763114-26-7

Basic information

• Product Name: 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)Methyl)benzoic acid
• Synonyms: 2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)Methyl]benzoic acid;(2-Fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylMethyl)benzoic acid)763114-26-7;Benzoic acid, 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluoro-;2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)Methyl);5-[(3,4-Dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluoro-Benzoic acid;2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl);2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)Methyl)benzoic acid;EOS-61877
• CAS NO: 763114-26-7
• Molecular Formula: C₁₆H₁₁FN₂O₃
• Molecular Weight: 298.2685432
• EINECS: 1592732-453-0
• Mol File: 763114-26-7.mol

Chemical Properties

• Appearance: /
• Density: 1.42
• Storage Temp.: Sealed in dry,Room Temperature
• PKA: 3.19±0.10(Predicted)
• CAS DataBase Reference: 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)Methyl)benzoic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)Methyl)benzoic acid(763114-26-7)
• EPA Substance Registry System: 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)Methyl)benzoic acid(763114-26-7)

Safety Data

• Hazardous Substances Data: 763114-26-7(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid is used as an intermediate in the synthesis of PARP inhibitors for cancer treatment. Its role in the development of these inhibitors is crucial, as PARP plays a significant role in DNA repair mechanisms, and its inhibition can lead to the death of cancer cells.
Used in the Synthesis of Olaparib:
Specifically, 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid is utilized in the synthesis of olaparib, a PARP polymerase inhibitor. Olaparib has been approved for the treatment of certain types of cancers, such as ovarian and breast cancer, and is being studied for its potential use in other cancer types as well. Its ability to inhibit PARP enzymes helps to exploit the synthetic lethality principle, where the combination of two mutations or deficiencies can lead to cell death, particularly in cancer cells with defects in DNA repair mechanisms.

Synthesis

Compound 3 (2.6g, 0.011mol)And 2-fluoro-5-formylbenzoic acid (2.1g, 0.012mol)Dissolved in anhydrous tetrahydrofuran (25ml), cooled to 0 ,Slowly add triethylamine (1.0ml, 0.007mol) dropwise, then warm up to room temperature for 5h, then slowly raise the temperature to 70 , add hydrazine hydrate (5.1ml, 0.107mol) for 3h, and drop to room temperature , Add appropriate amount of hydrochloric acid (2mol / L) to adjust the pH to acidic, no longer precipitate solids. Filter with suction, wash the product with water and ethyl acetate, and dry to obtain a yellow solid (1.9g, yield 83%)

InChI:InChI=1S/C16H11FN2O3/c17-13-6-5-9(7-12(13)16(21)22)8-14-10-3-1-2-4-11(10)15(20)19-18-14/h1-7H,8H2,(H,19,20)(H,21,22)

Synthetic route

4-(3-bromo-4-fluorobenzyl)phthalazin-1(2H)-one (1062292-60-7) + carbon dioxide (124-38-9) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Stage #1: 4-(3-bromo-4-fluorobenzyl)phthalazin-1(2H)-one With n-butyllithium In diethyl ether; hexane at -40 - -30℃; for 0.5h; Stage #2: carbon dioxide In diethyl ether; hexane for 0.333333h; Stage #3: With hydrogenchloride In water at 20℃; for 0.5h; Temperature;	95.1%

methyl 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-ylmethylene)benzoate → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Stage #1: methyl 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-ylmethylene)benzoate With hydrazine hydrate In tetrahydrofuran; water at 8 - 25℃; for 4h; Stage #2: With sodium hydroxide In tetrahydrofuran; water; acetone at 40℃; for 3.3h;	95%

2-fluoro-5-(3-oxo-1,3-dihydroisobenzofuranylidene methyl)benzonitrile (763114-25-6) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Stage #1: 2-fluoro-5-(3-oxo-1,3-dihydroisobenzofuranylidene methyl)benzonitrile With water; sodium hydroxide at 90℃; for 1h; Stage #2: With hydrazine hydrate at 70℃; for 18h;	93.7%
Stage #1: 2-fluoro-5-(3-oxo-1,3-dihydroisobenzofuranylidene methyl)benzonitrile With sodium hydroxide In water at 90℃; for 1h; Stage #2: With hydrazine hydrate In water at 70℃; for 18h;	93.69%
Stage #1: 2-fluoro-5-(3-oxo-1,3-dihydroisobenzofuranylidene methyl)benzonitrile With hydrazine hydrate at 8 - 25℃; for 4h; Stage #2: With water; sodium hydroxide In acetone at 20 - 90℃; for 1h;	91%

methyl 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoate → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
With sodium hydroxide In tetrahydrofuran; water at 20℃;	93%

C18H15FN2O3 → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
With potassium hydroxide In methanol for 6h; Reflux;	90.5%

ethyl 2-(2-(4-fluoro-3-carboxyphenyl)acetyl)benzoate → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
With sodium hydroxide; hydrazinium sulfate In water; isopropyl alcohol Reflux;	85.1%

dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (61260-15-9) + 2-fluoro-5-formyl-benzoic acid (550363-85-4) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Stage #1: dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate; 2-fluoro-5-formyl-benzoic acid With triethylamine In tetrahydrofuran at 0 - 20℃; for 5h; Stage #2: With hydrazine hydrate In tetrahydrofuran at 70℃; for 3h;	83%

(Z)-2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzonitrle + 2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzonitrile → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Stage #1: (Z)-2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzonitrle; 2-fluoro-5-[(E)-(3-oxo-2-benzofuran-1-ylidene)methyl]benzonitrile With sodium hydroxide In water at 90℃; for 0.5h; Stage #2: With hydrazine In water at 70℃; for 18h; Stage #3: With hydrogenchloride at 20℃; for 0.166667h; pH=4;	77%

(Z)-2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzonitrle → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
With sodium hydroxide; hydrazine hydrate In water	77%
Stage #1: (Z)-2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzonitrle With water; sodium hydroxide at 90℃; for 16h; Inert atmosphere; Stage #2: With hydrazine hydrate at 70℃; for 16h; Inert atmosphere;

2-fluoro-4-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzonitrile → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Stage #1: 2-fluoro-4-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzonitrile With water; sodium hydroxide at 90℃; for 1h; Stage #2: With hydrazine hydrate at 70℃; for 18h;	77%

4-(3-bromo-4-fluorobenzyl)phthalazin-1(2H)-one (1062292-60-7) + carbon monoxide (201230-82-2) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
With bis-triphenylphosphine-palladium(II) chloride; ethanol at 110℃; under 9120.61 Torr; for 6h; Autoclave;	71.1%

(Z)-2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzoic acid → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
With hydrazine hydrate In tetrahydrofuran Heating;

methyl phosphite (96-36-6, 868-85-9) + o-carboxybenzaldehyde (119-67-5) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (61260-15-9)

Conditions	Yield
With methanesulfonic acid; sodium methylate In methanol	A 95%, 95% B n/a

2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzonitrile (1021298-68-9) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Stage #1: 2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzonitrile With sodium hydroxide; water at 20 - 90℃; Stage #2: With hydrogenchloride; water at 60℃; for 0.666667h;
With hydrogenchloride; water at 20℃;
With sodium hydroxide In water

C16H9FO4 → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
With hydrazine hydrate at 70℃; for 18h; Inert atmosphere;	30.1 g
With hydrazine hydrate at 70℃; for 72h; Inert atmosphere;	2 g

o-carboxybenzaldehyde (119-67-5) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium; methanol / 0.5 h / 0 - 20 °C / Inert atmosphere 2.1: triethylamine / tetrahydrofuran / 15 - 20 °C 3.1: sodium hydroxide; water / 1 h / 90 °C 3.2: 70 °C 3.3: 20 °C / pH 3 - 4 View Scheme
Multi-step reaction with 3 steps 1.1: sodium methylate / methanol / 0.08 h / 0 °C / Inert atmosphere 1.2: 1 h / 20 °C 1.3: 10 °C / Cooling with ice 2.1: triethylamine / tetrahydrofuran / 1 h / 15 - 20 °C 3.1: sodium hydroxide / water / 1 h / 100 °C 3.2: 24 h / 70 °C 3.3: pH 4 View Scheme
Multi-step reaction with 5 steps 1: sodium / methanol / 0.5 h / 0 - 20 °C / Inert atmosphere 2: triethylamine / tetrahydrofuran / 15 - 20 °C 3: sodium hydroxide; water / 1 h / 90 °C 4: hydrazine hydrate / water / 70 °C 5: water; hydrogenchloride / 20 °C View Scheme

2-fluoro-5-formylbenzonitrile (218301-22-5) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / tetrahydrofuran / 15 - 20 °C 2.1: sodium hydroxide; water / 1 h / 90 °C 2.2: 70 °C 2.3: 20 °C / pH 3 - 4 View Scheme
Multi-step reaction with 4 steps 1: triethylamine / tetrahydrofuran / 15 - 20 °C 2: sodium hydroxide; water / 1 h / 90 °C 3: hydrazine hydrate / water / 70 °C 4: water; hydrogenchloride / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: Dimethyl phosphite; hydrogenchloride / water / 20 °C 1.2: 20 °C 2.1: sodium hydroxide / water / 20 - 70 °C 2.2: 20 - 70 °C / pH 4 - 6 View Scheme

3-bromo-4-fluorobenzaldehyde (77771-02-9) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: 1-methyl-pyrrolidin-2-one / 24 h / 170 °C 1.2: celite / 1 h / 80 °C 2.1: triethylamine / tetrahydrofuran / 15 - 20 °C 3.1: sodium hydroxide; water / 1 h / 90 °C 3.2: 70 °C 3.3: 20 °C / pH 3 - 4 View Scheme
Multi-step reaction with 5 steps 1: 1-methyl-pyrrolidin-2-one / 24 h / 170 °C 2: triethylamine / tetrahydrofuran / 15 - 20 °C 3: sodium hydroxide; water / 1 h / 90 °C 4: hydrazine hydrate / water / 70 °C 5: water; hydrogenchloride / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / tetrahydrofuran / 6 h / 30 °C 2.1: hydrazine hydrate / tetrahydrofuran / 1 h / 30 °C 2.2: 7 h / Reflux 3.1: n-butyllithium / diethyl ether; hexane / 0.5 h / -40 - -30 °C 3.2: 0.33 h 3.3: 0.5 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / tetrahydrofuran / 6 h / 30 °C 2.1: hydrazine hydrate / tetrahydrofuran / 1 h / 30 °C 2.2: 7 h / Reflux 3.1: bis-triphenylphosphine-palladium(II) chloride; ethanol / 6 h / 110 °C / 9120.61 Torr / Autoclave View Scheme

dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (61260-15-9) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / tetrahydrofuran / 15 - 20 °C 2.1: sodium hydroxide; water / 1 h / 90 °C 2.2: 70 °C 2.3: 20 °C / pH 3 - 4 View Scheme
Multi-step reaction with 2 steps 1.1: triethylamine / tetrahydrofuran / 1 h / 15 - 20 °C 2.1: sodium hydroxide / water / 1 h / 100 °C 2.2: 24 h / 70 °C 2.3: pH 4 View Scheme
Multi-step reaction with 4 steps 1: triethylamine / tetrahydrofuran / 15 - 20 °C 2: sodium hydroxide; water / 1 h / 90 °C 3: hydrazine hydrate / water / 70 °C 4: water; hydrogenchloride / 20 °C View Scheme

C16H10FNO3 → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrazine hydrate / water / 70 °C 2: water; hydrogenchloride / 20 °C View Scheme

2-fluoro-5-bromomethyl benzoic acid methyl ester (709-45-5) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: magnesium; triethylamine / acetonitrile / 2 h / 65 °C 2: sodium carbonate; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) / methanol; water / 4 h / Inert atmosphere; Reflux 3: sodium hydroxide / water; tetrahydrofuran / 20 °C View Scheme

C9H10BFO4 → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium carbonate; [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) / methanol; water / 4 h / Inert atmosphere; Reflux 2: sodium hydroxide / water; tetrahydrofuran / 20 °C View Scheme

2,3-dihydrophthalazine-1,4-dione (1445-69-8) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: trichlorophosphate / 4 h / 110 °C 2.1: zinc; ethylene dibromide; chloro-trimethyl-silane / tetrahydrofuran / 2 h / 0 °C 2.2: 2 h / 80 °C / Inert atmosphere 3.1: potassium hydroxide / methanol / 6 h / Reflux View Scheme

1-chloro-4-phthalazinone (2257-69-4) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: zinc; ethylene dibromide; chloro-trimethyl-silane / tetrahydrofuran / 2 h / 0 °C 1.2: 2 h / 80 °C / Inert atmosphere 2.1: potassium hydroxide / methanol / 6 h / Reflux View Scheme

3-hydroxy-1(3H)-isobenzofuranone (16859-59-9) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: dichloromethane / 0.42 h / 100 °C 2: triethylamine / dichloromethane / 0.33 h / 15 °C 3: sodium hydroxide; hydrazine hydrate / ethanol / 0.17 h / 70 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium methylate / methanol / 0.17 h / 0 °C 1.2: 1 h / 0 - 25 °C 2.1: triethylamine / tetrahydrofuran / 10 - 20 °C 3.1: sodium hydroxide; water / 1 h / 90 °C / Inert atmosphere 3.2: 18 h / 70 °C / Inert atmosphere 3.3: 0.17 h / 25 °C / pH 4 / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine; methanesulfonic acid / dichloromethane / 0.5 h 2.1: triethylamine / dichloromethane / 4 h / 6 - 20 °C 3.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; carbon monoxide / methanol / 8 h / 80 °C / 2585.81 Torr / Inert atmosphere 4.1: hydrazine hydrate / water; tetrahydrofuran / 4 h / 8 - 25 °C 4.2: 3.3 h / 40 °C View Scheme

phthalonitrile (91-15-6) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium tert-butylate / toluene / 5 h / 50 - 80 °C 1.2: 5 h / 90 - 95 °C 2.1: hydrazine hydrate; hydrogenchloride / water / 10 h / 65 - 70 °C / pH 2.5 - 3 View Scheme
Multi-step reaction with 3 steps 1.1: potassium tert-butylate / toluene / 5 h / 50 - 80 °C 1.2: 5 h / 90 - 95 °C 2.1: toluene-4-sulfonic acid / toluene; water / 7 h / 74 - 80 °C 3.1: hydrazine hydrate / toluene; water / 4 h / 30 - 45 °C 3.2: 1 h / 20 - 25 °C View Scheme

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

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium methylate / toluene / 3 h / 55 - 85 °C 1.2: 4 h / 50 - 95 °C 2.1: hydrazine hydrate; hydrogenchloride / water / 10 h / 65 - 70 °C / pH 2.5 - 3 View Scheme
Multi-step reaction with 2 steps 1.1: sodium methylate / toluene / 4 h / 50 - 85 °C 1.2: 4 h / 50 - 85 °C 2.1: hydrazine hydrate; hydrogenchloride / water / 10 h / 65 - 70 °C / pH 2.5 - 3 View Scheme
Multi-step reaction with 3 steps 1.1: sodium methylate / toluene / 3 h / 55 - 85 °C 1.2: 4 h / 50 - 95 °C 2.1: toluene-4-sulfonic acid / toluene; water / 7 h / 74 - 80 °C 3.1: hydrazine hydrate / toluene; water / 4 h / 30 - 45 °C 3.2: 1 h / 20 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium methylate / toluene / 4 h / 50 - 85 °C 1.2: 4 h / 50 - 85 °C 2.1: toluene-4-sulfonic acid / toluene; water / 7 h / 74 - 80 °C 3.1: hydrazine hydrate / toluene; water / 4 h / 30 - 45 °C 3.2: 1 h / 20 - 25 °C View Scheme

2-(4-fluoro-3-carboxyphenyl)acetylbenzoic acid → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
With hydrogenchloride; hydrazine hydrate In water at 65 - 70℃; for 10h; pH=2.5 - 3; Temperature; Reagent/catalyst;	27.8 g
Multi-step reaction with 2 steps 1.1: toluene-4-sulfonic acid / toluene; water / 7 h / 74 - 80 °C 2.1: hydrazine hydrate / toluene; water / 4 h / 30 - 45 °C 2.2: 1 h / 20 - 25 °C View Scheme

ethyl 4-fluoro-3-cyanobenzeneacetate → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium ethanolate / 1,2-dichloro-ethane / 6 h / 50 - 83 °C 1.2: 4 h / 50 - 83 °C 2.1: hydrazine hydrate; hydrogenchloride / water / 10 h / 65 - 70 °C / pH 2.5 - 3 View Scheme
Multi-step reaction with 3 steps 1.1: sodium ethanolate / 1,2-dichloro-ethane / 6 h / 50 - 83 °C 1.2: 4 h / 50 - 83 °C 2.1: toluene-4-sulfonic acid / toluene; water / 7 h / 74 - 80 °C 3.1: hydrazine hydrate / toluene; water / 4 h / 30 - 45 °C 3.2: 1 h / 20 - 25 °C View Scheme

5-(cyanomethyl)-2-fluorobenzonitrile (519059-09-7) → 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: potassium tert-butylate / toluene / 5 h / 50 - 80 °C 1.2: 5 h / 90 - 95 °C 2.1: hydrazine hydrate; hydrogenchloride / water / 10 h / 65 - 70 °C / pH 2.5 - 3 View Scheme
Multi-step reaction with 2 steps 1.1: potassium tert-butylate / tetrahydrofuran / 8 h / 50 - 64 °C 1.2: 5 h / 50 - 95 °C 2.1: hydrazine hydrate; hydrogenchloride / water / 10 h / 65 - 70 °C / pH 2.5 - 3 View Scheme
Multi-step reaction with 3 steps 1.1: potassium tert-butylate / toluene / 5 h / 50 - 80 °C 1.2: 5 h / 90 - 95 °C 2.1: toluene-4-sulfonic acid / toluene; water / 7 h / 74 - 80 °C 3.1: hydrazine hydrate / toluene; water / 4 h / 30 - 45 °C 3.2: 1 h / 20 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium tert-butylate / tetrahydrofuran / 8 h / 50 - 64 °C 1.2: 5 h / 50 - 95 °C 2.1: toluene-4-sulfonic acid / toluene; water / 7 h / 74 - 80 °C 3.1: hydrazine hydrate / toluene; water / 4 h / 30 - 45 °C 3.2: 1 h / 20 - 25 °C View Scheme

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + tert-butyl 1,6-diazaspiro[3.3]heptane-6-carboxylate (1272412-72-2) → tert-butyl 1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)-methyl)benzoyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 60℃; for 12h;	98%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + tert-butyl 1,4-diazepine-1-carboxylate (112275-50-0) → tert-butyl 4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)-1,4-diazepane-1-carboxylate (874116-49-1)

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere;	97%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 24h;
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 24h;

4-HYDROXYPIPERIDINE (5382-16-1) + 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) → 4-(4-fluoro-3-(4-hydroxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (1174043-15-2)

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl acetamide at 20℃; for 17h; Product distribution / selectivity;	97%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In ISOPROPYLAMIDE at 20℃; for 16h; Product distribution / selectivity;

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + 1-t-Butoxycarbonylpiperazine (57260-71-6) → tert-butyl 4-[2’-fluoro-5’-[(4’’-oxo-3’’H-phthalazin-1’’-yl)methyl]benzoyl]piperazine-1-carboxylate (763114-04-1)

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere;	96%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 2h;	96%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 15 - 25℃; for 2h; Product distribution / selectivity;	78%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + methyl 2-(2-(pyrrolidin-1-yl)ethylamino)propanoate (1069136-13-5) → 3-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-methyl-1-(2-(pyrrolidin-1-yl)ethyl)imidazolidine-2,4-dione (1069135-92-7)

Conditions	Yield
With diphenyl phosphoryl azide; triethylamine In acetonitrile at 85℃; for 1.25h;	95%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + 1-(cyclopropylcarbonyl)piperazine (59878-57-8) → olaparib

Conditions	Yield
Stage #1: 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran for 0.5h; Stage #2: 1-(cyclopropylcarbonyl)piperazine In tetrahydrofuran at 20℃; for 3h;	95%
With pivaloyl chloride; triethylamine In ethanol; dichloromethane at 20℃; for 4h;	91.5%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 30 - 50℃;	81.9%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + cyclopropyl (piperazin-1-yl)methanone hydrochloride (1021298-67-8) → olaparib

Conditions	Yield
Stage #1: 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 25℃; for 1h; Stage #2: cyclopropyl (piperazin-1-yl)methanone hydrochloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20 - 25℃; for 5.5h; Reagent/catalyst; Temperature; Solvent;	94.5%
With triethylamine In dichloromethane at -10 - 20℃; for 4h; Solvent;	92.2%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In acetonitrile at 5 - 20℃; Product distribution / selectivity;
With triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 8h; Solvent; Temperature; Reagent/catalyst;	18.92 g

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + N-cyclopropanoylpiperazinium p-toluenesulfonate → olaparib

Conditions	Yield
Stage #1: 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid With pivaloyl chloride; N-ethyl-N,N-diisopropylamine In acetone at 0 - 20℃; for 3h; Stage #2: N-cyclopropanoylpiperazinium p-toluenesulfonate With N-ethyl-N,N-diisopropylamine In acetone at 0 - 20℃; for 3h;	89.5%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + 4-(2-(pyrrolidin-1-yl)ethoxy)piperidine (1094533-75-1) → 4-(4-fluoro-3-(4-(2-(pyrrolidin-1-yl)ethoxy)piperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (1174044-05-3)

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 2h;	89%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + 1-(piperidin-1-yl)-2-(piperidin-4-yloxy)ethanone (902836-10-6) → 4-(4-fluoro-3-(4-(2-oxo-2-(piperidin-1-yl)ethoxy)piperidine-1-carbonyl)benzyl)phthalazin-1 (2H)-one (1174044-06-4)

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In ISOPROPYLAMIDE for 2h;	89%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + 4-(4-chloro-6-morpholinyl-1,3,5-triazin-2-yl)piperazine hydrochloride → C27H26ClFN8O3

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 6h;	88%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃;	87.7%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + N-(4-((4-methoxyphenyl)carbamoyl)phenyl)piperazine-1-carboxamide hydrochloride → 4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)-N-(4-((4-methoxyphenyl)carbamoyl)phenyl)piperazine-1-carboxamide

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	84.6%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + (S)-4-(4-chloro-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)-3-methylmorpholine hydrochloride → C28H28ClFN8O3

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 8h;	84.6%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + N-(4-((4-fluorophenyl)carbamoyl)phenyl)piperazine-1-carboxamide hydrochloride → 4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)-N-(4-((4-fluorophenyl)carbamoyl)phenyl)piperazine-1-carboxamide

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	83%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + 4-(piperidin-4-yl)butan-1-ol (57614-92-3) → C25H28FN3O3

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 25℃; Inert atmosphere;	83%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + 4-(2-chloro-7-methyl-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-4-yl)morpholine hydrochloride → 4-(3-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 6h;	82.5%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + trans-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester → tert-butyl 4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)-trans-2,5-dimethylpiperazine-1-carboxylate

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	81.3%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + 1,2,3-Benzotriazole (95-14-7) → 4-[3-(1H-benzotriazol-1-ylcarbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one

Conditions	Yield
With thionyl chloride; triethylamine In dichloromethane at 0 - 20℃; Reagent/catalyst;	81%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + 2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (896464-16-7) → tert-butyl 1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)-methyl)benzoyl)-1,7-diazaspiro[3.5]nonane-7-carboxylate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 60℃; for 12h;	81%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + 4-(2-propenoxy)piperidine (68848-53-3) → C24H24FN3O3 (1174043-46-9)

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 2h;	80%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + (±)-tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate → tert-butyl 7-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)-methyl)benzoyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 60℃; for 12h;	79%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + 2,8-diazaspiro[4,5]decane-8-carboxylic acid tert-butyl ester (236406-39-6) → tert-butyl 2-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)-methyl)benzoyl)-2,8-diazaspiro[4.5]decane-8-carboxylate

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 60℃; for 12h;	79%

2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid (763114-26-7) + 4-(4-chloro-6-(piperazin-1-yl)pyrimidin-2-yl)morpholine hydrochloride → C28H27ClFN7O3

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 4h;	79%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃;	78.9%

Upstream product

• 1379825-89-4 (Z)-2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzonitrle 
• 1379825-89-4 2-fluoro-5-[(E)-(3-oxo-2-benzofuran-1-ylidene)methyl]benzonitrile 
• 96-36-6 methyl phosphite 
• 119-67-5 o-carboxybenzaldehyde 
• 1021298-68-9 2-fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzonitrile 
• 218301-22-5 2-fluoro-5-formylbenzonitrile 
• 77771-02-9 3-bromo-4-fluorobenzaldehyde 
• 61260-15-9 dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate 
• 763114-25-6 2-fluoro-5-(3-oxo-1,3-dihydroisobenzofuranylidene methyl)benzonitrile 
• 709-45-5 2-fluoro-5-bromomethyl benzoic acid methyl ester 
• 1445-69-8 2,3-dihydrophthalazine-1,4-dione 
• 2257-69-4 1-chloro-4-phthalazinone 
• 16859-59-9 3-hydroxy-1(3H)-isobenzofuranone 
• 91-15-6 phthalonitrile 

Downstream Products

• 874116-49-1 tert-butyl 4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)-1,4-diazepane-1-carboxylate 
• 763111-49-5 4-[[4-fluoro-3-[(hexahydro-1H-1,4-diazepin-1-yl)carbonyl]phenyl]methyl]-1(2H)-phthalazinone 
• 763114-29-0 1-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoyl]piperidin-4-carboxylic acid methyl ester 
• 1069135-92-7 3-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-5-methyl-1-(2-(pyrrolidin-1-yl)ethyl)imidazolidine-2,4-dione 
• 763113-22-0 olaparib 
• 763114-04-1 tert-butyl 4-[2’-fluoro-5’-[(4’’-oxo-3’’H-phthalazin-1’’-yl)methyl]benzoyl]piperazine-1-carboxylate 
• 1174043-15-2 4-(4-fluoro-3-(4-hydroxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one 
• 1174043-85-6 4-(3-(4-tert-butoxypiperidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2h)-one 
• 1174043-92-5 4-(4-fluoro-3-(4-hydroxy-4-methylpiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one 
• 1174043-34-5 4-(4-fluoro-3-(4-(2-methoxyethoxy)piperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one 
• 1174043-46-9 C₂₄H₂₄FN₃O₃ 
• 1174043-16-3 4-[[4-fluoro-3-[(4-methoxy-1-piperidinyl)carbonyl]phenyl]methyl]-1(2H)-phthalazinone 
• 1174043-20-9 4-(3-(4-ethoxypiperidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one 
• 1174043-49-2 4-[[4-fluoro-3-(4-methoxy-4-methylpiperidine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one 

Relevant articles and documents

Preparation method of 2-fluoro-5-[(4-oxo-3H-2,3-diazanaphthalene)methyl]benzoic acid

The invention discloses a preparation method of 2-fluoro-5-[(4-oxo-3H-2,3-diazanaphthalene)methyl]benzoic acid, wherein the method comprises the steps: S1, preparation of (3-oxo-1,3-dihydroisobenzofuran-1-yl)dimethyl phosphate; S2, preparation of 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-yl methylene)bromobenzene; S3, preparation of 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-yl methylene)methyl benzoate; and S4, preparation of 2-fluoro-5-[(4-oxo-3H-2,3-diazanaphthalene)methyl]benzoic acid. The preparation method has the advantages of simple operation, mild reaction conditions, easy purification of the intermediates, increase of the total yield compared with the prior art, and reduction of the industrial cost.

Novel synthesis method of olaparib bulk drug

The invention introduces a novel synthesis method of an antitumor drug, namely olaparib. According to the invention, a dimer impurity is effectively removed by an acid-base pouring method in virtue of the different chemical properties that the dimer impurity cannot form salt and a previous intermediate of olaparib can form salt, and the HPLC purity of the obtained finished product can reach 99.9%. According to a route in the invention, the yield of the olaparib finished product is effectively improved, the total yield of six steps reaches 42.4%, and the route has important significance on industrial production of olaparib.

Novel preparation method of olaparib

The invention relates to a novel preparation method of olaparib. The novel preparation method comprises the following preparation steps: 1, reacting 4-methylphthalazin-1(2H)-one with NBS and AIBN in a reaction solvent; 2, carrying out a coupling reaction on 4-(bromomethyl)phthalazin-1(2H)-one and (4-fluoro-3-(methoxycarbonyl)phenyl)boric acid in a reaction solvent under the action of a catalyst and an alkali; 3, hydrolyzing methyl 2-fluoro-5-((4-oxo-3, 4-phthalazin-1-yl)methyl)benzoate in a reaction solvent under the action of alkali; and 4, reacting the 2-fluoro-5-((4-oxo-3, 4-dihydrophthalazin-1-yl)methyl)benzoic acid with cyclopropyl (piperazine-1-yl)methyl ketone hydrochloride in a reaction solvent under the action of a condensing agent and alkali to obtain a crude olaparib product, and recrystallizing to obtain the high-purity olaparib. According to the process of the novel preparation method, the total yield can be effectively improved, impurities caused by cyano hydrolysis can be obviously reduced, and the purity and quality of the prepared olaparib are improved.

Design, synthesis and activity evaluation of new phthalazinone parp inhibitors

Poly(ADP-ribose)polymerase (PARP) is a significant therapeutic target for the treatment of numerous human diseases. Olaparib has been approved as a PARP inhibitor. In this paper, a series of new compounds were designed and synthesized with Olaparib as the lead compound. In order to evaluate the inhibitory activities against PARP1 of the synthesized compounds, in vitro PARP1 inhibition assay and intracellular PARylation assay were conducted. The results showed that the inhibitory activities of the derivatives were related to the type of substituent and the length of alkyl chain connecting the aromatic ring. 3-(4,5-Dimethyl- 2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT)-based assay also proved that these compounds demonstrating strong inhibition to PARP1 also have high anti-proliferative activities against BRCA2-deficient cell line (Capan-1). Analysis of the entire results suggest that compound 23 with desirable inhibitory efficiency may hold promise for further in vivo exploration of PARP inhibition.

Preparation method of olaparib key intermediate

The invention provides a preparation method of an olaparib key intermediates 4-(3-bromo-4-fluorobenzyl)phthalazin-1(2H)-one (a compound shown as a formula IV) and 2-fluoro-5-[(4-oxo-3,4-dihydro-1-phthalazinyl)methyl]benzoic acid (a compound shown as a formula V). Specifically, (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonic acid dimethyl ester is used as a raw material to be subjected to a Wittig-Horner reaction with 3-bromo-4-fluorobenzaldehyde to obtain a formula III, the formula III and hydrazine hydrate are subjected to cyclization to obtain a formula IV, and the formula IV is subjected toa reaction with n-butyllithium and carbon dioxide to obtain an olaparib intermediate V. The method is economical and environment-friendly, and the yield is greatly improved.

Olaparib intermediate and preparation method of olaparib

The invention discloses an olaparib intermediate and a preparation method of olaparib, and the method comprises the following steps: suspending a compound II in a solvent, adding alkali, heating to areaction temperature, and reacting to obtain a compound III; mixing the compound III with a solvent, adding hydrazine hydrate and alkali, heating to a reaction temperature, and keeping the temperatureto react to a reaction end point to obtain a compound IV; and mixing and stirring the compound IV, a catalyst and a solvent, heating to a reaction temperature, adding thionyl chloride, carrying out aheat preservation reaction to the reaction end point, cooling, sequentially adding an alkali and cyclopropanoyl piperazine, carrying out a heat preservation reaction until the reaction is complete, and reacting to obtain olaparib according to a reaction formula shown in the specification. The method provided by the invention has the advantages of cheap and easily available raw materials, simple operation, mild reaction conditions, high purity and high yield of the obtained target product, no highly toxic substances, simple post-treatment and less three wastes, and meets the green and environment-friendly production requirements.

Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1)

Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.

ANTI-CANCER NUCLEAR HORMONE RECEPTOR-TARGETING COMPOUNDS

The disclosure relates to anti-cancer compounds derived from nuclear steroid receptor binders, to products containing the same, as well as to methods of their use and preparation.

Synthetic method of olaparib

The invention discloses a synthesis method of olaparib, which comprises the following steps: carrying out reaction on dimethyl phosphite and o-carboxybenzaldehyde to generate (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphate; enabling (3-oxo-1, 3-dihydroisobenzofuran-1-yl) dimethyl phosphate to react with 2-fluoro-5-formylbenzoic acid to generate 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoic acid; reacting 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoic acid with oxalyl chloride to generate 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoyl chloride; reacting 2-fluoro-5-[(4-oxo-3, 4-dihydro naphthyridine-1-yl) methyl] benzoyl chloride to react with piperazine cyclopropyl ketone, so as to generate olaparib. The invention provides a new olaparib synthesis route, the raw materials are easy to obtain, the operation post-treatment is simple, the reaction conditions of each step are mild, and the total yield reaches 93%.

Simple preparation method of 4-substituted methyl-1-(2H)-phthalazinone

The invention provides a simple preparation method of 4-substituted methyl-1-(2H)-phthalazinone (I). According to the method, condensation is carried out on a two G substituted benzene (II) and a compound represented by a formula III in the presence of a solvent A and an alkali, a compound represented by a formula IV is obtained through hydrolysis, and then, condensation is carried out on the compound represented by the formula IV or an esterification product of the compound represented by the formula IV and hydrazine hydrate to prepare 4-(pyridin-4-yl)-methyl-1-(2H)-phthalazinone (IA) or 4-(4-fluoro-3-carboxyphenyl)methyl-1-(2H)-phthalazinone (IB) which can be used for preparing vatalanib and olaparib. The preparation method is simple and convenient in technological process, is high in reaction reproducibility, is easy to operate, and is good in product stability and high in purity.