Olaparib

Base Information

• Chemical Name: Olaparib
• CAS No.: 763113-22-0
• Molecular Formula: C₂₄H₂₃FN₄O₃
• Molecular Weight: 434.47
• Hs Code.: 29339900
• Mol file: 763113-22-0.mol

Synonyms:4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one;1-(Cyclopropylcarbonyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoyl]piperazine;

Chemical Property of Olaparib

Chemical Property:

• Refractive Index: 1.702
• PKA: 12.07±0.40(Predicted)
• PSA: 86.37000
• Density: 1.43 g/cm³
• LogP: 2.22320
• Storage Temp.: -20°C
• Solubility.: Soluble in DMSO (up to 33 mg/ml) or in Ethanol (up to 1.7 mg/ml)

Purity/Quality:

99% ^*data from raw suppliers

Olaparib ^*data from reagent suppliers

Safty Information:

• Statements: 22-38-37-36
• Safety Statements: 24/25-37/39

MSDS Files:

SDS file from LookChem

Useful:

• Drug Interactions: In vitro, olaparib is a inhibitor of the CYP3S4 but the inducing agent of CYP2B6 upon the higher concentration achieved clinically. Olaparib has small or no inhibitory effects on other CYP isozymes. In vitro studies have ever shown that olaparib is the substrate of CYP3A4. According from a set of Drug-interaction test data (N = 57), when olaparib is administrated with itraconazole, a potent CYP3A inhibitor, in combination, the AUC and Cmax of olaparib were increased by 2.7-and 1.4-fold, respectively. The stimulation based on the physiologically pharmacokinetic (PBPK) model suggests a moderate inhibitor of CYP3A (fluconazole) can increase the AUC and Cmax of olaparib, respectively, by 2-and 1.1-fold. According a set of Drug-interaction test data (N = 22), when olaparib is administrated with rifampicin, a potent CYP3A inducer, in combination, the AUC and Cmax of olaparib were reduced by 87% and 71 %, respectively. Stimulation based on PBPK model suggests one kind of moderate CYP3A inducers (efavirenz) may reduce the AUC and Cmax of olaparib by 50-60% and 20-30%, respectively. In vitro studies have ever shown that olaparib is the substrate of P-gp and the inhibitors of BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. It is still not clear about the clinical relevance of these findings. The above information is edited by the lookchem of Dai Xiongfeng.
• Description: Olaparib, marketed by AstraZeneca under the brand name Lynparza , was approved in the USA in December 2014 as a targeted, single-agent therapy for the treatment of germline BRCA-mediated advanced ovarian cancer.Olaparib, originally developed by KuDOS pharmaceuticals and later by AstraZeneca, functions as a poly ADP ribose polymerase inhibitor and has been specifically approved for patients who have received three or more treatments of chemotherapy. In clinical trials, the drug prolonged progression- free survival for patients suffering from platinum-sensitive recurrent serous ovarian cancer. Olaparib is also currently in various phases of investigation for treatment of breast, gastric, prostate, pancreatic and non-small cell lung cancer. Many of the products generated by alkylating agents on DNA can be efficiently repaired by normal base excision repair (BER). Some poly(ADP-ribose) polymerases (PARPs) assist in the repair of single-strand DNA nicks, an important step in BER. Olaparib is a potent inhibitor of PARP1 and PARP2 (IC50 = 5 and 1 nM, respectively) but is less effective against the PARP tankyrase-1 (IC50 = 1.5 μM). It can be used in cells and in animals, alone or in combination therapy with alkylating agents, to block BER and increase cancer cell death.
• Uses: Olaparib is a potent poly(ADP-ribose) polymerase (PARP) inhibitor. Olaparib has been shown to induce significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Recent studies show that Olaparib increases radiosensitivity of a lung tumor xenograft, making it a potential candidate for use in combination with radiotherapy. Many of the products generated by alkylating agents on DNA can be efficiently repaired by normal base excision repair (BER). Some poly(ADP-ribose) polymerases (PARPs) assist in the repair of single-strand DNA nicks, an important step in BER. Olaparib is a potent inhibitor of PARP1 and PARP2 (IC50 = 5 and 1 nM, respectively) but is less effective against the PARP tankyrase-1 (IC50 = 1.5 μM). It can be used in cells and in animals, alone or in combination therapy with alkylating agents, to block BER and increase cancer cell death.[Cayman Chemical]
• Clinical Use: Human poly (ADP-ribose) polymerase enzymes inhibitor: Treatment of platinum-sensitive relapsed BRCAmutated high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer
• Drug interactions: Potentially hazardous interactions with other drugs Antibacterials: concentration possibly increased by ciprofloxacin, clarithromycin and erythromycin - avoid or reduce olaparib dose to 150 mg twice daily; avoid with rifabutin and rifampicin. Antidepressants: avoid with St John’s wort. Antiepileptics: avoid with carbamazepine, phenobarbital and phenytoin. Antifungals: concentration increased by itraconazole and possibly fluconazole - avoid or reduce olaparib dose to 150 mg twice daily. Antipsychotics: avoid with clozapine - increased risk of agranulocytosis. Antivirals: concentration possibly increased by boceprevir, ritonavir and telaprevir - avoid or reduce olaparib dose to 150 mg twice daily; avoid with nevirapine. Calcium channel blockers: concentration possibly increased by diltiazem and verapamil - avoid or reduce olaparib dose to 150 mg twice daily. Cobicistat: concentration possibly increased - avoid or reduce olaparib dose to 150 mg twice daily. Grapefruit juice: avoid concomitant use. Oestrogens and progestogens: possibly reduced contraceptive effect.

Technology Process of Olaparib

There total 17 articles about Olaparib which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield:

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) → olaparib (763113-22-0)

Guidance literature:

Multi-step reaction with 3 steps

1.1: triethylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere

1.2: 72 h / 50 °C / Inert atmosphere

2.1: hydrogenchloride / water; ethanol / 20 °C / Inert atmosphere

3.1: triethylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere

3.2: 72 h / 20 °C / Inert atmosphere

With hydrogenchloride; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In ethanol; water; N,N-dimethyl-formamide;

DOI:10.1021/acs.jmedchem.5b01324

Reference yield:

bromobenzene (108-86-1,52753-63-6) → olaparib (763113-22-0)

Guidance literature:

Multi-step reaction with 2 steps

1.1: potassium tert-butylate / toluene / 3 h / 90 °C

1.2: 24 h / 110 °C

2.1: C₆H₁₁N₂⁽¹⁺⁾*Cl^(1-)*AlCl₃ / 50 - 55 °C / Inert atmosphere

With C₆H₁₁N₂⁽¹⁺⁾*Cl^(1-)*AlCl₃; potassium tert-butylate; In toluene;

Reference yield:

3-bromo-4-fluorobenzaldehyde (77771-02-9) → olaparib (763113-22-0)

Guidance literature:

Multi-step reaction with 3 steps

1.1: sodium hydride / tetrahydrofuran / 2.5 h / 20 °C / Inert atmosphere

2.1: sodium methylate / methanol / Reflux

2.2: 3 h / pH 1

3.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; dmap; potassium bromide / N,N-dimethyl-formamide / 120 °C

With dmap; tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium methylate; sodium hydride; potassium bromide; In tetrahydrofuran; methanol; N,N-dimethyl-formamide;

upstream raw materials:

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid

2-fluoro-5-bromomethyl benzoic acid methyl ester

bromobenzene

2-fluoro-5-formylbenzonitrile

Downstream raw materials:

4-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one-8-d

Refernces

• 1、 Pedersen, Simon S.,Donslund, Aske S.,Mikkelsen, Jesper H.,Bakholm, Oskar S.,Papp, Florian,Jensen, Kim B.,Gustafsson, Magnus B. F.,Skrydstrup, Troels. "A Nickel(II)-Mediated Thiocarbonylation Strategy for Carbon Isotope Labeling of Aliphatic Carboxamides". . p. 7114 - 7123. Retrieved 2021/03/03.
• 2、 -. "Preparation method of olaparib". . . Retrieved 2019/09/17.