[ CAS No. 763111-47-3 ] {[proInfo.proName]}

Name: 763111-47-3|4-(4-Fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one|97%
Brand: Ambeed
SKU: A510198
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Quality Control of [ 763111-47-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Citations

Bioorthogonal CRISPR/Cas9-Drug Conjugate: A Combinatorial Nanomedicine Platform

Beha, Marcel Janis ; Kim, Joo-Chan ; Im, San Hae , et al. Adv. Sci.,2023,10(27):2302253. DOI: 10.1002/advs.202302253 PubMed ID: 37485817

Abstract: Bioconjugation of proteins can substantially expand the opportunities in biopharmaceutical development, however, applications are limited for the gene editing machinery despite its tremendous therapeutic potential. Here, a self-delivered nanomedicine platform based on bioorthogonal CRISPR/Cas9 conjugates, which can be armed with a chemotherapeutic drug for combinatorial therapy is introduced. It is demonstrated that multi-functionalized Cas9 with a drug and polymer can form self-condensed nanocomplexes, and induce significant gene editing upon delivery while avoiding the use of a conventional carrier formulation. It is shown that the nanomedicine platform can be applied for combinatorial therapy by incorporating the anti-cancer drug olaparib and targeting the RAD52 gene, leading to significant anti-tumor effects in BRCA-mutant cancer. The current development provides a versatile nanomedicine platform for combination treatment of human diseases such as cancer.

Keywords: bioorthogonal ; cancer therapy ; chemotherapeutic drugs ; combinatorial delivery ; CRISPR ; Cas9 ; gene editing ; nanomedicines ; unnatural amino acids

Purchased from AmBeed: 763111-47-3

Product Details of [ 763111-47-3 ]

CAS No. :	763111-47-3	MDL No. :
Formula :	C₂₀H₁₉FN₄O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MFFUYEOGICAKCK-UHFFFAOYSA-N
M.W :	366.39	Pubchem ID :	11726399
Synonyms :		Chemical Name :	4-(4-Fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one

Calculated chemistry of [ 763111-47-3 ] Expand+

Physicochemical Properties

Num. heavy atoms :	27
Num. arom. heavy atoms :	16
Fraction Csp3 :	0.25
Num. rotatable bonds :	4
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	107.8
TPSA :	78.09 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.46 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.57
Log Po/w (XLOGP3) :	1.52
Log Po/w (WLOGP) :	1.36
Log Po/w (MLOGP) :	2.7
Log Po/w (SILICOS-IT) :	3.84
Consensus Log Po/w :	2.4

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.24
Solubility :	0.209 mg/ml ; 0.000571 mol/l
Class :	Soluble
Log S (Ali) :	-2.77
Solubility :	0.625 mg/ml ; 0.0017 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-6.83
Solubility :	0.0000541 mg/ml ; 0.000000148 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.86

Safety of [ 763111-47-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 763111-47-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 763111-47-3 ]
Downstream synthetic route of [ 763111-47-3 ]

[ 763111-47-3 ] Synthesis Path-Upstream 1~10

1
[ 763114-04-1 ]
[ 763111-47-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With hydrogenchloride In ethanol; water at 20℃; for 3 h;	at room temperature 2A (13.6 g, 29 mmol) is dissolved into 30 ml in ethanol, adding 6 N hydrochloric acid solution of 60 ml and stirring 3 h. The reaction liquid concentrated to 50 ml, for 4 N of NH₄ OH adjusting pH to 10. In order to DCM (3 × 50 ml) extraction mixed solution, organic phase to 50 ml water washing after adding anhydrous sodium sulfate drying and a half hours. Filtering to remove the sodium sulfate, the filtrate overnight after standing separate products, filtered to obtain the title compound (white solid, 9.9 g, yield 92percent).
81%	With trifluoroacetic acid In dichloromethane at 10 - 30℃; for 3 h; Green chemistry; Large scale	General procedure: The compound of formula C (1.21 kg, 2.59 ml) was dissolved in dichloromethane (2.4 L) and stirred well. Trifluoroacetic acid (3.25 kg, 28.5 mo 1, the molar ratio of compound of formula C to trifluoroacetic acid Ratio of 1:11),Rose to 10 ° C ~ 30 ° C the reaction was stirred for 3h. Evaporation of methylene chloride and trifluoroacetic acid to the residue first added water (1.21L), filtered, the filtrate was taken, and then added n-hexane (1.21L) was extracted four times, the aqueous phase was taken, with ammonia to adjust PH to 8 ~ 10, stirring 1.5h, filtered, take the filter cake, dried to give Olaparib intermediate (Β) 0.78kg,Yield 82percent, purity 96.4percent). Only the extraction solvent in step (1) of Example 1 was replaced with butyl acetate, and the others were kept constant to afford the Olaparib intermediate (Β) (0.77 kg, yield 81percent, purity 99.8percent, impurity A' in an amount of 0.2percent).
58.5%	Stage #1: With hydrogenchloride; water In industrial methylated spirits at 15 - 25℃; for 0.5 h; Stage #2: With ammonia; water In dichloromethane	(b) 4-[4-Fluoro-3-(piperazine-1-carbonyl)-benzyl]-2H-phthalazin-1-one (B) To a stirred solution of industrial methylated spirits (IMS) (2200 ml) and concentrated HCI (4400 ml) was added compound C (2780.2 g) in portions at room temperature under nitrogen, the foaming was controlled by the addition rate. The solution was then stirred at 15 to 25⁰C for 30 minutes and sampled for completion (HPLC).Upon completion the solution was evaporated to remove any IMS and the aqueous extracted with CH₂CI₂ (2 x 3500 ml) before the pH was adjusted to >8 using concentrated ammonia. The resultant slurry was then diluted with water (10000 ml) and extracted with CH₂CI₂ (4 x 3500 ml), washed with water (2 x 2000 ml), dried over MgSO₄ (25Og) and evaporated. The crude product was then slurried in CH₂CI₂ (3500 ml) and added to MTBE (5000 ml). The resultant suspension was filtered and dried at 50⁰C overnight yielding 611.O g (58.5percent yield) of material with a purity of 94.12percent

Reference： [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 20, p. 6581 - 6591
[2] Patent: CN106946792, 2017, A, . Location in patent: Paragraph 0074; 0081-0084
[3] Patent: CN106928149, 2017, A, . Location in patent: Paragraph 0006; 0015; 0028; 0036; 0044-0046
[4] Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8683 - 8693
[5] Patent: WO2008/47082, 2008, A2, . Location in patent: Page/Page column 22

2
[ 763114-26-7 ]
[ 142-64-3 ]
[ 763111-47-3 ]

Yield	Reaction Conditions	Operation in experiment
60.1%	With piperazine; sulfuric acid In acetonitrile at 78 - 80℃;	A solution of 1-5 - [(3,4-dihydro-4-oxo-l-phthalazinyl) methyl] -2- fluorobenzoic acid (60.0 g, 0.20 mol)Suspended in 600 mL of acetonitrile,Anhydrous piperazine (43.0 g, 0.50 mol)Piperazine dihydrochloride (79.0 g, 0.50 mol)Concentrated sulfuric acid (2.78 ml, 0.04 mol)Heated to 78-80 ° C under reflux for 7 to 8 hours,Drop to room temperature,Concentrated under reduced pressure acetonitrile, water was added 1000ml, stirred for 30min; concentrated ammonia was added dropwise to a PH value of 7-8, stirred 2h, suction filtration,44.1 g of 1- [5 - [(3,4-dihydro-4-oxo-1-phthalazinyl) methyl] -2-fluorobenzoyl] piperazine was obtained in a yield of 60.1percent.1- [5 - [(3,4-dihydro-4-oxo-1-phthalazin-yl) methyl] -2-fluorobenzoyl] piperazine 1H NMR, (400 MHz) see Figure 1.

Reference： [1] Patent: CN106554316, 2017, A, . Location in patent: Paragraph 0027; 0028; 0029; 0030; 0031; 0032; 0033

3
[ 110-85-0 ]
[ 763111-47-3 ]

Reference： [1] Patent: WO2017/191562, 2017, A1, . Location in patent: Paragraph 18; 19

4
[ 763114-26-7 ]
[ 763111-47-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8683 - 8693
[2] Patent: CN106946792, 2017, A,
[3] Patent: WO2017/191562, 2017, A1,

5
[ 119-67-5 ]
[ 763111-47-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8683 - 8693
[2] Patent: WO2017/191562, 2017, A1,

6
[ 763114-25-6 ]
[ 763111-47-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8683 - 8693
[2] Patent: WO2017/191562, 2017, A1,

7
[ 61260-15-9 ]
[ 763111-47-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8683 - 8693

8
[ 218301-22-5 ]
[ 763111-47-3 ]

Reference： [1] Patent: WO2017/191562, 2017, A1,

9
[ 763114-26-7 ]
[ 763111-47-3 ]
[ 26289-39-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2292 - 2302

10
[ 70-18-8 ]
[ 1431328-64-1 ]
[ 763111-47-3 ]
[ 26289-39-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2292 - 2302

[ 763111-47-3 ] Synthesis Path-Downstream 1~108

Yield	Reaction Conditions	Operation in experiment
76%		b. Synthesis of 4-[4-Fluoro-3-(piperazine-1-carbonyl)benzyl]-2H-phthalazin-1-one (2) The synthesis was carried out according to the method described in (a) above using 2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid (B) to yield 4-[4-fluoro-3-(piperazine-1-carbonyl)benzyl]-2H-phthalazin-1-one (2) as a white crystalline solid (4.8 g, 76%); m/z [M+1]+ 367 (97% purity), deltaH 2.6-3.8 (8H, m), 4.4 (2H, s), 7.2-7.5 (3H, m), 7.7-8.0 (3H, m), 8.2-8.3 (1H, m), 12.6 (1H, s).

2
[ 763111-47-3 ]
[ 79-03-8 ]
4-[[4-fluoro-3-(4-propanoylpiperazine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With triethylamine; In dichloromethane; at 1 - 20℃; for 1h;	4-(4-Fluoro-3-(piperazin-1-yl-carbonyl)-benzyl)pyridazine-1(2H)one (5) (0.78 g, 2.13 mmol) was added to a 25 ml three-necked flask.Dichloromethane (6.5 ml) and triethylamine (0.52 g, 5.14 mmol) were added, and the mixture was stirred and cooled to 1-10 C.Propionyl chloride (236 mg, 2.56 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred for 1 h.TLC showed the reaction was complete; the reaction mixture was directly concentrated to dryness, and the residue was mixed with water and then stirred for 1 hour and then filtered.Obtained as an off-white solid.The yield was 50%.
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;	The appropriate acid chloride (0.24 mmol) was added to a solution of 4- [4-Fluoro-3- (piperazine-1-carbonyl) benzyl]-2H-phthalazin-l-one (2) (0.2 mmol) in dichloromethane (2 ml). Hunigs base (0.4 mmol) was then added and the reaction was stirred at room temperature for 16 hours.

Reference： [1]Patent: CN108383798,2018,A .Location in patent: Paragraph 0090; 0091; 0092; 0093
[2]Patent: WO2004/80976,2004,A1 .Location in patent: Page 73-74

3
[ 763111-47-3 ]
4-carbonylethylpyridine [ No CAS ]
C₂₆H₂₄FN₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 16h;	An appriopriate aldehyde (0.2 mmol) and 4- [4-FLUORO-3- (PIPERAZINE-L- carbonyl) BENZYL]-2H-PHTHALAZIN-1-ONE (2) (0.24 mmol) were dissolved in dichloromethane (2 ml). Sodium triacetoxyborohydride (0.28 mmol) and glacial acetic acid (6.0 mmol) were then added and stirred at room temperature for 16 hours. The reaction mixtures were then purified by preparative HPLC.

Reference： [1]Patent: WO2004/80976,2004,A1 .Location in patent: Page 87-88

4
[ 763111-47-3 ]
[ 4023-34-1 ]
olaparib [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; In dichloromethane; at 10 - 20℃; for 0.25h;Product distribution / selectivity;	(c) 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (A)To a stirred suspension of compound B (1290 g) in CH2CI2 (15480 ml) under nitrogen was added a pre-mixed solution of triethylamine (470 ml) and cyclopropane carbonyl chloride (306 ml) in CH2CI2 (1290 ml) dropwise with the temperature kept below 2O0C. The solution was then stirred at 10-15C for 15 minutes and sampled for completion. The reaction mixture was found to contain only 1.18% of starting material B and so the reaction was deemed complete and the batch was then worked-up.The reaction mixture was washed with water (7595 ml), 5% citric acid solution (7595 ml), 5% sodium carbonate solution (7595 ml) and water (7595 ml). The organic layer was then dried over magnesium sulfate (50Og).The CH2CI2 containing product layer was then isolated, filtered through Celite and charged to a 25I vessel. CH2CI2 (8445 ml) was then distilled out at atmospheric pressure and ethanol (10000 ml) added. Distillation was then continued with every 4000 ml of distillate that was removed being replaced with ethanol (4000 ml) until the head temperature reached 73.70C. The reaction volume was then reduced (to 7730 ml) by which time the head temperature had reached 78.90C and the solution was allowed to cool to 8C overnight. The solid was then filtered off, washed with ethanol (1290 ml) and dried at 700C overnight.Yield = 1377.3 g (90%). HPLC purity (99.34% [area %]). Contained 4.93% ethanol and 0.45% CH2CI2 by GC.
87%	With triethylamine; In dichloromethane; at 15 - 30℃; for 3h;Green chemistry;	Orapanib intermediate (B) (0.77 kg, 2.10 mol) obtained in step (1) and triethylamine (0.88 kg, 6.32 mol) were added to methylene chloride (5.0 L) and stirred to control temperature 15 CAdd dropwise cyclopropyl carbonyl chloride (0.35L, 3.83mo 1), the dropwise addition, the reaction was stirred at 20-30 C 3h.Add appropriate amount of water, stirring 2h, suction filtration to obtain olaparib (0.79kg, a yield of 87%, a purity of 99.7%).
67.5%	With triethylamine; In dichloromethane; at 0 - 20℃;	To the reaction kettle was added 6 L of dichloromethane,4- (4-fluoro-3- (piperazine-1-carbonyl) benzyl) phthalazin-1 (2-hydro) -one (400 g, 1.09 mol)Cooled to 0 C,Triethylamine (153 g, 210 mL, 1.51 mol) was slowly added,Cyclopropanecarbonyl chloride (130 g, 1.24 mol)Stir at room temperature,After TLC detection reaction,Add 3L of water,2L dichloromethane,Dispensing,The organic phase was removed by distillation under reduced pressure,To obtain 320 g of a yellow solid;HPLC purity 96.13%Yield 67.5%.

Reference： [1]Patent: WO2008/47082,2008,A2 .Location in patent: Page/Page column 23
[2]Patent: CN106928149,2017,A .Location in patent: Paragraph 0008; 0047-0049
[3]Patent: CN105985294,2016,A .Location in patent: Paragraph 0051; 0052; 0053

5
[ 763114-04-1 ]
[ 763111-47-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With hydrogenchloride; In ethanol; water; at 20℃; for 3h;	at room temperature 2A (13.6 g, 29 mmol) is dissolved into 30 ml in ethanol, adding 6 N hydrochloric acid solution of 60 ml and stirring 3 h. The reaction liquid concentrated to 50 ml, for 4 N of NH4 OH adjusting pH to 10. In order to DCM (3 × 50 ml) extraction mixed solution, organic phase to 50 ml water washing after adding anhydrous sodium sulfate drying and a half hours. Filtering to remove the sodium sulfate, the filtrate overnight after standing separate products, filtered to obtain the title compound (white solid, 9.9 g, yield 92%).
81%	With trifluoroacetic acid; In dichloromethane; at 10 - 30℃; for 3h;Green chemistry; Large scale;	General procedure: The compound of formula C (1.21 kg, 2.59 ml) was dissolved in dichloromethane (2.4 L) and stirred well. Trifluoroacetic acid (3.25 kg, 28.5 mo 1, the molar ratio of compound of formula C to trifluoroacetic acid Ratio of 1:11),Rose to 10 C ~ 30 C the reaction was stirred for 3h. Evaporation of methylene chloride and trifluoroacetic acid to the residue first added water (1.21L), filtered, the filtrate was taken, and then added n-hexane (1.21L) was extracted four times, the aqueous phase was taken, with ammonia to adjust PH to 8 ~ 10, stirring 1.5h, filtered, take the filter cake, dried to give Olaparib intermediate (Beta) 0.78kg,Yield 82%, purity 96.4%). Only the extraction solvent in step (1) of Example 1 was replaced with butyl acetate, and the others were kept constant to afford the Olaparib intermediate (Beta) (0.77 kg, yield 81%, purity 99.8%, impurity A' in an amount of 0.2%).
58.5%		(b) 4-[4-Fluoro-3-(piperazine-1-carbonyl)-benzyl]-2H-phthalazin-1-one (B) To a stirred solution of industrial methylated spirits (IMS) (2200 ml) and concentrated HCI (4400 ml) was added compound C (2780.2 g) in portions at room temperature under nitrogen, the foaming was controlled by the addition rate. The solution was then stirred at 15 to 250C for 30 minutes and sampled for completion (HPLC).Upon completion the solution was evaporated to remove any IMS and the aqueous extracted with CH2CI2 (2 x 3500 ml) before the pH was adjusted to >8 using concentrated ammonia. The resultant slurry was then diluted with water (10000 ml) and extracted with CH2CI2 (4 x 3500 ml), washed with water (2 x 2000 ml), dried over MgSO4 (25Og) and evaporated. The crude product was then slurried in CH2CI2 (3500 ml) and added to MTBE (5000 ml). The resultant suspension was filtered and dried at 500C overnight yielding 611.O g (58.5% yield) of material with a purity of 94.12%

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6581 - 6591
[2]Patent: CN106946792,2017,A .Location in patent: Paragraph 0074; 0081-0084
[3]Patent: CN106928149,2017,A .Location in patent: Paragraph 0006; 0015; 0028; 0036; 0044-0046
[4]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693
[5]Patent: WO2008/47082,2008,A2 .Location in patent: Page/Page column 22
[6]Chemical Communications,2019,vol. 55,p. 369 - 372
[7]Chinese Chemical Letters,2020,vol. 31,p. 404 - 408
[8]Inorganic Chemistry,2019,vol. 58,p. 16279 - 16291

6
[ 109-65-9 ]
[ 763111-47-3 ]
[ 848136-30-1 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6581 - 6591

7
[ 15159-40-7 ]
[ 763111-47-3 ]
4-[[4-fluoro-3-[4-(morpholine-4-carbonyl)piperazine-1-carbonyl]phenyl]methyl]-2H-phthalazin-1-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6581 - 6591

8
[ 763111-47-3 ]
[ 106-94-5 ]
[ 848136-35-6 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6581 - 6591

9
[ 763111-47-3 ]
[ 7051-34-5 ]
[ 848136-36-7 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6581 - 6591

10
[ 763111-47-3 ]
[ 594-44-5 ]
[ 1070772-13-2 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 6581 - 6591

11
[ 605680-62-4 ]
[ 763111-47-3 ]
[ 1356556-88-1 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere;	Step 3: Preparation of 4-(4-fluoro-3-(4-(2-methyl-2-((5-(trifluoromethyl) pyridin-2- yl)oxy) propanoyl)piperazine-l-carbonyl) benzyl) phthalazin-l(2H)-one.To a solution of 2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanoic acid (0.204 g, 0.81 mmol) in dry DMF (6 mL) was added TBTU (0.289 g, 0.90 mmol) at room temperature under atmosphere of nitrogen. To this 4-(4-fluoro-3-(piperazine-l- carbonyl)benzyl)phthalazin-l(2H)-one (0.3 g, 0.81 mmol) and DIPEA (0.303 mL, 1.74 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The progress of reaction was checked by TLC by using mobile phase 5 % methanol in chloroform. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2S04 and solvents were evaporated on a rotatory evaporator under reduced pressure to crude solid which was purified by the flash column chromatography using eluent chloroform : methanol (98.3 : 1.7) to afford 4-(4-fluoro-3-(4-(2-methyl-2-((5-(trifluoromethyl) pyridin-2-yl)oxy) propanoyl)piperazine-l-carbonyl) benzyl) phthalazin-l(2H)-one as white solid (0.230 g, 47 %).

Reference： [1]Patent: WO2012/14221,2012,A1 .Location in patent: Page/Page column 15; 17

12
[ 763111-47-3 ]
TCO-NHS ester [ No CAS ]
Olaparib-TCO [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 10593 - 10597
Angew. Chem.,2013,vol. 125,p. 10787 - 10791

13
[ 763111-47-3 ]
[ 1286255-40-0 ]

Reference： [1]Patent: US2013/309170,2013,A1

14
[ 763111-47-3 ]
4-[[4-fluoro-3-(4-(N-(2-aminoethyl)-5-oxo-pentanamide)piperazine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one [ No CAS ]

Reference： [1]Patent: US2013/309170,2013,A1
[2]Chemical Communications,2014,vol. 50,p. 4504 - 4507

15
[ 763111-47-3 ]
[ 1286255-39-7 ]

Reference： [1]Patent: US2013/309170,2013,A1

16
[ 763111-47-3 ]
4-[[4-fluoro-3-(4-(2-tosyl-acetyl)piperazine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one [ No CAS ]

Reference： [1]Patent: US2013/309170,2013,A1

17
[ 763111-47-3 ]
4-(4-fluoro-3-(4-(2-18F-fluoroacetyl)piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one [ No CAS ]

Reference： [1]Patent: US2013/309170,2013,A1

18
[ 763111-47-3 ]
C₃₅H₃₉FN₆O₅ [ No CAS ]

Reference： [1]Patent: US2013/309170,2013,A1

19
[ 763111-47-3 ]
C₃₆H₄₃FN₆O₆ [ No CAS ]

Reference： [1]Patent: US2013/309170,2013,A1

20
[ 763111-47-3 ]
[ 1191-25-9 ]
4-[[4-fluoro-3-(4-(6-hydroxyhexanoyl)piperazine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h;	4-[[4-Fluoro-3-(piperazine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one (11) (250 mg, 0.68 mmol), HBTU (337 mg, 0.89 mmol) and triethylamine (285 muL, 1.18 mmol) were added to a solution of 6-hydroxyhexanoic acid (180 mg, 1.36 mmol) in DMF (3.0 mL) and the reaction mixture was stirred at room temperature for 60 minutes, before dichloromethane (8 mL) and water (8 mL) were added, the organic phase separated and washed with water (3*8 mL). The organic phase was dried over MgSO4, volatiles removed in vacuo and the resulting crude material purified via HPLC, yielding the title compound as a clear solid (55.6 mg, 0.12 mmol, 17%).

Reference： [1]Patent: US2013/309170,2013,A1 .Location in patent: Paragraph 0164

21
[ 763111-47-3 ]
[ 1191-25-9 ]
4-[[4-fluoro-3-(4-(6-tosylhexanoyl)piperazine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one [ No CAS ]

Reference： [1]Patent: US2013/309170,2013,A1

22
[ 763111-47-3 ]
[ 79-14-1 ]
4-[[4-fluoro-3-(4-(2-hydroxyacetyl)piperazine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 0.666667h;	4-[[4-Fluoro-3-(piperazine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one (11) (86 mg, 0.24 mmol), HBTU (116 mg, 0.30 mmol) and triethylamine (164 muL, 1.18 mmol) were added to a solution of 2-hydroxyacetic acid (36 mg, 0.48 mmol) in DMF (1.5 mL) and the reaction mixture was stirred at room temperature for 40 minutes, before dichloromethane (4 mL) and water (4 mL) were added, the organic phase separated and washed with NaOH (0.2 M, 34 mL) and water (34 mL). The organic phase was dried over MgSO4, volatiles were removed in vacuo and the resulting crude material was purified via HPLC, yielding the title compound as a clear solid (24.3 mg, 0.06 mumol, 50%).

Reference： [1]Patent: US2013/309170,2013,A1 .Location in patent: Paragraph 0166

23
[ 108-55-4 ]
[ 763111-47-3 ]
C₂₅H₂₅FN₄O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 0.5h;	Glutaric anhydride (0.50 g, 4.37 mmol) and N,Ndiisopropylethylamine (2.28 mL, 13.11 mmol) were added to a solution of 4-[[4-Fluoro-3-(piperazine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one (2) (1.60 g, 4.37 mmol) in dichloromethane (50 mL) and the reaction mixture and stirred for 30 minutes. Water (50 mL) was then added and the reaction mixture stirred for another 30 minutes. The reaction mixture was acidified with HCl to pH 2, the organic phase separated and the aqueous phase extracted with dichloromethane (3*30 mL). The combined organic phases were dried over MgSO4 and volatiles removed in vacuo. The resulting crude material was purified using silica chromatography (0%-30% MeOH/DCM), yielding the pure product as an off-white solid (1.52 g, 3.16 mmol, 72%).

Reference： [1]Patent: US2013/309170,2013,A1 .Location in patent: Paragraph 0131; 0132
[2]Chemical Communications,2014,vol. 50,p. 4504 - 4507

24
[ 763111-47-3 ]
[ 1384575-86-3 ]
C₄₇H₄₀BF₃N₈O₈ [ No CAS ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 11050 - 11052

25
[ 763111-47-3 ]
[ 1384575-81-8 ]
C₄₀H₃₆BF₃N₆O₄ [ No CAS ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 11050 - 11052

26
[ 763111-47-3 ]
[ 1418275-26-9 ]
[ 1595287-53-8 ]

Reference： [1]Chemical Communications,2014,vol. 50,p. 4504 - 4507

27
[ 763111-47-3 ]
[ 1418275-27-0 ]
[ 1595287-52-7 ]

Reference： [1]Chemical Communications,2014,vol. 50,p. 4504 - 4507

28
[ 763111-47-3 ]
[ 1595287-54-9 ]

Reference： [1]Chemical Communications,2014,vol. 50,p. 4504 - 4507

29
[ 763111-47-3 ]
[ 1595287-55-0 ]

Reference： [1]Chemical Communications,2014,vol. 50,p. 4504 - 4507

30
[ 70-18-8 ]
[ 1431328-64-1 ]
[ 763111-47-3 ]
[ 26289-39-4 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2292 - 2302

31
[ 763114-26-7 ]
C₁₀H₁₂N₆O₆ [ No CAS ]
[ 763111-47-3 ]
[ 26289-39-4 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 2292 - 2302

32
[ 763111-47-3 ]
BODIPY 650/665 succinimidyl ester [ No CAS ]
[ 1622237-60-8 ]

Reference： [1]Molecular Cancer Therapeutics,2014,vol. 13,p. 986 - 995

33
C₁₆H₉FO₄ [ No CAS ]
[ 763111-47-3 ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693

34
[ 763111-47-3 ]
[ 1759-53-1 ]
olaparib [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.8%	In N,N-dimethyl acetamide; at 30 - 50℃; for 6h;	At 50 C,To the reaction kettle by adding N, N-dimethylacetamide 2000ml,Was added with stirring 4- (4-fluoro-3- (piperazine-1-carbonyl) benzyl) -1-naphthyridine (2-hydro) - one (40g, 0.109mol),HATU (48 g, 0.126 mol),Cyclopropanecarboxylic acid (12 g, 0.139 mol)Finally, N, N-diisopropylethylamine (0.218 mol, 28.17 g, 38 ml) was added,30 C for 6 hours,Add 800ml of water,Slowly precipitate solid,Filter,washing,dry,To give 44 g of a white solid,That is,HPLC purity 99.87%Yield 92.8%.

Reference： [1]Patent: CN105985294,2016,A .Location in patent: Paragraph 0035; 0036; 0037; 0038; 0039; 0040; 0041-0049
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 4103 - 4114

35
[ 763111-47-3 ]
[ 619-58-9 ]
4-[3’-[4’’-(4’’’-iodobenzoyl)piperazine-1’’-carbonyl]-4’-fluorobenzyl]-2H-phthalazin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃;	EXAMPLE A.3. Compound c-2 (127l): 4-(4-fluoro-3-(4-(4-iodobenzoyl)piperazine-1-carbonyl)benzyl)-phthalazin-1(2H)-one. A solution of 4-(4-fluoro-3-(piperazine-l-carbonyl)benzyl)phthalazin-l(2H)-one (10 mg, 0.0275 mmol), H BTU (16 mg, 0.0413 mmol) triethylamine (40 mu, 0.3 mmol) and 4-iodobenzoic acid (6 mg, 0.0245 mmol) in DM F (500 mu) was stirred overnight at room temperature. The crude product was purified by preparative HPLC and dried under vacuum, yielding a white solid (8.8 mg, 61% yield). XH NM R (CDCI3) delta = 10.48 (s, 1H), 8.40-8.39 (m, 1H), 7.74-7.66 (m, 5H), 7.27-7.26 (d, 2H), 7.09-7.07 (d, 2H), 4.22 (s, 2H), 3.73-3.14 (m, 8H). LC-ESI-MS (+) m/z = 597.1 [M+H+]+. H RMS-ESI [M-H+]" m/z calculated for [C27H22FIN4O3]" 595.0642, found 595.0640.

Reference： [1]Patent: WO2016/33293,2016,A1 .Location in patent: Paragraph 0149
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693
[3]Chemistry - A European Journal,2018,vol. 24,p. 937 - 943
[4]Organic Letters,2018,vol. 20,p. 1752 - 1755

36
[ 763111-47-3 ]
[ 618-51-9 ]
4-[3′-[4″-(3‴-iodobenzoyl)piperazine-1″-carbonyl]-4′-fluorobenzyl]-2H-phthalazin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20h;	EXAM PLE A.2. Compound c-1 (127l): 4-(4-fluoro-3-(4-(3-iodobenzoyl)piperazine-l-carbonyl)benzyl)- phthalazin-l(2H)-one. (0301) [0148] To a solution of 4-(4-fluoro-3-(piperazine-l-carbonyl)benzyl)phthalazin-l(2H)-one (10 mg, 0.0275 mmol), triethylamine (40 mu, 0.3 mmol) a nd H BTU (16 mg, 0.0413 mmol) in dimethyl formamide (DM F, 500 mu) was added to 3-iodobenzoic acid (6 mg, 0.0275 mmol). The mixtu re was stirred at room temperature for 20 h. The crude product was then purified by preparative HPLC and dried under vacuum, yielding a white solid (6.9 mg, 48% yield). 1H NM R (CDCIs) delta = 10.00 (s, 1H), 8.40-8.38 (m, 1H), 7.71-7.69 (m, 4H), 7.64-7.63 (m, 1H), 7.30-7.26 (m, 3H), 7.09 (m, 1H), 7.04-6.87 (m, 1H), 4.21 (s, 2H), 3.71-3.29 (m, 8H). LC-ESI-MS (+) m/z = 597.1 [M+H+]+. H RMS-ESI [M-H+]" m/z calculated for [C27H22FIN4O3]- 595.0642, found 595.0660.

Reference： [1]Patent: WO2016/33293,2016,A1 .Location in patent: Paragraph 0148
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693

37
[ 763111-47-3 ]
[ 82998-57-0 ]
4-[3′-[4″-(3‴-iodo-4‴-methylbenzoyl)piperazine-1″-carbonyl]-4′-fluorobenzyl]-2H-phthalazin-1-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693

38
[ 763111-47-3 ]
[ 68507-19-7 ]
4-[3′-[4″-(3‴-iodo-4‴-methoxybenzoyl)piperazine-1″-carbonyl]-4′-fluorobenzyl]-2H-phthalazin-1-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693

39
[ 763111-47-3 ]
[ 1878-69-9 ]
4-[3′-[4″-[2‴-(3-iodophenyl)acetyl]piperazine-1″-carbonyl]-4′-fluorobenzyl]-2H-phthalazin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%		EXAMPLE A.4. Compound c-3 (127l): 4-(4-fluoro-3-(4-(2-(3-iodophenyl)acetyl)piperazine-l-carbonyl)- benzyl)phthalazin-l(2H)-one. A solution of <strong>[1878-69-9]3-iodophenyl acetic acid</strong> (6.5 mg, 0.048 mmol), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) (10.5 mg, 0.055 mmol), N-hydroxy succinimide (NHS) and 600 mu DM F was stirred for 30 min at room temperature. Then, 4-(4-fluoro-3-(piperazine-l-carbonyl)benzyl)- phthalazin-l(2H)-one (10 mg, 0.0275 mmol) was added to the solution and the mixture was stirred at room temperature overnight. The reaction was washed with 500 mu of H20 and extracted with 500 mu dichloromethane (DCM). The resulting organic solution was purified on silica gel, using a gradient elution from neat DCM to DCM/hexane 5:1 to obtain the desired product as a white solid (3 mg, 20% yield). 1H NMR (CDCI3) delta = 9,82 (s, 1H), 8.40-8.38 (m, 1H), 7.71-7.69 (m, 2H), 7.55-7.53 (m, 1H), 7.51-7.50 (m, 2H), 7.25-7.24 (m, 2H), 7.09-6.90 (m, 3H), 4.20 (s, 2H), 3.64-3.31 (m, 8H), 2.84 (s, 2H). LC-ESI-MS (+) m/z = 633.1 [M+Na+]+. HRMS-ESI [M+H+]+ m/z calculated for [C28H24FIN403]+ 611.0955, found 611.0948.

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693
[2]Patent: WO2016/33293,2016,A1 .Location in patent: Paragraph 0150

40
[ 763111-47-3 ]
[ 1878-94-0 ]
4-[3′-[4″-[2‴-(4-iodophenoxy)acetyl]piperazine-1″-carbonyl]-4′-fluorobenzyl]-2H-phthalazin-1-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693

41
[ 763111-47-3 ]
[ 98-61-3 ]
4-[3′-[4″-[4‴-iodobenzenesulfonyl]piperazine-1″-carbonyl]-4′-fluorobenzyl]-2H-phthalazin-1-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693

42
[ 763111-47-3 ]
[ 586-76-5 ]
4-[3′-[4″-(4‴-bromobenzoyl)piperazine-1″-carbonyl]-4′-fluorobenzyl]-2H-phthalazin-1-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693

43
[ 61260-15-9 ]
[ 763111-47-3 ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693
[2]Inorganic Chemistry,2019,vol. 58,p. 16279 - 16291

44
[ 119-67-5 ]
[ 763111-47-3 ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693
[2]Patent: WO2017/191562,2017,A1

45
[ 763114-25-6 ]
[ 763111-47-3 ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693
[2]Patent: WO2017/191562,2017,A1

46
[ 763114-26-7 ]
[ 763111-47-3 ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693
[2]Patent: CN106946792,2017,A
[3]Patent: WO2017/191562,2017,A1
[4]Chinese Chemical Letters,2020,vol. 31,p. 404 - 408
[5]Inorganic Chemistry,2019,vol. 58,p. 16279 - 16291

47
[ 763111-47-3 ]
[ 68034-75-3 ]
4-(4-fluoro-3-(4-(3-(3-iodophenyl)propanoyl)piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃;	EXAMPLE A.6. Compound c-5 (127l): 4-(4-fluoro-3-(4-(3-(3-iodophenyl)propanoyl)piperazine-1-carbonyl)benzyl)phthalazin-l(2H)-one. A solution of 4-(4-fluoro-3-(piperazine-l-carbonyl)benzyl)phthalazin-l(2H)-one (10 mg, 0.0275 mmol), HBTU (16 mg, 0.0413 mmol) triethylamine (40 mu, 0.3 mmol) and 3-(3-iodophenyl)propionic acid (7.6 mg, 0.0275 mmol) in 400 mu of acetonitrile was stirred overnight at room temperature. The crude product was then purified by preparative HPLC and the isolated product dried at vacuum to obtain a white solid (5.1 mg, 38%). 1H NMR (CDCI3) delta = 10.33 (s, 1H), 8.41-8.39 (d, 1H), 7.71-7.63 (m, 3H), 7.51-7.45 (m, 2H), 7.27-7.25 (m, 2H), 7.12-6.92 (m, 3H), 4.22 (s, 2H), 3.65-3.12 (m, 8H), 2.88- 2.83 (m, 2H), 2.59-2.48 (m, 2H). LC-ESI-MS (+) m/z = 647.1 [M+Na+]+. HRMS-ESI [M+H+]+ m/z calculated for [C29H26FIN403 625.1112, found 625.1111.

Reference： [1]Patent: WO2016/33293,2016,A1 .Location in patent: Paragraph 0152

48
[ 763111-47-3 ]
[ 456-22-4 ]
4-[3′-[4″-(4‴-fluorobenzoyl)piperazine-1″-carbonyl]-4′-fluorobenzyl]-2H-phthalazin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; for 0.0833333h;	To 20 mg (54.5 muiotaetaomicronIota) of 4-(4-fluoro-3-(piperazine-l-carbonyl)benzyl)phthalazin-l(2H)-one dissolved in 1 mL of MeCN, 9.2 mg (65.5 muiotaetaomicronIota) 4-fluorobenzoic acid was added followed by 24.8 mg (65.5 muiotaetaomicronIota) of HBTU and 18 mu (131 muiotaetaomicronIota) of Et3N. The reaction mixture was stirred for 5 minutes and purified by H PLC to yield the compound as an orange solid (11.5 mg, 23.5 muiotaetaomicronIota, 43%). 1H-NM R (500 M Hz, CDC delta = 10.74 (s, 1H), 8.51-8.49 (d, 1H), 7.83-7.76 (m, 2H), 7.82 (s, 1H), 7.45-7.44 (m, 2H), 7.38-7.36 (m, 2H), 7.14-7.08 (m, 3H), 4.33 (s, 2H), 3.75-3.39 (m, 8H). MS-ES m/z [M + Na]+ = 511.2. H RMS-ESi m/z calculated for [C27 H22 N4 03 F2 Naf 511.1558, found 511.1569 [M + Na]+.

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 4103 - 4114
[2]Patent: WO2016/33293,2016,A1 .Location in patent: Paragraph 0147

49
[ 763111-47-3 ]
[ 1101867-66-6 ]
C₂₇H₂₂F⁽¹²³⁾IN₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In acetonitrile; at 32℃; for 3h;	To a solution of compound 1.3.2a dispersed in 200 mu of acetonitrile was added HBTU (500 mug, 131 mmol) and 1.4.2 (500 mug , 137 mmol). The reaction was kept at 32 C in a shaker for 3 hours at 700 rpm. The final product was isolated by HPLC employing a C18 Atlantis T3 column (4.6 x 250 mm, 5 muiotaeta) with the following eluents: water as solvent A and acetonitrile as solvent B, going from 5 % of B to 100% of B in 15 minutes and then 100% of B from 15.01 minutes to 25 minutes. The fractions containing the radioligand were dried in vacuum, obtaining a white solid as product.

Reference： [1]Patent: WO2016/33293,2016,A1 .Location in patent: Paragraph 0161

50
[ 763111-47-3 ]
<SUP>131</SUP>I-2,5-dioxopyrrolidin-1-yl 4-iodobenzoate [ No CAS ]
C₂₇H₂₂F⁽¹³¹⁾IN₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In acetonitrile; at 32℃; for 3h;	The dried radiola beled 131l-N HS-benzoate precursor was dissolved in 200 mu of acetonitrile and an excess of H BTU (1 mg, 2.6 nmol) and 4-(4-fluoro-3-(piperazine-l-carbonyl)benzyl)phthalazin- l(2H)-one (1 mg, 2.7 nmol) was added and allowed to react for 3 h at 32 C. The final product was purified by H PLC, using water and acetonitrile as solvents with a gradient elution from 5% to 100% of solvent B over 15 min and then 100% of B from 15 to 25 min. The retention time of C-2d was 13.1 min and its identity was esta blished by co-elution with the reference cold compound. The radiochemical yield was 72 ± 8 % (n=12) and the radiochemical purity > 95%. The collected fraction containing C-2d was concentrated to dryness under reduced pressure

Reference： [1]Patent: WO2016/33293,2016,A1 .Location in patent: Paragraph 0168

51
[ 763111-47-3 ]
[ 99-77-4 ]
4-[3′-[4″-(4‴-fluorobenzoyl)piperazine-1″-carbonyl]-4′-fluorobenzyl]-2H-phthalazin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A QMA cartridge containing cyclotron -produced [18F] fluoride ion was euted with a solution containing 9 mg Kryptofix [2.2,2] (4,7.13, 16,21,24- hexaoxa- l,10-diaza bicycloi8.8.8]hexacosane), 0.08 m L 0.15 M K2C03 and 1.92 m L MeCN into a 5 m L reaction vial. Water was removed azeotropically at 120 C. 500 mug of ethyl 4-nitrobenzoate dissolved in 100 mu of DMSO was then added to the reaction vial and heated to 150 C for 15 minutes. The reaction via l was then allowed to cool as 50 mu of 1M NaOH was added. The reaction mixture was stirred for 1 min and 50 mu of 1M HCI was added to quench. Then, 2 mg of 4-(4-fiuoro-3-(piperazine-l-carbonyl)benzyi)phthaiazin- l(2H)-one dissolved in 100 mu of DMSO was added , followed by 10 mg of HBT U dissolved in 100 mu of DMSO and 20 mu. of Et3N. The reaction mixture was stirred for 1 minute. 400 mu MeCN followed by 700 mu H20 was then added and the solution was injected onto a C6-Pheny analytical HPLC column and eluted under isocratic conditions (Method B: 30% acetonitrile in water for 35min). Compound C- 2f eluted at (tR = 25.5 min), which was well resolved from the nitro analogue (4-(4-fluoro-3-(4-(4- nitrobenzoyl)piperazine-l-carbonyl)benzyl)phthalazin-l(2H)-one; tR = 30.1 min). For intravenous administration, the product-containing fraction was passed through a CIS light-SepPak cartridge preconditioned with EtOH (10 m L) and water (10 mL). The cartridge was washed with water (3 m L) and C-2f was eluted using EtOH (400 mu). The solution was then diluted with 0.9% saline to 10% EtOH. The radiochemical purity of the final formulation was confirmed using analytical HPLC.

Reference： [1]Patent: WO2016/33293,2016,A1 .Location in patent: Paragraph 0171

52
[ 763111-47-3 ]
[ 1798-06-7 ]
4-(4-fluoro-3-(4-(2-(4-iodophenyl)acetyl)piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		EXAMPLE A.5. A solution of 4-iodophenyl acetic acid (6.5 mg, 0.048 mmol), EDC (10.5 mg, 0.055 mmol), NHS and 600 mu DMF was stirred for 30 min at room temperature. After this time, the 4-(4-fluoro-3- (piperazine-l-carbonyl)benzyl)phthalazin-l(2H)-one (10 mg, 0.0275 mmol) was added to the solution and the mixture was stirred at room temperature overnight. H20 (500 mu) was added, the mixture extracted with DCM (2 x 500 mu), and the combined extracts dried under vacuum. The crude mixture was purified by silica column chromatography (100% DCM), and the product obtained as a white solid (8.8 mg, 61%). 1H NMR (CDCI3) delta = 9.82 (s, 1H), 8.40-8.38 (m, 1H), 7.83-7.81 (d, 1H), 7.77- 7.75 (d, 1H), 7.70-7.69 (m, 2H), 7.63-7.56 (m, 3H), 7.00-6.89 (m, 3H), 4.20 (s, 2H), 3.63-3.11 (m, 8H), 2.84 (s, 2H). LC-ESI-MS (+) m/z = 632.9 [M+Na+]+. HRMS-ESI [M+H+]+ m/z calculated for [C28H24FIN403]+ 611.0955, found 611.0971.

Reference： [1]Patent: WO2016/33293,2016,A1 .Location in patent: Paragraph 0151

53
[ 763111-47-3 ]
[ 1643-29-4 ]
4-(4-fluoro-3-(4-(3-(4-iodophenyl)propanoyl)piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃;	4-(4-Fluoro-3-(piperazine-l-carbonyl)benzyl)phthalazin-l(2H)-one (10 mg, 0.0275 mmol) was mixed with HBTU (16 mg, 0.0413 mmol) triethylamine (40 mu, 0.3 mmol) and 4-iodo 3 phenyl propionic acid (7.6 mg, 0.0275 mmol) in 400 mu of acetonitrile, and the solution was stirred overnight at room temperature. The crude product was then purified by preparative HPLC and the isolated product dried at vacuum to obtain a white solid (7.5 mg, 45%). H NM R (CDCI3) delta = 9.71 (s, 1H), 8.40-8.38 (d, 1H), 7.70-7.69 (m, 2H), 7.64-7.63 (m, 1H), 7.55-7.52 (m, 2H), 7.27-7.25 (m, 2H), 7.00-6.97 (m, 1H), 6.91-6.87 (m, 2H), 4.20 (s, 2H), 3.64-3.11 (m, 8H), 2.87-2.85 (m, 2H), 2.63-2.47 (m, 2H). LC-ESI-MS (+) m/z = 647.1 [M+Na+]+. HRMS-ESI [M+Na+]+ m/z calculated for [C29H26FI N403Na]+ 647.0931, found 647.0941.

Reference： [1]Patent: WO2016/33293,2016,A1 .Location in patent: Paragraph 0153

54
[ 763111-47-3 ]
[ 88738-86-7 ]
(E)-3-(4-((4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-yl)methyl)phenyl)-N-hydroxyacrylicamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 4100 - 4109

55
[ 763111-47-3 ]
[ 88738-86-7 ]
methyl (E)-3-(4-((4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-yl)methyl)phenyl)prop-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	In acetonitrile; at 20℃;Inert atmosphere; Alkaline conditions;	General procedure: Compound 4 (400 mg, 1.09 mmol, 1 eq) was dissolved in acetonitrile(10 ml), and then 5a-c (1 eq) and DIEA (2 eq) were added.The mixture was stirred at room temperature for 2 h, and then theprecipitate was filtered, washed with water, acetonitrile and ethylether, and dried to give products 6a-c.4.1.2.1. Methyl (E)-3-(4-((4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl) benzoyl)piperazin-1-yl)methyl)phenyl)acrylate(6a). White powder; yield 64%; mp 160-162 C; 1H NMR(400 MHz, DMSO-d6) d 12.60 (s, 1H), 8.26 (dd, J = 7.7, 1.5 Hz, 1H),7.96 (d, J = 7.7 Hz, 1H), 7.91-7.85 (m, 1H), 7.85-7.78 (m, 1H),7.72-7.60 (m, 3H), 7.46-7.40 (m, 1H), 7.36 (d, J = 8.0 Hz, 2H),7.31 (dd, J = 6.5, 2.3 Hz, 1H), 7.26-7.17 (m, 1H), 6.63 (d,J = 16.1 Hz, 1H), 4.32 (s, 2H), 3.73 (s, 3H), 3.67-3.56 (m, 2H), 3.51(s, 2H), 3.23-3.10 (m, 2H), 2.45-2.34 (m, 2H), 2.32-2.18 (m, 2H).19F NMR (376 MHz, DMSO-d6) d-119.83. 13C NMR (101 MHz,DMSO-d6) d 166.6, 163.63, 159.2, 156.2 (d, J = 245.4 Hz), 144.7,144.2, 140.4, 134.7 (d, J = 3.2 Hz), 133.3, 132.8, 131.4,, 129.2,129.0, 128.6 (d, J = 3.9 Hz), 128.2, 127.8, 126.0, 125.3, 123.7 (d,J = 18.3 Hz), 117.4, 115.9, 115.7, 61.2, 52.6, 52.0, 51.3, 46.5, 41.3,36.3. HRMS (ESI) m/z calculated for [M+H]+ 541.2251, found541.2227.
64%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2h;Inert atmosphere;	example 2 B (1 eq) dissolved in anhydrous second grade nitrile, then adding to bromine methyl cinnamic acid methyl ester (1 eq) and DIEA (2 eq), under the protection of nitrogen reaction at room temperature 2 hours, the reaction produces a large amount of white precipitate. Slightly static delayed filtering and washing the filter cake to a small amount of acetonitrile, the title compound obtained (white solid, yield 64%).

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 4100 - 4109
[2]Patent: CN106946792,2017,A .Location in patent: Paragraph 0074; 0085-0088

56
[ 763111-47-3 ]
[ 7398-42-7 ]
methyl 2-(4-((4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl) benzoyl)piperazin-1-yl)methyl)phenyl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	In acetonitrile; at 20℃;Inert atmosphere; Alkaline conditions;	General procedure: Compound 4 (400 mg, 1.09 mmol, 1 eq) was dissolved in acetonitrile(10 ml), and then 5a?c (1 eq) and DIEA (2 eq) were added.The mixture was stirred at room temperature for 2 h, and then theprecipitate was filtered, washed with water, acetonitrile and ethylether, and dried to give products 6a?c.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 4100 - 4109

57
[ 763111-47-3 ]
[ 7398-42-7 ]
2-(4-((4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl) piperazin-1-yl)methyl)phenyl)-N-hydroxyacetamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 4100 - 4109

58
[ 763111-47-3 ]
[ 2417-72-3 ]
methyl 4-((4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl) benzoyl)piperazin-1-yl)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	In acetonitrile; at 20℃;Inert atmosphere; Alkaline conditions;	General procedure: Compound 4 (400 mg, 1.09 mmol, 1 eq) was dissolved in acetonitrile(10 ml), and then 5a-c (1 eq) and DIEA (2 eq) were added.The mixture was stirred at room temperature for 2 h, and then theprecipitate was filtered, washed with water, acetonitrile and ethylether, and dried to give products 6a-c.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 4100 - 4109

59
[ 763111-47-3 ]
[ 2417-72-3 ]
4-((4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl) piperazin-1-yl)methyl)-N-hydroxybenzamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 4100 - 4109

60
[ 763111-47-3 ]
[ 170908-81-3 ]
C₃₆H₄₅FN₈O₉ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3472 - 3476

61
[ 763111-47-3 ]
[ 62-23-7 ]
4-[3’-[4’’-(4’’’-nitrobenzoyl)piperazine-1’’-carbonyl]-4’-fluorobenzyl]-2Hphthalazin-1-one [ No CAS ]

Reference： [1]Chemical Communications,2017,vol. 53,p. 11008 - 11011
[2]Journal of Medicinal Chemistry,2018,vol. 61,p. 4103 - 4114

62
[ 763111-47-3 ]
4-[3’-[4’’-(4’’’-aminobenzoyl)piperazine-1’’-carbonyl]-4’-fluorobenzyl]-2Hphthalazin-1-one [ No CAS ]

Reference： [1]Chemical Communications,2017,vol. 53,p. 11008 - 11011

63
[ 763111-47-3 ]
4-[3’-[4’’-(4’’’-iodobenzoyl)piperazine-1’’-carbonyl]-4’-fluorobenzyl]-2H-phthalazin-1-one [ No CAS ]

Reference： [1]Chemical Communications,2017,vol. 53,p. 11008 - 11011

64
[ 110-85-0 ]
4-[3-(1H-benzotriazol-1-ylcarbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one [ No CAS ]
[ 763111-47-3 ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol; at 20℃;	To a solution of piperazine (VIII) (200 g) in isopropanol (500 mL) was added lot wise 4-[3-(1 - -benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl] phthalazin-1 (2/-/)-one (VII) (150 g) at room temperature and the resulting reaction mixture was stirred. After completion of the reaction, the solvent was distilled out and the residue was treated acetic acid (or any other organic or inorganic acid) and water to form salt, which was washed with organic solvent and then treated with base to produce solid material. The obtained solid material was filtered and washed with water (100 mL), then suck dried by using vacuum line to afford wet 4-[4-fluoro-3-(piperazin-1 - ylcarbonyl) benzyl] phthalazin-1 (2H)-one (IX). (Yield: 80%, HPLC purity: 99%)

Reference： [1]Patent: WO2017/191562,2017,A1 .Location in patent: Paragraph 18; 19

65
[ 763111-47-3 ]
[ 354996-72-8 ]
olaparib [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	In acetonitrile;	4-[4-fluoro-3-(piperazin-1 -ylcarbonyl) benzyl] phthalazin-1 (2H)-one (IX) (40.0 g, 0.1 1 mol) and 1 H-benzotriazol-1 -yl(cyclopropyl)methanone (X) (26 g, 0.14 mol) were stirred in acetonitrile (320 mL) and the progress of reaction was monitored by HPLC. After completion of reaction, the resulted precipitate was filtered and washed with acetonitrile (40.0 mL) then dried to afford Olaparib (I) as a white to off- white solid. The PXRD pattern of Olaparib thus obtained matches with Form-A as illustrated in figure-3. (Yield: 90%, HPLC purity: 99.99%)

Reference： [1]Patent: WO2017/191562,2017,A1 .Location in patent: Page/Page column 19; 20

66
[ 218301-22-5 ]
[ 763111-47-3 ]

Reference： [1]Patent: WO2017/191562,2017,A1
[2]Inorganic Chemistry,2019,vol. 58,p. 16279 - 16291

67
[ 763114-26-7 ]
[ 142-64-3 ]
[ 763111-47-3 ]

Yield	Reaction Conditions	Operation in experiment
60.1%	With piperazine; sulfuric acid; In acetonitrile; at 78 - 80℃;	A solution of 1-5 - [(3,4-dihydro-4-oxo-l-phthalazinyl) methyl] -2- fluorobenzoic acid (60.0 g, 0.20 mol)Suspended in 600 mL of acetonitrile,Anhydrous piperazine (43.0 g, 0.50 mol)Piperazine dihydrochloride (79.0 g, 0.50 mol)Concentrated sulfuric acid (2.78 ml, 0.04 mol)Heated to 78-80 C under reflux for 7 to 8 hours,Drop to room temperature,Concentrated under reduced pressure acetonitrile, water was added 1000ml, stirred for 30min; concentrated ammonia was added dropwise to a PH value of 7-8, stirred 2h, suction filtration,44.1 g of 1- [5 - [(3,4-dihydro-4-oxo-1-phthalazinyl) methyl] -2-fluorobenzoyl] piperazine was obtained in a yield of 60.1%.1- [5 - [(3,4-dihydro-4-oxo-1-phthalazin-yl) methyl] -2-fluorobenzoyl] piperazine 1H NMR, (400 MHz) see Figure 1.

Reference： [1]Patent: CN106554316,2017,A .Location in patent: Paragraph 0027; 0028; 0029; 0030; 0031; 0032; 0033

68
[ 763111-47-3 ]
[ 14047-29-1 ]
4-{3’-[4’’-(benzoyl-4’’’-boronic acid)piperazine-1’’-carbonyl]-4’-fluorobenzyl}-2H-phthalazin-1-one [ No CAS ]

Reference： [1]Chemistry - A European Journal,2018,vol. 24,p. 937 - 943
[2]Organic Letters,2019,vol. 21,p. 2488 - 2492

69
[ 763111-47-3 ]
[ 3353-68-2 ]
sodium (4-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-yl)-4-oxobutyl)dimethylsilanolate [ No CAS ]

Reference： [1]Patent: WO2017/214491,2017,A1

70
[ 763111-47-3 ]
[ 3353-68-2 ]
4,4'-(((4,4'-(4,4'-(1,1,3,3-tetramethyldisiloxane-1,3-diyl)bis(butanoyl))bis(piperazine-4,1-diyl-1-carbonyl))bis(4-fluoro-3,1-phenylene))bis(methylene))bis(phthalazin-1(2H)-one) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1h;	4,4'-(((4,4'-(4,4'-(1,1,3,3-tetramethyldisiloxane-1,3-diyl)bis(butanoyl))bis(piperazine-4,1- diyl-1-carbonyl))bis(4-fluoro-3,1-phenylene))bis(methylene))bis(phthalazin-1(2H)-one): (0224) [3]: (0225) [00132] A solution of 4,4'-(1,1,3,3-tetramethyldisiloxane-1,3-diyl)dibutyric acid (250 mg, 0.816 mmol) in dichlromethane(5 mL) was charged EDCI-HCl (396 mg, 2.042 mmol) and <strong>[763111-47-3]4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one</strong> (598 mg, 1.633 mmol) at room temperature and stirred for 1hh. After completion of the reaction (monitored by TLC), water (5 mL) was added in the reaction mixture and organic layer was separated to obtain crude compound. The crude compound was purified by CombiFlash chromatography using 1-10% MeOH in DCM to obtain 286mg, 38% yield of the title compound as an off white solid.1H NMR (400 MHz, DMSO-d6): delta 12.57 (s, 2H), 8.55 (d, J = 10.27 Hz, 2H), 8.23 (d, J = 7.83 Hz, 1H), 7.92-7.96 (m, 1H), 7.84-7.89 (m, 2H), 7.78-7.83 (m, 2H), 7.38-7.44 (m, 2H), 7.33 (br. s, 2H), 7.21 (t, J = 8.80 Hz, 2H), 4.44 (s, 2H), 4.30 (s, 2H), 3.49-3.62 (m, 14H), 3.33-3.38 (m, 4H), 3.08-3.18 (m, 2H), 2.25-2.38 (m, 4H), 1.44-1.55 (m, 2H), 0.46-0.54 (m, 2H), 0.14 (br. s, 3H), 0.13 (br. s, 3H), 0.04 (br. s, 3H), 0.03 (br. s, 3H); MS (ES+): m/z = 493.20 [Monomer M - 18]+; LCMS: tR = 0.792 min.

Reference： [1]Patent: WO2017/214491,2017,A1 .Location in patent: Paragraph 00132

71
[ 763111-47-3 ]
[ 180516-87-4 ]
4-(4-fluoro-3-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37 mg	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℃;Inert atmosphere;	A reaction mixture of amine precursor (51 mg, 0.139 mmol), 4-carboxylphenylboronic acid pinacol ester (38 mg, 0.153 mmol), HATU (60 mg, 0.158 mmol) and DIPEA (50 muL) in DMF (1 mL) was stirred at room temperature overnight. Water (10 mL) was added, and precipitate was filtered and rinsed with water, and then dissolved in ethyl acetate. After drying by magnesium sulfate, the solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford final product (37 mg) as white solid. M.P.: 288-291 C; 1H NMR (400MHz, CDCl3) delta 10.66 (s, 1H), 8.47 (s, 1H), 7.85-7.72 (m, 5H), 7.38-7.33 (m, 4H), 7.04 (m, 1H), 4.29 (s, 2H), 3.73 (m, 4H), 3.37 (m, 4H), 1.35 (s, 9H), 1.27 (s, 3H). 13C NMR (100MHz, CDCl3) delta 160.4, 145.5, 142.2, 135.0, 134.4, 133.7, 131.6, 129.5, 129.2, 128.3, 127.2, 126.1, 125.0, 121.5, 84.1, 37.7, 29.7, 24.8; HRMS m/z: calcd for C33H34BFN4O5+H, 597.2679; found 579.2661.

Reference： [1]Organic Letters,2018,vol. 20,p. 1752 - 1755
[2]Tetrahedron Letters,2018,vol. 59,p. 1963 - 1967

72
[ 763111-47-3 ]
4-[3′-[4″-(4‴-chloromethylbenzoyl)piperazine-1″-carbonyl]-4′-fluorobenzyl]-2-tert-butyloxycarbonylphthalazin-1-one [ No CAS ]