CN114685374B - Novel process for synthesizing Olaparib - Google Patents
Novel process for synthesizing Olaparib Download PDFInfo
- Publication number
- CN114685374B CN114685374B CN202011584050.0A CN202011584050A CN114685374B CN 114685374 B CN114685374 B CN 114685374B CN 202011584050 A CN202011584050 A CN 202011584050A CN 114685374 B CN114685374 B CN 114685374B
- Authority
- CN
- China
- Prior art keywords
- mixed solution
- room temperature
- stirring
- dichloromethane
- olaparib
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 229960000572 olaparib Drugs 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 102
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 66
- 239000011259 mixed solution Substances 0.000 claims abstract description 51
- 238000003756 stirring Methods 0.000 claims abstract description 34
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 claims abstract description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 230000003197 catalytic effect Effects 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000001514 detection method Methods 0.000 description 7
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 230000008034 disappearance Effects 0.000 description 4
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical class CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 239000012661 PARP inhibitor Substances 0.000 description 1
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a novel process for synthesizing Olaparib, which specifically comprises the following steps:
Description
Technical Field
The invention belongs to the field of medicine synthesis, and in particular relates to a novel process for synthesizing Olaparib.
Background
Olaparib (Olaparib) was the first PARP inhibitor marketed by mexNational African company was developed in 2014 at 12 and marketed in Europe and the United states under the trade name Lynparaza TM For the treatment of advanced ovarian cancer associated with a deficiency in the BRCA gene. The Olaparib structure contains bisacylpiperazine groups, and the prior synthesis method mostly adopts a method of protecting one piperazine amino group and then condensing with acid or acyl chloride, so that the method has the defects of long steps, high price condensing agent and serious increase of production cost. In view of the above, the invention provides a novel process for synthesizing Olaparib quickly and simply.
Disclosure of Invention
The invention provides a novel process for synthesizing Olaparib, which is characterized by comprising the following steps:
in an organic solvent, the compound of the formula I, piperazine and cyclopropanecarboxylic acid react under the action of acyl chloride and organic alkali to obtain the Olaparib.
The organic solvent is selected from one or more of dichloromethane, ethanol, THF and DMF; the acyl chloride is selected from trimethyl acetyl chloride, oxalyl chloride and SOCl 2 One of the following; the organic base is selected from one of triethylamine and pyridine. The above reaction is preferably carried out with the addition of a catalytic amount of DMAP (4-dimethylaminopyridine).
The invention provides a novel process for synthesizing Olaparib, which is characterized by comprising the following steps:
(1) Dissolving a compound shown in the formula I in dichloromethane, adding trimethyl acetyl chloride and triethylamine, and stirring for 10-15min at room temperature to obtain a mixed solution A;
(2) Dissolving cyclopropanecarboxylic acid in dichloromethane, adding trimethyl acetyl chloride and triethylamine, and stirring at room temperature for 15-20min to obtain a mixed solution B;
(3) Dissolving piperazine in dichloromethane, stirring at room temperature, simultaneously dropwise adding the mixed solution A and the mixed solution B, and continuing stirring at room temperature for reaction after the dropwise adding is finished to obtain the Olaparib.
The molar ratio of the compound of the formula I to the trimethylacetyl chloride in the step (1) is 1:1-1.5, preferably 1:1, and the triethylamine is 2-3 times of the trimethylacetyl chloride;
the molar ratio of cyclopropanecarboxylic acid to trimethylacetyl chloride in the step (2) is 1:1.2-1.5, preferably 1:1.2, and the amount of triethylamine is 2-3 times that of trimethylacetyl chloride;
the molar amount of the compound of formula I, cyclopropanecarboxylic acid and piperazine is 1:1:1-1.2, preferably 1:1:1.
The dropping speed of the mixed solution A in the step (3) is selected from 5-6ml/min; the drop velocity of the mixed solution B is 1.5-2.5 times, preferably 1.8-2.0 times of the drop velocity of the mixed solution A. In step (3) a catalytic amount of DMAP (4-dimethylaminopyridine) is preferably added, the molar amount of DMAP being preferably from 0.05 to 0.1 times that of the compound of formula I.
The amount of the organic solvent used in the steps (1), (2) and (3) of the present invention is preferably such that the reactants are sufficiently dissolved, and it is preferable to use an equal volume of methylene chloride in the steps (1) and (2).
Stopping the reaction when TLC detects the disappearance of the raw materials in the reaction time of the step (3); preferably the reaction time is 3-5 hours.
The novel process for synthesizing the olaparib optionally comprises the following step (4): washing the reaction solution in the step (3) with dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride in sequence, concentrating a dichloromethane phase under reduced pressure, and recrystallizing with ethyl acetate to obtain the pure Olaparib product. The concentration of the dilute hydrochloric acid is 1-4mol/L.
The HPLC purity of the pure Olaparib product is more than 99 percent, preferably more than 99.6 percent.
Compared with the prior art, the invention has the advantages that: (1) The synthesis process does not need to protect piperazine amino, and two carboxylic acids are directly reacted with piperazine with two amino groups exposed at the same time after being activated to construct a diacyl piperazine group; (2) The HPLC purity of the pure Olaparib product prepared by the method is more than 99 percent, preferably more than 99.6 percent.
Drawings
FIG. 1 is an HPLC plot of pure Olaparib prepared in example 1.
Detailed Description
The examples provided below are presented in more detail to facilitate a further understanding of the present invention. These examples are provided only for better understanding of the present invention and are not intended to limit the scope or practice of the present invention, and the embodiments of the present invention are not limited to the following.
Example 1
(1) Dissolving a compound (1 mmol) of the formula I in dichloromethane (15 mL), adding trimethylacetyl chloride (1 mmol) and triethylamine (2 mmol), and stirring at room temperature for 15min to obtain a mixed solution A;
(2) Cyclopropanecarboxylic acid (1 mmol) was dissolved in dichloromethane (15 mL), and trimethylacetyl chloride (1.2 mmol) and triethylamine (2.4 mmol) were added thereto, followed by stirring at room temperature for 20min to obtain a mixed solution B;
(3) Dissolving piperazine (1 mmol) in dichloromethane (30 mL), stirring at room temperature, simultaneously dropwise adding mixed solution A and mixed solution B (the dropwise adding speed of mixed solution A is 5mL/min, the dropwise adding speed of mixed solution B is 2.0 times of the dropwise adding speed of mixed solution A), adding catalytic amount of DMAP (0.1 mmol) after dropwise adding, continuing stirring at room temperature for reaction until TLC detection reaction is complete (about 3 hours), washing the reaction solution sequentially with dilute hydrochloric acid (1M), saturated sodium bicarbonate and saturated sodium chloride, concentrating the dichloromethane phase under reduced pressure, and recrystallizing with ethyl acetate to obtain pure Olaparib (328.2 mg, yield about 75.5%) (which is tested by NMR 1 H NMR、 13 The C NMR data are consistent with known reports with an HPLC purity of 99.61%, see FIG. 1).
Example 2
(1) Dissolving a compound (1 mmol) of the formula I in dichloromethane (20 mL), adding trimethylacetyl chloride (1.5 mmol) and triethylamine (4.5 mmol), and stirring at room temperature for 10min to obtain a mixed solution A;
(2) Cyclopropanecarboxylic acid (1 mmol) was dissolved in dichloromethane (20 mL), and trimethylacetyl chloride (1.5 mmol) and triethylamine (4.5 mmol) were added thereto, followed by stirring at room temperature for 15min to obtain a mixed solution B;
(3) Piperazine (1.2 mmol) was dissolved in dichloromethane (40 mL), mixed solution a and mixed solution B (mixed solution a has a dropping speed of 5mL/min; mixed solution B has a dropping speed of 1.8 times that of mixed solution a) were simultaneously added dropwise while stirring at room temperature, stirring at room temperature was continued after the addition was completed until the reaction was stopped (about 5 hours) after the TLC detection was completed, the reaction solution was washed with dilute hydrochloric acid (1M), saturated sodium bicarbonate and saturated sodium chloride in this order, and after concentrating the dichloromethane phase under reduced pressure, the pure olaparib (254.6 mg, yield about 58.6%) was obtained by recrystallization with ethyl acetate (HPLC detection was consistent with that of the olaparib product prepared in example 1, HPLC purity was 99.53%).
Example 3
(1) Dissolving a compound (1 mmol) of the formula I in dichloromethane (15 mL), adding oxalyl chloride (1 mmol) and triethylamine (2 mmol), and stirring at room temperature for 15min to obtain a mixed solution A;
(2) Cyclopropanecarboxylic acid (1 mmol) was dissolved in dichloromethane (15 mL), oxalyl chloride (1.2 mmol) and triethylamine (2.4 mmol) were added, and after stirring at room temperature for 20min, a mixture B was obtained;
(3) Piperazine (1 mmol) was dissolved in dichloromethane (30 mL), mixed solution a and mixed solution B (mixed solution a has a dropping speed of 5mL/min; mixed solution B has a dropping speed of 2.0 times that of mixed solution a) were added at the same time while stirring at room temperature, after the completion of the dropping, a catalytic amount of DMAP (0.1 mmol) was added, and after continuing the stirring reaction at room temperature for 3 hours, TLC detects the disappearance of the raw material of formula I, but the reaction system was complicated, the reaction was stopped, the reaction solution was washed with dilute hydrochloric acid (1M), saturated sodium bicarbonate and saturated sodium chloride in sequence, and after concentrating the dichloromethane phase under reduced pressure, the olaparib (81.3 mg, yield about 18.7%) was obtained by silica gel column chromatography (HPLC detection was consistent with the olaparib product prepared in example 1, HPLC purity was 96.25%).
Example 4
(1) The compound of formula I (1 mmol) was dissolved in dichloromethane (20 mL) and SOCl was added 2 (1.5 mmol) and triethylamine (4.5 mmol), and stirring at room temperature for 15min to obtain a mixed solution A;
(2) Cyclopropanecarboxylic acid (1 mmol) was dissolved in dichloromethane (20 mL) and SOCl was added 2 (1.5 mmol) and triethylamine (4.5 mmol), and stirring at room temperature for 20min to obtain a mixed solution B;
(3) Piperazine (1.2 mmol) was dissolved in dichloromethane (40 mL), mixed solution a and mixed solution B (mixed solution a has a dropping speed of 6mL/min; mixed solution B has a dropping speed of 1.8 times that of mixed solution a) were simultaneously added dropwise while stirring at room temperature, after the addition was completed, stirring at room temperature was continued for 5 hours, TLC was performed to detect disappearance of the raw material of formula I, but the reaction system was complicated, the reaction was stopped, the reaction solution was washed with dilute hydrochloric acid (1M), saturated sodium bicarbonate and saturated sodium chloride in this order, and after concentrating the dichloromethane phase under reduced pressure, the olapanib (36.4 mg, yield about 8.4%) was obtained by silica gel column chromatography (HPLC detection was consistent with the olapanib product prepared in example 1, HPLC purity was 96.32%).
Example 5
(1) Dissolving a compound (1 mmol) of the formula I in dichloromethane (15 mL), adding trimethylacetyl chloride (1 mmol) and triethylamine (2 mmol), and stirring at room temperature for 15min to obtain a mixed solution A;
(2) Cyclopropanecarboxylic acid (1 mmol) was dissolved in dichloromethane (15 mL), and trimethylacetyl chloride (1.2 mmol) and triethylamine (2.4 mmol) were added thereto, followed by stirring at room temperature for 20min to obtain a mixed solution B;
(3) Piperazine (1 mmol) was dissolved in dichloromethane (30 mL), mixed solution a and mixed solution B (mixed solution a has a dropping speed of 5mL/min; mixed solution B has a dropping speed of 5 mL/min) were added simultaneously while stirring at room temperature, after the addition, a catalytic amount of DMAP (0.1 mmol) was added and stirring at room temperature was continued for 3 hours, TLC was performed to detect disappearance of the starting material of formula I, but the reaction system was complicated, the reaction was stopped, the reaction solution was washed with dilute hydrochloric acid (1M), saturated sodium bicarbonate and saturated sodium chloride in this order, and after concentrating the dichloromethane phase under reduced pressure, the olaparib (192.3 mg, yield about 44.3%) was obtained by separation through silica gel column chromatography (HPLC detection was identical to that of the olaparib product prepared in example 1, HPLC purity was 97.82%).
Example 6
The compound of formula I (1 mmol) and cyclopropanecarboxylic acid (1 mmol) were dissolved in dichloromethane (30 mL), trimethylacetyl chloride (2.2 mmol) and triethylamine (4.4 mmol) were added, after stirring at room temperature for 20min, piperazine (1 mmol) and a catalytic amount of DMAP (0.1 mmol) were added, and after continuing stirring at room temperature for 3 hours, TLC detection showed that the reaction system was more complicated and that no Olaparib was found (no corresponding Olaparib spot on TLC plate).
Claims (3)
1. A process for synthesizing olaparib, characterized by comprising the steps of:
(1) Dissolving a compound shown in the formula I in dichloromethane, adding trimethyl acetyl chloride and triethylamine, and stirring for 10-15min at room temperature to obtain a mixed solution A;
(2) Dissolving cyclopropanecarboxylic acid in dichloromethane, adding trimethyl acetyl chloride and triethylamine, and stirring at room temperature for 15-20min to obtain a mixed solution B;
(3) Dissolving piperazine in dichloromethane, stirring at room temperature, simultaneously dropwise adding the mixed solution A and the mixed solution B, and continuing stirring at room temperature for reaction after the dropwise adding is finished to obtain Olaparib;
the molar usage of the compound of the formula I, cyclopropanecarboxylic acid and piperazine is 1:1:1-1.2;
the molar ratio of the compound in the formula I to the trimethylacetyl chloride in the step (1) is 1:1-1.5, and the dosage of triethylamine is 2-3 times of that of the trimethylacetyl chloride;
the molar ratio of cyclopropanecarboxylic acid to trimethylacetyl chloride in the step (2) is 1:1.2-1.5, and the dosage of triethylamine is 2-3 times of that of trimethylacetyl chloride;
the dropping speed of the mixed solution A in the step (3) is selected from 5-6ml/min; the drop velocity of the mixed solution B is 1.8-2.0 times of the drop velocity of the mixed solution A.
2. The process of claim 1, wherein a catalytic amount of DMAP is added in step (3).
3. The novel process as claimed in claim 1, characterized by the steps of: washing the reaction solution in the step (3) with dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride in sequence, concentrating a dichloromethane phase under reduced pressure, and recrystallizing with ethyl acetate to obtain the pure Olaparib product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011584050.0A CN114685374B (en) | 2020-12-28 | 2020-12-28 | Novel process for synthesizing Olaparib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011584050.0A CN114685374B (en) | 2020-12-28 | 2020-12-28 | Novel process for synthesizing Olaparib |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114685374A CN114685374A (en) | 2022-07-01 |
| CN114685374B true CN114685374B (en) | 2024-04-12 |
Family
ID=82130108
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011584050.0A Active CN114685374B (en) | 2020-12-28 | 2020-12-28 | Novel process for synthesizing Olaparib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114685374B (en) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101810612A (en) * | 2009-12-22 | 2010-08-25 | 北京欧凯纳斯科技有限公司 | Application of Piperlongumine compounds for resisting platelet aggregation |
| WO2011151436A2 (en) * | 2010-06-04 | 2011-12-08 | Euroscreen S.A. | Novel compounds, method for use them and pharmaceutical composition containing them |
| CN102372698A (en) * | 2010-08-10 | 2012-03-14 | 江苏恒瑞医药股份有限公司 | Phthalazinone derivative and its preparation method and use in medicine |
| 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 |
| CN106928149A (en) * | 2015-12-30 | 2017-07-07 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of preparation method of olaparib |
| CN108129397A (en) * | 2018-02-11 | 2018-06-08 | 北京耀诚惠仁科技有限公司 | A kind of synthetic method of olaparib |
| CN110790710A (en) * | 2019-11-07 | 2020-02-14 | 东南大学 | Synthetic method of olaparib |
| CN112047890A (en) * | 2020-10-20 | 2020-12-08 | 连云港杰瑞药业有限公司 | Preparation method of olaparib |
-
2020
- 2020-12-28 CN CN202011584050.0A patent/CN114685374B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101810612A (en) * | 2009-12-22 | 2010-08-25 | 北京欧凯纳斯科技有限公司 | Application of Piperlongumine compounds for resisting platelet aggregation |
| WO2011151436A2 (en) * | 2010-06-04 | 2011-12-08 | Euroscreen S.A. | Novel compounds, method for use them and pharmaceutical composition containing them |
| CN102372698A (en) * | 2010-08-10 | 2012-03-14 | 江苏恒瑞医药股份有限公司 | Phthalazinone derivative and its preparation method and use in medicine |
| CN106928149A (en) * | 2015-12-30 | 2017-07-07 | 石药集团中奇制药技术（石家庄）有限公司 | A kind of preparation method of olaparib |
| 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 |
| CN108129397A (en) * | 2018-02-11 | 2018-06-08 | 北京耀诚惠仁科技有限公司 | A kind of synthetic method of olaparib |
| CN110790710A (en) * | 2019-11-07 | 2020-02-14 | 东南大学 | Synthetic method of olaparib |
| CN112047890A (en) * | 2020-10-20 | 2020-12-08 | 连云港杰瑞药业有限公司 | Preparation method of olaparib |
Non-Patent Citations (1)
| Title |
|---|
| "环丙烷甲酰氯的合成;张克勋等;化工时刊;第17卷(第7期);第36页右栏 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114685374A (en) | 2022-07-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102307866A (en) | Method for preparing linezolid and intermediates thereof | |
| CN105175401A (en) | Preparation method of brexpiprazole | |
| CN112778303A (en) | Preparation method of CDK4/6 kinase inhibitor SHR6390 | |
| CN107382820B (en) | Synthetic method of 3-aryl isoindole derivative | |
| CN114634482B (en) | Diazonium difluoro methylation reagent and synthetic method and application thereof | |
| CN111072660B (en) | Simple preparation method of rilibatan | |
| CN111303020A (en) | Synthetic method of 5-chloro-2- (pyridine-3-yl) pyridine-3-amine | |
| CN114685374B (en) | Novel process for synthesizing Olaparib | |
| EP3527556B1 (en) | Method for preparing deuterated imidazole diketone compound | |
| CN113416150A (en) | Novel synthesis method of lobaplatin intermediate | |
| CN112979544B (en) | Preparation method of cabozitinib or salt thereof | |
| CN115043826B (en) | Sinomenine furazan derivatives, and preparation method and application thereof | |
| CN110922409A (en) | Method for preparing BTK inhibitor zebritinib | |
| CN111362873B (en) | Synthetic method of gatifloxacin metabolite | |
| CN115785122A (en) | Indole derivative piperidine compound and synthetic method thereof | |
| CN112624957A (en) | Synthetic method of 3-alkyl isoindolinone derivatives | |
| CN111253392B (en) | Method for preparing apixaban | |
| CN115124530A (en) | Preparation method of evodiamine | |
| CN108239040B (en) | Preparation method of nitric acid 2- (4-methylthiazol-5-yl) ethyl ester hydrochloride | |
| TW202210462A (en) | Method for preparing methyl (s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenylpropionate and salt thereof | |
| CN114907261B (en) | 2-phenylaminoquinoline derivative, preparation method and application thereof | |
| CN103554074B (en) | Preparation method of 3-trifluoromethyl coumarin derivative | |
| CN110563721A (en) | Preparation method of azasetron hydrochloride | |
| CN115232022B (en) | Preparation method of acetaminophen dimer derivative | |
| CN113292624B (en) | Synthesis method of abiraterone acetate impurity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Country or region after: China Address after: No. 69 Yinhai Second Road, Binhai New Area, Lijin County, Dongying City, Shandong Province, 257453 Applicant after: Shandong Daohe Pharmaceutical Co.,Ltd. Applicant after: Daohe (Weifang) Pharmaceutical Technology Co.,Ltd. Address before: 257000 Binhai fine chemical industry park, dongyinggang Economic Development Zone, Dongying City, Shandong Province Applicant before: SHANDONG DOYE PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Country or region before: China Applicant before: Shandong Daozhen Pharmaceutical Technology Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |