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CAS No. : | 763114-26-7 | MDL No. : | MFCD14636678 |
Formula : | C16H11FN2O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PAXLJNGPFJEKQX-UHFFFAOYSA-N |
M.W : | 298.27 | Pubchem ID : | 24811740 |
Synonyms : |
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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: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95%, 95% | With methanesulfonic acid; sodium methylate In methanol | b. 2-Fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)benzoic acid (B) Dimethyl phosphite (22.0 g, 0.2 mol) was added drop-wise to a solution of sodium methoxide (43.0 g) in methanol (100 ml) at 0° C. 2-Carboxybenzaldehyde (21.0 g, 0.1 mol) was then added portion-wise to the reaction mixture as a slurry in methanol (40 ml), with the temperature kept below 5° C. The resulting pale yellow solution was warmed to 20° C. over 1 hour. Methanesulphonic acid (21.2 g, 0.22 mol) was added to the reaction drop-wise and the resulting white suspension was evaporated in vacuo. The white residue was quenched with water and extracted into chloroform (3*100 ml). The combined organic extracts were washed with water (2*100 ml), dried over MgSO4, and evaporated in vacuo to yield (3-oxo-1,3-dihydro-isobenzofuran-1-yl)phosphonic acid dimethyl ester as a white solid (32.0 g, 95percent, 95percent purity). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: at 8 - 25℃; for 4 h; Stage #2: With water; sodium hydroxide In acetone at 20 - 90℃; for 1 h; |
S3, 10.6 g (40 mmol) of the solid obtained in the step S2 and 80 mL of water were added to the flask, and the mixture was cooled to 8 ° C, and 2.90 mL (60 mmol) of the mass fraction of 80percent hydrazine was added dropwise, and then returned to 25 ° C, and stirring was continued. , react 4h, then join4mL of acetone was stirred for 30min, then added with 13mL of 4mol / L NaOH aqueous solution heated to 90 ° C for 1h, cooled to room temperature, the aqueous phase was extracted with 45mL of methyl tert-butyl ether, and then adjusted to a pH of about 4 with hydrochloric acid, a white solid precipitated , filtered, 40mL cold water floatWashed and recrystallized from ethyl acetate to give 9.7 g of a white solid, yield: 91percent. |
91% | With hydrazine hydrate; sodium hydroxide In ethanol at 70℃; for 0.166667 h; | (3) A solution of sodium hydroxide (0.105 mol) in ethanol (50 mL) and hydrazine hydrate (17 mL) were stirred at a temperature of 70 ° C to obtain a homogeneous mixed solution pumped from the pump E 10 to the third mixing valve 11, pump E11. The flow rate was 2.2 mL/min; and the reaction effluent obtained in the step (2) was 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-ylmethylene)benzonitrile.(0.022 mol) flowed into the third mixing valve at a flow rate of 1.56 mL/min. After thorough mixing, the pump was pumped into a third microreactor in the third continuous microchannel reaction unit for reaction at a reaction temperature of 70 ° C and a residence time of 10 min, the first receiving device 13The reaction effluent was collected, the reaction effluent was cooled to room temperature, and 2 mol/L of dilute hydrochloric acid was added to adjust the pH to 4, stirred for 20 min, and then poured into water (50 mL) and ethyl acetate (50 mL), and the mixture was separated, filtered, washed. And dry to get the anti-tumor drug olapa2-fluoro-5-[(4-oxo-3,4-dihydronaphthyridin-1-yl)methyl]benzoic acid(Compound 3), the yield was 91percent. |
77% | Stage #1: at 90℃; for 1 h; Stage #2: at 70℃; for 18 h; |
13N sodium hydroxide solution (50 mL) was added to an aqueous solution (200 mL) containing compound f (37 g, 0.14 mol), and the mixture was heated to 90 ° C for 1 hour. After the reaction was reduced to 70 ° C, hydrazine hydrate (100 mL, 2 mol) was added and the temperature was stirred for 18 hours. The reaction solution was cooled to room temperature and the above system was adjusted to pH = 4 with 8N hydrochloric acid. The filter was washed twice with water (60 mL), twice with diethyl ether (50 mL) and dried in vacuo to give a white solid g: 5 - ((4-oxo-3,4-dihydrazizin-1-yl) methyl) benzoic acid (30.1 g, yield 77percent). |
70 g | Stage #1: With sodium hydroxide In water at 20 - 70℃; Stage #2: With hydrogenchloride; hydrazine hydrate In water at 20 - 70℃; |
The above semi dried compound 2-fluoro-5-[(3-oxo-2-benzofuran-1 {3H)- ylidene)methyl] benzonitrile (IV) as obtained by example-1 was suspended in water (500 imL) at room temperature followed by addition of aqueous solution of NaOH (50 g). The resulting reaction mixture was stirred at 60°C to 70 °C. After completion of the hydrolysis, it was cooled to room temperature and acidified by addition of cone. HCI until the pH was changed to 5-6. Then hydrazine hydrate (1 67 g) was added. The resulting reaction mass was stirred at 60°C to 70 °C. The reaction mass was cooled to room temperature, acidified by addition of cone. HCI until the pH was changed 4.0-4.5. The stirring was continued further at room temperature. The obtained precipitate was filtered and washed with water. The crude compound was purified by using isopropanol (or any other polar solvent) to afford pure 2- fluoro-5-[(4-oxo-3,4-di hydrophthalazin-1 -yl)methyl]benzoic acid (V) as a solid (70 g). (Yield: 68percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95%, 95% | With methanesulfonic acid; sodium methylate In methanol | b. 2-Fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)benzoic acid (B) Dimethyl phosphite (22.0 g, 0.2 mol) was added drop-wise to a solution of sodium methoxide (43.0 g) in methanol (100 ml) at 0° C. 2-Carboxybenzaldehyde (21.0 g, 0.1 mol) was then added portion-wise to the reaction mixture as a slurry in methanol (40 ml), with the temperature kept below 5° C. The resulting pale yellow solution was warmed to 20° C. over 1 hour. Methanesulphonic acid (21.2 g, 0.22 mol) was added to the reaction drop-wise and the resulting white suspension was evaporated in vacuo. The white residue was quenched with water and extracted into chloroform (3*100 ml). The combined organic extracts were washed with water (2*100 ml), dried over MgSO4, and evaporated in vacuo to yield (3-oxo-1,3-dihydro-isobenzofuran-1-yl)phosphonic acid dimethyl ester as a white solid (32.0 g, 95percent, 95percent purity). |
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.9% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20 - 23℃; | Example 1; 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (231 g, 1206.97 mmol) was added to 4-methoxypiperidine hydrochloride (183 g, 1206.97 mmol), 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (300 g, 1005.80 mmol) and 4-dimethylaminopyridine (30.7 g, 251.45 mmol) in DCM (4 L) at 23° C. The resulting suspension was stirred at room temperature over night. The reaction mixture was washed with 2M HCl (5 L) and 50percent saturated sodium carbonate (3 L) before being dried over MgSO4, filtered and reduced in-vacuo to give the crude product. This was then slurried in 750 ml of ethyl acetate for 5 days, and then filtered and dried at 45° C. for 5 hours to afford 4-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (compound 1)(290 g, 72.9percent).1H NMR (400.132 MHz, DMSO) δ 1.26-1.35 (1H, m), 1.40-1.49 (1H, m), 1.69-1.73 (1H, m), 1.84-1.89 (1H, m), 2.99-3.07 (1H, m), 3.25 (3H, s), 3.27-3.34 (2H, m), 3.39-3.44 (1H, m), 3.86-3.95 (1H, m), 4.33 (2H, s), 7.19-7.24 (1H, m), 7.33-7.35 (1H, m), 7.39-7.43 (1H, m), 7.81-7.91 (2H, m), 7.97 (1H, d), 8.27 (1H, d), 12.57 (1H, s); m/z (ES+) (M+H)+=396.31; HPLC tR=1.90 min.FIG. 1 shows the powder XRD pattern of the material produced, which is in Form C.FIG. 2 shows the DSC analysis of the material produced. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.6% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In DMA at 20℃; for 21 h; | a) Resynthesis of 2b O-Benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (45.5 g, 119.86 mmol) was added portionwise to a solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (27.5 g, 92.20 mmol), 4-methoxypiperidine (11.68 g, 101.42 mmol) and triethylamine (30.8 mL, 221.28 mmol) in DMA (450 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 21 hours. The solution was poured into water (2.5 litres) and extracted with EtOAc (*3), the combined extracts washed with brine (*3), dried (MgSO4), filtered and evaporated to a gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 100percent EtOAc in isohexane. Pure fractions were evaporated to dryness and slurried with EtOAc to afford 4-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (2b) (22.45 g, 61.6percent) as a white solid after filtration and vacuum drying. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 24h; | Preparation of tert-butyl 4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l -yl) methyl) benzoyl)- 1,4-diazepane- l-carboxylate2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl) methyl) benzoic acid (lOOmg, 0.335mmol), tert-butyl 1 ,4-diazepane-l -carboxylate (201mg, lmmol), HATU (255mg, 0.67mmol), and DIPEA (0.5ml, 2.88mmol) were dissolved in DMF (30ml) and stirred at room temperature for 24h. The reaction mixture was partitioned between DCM and water (50ml each), and the organic phase was washed with aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to get the crude product (370mg) as brown oil, used in next step without further purification.m/z [M-Boc-l ]" 379.HNMR(CDC13): delta 10.55-10.44 (lH, m), 8.43 (1H, m), 7.76 (3H, m), 7.27 (2H, m), 7.05-6.98 (1H, m), 4.26 (2H, s), 3.78-3.26 (8H, m), 2.10-1.55 (2H, m), 1.47 (9H, s) | |
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 24h; | 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin- 1 -yl)methyl)benzoic acid (100 mg, 0.335 mmol), tert-butyl10161] 1,4-diazepane-1-carboxylate (201 mg, 1 mmol),HATU (255 mg, 0.67 mmol), and DIPEA (0.5 ml, 2.88 mmol)were dissolved in DMF (30 ml) and stirred at room temperature for 24 h. The reaction mixture was partitioned between DCM and water (50 ml each), and the organic phase was washed with aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to get the crude product (370 mg) as brown oil, used in next step without further purification. m/z [M-Boc] 37910163] 1HNMR (CDC13): delta 10.55-10.44 (1H, m), 8.43 (1H,m), 7.76 (3H, m), 7.27 (2H, m), 7.05-6.98 (1H, m), 4.26 (2H, s), 3.78-3.26 (8H, m), 2.10-1.55 (2H, m), 1.47 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | To a suspension of 2-FLUORO-5- (3-OXO-3H-ISOBENZOFURAN-L- ylidenemethyl) benzonitrile in water (200 ml) was added aqueous sodium hydroxide (26.1 g in 50 ml water) solution and the reaction mixture was heated under nitrogen to 90oC for 30 minutes. The reaction mixture was partially cooled to 70oC, and hydrazine hydrate (100 ml) was added and stirred for 18 hours at 70oC. The reaction was cooled to room temperature and acidified with 2M HC1 to pH 4. The mixture was stirred for 10 min and filtered. The resulting solid was washed with water, hexane, ether, ethyl acetate and dried to yield 2-FLUORO-5- (4-OXO-3, 4- dihydrophthalazin-1-ylmethyl) benzoic acid as a pale pink powder (30.0 g, 77 %). m/z [M+1] + 299 (96 % purity), 5H 4.4 (2H, s), 7.2-7. 3 (1H, m), 7.5-7. 6 (1H, m), 7. 8-8.0 (4H, m), 8.2-8. 3 (1H, m), 12.6 (LH, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 20℃; for 16h; | 2-FLUORO-5- (4-OXO-3, 4-DIHYDROPHTHALAZIN-1-YLMETHYL) BENZOIC acid (B) (0.24 mmol) was added to a solution of the appropriate amine (0.2 mmol) in dimethylacetamide (2 ml). 2-(1H-BENZOTRIAZOL-1-YL)-1, 1, 3,3- tetramethyluronium hexafluorophosphate (0.3 mmol) and Hunigs base (0.4 mmol) were then added and the reaction was stirred at room temperature for 16 hours. The reaction mixtures were then purified by preparative HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium hydroxide; hydrazine hydrate; In water; | To a suspension of 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-ylidenemethyl)benzonitrile in water (200 ml) was added aqueous sodium hydroxide (26.1 g in 50 ml water) solution and the reaction mixture was heated under nitrogen to 90 C. for 30 minutes. The reaction mixture was partially cooled to 70 C., and hydrazine hydrate (100 ml) was added and stirred for 18 hours at 70 C. The reaction was cooled to room temperature and acidified with 2M HCl to pH 4. The mixture was stirred for 10 min and filtered. The resulting solid was washed with water, hexane, ether, ethyl acetate and dried to yield 2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid as a pale pink powder (30.0 g, 77%). m/z [M+1]+ 299 (96% purity), deltaH 4.4 (2H, s), 7.2-7.3 (1H, m), 7.5-7.6 (1H, m), 7.8-8.0 (4H, m), 8.2-8.3 (1H, m), 12.6 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With diphenyl phosphoryl azide; triethylamine; In acetonitrile; at 85℃; for 1.25h; | A solution of methyl 2-(2-(pyrrolidin-1-yl)ethylamino)propanoate (32)(135 g, 613.54 mmol) in acetonitrile (1226 ml, 6.7 vol) was added dropwise to a stirred slurry of <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid</strong> (33)(183 g, 613.54 mmol), and triethylamine (188 ml, 1349.79 mmol) in acetonitrile (20 vol) (3652 ml) at 85 C., over a period of 10 minutes under nitrogen. To the resulting suspension was added a solution of diphenyl phosphorazidate (145 ml, 674.90 mmol) in acetonitrile (604 ml, 3.3 vol) dropwise over 5 minutes and the reaction was allowed to stir for 1 hour. The reaction mixture was evaporated to dryness and redissolved in DCM (1830 ml, 10 vol), and washed sequentially with water (1830 ml×2, 10 vol×2), saturated NaHCO3 (1830 ml, 10 vol), and saturated brine (1830 ml, 10 vol). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 3 to 5% methanolic ammonia in DCM. Pure fractions were evaporated to dryness to afford 3-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl )methyl)phenyl)-5-methyl-1-(2-(pyrrolidin-1-yl)ethyl)imidazolidine-2,4-dione (9)(271 g, 95%) as a white foam. 1H NMR (400.132 MHz, DMSO) delta 1.41 (3H, d), 1.60-1.72 (4H, m), 2.46 (4H, d), 2.55-2.66 (2H, m), 3.20-3.31 (1H, m), 3.65 (1H, t), 4.31-4.44 (3H, m), 7.34 (2H, dd), 7.46-7.53 (1H, m), 7.84 (1H, td), 7.90 (1H, td), 7.98 (1H, d), 8.27 (1H, dd), 12.62 (1H, s) |
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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | <strong>[763114-26-7]5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid</strong> (8.9 g, 30.0 mmol), 1 - tert-butoxycarbonyl piperazine (6.70 g, 36.0 mmol), HBTU (13.6 g, 36.0 mmol) and TEA (8.3 ml, 60.0 mmol) is added to the 250 ml round-bottom flask, add DMF 60 ml, stir at room temperature 2 h. Adding 60 ml water, the mixed solution is put in 5 C, more than 1 h after filtering, and sequentially to cooling of the DMF - H2O (1:1) (2 × 20 ml), water (2 × 20 ml), cooling of the isopropanol (2 × 20 ml) and cooled ethyl ether (2 × 20 ml) washing the filter cake, dried to obtain the title compound (13.6 g, white solid, yield 96%). |
78 - 100% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 15 - 25℃; for 2h;Product distribution / selectivity; | Example 1 : Synthesis of compound AStarting material (D) was synthesised by the method disclosed in WO 2004/080976MethodsPreparative HPLCSamples were purified with a Waters mass-directed purification system utilising a Waters 600LC pump, Waters Xterra C18 column (5 mum 19 mm x 50 mm) and Micromass ZQ mass spectrometer, operating in positive ion electrospray ionisation mode. Mobile phases A (0.1% formic acid in water) and B (0.1 % formic acid in acetonitrile) were used in a gradient; 5% B to100% over 7 min, held for 3 min, at a flow rate of 20 ml/ min.Analytical HPLC-MS Analytical HPLC was carried out with a Spectra System P4000 pump and Jones Genesis C18 column (4 mum, 50 mm x 4.6 mm). Mobile phases A (0.1 % formic acid in water) and B (acetonitrile) were used in a gradient of 5 % B for 1 min rising to 98 % B after 5 min, held for 3 min at a flow rate of 2 ml / min. Detection was by a TSP UV 6000LP detector at 254 nm UV and range 210-600 nm PDA. The Mass spectrometer was a Finnigan LCQ operating in positive ion electrospray mode.NMR1H NMR spectra were recorded using Bruker DPX 300 spectrometer at 300 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. <n="24"/>(a) 4-[2-Fluoro-5-(4-oxo-3, 4-dihydro-phthalazin- i-ylmethylj-benzoylj-piperazine-i-carboxylic acid tert-butyl ester (C)To a stirred solution of the starting material D (850 g) in dimethylacetamide (DMA) (3561 ml) at room temperature under nitrogen was added HBTU (2-(1 H-benzotriazol-1-yl)-1 , 1 ,3,3- tetramethyluronium hexafluorophosphate) (1402 g) in one portion. Hnig's base (JPr2NEt, 1096 ml) was then added with the temperature kept between 15 to 250C followed by a solution of 1- Boc-piperazine (637 g) in DMA (1428 ml) with the temperature kept between 15 to 25C.The solution was stirred at room temperature for 2 hours and sampled for completion (HPLC). Upon completion the solution was added to vigorously stirred water (17085 ml) with the temperature kept between 15 to 250C and the solid filtered off, washing with water (2 x 7131 ml), hexane (2 x 7131 ml) and methyl tert-butyl ether (MTBE) (2 x 3561 ml). The solid was then dried overnight and then sampled for water content and chemical purity.This reaction was then repeated, see table:a. Greater than 100% yield attributed to non-representative sampling |
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 24h; | Preparation of tert-butyl4-(2-fluoro-5 -((4-0X0-3 ,4-dihydrophthalazin- 1 -yl )methyl)benzoyl)piperazin- 1 - -carboxylate2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl)benzoic acid (lOOmg, 0.33mmol), tert-butyl piperazine-1 -carboxylate (187.3mg, l .Ommol), HATU (255mg, 0.67mmol), and DIPEA (0.5ml, 3.0mmol) were dissolved in DMF (25ml) and stirred at room temperature for 24h. The reaction mixture was partitioned between DCM and water (50ml each), and the organic phase was washed with aqueous sodium bicarbonate and brine, dried over sodium sulphate, filtered, and concentrated to get the crude product. Then the crude product was purified by column chromatography on silica gel (Petroleum ether : Ethyl Acetate=l :3) to afford target compound (l OOmg, 64%) as a white solid.'HNMR CDCh): delta 10.39(1H. s), 8.47(1H, m), 7.79-7.70(3H, m), 7.34-7.26(2H, m), 7.04(1 H, m), 4.28(2H, s), 3.75-3.27(8H, m), 1.47(9H, s) |
100 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℃; for 24h; | Preparation of tert-butyl-4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-carboxylate <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid</strong> (100 mg, 0.33 mmol), tert-butyl piperazine-1-carboxylate (187.3 mg, 1.0 mmol), HATU (255 mg, 0.67 mmol), and DIPEA (0.5 ml, 3.0 mmol) were dissolved in DMF (25 ml) and stirred at room temperature for 24 h. The reaction mixture was partitioned between DCM and water (50 ml each), and the organic phase was washed with aqueous sodium bicarbonate and brine, dried over sodium sulphate, filtered, and concentrated to get the crude product. Then the crude product was purified by column chromatography on silica gel (Petroleum ether:Ethyl Acetate=1:3) to afford target compound (100 mg, 64%) as a white solid. 1HNMR (CDCl3): delta 10.39 (1H, s), 8.47 (1H, m), 7.79-7.70 (3H, m), 7.34-7.26 (2H, m), 7.04 (1H, m), 4.28 (2H, s), 3.75-3.27 (8H, m), 1.47 (9H, s) |
To a stirred suspension of <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid</strong> (0.1 g, 0.335 mmol) in DMA (4 mL) was added HBTU (0.15 g, 0.402 mmol, 1.2 eq) at 0 C and the mixture was stirred for 10 min. DIPEA (0.17 mL, 1 mmol, 3 eq) and tert-butyl piperazine-1-carboxylate (0.075 g, 0.402 mmol, 1.2 eq) were then successively added to the reaction mixture at 0 C and the resultant reaction mixture was stirred at RT for 75 min. The reaction was monitored by TLC. After completion, water (10 mL) was added and the resulting precipitate was filtered via a Buechner funnel. The product obtained was washed with water (10 mL × 2) and n-pentane (10 mL × 2), dried under reduced pressure to afford tert-butyl 4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin -1- yl)methyl)benzoyl)piperazine-1-carboxylate which was taken to next step without further purification. LC-MS 467 [M+H]+. |
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%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(c) 2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D) 2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzonitrile (ED) (9.60 g, 34.37 mmol) and water (40 ml) were stirred at 200C. 2M Sodium hydroxide (36 ml, 72.00 mmol) was added, the reaction mixture warmed to 9O0C and held at this temperature overnight. The reaction mixture was cooled to room temperature and filtered. The filter pad was washed with water (10 ml) and the combined filtrate added to 2M HCI (56 ml, 112.00 mmol) at 600C over 40 minutes. The resulting suspension was cooled to 50C and filtered, washed with water (57 ml) and dried in vacuo at up to 6O0C to give the title compound as a white solid (9.72 g).Mass Spectrum: MH+ 2991 H NMR (400MHz. DMSO-d6) delta: 4.36 (s, 2H), 7.24 (dd, 1 H), 7.59 (m, 1 H), 7.84 (dt, 2H), 7.90(dt, 1 H), 7.98 (d, 1 H), 8.27 (dd, 1 H), 12.59 (s, 1 H), 13.22 (br s, 1 H). | ||
With hydrogenchloride; water; at 20℃; | Preparation of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid To the mixture of 2-fluoro-5-((3-oxoisobenzofuran-1(3H)-ylidene)methyl)benzonitrile (1.2 g, 4.5 mmol) in water (6.5 ml) was added aqueous sodium hydroxide (0.84 g in 1.6 ml of water) drop-wise, then heated at 90 for 1 h. After cooled to 70, hydrazine hydrate (6.4 ml) was added and the reaction mixture was heated at 70 for overnight. Then the reaction mixture was cooled to room temperature, and adjusted to PH 3-4 by adding aqueous HCl (2N). The precipitated solid was collected by filtration, washed with water, and dried in vacuo to afford the target compound (0.9 g, 70%) as a pink solid, used in next step without further purification. m/z [M-1]- 296.90 1HNMR (DMSO-d6): delta 13.22 (1H, brs), 12.61 (1H, s), 8.27 (1H, m), 7.99-7.81 (4H, m), 7.59 (1H, m), 7.25 (1H, m), 4.36 (2H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.2% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In ISOPROPYLAMIDE; at 20℃; | Example 31; (a) 4-(3-(4-tert-butoxypiperidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (70) A solution of <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid</strong> (1) (650 mg, 2.18 mmol) and 4-tert-butoxypiperidine (350 mg, 2.23 mmol) in N,N-dimethylacetamide (11 mL) was treated with triethylamine (0.750 mL, 5.38 mmol) and O-benzotriazol-1-yl-N,N,N',N'-tetra-methyluronium hexafluorophosphate (1.15 g, 3.03 mmol) The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was poured onto water (200 mL) and resultant solid collected by suction filtration and dried to afford the crude product, which was purified by flash silica chromatography, elution gradient 2 to 10% methanol in dichloromethane. Pure fractions were evaporated to dryness and dried under vacuum to afford the desired material as a white solid (460 mg, 48.2% yield); 1H NMR (400.132 MHz, DMSO) delta 1.14 (9H, s), 1.19-1.38 (2H, m), 1.53-1.60 (1H, m), 1.70-1.77 (1H, m), 3.02-3.10 (1H, m), 3.16-3.28 (2H, m), 3.70-3.77 (1H, m), 4.02-4.10 (1H, m), 4.33 (2H, s), 7.20 (1H, t), 7.31-7.35 (1H, m), 7.38-7.42 (1H, m), 7.81-7.90 (2H, m), 7.97 (1H, d), 8.27 (1H, dd), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=2.13 (M+H 438.2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.1% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl acetamide; at 20℃; for 5h; | Example 6 4-(4-fluoro-3-(3H-spiro[isobenzofuran-1,4'-piperidine]-1'-ylcarbonyl)benzyl)phthalazin-1(2H)-one (9) A solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (144 mg, 0.48 mmol) and <strong>[37663-44-8]3H-spiro[isobenzofuran-1,4'-piperidine]hydrochloride</strong> (109 mg, 0.48 mmol) in N,N-dimethylacetamide (2 mL) was treated with triethylamine (0.168 mL, 1.21 mmol) and O-Benzotriazol-1-yl-N,N,N',N'-tetra-methyluronium hexafluorophosphate (256 mg, 0.68 mmol). The resulting mixture was stirred at ambient temperature for 5 hours, before being filtered and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5mu silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1percent NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness and lyophilised to afford the desired compound as a white solid (118 mg, 52.1percent yield); 1H NMR (400.132 MHz, DMSO) delta 1.53-1.62 (2H, m), 1.73-1.83 (3H, m), 1.91-1.99 (1H, m), 3.10-3.18 (1H, m), 4.40 (2H, s), 4.54-4.60 (1H, m), 5.03-5.11 (2H, m), 7.26-7.37 (5H, m), 7.45-7.50 (2H, m), 7.83-7.93 (2H, m), 8.02 (1H, d), 8.30 (1H, d), 12.13-12.59 (1H, br s); m/z (LC-MS, ESI+), RT=2.14 (M+H 470.9). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.63% | Stage #1: 2-fluoro-5-[(4’-oxo-3’H-phthalazin-1’-yl)methyl]benzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 25℃; for 0.166667h; Stage #2: 4-methylpiperidin-4-ol hydrochloride With triethylamine In N,N-dimethyl-formamide at 25℃; for 2h; | 35.a (a) 4-(4-fluoro-3-(4-hydroxy-4-methylpiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (74) O-Benzotriazol-1-yl-N,N,N',N'-tetra-methyluronium hexafluorophosphate (572 mg, 1.51 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (300 mg, 1.01 mmol) and triethylamine (0.308 mL, 2.21 mmol) in N,N-dimethylformamide (3 mL) at 25° C. under an air atmosphere. The resulting solution was stirred at 25° C. for 10 minutes. A solution of 4-methylpiperidin-4-ol hydrochloride (154 mg, 1.02 mmol) and triethylamine (0.308 mL, 2.21 mmol) in N,N-dimethylformamide (1 mL) was added dropwise and the resulting solution stirred at 25° C. for 2 hours. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with water (3*50 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a gum (94 mg, 23.63% yield); 1H NMR (400.132 MHz, DMSO) δ 1.13 (3H, s), 1.29-1.47 (4H, m), 3.20-3.28 (4H, m), 4.32 (2H, s), 4.41 (1H, s), 7.19 (1H, d), 7.31 (1H, dd), 7.38-7.42 (1H, m), 7.83 (1H, td), 7.88 (1H, td), 7.96 (1H, d), 8.27 (1H, dd), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=1.45 (M+H 396.4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.3% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl acetamide; at 20℃; for 4.5h; | Example 4 4-(4-fluoro-3-(4-(2-methoxyethoxy)piperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (7) A solution of <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid</strong> (1) (150 mg, 0.50 mmol) in N,N-dimethylacetamide (4 mL) was treated with 4-(2-methoxyethoxy)piperidine hydrochloride (103 mg, 0.53 mmol) and triethylamine (0.210 mL, 1.51 mmol). O-Benzotriazol-1-yl-N,N,N',N'-tetra-methyluronium hexafluorophosphate (253 mg, 0.67 mmol) was added and the resulting solution was stirred at ambient temperature for 4.5 hours. The crude reaction mixture was filtered before being purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5mu silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness and lyophilised to afford a gum, which was taken up in a small amount of diethyl ether and dichloromethane and allowed to evaporate before drying under vacuum, at 55 C., for 2 hours to afford the desired compound as a white solid (151 mg, 68.3% yield); 1H NMR (400.132 MHz, DMSO) delta 1.28-1.36 (1H, m), 1.40-1.49 (1H, m), 1.68-1.75 (1H, m), 1.82-1.90 (1H, m), 2.99-3.06 (1H, m), 3.25 (3H, s), 3.26-3.32 (2H, m), 3.44 (2H, t), 3.53-3.58 (3H, m), 3.90-3.98 (1H, m), 4.33 (2H, s), 7.21 (1H, t), 7.33-7.35 (1H, m), 7.39-7.43 (1H, m), 7.81-7.91 (2H, m), 7.97 (1H, d), 8.27 (1H, dd), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=1.65 (M+H 440.6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.6% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In DMA at 20℃; for 21h; | 47.a a) Resynthesis of 2b O-Benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (45.5 g, 119.86 mmol) was added portionwise to a solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (27.5 g, 92.20 mmol), 4-methoxypiperidine (11.68 g, 101.42 mmol) and triethylamine (30.8 mL, 221.28 mmol) in DMA (450 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 21 hours. The solution was poured into water (2.5 litres) and extracted with EtOAc (*3), the combined extracts washed with brine (*3), dried (MgSO4), filtered and evaporated to a gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness and slurried with EtOAc to afford 4-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (2b) (22.45 g, 61.6%) as a white solid after filtration and vacuum drying. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.4% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl acetamide; at 20℃; | c) Resynthesis of 2f A solution of <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid</strong> (1) (27.07 g, 90.76 mmol) and 4-ethoxypiperidine (12.11 g, 93.73 mmol) in N,N-dimethylacetamide (422 ml) was treated with triethylamine (31.6 ml, 226.89 mmol) and stirred for 5 minutes before portionwise addition, over 10 minutes, of O-benzotriazol-1-yl-N,N,N',N'-tetra-methyluronium hexafluorophosphate (48.6 g, 128.15 mmol). The resulting solution was stirred at ambient temperature, under nitrogen, overnight, before being poured onto water (2.5 L). The mixture was split into two batches and each batch was extracted with ethyl acetate (2*750 mL). Combined extracts were washed with brine (~500 mL per batch) and dried over magnesium sulfate, filtered and evaporated to afford an amber gum (54 g), which was purified by flash silica chromatography, eluding isocratically with neat EtOAc. Pure fractions were evaporated to dryness to afford a sticky foam, which was dissolved, with gentle heating in a small amount (~50 mL) of EtOAc. This solution was then concentrated a little by rotary evaporation and left to stand. The resultant solid was slurried in ethyl acetate for ~7 hours before standing overnight. The solid was then collected by suction filtration and dried, under vacuum, at 55 C., for several hours to afford the product as a white solid (20.1 g). This material required further purification, thus material was taken up in diethyl ether (~75-100 mL) and stirred for 2 hours. Solid was then again collected by suction filtration and dried before combining with material which had been kept separate and slurried in ethyl acetate (~60 mL) for several hours. Mixture was stood over a weekend before collecting solid by suction filtration, washing with a little more ethyl acetate and drying under vacuum, at 55 C., to constant weight to afford 4-(3-(4-ethoxypiperidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (2f) (21.70 g, 58.4%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.7% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 25℃; for 4h; | (d) 4-[[4-fluoro-3-(4-methoxy-4-methylpiperidine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one (24) O-(1H-Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.597 g, 1.57 mmol) was added in one portion to <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid</strong> (1) (0.188 g, 0.63 mmol) and triethylamine (0.193 mL, 1.39 mmol) in N,N-dimethylformamide (2 mL) at ambient temperature under an air atmosphere. The resulting solution was stirred at 25 C. for 15 minutes. A solution of 4-methoxy-4-methylpiperidine (23) (89.5 mg, 0.69 mmol) in N,N-dimethylformamide (1 mL) was added dropwise and the resulting solution was stirred at 25 C. for 4 hours. The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5mu silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a solid (0.110 g, 42.7%); 1H NMR (400.132 MHz, DMSO) delta 1.11 (3H, s), 1.25-1.34 (1H, m), 1.42 (1H, td), 1.56 (1H, d), 1.75 (1H, dd), 3.10-3.18 (4H, m), 4.09 (3H, q), 4.32 (2H, s), 7.21 (1H, t), 7.31 (1H, dd), 7.39-7.43 (1H, m), 7.83 (1H, td), 7.88 (1H, td), 7.96 (1H, dd), 8.27 (1H, dd), 12.57 (1H, s); m/z (LC-MS, ESI+), RT=1.79 (M+H 409). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.6% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 25℃; for 4h; | Example 8 4-(4-fluoro-3-(4-isopropoxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (11) A solution of 4-isopropoxypiperidine hydrochloride (120 mg, 0.67 mmol) and triethylamine (0.206 mL, 1.48 mmol), in N,N dimethylformamide (2 mL) was added in one portion to a stirred solution of <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid</strong> (1) (200 mg, 0.67 mmol), triethylamine (0.206 mL, 1.48 mmol) and O-Benzotriazol-1-yl-N,N,N',N'-tetra-methyluronium hexafluorophosphate (381 mg, 1.01 mmol) in N,N dimethylformamide (2 mL) at 25 C. The resulting solution was stirred at 25 C. for 4 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5mu silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (172 mg, 60.6% yield); 1H NMR (399.902 MHz, DMSO) delta 1.06-1.11 (6H, m), 1.21-1.46 (2H, m), 1.61-1.87 (2H, m), 3.04 (1H, t), 3.62 (2H, td), 3.70 (1H, quintet), 3.92-4.01 (1H, m), 4.07 (1H, q), 4.33 (2H, s), 7.19-7.25 (1H, m), 7.32-7.37 (1H, m), 7.38-7.44 (1H, m), 7.81-7.92 (2H, m), 7.96-8.00 (1H, m), 8.26-8.29 (1H, m), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.98 (M+H 424.6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 2h; | 12.c (c) 4-(3-(4-(difluoromethoxy)piperidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (19) 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), 4-(difluoromethoxy)piperidine (18) (0.101 g, 0.67 mmol) and O-benzotriazol-1-yl-N,N,N',N'-tetra-methyluronium hexafluorophosphate (0.381 g, 1.01 mmol) were added to N,N-dimethylformamide (30 mL). To this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and the reaction was stirred for 2 hours before being purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to the desired compound as a white solid (0.266 g, 92%); 1H NMR (400.132 MHz, DMSO) δ 1.53-1.45 (1H, m), 1.65-1.56 (1H, m), 1.83-1.74 (1H, m), 1.98-1.92 (1H, m), 3.15-3.09 (1H, m), 3.40-3.26 (2H, m), 4.01-3.91 (1H, m), 4.33 (2H, s), 4.41-4.35 (1H, m), 6.75 (1H, t), 7.22 (1H, t), 7.38-7.36 (1H, m), 7.44-7.40 (1H, m), 7.83 (1H, t), 7.88 (1H, t), 7.97 (1H, d), 8.27 (1H, d), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.98 (M+H 432). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 25℃; for 10h; | Example 13 4-[[4-fluoro-3-[4-(oxolan-2-ylmethoxy)piperidine-1-carbonyl]phenyl]methyl]-2H-phthalazin-1-one (20) O-Benzotriazol-1-yl-N,N,N',N'-tetra-methyluronium hexafluorophosphate (509 mg, 1.34 mmol) was added, in one portion, to <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid</strong> (200 mg, 0.67 mmol) and triethylamine (0.206 mL, 1.48 mmol) in N,N-dimethylformamide (2.5 mL), at 25 C. under an air atmosphere. The resulting solution was stirred at 25 C. for 10 minutes. A solution of 4-((tetrahydrofuran-2-yl)methoxy)piperidine hydrochloride (164 mg, 0.74 mmol) and triethylamine (0.206 mL, 1.48 mmol) in N,N-dimethylformamide (1 mL) was then added dropwise and the resulting solution stirred at 25 C. for 10 hours. The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5mu silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a solid (238 mg, 76%); 1H NMR (400.132 MHz, DMSO) delta 1.01 (2H, dt), 1.31-1.37 (1H, m), 1.43-1.50 (1H, m), 1.51-1.58 (1H, m), 1.68-1.73 (1H, m), 1.74-1.93 (4H, m), 3.00-3.07 (1H, m), 3.17-3.18 (1H, m), 3.39 (2H, d), 3.53-3.59 (1H, m), 3.70-3.75 (1H, m), 3.90 (2H, ddd), 4.33 (2H, s), 7.21 (1H, t), 7.33-7.35 (1H, m), 7.39-7.43 (1H, m), 7.83 (1H, td), 7.89 (1H, td), 7.97 (1H, d), 8.27 (1H, dd), 12.56 (1H, s) m/z (LC-MS, ESI+), RT=1.71 (M+H 466.5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.2% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In ISOPROPYLAMIDE; at 20℃; for 72h; | Example 19 4-(3-(4-(cyclopentyloxy)piperidine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (36) Triethylamine (0.280 ml, 2.01 mmol) was added in one portion to <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid</strong> (1) (200 mg, 0.67 mmol), 4-(cyclopentyloxy)piperidine hydrochloride (113 mg, 0.67 mmol) and O-benzotriazol-1-yl-N,N,N',N'-tetra-methyluronium hexafluorophosphate (331 mg, 0.87 mmol) in DMA (2 ml) at 20 C. under air. The resulting mixture was stirred at 20 C. for 3 days. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5mu silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (112 mg, 37.2% yield); 1H NMR (400.132 MHz, DMSO) delta 1.23-1.72 (11H, m), 1.81-1.87 (1H, m), 3.00-3.06 (1H, m), 3.22-3.27 (2H, m), 3.52-3.59 (1H, m), 3.96-4.04 (2H, m), 4.33 (2H, s), 7.18-7.23 (1H, m), 7.34 (1H, d), 7.38-7.42 (1H, m), 7.81-7.91 (2H, m), 7.97 (1H, d), 8.26 (1H, d), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=2.30 (M+H 450.1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 2h; | (f) 4-(4-fluoro-3-(4-(2-(pyrrolidin-1-yl)ethoxy)piperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (110) <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid</strong> (1) (0.20 g, 0.67 mmol) and HBTU (0.381 g, 1.01 mmol) were added to DMF (4 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 4-(2-(pyrrolidin-1-yl)ethoxy)piperidine (109) (0.133 g, 0.67 mmol). The reaction was stirred for 2 hours before being evaporated to dryness and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5mu silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (0.287 g, 89% yield); 1H NMR (400.132 MHz, CDCl3) delta 1.65-1.81 (6H, m), 1.87-1.96 (3H, m), 2.53-2.61 (3H, m), 2.65-2.72 (2H, m), 3.04-3.14 (1H, m), 3.38-3.57 (3H, m), 3.61 (2H, t), 3.97-4.06 (1H, m), 4.28 (2H, s), 7.01 (1H, t), 7.21-7.33 (2H, m), 7.68-7.80 (3H, m), 8.43-8.48 (1H, m), 9.85-9.95 (1H, m); m/z (LC-MS, ESI+), RT=1.88 (M+H 479.5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; for 2h; | (c) 4-(4-fluoro-3-(4-(2-oxo-2-(piperidin-1-yl)ethoxy)piperidine-1-carbonyl)benzyl)phthalazin-1 (2H)-one (113); <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid</strong> (1) (0.20 g, 0.67 mmol) and HBTU (0.381 g, 1.01 mmol) were added to DMA (4 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 1-(piperidin-1-yl)-2-(piperidin-4-yloxy)ethanone (112) (0.152 g, 0.67 mmol). The reaction was stirred for 2 hours before being evaporated to dryness and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5mu silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material (0.303 g, 89% yield); 1H NMR (400.132 MHz, DMSO) delta 1.07-1.39 (8H, m), 1.46-1.56 (1H, m), 1.61-1.71 (1H, m), 2.76-2.85 (1H, m), 3.02-3.09 (2H, m), 3.10-3.20 (4H, m), 3.34-3.41 (1H, m), 3.66-3.75 (1H, m), 3.90-3.93 (2H, m), 4.08-4.12 (2H, m), 6.99 (1H, t), 7.09-7.21 (2H, m), 7.57-7.69 (1H, m), 7.72-7.76 (1H, m), 8.02-8.06 (2H, m), 12.34 (1H, s); m/z (LC-MS, ESI+), RT=1.76 (M+H 507.5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.9% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20 - 23℃;Product distribution / selectivity; | Example 1; 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (231 g, 1206.97 mmol) was added to <strong>[4045-25-4]4-methoxypiperidine hydrochloride</strong> (183 g, 1206.97 mmol), 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (300 g, 1005.80 mmol) and 4-dimethylaminopyridine (30.7 g, 251.45 mmol) in DCM (4 L) at 23 C. The resulting suspension was stirred at room temperature over night. The reaction mixture was washed with 2M HCl (5 L) and 50% saturated sodium carbonate (3 L) before being dried over MgSO4, filtered and reduced in-vacuo to give the crude product. This was then slurried in 750 ml of ethyl acetate for 5 days, and then filtered and dried at 45 C. for 5 hours to afford 4-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (compound 1)(290 g, 72.9%).1H NMR (400.132 MHz, DMSO) delta 1.26-1.35 (1H, m), 1.40-1.49 (1H, m), 1.69-1.73 (1H, m), 1.84-1.89 (1H, m), 2.99-3.07 (1H, m), 3.25 (3H, s), 3.27-3.34 (2H, m), 3.39-3.44 (1H, m), 3.86-3.95 (1H, m), 4.33 (2H, s), 7.19-7.24 (1H, m), 7.33-7.35 (1H, m), 7.39-7.43 (1H, m), 7.81-7.91 (2H, m), 7.97 (1H, d), 8.27 (1H, d), 12.57 (1H, s); m/z (ES+) (M+H)+=396.31; HPLC tR=1.90 min.FIG. 1 shows the powder XRD pattern of the material produced, which is in Form C.FIG. 2 shows the DSC analysis of the material produced. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | S3, 10.6 g (40 mmol) of the solid obtained in the step S2 and 80 mL of water were added to the flask, and the mixture was cooled to 8 C, and 2.90 mL (60 mmol) of the mass fraction of 80% hydrazine was added dropwise, and then returned to 25 C, and stirring was continued. , react 4h, then join4mL of acetone was stirred for 30min, then added with 13mL of 4mol / L NaOH aqueous solution heated to 90 C for 1h, cooled to room temperature, the aqueous phase was extracted with 45mL of methyl tert-butyl ether, and then adjusted to a pH of about 4 with hydrochloric acid, a white solid precipitated , filtered, 40mL cold water floatWashed and recrystallized from ethyl acetate to give 9.7 g of a white solid, yield: 91%. | |
91% | With hydrazine hydrate; sodium hydroxide; In ethanol; at 70℃; for 0.166667h; | (3) A solution of sodium hydroxide (0.105 mol) in ethanol (50 mL) and hydrazine hydrate (17 mL) were stirred at a temperature of 70 C to obtain a homogeneous mixed solution pumped from the pump E 10 to the third mixing valve 11, pump E11. The flow rate was 2.2 mL/min; and the reaction effluent obtained in the step (2) was 2-fluoro-5-(3-oxo-3H-isobenzofuran-1-ylmethylene)benzonitrile.(0.022 mol) flowed into the third mixing valve at a flow rate of 1.56 mL/min. After thorough mixing, the pump was pumped into a third microreactor in the third continuous microchannel reaction unit for reaction at a reaction temperature of 70 C and a residence time of 10 min, the first receiving device 13The reaction effluent was collected, the reaction effluent was cooled to room temperature, and 2 mol/L of dilute hydrochloric acid was added to adjust the pH to 4, stirred for 20 min, and then poured into water (50 mL) and ethyl acetate (50 mL), and the mixture was separated, filtered, washed. And dry to get the anti-tumor drug olapa2-fluoro-5-[(4-oxo-3,4-dihydronaphthyridin-1-yl)methyl]benzoic acid(Compound 3), the yield was 91%. |
77% | 13N sodium hydroxide solution (50 mL) was added to an aqueous solution (200 mL) containing compound f (37 g, 0.14 mol), and the mixture was heated to 90 C for 1 hour. After the reaction was reduced to 70 C, hydrazine hydrate (100 mL, 2 mol) was added and the temperature was stirred for 18 hours. The reaction solution was cooled to room temperature and the above system was adjusted to pH = 4 with 8N hydrochloric acid. The filter was washed twice with water (60 mL), twice with diethyl ether (50 mL) and dried in vacuo to give a white solid g: 5 - ((4-oxo-3,4-dihydrazizin-1-yl) methyl) benzoic acid (30.1 g, yield 77%). |
67% | 2-Fluoro-5-[(3?-oxo-2?- benzofuran-l?-ylidene)methyl]benzonitrile (0.50 g, 1.89 mmol) was suspended in water (3 mL) and 13 M NaOH was added (0.67 mL). The mixture was heated to 90C and stirred for 24 h, after which it was cooled to 70C, followed by the addition of hydrazine monohydrate (1.34 mL, 26.9 mmol) and a further 72 h of stirring. The mixture was then cooled to room temperature and acidified with 8 M HC1 to an approximate pH of 4. The solid precipitate was collected by vacuum filtration and washed with water (3 x 25 mL) and Et20 (4 x 25 mL) affording 2-Fluoro-5-((4-oxo3,4-dihydrophthalazin-l-yl)methyl)benzoic acid (0.38 g, 67%) as a red solid (Menear, K.A., et al., ibid.). *H NMR (400 MHz, DMSO-d6) d = 12.57 (s, 1H), 8.26 (dd, J = 7.8, 0.8 Hz, 1H), 7.98 (d, / = 7.9 Hz, 1H), 7.93 - 7.86 (m, 1H), 7.86 - 7.79 (m, 2H), 7.61 - 7.54 (m, 1H), 7.23 (dd, J 10.8, 8.5 Hz, 1H), 4.35 (s, 2H); {}1^ NMR (376 MHz, DMSO-d6) d = -114.0; Mp: 217 - 219C. Data is in accordance with known literature (Menear, K.A., et al., ibid.). 4-(3-(4-(cyclopropanecabonyl)piperazine-l-carbnonyl)-4-fluorobenzyl)phthalazin- l(2H)-one (Olaparib) | |
Preparation of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-l-yl)methyl)benzoic acidTo the mixture of 2-fluoro-5-((3-oxoisobenzofuran-l(3H)-ylidene)methyl)benzonitrile (1.2g, 4.5mmol) in water (6.5 ml) was added aqueous sodium hydroxide (0.84g in 1.6ml of water) drop- wise, then heated at 90 C for 1 h. After cooled to 70 C , hydrazine hydrate (6.4ml) was added and the reaction mixture was heated at 70 C for overnight. Then the reaction mixture was cooled to room temperature, and adjusted to PH 3~4 by adding aqueous HCl (2N). The precipitated solid was collected by filtration, washed with water, and dried in vacuo to afford the target compound (0.9g, 70%) as a pink solid, used in next step without further purification.m/z [M-l]" 296.901HNMR(DMSO-d6): delta 13.22(1H, brs), 12.61(1H, s), 8.27(1H, m), 7.99-7.81(4H, m), 7.59(1H, m), 7.25(1H, m), 4.36(2H, s) | ||
Step 50.2: Synthesis of 2-Fluoro-5-[(4-oxo-3H-phthalazin-l-yl)methyl]benzoic Acid (5.2).[0242] As such, to a stirred suspension of 50.1 (-10 mmol) in water (20 mL) was added aqueous NaOH (10 N, 5 mL). The reaction was subsequently heated to 100 C for 1 h. After the reaction mixture was cooled to roughly 70 C and hydrazine hydrate (5.0 mL, 100 mmol) was added. The mixture was stirred at 70 C for 24 h. The reaction was cooled room temperature and acidified with HC1 (8 N, ca. 80 mL) to pH 4. After reaction was again cooled to room temperature, the solid was collected with filtration, washed with water (10 mL), ether (3 x 10 mL) and was dried to produce compound 50.2 (2.41 g) as a white solid. MS (ESI+) m/z = 299 (M+H). | ||
A solution of 26.52 g of 2-fluoro-5- (3-oxo-1,3H-dihydroisobenzofuranylidene) benzonitrile was added to 300 ml of water, stirred, 9.60 g of LiOH was added and the temperature was raised to 100 C. , The reaction for about 1h, add hydrazine hydrate 57.6ml, continue stirring reaction 6h reaction is completed, cooling to room temperature, the reaction solution with ethyl acetate 150ml extraction twice, the water phase with 2M hydrochloric acid solution transferred to the pH of about 3, After stirring for about 0.5 h, the filter cake was washed with water, and the filter cake was purified by ethanol. The filtrate was filtered and dried. The orange-red solid, 2-fluoro-5 - ((4-oxo-3,4-dihydrophthalazine- - yl) methyl) benzoic acid, HPLC purity greater than 98%. | ||
70 g | The above semi dried compound 2-fluoro-5-[(3-oxo-2-benzofuran-1 {3H)- ylidene)methyl] benzonitrile (IV) as obtained by example-1 was suspended in water (500 imL) at room temperature followed by addition of aqueous solution of NaOH (50 g). The resulting reaction mixture was stirred at 60C to 70 C. After completion of the hydrolysis, it was cooled to room temperature and acidified by addition of cone. HCI until the pH was changed to 5-6. Then hydrazine hydrate (1 67 g) was added. The resulting reaction mass was stirred at 60C to 70 C. The reaction mass was cooled to room temperature, acidified by addition of cone. HCI until the pH was changed 4.0-4.5. The stirring was continued further at room temperature. The obtained precipitate was filtered and washed with water. The crude compound was purified by using isopropanol (or any other polar solvent) to afford pure 2- fluoro-5-[(4-oxo-3,4-di hydrophthalazin-1 -yl)methyl]benzoic acid (V) as a solid (70 g). (Yield: 68%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.0% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 12.0h;Inert atmosphere; | 2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (500 mg, 1.68 mmol) was dissolved in 10 mL of N, N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (830 mg, 2.52 mmol), <strong>[126069-70-3]2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine</strong> 12c (384 mg, 2 mmol) and N, N-diisopropylethylamine (1 mL, 5 mmol). After stirring for 12 hours, the resulting residue was purified by silica gel column chromatography with elution system A to obtain 4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 12 (200 mg, yield 25.0%) as a white solid. MS m/z (ESI): 472.1[M+1] 1H NMR (400 MHz, CDCl3): delta 10.29 (br. s, 1H), 8.47 (m, 1H), 7.80 (m, 3H), 7.37 (m, 2H), 7.25 (m, 1H), 6.50 (m, 1H), 4.67 (s, 2H), 4.28 (m, 2H), 4.14 (m, 2H), 3.73 (m, 2H) |
25.0% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 12.0h; | 2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (500 mg, 1.68 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (830 mg, 2.52 mmol), 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-c]pyrazine 12c (384 mg, 2 mmol) and N,N-diisopropylethylamine (1 mL, 5 mmol). After stirring for 12 hours, the resulting residue was purified by silica gel column chromatography with elution system A to obtain 4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,2-c]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 12 (200 mg, yield 25.0%) as a white solid. MS m/z (ESI): 472.1[M+1] 1H NMR (400 MHz, CDCl3): delta 10.29 (br. s, 1H), 8.47 (m, 1H), 7.80 (m, 3H), 7.37 (m, 2H), 7.25 (m, 1H), 6.50 (m, 1H), 4.67 (s, 2H), 4.28 (m, 2H), 4.14 (m, 2H), 3.73 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.0% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 20h;Inert atmosphere; | 2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (360 mg, 1.20 mmol) was dissolved in 10 mL of N, N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (600 mg, 1.80 mmol), <strong>[233278-56-3]5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine</strong> 16a (150 mg, 1.20 mmol, prepared according to a known method disclosed by 'patent application ') and N, N-diisopropylethylamine (0.4 mL, 2.40 mmol). After stirring for 20 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-4-fluorophenyl]methyl]-2H-phthalazin-1-one 16 (100 mg, yield 21.0%) as a yellow solid. MS m/z (ESI): 405.1 [M+1] 1H NMR (400 MHz, CDCl3): delta 10.47 (br. s, 1H), 8.51-8.49 (m, 1H), 7.99-1.77 (m, 4H), 7.42-7.30 (m, 2H), 7.30-7.12 (m, 1H), 4.76 (m, 2H), 4.37-4.28 (m, 4H), 3.77-3.73 (m, 2H) |
21.0% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 20h; | Example 16 4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (360 mg, 1.20 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (600 mg, 1.80 mmol), <strong>[233278-56-3]5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine</strong> 16a (150 mg, 1.20 mmol, prepared according to a known method disclosed by "patent application WO2009090055") and N,N-diisopropylethylamine (0.4 mL, 2.40 mmol). After stirring for 20 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 16 (100 mg, yield 21.0%) as a yellow solid. MS m/z (ESI): 405.1 [M+1] 1H NMR (400 MHz, CDCl3): delta 10.47 (br. s, 1H), 8.51-8.49 (m, 1H), 7.99-1.77 (m, 4H), 7.42-7.30 (m, 2H), 7.30-7.12 (m, 1H), 4.76 (m, 2H), 4.37-4.28 (m, 4H), 3.77-3.73 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.4% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 12.0h;Inert atmosphere; | 2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (780 mg, 2.65 mmol) was dissolved in 15 mL of N, N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (1.80 g, 4.77 mmol), <strong>[681249-57-0]2-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine</strong> 19a (560 mg, 2.92 mmol, prepared according to a known method disclosed by 'patent application ') and N, N-diisopropylethylamine (1.4 mL, 7.95 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 30 mL of H2O, extracted with ethyl acetate (30 mL*3). The organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 19 (205 mg, yield 16.4%) as a light yellow solid. MS m/z (ESI): 473.1 [M+1] 1H NMR (400 MHz, CDCl3): delta 10.67 (br. s, 1H), 8.48 (s, 1H), 7.77 (m, 3H), 7.42 (m, 2H), 7.11 (t, 1H), 5.10 (s, 1H), 4.75 (s ,1H),4.39 (s, 2H), 4.32 (d, 3H), 3.88 (s, 1H) |
16.4% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In water; N,N-dimethyl-formamide; for 12.0h; | Example 19 4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (780 mg, 2.65 mmol) was dissolved in 15 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.80 g, 4.77 mmol), <strong>[681249-57-0]2-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine</strong> 19a (560 mg, 2.92 mmol, prepared according to a known method disclosed by "patent application WO2009025784") and N,N-diisopropylethylamine (1.4 mL, 7.95 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure, added with 30 mL of H2O, extracted with ethyl acetate (30 mL*3). The organic phase was combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 19 (205 mg, yield 16.4%) as a light yellow solid. MS m/z (ESI): 473.1 [M+1] 1H NMR (400 MHz, CDCl3): delta 10.67 (br. s, 1H), 8.48 (s, 1H), 7.77 (m, 3H), 7.42 (m, 2H), 7.11 (t, 1H), 5.10 (s, 1H), 4.75 (s, 1H), 4.39 (s, 2H), 4.32 (d, 3H), 3.88 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.7% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 12h;Inert atmosphere; | 4-[[3-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 3 mL of N, N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (568 mg, 1.50 mmol), <strong>[71257-38-0]1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine</strong> 2c (210 mg, 1.50 mmol) and N, N-diisopropylethylamine (350 muL, 2 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 2 (15 mg, yield 3.7%) as a white solid. MS m/z (ESI): 403.1 [M+1] 1H NMR (400 MHz, CDCl3): delta 10.19 (br. s, 1H), 8.51 (d, 1H), 7.82 (m, 3H), 7.41 (m, 2H), 7.13 (m, 1H), 6.65 (m, 1H), 6.24 (m, 1H), 5.81 (m, 1H), 4.97 (s, 1H), 4.59 (s, 1H), 4.33 (s, 2H), 4.13 (m, 1H), 4.00 (m, 1H), 3.71 (m, 1H), 2.85 (m, 1H) |
3.7% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 12h; | Step 3 4-[[3-(3,4-dihydro-1H-pyrrolo[1,2-c]pyrazine-2-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (300 mg, 1 mmol) was dissolved in 3 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (568 mg, 1.50 mmol), <strong>[71257-38-0]1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine</strong> 2c (210 mg, 1.50 mmol) and N, N-diisopropylethylamine (350 muL, 2 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-(3,4-dihydro-1H-pyrrolo[1,2-c]pyrazine-2-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 2 (15 mg, yield 3.7%) as a white solid. MS m/z (ESI): 403.1 [M+1] 1H NMR (400 MHz, CDCl3): delta 10.19 (br. s, 1H), 8.51 (d, 1H), 7.82 (m, 3H), 7.41 (m, 2H), 7.13 (m, 1H), 6.65 (m, 1H), 6.24 (m, 1H), 5.81 (m, 1H), 4.97 (s, 1H), 4.59 (s, 1H), 4.33 (s, 2H), 4.13 (m, 1H), 4.00 (m, 1H), 3.71 (m, 1H), 2.85 (m, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.3% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 12h;Inert atmosphere; | 2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (323 mg, 1.08 mmol) was dissolved in 5 mL of N, N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (614 mg, 1.63 mmol), <strong>[91476-80-1]5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine</strong> 4c (200 mg, 1.63 mmol) and N, N-diisopropylethylamine (0.4 mL, 2.16 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-(6,8-dihydro-5H-imidazo[1,2-a]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 4 (10 mg, yield 2.3%) as a white solid. MS m/z (ESI): 404.1 [M+1] 1H NMR (400 MHz, CDCl3): delta 10.07 (br. s, 1H), 8.53 (d, 1H), 7.96 (m, 1H), 7.83 (m, 3H), 7.51 (m, 1H), 7.30 (m, 2H), 6.01 (t, 1H), 4.73 (d, 2H), 4.35 (s, 2H), 1.60 (m, 2H), 1.34 (m, 2H) |
2.3% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 12h; | Step 3 4-[[3-(6,8-dihydro-5H-imidazo[1,2-c]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (323 mg, 1.08 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (614 mg, 1.63 mmol), <strong>[91476-80-1]5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine</strong> 4c (200 mg, 1.63 mmol) and N, N-diisopropylethylamine (0.4 mL, 2.16 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-(6,8-dihydro-5H-imidazo[1,2-c]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 4 (10 mg, yield 2.3%) as a white solid. MS m/z (ESI): 404.1 [M+1] 1H NMR (400 MHz, CDCl3): delta 10.07 (br. s, 1H), 8.53 (d, 1H), 7.96 (m, 1H), 7.83 (m, 3H), 7.51 (m, 1H), 7.30 (m, 2H), 6.01 (t, 1H), 4.73 (d, 2H), 4.35 (s, 2H), 1.60 (m, 2H), 1.34 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With O-(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; | Synthesis of 4-(3 -(5-benzyloctahydropyrrolo[3 ,4-c]pyrrole-2-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one: To a solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin- I -yl)methyl)benzoic acid (I g, 3.35 rnmol) in dry DMF (15 mL) was added TBTLJ (1.292 g, 4.02 mmol) at room temperature under atmosphere of nitrogen. To this 2-benzyloctahydropyrrolo[3,4-c]pyrrole (0.678 g, 3.35 mmol) and DIPEA (1.32 rnL,6.71 rnmol) 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 Na2SO4 and solvents were evaporatedon a rotatory evaporator under reduced pressure to crude solid which was purified by the flash column chromatography using eluent chloroform methanol (97 3) to afford 4-(3 -(5-benzy loctahydropyrro lo [3 ,4-c]pyrrole-2-carbonyl)-4-fl uorobenzyl) phthalazin-l(21-1)-one as white solid (1.19 g, 74%).H-NMR (400 MHz, DMSO-d6)oe 12.59 (s, IH), 8.25 (dd, J 7.6 Hz & 0.6 Hz, 1K),7.94 (d, J 7.6 Hz, I H), 7.86 - 7.80 (m, 2H), 7.35 (m, I H), 7.32 (dd, I H), 5.29 - 7.24(m, 41-1), 7.23 -7.20 (m, 2H), 4.32 (s, 2H ), 3.63 (m, 1K), 3.47 (m, 11-1), 3.46 (m, 2H),3.36 (m, 1 H), 2.9 (dd, I H), 2.60 -2.8 (m, 3H), 2.51 -2.49 (m, 2K), 2.1 (m, I H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium hydroxide; In tetrahydrofuran; water; at 20℃; | To the reaction flask was added compound 5 (prepared in Example 2-2, 287.3g,0.92mol), 1.5LTHF, 1.5L of water and 2.3mol of NaOH, stirred for 2-3 hours at room temperature, and concentrated under reduced pressure to remove THF. To the reactionflask was slowly dropped 2L of concentrated hydrochloric acid (1mol / L), to precipitate a solid gradually drops completion continues to cool under stirring 2h, filtration, the filter cake washed with water and dried to give compound 6 (256.5g, 0.86mol), income yield 93%, HPLC purity 99.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 2h;Inert atmosphere; Alkaline conditions; | Compound 1 (298 mg, 1 mmol) and 2 (205 mg, 1 mmol) weredissolved in DMF (5 ml), and then EDCI (288 mg, 1.5 mmol), DIEA(250 mL, 1.5 mmol), and HOBT (203 mg, 1.5 mmol) were added subsequently.The mixture was stirred at room temperature for 2 hand then poured into water (50 ml). The precipitate was filtered,washed with water and ethyl ether, and dried to give product 3(300 mg) as tan solid. Yield 62%; mp 123-125 C; 1H NMR(400 MHz, DMSO-d6) d 12.61 (s, 1H), 8.40-8.30 (m, 1H), 8.27 (dd,J = 7.6, 1.5 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.92-7.86 (m, 1H),7.86-7.79 (m, 1H), 7.68-7.58 (m, 3H), 7.53-7.48 (m, 1H), 7.48-7.43 (m, 1H), 7.28 (d, J = 7.9 Hz, 2H), 7.23-7.15 (m, 1H), 6.59(d, J = 16.1 Hz, 1H), 4.32 (s, 2H), 3.72 (s, 3H), 3.51-3.42 (m, 2H),2.84 (t, J = 7.2 Hz, 2H). 19F NMR (376 MHz, DMSO-d6) d-117.70.13C NMR (101 MHz, DMSO-d6) d 166.6, 163.4, 159.27, 157.7 (d,J = 248.5 Hz), 144.8, 144.3, 142.2, 134.2 (d, J = 3.3 Hz), 133.4,132.3, 132.2, 131.9, 131.4, 129.8 (d, J = 3.0 Hz), 129.2, 129.0,128.2, 127.8, 126.0, 125.4, 123.9 (d, J = 15.2 Hz), 117.0, 116.1,115.9, 51.3, 40.4, 36.4, 34.7. HRMS (ESI) m/z calculated for[M+Na]+ 508.1649, found 508.1642. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | <strong>[763114-26-7]5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid</strong> (298 mg, 1 mmol) and example 1 C (205 mg, 1 mmol) dissolved in DMF (5 ml) in, adding EDCI (288 mg, 1.5 mmol), DIEA (250 mul, 1.5 mmol) and HOBT (203 mg, 1.5 mmol). Stirr at room temperature 2 hours after the reaction solution is poured into water (50 ml) in. Filtering and water, the cake is washed with ethyl acetate, dried to obtain the title compound (white solid, 300 mg, yield 62%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.1% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 44℃; for 6h; | General procedure: To a solution of carboxylic acid (1.17 mmol), HBTU (0.4495 g, 1.18 mmol), and DIPEA (0.5 mL,2.21 mmol) in anhydrous DMF (20 mL), a solution of NICD (0.4186 g 1.17 mmol) in anhydrous DMF (10 mL) was added at 44 C. After the mixture was stirred for 6 h, it was diluted with CH2Cl2 (100 mL) and extracted with water (250 mL3). The organic phase was dried with Na2SO4 and concentrated under reduced pressure. The residue was purified via column chromatography on silica gel with ethyl acetate/ methanol (V:V = 8:1) to afford the compound as dark green solids. |
60.1% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 40℃; for 1.5h; | The NICD compound (0.4186 g, 1.17 mmol) was dissolved in 20 mL DMF.Another 2-fluoro-5-(4-substituted-3,4-dihydropyridazin-1-yl)methylbenzoic acid (0.3090 g, 1.14 mmol), HBTU (0.4495 g, 1.18 mmol), DIPEA(0.1 mL) was added to 50 mL of DMF to dissolve the compound, and the NICD solution was added to the above stirred solution at 40 C. After stirring in a bath for 90 min, TLC detects the end of the reaction and stops the reaction. Add 100×3 mL of dichloromethane, extract three The organic phase was combined, concentrated to 100 mL, and extracted three times with 250×3 mL of distilled water. The organic phase was concentrated and organic solvent was recovered. Agent, silica gel column chromatography, ethyl acetate:methanol = 8:1, to give the target compound 8-N-[2-fluoro-5-(4-oxo-3,4-Dihydropyridazin-1-yl)methyl]benzamide isoviochronine 0.4565 g, yield 60.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With thionyl chloride; triethylamine; In dichloromethane; at 0 - 20℃; | Thionylchloride (22.0 mL) was added to a cold and stirring solution of 1 H- benzotriazole (VI) (85 g) and triethylamine (148 mL) in methylene chloride (700 mL). The resulting reaction mass stirred at 0-10 C. Then 2-fluoro-5-[(4-oxo-3, 4- dihydro-phthalazin-1 -yl) methyl] benzoic acid (V) (70 g) was added at 0-10 C and the resulting suspension was stirred at room temperature till completion of reaction. The organic volatiles of reaction mass were removed under reduced pressure after completion of the reaction. The crude compound was re-crystallized in water/isopropanol and dried under vacuum at 50-60 C to afford 4-[3-(1 H- benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl] phthalazin-1 (2 -/)-one (VII) as a white solid (84 g). The PXRD pattern of 4-[3-(1 H-benzotriazol-1 -ylcarbonyl)-4- fluorobenzyl] phthalazin-1 (2H)-one (VII) as thus obtained is illustrated in figure-4. (Yield: 81 %, HPLC purity: 99%) 1H NMR (300 MHz, DMSO-£/6): delta 12.63 (s, 1 H), 8.30-8.25 (m, 3H), 8.04-8.01 (d, 1 H, J = 7.8 Hz), 7.95-7.81 (m, 4H), 7.77-7.72 (m, 1 H), 7.69 -7.63 (m, 1 H), 7.46-7.40 (m, 1 H), 4.43 (s, 2H); 13C NMR (75 MHz, DMSO- d6): delta 164.00, 160.41 , 159.85, 157.08, 145.93, 145.21 , 135.78, 135.66, 135.10, 135.06, 133.99, 132.12, 132.03, 131 .56, 131 .29, 129.55, 128.34, 127.44, 126.52, 125.91 , 121 .38, 121 .20, 120.68, 1 16.91 , 1 16.63, 1 14.47, 36.89; MS (ESI): m/z [M+H] calcd. for C22H15FN5O2: 400.3; found: 400.3. |
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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | To a solution of Compound e (37 g, 0.14 mol) dissolved in water (200 mL), a 13 N sodium hydroxide solution (50 mL) was added, heated to 90C, and stirred for 1 hr. The reaction system was cooled to 70C, added with hydrazine hydrate (100 mL, 2 mol), and stirred for 18 hrs while the temperature was maintained. The reaction solution was cooled to room temperature, adjusted to pH 4 with 8 N hydrochloric acid, and filtered. The filter cake was sequentially washed with water (60 mLx2) and then diethyl ether (50 mL x 3), and dried under vacuum to obtain Compound f: 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid as a white solid (30.1 g, yield 77%). MS (ESI) m/z: [M+H]+=299. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 60℃; for 12h; | General procedure: Boronic ester compounds 35, 41-42, 51-52, 59-60, 67-68, 75-76, 83-84, 91-92, and 99-100 can be developed from the following procedure outlined in Scheme 5. Reagents and conditions: (i) a, CBr4, Ph3P, CH2CI2, 0-23 C, 4 h; (ii) as described in Fu, J. Am. Chem. Soc. 2006, 128, 5360; (iii) as described in Mach, Tetrahedron Lett. 2017, 58, 466; (iv) 1 : d, bis(pinacolato)diboron (ILpim), Pd2(dba)3 (2 mol %), RuPhos (4 mol %), KOAc (3.0 equiv), dioxane, 110 C, 1 h; 2: CF OOH, CH2CI2, rt, 2 h; (v) g, 9, HOBt hydrate, EDC HC1, TEA, THF, 60 C, 12 h |
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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.39% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a 250 ml three-necked flask was added 10.0 g (33.5 mmol) of 2-fluoro-5-((4-oxo-3,4-dihydropyridazin-1-yl)methyl)benzoic acid,Thiomorpholine 1,1-dioxide hydrochloride 4.5g (40.2mmol), HBTU 15.0g (40.2mmol), DIPEA 6.5g (50.3mmol), DMF 100ml, stirring at room temperature for 1h,Gradual solid precipitation, LCMS followed the reaction until 2-fluoro-5-((4-oxo-3,4-dihydropyridazin-1-yl)methyl)benzoic acid was completely reacted, filtered, and filtered cake Dilute with 100 ml of DMF, 100 ml of water and 100 ml of acetone.Drying at 45 C in vacuo gave 4-(3-(1,1-dioxothiomorpholine-4-carbonyl)-4-fluorobenzyl)pyridazine-1(2H)-one 10.5 g, yield: 75.39%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.85% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a 250 ml three-necked flask was added 10.0 g (33.5 mol) of <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydropyridazin-1-yl)methyl)benzoic acid</strong>,Morpholine 3.5g (40.2mmol), HBTU 15.0g (40.2mmol), DIPEA 6.5g (50.3mmol), DMF 100ml, stirred at room temperature for 1h.Gradual solid precipitation, LCMS followed the reaction until <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydropyridazin-1-yl)methyl)benzoic acid</strong> was completely reacted, filtered, and filtered cake Dilute with 100 ml of DMF, 100 ml of water and 100 ml of acetone.Drying at 45 C in vacuo gave 4-(4-fluoro-3-(morpholine-4-carbonyl)benzyl)pyridazine-1(2H)-one 8.6 g, yield: 69.85%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.23% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | To a 250 ml three-necked flask was added 10.0 g (33.5 mmol) of <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydropyridazin-1-yl)methyl)benzoic acid</strong>, thiomorpholine Oxide hydrochloride 6.9 g (40.2 mmol), HBTU 15.0 g (40.2 mmol), DIPEA 6.5 g (50.3 mmol), DMF 100 ml, stirred at room temperature for 1h. Gradual solid precipitation, LCMS followed the reaction until <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydropyridazin-1-yl)methyl)benzoic acid</strong> was completely reacted, filtered, and the filter cake Dilute with 100 ml of DMF, 100 ml of water and 100 ml of acetone.Drying at 45 C in vacuo gave 4-(4-fluoro-3-(thiomorpholine-4-carbonyl)benzyl)pyridazine-1(2H)-one 8.0 g, yield: 62.23%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.5% | With potassium hydroxide; In methanol; for 6h;Reflux; | (3) The product of the previous step (652 mg, 1 mmol) was weighed, added to 10 mL of methanol, stirred, and then added with potassium hydroxide solution (10 mL, 1 mol/L), and reacted under reflux for 6 h. The system was cooled, extracted with dichloro (20 mL×3), taken with water, pH 3, solid precipitated, suction filtered, and dried to give 2-fluoro-5-[(4-carbonyl-3,4-dihydroindole) Pyrazin-1-yl)methyl]benzoic acid 0.548, yield 90.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 60℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 60℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.6% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | 2-Fluoro-5-((4-oxo-3,4-dihydropyridazin-1-yl)methyl)benzoic acid (II)(1.5g, 5.0mmol) andN-(4-((4-Methoxyphenyl)carbamoyl)phenyl)piperazine-1-carboxamide hydrochloride (VI-1) (1.95 g, 5.0 mmol) dissolved in 10 mL N, N - in dimethylformamide,Add PyBOP (3.1 g, 6.0 mmol),N,N-diisopropylethylamine (2.3 g, 17.8 mmol),After stirring at room temperature overnight, TLC detected the reaction of the starting material completely.The reaction solution was slowly poured into 60 mL of water and stirred for 1 hour.The solid is precipitated, filtered, and the filter cake is washed with water.Separation by column chromatography (eluent: methylene chloride:methanol = 50:1) gave 2.7 g of white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | 2-Fluoro-5-((4-oxo-3,4-dihydropyridazin-1-yl)methyl)benzoic acid (II) (1.5 g, 5.0 mmol) andInterbodyN-(4-((4-fluorophenyl)carbamoyl)phenyl)piperazine-1-carboxamide hydrochloride(VI-3) (1.9 g, 5.0 mmol) was dissolved in 10 mL of N,N-dimethylformamide.Add PyBOP (3.1 g, 6.0 mmol),N,N-diisopropylethylamine (2.3 g, 17.8 mmol),After stirring at room temperature overnight,TLC detection of the raw material reaction is complete,The reaction solution was slowly poured into 60 mL of water and stirred for 1 hour to precipitate a large amount of solid, which was filtered with suction. The filter cake was washed with water and separated by column chromatography (eluent: dichloromethane:methanol = 50:1) to give a pale pink solid.2.5 g, yield 83.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 5h; | 4-(4-Fluoro-3-carboxy-benzyl)pyridazine-1(2H)one (34) (656 mg, 2.20 mmol) was added to a 25 ml three-necked flask.Methylene chloride (8 ml), 3-methyl-2-butenoylpiperazine hydrochloride (Compound 33) (0.68 g, 3.30 mmol), HOBT (0.54 g, 3.96 mmol), EDCI (0.78 g, 3.96 mmol), and DIPEA (0.85 g, 6.60 mmol), stirred and stirred at room temperature for 5 h.After the reaction is completed, the reaction solution is directly concentrated to dryness, and the residue is added with water and beat, stirred for 1 hour, and then filtered.Obtained as an off-white solid, which was purified using silica gel column.The white solid product (710 mg) was obtained in a yield of 72%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | <strong>[763114-26-7]2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid</strong>0.05 g (0.1508 mmol) was dissolved in 5 ml of dichloromethane.EDCI 0.0516g (0.268mmol) was added in sequenceAnd HOBT 0.0362g (0.268mmol),A few drops of DMF were added to aid dissolution. After stirring at room temperature for 1 h,Add DIEA (1.88 ml, 13, 4 mmol),Further added 0.551 g (0.268 mmol) of 2-chloro-5,6,7-tetrahydropyrido[4,3-d]pyrimidine hydrochloride.Stirring was continued at room temperature for 24 h. The reaction solution was sequentially treated with 20 ml of a 2 mol/l HCl solution.The mixture was washed 3 times with 2 mol/l NaOH solution and water, and dried over anhydrous sodium sulfate.Column chromatography (petroleum ether: ethyl acetate = 1:1)A white solid of 26.789 mg was obtained.The yield was 40%. Mp: 222.7-223.3 C. The purity is 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 60℃; for 12h; | General procedure: The desired free-amine intermediate (7a-f, 10a-b, or 13) (1.0mmol), 8 (1.0mmol), HOBt hydrate (1.0mmol), EDC hydrochloride (1.0mmol), and Et3N (2.0mmol) were stirred in 5mL of THF at 60C for 12h. A saturated NaHCO3 (aq) solution (15mL) was then added to the crude reaction mixture and stirred at room temp for 1h. The reaction mixture was extracted with CH2Cl2 (3×20mL) to afford the crude product. The residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with 10% 7N NH3 in MeOH solution/CH2Cl2 to give the target compounds 9a-f, 11a-b, and 14. Compounds were analyzed for purity using LCMS, 1H and 13C NMR spectroscopy, and, if necessary, purified further using a Biotage SNAP flash purification cartridge, eluting with a 10% 7N NH3 in MeOH solution/EtOAc. It should be noted; the following yields of the target compounds were not optimized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 60℃; for 12h; | General procedure: The desired free-amine intermediate (7a-f, 10a-b, or 13) (1.0mmol), 8 (1.0mmol), HOBt hydrate (1.0mmol), EDC hydrochloride (1.0mmol), and Et3N (2.0mmol) were stirred in 5mL of THF at 60C for 12h. A saturated NaHCO3 (aq) solution (15mL) was then added to the crude reaction mixture and stirred at room temp for 1h. The reaction mixture was extracted with CH2Cl2 (3×20mL) to afford the crude product. The residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with 10% 7N NH3 in MeOH solution/CH2Cl2 to give the target compounds 9a-f, 11a-b, and 14. Compounds were analyzed for purity using LCMS, 1H and 13C NMR spectroscopy, and, if necessary, purified further using a Biotage SNAP flash purification cartridge, eluting with a 10% 7N NH3 in MeOH solution/EtOAc. It should be noted; the following yields of the target compounds were not optimized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 60℃; for 12h; | The synthesis of 16 was adapted from previously reported literature conditions [16,24,25]. A solution of 5a (6.0mmol) in 12 THF (20mL) at 0C was treated with 13 triphenylphosphine (10mmol), followed by 65 CBr4 (10mmol). After 1h, the reaction mixture was warmed to room temp, and stirred for an additional 2h. Next, the solvent was removed under reduced pressure to afford a crude oily residue. The subsequent residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with a 1:20 EtOAc/hexanes gradient, to afford 15 15 as a white solid. (Yield 26%) 1H NMR (500MHz, CDCl3) delta 4.27-4.24 (quint, J=7.3Hz, 1H), 3.89 (s, 2H), 3.86 (s, 2H), 2.83-2.79 (m, 2H), 2.57-2.52 (m, 2H), 1.37 (s, 9H). 13C NMR (125MHz, CDCl3) delta 156.0, 79.4, 61.0, 60.7, 45.6, 36.4, 35.6, 28.3; LC-MS (ESI) m/z: 176.18 [M-Boc]. A 40mL vial was charged with 67 NiI2 (0.20mmol), 68 trans-2-aminocyclohexanol hydrochloride (0.20mmol), 69 (4-fluorophenyl)boronic acid (2.0mmol), NaHMDS (4.0mmol), and 2-methyl-2-butanol (1.0mL). The reaction was purged with N2 for 5min, followed by the addition of 15 15 (2.0mmol) in 2.5mL of 70 2-methyl-2-butanol. The reaction mixture was heated to 80C and stirred vigorously for 12h. After which, the crude reaction mixture was filtered and the solvent was removed under reduced pressure. The subsequent residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with a 1:5 EtOAc/hexanes gradient, to afford the Boc-protected precursor of 16 as a white solid. (Yield 74%). The intermediate was then dissolved in 71 CH2Cl2 (2mL), followed by dropwise addition of 72 CF3COOH (2mL), and stirred at room temperature for 3h. Volatiles were then removed under reduced pressure and the crude product was neutralized with a saturated NaHCO3 (aq) solution (10mL). The reaction mixture was extracted with CH2Cl2 (3×20mL), and the organic layers were combined, dried, and concentrated to afford the free-amine intermediates (16) as light-tan solid. Finally, 16 (1.0mmol), 8 (1.0mmol), 73 HOBt hydrate (1.0mmol), 74 EDC hydrochloride (1.0mmol), and 75 Et3N (2.0mmol) were stirred in 5mL of 12 THF at 60C for 12h. A saturated 76 NaHCO3 (aq) solution (15mL) was then added to the crude reaction mixture and stirred at room temp for 1h. The reaction mixture was extracted with CH2Cl2 (3×20mL) to afford the crude product. The residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with 10% 7N NH3 in 77 MeOH solution/CH2Cl2 to give the target compounds 17 17 as a soft white solid. (Yield 18%) 1H NMR (500MHz, CDCl3) (reported as mixture of rotamers) delta 11.38 (m, 1H), 8.48-8.46 (m, 1H), 7.77-7.71 (m, 3H), 7.52-7.49 (m, 1H), 7.34-7.29 (m, 1H), 7.10-7.06 (m, 2H), 7.01-6.93 (m, 3H), 4.29-4.28 (m, 3H), 4.16 (s, 1H), 4.08 (s, 1H), 3.94 (s, 1H), 3.42-3.25 (m, 1H), 2.64-2.60 (m, 1H), 2.58-2.54 (m, 1H), 2.31-2.27 (m, 1H), 2.24-2.19 (m, 1H). 13C NMR (125MHz, CDCl3) (reported as mixture of rotamers) delta 166.1, 166.0, 160.9, 160.4 (2xC) (d, J1C-F=244.7Hz, J2C-F=244.7Hz), 157.0 (JC-F=250.4Hz), 145.7, 140.0 (d, JC-C-C-C-F=2.8Hz), 139.9 (d, JC-C-C-C-F=2.7Hz), 134.1, 134.0 (d, JC-C-C-F=8.1Hz), 133.7, 132.2 (d, JC-C-C-F=8.2Hz), 131.6, 130.2, 129.6, 128.4, 127.7 (d, JC-C-C-C-F=3.2Hz), 127.6 (d, JC-C-C-C-F=2.8Hz), 127.2, 125.2, 122.4 (d, JC-C-F=17.2Hz), 122.3 (d, JC-C-F=17.2Hz), 116.3 (d, JC-C-F=22.7Hz), 115.1 (d, JC-C-F=21.2Hz), 64.0, 63.9, 61.9, 61.8, 61.4, 59.3, 40.4, 37.8, 34.4, 34.2, 33.6, 33.3; LC-MS (ESI) m/z: 472.14 [M+H]. |
18% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 60℃; for 12h; | General procedure: A solution of compound a (6.0 mmol) in THF (20 mL) at 0 C was treated with triphenylphosphine (10 mmol), followed by CBr4 (10 mmol). After 1 h, the reaction mixture was warmed to room temp, and stirred for an additional 2 h. Next, the solvent was removed under reduced pressure to afford a crude oily residue. The subsequent residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with a 1 :20 EtO Ac/hexanes gradient, to afford compound b as a white solid. (Yield 26%) 'H NMR (500 MHz, CDCb) d 4.27- 4.24 (quint, J = 7.3 Hz, 1H), 3.89 (s, 2H), 3.86 (s, 2H), 2.83-2.79 (m, 2H), 2.57-2.52 (m, 2H), 1.37 (s, 9H). 13C NMR (125 MHz, CDCb) d 156.0, 79.4, 61.0, 60.7, 45.6, 36.4, 35.6, 28.3; LC-MS (ESI) m/z: 176.18 [M-Boc] A 40 mL vial was charged with Nib (0.20 mmol), trans-2- aminocyclohexanol hydrochloride (0.20 mmol), NaHMDS (4.0 mmol), and 2-methyl-2-butanol (1.0 mL). The reaction was purged with N2 for 5 min, followed by the addition of compound b (2.0 mmol) in 2.5 mL of 2-methyl-2-butanol. The reaction mixture was heated to 80 C and stirred vigorously for 12 h. After which, the crude reaction mixture was filtered and the solvent was removed under reduced pressure. The subsequent residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with a 1 :5 EtO Ac/hexanes gradient, to afford the Boc-protected precursor (compound d) as a white solid. (Yield 74%). The intermediate was then dissolved in CH2CI2 (2 mL), followed by dropwise addition of CF3COOH (2 mL), and stirred at room temperature for 3 h. Volatiles were then removed under reduced pressure and the crude product was neutralized with a saturated NaHC03 (aq) solution (10 mL). The reaction mixture was extracted with CH2CI2 (3 x 20 mL), and the organic layers were combined, dried, and concentrated to afford the free-amine intermediate, i.e., 6-(4-fluorophenyl)-2-azaspiro[3.3]heptane, as light-tan solid. Finally, intermediate 6-(4-fluorophenyl)-2-azaspiro[3.3]heptane (1.0 mmol), 16 (1. 0 mmol), HOBt hydrate (1.0 mmol), EDC hydrochloride (1.0 mmol), and Et3N (2.0 mmol) were stirred in 5 mL of THF at 60 C for 12 h. A saturated NaHCCb (aq) solution (15 mL) was then added to the crude reaction mixture and stirred at room temp for 1 h. The reaction mixture was extracted with CH2CI2 (3 x 20 mL) to afford the crude product. The residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with 10% 7N NHi in MeOH solution/CFLCh to give the target compound 39 as a soft white solid. (Yield 18%) NMR (500 MHz, CDCh) (reported as mixture of rotamers) d 11.38 (m, 1H), 8.48-8.46 (m, 1H), 7.77-7.71 (m, 3H), 7.52-7.49 (m, 1H), 7.34-7.29 (m, 1H), 7.10-7.06 (m, 2H), 7.01-6.93 (m, 3H), 4.29-4.28 (m, 3H), 4.16 (s, 1H), 4.08 (s, 1H), 3.94 (s, 1H), 3.42-3.25 (m, 1H), 2.64-2.60 (m, 1H), 2.58-2.54 (m, 1H), 2.31-2.27 (m, 1H), 2.24-2.19 (m, 1H). 13C NMR (125 MHz, CDCh) (reported as mixture of rotamers) d 166.1, 166.0, 160.9, 160.4 (2xC) (d, JIC-F = 244.7 Hz, J2C-F = 244.7 Hz), 157.0 (JC-F = 250.4 Hz), 145.7, 140.0 (d, JC-C-C-C-F = 2.8 Hz), 139.9 (d, JC-C-C-C-F = 2.7 Hz), 134.1, 134.0 (d, JC-C-C-F = 8.1 Hz), 133.7, 132.2 (d, JC-C-C-F = 8.2 Hz), 131.6, 130.2, 129.6, 128.4, 127.7 (d, JC-C-C-C-F = 3.2 Hz), 127.6 (d, JC-C-C-C-F = 2.8 Hz), 127.2, 125.2, 122.4 (d, JC-C-F = 17.2 Hz), 122.3 (d, JC-C-F = 17.2 Hz), 116.3 (d, JC-C-F = 22.7 Hz), 115.1 (d, JC-C-F = 21.2 Hz), 64.0, 63.9, 61.9, 61.8, 61.4, 59.3, 40.4, 37.8, 34.4, 34.2, 33.6, 33.3; LC-MS (ESI) m/z: 472.14 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 60℃; for 12h; | Compounds 8 (1.0mmol), 2-(piperidin-4-yloxy)ethan-1-ol (1. 0mmol), 73 HOBt hydrate (1.0mmol), 74 EDC hydrochloride (1.0mmol), and 75 Et3N (2.0mmol) were stirred in 5mL of 12 THF at 60C for 12h. A saturated 76 NaHCO3 (aq) solution (15mL) was then added to the crude reaction mixture and stirred at room temp for 1h. The reaction mixture was extracted with CH2Cl2 (3×20mL) to afford the crude product. The residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with 10% 7N NH3 in 77 MeOH solution/CH2Cl2 to give the target compounds 15 15 as a white crystalline solid. (Yield 38%) 1H NMR (500MHz, CDCl3) delta 11.78 (s, 1H), 8.42-8.40 (m, 1H), 7.69-7.67 (m, 3H), 7.28-7.26 (m, 1H), 7.25-7.26 (m, 1H), 6.97-6.93 (m, 1H), 4.24 (m, 2H), 4.01 (bs, 1H), 3.69-3.68 (m, 2H), 3.57-3.50 (m, 3H), 3.43 (bs, 2H), 3.05 (bs, 1H), 2.81 (bs, 1H), 1.91-1.88 (m, 1H), 1.73 (bs, 1H), 1.68-1.62 (m, 1H), 1.52 (bs, 1H); 13C NMR (125MHz, CDCl3) delta 164.8, 160.9, 156.0 (d, JC-F=246.9Hz), 145.7, 134.2 (d, JC-C-C-C-F=3.1Hz), 133.6, 131.5, 131.1 (d, JC-C-C-F=7.8Hz), 129.5, 128.9 (d, JC-C-C-F=3.5Hz), 128.2, 127.0, 125.1, 124.5 (d, JC-C-F=18.6Hz), 116.1 (d, JC-C-F=22.0Hz), 74.2, 69.4, 61.8, 44.3, 39.0, 37.7, 31.3, 30.5; LC-MS (ESI) m/z: 426.06 [M+H]. |
38% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 60℃; for 12h; | Compound 9 (1.0 mmol), 2-(piperidin-4-yloxy)ethan-l-ol (1.0 mmol), HOBt hydrate (1.0 mmol), EDC hydrochloride (1.0 mmol), and ELN (2.0 mmol) were stirred in 5 mL of THF at 60 C for 12 h. A saturated NaHCCh (aq) solution (15 mL) was then added to the crude reaction mixture and stirred at room temp for 1 h. The reaction mixture was extracted with CH2CI2 (3 x 20 mL) to afford the crude product. The residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with 10% 7N ML in MeOH solution/CH2Ch to give the target compound b as a white crystalline solid. (Yield 38%) NMR (500 MHz, CDCh) d 11.78 (s, 1H), 8.42-8.40 (m, 1H), 7.69-7.67 (m, 3H), 7.28-7.26 (m, 1H), 7.25-7.26 (m, 1H), 6.97-6.93 (m, 1H), 4.24 (m, 2H), 4.01 (bs, 1H), 3.69-3.68 (m, 2H), 3.57-3.50 (m, 3H), 3.43 (bs, 2H), 3.05 (bs, 1H), 2.81 (bs, 1H), 1.91-1.88 (m, 1H), 1.73 (bs, 1H), 1.68-1.62 (m, 1H), 1.52 (bs, 1H); 13C NMR (l25 MHz, CDCh) d 164.8, 160.9, 156.0 (d, JC-F = 246.9 Hz), 145.7, 134.2 (d, JC-C-C-C-F = 3.1 Hz), 133.6, 131.5, 131.1 (d, JC-C-C-F = 7.8 Hz), 129.5, 128.9 (d, JC-C-C-F = 3.5 Hz), 128.2, 127.0, 125.1, 124.5 (d, JC-C-F = 18.6 Hz), 116.1 (d, JC-C-F = 22.0 Hz), 74.2, 69.4, 61.8, 44.3, 39.0, 37.7, 31.3, 30.5; LC-MS (ESI) m/z: 426.06 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 60℃; for 12h; | General procedure: The desired free-amine intermediate (7a-f, 10a-b, or 13) (1.0mmol), 8 (1.0mmol), HOBt hydrate (1.0mmol), EDC hydrochloride (1.0mmol), and Et3N (2.0mmol) were stirred in 5mL of THF at 60C for 12h. A saturated NaHCO3 (aq) solution (15mL) was then added to the crude reaction mixture and stirred at room temp for 1h. The reaction mixture was extracted with CH2Cl2 (3×20mL) to afford the crude product. The residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with 10% 7N NH3 in MeOH solution/CH2Cl2 to give the target compounds 9a-f, 11a-b, and 14. Compounds were analyzed for purity using LCMS, 1H and 13C NMR spectroscopy, and, if necessary, purified further using a Biotage SNAP flash purification cartridge, eluting with a 10% 7N NH3 in MeOH solution/EtOAc. It should be noted; the following yields of the target compounds were not optimized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 60℃; for 12h; | General procedure: The desired free-amine intermediate (7a-f, 10a-b, or 13) (1.0mmol), 8 (1.0mmol), HOBt hydrate (1.0mmol), EDC hydrochloride (1.0mmol), and Et3N (2.0mmol) were stirred in 5mL of THF at 60C for 12h. A saturated NaHCO3 (aq) solution (15mL) was then added to the crude reaction mixture and stirred at room temp for 1h. The reaction mixture was extracted with CH2Cl2 (3×20mL) to afford the crude product. The residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with 10% 7N NH3 in MeOH solution/CH2Cl2 to give the target compounds 9a-f, 11a-b, and 14. Compounds were analyzed for purity using LCMS, 1H and 13C NMR spectroscopy, and, if necessary, purified further using a Biotage SNAP flash purification cartridge, eluting with a 10% 7N NH3 in MeOH solution/EtOAc. It should be noted; the following yields of the target compounds were not optimized. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | The olapanic acid intermediate (50 mg, M = 297.6, 0.168 mmol), HBTU (82 mg, M = 379.24,0.2184 mmol), HOBT (6.8 mg, M = 135.12, 0.05 mmol) was dissolved in 5 ml of dry THF (2 ml of DMF solvent) and stirred at room temperature for half an hour, DIPEA (0.86 ml, 65.14 mg, 0.504 mmol, M = 129.24, ), plus 4-piperidine22.32 mg of ketone (M = 148.05 hydrochloric acid form 0.1508 mmol) was stirred at 50 C overnight. Dichloromethane extraction, washing with water 3 times, and washing with brine to obtain intermediate 1, N-[5-[(3,4-dihydro-4-oxo-1-pyridazinyl)methyl]-2- Fluorobenzoyl] piperidine-4-ketone. Ethyl acetate: petroleum ether = 3:1 column chromatography to give 25.79 mg. The yield was 40%. | |
40% | 2-fluoro-5-[(4-oxo-3,4-dihydronaphthyridin-1-yl)methyl]benzoic acid (50 mg, 0.17 mmol), HBTU (82 mg, 0.22 mmol), and HOBT (6.8 mg, 0.05 mmol) were dissolved in 5 ml of dry THF (2 ml of DMF solvent) and stirred at room temperature for half an hour, followed by addition of DIPEA (65.14 mg, 0.50 mmol) and piperidin-4-one (22.32 mg, 0.1508 mmol). And the resulting solution was stirred under 50C overnight. The reaction mixture with dichloromethane was washed 3 times with water. The material was placed on a silica gel column and eluted with PE /EA to give 25.79 mg. The yield was 40%. Mp: 230.8-233.8 . 1H NMR (400 MHz, Chloroform-d)delta11.26 - 10.69 (m, 1H), 8.51 (s, 1H), 7.79 (d, 3H), 7.39 (d, 2H), 7.09 (m, 1H), 4.33 ( s, 2H), 4.20-3.92 (m, 2H), 3.63 (s, 2H), 2.61 (m, 2H), 2.46 (s, 2H).13C NMR (101 MHz, Chloroform-d) delta 206.43 , 165.36 , 160.52 , 145.52 , 134.45 , 133.72 , 131.68 , 129.53 , 129.21 , 128.32 , 127.23 , 125.00 , 116.34 , 116.12 , 45.77 , 41.30 , 41.22 , 40.75 , 37.68. LC-MS (ESI) m/z: 380. 1 [M +H]+. Purities of compound 1 determined by HPLC, were > 95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.7% | With (benzotriazole-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; | Intermediate V (534 mg, 1.79 mmol), intermediate IV-1 (310 mg, 1.79 mmol) andPyBOP (1.12 g, 2.15 mmol) was added to a 100 mL reaction flask, dissolved by the addition of 20 mL of DMF, and then DIEA (0.81 g, 6.27 mmol) was added and reacted at 25 C.TLC (dichloromethane: methanol = 20:1) was used to monitor the completion of the reaction, and the reaction solution was poured into 100 mL of water.A large amount of yellow solid was precipitated, stirred for 10 min, suction filtered, washed with water, dried.Purification by crude column chromatography (dichloromethane:methanol = 100:1 to 80:1) eluted to afford product (I-1) 420 mg, yield 51.7%. |
51.7% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 10℃; | <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid</strong> (534 mg, 1.79 mmol) as intermediate V, compound IV 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (310 mg, 1.79 mmol)PyBOP (1.12 g, 2.15 mmol) was added to a 100 mL reaction flask, dissolved by the addition of 20 mL of DMF, and then DIEA (0.81 g, 6.27 mmol) was added and reacted at 10 C.TLC (dichloromethane: methanol = 20:1) was used to monitor the completion of the reaction. The reaction mixture was poured into 100 mL of water, and a large amount of yellow solid was precipitated, stirred for 10 min, filtered, washed with water, dried, and then purified. =100:1~80:1 gradient elution) purification,The mass of the compound I-1 was 420 mg, and the yield was 51.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.6% | With (benzotriazole-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; | Intermediate V (648 mg, 2.17 mmol), intermediate X (470 mg, 2.17 mmol) and PyBOP (1.36 g, 2.61 mmol) were added to a 100 mL reaction flask.The mixture was dissolved by adding 30 mL of DMF, and then DIEA (0.98 g, 7.58 mmol) was added, and the mixture was reacted at 25 C.TLC (dichloromethane: methanol = 20:1) was used to monitor the completion of the reaction, and the reaction solution was poured into 120 mL of water.A large amount of yellow solid was precipitated, stirred for 10 min, suction filtered, washed with water and dried.Purification by crude column chromatography (dichloromethane:methanol = 100:1 to 20:1) afforded product (I-9), yield: 43.6%, 470 mg. |
43.6% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; | <strong>[763114-26-7]2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid</strong> (648 mg, 2.17 mmol), Intermediate X (470 mg) , 2.17 mmol) and PyBOP (1.36 g, 2.61 mmol) were added to a 100 mL reaction flask, stirred by adding 30 mL of DMF, and then DIEA (0.98 g, 7.58 mmol) was added and reacted at 25 C. The reaction of the starting material was monitored by TLC (dichloromethane:methanol = 20:1). The reaction mixture was poured into 120 mL of water, and a large amount of yellow solid was precipitated, stirred for 10 min, filtered, washed with water and dried. Purification by crude column chromatography (dichloromethane: methanol = 100:1 to 20:1).The mass of the compound I-9 was 470 mg, and the yield was 43.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.9% | With (benzotriazole-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; | Intermediate V (1.05 g, 3.52 mmol), intermediate XI (0.7 g, 3.53 mmol)PyBOP (2.21 g, 4.25 mmol) was added to a 100 mL reaction flask.Add 40 mL of DMF and stir to dissolve, then add DIEA (1.59 g, 12.30 mmol) and react at 25 C.The reaction of the starting material was monitored by TLC (dichloromethane:methanol = 20:1), and the reaction mixture was poured into 160 mL of water to precipitate a large amount of yellow solid.Stir for 10 min, filter by suction, wash the cake with water and dry.Crude column chromatography (dichloromethane: methanol = 100:1 to 80:1)Purification gave product (XII) 1.04 g. The yield was 61.9%. |
61.9% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; | Intermediate V (1.05 g, 3.52 mmol), intermediate XI (0.7 g, 3.53 mmol) and PyBOP (2.21 g, 4.25 mmol) were added to a 100 mL reaction flask, dissolved in 40 mL of DMF and added to DIEA (1.59 g, 12.30 mmol), 25 C reaction. TLC (dichloromethane: methanol = 20:1) was used to monitor the completion of the reaction. The reaction solution was poured into 160 mL of water and precipitated.A large amount of yellow solid. Stir for 10 min, filter by suction, wash the cake with water and dry. Purification by crude column chromatography (dichloromethane:methanol = 100:1 to 80:1) afforded product (XII) 1.04 g. The yield was 61.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 2.5h; | To the solution of compound 4 (7 g, 14.0 mmol, 1.0 eq) in the DCM (175 mL) and DMF (10 mL) were added EDCI (3.0 g, 15.4 mmol, 1.1 eq), TEA (20 mL), HOBT (2.3 g, 16.8 mmol, 1.2 eq) and compound 5 (4.6 g, 15.4 mmol, 1.1 eq) at 0 C. The reaction mixture was stirred at room temperature for 2.5 d. The precipitate was filtered, rinsed with DCM (200 mL), EtOAc (150 mL×3) and H2O (200 mL×2) successively and then dried. The solid obtained was rinsed with EtOAc (300 mL) and dried at 65 C. overnight to afford the product 6 (7.4 g, 71%). 1H NMR (400 MHz, DMSO) delta 12.60 (s, 1H), 9.85 (s, 1H), 8.63 (d, J=3.5 Hz, 1H), 8.26 (d, J=7.7 Hz, 2H), 8.14-8.02 (m, 2H), 7.98 (d, J=8.0 Hz, 1H), 7.90 (t, J=7.4 Hz, 1H), 7.83 (t, J=7.4 Hz, 1H), 7.67 (d, J=12.0 Hz, 1H), 7.50-7.36 (m, 3H), 7.25 (t, J=8.9 Hz, 1H), 4.83 (dt, J=13.6, 6.7 Hz, 1H), 4.34 (s, 2H), 3.84-3.72 (m, 2H), 3.33 (m, 2H), 3.23-3.13 (m, 2H), 3.09-2.99 (m, 2H), 2.63 (s, 3H), 1.61 (d, J=6.8 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.32% | At room temperature, 1.23 g (0.0041 mol) of IV, 30 mL of dichloromethane were sequentially added to a 100 mL round bottom flask, 0.80 g (0.006 mol) of N, N-diisopropylethylamine (DIPEA) was added, and dissolved by stirring . Add 2- (7-benzobenzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate (HATU) 2.36 g (0.006 mol), and stir at room temperature for 1 h. A dichloromethane solution of the step reaction product IX111.14g (0.004mol) was added dropwise, and the addition was completed within 20 minutes. The reaction was carried out at room temperature for 18 hours. The reaction was monitored by TLC until the product point disappeared or faded, which was regarded as the end point of the reaction. After the reaction, the reaction solution was poured into 40 mL of water, stirred at room temperature for 0.5 h, and left to separate. The aqueous phase was extracted with dichloromethane 10 mL × 3. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Ethyl acetate (v / v) = 6: 1 was used as a mobile phase to separate by column chromatography to obtain X11 as a pale yellow solid with a yield of 19.32%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.54% | At room temperature, 1.23 g (0.0041 mol) of IV, 30 mL of dichloromethane were sequentially added to a 100 mL round bottom flask, 0.80 g (0.006 mol) of N, N-diisopropylethylamine (DIPEA) was added, and dissolved by stirring . Add 2- (7-benzobenzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate (HATU) 2.36 g (0.006 mol), and stir at room temperature for 1 h. A dichloromethane solution of 100.94 g (0.004 mol) of the reaction product IX was added dropwise, and the addition was completed within 20 min. The reaction was carried out at room temperature for 18 hours. The reaction was monitored by TLC until the product point disappeared or faded, which was regarded as the end point of the reaction. After the reaction, the reaction solution was poured into 40 mL of water, stirred at room temperature for 0.5 h, and allowed to stand for liquid separation. The aqueous phase was extracted with dichloromethane 10 mL × 3. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Ethyl acetate (v / v) = 6: 1 was used as a mobile phase to separate by column chromatography to obtain white solid X10 with a yield of 16.54%. T |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.7% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; | 2-Fluoro-5-((4-oxo-3,4-dihydropyridazinyl)methyl)benzoic acid (II) (7.53 g, 25.25 mmol), 4-(4-chloro-6-morpholinyl-1,3,5-triazin-2-yl)piperazine hydrochloride (III-1) (8.10 g, 25.22 mmol) and PyBOP (14.40 g, 27.67 mmol) were added to a 250 mL three-necked flask and added 100 mL of DMF was stirred and dissolved, and then DIEA (12.50 mL, 75.63 mmol) was added and reacted at 25 C for 6-8 hours.TLC (dichloromethane: methanol = 20:1) was used to detect the completion of the reaction of the starting material II, the reaction was stopped, the reaction solution was poured into 300 mL of water, a large amount of solid was precipitated, stirred for 15 minutes, and then suction filtered, the filter cake was washed with water, dried, and column chromatography Purification (eluent: dichloromethane:methanol = 100:1 to 40:1 gradient elution)obtained pale yellow solid (IV-l) 12.50g, yield 87.7% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.6% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 8h; | II (0.45 g, 1.49 mmol), (S)-4-(4-chloro-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)-3-methylmorpholine hydrochloride (III-2) (0.50 g, 1.49 mmol) and PyBOP (0.93 g, 1.79 mmol) were added to a 50 mL three-necked flask, dissolved in 15 mL of DMF, and then added to DIEA (0.84 mL, 4.47 mmol). The reaction was carried out at 25 C for 8 hours.TLC (dichloromethane: methanol = 20:1) was used to detect the completion of the reaction of the starting material II, the reaction was stopped, the reaction solution was poured into 50 mL of water, a large amount of solid was precipitated, stirred for 5 minutes, suction filtered, and the filter cake was washed with water and dried to give a pale yellow color. The solid (IV-2) was 0.73 g, and the yield was 84.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.9% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; | Compound II (436 mg, 1.46 mmol), compound III-3 (468 mg, 1.46 mmol) and PyBOP (912 mg, 1.75 mmol) were added to a 25 mL three-necked flask, dissolved in 10 mL of DMF, and then added to DIEA (0.76 mL, 4.38 mmol). ), react at 25 C for 4 to 6 hours. The reaction of the starting material II was detected by TLC (dichloromethane:methanol = 10:1), and the reaction was stopped. The reaction solution was poured into 30 mL of water, a large amount of solid was precipitated, stirred for 10 minutes, suction filtered, and the filter cake was washed with a small amount of water and dried to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol = 100:1 to 50:1 gradient) Remove), 650mg of yellow solid, yield 78.9% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.1% | With sodium hydroxide; hydrazinium sulfate; In water; isopropyl alcohol;Reflux; | hydrazine sulfate (NH2NH2·H2SO4, 60g, 461.1mmol) was added to a 2000 mL flask.NaOH (36.9 g, 923 mmol) and water (400 mL) were added and the system was heated to a clear solution.Then, ethyl 2-(2-(4-fluoro-3-carboxyphenyl)acetyl)benzoate (formula I, R=Et) (152 g, 460.1 mmol) was added to the reaction system.A solution of isopropanol (500 mL) was added and the system was heated to reflux overnight.The system was cooled to room temperature, then the system was added 1N diluted HCl to adjust pH 5-6, and the mixture was stirred at room temperature for 4 hours.Filter and filter cake water for 2 times (2 x 100 mL). The obtained solid was dried by air blowing (65 C).2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (Formula II, yellow solid, 116.8 g, 85.1%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 60℃; for 12h; | 3 General procedure: Compounds 26, 28-29, 31, 33, 37, 47, 55, 63, 71, 79, 87, and 95 can be synthesized following the procedure in Scheme 3Reagents and conditions: (i) commercially available amine alcohol (a), NaH, DMF, rt, 3 h; (ii) c, 9, HOBt hydrate, EDC HC1, TEA, THF, 60 °C, 12 h. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 25℃;Inert atmosphere; | Compound IX-1 (5.96 g, 20.0 mmol) under nitrogenAnd compound 4 (3.14 g, 20.0 mmol) were added to a solution containing anhydrous DMF (100 mL)Three-neck reaction flask, followed by HBTU (8.3g, 22.0mmol)It reacted with triethylamine (4.0 g, 40.0 mmol) at 25 C until the main raw material compound 1 disappeared. The reaction system was then poured into ice water (800 mL),The mixed system was extracted with DCM (200mL * 3).The DCM phase was washed with a saturated sodium chloride solution, dried, and concentrated to obtain a crude product.Crude products quickly pass through the column (200 300 mesh silica gel,The mobile phase was DCM: MeOH = 100: 1 40: 1, v / v) to obtain compound X-17.4g,The yield was 83%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.7% | With triethylamine; 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 25℃; for 12h;Inert atmosphere; | Add a 2-1 structure compound (1 mmol) to 25 mL of three necks,Compound of structure IV (1 mmol)Add 10mL of anhydrous DMF (N, N-dimethylformamide) to dissolve,Then HATU (10.5 mmol, 2- (7-benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate)And TEA (10.5 mmol, triethylamine),The reaction was performed at 25 C for 12 hours under a nitrogen atmosphere.After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a purified white crude product.Silica gel chromatography gave a pale yellow solid represented by the following formula (1-1) in a yield of 52.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.9% | 0.5 g of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl) methyl) benzoic acid (0.0017 mol),0.35g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.0065mol) and0.25 g of 1-hydroxybenzotriazole (0.0065 mol) was dissolved in 10 ml of N, N-dimethylformamide and stirred at room temperature for 30 mins.0.23 ml of triethylamine (0.0017 mol) was slowly added dropwise, and then 0.33 g of methyl 4- (aminomethyl) benzoate (0.002 ml) was added, and the reaction was carried out at room temperature overnight.After the reaction was monitored by TLC, water and ethyl acetate were added for extraction (15 ml × 3), and the organic layers were combined.It was dried over anhydrous sodium sulfate and purified by column chromatography to obtain 0.5 g of a white solid with a yield of 66.9%. The product was directly used in step three. | |
General procedure: To a solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1.0 equiv) in DMF was added HOBT (1.2 equiv) and EDCI (1.2 equiv), and the mixture was stirred for thirty minutes at room temperature. Triethylamine and corresponding 5a-5e was added, and then reaction was stirred for 8 h at room temperature. Then it was quenched by H2O. The mixture was washed with brine and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by chromatography on a silica gel chromatography (petroleum ether/ethyl acetate = 1:1 to 1:20) to give corresponding products 6a-6e (yield 43%-62%) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | The synthetic route is: Compound 3 (2.6g, 0.011mol)And 2-fluoro-5-formylbenzoic acid (2.1g, 0.012mol)Dissolved in anhydrous tetrahydrofuran (25ml), cooled to 0 ,Slowly add triethylamine (1.0ml, 0.007mol) dropwise, then warm up to room temperature for 5h, then slowly raise the temperature to 70 , add hydrazine hydrate (5.1ml, 0.107mol) for 3h, and drop to room temperature , Add appropriate amount of hydrochloric acid (2mol / L) to adjust the pH to acidic, no longer precipitate solids. Filter with suction, wash the product with water and ethyl acetate, and dry to obtain a yellow solid (1.9g, yield 83%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 12h; | 13 2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl) methyl]benzoic acid 1a (780 mg, 2.65 mmol) was dissolved in 15 mL of N,N-dimethylformamide, and then benzotriazole-N,N,N',N'-tetramethyl urea hexafluorophosphate (1.80 g, 4.77 mmol), 2-(trifluoromethyl)-5,6,7,8-tetrahydrogen-[1,2,4]triazolo[1,5-α]pyrazine (560 mg, 2.92 mmol, prepared by the well-known method in international patent application publication No. WO2009025784) and N,N-diisopropylethylamine (1.4 mL, 7.95 mmol) were added and the resulting mixture was reacted for 12 hours. The reaction mixture was concentrated under reduced pressure, added with 30 mL of water, extracted with ethyl acetate (30 mL*3), and then the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried by anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was eluted and purified with methanol/dichloromethane by thin layer chromatography, and then 4-[[3-[[2-(trifluoromethyl)-5,6,7, 8-tetrahydro-[1,2,4]triazolo[1,5-α]pyrazine-7-yl]carbonyl]-4-fluorophenyl]methyl-1(2H)-phthalazinone (210 mg, pale yellow solid) was obtained. No significant characteristic peaks were detected by XRPD, as shown in . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: 1,1'-carbonyldiimidazole / dichloromethane / 1 h / 20 °C 1.2: 1 h / 15 - 20 °C 2.1: potassium carbonate; water / methanol / 0 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95 % | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dimethyl sulfoxide at 10 - 40℃; | 1-2 Example 1 Add DMSO 275.0 g to a 500 ml reaction flask and cool down by 10-15 °C. Intermediate 3-1 (25g), intermediate 2 (30.80g, 1eq), EDCI 25.15g (1.27eq), HOBT 17.73g (1.27eq) and triethylamine 22.13g were added under stirring, and the reaction was raised to 30-40 °C to complete. Filtration, the filtrate is added to 1400ml of purified water to precipitate a large amount of solids, filtered. The filter cake was beaten in 50 °C warm water for 5h, filtered, the filter cake was dried, and fluzoparib was obtained 46.34g, the yield was 95%, and the purity of the product was 99.4% by HPLC. |
Tags: 763114-26-7 synthesis path| 763114-26-7 SDS| 763114-26-7 COA| 763114-26-7 purity| 763114-26-7 application| 763114-26-7 NMR| 763114-26-7 COA| 763114-26-7 structure
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H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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