Name: 763113-22-0|4-(3-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one|98%
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1
[ 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

2
[ 763114-26-7 ]
[ 59878-57-8 ]
olaparib [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%		To the reaction flask was added compound 6 (prepared in Example 3-2, 256.5g,0.86mol), CDI (139.45g, 0.86mol), 1.6LTHF, after stirring for 0.5h Compound 7 (138.8g,0.90mol) at room temperature The reaction 3h, after completion of the reaction, water was added to quench the reaction, of THF was distilled off under reduced pressure, theresidue was dissolved in ethyl acetate was added, the organic phase was separated,washed with water three times, the organic phase was dried over anhydrous Na 2SO 4Dried,filtered and concentrated to give Ola Trapani (356.3g, 0.82mol), yield 95%, HPLC purity 99.8%.
91.5%	With pivaloyl chloride; triethylamine; In ethanol; dichloromethane; at 20℃; for 4h;	(4) The product of the previous step (0.3 g, 1 mmol) was weighed, dissolved in 5 mL of dichloromethane, and trimethylacetyl chloride (121 yL, 1 mmol) and triethylamine (208 mL, 1.5 mmol) were stirred at room temperature. The reaction was clarified until the solution was clarified. 1 - (cyclopropylcarbonyl)-pyridazine (0.3 g, 2 mmol) was dissolved in 5 mL of ethanol, added dropwise to the above clear solution, reacted at room temperature for 4 h, and extracted with dichloromethane (15 mL). The organic phase was washed with water, and the organic layer was dried over anhydrous sodium sulfate, and then evaporated to dryness to afford ololani (0.4 g, 0.9 mmol), yield 91.5%, purity 99.8%.
81.9%	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℃;	In a 500 mL reaction flask, 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (Formula II, 15.0 g, 50.3 mmol) and DMF ( 100ml),After the addition, the system was stirred for 0.5 h to dissolve the system, and then 1-cyclopropyl-formylpiperazine (8.55 g, 55.4 mmol) and HBTU (21.0 g, 55.4 mmol) were added.DIPEA (8.5 g, 65.8 mmol) was then added dropwise to the system.The dropping process controls the reaction temperature not to be higher than 50 C, and the system is kept at 30 ± 5 C overnight after the addition.After the reaction was completed, the mixture was filtered, and the filter cake was washed with 1 L of purified water, and then the filter cake was transferred to a 1 L reaction flask.Purified water (500 mL) was added, kept at 30 ± 5 C, and stirred for 1 h.After suction filtration, the filter cake was washed with purified water (100 mL) and blast dried for about 24 h.The crude product (19.7 g) was obtained, and the crude material was recrystallized from DMF (75 ml)17.9g, 81.9%).

34%		To a solution of 2-Fluoro-5-((4-oxo3,4-dihydrophthalazin-l-yl)methyl)benzoic acid (50 mg, 0.168 mmol) in DMA (1 mL) was added DIPEA (56 L, 0.336 mmol) and HBTU (64 mg, 0.170 mmol). The reaction mixture was stirred for 1 hour before addition of cyclopropylpiperazine-l-ylmethanone (0.170 mmol) was carried out. The reaction mixture was stirred at room temperature for 48 h. The reaction mixture was then extracted with DCM (3 x 5 mL) and washed with water (3 x 20 mL). The organic layers were collected, dried with MgS04 and the excess solvent removed in vacuo. Purification via reverse phase HLPC was carried out affording 4-(3-(4 (cyclopropanecarbonyl) piperazine- l-carbonyl)-4- fluorobenzy phthalazin- 1 (2//)-one (olaparib) (25 mg, 34%) as a white solid. *H NMR (400 MHz, CDCh) d = 10.65 (s, 1H), 8.44 - 8.37 (m, 1H), 7.75 - 7.61 (m, 3H), 7.34 - 7.22 (m, 2H), 6.97 (t, J = 8.9 Hz, 1H), 4.22 (s, 2H), 3.90 - 3.09 (m, 8H), 1.79 - 1.52 (s, 3H), 0.99 - 0.88 (m, 2H), 0.81 - 0.63 (s, 2H); {}1^ NMR (376 MHz, CDCb) d = - 117.6; Mp: 69 - 7lC. Data is in accordance with known literature (Menear, K.A., et al., ibid.).
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 3 - 20℃; for 3.5h;Product distribution / selectivity;	Example 2: Alternative synthesis of Compound A using i-fcyclopropylcarbonyl) piperazineMethods (also for Examples 3 & 4)NMR1H NMR spectra were recorded using Bruker DPX 400 spectrometer at 400 MHz. Chemical shifts were reported in parts per million (ppm) on the delta scale relative to tetramethylsilane internal standard. Unless stated otherwise all samples were dissolved in DMSOd6.Mass SpectraMass spectra were recorded on an Agilent XCT ion trap mass spectrometer using tandem mass spectrometry (MS/MS) for structural confirmation. The instrument was operated in a positive ion elctrospray mode.(a) 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (Compound A)2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D)(15.23g, 51.07 mmol) was suspended with stirring under nitrogen in acetonitrile (96 ml). Diisopropylethylamine (19.6 ml, 112.3 mmol) was added followed by 1-cyclopropylcarbonylpiperazine (l)(9.45g, 61.28 mmol) and acetonitrile (1 ml). The reaction mixture was cooled to 18C. O-Benzotriazol-1-yl- tetramethyluronium hexafluorophosphate (25.18g, 66.39 mmol) was added over 30 minutes and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was cooled to 3C and maintained at this temperature for 1 hour, before being filtered. The filter cake was washed with cold (3C) acetonitrile (20 ml) before being dried in vacuo at up to 4O0C to give the title compound as a pale yellow solid (20.21 g).Mass Spectrum: MH+ 4351H NMR (400MHz. DMSO-d6) delta: 0.70 (m, 4H), 1.88 (br s, 1 H), 3.20 (br s, 2H), 3.56 (m, 6H), 4.31 (s, 2H), 7.17 (t, 1 H), 7.34 (dd, 1 H), 7.41 (m, 1 H), 7.77 (dt, 1 H), 7.83 (dt, 1 H), 7.92 (d, 1 H), 8.25 (dd, 1 H), 12.53 (s, 1 H).
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 3 - 20℃; for 3.5h;	(a) 4-[3-(4-Cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one (Compound A)2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D)(15.23g, 51.07 mmol) was suspended with stirring under nitrogen in acetonitrile (96 ml). Diisopropylethylamine (19.6 ml, 112.3 mmol) was added followed by 1-cyclopropylcarbonylpiperazine (l)(9.45g, 61.28 mmol) and acetonitrile (1ml). The reaction mixture was cooled to 18C. O-Benzotriazol-1-yl- tetramethyluronium hexafluorophosphate (25.18g, 66.39 mmol) was added over 30 minutes and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was cooled to 3C and maintained at this temperature for 1 hour, before being filtered. The filter cake was washed with cold (3C) acetonitrile (20 ml) before being dried in vacuo at up to 400C to give the title compound as a pale yellow solid (20.21 g).Mass Spectrum: MH+ 4351H NMR (400MHz, DMSO-d6) delta: 0.70 (m, 4H), 1.88 (br s, 1H), 3.20 (br s, 2H), 3.56 (m, 6H), 4.31 (s, 2H), 7.17 (t, 1H), 7.34 (dd, 1 H), 7.41 (m, 1H), 7.77 (dt, 1H), 7.83 (dt, 1H), 7.92 (d, 1H), 8.25 (dd, 1 H)1 12.53 (S1 1H).

Reference： [1]Patent: CN105820126,2016,A .Location in patent: Paragraph 0057; 0058
[2]Patent: CN108129397,2018,A .Location in patent: Paragraph 0044; 0049; 0077
[3]Patent: CN110078671,2019,A .Location in patent: Paragraph 0030-0031
[4]Patent: WO2019/186135,2019,A1 .Location in patent: Page/Page column 62-63; 65
[5]Journal of Medicinal Chemistry,2008,vol. 51,p. 6581 - 6591
[6]Patent: WO2008/47082,2008,A2 .Location in patent: Page/Page column 24
[7]Patent: WO2009/50469,2009,A1 .Location in patent: Page/Page column 12; 13

3
[ 763114-26-7 ]
[ 1021298-67-8 ]
[ 763113-22-0 ]

Yield	Reaction Conditions	Operation in experiment
94.5%	Stage #1: 2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoic acid With N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-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;	5 A method for preparing olaparib, comprising the steps of: adjusting a temperature to 25 °C, 2-fluoro-5-[(4-oxo-3,4-dihydronaphthyridin-1-yl)- yl] benzoic acid in tetrahydrofuran was added, in batches 1-ethyl - (3-dimethylaminopropyl) carbodiimide hydrochloride, stirred for 1h resulting solution was incubated as A; 1-cyclopropyl Formylpiperazine hydrochloride, N,N-diisopropylethylamine was added to tetrahydrofuran, stirred at room temperature for 30 min to obtain solution B; solution A was added dropwise to solution B, the temperaturewasadjustedto 25 °C, the reaction was kept for 5 h, and the temperature was lowered. To the temperature of 20 °C, and then quenched with water, control the temperature below 25 °C, concentrate to remove tetrahydrofuran, add the recrystallization solvent ethyl acetate and activated carbon, warmed to reflux, filtered hot, the filtrate was recrystallized, followed by water,Washed with ethyl acetate and dried to obtain olaparib;
92.2%	With triethylamine In dichloromethane at -10 - 20℃; for 4h;	2 Example 2: A preparation method of olaparib includes the following steps: Combine 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (10g, 33.53mmol) and 1-cyclopropylformylpiperazine hydrochloride (5.17g, 33.53mmol) was added to 120g of dichloromethane, triethylamine (10.18g, 100.6mmol) was added, Cool down, add ethyl chloroformate (4.37g, 40.23mmol) dropwise at -10°C for about 1h, keep the reaction for 2h, then remove the freezing, warm to room temperature and react for 1h. After the completion of the reaction, 100g of water was added dropwise to the reaction solution for liquid separation, the organic phase was washed twice with 100ml×2 water, and concentrated under reduced pressure to obtain a solid. The solid was added to absolute ethanol, stirred and refluxed to dissolve, added 0.5g of activated carbon, stirred for 20 minutes, and then added water dropwise. After the solid was precipitated, the temperature was kept and stirred for 1 hour, cooled to 0°C, filtered, and dried to obtain 13.4g of olaparib, with a yield. 92.2%, purity 99.73% (HPLC area normalization method).
91.5%	With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 10℃; for 10h;	1-2 Example 1 Add 1000ml DMF to the reaction flask, cool down to 0-10°C , 2-fluoro-5-((3,4-dihydro-4-oxo-1-phthalazinyl)methyl)benzoic acid(100.0 g),1-Cyclopropylformylpiperazine hydrochloride (73.5g), EDCI (115g) and HOBt (52.1g), N,N-diisopropylethylamine (77.8g), in the range of 0 to 10°C reaction for 10 hours, Slowly add purified water to the system, continue stirring for 2 hours, filter, and rinse the filter cake with purified water;Drying in vacuum at 65±5° C. obtained 44.5 g of new crystal form Q1 of olaparib with a yield of 91.5%.

85.2%	With O-(6-chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 5h;	1.4 Step 4:The 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (213.0g, 0.71mol),cyclopropyl(piperazin-1-yl)methanone Hydrochloride(135.8g, 0.71mol),DIEA (109.9g, 0.85mol) was placed in acetonitrile (1000ml), HCTU (351.6g, 0.85mol) was added at room temperature,The reaction was incubated for 5 hours, and the reaction was monitored by TLC. After the reaction was completed, the acetonitrile was removed under reduced pressure, and 500 ml of water was added to quench the reaction.Then ethyl acetate (800 ml) was added, and the organic layer was dried, filtered, and concentrated to obtain an off-white solid.The off-white solid obtained above was placed in DMF (750ml), the temperature was raised to 80°C, and the solid was dissolved.After hot filtration, the temperature was lowered to room temperature, and a solid was precipitated. The mixture was stirred at room temperature for 2 hours, filtered, and the filter cake was dried to obtain 262.3 g of a white solid with a yield of 85.2%.
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In acetonitrile at 5 - 20℃;	3.b (b) Compound A; 2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D)(0.95g, 3.19 mmol) was suspended with stirring under nitrogen in acetonitrile (4 ml). 2-(1 H-benzotriazol-1-yl)-1 ,1 ,3,3- tetramethyluronium hexafluorophosphate (HBTU) (1.45g, 3.83 mmol) was added followed by 1-cyclopropylcarbonylpiperazine HCI salt (l')(0.73g, 3.83 mmol). Diisopropylethylamine (1.39ml, 7.98 mmol) was added over 3 minutes and the reaction mixture was stirred for overnight at room temperature. The reaction mixture was cooled to 50C and maintained at this temperature for 1 hour, before being filtered. The filter cake was washed with cold (30C) acetonitrile (2 ml) before being dried in vacuo at up to 400C to give the title compound as a pale yellow solid (0.93g).
18.92 g	With triethylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 8h;	3.4 Synthesis of Olaparib A solution of 14.91 g of 2-fluoro-5 - ((4-oxo-3,4-dihydrophthalazin-1-yl) methyl) benzoic acid was added 11.44 g of 1-cyclopropyl formylpiperazine hydrochloride, G DCC, 150 ml of methylene chloride. After stirring for about 15 minutes, 12.66 g of triethylamine was added. After 8 h at 20 ° C, the reaction solution was added to 100 ml of methylene chloride and dissolved with saturated NaHCO3Washed with 10 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The concentrate was recrystallized from 30 ml of methanol, filtered and dried to give a white color Solid 18.92g, HPLC purity greater than 99.5%.
159.2 g	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In acetonitrile at 25℃; for 3h;	1-3; 5; 7-9 (3) 1900 ml of acetonitrile, 133.69 g of compound IIc, 247.14 g of DIEA and 290.08 g of HBTU were sequentially added to the 5L reaction flask, 190.00 g of compound V was added in batches, the temperature was controlled at 25°C, and the reaction was carried out for 3 hours. Suction filtration, rinse with acetonitrile, add the filter cake into 1900ml of water, stir at 25°C for 2 hours, suction filter, and blow dry the filter cake at 60°C for 20 hours to obtain olaparib solid 190g, purity 99.40%, impurity D content 0.17 %.
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In acetonitrile at 25℃; for 3h;	2.3; 4.3; 5.3; 6.3 (3) 1900ml of acetonitrile, 133.69g of compound IIc, 247.14g of DIEA and 290.08g of HBTU were sequentially added to the 5L reaction flask,190.00 g of compound V was added in batches, the temperature was controlled at 25°C, and the reaction was carried out for 3 hours.Suction filtration, rinse with acetonitrile, add the filter cake to 1900ml of water, stir at 25°C for 2 hours, suction filter, and blow dry the filter cake at 60°C for 20h,190 g of olaparib solid was obtained, with a purity of 99.40% and an impurity D content of 0.17%.

Reference： [1]Current Patent Assignee: HEFEI CHUANGXIN MEDICAL TECH - CN109535082, 2019, A Location in patent: Paragraph 0058; 0064; 0070; 0076; 0083; 0084; 0085; 0093
[2]Current Patent Assignee: JARI PHARMACEUTICAL - CN112047890, 2020, A Location in patent: Paragraph 0038-0041
[3]Current Patent Assignee: ZILUO PHARMACEUTICAL CO LTD - CN114249695, 2022, A Location in patent: Paragraph 0020; 0063-0066
[4]Current Patent Assignee: BEIJING MESOCHEM TECH - CN113234024, 2021, A Location in patent: Paragraph 0020; 0026
[5]Current Patent Assignee: ASTRAZENECA PLC - WO2008/47082, 2008, A2 Location in patent: Page/Page column 25-26
[6]Current Patent Assignee: GUANGZHOU RENHENG PHARMACEUTICAL TECH - CN106905243, 2017, A Location in patent: Paragraph 0066; 0067
[7]Current Patent Assignee: JILIN SIHUAN PHARMA; JILIN HUIKANG PHARMACEUTICAL; BEIJING SIHUAN PHARM - CN114075159, 2022, A Location in patent: Paragraph 0059; 0107-0116; 0137-0158
[8]Current Patent Assignee: JILIN HUIKANG PHARMACEUTICAL; JILIN SIHUAN PHARMA; BEIJING SIHUAN PHARM - CN114075143, 2022, A Location in patent: Paragraph 0153; 0158-0159; 0164-0165; 0169-0170; 0174

4
[ 1062292-60-7 ]
[ 201230-82-2 ]
[ 59878-57-8 ]
olaparib [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With dmap; tetrakis(triphenylphosphine) palladium(0); potassium bromide; In N,N-dimethyl-formamide; at 120℃;	c. In the round bottom flask, the compound V29.14g was sequentially added.1-cyclopropionylpiperazine 13.34g, pd(PPh3)4 4.99g,0.173 mol of 4-dimethylaminopyridine, 10.29 g of potassium bromide, 500 ml of N,N-dimethylformamide, and then placed on a condenser, which was evacuated and flushed into CO.Repeatedly, then a balloon filled with carbon monoxide is placed on the upper end of the condenser.The temperature was controlled at 120 C, the reaction was continuously stirred, and the reaction was monitored by TLC.After the reaction is over, the temperature is lowered to room temperature and mixed.The extract was extracted with ethyl acetate, washed with purified water and dried over anhydrous sodium sulfate.Vacuum drying to obtain Olaparib (I) 36.48g, yield 97%The purity is 99.93%.
96%	With dmap; tetrakis(triphenylphosphine) palladium(0); potassium bromide; In N,N-dimethyl-formamide; at 120℃;	The round bottom flask is sequentially added in the compound V 26.99 g, 1 - cyclopropanecarboxylic formyl piperazine 12.49 g, 4.7 gpd (PPh3)4, 4 - Dimethylamino pyridine (0.162 muM), potassium bromide 9.64 g, N, N - dimethyl formamide 500 ml, then covering with the condenser tube, will be its evacuation and into the CO, repeatedly, in the condenser and then the upper end of the sleeve is a balloon filled with carbon monoxide. The temperature control in the 120 C, continuously stirring reaction, for monitoring the reaction TLC, to be after the reaction temperature to the room temperature, the mixture of ethyl acetate extraction, purified water washing, anhydrous sodium sulfate drying, vacuum drying to obtain aurar handkerchief nepal (I) 33.81 g, yield 96%, purity 99.93%.

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 6142 - 6147
[2]Patent: CN108586355,2018,A .Location in patent: Paragraph 0043; 0047
[3]Patent: CN108191769,2018,A .Location in patent: Paragraph 0047-0055
[4]Journal of labelled compounds and radiopharmaceuticals,2012,vol. 55,p. 411 - 418
[5]Organic Letters,2019,vol. 21,p. 5775 - 5778

5
[ 763113-22-0 ]
[ 1613320-65-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With η⁴-cycloocta-1,5-diene(1,3-dimesitylimidazoline-2-ylidene)(triphenylphosphine)iridium(I) hexafluorophosphate; hydrogen chloride; zinc In dichloromethane; water-d2 at 20℃; for 72h; Glovebox; Inert atmosphere;
99%	With η⁴-cycloocta-1,5-diene(1,3-dimesitylimidazoline-2-ylidene)(triphenylphosphine)iridium(I) hexafluorophosphate; deuterium In dichloromethane at 20℃; for 72h; Sealed tube;

Reference： [1]Modvig, Amalie; Andersen, Thomas L.; Taaning, Rolf H.; Lindhardt, Anders T.; Skrydstrup, Troels [Journal of Organic Chemistry, 2014, vol. 79, # 12, p. 5861 - 5868]
[2]Flinker, Mathias; Yin, Hongfei; Juhl, René W.; Eikeland, Espen Z.; Overgaard, Jacob; Nielsen, Dennis U.; Skrydstrup, Troels [Angewandte Chemie - International Edition, 2017, vol. 56, # 50, p. 15910 - 15915][Angew. Chem., 2017, vol. 56, # 50, p. 15910 - 15915,6]

6
[ 763114-04-1 ]
[ 763113-22-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: hydrogenchloride / water monomer; ethanol / 20 °C / Inert atmosphere 2.1: triethylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 2.2: 72 h / 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1.1: propan-2-one; water monomer / 4 h / 56.9 - 65 °C 2.1: potassium carbonate / ethyl acetate; water monomer / 1 h / 20 °C 2.2: 2 h / 20 °C
	Multi-step reaction with 2 steps 1: hydrogenchloride / water monomer; ethanol / 3 h / 20 °C 2: N,N-dimethyl-formamide; tetrahydrofuran; acetonitrile / 16 h / 20 °C / Glovebox; Inert atmosphere; Sealed tube

Multi-step reaction with 2 steps 1: hydrogenchloride / ethanol / 1 h 2: triethylamine / dichloromethane / 0.25 h / 10 - 15 °C

Reference： [1]Zmuda, Filip; Malviya, Gaurav; Blair, Adele; Boyd, Marie; Chalmers, Anthony J.; Sutherland, Andrew; Pimlott, Sally L. [Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8683 - 8693]
[2]Current Patent Assignee: SCINOPHARM TAIWAN, LTD. - US2018/57464, 2018, A1
[3]Pedersen, Simon S.; Donslund, Aske S.; Mikkelsen, Jesper H.; Bakholm, Oskar S.; Papp, Florian; Jensen, Kim B.; Gustafsson, Magnus B. F.; Skrydstrup, Troels [Chemistry - A European Journal, 2021, vol. 27, # 24, p. 7114 - 7123]
[4]Current Patent Assignee: SHENZHEN LANGRUN INVESTMENT CO., LTD. - CN114276301, 2022, A

7
[ 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

8
[ 61260-15-9 ]
[ 763113-22-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: triethylamine / tetrahydrofuran / 48 h / 0 - 20 °C / Inert atmosphere 2.1: sodium hydroxide / lithium hydroxide monohydrate / 24 h / 90 °C / Inert atmosphere 3.1: hydrazine hydrate monohydrate / 72 h / 70 °C / Inert atmosphere 4.1: triethylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 4.2: 72 h / 50 °C / Inert atmosphere 5.1: hydrogenchloride / lithium hydroxide monohydrate; ethanol / 20 °C / Inert atmosphere 6.1: triethylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 6.2: 72 h / 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 5 h / 20 °C 2.1: lithium hydroxide monohydrate / lithium hydroxide monohydrate / 1 h / 100 °C 2.2: 6 h / 20 °C 3.1: dicyclohexyl-carbodiimide; triethylamine / dichloromethane / 8 h / 20 °C
	Multi-step reaction with 3 steps 1.1: triethylamine / tetrahydrofuran / 5 h / 0 - 20 °C 1.2: 3 h / 70 °C 2.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 3.1: potassium carbonate; 4-dimethylaminopyridine / acetonitrile / 6 h / 0 - 20 °C / Inert atmosphere

	Multi-step reaction with 5 steps 1.1: triethylamine / tetrahydrofuran / 12 h / 0 - 20 °C 2.1: sodium hydroxide; lithium hydroxide monohydrate / 1 h / 90 °C 2.2: 12 h / 70 - 75 °C 3.1: dichlorosulfoxide; N,N-dimethyl-formamide / 4 h / Reflux 4.1: dichloromethane / 3 h / -5 - 5 °C 5.1: triethylamine / dichloromethane / 1 h / -5 - 5 °C
	Multi-step reaction with 6 steps 1.1: triethylamine / 6 h / 50 °C / Inert atmosphere; Industrial scale 2.1: hydrazine monohydrate / tetrahydrofuran / 2 h / 10 °C / Inert atmosphere; Industrial scale 2.2: 9 h / 65 °C / Inert atmosphere; Industrial scale 3.1: magnesium / tetrahydrofuran / 20 °C / Industrial scale 3.2: 1 h / -15 °C / pH 4 / Industrial scale 4.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 18 h 4.2: 1 h / 100 °C 5.1: hydrogenchloride / ethanol / 1 h 6.1: triethylamine / dichloromethane / 0.25 h / 10 - 15 °C
	Multi-step reaction with 3 steps 1.1: triethylamine / 1 h 2.1: sodium hydroxide / lithium hydroxide monohydrate / 0.5 h / 75 °C 2.2: 20 h / 80 °C 3.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / acetonitrile / 3 h / 25 °C
	Multi-step reaction with 3 steps 1.1: triethylamine / 1 h 2.1: sodium hydroxide; lithium hydroxide monohydrate / 2.5 h / 75 °C 2.2: 20 h / 80 °C 3.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / acetonitrile / 3 h / 25 °C

Reference： [1]Zmuda, Filip; Malviya, Gaurav; Blair, Adele; Boyd, Marie; Chalmers, Anthony J.; Sutherland, Andrew; Pimlott, Sally L. [Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8683 - 8693]
[2]Current Patent Assignee: GUANGZHOU RENHENG PHARMACEUTICAL TECH - CN106905243, 2017, A
[3]Current Patent Assignee: SOUTHEAST UNIVERSITY - CN110790710, 2020, A
[4]Current Patent Assignee: NANJING YEWIN PHARMACENTICAL - CN112979557, 2021, A
[5]Current Patent Assignee: SHENZHEN LANGRUN INVESTMENT CO., LTD. - CN114276301, 2022, A
[6]Current Patent Assignee: JILIN SIHUAN PHARMA; JILIN HUIKANG PHARMACEUTICAL; BEIJING SIHUAN PHARM - CN114075159, 2022, A
[7]Current Patent Assignee: JILIN HUIKANG PHARMACEUTICAL; JILIN SIHUAN PHARMA; BEIJING SIHUAN PHARM - CN114075143, 2022, A

9
[ 119-67-5 ]
[ 763113-22-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: sodium methoxide / methanol / 2 h / 0 - 20 °C / Inert atmosphere 1.2: 0.5 h / Inert atmosphere 2.1: triethylamine / tetrahydrofuran / 48 h / 0 - 20 °C / Inert atmosphere 3.1: sodium hydroxide / lithium hydroxide monohydrate / 24 h / 90 °C / Inert atmosphere 4.1: hydrazine hydrate monohydrate / 72 h / 70 °C / Inert atmosphere 5.1: triethylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 5.2: 72 h / 50 °C / Inert atmosphere 6.1: hydrogenchloride / lithium hydroxide monohydrate; ethanol / 20 °C / Inert atmosphere 7.1: triethylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 7.2: 72 h / 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: 3 h / 100 °C / Inert atmosphere 2.1: tetrahydrofuran / 5 h / 20 °C 3.1: lithium hydroxide monohydrate / lithium hydroxide monohydrate / 1 h / 100 °C 3.2: 6 h / 20 °C 4.1: dicyclohexyl-carbodiimide; triethylamine / dichloromethane / 8 h / 20 °C
	Multi-step reaction with 5 steps 1.1: Dimethyl phosphite; hydrogenchloride / lithium hydroxide monohydrate / 20 °C 1.2: 20 °C 2.1: sodium hydroxide / lithium hydroxide monohydrate / 20 - 70 °C 2.2: 20 - 70 °C / pH 4 - 6 3.1: dichlorosulfoxide; triethylamine / dichloromethane / 0 - 20 °C 4.1: isopropanol / 20 °C 5.1: acetonitrile

	Multi-step reaction with 4 steps 1.1: anhydrous sodium formate / methanol / 0.25 h / 0 °C 1.2: 4 h / 20 °C 1.3: 0.17 h 2.1: triethylamine / tetrahydrofuran / 5 h / 0 - 20 °C 2.2: 3 h / 70 °C 3.1: oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 4.1: potassium carbonate; 4-dimethylaminopyridine / acetonitrile / 6 h / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: sodium methoxide / methanol / 0.5 h / 20 °C 1.2: 2 h / 20 °C 2.1: triethylamine / 1 h 3.1: sodium hydroxide / lithium hydroxide monohydrate / 0.5 h / 75 °C 3.2: 20 h / 80 °C 4.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / acetonitrile / 3 h / 25 °C
	Multi-step reaction with 4 steps 1.1: sodium methoxide / methanol / 0.5 h / 20 °C 1.2: 2 h / 20 °C 2.1: triethylamine / 1 h 3.1: sodium hydroxide; lithium hydroxide monohydrate / 2.5 h / 75 °C 3.2: 20 h / 80 °C 4.1: N-ethyl-N,N-diisopropylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / acetonitrile / 3 h / 25 °C

Reference： [1]Zmuda, Filip; Malviya, Gaurav; Blair, Adele; Boyd, Marie; Chalmers, Anthony J.; Sutherland, Andrew; Pimlott, Sally L. [Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8683 - 8693]
[2]Current Patent Assignee: GUANGZHOU RENHENG PHARMACEUTICAL TECH - CN106905243, 2017, A
[3]Current Patent Assignee: ALEMBIC PHARMACEUTICALS LIMITED - WO2017/191562, 2017, A1
[4]Current Patent Assignee: SOUTHEAST UNIVERSITY - CN110790710, 2020, A
[5]Current Patent Assignee: JILIN SIHUAN PHARMA; JILIN HUIKANG PHARMACEUTICAL; BEIJING SIHUAN PHARM - CN114075159, 2022, A
[6]Current Patent Assignee: JILIN HUIKANG PHARMACEUTICAL; JILIN SIHUAN PHARMA; BEIJING SIHUAN PHARM - CN114075143, 2022, A

10
[ 763114-25-6 ]
olaparib [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 8683 - 8693
[2]Patent: WO2017/191562,2017,A1
[3]Patent: WO2019/186135,2019,A1

11
[ 763114-26-7 ]
[ 763113-22-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: triethylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 1.2: 72 h / 50 °C / Inert atmosphere 2.1: hydrogenchloride / water monomer; ethanol / 20 °C / Inert atmosphere 3.1: triethylamine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 3.2: 72 h / 20 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: thionyl chloride; triethylamine / dichloromethane / 0 - 20 °C 2: isopropanol / 20 °C 3: acetonitrile
	Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / propan-2-one / 1 h / 20 - 30 °C 2.1: propan-2-one / 1 h / 20 °C 3.1: propan-2-one; water monomer / 4 h / 56.9 - 65 °C 4.1: potassium carbonate / ethyl acetate; water monomer / 1 h / 20 °C 4.2: 2 h / 20 °C

	Multi-step reaction with 3 steps 1: thionyl chloride; N,N-dimethyl-formamide / 4 h / Reflux 2: dichloromethane / 3 h / -5 - 5 °C 3: triethylamine / dichloromethane / 1 h / -5 - 5 °C
	Multi-step reaction with 3 steps 1.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 18 h 1.2: 1 h / 100 °C 2.1: hydrogenchloride / ethanol / 1 h 3.1: triethylamine / dichloromethane / 0.25 h / 10 - 15 °C

Reference： [1]Zmuda, Filip; Malviya, Gaurav; Blair, Adele; Boyd, Marie; Chalmers, Anthony J.; Sutherland, Andrew; Pimlott, Sally L. [Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8683 - 8693]
[2]Current Patent Assignee: ALEMBIC PHARMACEUTICALS LIMITED - WO2017/191562, 2017, A1
[3]Current Patent Assignee: SCINOPHARM TAIWAN, LTD. - US2018/57464, 2018, A1
[4]Current Patent Assignee: NANJING YEWIN PHARMACENTICAL - CN112979557, 2021, A
[5]Current Patent Assignee: SHENZHEN LANGRUN INVESTMENT CO., LTD. - CN114276301, 2022, A

12
C₁₉H₁₃FN₄O₂ [ No CAS ]
[ 59878-57-8 ]
olaparib [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine; In dichloromethane; at 0 - 10℃; for 1.5h;Industrial scale;	The active amide intermediate prepared in step 1 was dissolved in 10 ml of methylene chloride,The solution was cooled to 0 to 10 C and then added dropwise to a solution of 1-cyclopropylcarbamoylpiperazine (2.62 g, 17 mmol) and triethylamine (7.1 ml, 51 mmol) in 20 ml of dichloromethane for 1.5 hours at 0 to 10 C , Washed with 30 ml of water 3 times, the organic layer concentrated dry, add ethanol - water mixture (1: 2, v / v) 50 ml,And the filtrate was stirred at 0-5 C for 10 hours. The filtrate was filtered and dried to obtain 6.8 g of orapani. The yield was 92.0% and the purity was 99.87%.

Reference： [1]Patent: CN105503739,2016,A .Location in patent: Paragraph 0022; 0043; 0044

13
olaparib [ No CAS ]
[ 229625-50-7 ]
di-tert-butyl (4-((3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorophenyl)methyl)-1-oxo-1,2-dihydrophthalazin-2-yl)methyl phosphate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With caesium carbonate In N,N-dimethyl acetamide at 60℃;	1.1 step 1: (4- (3- (4- (cyclopropylcarbonyl) piperazine-1-carbonyl) -4-fluorophenyl) -1-oxophthalazin-1 (2H) one (150 mg, 0.346 mmol) In 3 mLDimethylacetamidein,Cesium carbonate (284 mg, 0.865 mmol) was added,(Chloromethyl) phosphate di-tert-butyl ester (134 mg, 0.519 mmol).60 degrees Celsius stirring2 smallAfter the trial,Saturated aqueous ammonium chloride solution was added to the reaction system,Extracted with ethyl acetate (10 mL x 3).Consolidate organic phase, smallAfter trial smallconcentrate,The crude product was chromatographed on silica gel (eluent: dichloromethane: methanol = 80: 1)(1H) -yl) methylphosphonium chloride (4- (3- (4- (cyclopropylcarbonyl) piperazine-1-carbonyl) -4-fluorophenyl) -1-oxophthalazin-Acid di-tert-butyl ester (150 mg, 70%),Colorless oily liquid.

Reference： [1]Current Patent Assignee: BEIJING JIANQIAO MEDICINE TECH - CN106146557, 2016, A Location in patent: Paragraph 0023; 0024

14
[ 108-86-1 ]
[ 763113-22-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium <i>tert</i>-butylate / toluene / 3 h / 90 °C 1.2: 24 h / 110 °C 2.1: C₆H₁₁N₂⁽¹⁺⁾Cl^(1-)AlCl₃ / 50 - 55 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1.1: potassium <i>tert</i>-butylate / toluene / 3 h / 90 °C 1.2: 24 h / 110 °C 2.1: C₆H₁₁N₂⁽¹⁺⁾Cl^(1-)AlCl₃ / 50 - 55 °C

Reference： [1]Current Patent Assignee: LUOXIN PHARMACEUTICALS GROUP STOCK CO LTD - CN107266370, 2017, A
[2]Current Patent Assignee: LUOXIN PHARMACEUTICALS GROUP STOCK CO LTD - CN107325055, 2017, A

15
[ 332851-19-1 ]
[ 49546-86-3 ]
[ 763113-22-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	With C₆H₁₁N₂⁽¹⁺⁾Cl^(1-)AlCl₃ at 50 - 55℃; Inert atmosphere;	3; 4 Example 3 Preparation of ionic liquids: In the reactor equipped with a stirrer,Under the protection of nitrogen 0.1mol [Emim] Cl,Slowly add 0.26mol AlCl3 in batches,After stirring at about 40 ° C for 3 hours,Make sure the reaction is complete,A colorless and transparent [Emim] Cl-AlCl3 ionic liquid was obtained. Preparation of olaparib: Compound 5 (0.03 mol) was mixed with [Emim] Cl-AlCl3 (0.03 mol) ionic liquid in a bottle, stirred,Warmed to 50 ~ 55 ,Compound 2 (0.02 mol) was slowly added dropwise over 30 min,After 3 ~ 4h reaction stopped stirring.Drop to room temperature, Products and ionic liquids automatically stratified,Product layer was poured into chloroform extraction,Keep the organic phase,Toluene wash,Suction filtration,Drying under reduced pressure,8.15 g of olaparib (Compound 1)Yield 93.79%.In the reaction flask was added crude Orapanib 5g, was added 50mL ethyl acetate mixture of petroleum ether (ethyl acetate, stoneThe volume ratio of the oil is 2.0: 1), slowly heated to 50 ~ 55 , incubated for 20min, continue to heat up to 70 ~ 75 , stirringMixing, stirring until the crude dissolved 1.5h, to obtain a crude solution of Orapanib; to the crude solution was added activated carbon0.05g, insulation decolorization 20min, heat filtration, collecting the filtrate; slow cooling, the filtrate temperature was reduced to 20 ~ 25 , heat preservation, controlStirring speed of 20 rev / min, stirring for 30min; then the filtrate was cooled to 0 ° C and below, controlling the stirring speed of 15 rev / min,Adding seed crystal 0.125g, controlling the temperature and stirring speed raise crystal 1.5h, filtering, the filter cake is mixed with a little ethyl acetate petroleum etherSolution rinsed, suction filtered, dried under reduced pressure to give 4.75g of Orapanib quality, yield 95%. Orapamil obtained in this example was purifiedProduct purity of 99.96%, 0.02% single-doped (double-substituted impurities), total miscellaneous 0.04%.
93.79%	With C₆H₁₁N₂⁽¹⁺⁾Cl^(1-)AlCl₃ at 50 - 55℃;	7 Preparation of Orapanib Compound 5 (0.03 mol) was mixed with [Emim] Cl-AlCl3 (0.03 mol) ionic liquid in a bottle,Stirring,Warmed to 50 ~ 55 ,Compound 2 (0.02 mol) was slowly added dropwise over 30 min,After 3 ~ 4h reaction stopped stirring.Drop to room temperature, Products and ionic liquids automatically stratified,Product layer was poured into chloroform extraction,Keep the organic phase,Toluene wash,Suction filtration,Drying under reduced pressure,I was olaparib 8.15g,Yield 93.79%,Purity 99.95%Ionic liquid layer can be recycled.

Reference： [1]Current Patent Assignee: LUOXIN PHARMACEUTICALS GROUP STOCK CO LTD - CN107266370, 2017, A Location in patent: Paragraph 0045; 0046; 0047; 0048; 0049; 0050; 0051; 0052
[2]Current Patent Assignee: LUOXIN PHARMACEUTICALS GROUP STOCK CO LTD - CN107325055, 2017, A Location in patent: Paragraph 0043-0043

16
[ 763113-22-0 ]
[ 106-96-7 ]
[ 2155827-08-8 ]

Yield	Reaction Conditions	Operation in experiment
47%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide; toluene at 4 - 20℃; Inert atmosphere;	General method for the synthesis of Olaparib prodrug Olaparib (AZD2281 , MedChem Express LLC (MCE)) (10 mg, 0.03 mmol) was dissolved in dry DMF (1 mL) under N2 atmosphere. The mixture was then cooled to 4 °C in an ice bath. Propargyl bromide solution 80 wt. % in toluene (8 μL, 0.05 mmol) was diluted in dry DMF (250 μL) and added to the mixture. Then, DBU (9 μL, 0.06 mmol) in dry DMF (250 μL) was added dropwise to the mixture. The mixture was stirred overnight and allowed to warm up to room temperature (r.t.). The solvents were then removed in vacuo, the crude redissolved with CH2CI2 (5 mL), and washed with H2O (5 mL). The aqueous layer was washed with CH2CI2 (3 x 5 mL) and the combined organic layers dried over MgS04, filtered, and concentrated in vacuo. The crude was purified by Merck TLC Silica gel 60 F254 plates semipreparative using 5% MeOH in DCM. The synthetic method described above gave a white solid (6 mg, 47% yleld); f 0.39 (5% MeOH in DCM. 1H NMR (500 MHz, CDCI3) δ 8.51 (m, 1 H), 7.77 (m, 2H), 7.71 (m, 1 H), 7.36 (m, 2H), 7.07 (t, J = 8.9, 1 H), 5.04 (d, J = 2.5, 2H), 4.33 (s, 2H), 3.79 (m, 4H), 3.62 (m, 2H), 3.35 (m, 2H), 2.35 (t, J = 2.4, 1 H), 1.72 (m, 1 H), 1.28 (t, J = 7.1 , 2H), 1.03 (dd, J = 4.6, 2.9, 2H). 13C NMR (126 MHz, CDCI3) δ 172.35 (C=0), 171.15 (C=0), 158.73 (C), 158.02 (C), 156.05 (C), 145.01 (C), 134.44-134.41 (d, C), 133.33 (CH), 131.69-131.61 (d, CH)2, 129.15 (C), 128.28 (C), 127.65 (CH)2, 124.93 (CH), 116.31-116.14 (d, CH), 77.22 (CH), 72.43 (C), 60.39 (CH2)2, 53.49 (CH2)2, 40.73 (CH2), 37.81 (CH2), 1 1.04 (CH), 7.70 (CH2)2. HRMS (ESI) m/z [M + H]+ calcd for 473.19835; found, 473.19410.

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF EDINBURGH - WO2017/199028, 2017, A1 Location in patent: Page/Page column 54; 55

17
[ 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

18
[ 2191454-50-7 ]
[ 4023-34-1 ]
[ 763113-22-0 ]

Yield	Reaction Conditions	Operation in experiment
98.7%	Stage #1: 4-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoyl]piperazinium p-toluenesulfonate With potassium carbonate In water; ethyl acetate at 20℃; for 1h; Stage #2: cyclopropanecarboxylic acid chloride In water; ethyl acetate at 20℃; for 2h;	5 Preparation of Olaparib from 4-[2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-benzoyl]-piperazinium p-toluenesulfonate (compound J) Preparation of Olaparib from 4-[2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-benzoyl]-piperazinium p-toluenesulfonate (compound J) To a 3-neck 50 mL flask equipped with a 2.5 cm stir bar, thermometer and N2 inlet, EtOAc (20 mL, 10 vol) and water (10 mL, 5 vol) were added. And then, compound J (2.01 g, 3.73 mmol, 1.00 equiv.) and K2CO3 (1.54 g, 11.1 mmol, 3.00 equiv.) were added to the above flask. The resulting suspension was stirred at room temperature for not less than 1 hour to form a clear bi-phasic solution. Cyclopropanecarbonyl chloride (0.41 mL, 4.46 mmol, 1.2 equiv.) was added to the above clear solution at room temperature. After the addition, the mixture was stirred at room temperature for 2 hours. Upon completion, the suspension was cooled to about 0° C. and stirred for additional 2 hours. The suspension was filtered through a Buchner funnel to give a pale-yellow cake. The pale-yellow cake was washed with water (6.0 mL, 3 vol.) for three times and EtOAc (4 mL, 2 vol.) once, and then dried at not more than 60° C. under vacuum to afford olaparib (1.60 g, 3.68 mmol, 98.7% Yield). 1H NMR (400 MHz, DMSO-d6) δ: 0.74 (m, 4H), 1.94 (br, 1H), 3.19 (br, 2H), 3.37-3.74 (m, 6H), 4.33 (s, 2H), 7.24 (t, J=8.8 Hz, 1H), 7.37 (m, 1H), 7.44 (m, 1H), 7.83 (dt, J=7.4 and 0.8 Hz, 1H), 7.89 (t, J=7.1 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 8.26 (dd, J=7.9 and 1.0 Hz, 1H), 12.59 (s, 1H)

Reference： [1]Current Patent Assignee: SCINOPHARM TAIWAN, LTD. - US2018/57464, 2018, A1 Location in patent: Paragraph 0122; 0123; 0124

19
[ 763114-26-7 ]
N-cyclopropanoylpiperazinium p-toluenesulfonate [ No CAS ]
olaparib [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.5%		<strong>[763114-26-7]5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid</strong> (compound D) (1.012 g, 3.393 mmol, 1.0 equiv.) and acetone (10.0 mL, 10 vol.) were charged to a 3-neck 50 mL flask equipped with a 2 cm stir bar, thermal couple and N2 inlet. The resulting suspension was cooled to 0 C. N,N-diisopropylethylamine (DIPEA) (0.67 mL, 4.1 mmol, 1.2 equiv.) was added dropwise to the above resulting suspension at 0 C., followed by addition of pivaloyl chloride (0.50 mL, 4.1 mmol, 1.2 equiv.) at 0 C. After the addition, the resulting mixture was warmed to room temperature and stirred for 3 hours. Upon completion, the mixture was cooled to 0 C. N-cyclopropanoyl piperazinium p-toluenesulfonate (compound A) (1.21 g, 4.00 mmol, 1.1 equiv.) was added in portions at 0 C., and then acetone (0.5 mL) was added to rinse. Subsequently, N,N-diisopropylethylamine (DIPEA) (0.83 mL, 5.0 mmol, 1.5 equiv.) was added dropwise to the above flask at 0 C. After the addition, the resulting mixture was warmed to room temperature and stirred for 3 hours. Upon completion, the suspension was diluted with NaHCO3(aq) (20 mL) and EtOAc (20 mL), and then stirred for 1 hour at 0 C. in an ice bath. After stirring, the mixture was filtered through a Buchner funnel to afford off-white solids. The filtrate was extracted with EtOAc (20 mL) three times. The combined organic part was washed with NaHCO3(aq) (20 mL), water (20 mL), and NaCl(aq) (20 mL) to give a clear EtOAc solution. The above resulting off-white solids were combined with the EtOAc solution and concentrated. The resulting solids were dissolved in methanol (MeOH) (25 mL) and stirred at 65 C., followed by slow addition of water (50 mL). The resulting clear solution was cooled to room temperature and stirred overnight. The slurry was filtered through a Buchner funnel. The obtained wet cake was washed with water (25 mL) twice and dried at not more than 60 C. under vacuum overnight to afford olaparib as off-white solid (1.32 g, 3.04 mmol, 89.5% Yield). 1H NMR (400 MHz, DMSO-d6) delta: 0.74 (m, 4H), 1.94 (br, 1H), 3.20 (br, 2H), 3.37-3.75 (m, 6H), 4.33 (s, 2H), 7.24 (t, J=8.8 Hz, 1H), 7.38 (m, 1H), 7.44 (m, 1H), 7.83 (dt, J=7.4 and 0.8 Hz, 1H), 7.89 (t, J=7.1 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 8.26 (dd, J=7.9 and 1.0 Hz, 1H), 12.60 (s, 1H).

Reference： [1]Patent: US2018/57464,2018,A1 .Location in patent: Paragraph 0110; 0111; 0112

20
[ 1021298-68-9 ]
[ 59878-57-8 ]
olaparib [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.5%		Add Compound III 25.82 g to the reaction flask.Purified water 100ml,Stir at room temperature,Then add 22.4M sodium hydroxide 92.4ml,The mixture temperature was heated to 100 C,Stir 12h, cool to room temperature, filter, wash,The combined filtrate was acidified with 46.2 ml of 2M diluted hydrochloric acid for 30 min,Then, 500 ml of methanol, 18.70 g of triethylamine, and 14.25 g of 1-cyclopropanecarbonylpiperazine are added successively.At a reaction temperature of 20-25C, the reaction is stirred for 10 hours. After the reaction is completed, it is cooled to 0C and filtered.38.66 g of solids were obtained with a yield of 96.2% and a purity of 99.89%. The refining of olaparib (I)30g of crude oleapani was placed in a dissolving tank81.82 ml of isopropanol and 818.2 ml of acetone were added and the temperature was controlled at 45-50C.Stir and dissolve. After the crude product is completely dissolved, add charcoal to decolorize it for 30 minutes.The decolorization reaction was followed by hot filtration and the filtrate was stirred at room temperature for crystallization.Then cool down to 0 ~ 10 C for 4 hours, filter, and wash with acetone,Filtration, drying, that is, olaparib 28.35g,The yield was 94.5%, the purity was 99.99%, the mononuclear 0.05%, and the total heterologous 0.11%.

Reference： [1]Patent: CN108101852,2018,A .Location in patent: Paragraph 0020; 0039-0043

21
[ 763113-22-0 ]
[ 5292-43-3 ]
[ 2230548-38-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: olaparib; bromoacetic acid <i>tert</i>-butyl ester With sodium carbonate In N,N-dimethyl-formamide at 75℃; for 24h; Stage #2: With trifluoroacetic acid In dichloromethane; water at 20℃; for 1h;	A flask was charged with olaparib (100 mg, 0.230 mmol) and sodium carbonate (122 mg, 1.15 mmol). DMF (5 mL) and tert-butyl bromoacetate (170 μL, 1.15 mmol) were added, and the reaction stirred at 75 °C for 24 h. After 24 h, the reaction was cooled to room temperature, diluted with ethyl acetate (75 mL), and washed with IN HC1 (2 x 30 mL) and brine (30 mL). The organic layer was dried with magnesium sulfate, and the solvent removed in vacuo. The remaining oil was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) and water (0.10 mL). The reaction was stirred at room temperature for 1 h, and all solvent was removed in vacuo. The remaining oil was redissolved in 1 : 1 DMF:water (5 mL), and this solution was purified by prep HPLC (5% to 65% acetonitrile in water with 0.1% = 493.4 (M+l).

Reference： [1]Current Patent Assignee: ROCK CREEK ADVISORS LLC - WO2018/112176, 2018, A1 Location in patent: Paragraph 00372

22
[ 763113-22-0 ]
[ 50-00-0 ]
[ 126049-37-4 ]
[ 108-00-9 ]
[ 76-05-1 ]
[ 503-38-8 ]
[ 2305916-69-0 ]

Yield	Reaction Conditions	Operation in experiment
38%	Stage #1: olaparib; formaldehyd; N,N-dimethylethylenediamine In ethanol at 80℃; for 2h; Stage #2: (4-(pyridin-2-yldisulfanyl)phenyl)methanol; trichloromethyl chloroformate With pyridine; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; ethanol at 20℃; for 2h; Stage #3: trifluoroacetic acid	A flask was charged with 8B (92.0 mg, 0.369 mmol), and this was dissolved in THF (5 mL) and pyridine (30 μL, 0.37 mmol). Diphosgene (24.3 μL, 0.203 mmol) was added, and the reaction stirred at room temperature for 1 h. In another vial, olaparib (100 mg, 0.230 mmol) was charged, and ethanol (4 mL), 37%) formaldehyde (51 μL, 0.690 mmol), and N,N-dimethylethylenediamine (251 μL, 2.30 mmol) were added. The vial was capped, and stirred at 80 °C for 2 h. The reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), and the ethyl acetate washed with saturated sodium bicarbonate (2 x 15 mL) and brine (15 mL). The organic layer was dried with magnesium sulfate, and the solvent removed in vacuo. The remaining residue was dissolved in THF (3 mL), and added to the 8B/diphosgene mixture from above. Diisopropylethylamine (200 μL, 1.15 mmol) was added, and the reaction stirred at room temperature for 2 h. The reaction was concentrated in vacuo, and the remaining residue dissolved in DMF (2 mL), and purified by preparative HPLC (15% to 65%> acetonitrile in water with 0.1%> TFA) to provide 8C trifluoroacetate salt (82.1 mg, 88.9 μπιο, 38%> yield).

Reference： [1]Current Patent Assignee: ROCK CREEK ADVISORS LLC - WO2018/112176, 2018, A1 Location in patent: Paragraph 00387-00388

23
[ 913168-10-2 ]
[ 763113-22-0 ]
[ 50-00-0 ]
[ 64-19-7 ]
[ 108-00-9 ]
[ 2306055-48-9 ]

Yield	Reaction Conditions	Operation in experiment
18%	Stage #1: olaparib; formaldehyd; N,N-dimethylethylenediamine In ethanol; water at 80℃; for 2h; Stage #2: 1H-benzo[d][1,2,3]triazol-1-yl (2-(pyridin-2-yldisulfaneyl)ethyl) carbonate With dmap; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h; Stage #3: acetic acid	A vial was charged with olaparib (107 mg, 0.246 mmol), and ethanol (4 mL), 37% aqueous formaldehyde (54.5 μL, 0.738 mmol) and N,N-dimethylethylenediamine (269 μL, 2.46 mmol) were added. The vial was capped, and stirred at 80 °C for 2 h. The reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), and the ethyl acetate washed with saturated sodium bicarbonate (2 x 15 mL) and brine (15 mL). The organic layer was dried with magnesium sulfate, and the solvent removed in vacuo. The remaining residue was dissolved in DMF (5 mL), and 5A (172 mg, 0.493 mmol), diisopropylethylamine (215 μL, 1.23 mmol) and DMAP (30.1 mg, 0.246 mmol) were added. The reaction was stirred at room temperature for 1 h. The crude reaction mixture was then purified by preparative HPLC (5% to 75% acetonitrile in water with 0.1% TFA) to give a mixture of the product contaminated with 2-(2- pyridinyldithio)ethanol. A second purification, re-loading the mixture onto the column, then running 100 mM ammonium acetate (50 ml) through the column, followed by a gradient of 5% to 55% acetonitrile in water with 0.2% AcOH, provided pure 5B acetate salt (36.2 mg, 44.8 μιηο, 18% yield). LCMS M/Z = 748.5 (M + 1)

Reference： [1]Current Patent Assignee: ROCK CREEK ADVISORS LLC - WO2018/112176, 2018, A1 Location in patent: Paragraph 00378

24
[ 77771-02-9 ]
[ 763113-22-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran / 2.5 h / 20 °C / Inert atmosphere 2.1: sodium methylate / methanol / Reflux 2.2: 3 h / pH 1 3.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; dmap; potassium bromide / N,N-dimethyl-formamide / 120 °C
	Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 2.5 h / 20 °C / Inert atmosphere 2.1: sodium ethanolate / ethanol / 1 h / Reflux 2.2: 3 h / pH 1 3.1: potassium bromide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; dmap / N,N-dimethyl-formamide / 120 °C

Reference： [1]Current Patent Assignee: LUOXIN PHARMACEUTICALS GROUP STOCK CO LTD - CN108191769, 2018, A
[2]Current Patent Assignee: LUOXIN PHARMACEUTICALS GROUP STOCK CO LTD - CN108586355, 2018, A

25
[ 87-41-2 ]
[ 763113-22-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran / 2.5 h / 20 °C / Inert atmosphere 2.1: sodium methylate / methanol / Reflux 2.2: 3 h / pH 1 3.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; dmap; potassium bromide / N,N-dimethyl-formamide / 120 °C
	Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 2.5 h / 20 °C / Inert atmosphere 2.1: sodium ethanolate / ethanol / 1 h / Reflux 2.2: 3 h / pH 1 3.1: potassium bromide; tetrakis(triphenylphosphine) palladium⁽⁰⁾; dmap / N,N-dimethyl-formamide / 120 °C

Reference： [1]Current Patent Assignee: LUOXIN PHARMACEUTICALS GROUP STOCK CO LTD - CN108191769, 2018, A
[2]Current Patent Assignee: LUOXIN PHARMACEUTICALS GROUP STOCK CO LTD - CN108586355, 2018, A

26
[ 763113-22-0 ]
[ 61413-67-0 ]
[ 2243897-15-4 ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: olaparib With sodium hydride In tetrahydrofuran at 1 - 10℃; for 0.5h; Stage #2: chloromethyl n-dodecanoate In tetrahydrofuran for 0.5h;	16 Example 16: Synthesis of (4-(4-Fluoro-3-(1-(cyclopropanoyl)piperazin-4-yl-carbonyl)-benzyl)-1-oxophthalazine-2(1H)-yl)methanol laurate 4-(4-Fluoro-3-(1-(cyclopropanoyl)piperazin-4-yl-carbonyl)-benzyl)pyridazine-1(2H)one (IV) (678 mg, 1.56 mmol) was added Into a 25ml double-mouth bottle,Add anhydrous THF (14 ml), cool to 1-10 ° C, then add sodium hydride (60%, 125 mg, 3.13 mmol), stir for 30 minutes,Methyl chlorolaurate (465 mg, 1.87 mmol) was added and stirring was continued for 30 min.The reaction was completely monitored by TLC, and the silica gel column was purified by column.The solid product (585 mg) was obtained in a yield of 58%.

Reference： [1]Current Patent Assignee: SHANGHAI BIOBOND PHARMACEUTICAL - CN108383798, 2018, A Location in patent: Paragraph 0133; 0134; 0135; 0136

27
[ 2375101-76-9 ]
[ 763113-22-0 ]

Yield	Reaction Conditions	Operation in experiment
75.1%	With hydrazine hydrate In 1,4-dioxane at 102℃; for 6h;	5 5. Preparation of olaparib In a 500 mL reaction flask, 2-(2-(3-(4-(cyclopropylcarbonyl)piperazine-1-carbonyl)-4-fluorophenyl)acetyl)benzoic acid ethyl ester (formula IV) was added sequentially. , R=Et)(15.0 g, 32.16 mmol) and dioxane (150 mL) were stirred until the system was dissolved. Subsequently, 80% hydrazine hydrate (2.43 g, 38.9 mmol) was added dropwise to the reaction system.After the completion of the dropwise addition, the system was heated to reflux (102 ° C), and after 6 hours of reaction, the starting material disappeared by TLC, and the reaction was completed.After the reaction, the system was naturally cooled to room temperature. After suction filtration, the filter cake was washed with purified water (50 mL).It was air-dried at 75 ° C for about 24 hours to obtain a crude product (12.7 g).The crude product using DMF (50mL) olaparib recrystallized (white solid, 10.5g, 75.1%).

Reference： [1]Current Patent Assignee: NANJING JUNRUO BIOMEDICAL RES INSTITUTE; HAIMEN BAIKANG PHARMACEUTICAL; JIANGSU JUNRUO PHARMACEUTICAL - CN110078671, 2019, A Location in patent: Paragraph 0036-0037

28
[ 763113-22-0 ]
[ 32315-10-9 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
13 g	Stage #1: bis(trichloromethyl) carbonate; C₃₅H₇₀NO₉PS₂ With dmap In dichloromethane at 20℃; for 2h; Inert atmosphere; Stage #2: olaparib In dichloromethane for 3h;	17 Synthesis of Twenty-two Carbonic Acid-sn-2-Olapanilide Ethyl Ethyl Dithiopropionate Glycerol Phosphate Phosphate (see Figure 16 for route) 0.30 g of docosyl carbonate-sn-2-hydroxyethyl dithiopropionate glycerol phosphate choline,0.10 g of triphosgene (BTC) was uniformly mixed in 100 mL of anhydrous dichloromethane.0.15 g of DMAP in dichloromethane was slowly added dropwise under a nitrogen atmosphere.The reaction was stirred at room temperature for 2 h. To the above system, 0.1 g of Olaparib was added.Reaction for 3 h. After that, the crude product was washed with aq. The product was purified by column chromatography to give the product, behenic acid-sn-2-olapaniurinate, ethyl dithiopropionate, glycerol phosphate, 0.22 g,It is a white solid.

Reference： [1]Current Patent Assignee: SOUTHEAST UNIVERSITY - CN110025789, 2019, A Location in patent: Paragraph 0156-0159

29
C₁₆H₁₀ClFN₂O₂ [ No CAS ]
[ 59878-57-8 ]
olaparib [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With dmap; potassium carbonate; In acetonitrile; at 0 - 20℃; for 6h;Inert atmosphere;	The synthetic route is: Piperazine cyclopropyl ketone (1.1g, 0.0071mol)Soluble in 25ml anhydrous acetonitrile,Add potassium carbonate (4.0g, 0.029mol), cool to 0 , nitrogen protection,Stir vigorously. Compound 5 (2.1g, 0.0066mol),Dissolve with 20ml of anhydrous acetonitrile and slowly add dropwiseAfter the addition, the temperature was raised to room temperature, a small amount of DMAP (0.5g, 0.0041mol) was added, and the reaction was carried out for 6h.Concentrate under reduced pressure, add 40ml of water, adjust the pH to 8 with sodium bicarbonate, extract with ethyl acetate, concentrate under reduced pressure to remove the solvent, recrystallize with ethyl acetate, filter to obtain light red solid, decolorize with a small amount of activated carbon, filter and concentrate It was dried to obtain a white solid (2.8g, yield 93%).

Reference： [1]Patent: CN110790710,2020,A .Location in patent: Paragraph 0070-0076

30
[ 763113-22-0 ]
[ 110-16-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
93%	In ethanol; n-heptane at 20℃; for 3h;	1-11 Example 1 Weigh 900 mg of olaparib and 240 mg of maleic acid, add 15 mL of n-heptane and 250 μL of ethanol to obtain a suspension, place the suspension at room temperature, stir for 3 hours, and filter.The obtained white solid was dried at 40°C to obtain a solid sample of olaparib and maleic acid co-crystal, with a yield of 93.0%

Reference： [1]Current Patent Assignee: TIANJIN UNIVERSITY OF TECHNOLOGY - CN111689905, 2020, A Location in patent: Paragraph 0037-0058

31
[ 763113-22-0 ]
[ 57-13-6 ]
[ 1970203-61-2 ]

Yield	Reaction Conditions	Operation in experiment
84%	In ethyl acetate at 20℃; for 1h;	1-8 Example 1 Weigh 1000 mg of olaparib and 276 mg of urea, add 15 mL of ethyl acetate to obtain a suspension, stir the suspension at room temperature for 1 h, filter, and dry the obtained white solid at 40°C to obtain olaparib and The yield of the solid sample of urea co-crystal was 84%.
	In ethanol at 50 - 60℃;	1-4 Example 1 Take 100 mg of olaparib free base crystal form A, 100 mg of urea, add 1 mL of ethanol, completely dissolve at 60 °C, and then slowly cool down to 50 °C. After the solution appears solid, continue to cool down to room temperature and filter to obtain 160 mg of white solid wet product , with a purity of 99.9%.The diffraction peak data of the X-ray powder diffraction pattern are shown in Table 1, the XRD pattern is shown in FIG. 1 , and the1H-NMR pattern is shown in FIG. 4 .The obtained eutectic was characterized by X-ray single crystal diffraction, the crystal structure data are shown in Table 2, and the single crystal structure diagram is shown in FIG. 6 .

Reference： [1]Current Patent Assignee: TIANJIN UNIVERSITY OF TECHNOLOGY - CN111995582, 2020, A Location in patent: Paragraph 0037-0052
[2]Current Patent Assignee: CHENGDU SHUDE PHARMACOLOGICAL - CN114539161, 2022, A Location in patent: Paragraph 0055-0068

32
[ 1062292-60-7 ]
[ 763113-22-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / 1,4-dioxane / 72 h / 80 °C / Glovebox; Sealed tube 2: hydrogenchloride / water monomer; ethanol / 3 h / 20 °C 3: N,N-dimethyl-formamide; tetrahydrofuran; acetonitrile / 16 h / 20 °C / Glovebox; Inert atmosphere; Sealed tube
	Multi-step reaction with 4 steps 1.1: magnesium / tetrahydrofuran / -30 °C 1.2: 1 h / -10 °C / pH 3.5 2.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 18 h 2.2: 1 h / 100 °C 3.1: hydrogenchloride / ethanol / 1 h 4.1: triethylamine / dichloromethane / 0.25 h / 10 - 15 °C

Reference： [1]Pedersen, Simon S.; Donslund, Aske S.; Mikkelsen, Jesper H.; Bakholm, Oskar S.; Papp, Florian; Jensen, Kim B.; Gustafsson, Magnus B. F.; Skrydstrup, Troels [Chemistry - A European Journal, 2021, vol. 27, # 24, p. 7114 - 7123]
[2]Current Patent Assignee: SHENZHEN LANGRUN INVESTMENT CO., LTD. - CN114276301, 2022, A

33
[ 763113-22-0 ]
[ 2617617-66-8 ]
[ 2617617-67-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: olaparib With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.0833333h; Inert atmosphere; Stage #2: 6-azidohexyl N-(2-methoxyethyl)-N-chloromethylcarbamate In tetrahydrofuran at -78℃; for 2h; Inert atmosphere;	4.2 Step 2. 6-Azidohexyl N-(2-methoxyethyl)-N-(methylene-olaparib) carbamate. In a heat-gun/vacuum dried round bottom flask, olaparib (10.8 mg, 24.9 pmol, 0.02 M final concentration) was suspended in 1.0 mL of THF under N2. The suspension was cooled in a - 78 °C acetone/dry ice bath, and a 1.0 M solution of NaHMDS (30 pL, 30 pmol) in THF was added. After stirring at -78 °C for 5 min, the reaction was air-warmed for 5 min, during which time the reaction became orange in color. After recooling to -78 °C, a 0.3 M solution of 6- azidohexyl /V-(2-methoxyethyl)-.V-chloromethyl carbamate (108 pL, 32.4 pmol) in THF was added. The cold bath was removed, and the orange reaction was air-warmed. Within 20 min, the color changed from orange to bright yellow. After 2 h, the reaction mixture was partitioned between 20 mL of 1:1 EtOAc:H20. The layers were separated, and the organic phase was washed with H2O and brine (10 mL each). The organic layer was then separated, dried over MgSCL, filtered, and concentrated by rotary evaporation. The crude concentrate was loaded onto a SiliaSep 4 g column, and product was eluted with a step-wise gradient of acetone in hexane (0%, 20%, 40%; 30 mL each then 60%, 80%; 40 mL each). Clean product- containing fractions were combined and concentrated to dryness to provide the title compound (6 mg, 9 pmol, 37% yield) as a colorless film. Cis HPLC, purity was determined at 280 nm: 92.1% (RV = 10.56 mL). LC-MS (m/z): calc, 691.3; obsd, 691.4 [M+H]+.

Reference： [1]Current Patent Assignee: PROLYNX LLC - WO2021/41964, 2021, A1 Location in patent: Paragraph 0090-0091

34
[ 763113-22-0 ]
[ 2617617-62-4 ]
[ 2617617-47-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: olaparib With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.0833333h; Inert atmosphere; Stage #2: 7-azido-1-(methylsulfonyl)-2-heptyl N-(2-methoxyethyl)-N-chloromethylcarbamate In tetrahydrofuran at -78℃; for 2h; Inert atmosphere;	4.2 Step 2. 7 -Azido-l -(methylsulfonyl)-2-heptyl N-(2-methoxyethyl)-N-(methylene- olaparib) carbamate. In a heat-gun/vacuum dried round bottom flask, olaparib (44 mg, 0.10 mmol, 0.05 M final concentration) was suspended in 1.5 mL of THF under N2. The suspension was cooled in a -78 °C acetone/dry ice bath, and a 1.0 M solution of NaHMDS (100 pF, 100 pmol) in THF was added. The suspension turned purple. After stirring at -78 °C for 5 min, the reaction was air-warmed for 5 min. After recooling to -78 °C, a 0.3 M solution of 7-azido-l-(methylsulfonyl)-2-heptyl A-(2-methoxyethyl)- V-chloromethyl carbamate (0.43 mF, 0.13 mmol) in THF was added. The purple color was immediately consumed, and the resulting orange reaction was air-warmed. Within 20 min, the color changed from orange to bright yellow. After 2 h, the reaction mixture was partitioned between 40 mF of 1:1 EtOAc:H20. The layers were separated, and the organic phase was washed with H2O and brine (20 mF each). The organic layer was then separated, dried over MgSCL, filtered, and concentrated by rotary evaporation. The crude concentrate was purified by preparative HPFC. Clean product-containing fractions were combined and concentrated to by -50% to remove MeCN. The resulting aqueous concentrate was extracted with 40 mF EtOAc, and the organic phase was washed with H2O, NaHCCL (sat aq), and brine (40 mF each). The organic layer was then dried over MgSCL, filtered, and concentrated to dryness by rotary evaporation to provide the title compound (20 mg, 26 pmol, 26% yield) as a colorless oil.Ci8HPFC, purity was determined at 280 nm: 88.0% (RV = 9.87 mF).FC-MS (m/z): calc, 783.3; obsd, 783.4 [M+H]+.

Reference： [1]Current Patent Assignee: PROLYNX LLC - WO2021/41964, 2021, A1 Location in patent: Paragraph 0090; 0094

35
[ 763113-22-0 ]
[ 110-17-8 ]
[ 2624130-83-0 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol at 60℃; Autoclave;	1 Process to prepare Olaparib and fumaric acid (1:1) co-crystal: Dissolved Olaparib (10 g) and Fumaric acid (2.66 g) (1:1 mole/mole) in methanol (400 ml) at 60°C. Distilled off solvent under vacuum by using Buchi rotavapor at 60°C to get oily residue. Cooled the residue to 22°C-25°C. Collected the solid material and dried in VTD at 40°C for lhr to obtain the title compound. (0076) H-NMR reveals a molar ratio of Olaparib to fumaric acid of about 1:1. The crystallinity was confirmed by powder X-ray diffraction pattern as depicted in Fig 1. The DSC in Fig 2. gave an onset melting point at about 193.86°C. The product showed weight loss about 0.291% up to about 150°C by thermogravimetric analysis (TGA)
	In methanol at 20 - 40℃; for 12h;	1-7 In this example, a eutectic crystal form α of olaparib and fumaric acid was prepared, and the specific process was as follows: Weigh 600 mg of olaparib and 160 mg of fumaric acid, add 10 mL of n-heptane and 200 μL of methanol to obtain a suspension, place the suspension at room temperature and stir for 12 h, filter, and dry the white solid at 40°C under vacuum to obtain The eutectic form α of olaparib and fumaric acid.

Reference： [1]Current Patent Assignee: CIPLA LTD - WO2021/44437, 2021, A1 Location in patent: Page/Page column 12
[2]Current Patent Assignee: TIANJIN UNIVERSITY OF TECHNOLOGY - CN113636979, 2021, A Location in patent: Paragraph 0048-0104

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CAS No. :	763113-22-0	MDL No. :	MFCD13185161
Formula :	C₂₄H₂₃FN₄O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FDLYAMZZIXQODN-UHFFFAOYSA-N
M.W :	434.46	Pubchem ID :	23725625
Synonyms :	AZD2281;KU0059436;Olaparib. trade name Lynparza.;KU59436

Num. heavy atoms :	32
Num. arom. heavy atoms :	16
Fraction Csp3 :	0.33
Num. rotatable bonds :	6
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	125.21
TPSA :	86.37 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-7.6 cm/s

Log Po/w (iLOGP) :	2.84
Log Po/w (XLOGP3) :	1.9
Log Po/w (WLOGP) :	1.94
Log Po/w (MLOGP) :	3.09
Log Po/w (SILICOS-IT) :	4.14
Consensus Log Po/w :	2.78

[ CAS No. 763113-22-0 ] {[proInfo.proName]}

Quality Control of [ 763113-22-0 ]

Related Doc. of [ 763113-22-0 ]

Product Details of [ 763113-22-0 ]

Calculated chemistry of [ 763113-22-0 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 763113-22-0 ]

Application In Synthesis of [ 763113-22-0 ]

[ 763113-22-0 ] Synthesis Path-Downstream 1~35

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

Log S (ESOL) :	-3.7
Solubility :	0.0858 mg/ml ; 0.000197 mol/l
Class :	Soluble
Log S (Ali) :	-3.34
Solubility :	0.2 mg/ml ; 0.000461 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-6.61
Solubility :	0.000108 mg/ml ; 0.000000248 mol/l
Class :	Poorly soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.15

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:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling