54g, yield 90.5%.
(4) product (0.3g, 1mmol) in previous step is weighed, is dissolved in the dichloromethane of 5mL, measures pivaloyl Chlorine (121 μ L, 1mmol) and triethylamine (208mL, 1.5mmol) are stirred to react in room temperature condition, until solution is clarified, weigh 1- (cyclopropyl carbonyl)-piperazine (0.3g, 2mmol) is dissolved in the ethyl alcohol of 5mL, is added drop-wise in above-mentioned clear solution, reacts at room temperature 4h, uses Dichloromethane 15mL, extraction, adds water washing organic phase, anhydrous sodium sulfate drying organic phase, be spin-dried for obtaining olaparib (0.4g, 0.9mmol), yield 91.5%, purity 99.8%.
Embodiment 2
The molar ratio of phthalylhydrazine and phosphorus oxychloride in step (1) is 1:4 (i.e. phthalylhydrazine 8.1g, three Chlorethoxyfos 40mL), other steps obtain the chloro- 4- carbonyls phthalazines 8.4g of 1-, yield 93.2% with embodiment 1.
Embodiment 3
The molar ratio of phthalylhydrazine and phosphorus oxychloride in step (1) is 1:3 (i.e. phthalylhydrazine 8.1g, three Chlorethoxyfos 30mL), other steps obtain the chloro- 4- carbonyls phthalazines 7.9g of 1-, yield 87.8% with embodiment 1.
Embodiment 4
The molar ratio of phthalylhydrazine and phosphorus oxychloride in step (1) is 1:6 (i.e. phthalylhydrazine 8.1g, three Chlorethoxyfos 60mL), other steps obtain the chloro- 4- carbonyls phthalazines 8.5g of 1-, yield 94.4% with embodiment 1.
Embodiment 5
Reaction temperature is 100 DEG C in step (1), other steps obtain the chloro- 4- carbonyls phthalazines 8.1g of 1-, receive with embodiment 1 Rate is 90%.
Embodiment 6
Reaction temperature is 120 DEG C, reaction time 3h in step (1), other steps obtain the chloro- 4- carbonyls of 1- with embodiment 1 Base phthalazines 8.5g, yield 94.4%.
Embodiment 7
Fluoro- 5- bromomethyl-benzoic acid ethyl esters of zinc powder, 2- in step (2), the chloro- 4- carbonyls phthalazines of 1- molar ratio be 10:10: 2 (i.e. zinc powder is the chloro- 4- carbonyls phthalazines 0.76g of fluoro- 5- bromomethyl-benzoic acid ethyl esters 1.305g, the 1- of 654mg, 2-), other steps With embodiment 1, the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] ethyl benzoate 0.61g is obtained, yield is 90%.
Embodiment 8
Fluoro- 5- bromomethyl-benzoic acid ethyl esters of zinc powder, 2- in step (2), the chloro- 4- carbonyls phthalazines of 1- molar ratio be 10:2:2 (i.e. zinc powder is the chloro- 4- carbonyls phthalazines 1.14g of fluoro- 5- bromomethyl-benzoic acid ethyl esters 1.305g, the 1- of 654mg, 2-), other steps are same Embodiment 1, obtains the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] ethyl benzoate 0.6g, and yield is 87.4%.
Embodiment 9
The catalyst used in step (2) is pair (bis- Ya Benzyl benzylacetone) palladium (7.6mg) and catalyst four (triphenylphosphine) Palladium (38mg) other steps obtain the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] benzoic acid second with embodiment 1 Ester 0.63g, yield 91.8%.
Embodiment 10
The catalyst used in step (2) is pair (bis- Ya Benzyl benzylacetone) palladium (7.6mg), other steps obtain with embodiment 1 To the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] ethyl benzoate 0.62g, yield 90.3%.
Embodiment 11
The catalyst used in step (2) is three (dibenzalacetone) two palladium (6mg) and catalyst four (triphenylphosphine) Palladium (30mg) other steps obtain the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] benzoic acid second with embodiment 1 Ester 0.64g, yield 93.3%.
Embodiment 12
In step (3), the molar ratio 1 of product and potassium hydroxide in step (2):5, other steps are the same as embodiment 1.It obtains The fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] benzoic acid 0.36g, yield 60.3%.
Embodiment 13
In step (3), the molar ratio 1 of product and potassium hydroxide in step (2):20, other steps are the same as embodiment 1. To the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] benzoic acid 0.53g, yield 88.8%.
Embodiment 14
In step (3), using lithium hydroxide, other steps obtain the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydros with embodiment 1 Phthalazines -1- bases) methyl] benzoic acid 0.49g, yield 82.1%.
Embodiment 15
In step (4), product, trimethyl-aceyl chloride, triethylamine and 1- (cyclopropyl carbonyl)-piperazine in step (3) Molar ratio is 1:1.5：2：2.5, other steps obtain olaparib 0.4g, yield 91.5% with embodiment 1.
The foregoing is merely a prefered embodiment of the invention, is not intended to limit the invention, all in substantive content of the present invention On any modification, equivalent replacement and the simple modifications made etc., should all be included in the protection scope of the present invention.

Claims (10)

1. a kind of synthetic method of olaparib, which is characterized in that the synthetic method includes the following steps：
(1) phthalylhydrazine is added in phosphorus oxychloride, the reaction generation chloro- 4- carbonyls phthalazines of 1-；
(2) the chloro- 4- carbonyls phthalazines of 1- under the effect of the catalyst, it is fluoro- that generation 2- is reacted with the fluoro- 5- bromomethyl-benzoic acid ethyl esters of 2- 5- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] ethyl benzoate；
(3) the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] ethyl benzoate hydrolysis generation 2- fluoro- 5- [(4- carbonyls Base -3,4- dihydro phthalazines -1- bases) methyl] benzoic acid；
(4) the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] benzoic acid is through acylation, with 1- (cyclopropyl carbonyl) - Piperazine condensation reaction generation olaparib.
2. the synthetic method of olaparib according to claim 1, which is characterized in that in step (1), reaction temperature is 100~120 DEG C, the reaction time is 3~4h.
3. the synthetic method of olaparib according to claim 1, which is characterized in that in step (1), phthalylhydrazine Molar ratio with phosphorus oxychloride is 1：3~6.
4. the synthetic method of olaparib according to claim 1, which is characterized in that in step (2), generate the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] ethyl benzoate the specific steps are：
1. zinc powder, glycol dibromide, trim,ethylchlorosilane, the fluoro- 5- bromo methyl acids of 2- are added in tetrahydrofuran solvent Ethyl ester reacts 1~3h at 0~60 DEG C, obtains zincon solution；
2. and then the chloro- 4- carbonyls phthalazines of 1-, catalyst and the zincon solution in 1. walking are added in tetrahydrofuran solvent, 60~ 85 DEG C of 2~6h of reaction, obtain the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] ethyl benzoate.
5. the synthetic method of olaparib according to claim 4, which is characterized in that the fluoro- 5- bromomethyls benzene first of zinc powder, 2- The molar ratio of acetoacetic ester and the chloro- 4- carbonyls phthalazines of 1- is 10：10~2：2.
6. the synthetic method of olaparib according to claim 4, which is characterized in that catalyst is Pd [(C6H5)3P]4、Pd (dba)2、Pd2(dba)3At least one of.
7. the synthetic method of olaparib according to claim 1, which is characterized in that in step (3), generate the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] benzoic acid the specific steps are：In the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydros Phthalazines -1- bases) methyl] ethyl benzoate ethanol solution in, add in lye, 2~6h of back flow reaction, hydrolysis obtain the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] benzoic acid.
8. the synthetic method of olaparib according to claim 7, which is characterized in that lye is potassium hydroxide solution or hydrogen The molar ratio of lithia solution, the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] ethyl benzoates and lye is 1：5~20.
9. the synthetic method of olaparib according to claim 1, which is characterized in that in step (4), generate olaparib The specific steps are：
1. in dichloromethane solvent, 2- fluoro- 5- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] benzoic acid, front three are added in Base chloroacetic chloride, triethylamine, 20~30 DEG C of 2~3h of reaction, obtain the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] Chlorobenzoyl chloride；
2. 1- (cyclopropyl is added in the fluoro- 5- of 2- [(4- carbonyl -3,4- dihydro phthalazines -1- bases) methyl] chlorobenzoyl chloride 1. walked Carbonyl)-piperazine ethanol solution, 20~30 DEG C reaction 2~3h, obtain olaparib.
10. the synthetic method of olaparib according to claim 9, which is characterized in that 2- fluoro- 5- [(4- carbonyls -3,4- Dihydro phthalazines -1- bases) methyl] benzoic acid, trimethyl-aceyl chloride, triethylamine and 1- (cyclopropyl carbonyl)-piperazine molar ratio be 1：1~1.5：1.5~2：2~2.5.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110078671A (en) * 2019-06-02 2019-08-02 江苏君若医药有限公司 The preparation method of olaparib

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009089263A2 (en) * 2008-01-07 2009-07-16 Ardea Biosciences Inc. Novel compositions and methods of use
CN105820126A (en) * 2016-05-12 2016-08-03 山东罗欣药业集团恒欣药业有限公司 Preparing method for Olaparib

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009089263A2 (en) * 2008-01-07 2009-07-16 Ardea Biosciences Inc. Novel compositions and methods of use
CN105820126A (en) * 2016-05-12 2016-08-03 山东罗欣药业集团恒欣药业有限公司 Preparing method for Olaparib

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AMÉLIE BRUEL ET AL.: "Synthesis of new pyridazino[4,5-b]indol-4-ones and pyridazin-3 (2H)-one analogs as DYRK1A inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
JIE JACK LI: "《有机人名反应及机理》", 30 September 2003, 华东理工大学出版社 *
XIAOYAN PAN ET AL.: "Expanding the structural diversity of Bcr-Abl inhibitors: Hybrid molecules based on GNF-2 and Imatinib", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
陈立功 等: "《药物中间体合成工艺》", 30 June 2001, 化学工业出版社 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110078671A (en) * 2019-06-02 2019-08-02 江苏君若医药有限公司 The preparation method of olaparib

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