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CAS No. : | 1007882-59-8 | MDL No. : | MFCD16620748 |
Formula : | C12H18BrN3O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GAZHEEFWONCMGH-QMMMGPOBSA-N |
M.W : | 316.19 | Pubchem ID : | 56605192 |
Synonyms : |
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.67 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 76.12 |
TPSA : | 58.22 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.57 cm/s |
Log Po/w (iLOGP) : | 2.72 |
Log Po/w (XLOGP3) : | 2.33 |
Log Po/w (WLOGP) : | 2.54 |
Log Po/w (MLOGP) : | 1.43 |
Log Po/w (SILICOS-IT) : | 2.17 |
Consensus Log Po/w : | 2.24 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.21 |
Solubility : | 0.195 mg/ml ; 0.000617 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.19 |
Solubility : | 0.203 mg/ml ; 0.000643 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.18 |
Solubility : | 0.207 mg/ml ; 0.000656 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.22 |
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 |
---|---|---|
30% | With N-Bromosuccinimide In dichloromethane at -10℃; for 3h; | 2.4 2.4 preparation of intermediate XHIa (PG= Boc)XXIV Xllla; N-Bromosuccinimide (47.2 g, 0.26 mol) was added portion wise over 1 hour to a cooled (ice-ethanol bath, -10 °C) solution of XXIV (63.0 g, 0.26 mol) in CH2C12 (1.5 L) and stirred at similar temperature for 2 hours. The reaction mixture was concentrated in vacuum and the residue was purification by preparatory HPLC to provide 25.3 g (30%) of Xllla as a pale yellow solid.1H NMR: CD3OD 400Mhzδ 6.99-7.03 (s,lH), 4.77-4.90 (m, 1H), 3.61-3.68 (m, 1H), 3.42-3.50 (m, 1H), 2.20-2.39 (m, 1H), 1.89-2.05 (m, 3H), 1.47 (s, 3H), 1.27 (s, 6H). |
Stage #1: (S)-tert-butyl 2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate With 1H-imidazole; N-Bromosuccinimide In dichloromethane Cooling with ice; Stage #2: With ammonia In methanol | 120.2 NBS (838.4 mg, 4.71 mmol) was added in batches over 15 minutes to a cooled (ice/water) CH2Cl2 (20 mL) solution of imidazole (1.06 g, 4.50 mmol). The reaction mixture was stirred for 75 minutes and concentrated. The crude material was purified by RPLC to separate the mono bromide from its dibromo analog and the starting material. The HPLC elute was neutralized with excess NH3ZMeOH, and the volatile component was removed in vacuo. The residue was partitioned between CH2Cl2 and water, and the aqueous layer was extracted with water. The combined organic phase was dried (MgSO4), filtered, and concentrated to provide compound as a white solid (374 mg). 1H NMR (DMSO) δ: 12.12 (br s, 1H), 7.10 (m, 1H), 4.70 (m, 1H), 3.31 (m, 1H; overlapped with water signal), 2.25-1.73 (m, 4H), 1.39/1.17 (s, 3.8H + 5.2H). | |
Multi-step reaction with 3 steps 1: N-Bromosuccinimide / dichloromethane / 1.25 h / Cooling with ice 2: N-Bromosuccinimide / tetrahydrofuran / 20 °C / Inert atmosphere 3: sodium sulfite / ethanol; water / Reflux |
Stage #1: (S)-tert-butyl 2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate With N-Bromosuccinimide In tetrahydrofuran Stage #2: With sodium sulfate In ethanol; water Reflux; | ||
Stage #1: (S)-tert-butyl 2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate With N-Bromosuccinimide In tetrahydrofuran Stage #2: With sodium sulfite In ethanol; water Reflux; | ||
Multi-step reaction with 2 steps 1: N-Bromosuccinimide / tetrahydrofuran / 3 h / 20 °C / Inert atmosphere 2: ethanol; sodium sulfite; water / 24 h / 90 °C | ||
Multi-step reaction with 2 steps 1: N-Bromosuccinimide / tetrahydrofuran / 25 °C / Inert atmosphere 2: sodium sulfite / ethanol; water / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In tetrahydrofuran; water at 75℃; Inert atmosphere; | 189.b.8 A suspension of the boronate from above (2 mmol), /ert-butyl 2-(2-bromo-lH- imidazol-5-yl) pyrrolidine- 1 -carboxylate (2.4 mmol), Pd(dppf) Cl2 (200 mg), Na2CO3 (3 mmol) and in TΗF/Η2O (10:1, 33 mL) was refluxed at 75°C overnight under N2 protection. The mixture was cooled and filtered, and the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL), washed with brine and dried over anhydrous sodium sulfate. After concentrated in vacuo, the residue was purified by column chromatography to afford the desired compound. MS (ESI) m / e (M+)rt):70. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In tetrahydrofuran; water Inert atmosphere; Reflux; | 203.4 A suspension of the bromoimidazole from Example 192 (5 mmol), the boronate ester from step 3 (2 mmol), Pd(dppi)Cl2 (146 mg, 0.2 mmol) and Na2CO3 (636 mg, 6 mmol) was refluxed in THFVH2O (10:1, 33 mL) overnight under N2 protection. The mixture was cooled and filtered, and the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL), washed with brine and dried over anhydrous sodium sulfate. The solution was concentrated, and the resulting residue was purified by column chromatography (PE / EtOAc = 8:1) to afford the desired compound. MS (ESI) m/e (M+H4): 683. | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water Inert atmosphere; Reflux; | 203.4 STEP 4 A suspension of the bromoimidazole from Example 192 (5 mmol), the boronate ester from step 3 (2 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol) and Na2CO3 (636 mg, 6 mmol) was refluxed in THF/H2O (10:1, 33 mL) overnight under N2 protection. The mixture was cooled and filtered, and the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL), washed with brine and dried over anhydrous sodium sulfate. The solution was concentrated, and the resulting residue was purified by column chromatography (PE/EtOAc=8:1) to afford the desired compound. MS (ESI) m/e (M+H+): 683. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In tetrahydrofuran; water at 100℃; Inert atmosphere; | 213.3 A suspension of the product from step 2 (1.2 g, 2.6 mmol), bromoimidazole from Example 192 (2 g, 6.3 mmol), Na2CO3 (1.3 g, 12 mmol) and Pd(dρpf)Cl2 (220 mg, 0.3 mmol) in THF/H2O (36 ml) was stirred at 100°C under N2 protection overnight. The reaction mixture was concentrated and purified by chromatography on silica gel to give the desired compound. MS (ESI) m/e (M+H4): 666. | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water at 100℃; Inert atmosphere; | 213.3 STEP 3 A suspension of the product from step 2 (1.2 g, 2.6 mmol), bromoimidazole from Example 192 (2 g, 6.3 mmol), Na2CO3 (1.3 g, 12 mmol) and Pd(dppf)Cl2 (220 mg, 0.3 mmol) in THF/H2O (36 ml) was stirred at 100° C. under N2 protection overnight. The reaction mixture was concentrated and purified by chromatography on silica gel to give the desired compound. MS (ESI) m/e (M+H+): 666. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dmap; triethylamine In dichloromethane for 1h; | 1-467.1-467a Step l-467a. (S)-tert-butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (prepared according to WO 2008/021927, 0.500 g, 1.58 mmol) in CH2Cl2 (16 mL) was treated with triethyl amine (0.66 mL, 4.75 mmol), di-tert-butyl dicarbonate (0.518 g, 0.237 mmol) and DMAP (38.7 mg, 0.316 mmol) for 1 hours before being evaporated to dryness. The residue was purified by flash column chromatography(silica, hexanes-ethyl acetate) to give the desired compound as a white solid (0.650 g, 98%). ESIMS m/z = 416.11, 418.11 [M+H]+. |
98% | With dmap; triethylamine In dichloromethane for 1h; | 467.467a Step 467a. (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (prepared according to WO 2008/021927, 0.500 g, 1.58 mmol) in CH2Cl2 (16 mL) was treated with triethyl amine (0.66 mL, 4.75 mmol), di-tert-butyl dicarbonate (0.518 g, 0.237 mmol) and DMAP (38.7 mg, 0.316 mmol) for 1 hours before being evaporated to dryness. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a white solid (0.650 g, 98%). ESIMS m/z=416.11, 418.11 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate In 1,2-dimethoxyethane; water at 90℃; for 14h; Inert atmosphere; | 1-474.1-474c Step l-474c. A mixture of the compound from step l-474b (0.163 g, 0.290 mmol), (S)-tert-butyl 2-(5-bromo- 1 H-imidazol-2-yl)pyrrolidine- 1 -carboxylate (prepared according to WO 2008/021927, 0.137 g, 0.434 mmol), Pd(PPh3)4, (33.4 mg, 28.9 μmol) and NaHCO3 (97.2 mg, 1.16 mmol) in DME (6 mL) and H2O (2 mL) was degassed and heated at 90 0C under N2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc - H2O). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow solid (0.122 g, 60% purity). ESIMS m/z = 673.29 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium carbonate In tetrahydrofuran; water for 15h; Inert atmosphere; Reflux; | 13.B A suspension of Compound 13b (467 mg, 1.09 mmol, prepared as described in theJournal of the American Chemical Society, 127: 8; 2005; 2406 - 2407), (S)-tert-butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (2.18 mmol), Pd(dppf)2Cl2 (0.109 mol), Na2CO3 (6.52 mmol) in THF/H2O (10:1, 20 mL) was put under N2 atmosphere, then heated to reflux and allowed to stir at this temperature for about 15 hours. The reaction mixture was cooled to room temperature and filtered and the filtrate was washed with water (20 mL) and extracted with EtOAc (50 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue obtained was purified using column chromatography (Gradient Pet ether: Ethyl Acetate from 10: 1 to 1:9) to provide Compound 13c (706 mg, 61% yield). MS (ESI) m/e (M+H)+: 649 |
61% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water for 15h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of compound Int-lla (0.5 g, 1.58 mmol, prepared as described in U.S. Patent Publication No. US20090068140) in DME (15 mL) at room temperature under N2 was added PdCl2(dppf)2 (258 mg, 0.30 mmol). The reaction mixture was allowed to stir at 100 0C for 5 minutes, then a solution of compound Int-llb (592 mg, 3.16 mmol) and K2CO3 (654 mg, 4.74 mmol) in 15 mL H2O was added to the reaction mixture in 3 portions over 10 minutes. The resulting reaction was allowed to stir for an additional 30 minutes, after which time thin-layer chromatography analysis indicated consumption of compound Int-7a. The reaction was allowed to stir for an additional 30 minutes, then was concentrated in vacuo, and the residue obtained was taken up in 150 mL ethyl acetate. The organic phase was separated, washed with water (50 mL), brine and dried over sodium sulfate. After filtration, the organic layer was concentrated in vacuo and the resulting residue was purified using flash liquic chromatography (0% to 100% EtOAc/Hexane) to provide 600 mg of compound Int-llc (>; 85% purity, theory 597 mg). HPLC (C18 column Gemini 5u HOA, 150X21.2 mm, 5 micron). FABMS: MH+ = 379 | ||
To a solution of Compound Int-7d (0.5 g, 1.58 mmol) in DME (15 mL) at room temperature under N2 was added PdCl2(dppf)2 (258 mg, 0.30 mmol). The reaction mixture was allowed to stir at 100 0C for 5 minutes, then a solution of compound Int-19a (592 mg, 3.16 mmol) and K2CO3 (654 mg, 4.74 mmol) in 15 mL H2O was added to the reaction mixture in 3 portions over 10 minutes. The resulting reaction was allowed to stir for an additional 30 minutes, after which time thin-layer chromatography analysis indicated consumption of compound Int-7a. The reaction was allowed to stir for an additional 30 minutes, then was concentrated in vacuo, and the residue obtained was taken up in 150 niL ethyl acetate. The organic phase was separated, washed with water (50 rnL), brine and dried over sodium sulfate. After filtration, the organic layer was concentrated in vacuo and the resulting residue was purified using flash liquic chromatography (0% to 100% EtOAc/Hexane) to provide 600 mg of compound Int-19b (>; 85% purity, theory 597 mg). HPLC (C18 column Gemini 5u HOA, 150X21.2 mm, 5 micron). FABMS: MH+ = 379 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester; (S)-tert-butyl 2-(6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1Hbenzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate With potassium carbonate In 1,2-dimethoxyethane; water at 90℃; for 18h; Stage #2: trifluoroacetic acid In water; acetonitrile | AK1 A mixture of 2-{6-[4- (4,4,5,5-Tetramethyl-[ 1 ,3,2]dioxaborolan-2-yl)-phenyl]- 1 H-benzoimidazol-2-yl } -pyrrolidine- 1 - carboxylic acid tert-butyl ester (0.1 16 g), 2-(5-Bromo-1H-imidazol-2-yl)-pyrrolidine-1- carboxylic acid tert-butyl ester (0.1 12 g, prepared according to WO2008021927 A2) and Pd(PPh3)4 (0.014 g) in 2.0M potassium carbonate solution (0.35 mL) and dimethoxyethane (1.0 mL) was heated at 90°C for 6 hours. Additional Pd(PPh3)4 (0.014 g) was added and reaction continued for 12 hours. Reaction mixture was cooled, diluted with ethyl acetate, washed with H2O, brine, dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 1 to 30% isopropanol/hexanes) and preparative reverse phase HPLC (Gemini, 5 to 100% ACN/H2O + 0.1% TFA) to give 2-(6-{4-[2-(l-/ert-butylcarbamyl-pyrrolidin-2-yl)-3H-imidazol- 4-yl]-phenyl}-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid /erf-butyl ester (0.035 g) as a bis-TFA salt: LCMS-ESI+: CaIcd. for C34H43N6O4: 599.74 (M+H+); Found: 599.1 (M+H+). A reaction side-product was also isolated and determined to be 2-(6-{4'-[2-(l-tert- butylcarbamyl-pyrrolidin-2-yl)-3H-benzoimidazol-5-yl]-biphenyl-4-yl}-1H-benzoimidazol-2- yl)-pyrrolidine-1-carboxylic acid terf -butyl ester (0.013 g) as the bis-TFA salt: LCMS-ESI+: CaIcd. for C44H49N6O4: 725.89. (M+H+); Found: 725.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium sulfite In ethanol; water for 15h; Reflux; | 7.E To a suspension of Int-7e (230 g, 0.58 mol) in ethanol/H2O (1:1 ratio, 3000 ml) was added Na2SO3 (733 g, 5.8 mol). The resulting mixture was allowed to stir at mild reflux for about 15 hours. After cooling to room temperature, the mixture was extracted with dichloromethane twice and the combined organic layers was concentrated in vacuo to a semi-solid. The resulting residue was purified using chromatography on silica gel to provide Compound Int-7d. MS (ESI) m/e (M+H+): 317. | |
With sodium sulfite In ethanol; water Reflux; | 3.B To a suspension of Int-3a (230 g, 0.58 mol) in EtOH/H20 (1 : 1 ratio, 3000 ml) was added Na2S03 (733 g, 5.8 mol). The resulting mixture was stirred at mild reflux overnight. After cooling to room temperature, the mixture was extracted with dichloromethane twice and the combined organic layers was concentrated under vacuum to a semi-solid. The resulting residue was purified by chromatography on silica gel to give the desired Int-2d. MS (ESI) m/e (M+H+): 317. | |
With ethanol; water; sodium sulfite at 90℃; for 24h; | 15.9 Step 9(2S) -1- tert-butoxycarbonyl-2- (5-bromo--1H- imidazol-2-yl) pyrrolidinePreparation 9.58 g of the compound prepared in Step 8 were weighed(2S) -1- tert-butoxycarbonyl-2- (4,5-Dibromo -1H- imidazol-2-yl) pyrrolidineAnd 3.0 g of sodium sulfiteIn a 100 mL reaction flask,50 mL of a 1: 1 by volume ethanol / water mixed solution was added,90 reaction 24h,filter,concentrate,Column chromatography gave the title compound. |
With sodium sulfite In ethanol; water Reflux; | 192.4 STEP 4 To a suspension of compound from step 8 3 (230 g, 0.58 mol) in 10 EtOH/326 H2O (3000 ml) was added 369 Na2SO3 (733 g, 5.8 mol). The resulting mixture was stirred under reflux overnight. After cooling to RT, the mixture was extracted by DCM and concentrated under vacuum. The resulting residue was purified by chromatography on silica gel to give the desired 370 bromo imidazole target. MS (ESI) m/e (M+H+): 317. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium hydrogencarbonate In water; toluene Reflux; | 2.7 2.7 reparation of intermediate XVIIb (A= PG= Boc); To boronic ester XVIb (1.22 g, 2.26 mmol), bromide Xllla (1072 mg, 3.39 mmol), sodium bicarbonate (380 mg, 4.52 mmol), Pd(dppf)Cl2 (166 mg, 0.226 mmol) in toluene (50 mL), was added water (1 mL). The resulting mixture was heated at reflux overnight. The reaction mixture was filtered, evaporated to dryness and purified by column chromatography by gradient elution with heptane to ethyl acetate. The collected fractions containing the product were pooled and the volatiles were removed under reduced pressure. The residue (960 mg, 65 %) was used as such in the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 90℃; for 24h; Inert atmosphere; | M1b A mixture of Cul (10.8 mg, 0.057 mmol) and Pd(Ph3P)4 (55 mg, 0.048 mmol) was added to a DMF (6 mL) solution of Intermediate Mia (505 mg, 1.50 mmol), (5)-tert-butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l -carboxylate (328.5 mg, 1.039 mmol; for its preparation, see PCT Publication No. WO 2008/021927) and Et3N (0.4 mL, 2.87 mmol), purged with nitrogen and heated at 90 °C for 24 h. The reaction mixture was concentrated to remove primarily the excess Et3N, and the residue was diluted with MeOH and submitted to a reverse phase HPLC purification (MeOH/water/TFA; column: PHENOMENEX Luna, 30X100 mm S10). The fractions containing the coupled product were neutralized with excess NH3/MeOH (2.0 N) and the volatile component was removed in vacuo. The residue was partitioned between (¾(¾ and dilute NaHC03 solution. The aqueous phase was extracted with (¾(¾ (2x), and the combined organic phase was dried (MgS04) and evaporated in vacuo to afford Intermediate Mlb as a light yellow semi-solid foam (160.8 mg). 'H NMR (DMSO-d6, δ = 2.50 ppm, 400 MHz): 12.51-11.88 ('m', 2H), 7.82-7.15 (m, 6H), 4.78 (m, 2H), 3.52 (m, 2H), 3.39-3.30 (m, 2H), 2.27-1.77 (m, 8H), 1.40 (s, 7.45H), 1.18/1.16 (two overlapping 's', 10.55H). LC/MS: Anal. Calcd. for (M+H)+ C32H4iN604: 573.32; found, 573.27. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: C12H7Br2NO4 With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 120℃; for 3h; Stage #2: With potassium acetate; bis(pinacol)diborane In 1,4-dioxane at 110℃; Inert atmosphere; Stage #3: (S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester; trifluoroacetic acid | 1.C; 1.D; 1.E A solution of Int-lb (6.0 g, 14 mmol) and t-BuOK (1.73 g, 15.4 mmol) inDMF (20 mL) was stirred at 120 °C for 3 hr. Then the mixture was cooled and poured into 60 mL of ice-water. The mixture was then extracted withdichloromethane three times, the combined organic layers were concentrated in vacuo, and the crude products were purified by chromatography on silica gel to give an inseparable mixture compound Int-lc and Int-ld (87%). 1H MR (CDC13) δ: 7.01- 7.05 (m, 4 H), 6.72-6.74 (d, J=8.4 Hz, 2 H). To a solution of the mixture of isomers Int-lc and Int-ld (1 mmol) in 1,4- dioxane was added bispinacol borate (2.2 mmol), [Ι, - bis(diphenylphosphino)ferrocene]dichloro palladium, Pd(dppf)Cl2, (0.02 mmol) and KOAc (2.4 mmol). The reaction mixture was stirred under N2 and heated to 110 °C overnight. The reaction mixture was then cooled and the solvent removed. The residue was purified by column chromatography on silica gel (Gradient petroleum ether: Ethyl Acetate from 20: 1 to 10: 1) to afford the mixture of isomeric boronate esters Int-le and Int-lf which was used directly in the next reaction. A suspension of the isomeric boronate esters Int-le and Int-lf (2 mmol), (S)- tert-butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (4.2 mmol), [Ι, - bis(diphenylphosphino)ferrocene]dichloro palladium, Pd(dppf)2Cl2, (200 mg), Na2C03 (3 mmol) and in THF/H20 (10: 1, 33 mL) was refluxed at 75 °C overnight under N2 protection. (S)-tert-butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l- carboxylate was obtained by the procedure described in Example 2. The mixture was cooled and filtered and the filtrate was washed with water (50 mL) and extracted with ethyl acetate (100 mL), washed with brine and dried over anhydrous sodium sulfate. After concentrating, the residue was purified by column chromatography (Pet ether: Ethyl acetate gradient from 8: 1 to 5: 1) to afford a mixture of the desired products. The Boc pyrrolidines (1.3 mmol) were subsequently added into a TFA/dichloromethane (1 tol, 10 mL) mixture and the resulting solution was stirred at room temperature for 3 hr. When the reaction was complete by TLC, the mixture was concentrated and dried under high vacuum to give the crude products Int-lg and Int- lh which were used in the next reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: C12H7Br2NO4 With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 120℃; for 3h; Stage #2: With potassium acetate; bis(pinacol)diborane In 1,4-dioxane at 110℃; Inert atmosphere; Stage #3: (S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester; N-methoxycarbonyl-L-valine | 1.C; 1.D; 1.E; 1.F A solution of Int-lb (6.0 g, 14 mmol) and t-BuOK (1.73 g, 15.4 mmol) inDMF (20 mL) was stirred at 120 °C for 3 hr. Then the mixture was cooled and poured into 60 mL of ice-water. The mixture was then extracted withdichloromethane three times, the combined organic layers were concentrated in vacuo, and the crude products were purified by chromatography on silica gel to give an inseparable mixture compound Int-lc and Int-ld (87%). 1H MR (CDC13) δ: 7.01- 7.05 (m, 4 H), 6.72-6.74 (d, J=8.4 Hz, 2 H). To a solution of the mixture of isomers Int-lc and Int-ld (1 mmol) in 1,4- dioxane was added bispinacol borate (2.2 mmol), [Ι, - bis(diphenylphosphino)ferrocene]dichloro palladium, Pd(dppf)Cl2, (0.02 mmol) and KOAc (2.4 mmol). The reaction mixture was stirred under N2 and heated to 110 °C overnight. The reaction mixture was then cooled and the solvent removed. The residue was purified by column chromatography on silica gel (Gradient petroleum ether: Ethyl Acetate from 20: 1 to 10: 1) to afford the mixture of isomeric boronate esters Int-le and Int-lf which was used directly in the next reaction. A suspension of the isomeric boronate esters Int-le and Int-lf (2 mmol), (S)- tert-butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (4.2 mmol), [Ι, - bis(diphenylphosphino)ferrocene]dichloro palladium, Pd(dppf)2Cl2, (200 mg), Na2C03 (3 mmol) and in THF/H20 (10: 1, 33 mL) was refluxed at 75 °C overnight under N2 protection. (S)-tert-butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l- carboxylate was obtained by the procedure described in Example 2. The mixture was cooled and filtered and the filtrate was washed with water (50 mL) and extracted with ethyl acetate (100 mL), washed with brine and dried over anhydrous sodium sulfate. After concentrating, the residue was purified by column chromatography (Pet ether: Ethyl acetate gradient from 8: 1 to 5: 1) to afford a mixture of the desired products. The Boc pyrrolidines (1.3 mmol) were subsequently added into a TFA/dichloromethane (1 tol, 10 mL) mixture and the resulting solution was stirred at room temperature for 3 hr. When the reaction was complete by TLC, the mixture was concentrated and dried under high vacuum to give the crude products Int-lg and Int- lh which were used in the next reaction without further purification. To a mixture of Int-lg and Int-lh (600.0 mg, 1.0 mmol), (s)- Valinemethylcarbamate (2.2 mmol) and DIPEA/NMM (0.2 mL) in DMF (3 mL) was added HATU (2.2 mmol). The resulting mixture was stirred at room temperature for 4 hours.The mixture was purified by reverse phase HPLC (Syrergi, 30x 100mm, CH3CN-H20- 0.1% TFA) to give the desired targets. The isomers were separated by preparative HPLC.Compound 1: 1H- MR: (CD3OD) δ: 7.02 -7.17 (m, 6 H), 6.71-6.73 (m, 2 H), 5.05- 5.06 (m, 2 H), 4.12-4.14 (m, 2 H), 3.89-3.90 (m, 2 H), 3.76-3.78 (m, 2 H), 3.55 (s, 6 H), 1.91-2.24 (m, 10 H), 0.80-0.89 (m, 12 H). MS (ESI) m/z (M+H)+: 769 Compound 2: 1H- MR: (CD3OD) δ: 7.69 (s, 2 H), 7.22-7.24 (m, 4 H), 6.94-6.96 (d, J=8.8 Hz, 2 H), 5.10-5.14 (m, 2 H), 4.12-4.14 (m, 2 H), 4.00-4.03 (m , 2 H), 3.79-3.82 (m, 2 H), 3.56 (s, 6 H), 2.43-2.46 (m, 2 H), 1.95-2.18 (m, 8 H), 0.78-0.88(m, 12 H). MS (ESI) m/z (M+H)+: 769 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In tetrahydrofuran; water at 75℃; Inert atmosphere; | 6.F A suspension of Int-6e (1.5 g, 3.3 mmol), (S)-tert-butyl 2-(5-bromo-lH- imidazol-2-yl) pyrrolidine- 1-carboxylate (6.6 mmol), Pd(dppf)Cl2 (0.1 mmol), Na2C03 (10 mmol) in THF/H20 (5: 1, 30 mL) was refluxed at 75°C overnight under N2 protection. The reaction mixture was cooled and the precipitate was filtered and discarded. The filtrate was washed with water (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (gradient: MeOH/DCM (0.5% - 2%)) to afford 1.1 g of Int-6f. MS (ESI) m/e (M+H)+: 668. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.3% | With sodium carbonate In tetrahydrofuran; water for 15h; Inert atmosphere; | 18.C Preparation of Compound Int-18cA suspension of Int-7d (1.58 g, 5.00 mmol), Int-18b (1.03 g, 2.00 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol), and Na2C03 (636 mg, 6 mmol) were refluxed in THF/H20 (10: 1, 33 mL) for about 15 hours under N2 protection. The mixture was cooled, filtered, and the filtrate was washed with water (50 mL) then extracted with EtOAc (100 mL), washed with brine and dried over anhydrous sodium sulfate. The solution was concentrated and the residue obtained was purified using column chromatography (petroleum ether/ethyl acetate = 8: 1→5: 1) to provide Int-18c (61.3 % yield). MS (ESI) m/z (M+H)+: 736. |
61.3% | With sodium carbonate In tetrahydrofuran; water for 15h; Inert atmosphere; | 18.C Preparation of Compound Int-18cA suspension of Int-7d (1.58 g, 5.00 mmol), Int-18b (1.03 g, 2.00 mmol), Pd(dppf)Cl2 (146 mg, 0.2 mmol), and Na2C03 (636 mg, 6 mmol) were refluxed in THF/H20 (10: 1, 33 mL) for about 15 hours under N2 protection. The mixture was cooled, filtered, and the filtrate was washed with water (50 mL) then extracted with EtOAc (100 mL), washed with brine and dried over anhydrous sodium sulfate. The solution was concentrated and the residue obtained was purified using column chromatography (petroleum ether/ethyl acetate = 8: 1→5: 1) to provide Int-18c (61.3 % yield). MS (ESI) m/z (M+H)+: 736. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With potassium carbonate In 1,2-dimethoxyethane; water at 90℃; for 12h; Inert atmosphere; | 22.G Step G - Preparation of Compound Int-22gn -To a flask charged with Int-22f (0.36 g, 0.70 mmol) was added Int-7d (0.53 g, 1.7 mmol), PdCl2(dppf) (0.20 g, 0.28 mmol), K2C03 (0.48 g, 3.5 mmol), and DME7H20 (8 mL/2 mL). The mixture was degassed under house vacuum and filled with N2 six times, heated to 90 °C, and was allowed to stir for 12 hours. The mixture was cooled to room temperature and was partitioned between CH2C12 (15 mL) and water (4 mL). The layers were separated and the aqueous layer was extracted with CH2C12 (2 x 15 mL). The organic layers were combined and were washed with brine (1 x 7 mL). The organic layer dried (Na2S04), filtered, and concentrated in vacuo. The crude product was purified using preparative thin- layer chromatography using 6 x 1000 μΜ plates and a 20: 1 mixture of CH2Cl2/MeOH (7N H3) as eluent to provide 0.25 g (49%) of Int-22g as a yellow solid. MS (ESI) m/e (M+H) +: 734. |
49% | With potassium carbonate In 1,2-dimethoxyethane; water at 90℃; for 12h; Inert atmosphere; | 22.G Step G - Preparation of Compound Int-22gn -To a flask charged with Int-22f (0.36 g, 0.70 mmol) was added Int-7d (0.53 g, 1.7 mmol), PdCl2(dppf) (0.20 g, 0.28 mmol), K2C03 (0.48 g, 3.5 mmol), and DME7H20 (8 mL/2 mL). The mixture was degassed under house vacuum and filled with N2 six times, heated to 90 °C, and was allowed to stir for 12 hours. The mixture was cooled to room temperature and was partitioned between CH2C12 (15 mL) and water (4 mL). The layers were separated and the aqueous layer was extracted with CH2C12 (2 x 15 mL). The organic layers were combined and were washed with brine (1 x 7 mL). The organic layer dried (Na2S04), filtered, and concentrated in vacuo. The crude product was purified using preparative thin- layer chromatography using 6 x 1000 μΜ plates and a 20: 1 mixture of CH2Cl2/MeOH (7N H3) as eluent to provide 0.25 g (49%) of Int-22g as a yellow solid. MS (ESI) m/e (M+H) +: 734. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In 1,4-dioxane at 80℃; for 15h; | 20.B To a 40 mL vial was added Int-20a (182 mg, 0.336 mmol), bis(pinacolato)diboron (89.7 mg, 0.353 mmol), Pd2(dba)3 CHCl3 (35 mg, 0.034 mmol), X-phos (32 mg, 0.067 mmol), and KOAc (98 mg, 1.0 mmol). The vial was degassed, refilled with N2, and capped. Dioxane was added via a syringe and the solution was allowed to stir at 120 °C for 2 hours. (S)- rt-butyl-2-(5-bromo-lH-imidazol-2- yl)pyrrolidine-l -carboxylate (116.9 mg, 0.37 mmol), Pd(dppf)2Cl2 dichloromethane (28 mg, 0.034 mmol), and K2CO3 (1M, 1.0 mL, 1.0 mmol) were added. The reaction was allowed to stir at 80 °C for about 15 hours, then was cooled to room temperature. The aqueous layer were separated and extracted with 5 mL EtOAc. The organic extracts were combined and dried over Na2S04, filtered and concentrated in vacuo. The residue obtained was purified using flash column chromatography on silica gel (43 g, A:dichloromethane; B: 10% MeOH in EtOAc: A/B: 0% to 80%) to provide Compound Int- 20b (191 mg, 89.9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In tetrahydrofuran; water for 15h; Reflux; Inert atmosphere; | 23.C A suspension of Int-23b (550 mg, 1.0 mmol), tert-butyl 2-(2-bromo-lH- imidazol-5-yl) pyrrolidine- 1-carboxylate (2.4 mmol), Pd(dppf) Cl2 (200 mg), Na2CC>3 (3 mmol) and in THF/H20 (10: 1, 33 mL) was allowed to stir at reflux for about 15 hours under N2. The reaction mixture was cooled to room temperature and filtered, and the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified using column chromatography on silica gel to provide Compound Int-23c (160 mg). MS (ESI) m / e (M+H+): 768. | |
With sodium carbonate In tetrahydrofuran; water for 15h; Inert atmosphere; Reflux; | 23.C A suspension of Int-23b (550 mg, 1.0 mmol), tert-butyl 2-(2-bromo-lH- imidazol-5-yl) pyrrolidine- 1-carboxylate (2.4 mmol), Pd(dppf) Cl2 (200 mg), Na2C03 (3 mmol) and in THF/H20 (10: 1, 33 mL) was allowed to stir at reflux for about 15 hours under N2. The reaction mixture was cooled to room temperature and filtered, and the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified using column chromatography on silica gel to provide Compound Int-23c (160 mg). MS (ESI) m / e (M+H+): 768. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate at 95℃; for 12h; | 46.A To a cooled flask containing the crude bisboronate above was added bromo imidazole Int-4f (4.6 g, 14.5 mmol), PdCl2dppf CH2Cl2 (1.6 g, 1.98 mmol), and 1 M K2C03 (-20 mL). The flask was flushed with N2, capped, and heated to 95 °C. After 12 hours at 95 °C and the mixture was cooled to room temperature and the mixture diluted with EtOAc (100 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 75 mL). The organic layers were combined and were washed with brine (1 x 50 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The crude material was purified using RS ISCO Gold 220 gm column using a gradient of 100% CH2C12 to 92/8 % CH2Cl2/MeOH to provide 2.0 (39%) of Int-46a as a brown solid.LC-MS M+H = 769.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.9% | Stage #1: C28H27ClF2N4O3 With potassium acetate; bis(pinacol)diborane; XPhos In 1,4-dioxane at 120℃; for 2h; Inert atmosphere; Stage #2: (S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester With potassium carbonate In 1,4-dioxane at 80℃; for 15h; Inert atmosphere; | 20.B To a 40 mL vial was added Int-20a (182 mg, 0.336 mmol),bis(pinacolato)diboron (89.7 mg, 0.353 mmol), Pd2(dba)3-CHC13 (35 mg, 0.034 mmol), X- phos (32 mg, 0.067 mmol), and KOAc (98 mg, 1.0 mmol). The vial was degassed, refilled with N2, and capped. Dioxane was added via a syringe and the solution was allowed to stir at 120 °C for 2 hours. (2Cl2-dichloromethane (28 mg, 0.034 mmol), and K2C03 (1M, 1.0 mL, 1.0 mmol) were added. The reaction was allowed to stir at 80 °C for about 15 hours, then was cooled to room temperature. The aqueous layer were separated and extracted with 5 mL EtOAc. The organic extracts were combined and dried over Na2S04, filtered and concentrated in vacuo. The residue obtained was purified using silica gel chromatography (43 g, A: dichloromethane; B: 10% MeOH in EtOAc: A/B: 0% to 80%) to provideCompound Int-20b (191 mg, 89.9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2,7-dibromo-4,5,9,10-tetrahydropyrene; bis(pinacol)diborane With potassium acetate In 1,4-dioxane at 90℃; for 8h; Inert atmosphere; sealed tube; Stage #2: (S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester With potassium carbonate In 1,4-dioxane; water; dimethyl sulfoxide at 100℃; for 14h; Inert atmosphere; sealed tube; | AN To a solution of 2,7-dibromo-4,5,9,10-tetrahydropyrene (873 mg, 2.4 mmol) in dioxane (30 mL) was added bis(pinacolato)diboron (1.46 mg, 5.75 mmol), Pd(dppf)2Cl2 (351 mg, 0.48 mmol), and KOAc (1.41 mg, 14.4 mmol). The solution was degassed with N2 for 10 min, and then the sealed tube was heated to 90 °C for 8 h. The reaction mixture was cooled to rt, then (S)-tert- butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (1.67 g, 5.28 mmol), Pd(PPh3)4 (555 mg, 0.48 mmol), and K2C03 (2M in H20, 7.2 mL, 14.4 mmol) was added with DMSO (30 mL). The solution was degassed with N2 for 10 min, then the tube was sealed and heated to 100 °C for 14 h. The mixture was cooled to rt, diluted with EtOAc, and washed with sat. NaHC03, brine, dried with MgS04, and concentrated. The residue was purified by silica gel chromatography to yield product (699 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2,7-dibromo-4,5,9,10-tetrahydropyrene With potassium acetate; bis(pinacol)diborane In 1,4-dioxane at 90℃; for 8h; Inert atmosphere; sealed tube; Stage #2: (S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester With potassium carbonate In 1,4-dioxane; water; dimethyl sulfoxide at 100℃; for 14h; Inert atmosphere; sealed tube; | AG To a solution of 2,7-dibromo-4,5,9,10-tetrahydropyrene (873 mg, 2.4 mmol) in dioxane (30 mL) was added bis(pinacolato)diboron (1.46 mg, 5.75 mmol), Pd(dppf)2Cl2 351 mg, 0.48 mmol), and KOAc (1.41 mg, 14.4 mmol). The solution was degassed with N2 for 10 min, and then the sealed tube was heated to 90 °C for 8 h. The reaction mixture was cooled to rt, then (S)-tert- butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (1.67 g, 5.28 mmol), Pd(PPh3)4 (555 mg, 0.48 mmol), and K2C03 (2M in H20, 7.2 mL, 14.4 mmol) was added with DMSO (30 mL). The solution was degassed with N2 for 10 min, then the tube was sealed and heated to 100 °C for 14 h. The mixture was cooled to rt, diluted with EtOAc, and washed with sat. NaHC03, brine, dried over MgS04, and concentrated. The residue was purified by silica gel chromatography to yield product (115 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With potassium carbonate In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide at 85℃; for 18h; Inert atmosphere; | BI To a solution of 2, 7-bis (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) phenanthrene (250 mg, 0.58 mmol), (S)-tert-butyl 2-(4-bromo-lH-imidazol- 2-yl)pyrrolidine-l -carboxylate (459 mg, 1.45 mmol), tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.03 mmol) and dichloro[l,l'-bis(diphenylphosphino)ferrocene]palladium(II) (43 mg, 0.06 mmol) in a mixture of 1 ,2-dimethoxyethane (5.0 mL) and dimethylformamide (1 mL) was added a solution of potassium carbonate (2M in water, 1.8 mL, 3.4 mmol). The resulting mixture was degassed and then heated to 85°C under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2S04), and concentrated. The crude residue was purified by flash chromatography to yield (2S,2'S)-tert-butyl 2,2'-(5,5'-(phenanthrene-2,7-diyl)bis(lH-imidazole- 5 ,2-diyl))dipyrrolidine- 1 -carboxylate (237 mg, 38%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium carbonate In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide at 85℃; for 2h; Inert atmosphere; | BD A mixture of 2,2'-(9-(propan-2-ylidene)-9H-fluorene-2,7- diyl)bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolane) (90 mg, 0.20 mmol), (S)-tert-butyl 2-(5- bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (155 mg, 0.50 mmol),tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), PdC idppf) (15 mg, 0.02 mmol), 2M aqueous potassium carbonate (0.60 mL, 1.2 mmol), dimethoxyethane (1.7 mL) and dimethylformamide (0.3 mL) was degassed with argon for 15 minutes. The reaction was then heated to 85 °C for 2 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgS04) and concentrated. The resulting crude material was purified by flash column chromatography to yield tert-butyl 2,2'-(5,5'-(9-(propan-2-ylidene)-9H-fluorene-2,7- diyl)bis(lH-imidazole-5,2-diyl))dipyrrolidine-l-carboxylate (70 mg, 53%). LCMS-ESf :calculated for C40H4gN6O4: 676.37; observed [M+l]+: 677.19 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With potassium carbonate In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide at 85℃; for 16h; Inert atmosphere; | BE A mixture of 6,1 l-bis(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)dibenzo( /z]quinoxaline (270 mg, 0.55 mmol), (S)-tert-buty 2-(5-bromo-lH- imidazol-2-yl)pyrrolidine-l-carboxylate (435 mg, 1.40 mmol),tetrakis(triphenylphosphine)palladium(0) (65 mg, 0.06 mmol), PdCl2(dppf) (40 mg, 0.06 mmol), 2M aqueous potassium carbonate (1.65 mL, 3.3 mmol), dimethoxyethane (4.6 mL) and dimethylformamide (0.9 mL) was degassed with argon for 15 minutes. The reaction was then heated to 85 °C for 16 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgS04) and concentrated. The resulting crude material was purified by flash column chromatography to (2S,2'S)-tert-butyl 2,2'-(5,5'-(dibenzo[ /¾]quinoxaline-6,l 1- diyl)bis(lH-imidazole-5,2-diyl))dipyrrolidine-l-carboxylate (150 mg, 39%). LCMS-ESI+: calculated for C4oH44Ng04: 700.35; observed [M+l]+: 701.21. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With potassium carbonate In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide at 85℃; for 3h; Inert atmosphere; | BG A mixture of 2,6-bis(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-4H-cyclopenta[rfe/Jphenanthren-4-one (260 mg, 0.57 mmol), (S)-tert- butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (455 mg, 1.44 mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol), PdCl2(dppf) (45 mg, 0.06 mmol), 2M aqueous potassium carbonate (1.75 mL, 3.5 mmol), dimethoxyethane (5.0 mL) and dimethylformamide (1.0 mL) was degassed with argon for 15 minutes. The reaction was then heated to 85 °C for 3 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgS04) and concentrated. The resulting crude material was purified by flash column chromatography to (2iS,2'S)-teri-butyl 2,2'-(5,5'-(4-oxo-4H- cyclopenta[^e Jphenanthrene-2,6-diyl)bis(lH-imidazole-5,2-diyl))dipyrrolidine-l-carboxylat^ (148 mg, 38%). LCMS-ESI+: calculated for C39H42N605: 674.32; observed [M+l]+: 675.09. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium carbonate In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide at 85℃; for 18h; Inert atmosphere; | BH To a solution of 2,7-bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenanthrene-9-carbonitrile (147 mg, 0.32 mmol), (S)-tert-butyl 2-(4-bromo-lH-imidazol-2- yl)pyrrolidine-l-carboxylate (255 mg, 0.8 mmol), tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.02 mmol) and dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium(II) (24 mg, 0.03 mmol) in a mixture of 1,2-dimethoxyethane (5.0 mL) and dimethylformamide (1 mL) was added a solution of potassium carbonate (2M in water, 0.5 mL, 0.96 mmol). The resulting mixture was degassed and then heated to 85 °C under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2S04), and concentrated. The crude residue was purified by flash chromatography to yield (2S, 2'S)-tert-butyl 2, 2'-(5, 5'-(9-cyanophenanthrene-2, 7-diyl)bis(lH- imidazole-5,2-diyl))dipyrrolidine- 1 -carboxylate (119 mg, 55%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide at 85℃; for 18h; Inert atmosphere; | BJ To a solution of methyl (S)-3 -methyl- 1-oxo-l - ((lR,3S,4S)-3-(5-(7-(4,4,5,5-tetoamethyLyl)-lH-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)butan-2-ylcarbamate (-0.67 mmol), (S)- tert-butyl 2-(4-bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (266 mg, 0.84 mmol), tetrakis(triphenylphosphine) palladium(O) (23 mg, 0.02 mmol) and dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium(II) (30 mg, 0.04 mmol) in a mixture of 1,2- dimethoxyethane (10.0 mL) and dimethylformamide (2 mL) was added a solution of potassium carbonate (2M in water, 1.0 mL, 2.0 mmol). The resulting mixture was degassed and then heated to 85°C under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2S04), and concentrated. The crude residue was purified by flash chromatography to yield S)-tert-butyl 2- (5-(7-(2-((lR,3S,4S)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo [2.2.1 ]heptan-3 -yl)- 1 H-imidazol-5-yl)-9, 10-dihydrophenanthren-2-yl)- 1 H-imidazol-2- yl)pyiTolidine-l-carboxylate (182 mg, 56%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In 1,4-dioxane; water; dimethyl sulfoxide at 100℃; for 20h; sealed tube; | AN Methyl (S)-3 -methyl- 1 -oxo- 1 -((S)-2-(5-(7-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)-4,5,9, 10-tetrahydropyren-2-yl)- 1 H-imidazol-2-yl)pyrrolidin- 1 -yl)butan-2-ylcarbamate (139 mg, 0.22 mmol) and (S)-tert-butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (77 mg, 0.24 mmol) were dissolved in dioxane (2 mL) and DMSO (2 mL). Pd(dppf)2Cl2 (16 mg, 0.022 mmol), Pd(PPh3)4 (25 mg, 0.022 mmol), and K2C03 (2M in H20, 0.33 mL, 0.66 mmol). The tube was sealed and heated to 100 °C for 20 h. The mixture was cooled to rt, diluted with EtOAc, and washed with sat. NaHC03, brine, dried with MgS04, and concentrated. The residue was purified by silica gel chromatography to yield product (54.5 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methyl (S)-1-((S)-2-(7-(6-bromobenzo[b]thiophen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate With potassium acetate; bis(pinacol)diborane In 1,4-dioxane at 90℃; for 18h; Inert atmosphere; sealed tube; Stage #2: (S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester With potassium carbonate In 1,4-dioxane; water; dimethyl sulfoxide at 100℃; for 23h; Inert atmosphere; sealed tube; | AO To a solution of methyl (S)-l-((S)-2-(7-(6-bromobenzo[b]thiophen-2-yl)-lH-naphtho[l,2- d]imidazol-2-yl)pyrrolidin-l-yl)-3 -methyl- l-oxobutan-2-ylcarbamate (221 mg, 0.37 mmol) in dioxane (5 mL) was added bis(pinacolato)diboron (111 mg, 0.44 mmol), Pd(dppf)2Cl2 (27 mg, 0.037 mmol), and OAc (107 mg, 1.1 mmol). The solution was degassed with N2 for 10 min, and then the sealed tube was heated to 90 °C for 18 h. The reaction mixture was cooled to rt, then methyl (S)-tert-butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (127 mg, 0.4 mmol), Pd(PPh3)4 (43 mg, 0.037 mmol), and K2C03 (2M in H20, 0.54 mL, 1.1 mmol) was added with DMSO (5 mL). The solution was degassed with N2 for 10 min, then the tube was sealed and heated to 100 °C for 23 h. The mixture was cooled to rt, diluted with EtOAc, and washed with sat. NaHC03, brine, dried with MgS04, and concentrated. The residue was purified by silica gel chromatography to yield product (52.8 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide at 85℃; for 18h; Inert atmosphere; | MM tert-butyl(2S)-2-[5-(2-{(2S,4S)-l-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrroli din-2-yl}-l,ll- dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-9-yl)-lH-imidazol-2-yl]pyrrolidine-l- carboxylate To a solution of (2S, 4S)-methyl{4-(methoxymethyl)-2-[(9-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,l l-dihydroiso chromeno[4',3':6,7]naphtho[l,2-d]imidazol-2-yl)pyrrolidin-lyl]- 3 -methyl- l-oxobutan-2-yl} carbamate (0.69 mmol), (S)-tert-butyl 2-(5-bromo-lH-imidazol-2- yl)pyrrolidine-l -carboxylate (220 mg, 0.69 mmol), tetrakis(triphenylphosphine) palladium(O) (24 mg, 0.02 mmol) and dichloro[l,l'-bis(diphenylphosphino) ferrocene]palladium(II) (31 mg, 0.04 mmol) in a mixture of 1 ,2-dimethoxyethane (6.0 mL) and dimethylformamide (1.0 mL) was added a solution of potassium carbonate (2M in water, 1.04 mL, 2.0 mmol). The resulting mixture was degassed and then heated to 85 °C under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2S04), and concentrated. The crude residue was purified by flash chromatography to yield (tert-butyl (2S)-2-[5- (2-{(2S,4S)-l -[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl} -1 ,11 - dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-9-yl)-lH-imidazol-2-yl]pyrrolidine-l- carboxylate (145 mg, 27%). |
27% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide at 85℃; for 18h; Inert atmosphere; | AM To a solution of (2S,4S)-methyl {4-(methoxymethyl)-2-[(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1yl]-3-methyl-1-oxobutan-2-yl}carbamate (0.69 mmol), (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (220 mg, 0.69 mmol), tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.02 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (31 mg, 0.04 mmol) in a mixture of 1,2-dimethoxyethane (6.0 mL) and dimethylformamide (1.0 mL) was added a solution of potassium carbonate (2M in water, 1.04 mL, 2.0 mmol). The resulting mixture was degassed and then heated to 85° C. under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield (tert-butyl (2S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (145 mg, 27%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water at 85℃; for 16h; Inert atmosphere; | NB Jeri-butyl (2S)-2-[5-(2-{(2S,4S)-l-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-l,ll- dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-9-yl)-lH-imidazol-2-yl]pyrrolidine-l- carboxylate Jeri-butyl (2S)-2-[5-(2-{(2S,4S)-l-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-l,ll- dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-9-yl)-lH-imidazol-2-yl]pyrrolidine-l- carboxylate Methyl [(2S)-3-methyl-l-{(2S,4S)-4-methyl-2-[9-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-l , 11 -dihydroisochromeno[4',3':6,7]naphtho[l ,2-d]imidazol-2-yl]pyrrolidin-l -yl} -1 -oxobutan-2- yl]carbamate (298 mg, 0.47 mmol), (S)-fert-butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l- carboxylate (443 mg, 1.4 mmol), Pd(PPh3)4 (54 mg, 0.05 mmol), PdCl2(dppf)2 (36 mg, 0.05 mmol), and K2C03 (2M in H20, 0.78 mL, 1.55 mmol) were combined in DME (5 mL). The mixture was degassed with bubbling N2 for 10 min the heated to 85 °C for 16 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCC and brine. The organics were dried over MgSO filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0%> to 30%> MeOH/EtOAc) to afford fert-butyl (2S)-2- [5-(2- {(2S,4S)-1 -[N-(methoxycarbonyl)-L-valyl] -4-methylpyrrolidin-2-yl} -1,11- dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-9-yl)-lH-imidazol-2-yl]pyrrolidine-l- carboxylate (84 mg, 24%>). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide at 85℃; for 6h; Inert atmosphere; | OQ Tert-butyl (2S)-2-[5-(2-{(2S,4S)-4-ethoxy-l-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-l,ll- dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-9-yl)-lH-imidazol-2-yl]pyrrolidine-l- carboxylate To a solution of methyl [(2S)-l-{(2S,4S)-4-ethoxy-2-[9-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,l l-dihydroisochromeno[4',3':6,7]naphtho[l,2-d]imidazol-2-yl]pyrrolidin-l-yl}- 3 -methyl- 1 -oxobutan-2-yl] carbamate (0.41 g, 0.61 mmol) in a mixture of DME (6.1 mL) and DMF (1.0 mL) was added (S)-tert-butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (0.39 g, 1.2 mmol), tetrakis(triphenylphosphine)palladium (0.021 g, 0.018 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (0.030 g, 0.041 mmol), and aqueous potassium carbonate (2M, 1.0 mL, 2.0 mmol). The solution was degasses with argon for 5 min and heated, with stirring, to 85 °C for 6 h. The solution was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine. The aqueous layers were backextracted with EtOAc (3x). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100 % EtOAc(w/5%> MeOH)/Hexanes to 80% MeOH/EtOAc) to afford tert-butyl (2S)-2-[5-(2- {(2S,4S)-4-ethoxy-l-[N- (methoxycarbonyl)-L-valyl]pyrrolidin-2-yl} -1 , 11 -dihydroisochromeno[4',3':6,7]naphtho[l ,2- d]imidazol-9-yl)-lH-imidazol-2-yl]pyrrolidine-l -carboxylate (0.16 g, 33%). |
33% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide at 85℃; for 6h; Inert atmosphere; | BZ To a solution of methyl [(2S)-1-{(2S,4S)-4-ethoxy-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate (0.41 g, 0.61 mmol) in a mixture of DME (6.1 mL) and DMF (1.0 mL) was added (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.39 g, 1.2 mmol), tetrakis(triphenylphosphine)palladium (0.021 g, 0.018 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.030 g, 0.041 mmol), and aqueous potassium carbonate (2M, 1.0 mL, 2.0 mmol). The solution was degasses with argon for 5 min and heated, with stirring, to 85° C. for 6 h. The solution was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine. The aqueous layers were backextracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100% EtOAc (w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford tert-butyl (2S)-2-[5-(2-{(2S,4S)-4-ethoxy-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (0.16 g, 33%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide at 85℃; for 3h; Inert atmosphere; | LZ tert-butyl (2R)-2-[5-(2-{(2S)-l-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-3,7- dihydroisochromeno[3',4':5,6]naphtho[l,2-d]imidazol-9-yl)-lH-imidazol-2-yl]pyrrolidine-l- carboxylate tert-butyl (2R)-2-[5-(2-{(2S)-l-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-3,7- dihydroisochromeno[3',4':5,6]naphtho[l,2-d]imidazol-9-yl)-lH-imidazol-2-yl]pyrrolidine-l- carboxylateA mixture of Pentacyclic Intermediate methyl [(2S)-3-methyl-l-oxo-l- {(2S)-2-[9-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3',4':5,6]naphtho[l,2-d]imidazol-2- yl]pyrrolidin-l-yl}butan-2-yl]carbamate (780 mg, 1.3 mmol), (S) -tert-butyl 2-(5-bromo-lH-imidazol- 2-yl)pyrrolidine-l-carboxylate (450 mg, 1.4 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.03 mmol), PdC dppf) (60 mg, 0.08 mmol), 2M aqueous potassium carbonate (1.9 mL, 3.9 mmol), dimethoxyethane (10 mL) and dimethylformamide (2 mL) was degassed with argon for 15 minutes. The reaction was then heated to 85 °C for 3 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgS04) and concentrated. The resulting crude material was purified by flash column chromatography (EtOAc/MeOH) to yield Intermediate tert-butyl (2R)-2-[5-(2- {(2S)-l -[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl} -3,7-dihydroisochromeno[3',4':5,6]naphtho[l ,2- d]imidazol-9-yl)-lH-imidazol-2-yl]pyrrolidine-l -carboxylate (390 mg, 43% yield). |
43% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide at 85℃; for 3h; Inert atmosphere; | AE A mixture of Pentacyclic Intermediate methyl [(2S)-3-methyl-1-oxo-1-{(2S)-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}butan-2-yl]carbamate (780 mg, 1.3 mmol), (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (450 mg, 1.4 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.03 mmol), PdCl2(dppf) (60 mg, 0.08 mmol), 2M aqueous potassium carbonate (1.9 mL, 3.9 mmol), dimethoxyethane (10 mL) and dimethylformamide (2 mL) was degassed with argon for 15 minutes. The reaction was then heated to 85° C. for 3 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO4) and concentrated. The resulting crude material was purified by flash column chromatography (EtOAc/MeOH) to yield Intermediate tert-butyl (2R)-2-[5-(2-{(2S)-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-3,7-dihydroisochromeno[3′,4′:5,6]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (390 mg, 43% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In 1,4-dioxane; methanol; dichloromethane at 40℃; for 1h; | OS Methyl (2S,3R)-l-((S)-2-(5-bromo-lH-imidazol-2-yl)pyrrolidin-l-yl)-3-methoxy-l-oxobutan-2- ylcarbamate To a solution of (S)-tert-butyl 2-(5-bromo-lH-imidazol-2-yl)pyrrolidine-l -carboxylate (1.00 g, 3.2 mmol) in a mixture of CH2C12 (30 mL) and MeOH (5 mL) was added HCI (in dioxane, 4 M, 11.5 mL, 46.0 mmol). The solution was stirred at 40 °C for lh, cooled to room temperature, and concentrated to dryness under reduced pressure. To the crude intermediate suspended in CH2C12 (30 mL) was added (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (0.67 g, 3.5 mmol), HATU (1.47 g, 3.8 mmol), and DIPEA (1.00 mL, 6.0 mmol), The resulting solution was stirred at room temperature for 24 h. DMF (2 mL) and aqueous LiOH (2.5 M, 1 mL) were added and the reaction was concentrated to dryness under reduced pressure. The crude material was diluted with EtOAc and washed with H20 and brine. The aqueous layers were backextracted with EtOAc. The combined organic layers were dried over Na2S04 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20%> to 100 % EtOAc(w/5%> MeOH)/CH2Cl2) to afford methyl (2S,3R)-l-((S)-2-(5-bromo-lH-imidazol-2-yl)pyrrolidin-l -yl)-3-methoxy-l- oxobutan-2-ylcarbamate (1.2g, 100%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.2 g | Stage #1: (S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester With hydrogenchloride In methanol; dichloromethane at 40℃; for 1h; Stage #2: (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 24h; | CB To a solution of (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.00 g, 3.2 mmol) in a mixture of CH2Cl2 (30 mL) and MeOH (5 mL) was added HCl (in dioxane, 4 M, 11.5 mL, 46.0 mmol). The solution was stirred at 40° C. for 1 h, cooled to room temperature, and concentrated to dryness under reduced pressure. To the crude intermediate suspended in CH2Cl2 (30 mL) was added (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (0.67 g, 3.5 mmol), HATU (1.47 g, 3.8 mmol), and DIPEA (1.00 mL, 6.0 mmol), The resulting solution was stirred at room temperature for 24 h. DMF (2 mL) and aqueous LiOH (2.5 M, 1 mL) were added and the reaction was concentrated to dryness under reduced pressure. The crude material was diluted with EtOAc and washed with H2O and brine. The aqueous layers were backextracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100% EtOAc (w/5% MeOH)/CH2Cl2) to afford methyl (2S,3R)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate (1.2 g, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.8 kg | Stage #1: (S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester; (S)-6-phenyl-3,10-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo-[5,6][1,3]oxazino-[3,4-a]indole With tris-(dibenzylideneacetone)dipalladium(0); (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; potassium carbonate In 1,2-dimethoxyethane at 20 - 80℃; for 16.5h; Inert atmosphere; Stage #2: 4-nitro-benzoic acid In toluene at 60℃; | |
3.8 kg | Stage #1: (S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester; (S)-6-phenyl-3,10-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo-[5,6][1,3]oxazino-[3,4-a]indole With (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; potassium carbonate In tetrahydrofuran; methanol; 1,2-dimethoxyethane at 77℃; for 16.5h; Inert atmosphere; Large scale; Stage #2: 4-nitro-benzoic acid In tetrahydrofuran; methanol; 1,2-dimethoxyethane; toluene at 60℃; for 1h; Inert atmosphere; Large scale; | 8 Preparation of Intermediate Compound 10 To a 75 L round bottomed flask equipped with an overhead stirrer and a nitrogen inlet was charged 32 L DME, which was degassed with nitrogen. Compound 8 (1.92 kg, 4.22 mol), B(pin)2 (2.36 kg, 9.28 mol) and potassium acetate (2.07 kg, 21.1 mol) were charged to the flask as solids, and the flask was further purged with nitrogen. To a 3 -neck 12 L round bottomed flask equipped with an overhead stirrer and a nitrogen inlet was charged 4 L methanol-THF which was then degassed with nitrogen. Pd2dba3 (0.039 kg, 0.042 mol) and CataCXium A (0.060 kg, 0.169 mol) were then charged as solids, and the mixture aged under nitrogen for 30mins, formed dark red solution. The catalyst solution was transferred to the 75 L flask under nitrogen, and the solution was heated to reflux (80-83°C) and aged for 4 hours. The reaction was cooled down to room temperature, at which time 10 L degassed water was charged the reaction flask. At this time, potassium carbonate (3.50 kg, 25.3 mol) and 14 (3.03 kg, 9.49 mol), were charged under nitrogen. To a 3 -neck 12L round bottom flask equipped with an overhead stirrer and a nitrogen inlet was charged 4 L methanol-THF which was then degassed with nitrogen. Pd2dba3 (0.068 kg, 0.074 mol) and Am-Phos (0.078 kg, 0.295 mol) were charged as solids, and the solution aged at room temperature for 30 minutes. The solution was then transferred to the 75 L reaction flask under nitrogen. The reaction was heated to reflux (approximately 77°C) under nitrogen and aged for 16 hours. The reaction was then cooled to room temperature, and transferred to a 170 L cylindrical vessel along with 20 L ethyl acetate and 30 L water. The mixture was stirred for 30mins, and the aqueous layer was cut. To the organic layer was added 20L 20 wt% aqueous glycolic acid and the mixture was aged at room temperature for 30 minutes with stirring. The aqueous layer was separated and retained, and the organics extracted again with 10 L 20 wt% glycolic acid. The aqueous cuts were combined, and 20 L methanol-THF was added. The mixture was basified to a pH of 9 using 28% ammonium hydroxide. The aqueous layer was then cut and discarded. The organic layer was washed with 10 wt%> aqueous Na2SO3 and brine. The organic layer was charged into a 75 L flask, then 1 kg MP-TMT and 600 g Darco-KB was charged, and stirred for 2 hours. The mixture was filtered and washed with 4 L methanol-THF twice. The solution was concentrated and flushed with toluene, maintaining a 25 L volume and reducing the methanol-THF content below 2% as determined by HNMR. The toluene mixture was heated to 60 °C to a solution, at which time 4-nitrobenzoic acid (1.410 kg, 8.44 mol) was charged as a solid, and the mixture aged 1 hour. The solution was then slowly cooled to room temperature and aged overnight. At this time the slurry was cooled to 5 °C and filtered. The solids were washed with cold toluene (4 L), then dried under nitrogen. Nitro benzoate salt 10 was obtained as a yellow solid (3.80 kg, 82% overall yield). 1H NMR (DMSO, 500 MHz): δ = 8.32 (dt, 4H, J= 9.0, 2.0 Hz), 8.18 (dt, 4H, J= 9.0, 2.0 Hz), 7.99 (s, 1H), 7.79 (d, 1H, J= 8.0 Hz), 7.71 (s, 1H), 7.54-7.46 (m, 3H), 7.42-7.37 (m, 2H), 7.30-7.27 (m, 4H), 7.08 (s, 1H), 7.01 (m, 2H), 4.82 (m, 2H), 3.55 (br s, 2H), 3.37 (m, 2H), 2.32-2.10 (m, 2H), 2.08-1.83 (m, 6H), 1.41-1.16 (m, 18H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.2% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water at 75℃; for 0.15h; Inert atmosphere; | 19.7 Step 7 A suspension of 36g (2.7 g, 3.51 mmol), Cap 7a (1.22 g, 3.86 mmol), Pd(dppf)2Cl2 (256 mg, 0.35 mmol) and Na2C03 (1.2 g, 10.5 mmol) in THF/H20 (5: 1, 36 mL) was refluxed at 75°C for about 15 hours under N2 atmosphere. After that, the mixture was filtered, and the filtrate was washed with water (50 mL) and extracted with ethyl acetate (100 mL), washed with brine and dried over anhydrous sodium sulfate. After concentration in vacuo, and the resutling residue was purified using Si02 chromatography, eluting with DCM: MeOH (5/1-3/1) to provide 36h (2.0 g, 65.2 %) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With trifluoroacetic acid In dichloromethane at 25℃; for 2h; | 10.1 Step 1 Compound cap 7a was prepared in Example 7 of WO 2012/040923 Al . Compound cap 7a (50 g, 0.16 mol) was added into TFA/DCM (1 : 1, lOmL). The mixture was stirred at 25 °C for 2 hours; then concentrated in vacuo and dried under high vacuum to provide compound cap 7b (34.4 g, 100% yield). LC/MS: Anal. Calcd. For [M+H]+ C7H10BrN3: 216.01; found 216.1 |
100% | With trifluoroacetic acid In dichloromethane at 25℃; for 2h; | 10.1 Example 10 Compound cap 7a (50 g, 0.16 mol) was added into TFA/DCM (1 : 1, lOmL). The mixture was stirred at 25 °C for 2 hours; then concentrated in vacuo and dried under high vacuum to provide compound cap7b (34.4 g, 100% yield). LC/MS: Anal. Calcd. For [M+H]+ C7H10BrN3 : 216.01; found 216.1. |
100% | With trifluoroacetic acid In dichloromethane at 25℃; for 2h; | 1 Step 1 (0274) Compound cap 2a was prepared in Example 7 of WO 2012/040923 Al . (0275) Compound cap 2a (50 g, 0.16 mmol) was added into TFA/DCM (1 : 1, lOmL). The mixture was stirred at 25°C for 2 hours; then concentrated and dried under high vacuum to give to desired product cap 2b (34.4 g, 100% yield). LC/MS: Anal. Calcd. For [M+H]+ C7Hi0BrN3: 216.01; found 216.1. |
410 mg | With hydrogenchloride In ethyl acetate at 20℃; for 3h; | 1 Step 1: Synthesis of Compound BB-14 Compound BB-14-1 (600 mg, 1.90 mmol) was dissolved in ethyl acetate (5 mL) and added in hydrogen chloride/ethyl acetate (HCl/EA, 4 mol/L, 20 mL), stirred at room temperature for 3 h. After the reaction was complete as detected by TLC, the solvent was removed by a rotary evaporator thereby obtaining the white solid intermediate (410 mg). The white solid intermediate (410 mg, 1.63 mmol), N-Moc-L-valine (BB-2-6, 399 mg, 2.09 mmol), and DIPEA (735 mg, 5.70 mmol) were dissolved in DMF (10 mL), HATU (1.08 g, 2.84 mmol) was added. The reaction mixture was stirred at room temperature overnight. After the reaction was complete as detected by TLC, the reaction was quenched with H2O (10 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, filtrated, the filtrate was concentrated under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (PE/EtOAc=1/1→pure EtOAc) to deliver the target compound BB-14 (white solid, 306 mg, yield 43.2%). MS m/z: 374.9 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water at 80℃; for 0.15h; Inert atmosphere; | 20.8 Step 8 A mixture of 74h (0.8 g, 1 mol), Cap 7a (0.46 g, 1.5 mmol), Na2C03 (0.3 g, 3 mol) and Pd(dppf)Cl2 (150 mg, 0.2 mmol) in THF/H20 (v/v=5/l, 9 mL) was stirred at 80°C under N2 atmospherefor about 15 hours. After that, the mixture was washed with water and extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The resulting solution was then filtered, concentrated in vacuo, the residue was purified using Si02 chromatography, eluting with petroleum ether: ethyl acetate (1/1-1/4) to provide 74i (0.7 g, 78%). LC/MS: Anal. Calcd. For [M+H]+ C47H54FN907S: 908.39; found 908.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
360 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 85℃; for 16h; Inert atmosphere; Sealed tube; | 24.6 Step 6 To the mixture of 219e (580 mg, 0.733 mmol) in dioxane, was added Cap7a (348 mg, 1.100 mmol), PdCl2(dppf)2 (53.7 mg, 0.073 mmol), aqueous K2C03 solution (2.93 mL, 2.93 mmol). The mixture was placed in a sealed tube and heated at 85 °C for 16h. The mixture was cooled and separated. The organic layer was purified using column chromatography on silica gel (50g supelco), eluting with DCM/EtOAc/MeOH (60/46/4 then 20/72/8), to provide219f (360 mg, 54.5 % yield) as a yellow gum |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water; N,N-dimethyl-formamide at 80℃; for 0.15h; Inert atmosphere; | 38.6 Step 6 A suspension of 538f (1.1 g, 1.38 mmol), Cap 7a (0.664 g, 2.07 mmo Na2C03 (0.293 g, 2.76 mmol) and Pd(dppf)Cl2 (202 mg, 0.276 mmol) in THF/DMF/H20 (v/v=5/l/l, 21 mL) was allowed to stir at 80°C for about 15 hours under N2 atmosphere. The resulting reaction was then washed with water and extracted with ethyl acetate, washed with brine and dried over anhydrous Na2S04.After filtrated, the filtrate was concentrated in vacuo, the resulting residue was purified using flash column chromatography on silica gel, eluting with ethyl acetate: methanol (100/1-50/1) to provide 538g (0.9 g, 72%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water; N,N-dimethyl-formamide at 80℃; for 0.15h; Inert atmosphere; | 40.6 Step 6 A suspension of 557f (680 mg, 0.84 mmol), Cap 7a (291 mg, 0.92 mmol), Na2C03 (218 mg, 2.1 mmol) and Pd(dppf)Cl2 (31 mg, 0.04 mmol) in THF/H20/DMF (v/v=5/2/l, 30 mL) was allowed to stir at 80°C for about 15 hours under N2 atmosphere. The resulting reaction was then washed with water and extracted with ethyl acetate, washed with brine and dried over anhydrous Na2S04. After filtrated, the filtrate was concentrated in vacuo, the resulting residue was purified using flash column chromatography on silica gel, eluting with ethyl acetate: methanol (100/1-50/1) to provide 557g (460 mg, 60 %) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.2% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90℃; for 5h; Inert atmosphere; Sealed tube; | 21.1 Step 1 A mixture of 27f (1.6 g, 2.322 mmol, Cap7a (0.881 g, 2.79 mmol), K2C03 (962 mg, 6.96 mmol) and Pd(dppf)Cl2 (284 mg, 0.348 mmol), 15 ml Dioxane/ 2 ml H20 in pressure tube was purged with nitrogen and vacuumed 2 times and stirred at 90°C for 5 hours. After that, the mixture was washed with water and extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The resulting solution was then filtered, concentrated in vacuo, and the residue was purified using Si02 chromatography, eluting with chromatography Ethyl acetate/Hexane (0% to 100%) to provide305a (1.1 g, 53.2 % yield). LC/MS: Anal. Calcd. For [M+H]+ C47H52FN906S: 890.37; found 890.75 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water at 80℃; for 15h; Inert atmosphere; | 20.8 Example 20 A mixture of 74h (0.8 g, 1 mol), Cap 7a (0.46 g, 1.5 mmol), Na2C03 (0.3 g, 3 mol) and Pd(dppf)Cl2 (150 mg, 0.2 mmol) in THF/H20 (v/v=5/l, 9 mL) was stirred at 80°C under N2 atmospherefor about 15 hours. After that, the mixture was washed with water and extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was purified using Si02 chromatography, eluting with petroleum ether: ethyl acetate (1/1-1/4) to provide74i (0.7 g, 78%). LC/MS: Anal. Calcd. For [M+H]+ C47H54FN907S: 908.39; found 908.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.2% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90℃; for 5h; Inert atmosphere; Sealed tube; | 21.1 Example 21 A mixture of 27f ( 1.6 g, 2.322 mmol, Cap7a (0.881 g, 2.79 mmol), K2C03 (962 mg, 6.96 mmol) and Pd(dppf)Cl2 (284 mg, 0.348 mmol), 15 ml Dioxane/ 2 ml H20 in pressure tube was purged with nitrogen and vacuumed 2 times and stirred at 90°C for 5 hours. After that, the mixture was washed with water and extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was purified using Si02 chromatography, eluting with chromatography Ethyl acetate/Hexane (0% to 100%) to provide305a (1.1 g, 53.2 % yield). LC/MS: Anal. Calcd. For [M+H]+ C47H52FN906S: 890.37; found 890.75 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water at 75℃; for 15h; Inert atmosphere; Overall yield = 65.2 %; Overall yield = 2 g; | 19.7 Example 19 A suspension of 36g (2.7 g, 3.51 mmol), Cap 7a (1.22 g, 3.86 mmol), Pd(dppf)2Cl2 (256 mg, 0.35 mmol) and Na2C03 (1.2 g, 10.5 mmol) in THF/H20 (5: 1, 36 mL) was refluxed at 75°C for about 15 hours under N2 atmosphere. After that, the mixture was filtered, and the filtrate was washed with water (50 mL) and extracted with ethyl acetate (100 mL), washed with brine and dried over anhydrous sodium sulfate. After concentration in vacuo, the residue was purified using Si02 chromatography, eluting with DCM: MeOH (5/1-3/1) to provide 36h (2.0 g, 65.2 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
730 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 85℃; for 16h; Inert atmosphere; Sealed tube; | 24.6 Example 24 To the mixture of 219e (580 mg, 0.733 mmol) in dioxane, was added Cap7a (348 mg, 1.100 mmol), PdCl2(dppf)2 (53.7 mg, 0.073 mmol), aqueous K2C03 solution (2.93 mL, 2.93 mmol). The mixture was placed in a sealed tube and heated at 85 °C for 16h. The mixture was cooled and separated. The organic layer was purified using column chromatography on silica gel (50g supelco), eluting with DCM/EtOAc/MeOH (60/46/4 then 20/72/8), to provide219f (360 mg, 54.5 % yield) as a yellow gum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water for 0.15h; Inert atmosphere; Reflux; | 77.1 Step 1 Compound 6d was made in Example 35. The compound 6d (2.5 g, 4.07 mmol), cap 31a (2.58 g, 8.16 mmol), Pd(dppf)Cl2 (0.26 mg, 0.9 mmol) and Na2C03 (1.73 g, 16.3 mmol) in THF/H20 (64 mL/8 mL) was refluxed for about 15 hours under N2 atmosphere. After filtration, the filtrate was washed with water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine and dried over Na2S04. After filtration and concentration, the residue obtained was purified using Si02 chromatography (40 g, Hexane/EtOAc 20% to 50%) to provide 303b (2.4 g, 70% yield). LC/MS: Anal. Calcd. For [M+H]+ C46H50FN7O5S: 832.36; found 832.6. Step 2 The compound of 303b (1.6 g) was separated by SFC by using the following conditions to provide 303c (0.6 g, 75 %). Column: OD-3 250x4.6mm I D., 5um Solvent: 40% of iso-propanol (0.05% DEA) in C02Flow rate: 2.5mL/min Wavelength: 220 nm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water at 75℃; for 0.15h; Inert atmosphere; | 37.4 Step 4 General procedure: A suspension of 9c (3.4 g, 6.6 mmol), cap 32a (2.5 g, 7.9 mmol), Pd(dppf)Cl2 (241 mg, 0.33 mmol) and Na2C03 (2 g, 19.8 mmol) in THF/H20 (5: 1, 36 mL) was refluxed at 75°C for about 15 hours under N2 atmosphere. After that, the mixture was filtered, the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL), washed with brine and dried over anhydrous sodium sulfate. After being concentrated in vacuo, the residue obtained was purified using Si02 chromatography (petroleum ether / ethyl acetate = 8 : 1 to 3 : 1) to provide 9d (3.4 g, 82 % yield) |
82% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water at 75℃; for 15h; Inert atmosphere; | 37.4 Step 4 A suspension of 9c (3.4 g, 6.6 mmol), cap 32a (2.5 g, 7.9 mmol), Pd(dppf)Cl2 (241 mg, 0.33 mmol) and Na2C03 (2 g, 19.8 mmol) in THF/H20 (5: 1, 36 mL) was refluxed at 75°C for about 15 hours under N2 atmosphere. After that, the mixture was filtered, the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL), washed with brine and dried over anhydrous sodium sulfate. After being concentrated in vacuo, the residue obtained was purified using Flash column chromatography on silica gel (petroleum ether / ethyl acetate = 8: 1 to 3: 1) to provide 9d (3.4 g, 82 % yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water at 100℃; for 0.15h; Inert atmosphere; | 45.7; 46.4 Step 7 A suspension of the compound 58f (3.5 g, 4.4 mmol), cap 31a (1.7 g, 5.28 mmol), Na2C03 (933 mg, 8.8 mmol) and Pd(dppf)Cl2 (161 mg, 0.22 mmol) in THF/H20 (48 mL, 5: 1) was stirred at 100°C under N2 atmosphere for about 15 hours. LCMS and TLC were detected the reaction. Separated the water phase through the separatory funnel, and the organic phase was concentrated in vacuo and purified using Si02 chromatography (eluent: DCM/MeOH from 100: 1 to 50: 1) to provide the compound 58g (2.1 g, 53%). LC/MS Anal. Calcd. For [M+H]+ C48H53FN807S: 905.37; found 905.5. A suspension of the compound 59d (4 g, 5.03 mmol), cap 31a (1.9 g, 6.03 mmol), Na2C03 (1.07 g, 10.1 mmol) and Pd(dppf)Cl2 (184 mg, 0.25 mmol) in THF/H20 (48 mL, 5: 1) was stirred at 100°C under N2 atmosphere for about 15 hours. LCMS and TLC were detected the reaction. Separated the water phase through the separatory funnel, and the organic phase was concentrated in vacuo and purified using Si02 chromatography (eluent: DCM/MeOH from 100: 1 to 30: 1) to provide the compound 59e (2.2 g, 49% yield). LC/MS Anal. Calcd. For [M+H]+ C48H53FN807S: 905.37; found 905.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.3% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water at 80℃; for 0.15h; Inert atmosphere; | 49.4 Step 4 A suspension of the compound 67d (3 g, 5.8 mmol), cap 31a (2 g, 6.4 mmol), Pd(dppf)Cl2 (0.42 g,0.58 mmol), Na2C03 (1.84 g, 17.4 mmol) and in THF/H20 (5: 1, 96 mL) was refluxed at 80°C for about 15 hours under N2 atmosphere. After that, the mixture was filtered; the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL), washed with brine and dried over anhydrous sodium sulfate. After being concentrated in vacuo, the residue obtained was purified using Si02 chromatography (petroleum ether: ethyl acetate = 1 : 1) to provide compound 67e (3.05 g, 83.3% yield). LC/MS: Anal. Calcd. For [M+H]+ C34H32C1FN403S: 631.19; found 631.2. Step 5 The compound 67e-l was separated from compound 67e (3.05 g) by SFC using the following condition: Column: Chiralcel OJ-3 50*4.6mm I D. Mobile phase: 40% methanol (0.05% DEA) in C02 Flow rate: 4.0 mL/min Wavelength: 220 nm Compound 67e-l (1.88 g, 60% yield). LC/MS: Anal. Calcd. For [M+H]+ C34H32C1FN403S: 631.19; found 631.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.3% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water; N,N-dimethyl-formamide for 0.15h; Inert atmosphere; Reflux; | 59.4 Step 4 A suspension of 128d (1.0 g, 1.84 mmol), cap 31a, Pd(dppf)Cl2 (130 mg, 0.18 mmol), Na2C03 (1 g, 9.2 mmol) in THF/H20/DMF (5:2: 1, 32 mL) was refluxed for about 15 hours under N2 atmosphere. Then the reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was dried over Na2S04. After filtration and concentration, the residue obtained was purified using Si02 chromatography (10 g, Hexane/EtOAc 0% to 10%) to provide 128e (1 g, 83.3% yield). LC/MS: Anal. Calcd. For [M+H]+ C33H31C12FN403S: 653.2; found 653.2. Step 5 The compound of 128e (1 g) was separated by SFC by using the following conditions to provide 128f (0.42 g, 84 %). Column: AD 250mm*50mm, 10um Solvent: Supercritical C02 , B: EtOH(0.05% H3H2O), A:B =50:50 Flow rate: 220 mL/min Wavelength: 220 nm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water; N,N-dimethyl-formamide for 0.15h; Inert atmosphere; Reflux; | 59.9 Step 9 A suspension of 128i (550 mg, 0.68 mmol), cap 31a (237 mg, 0.75 mmol), Pd(dppf)Cl2 (50 mg, 0.068 mmol), Na2C03 (216 mg, 2.04 mmol) and THF/H20/DMF (5:2: 1, 32 mL) was refluxed for about 15 hours under N2 atmosphere. Then the reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was dried over Na2S04. After filtration and concentration, the residue obtained was purified using Si02 chromatography (4 g, DCM/MeOH 0% to 5%) to provide 128j (0.5 g, 80%). LC/MS: Anal. Calcd. For [M+H]+ C49H55FN807S: 918.4; found 918.6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.7% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water at 90℃; for 0.15h; Inert atmosphere; | 60.6 Step 6 A suspension of 144e (0.9 g, 1.3 mmol), cap 31a (0.5 g, 1.4 mmol), Na2C03 (400 mg, 3.9 mmol) and Pd(dppf)Cl2 (100 mg, 0.13 mmol) in THF/H20 (20 mL) was stirred at 90°C under N2 for about 15 hours. The reaction mixture was concentrated in vacuo and purified using Si02 chromatography (10 g, DCM/MeOH 1% to 3%) to provide 144f (0.8 g, 70.7% yield). LC/MS: Anal. Calcd. For [M+H]+ C47H53FN806S: 877.4; found 877.5. Step 7 The two diastereo isomers of 144f (1 g) were separated by SFC by using the following conditions. Column: OZ-H Solvent: ETOH (0.05%DEA) Flow rate: 2 mL/min Wavelength: 220 nm 144g (305 mg, 61% yield). LC/MS: Anal. Calcd. For [M+H]+ C47H53FN806S: 877.4; found 877.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water at 80℃; for 0.15h; Inert atmosphere; | 66.5 Step 5 A suspension of 190d (4.4 g, 8.4 mmol), cap 31a (3.2 g, 8.4 mmol), Na2C03 (2.2 g, 21.0 mmol) and Pd(dppf)Cl2 (310 mg, 0.42 mmol) in THF/H20 (v/v=5/l, 120 mL) was stirred at 80°C for about 15 hours under N2 atmosphere. After that, the mixture was washed with water and extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. After being concentrated in vacuo, the residue obtained was purified using Si02 chromatography (80 g, EtOAc/Hexane 10% to 50%) to provide 190e (4.5 g, 77% yield). LC/MS: Anal. Calcd. For [M+H]+ C36H35C1FN504S: 688.21; found 688.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.5% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water at 80℃; for 0.15h; Inert atmosphere; | 71.7 Step 7 A suspension of 234g (2.8 g, 3.6 mmol), cap 31a (1.42 g, 4.3 mmol), Pd(dppf)Cl2 (0.26 g, 0.36 mmol), Na2C03 (1.1 g, 10.8 mmol) and in THF/H20 (5: 1, 60 mL) was refluxed at 80°C for about 15 hours under N2 atmosphere. Then the reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was dried over Na2S04. After filtration and concentration, the residue obtained was purified using Si02 chromatography (30 g, DCM/MeOH 0% to 5%) to provide 234h (2 g, 62.5% yield). Step 8 The compound of 234h (2 g) was separated by SFC by using the following conditions to provide 234i (0.8 g, 75 % yield). Column: OZ-H 250mm*50mm, 10um Solvent: Supercritical C02, B: MeOH (0.05% DEA), A:B =50:50 Flow rate: 220 mL/min Wavelength: 220 nm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In tetrahydrofuran; water for 0.15h; Inert atmosphere; Reflux; | 74.7 Step 7 A mixture of 250g (3.1 g, 5.8 mmol), cap 31a (2.19 g, 6.19 mmol), Pd(dppf)2Cl2 (420 mg, 0.58 mmol) and Na2C03 (1.23 g, 11.6 mmol) in THF/H20 (5: 1, 120 mL) was refluxed for about 15 hours under N2 atmosphere. Then the reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was dried over Na2S04. After filtration and concentration, the residue obtained was purified using Si02 chromatography (10 g, EtOAc/Hexane 20% to 40%) to provide 250h (2.9 g, 77% yield). LC/MS: Anal. Calcd. For [M+H]+ C35H34C1FN403S: 645.20; found 645.4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 80℃; for 0.15h; Inert atmosphere; Sealed tube; | 80.4 Step 4 To the reaction mixture of510d (0.68 g, 1.12 mmol) was added cap 31a (0.778 g, 2.462 mmol), Pd(dppf)Cl2 (137mg, 0.168mmol), and 1M K2C03 aq (5.6 mL). The mixture was sealed and degassed and stirred at 80 °C for about 15 hours. EtOAc (-50 mL) and water was added and the mixture was filtered through a celite pad. The filtrate was seprated and the aqeous phase was extracted with EtOAc (20 mL x 2). The organic layer was combined and washed with brine, dried over Na2S04, and concentrated in vacuo. The crude material was purified on a ISCO column (40 g) and eluted with EtOAc: Hex 0% to 50% then 80% to provide 510e (0.4g, 43% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
308.4 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90℃; for 5h; Sealed tube; Inert atmosphere; | 85.6 Step 6 A mixture of 658f from a previous step, cap 31a (238 mg, 0.754 mmol), K2C03 (261 mg, 1.885 mmol) and Pd(dppf)Cl2 (61.6 mg, 0.075 mmol) in 5 mL dioxane/ 1 mL H20 at pressure tube was purged with nitrogen and vacuumed 2 times and stirred at 90°C for 5 hours. After that, the mixture was washed with water and extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. After being concentrated in vacuo, the residue obtained was purified using Si02 chromatography, eluting with chromatography Ethyl acetate/Hexane (0% to 100%) to provide 658g (308.4 mg, 53.5% yield). LC/MS: Anal. Calcd. For [M+H]+ C50H57FN8O6S: 917.10; found 918.24 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
640 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90℃; for 5h; Sealed tube; Inert atmosphere; | 84.6 Step 6 A mixture of 650f from a previous step, cap 31a (339 mg, 1.071 mmol), K2C03 (444 mg, 3.21 mmol) and Pd(dppf)Cl2 (131 mg, 161 mmol) 10 mL Dioxane/ 1.5 ml H20 in pressure tube was purged with nitrogen and vacuumed 2times and stirred at 90°C for 5 hours. After that, the mixture was washed with water and extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. After being concentrated in vacuo, the residue obtained was purified using Si02 chromatography, eluting with chromatography Ethyl acetate/Hexane (0% to 100%) to provide 650g (640 mg, 65.2% yield). LC/MS: Anal. Calcd. For [M+H]+ C46H48F4N806S: 916.68; found 918.05 Step 7 Compound 650h was separated from 650g (640 mg) by the following SFC conditions: Column: OZ-H, Mobile phase: 50% MeOH +0.05%DEA Compound 650h (Isomer B, 120 mg). LC/MS: Anal. Calcd. For [M+H]+ C46H48F4N806S: 916.68; found 918.16 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; palladium diacetate; potassium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere; Glovebox; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; palladium diacetate; potassium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere; Glovebox; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; palladium diacetate; potassium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere; Glovebox; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; palladium diacetate; potassium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere; Glovebox; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; palladium diacetate; potassium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere; Glovebox; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; palladium diacetate; potassium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere; Glovebox; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; palladium diacetate; potassium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere; Glovebox; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With (4-(N,N-dimethylamino)phenyl)-di-tert-butylphosphine; palladium diacetate; potassium carbonate In 1,2-dimethoxyethane; water at 80℃; Inert atmosphere; Glovebox; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.15 g | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate In tetrahydrofuran; water at 95℃; Inert atmosphere; | 5.8 Step 8- Synthesis of compound 2 A suspension of 1i (300 mg, 0.6 mmol), Cap2 (415 mg, 1.3 mmol), Pd(dppf)2Cl2(44 mg, 0.03 mmol), Na2CO3(0.318 g, 3 mmol) and in THF/H2O (10: 1, 25 mL) was refluxed at 95°C overnight under N2 protection. After that, the mixture was filtered, and the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by SiO2 chromatography, eluting with DCM: methanol (100/1-50/1) to afford compound 2 (0.15 g). |
0.15 g | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate In tetrahydrofuran; water at 95℃; Inert atmosphere; | 5.8 Step 8- Synthesis of compound 2 A suspension of 1i (300 mg, 0.6 mmol), Cap2 (415 mg, 1.3 mmol), Pd(dppf)2Cl2(44 mg, 0.03 mmol), Na2CO3(0.318 g, 3 mmol) and in THF/H2O (10: 1, 25 mL) was refluxed at 95°C overnight under N2 protection. After that, the mixture was filtered, and the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by SiO2 chromatography, eluting with DCM: methanol (100/1-50/1) to afford compound 2 (0.15 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.26 g | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate In tetrahydrofuran; water at 95℃; Inert atmosphere; | 5.7 Step 7- Synthesis of compound 4 A suspension of 3g (382 mg, 0.78 mmol), Cap2 (542 mg, 1.7 mmol),Pd(dppf)2Cl2(57 mg, 0.03 mmol), Na2C03(0.413 g, 3.9 mmol) and in THF/H20 (10: 1, 25 mL) was refluxed at 95°C overnight under N2protection. After that, the mixture was filtered, and the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration andconcentration, the residue was purified by Si02chromatography, eluting with DCM: methanol (100/1-50/1) to afford the compound 4 (0.26 g). |
0.26 g | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate In tetrahydrofuran; water at 95℃; Inert atmosphere; | 5.7 Step 7- Synthesis of compound 4 A suspension of 3g (382 mg, 0.78 mmol), Cap2 (542 mg, 1.7 mmol),Pd(dppf)2Cl2(57 mg, 0.03 mmol), Na2C03(0.413 g, 3.9 mmol) and in THF/H20 (10: 1, 25 mL) was refluxed at 95°C overnight under N2protection. After that, the mixture was filtered, and the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration andconcentration, the residue was purified by Si02chromatography, eluting with DCM: methanol (100/1-50/1) to afford the compound 4 (0.26 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate In tetrahydrofuran; water at 95℃; Inert atmosphere; | 7.7 Step 7- Synthesis of compound 7h A suspension of compound 7g (330 mg, 0.58 mmol), Cap2 (426 mg, 1.28 mmol), Pd(dppf)2Cl2 (42 mg, 0.058 mmol), Na2CO3(0.307 g, 2.9 mmol) and in THF/H2O (10: 1, 20 mL) was refluxed at 95°C overnight under N2 protection. After that, the mixture was filtered, and the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration andconcentration, the residue was purified by SiO2 chromatography, eluting with DCM: methanol (100/1-50/1) to afford compound 7h (0.2 g, 44%). |
44% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate In tetrahydrofuran; water at 95℃; Inert atmosphere; | 7.7 Step 7- Synthesis of compound 7h A suspension of compound 7g (330 mg, 0.58 mmol), Cap2 (426 mg, 1.28 mmol), Pd(dppf)2Cl2 (42 mg, 0.058 mmol), Na2CO3(0.307 g, 2.9 mmol) and in THF/H2O (10: 1, 20 mL) was refluxed at 95°C overnight under N2 protection. After that, the mixture was filtered, and the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration andconcentration, the residue was purified by SiO2 chromatography, eluting with DCM: methanol (100/1-50/1) to afford compound 7h (0.2 g, 44%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate In tetrahydrofuran; water at 95℃; Inert atmosphere; | 8.6 Step 6- Synthesis of compound 18g A suspension of 18f (970 mg, 1.8 mmol), Cap 2 (1.28 g, 4 mmol), Pd(dppf)2Cl2(135 mg, 0.18 mmol), Na2CO3(0.98 g, 9.2 mmol) and in THF/H2O (10:1, 50 mL) was refiuxed at 95°C overnight under N2 protection. After that, the mixture was filtered, and the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by Si02chromatography, eluting with DCM: methanol (100/1-50/1) to afford the product compound 18g (0.7 g, 53%). |
53% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate In tetrahydrofuran; water at 95℃; Inert atmosphere; | 8.6 Step 6- Synthesis of compound 18g A suspension of 18f (970 mg, 1.8 mmol), Cap 2 (1.28 g, 4 mmol), Pd(dppf)2Cl2(135 mg, 0.18 mmol), Na2CO3(0.98 g, 9.2 mmol) and in THF/H2O (10:1, 50 mL) was refiuxed at 95°C overnight under N2 protection. After that, the mixture was filtered, and the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by Si02chromatography, eluting with DCM: methanol (100/1-50/1) to afford the product compound 18g (0.7 g, 53%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate In tetrahydrofuran; water at 95℃; Inert atmosphere; | 9.12 Step 12- Synthesis of compound 22n A suspension of compound 22m (300 mg, 0.75 mmol), Cap 2 (263 mg, 0.83 mmol), Pd(dppf)2Cl2(30 mg, 0.04 mmol), Na2CO3(0.2 g, 1.9 mmol) and in THF/H2O (10: 1, 30 mL) was refluxed at 95°C overnight under N2protection. After that, the mixture was filtered, and the filtrate was washed with water and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by Si02chromatography, eluting with DCM: methanol (100/1-30/1) to afford the compound 22n (0.3 g, 78%). |
78% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate In tetrahydrofuran; water at 95℃; Inert atmosphere; | 9.12 Step 12- Synthesis of compound 22n A suspension of compound 22m (300 mg, 0.75 mmol), Cap 2 (263 mg, 0.83 mmol), Pd(dppf)2Cl2(30 mg, 0.04 mmol), Na2CO3(0.2 g, 1.9 mmol) and in THF/H2O (10: 1, 30 mL) was refluxed at 95°C overnight under N2protection. After that, the mixture was filtered, and the filtrate was washed with water and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by Si02chromatography, eluting with DCM: methanol (100/1-30/1) to afford the compound 22n (0.3 g, 78%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 15 Preparation of Intermediate Compound Int-15c (0321) (0322) To a solution of compound Int-7d (0.5 g, 1.58 mmol) in DME (15 mL) at room temperature under N2 was added PdCl2(dppf)2 (258 mg, 0.30 mmol). The reaction mixture was allowed to stir at 100 C for 5 minutes, then a solution of compound Int-15b (592 mg, 3.16 mmol) and K2CO3 (654 mg, 4.74 mmol) in 15 mL H2O was added to the reaction mixture in 3 portions over 10 minutes. The resulting reaction was allowed to stir for an additional 30 minutes, after which time thin-layer chromatography analysis indicated consumption of compound Int-7a. The reaction was allowed to stir for an additional 30 minutes, then was concentrated in vacuo, and the resulting residue was taken up in 150 mL ethyl acetate. The organic phase was separated, washed with water (50 mL), brine and dried over sodium sulfate. After filtration, the organic layer was concentrated in vacuo and the resulting residue was purified using flash liquid chromatography (0% to 100% EtOAc/Hexane) to provide 600 mg of compound Int-15c (> 85% purity, theory 597 mg). HPLC (C18 column Gemini 5u 110A, 150X21.2 mm, 5 micron). FABMS: MH+ = 379 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In tetrahydrofuran; water at 75℃; Inert atmosphere; | |
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; sodium carbonate In tetrahydrofuran; water at 75℃; Inert atmosphere; | 9.7 A suspension of compound 9H (1140 mg, 1.83 mmol) , Br-imidazole-1 (2.2 mmol) , Pd(dppf)2Cl2 (0.1 mmol) , Na2CO3 (5.5 mmol) and in THF/H2O (10: 1, 10 mL) was refluxed at 75 overnight under N2. The mixture was then filtered, and the filtrate was washed with water (50 mL) and extracted with ethyl acetate (100 mL) , and the organic extract was washed with brine, dried over anhydrous sodium sulfate. and concentrated in vacuo. The residue obtained was purified using flash column chromatography on silica gel (petroleum ether /ethyl acetate 8: 1 to 5: 1) to provide compound 9I. MS (ESI) m /e (M+H+) : 842. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; for 15h; | 18.10 Step 101-tert-butoxycarbonyl - (S) -2- (5- (2- (2 - ((2S) -1- tert-butoxycarbonyl-pyrrol-2-yl) lH-benzo [d] imidazol -6 - yl) -5-phenyl -5H- benzo [e] pyrazolo [1,5-c] [1,3] oxazin-8-yl) lH-imidazol-2-yl) pyrrolePreparation The compound prepared in step 9 was used1-tert-butoxycarbonyl - (S) -2- (6- (8- (4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl) 5-phenyl--5H- benzo [e] pyrazolo [1,5-c] [1,3] oxazin-2-yl) lH-benzo [d] imidazol-2-yl) pyrroleAnd (2S) -1-tert-butoxycarbonyl-2- (5-bromo-1H-imidazol-2-yl) pyrrole,The title compound was prepared according to the procedure of Example 15, Step 10. 523 mg of the compound prepared in Step 5 were weighed5-phenyl-8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2- (4- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -5H- benzo [e] pyrazolo [1,5-c] [1,3 ] OxazineIn a dry 100 ml two-necked flask,631 mg of the compound prepared in Step 9 was added(2S) -1- tert-butoxycarbonyl-2- (5-bromo--1H- imidazol-2-yl) pyrrolidine,83 mg Pd (dppf) Cl2,0.39 g cesium carbonate,3 mL of water and 9 mL of 1,4-dioxane,Under nitrogen protection, the reaction was carried out at 100 for 15 h,After completion of the reaction,The reaction solution was cooled to room temperature,Add 50 mL of water,Stirring at room temperature for 2h,Extraction with ethyl acetate (3 x 60 mL)The organic phases were combined,dry,filter,concentrate,Column chromatography gave the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; for 15h; | 15.10 Step 101-tert-butoxycarbonyl - (S) -2- (5- (2- (4- (2 - ((2S) -1- tert-butoxycarbonyl-pyrrol-2-yl) lH-imidazol-5-yl ) phenyl) -5-phenyl -5H- benzo [e] pyrazolo [1,5-c] [1,3] oxazin-8-yl) lH-imidazol-2-yl) pyrrolePreparation 523 mg of the compound prepared in Step 5 were weighed5-phenyl-8- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2- (4- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -5H- benzo [e] pyrazolo [1,5-c] [1,3 ] OxazineIn a dry 100 ml two-necked flask,631 mg of the compound prepared in Step 9 was added(2S) -1- tert-butoxycarbonyl-2- (5-bromo--1H- imidazol-2-yl) pyrrolidine,83 mg Pd (dppf) Cl2,0.39 g cesium carbonate,3 mL of water and 9 mL of 1,4-dioxane,Under nitrogen protection, the reaction was carried out at 100 for 15 h,After completion of the reaction,The reaction solution was cooled to room temperature,Add 50 mL of water,Stirring at room temperature for 2h,Extraction with ethyl acetate (3 x 60 mL)The organic phases were combined,dry,filter,concentrate,Column chromatography gave the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
337 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In water; toluene at 90℃; for 16h; Inert atmosphere; | 3 Example 3The preparation process is as follows: To a 50-ml three-necked flask, DSV210 (270 mg), pinacol diboronate (371 mg), potassium phenoxide (KOPh) (351 mg), Pd(PPh3)4 (80 mg), toluene (10 ml) were replaced by nitrogen. 3 Times, reaction at 90°C for 10h, cooling, addingDSV208 (500 mg), sodium carbonate aqueous solution (1M, 2.7 ml), PdCl2 (dppf) (50 mg), toluene (10 ml), nitrogen substitution three times, reaction at 90° C. for 16 h. The crystals were cooled, and separated by column chromatography to give 337 mg of an off-white solid DSV103 in a yield of 80.2% and a purity of 96.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: C28H26BrN3O2 With tetrakis(triphenylphosphine) palladium(0); potassium acetate; bis(pinacol)diborane In 1,4-dioxane at 85℃; for 14h; Inert atmosphere; Stage #2: (S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In 1,2-dimethoxyethane; water at 90℃; for 14h; Inert atmosphere; Stage #3: N-methoxycarbonyl-L-valine Further stages; | 448; 474.474b; 474.474c; 475; 477 Step 474b. A mixture of the compound from step 474a (0.214 g, 0.415 mmol), bis-(pinacolato) diboron (0.211 g, 0.829 mmol) and potassium acetate (0.102 g, 1.04 mmol) in 1,4-dioxane (8 mL) was added Pd(PPh3)4 (23.9 mg, 20.7 μmol). The resultant mixture were degassed and heated up at 85° C. under N2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc-water). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a light yellow oil (0.163 g, 60% purity). ESIMS m/z=564.17 [M+H]+.; Step 474c. A mixture of the compound from step 474b (0.163 g, 0.290 mmol), (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (prepared according to WO 2008/021927, 0.137 g, 0.434 mmol), Pd(PPh3)4, (33.4 mg, 28.9 μmol) and NaHCO3 (97.2 mg, 1.16 mmol) in DME (6 mL) and H2O (2 mL) was degassed and heated at 90° C. under N2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc-H2O). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow solid (0.122 g, 60% purity). ESIMS m/z=673.29 [M+H]+.; Example 475 The title compound was synthesized from the compound from Example 474 using procedures similar to that described in Example 448 after HPLC purification. ESIMS m/z=787.20 [M+H]+.; Example 448; Step 448a. A solution of the compound of Example 447 (0.104 g, 0.163 mmol) in 1,4-dioxane (1 mL) was treated with HCl in 1,4-dioxane (4 M, 4 mL) at rt for 30 minutes. The volatiles were evaporated off to give the crude desired compound as a yellow solid which was directly used in the next step. ESIMS m/z=439.24 [M+H]+.; Step 448b. A mixture of the crude compound of step 448a (0.163 mmol at most) and (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (prepared according to WO 2008/021927, 71.3 mg, 0.408 mmol) in DMF (3 mL) was treated with HATU (0.142 g, 0.375 mmol) in the presence of DIPEA (0.41 mL, 3.26 mmol) for 2 hours at rt and the volatiles were evaporated off to provide a brown syrup. It was purified by flash column chromatography (silica, CH2Cl2-MeOH) to give the title compounds as a white solid (89.5 mg, 2 steps 73%). The regio- and stereochemistry of the olefinic double bond was not determined. ESIMS m/z=753.39 [M+H]+.; Example 477 The title compound was synthesized and purified as a minor product in example 475. ESIMS m/z=789.21 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: C28H26BrN3O2 With tetrakis(triphenylphosphine) palladium(0); potassium acetate; bis(pinacol)diborane In 1,4-dioxane at 85℃; for 14h; Inert atmosphere; Stage #2: (S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In 1,2-dimethoxyethane; water at 90℃; for 14h; Inert atmosphere; | 474.474b; 474.474c; 476 Step 474b. A mixture of the compound from step 474a (0.214 g, 0.415 mmol), bis-(pinacolato) diboron (0.211 g, 0.829 mmol) and potassium acetate (0.102 g, 1.04 mmol) in 1,4-dioxane (8 mL) was added Pd(PPh3)4 (23.9 mg, 20.7 μmol). The resultant mixture were degassed and heated up at 85° C. under N2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc-water). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by flash column chromatography (silica, hexanes-ethyl acetate) to give the desired compound as a light yellow oil (0.163 g, 60% purity). ESIMS m/z=564.17 [M+H]+.; Step 474c. A mixture of the compound from step 474b (0.163 g, 0.290 mmol), (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (prepared according to WO 2008/021927, 0.137 g, 0.434 mmol), Pd(PPh3)4, (33.4 mg, 28.9 μmol) and NaHCO3 (97.2 mg, 1.16 mmol) in DME (6 mL) and H2O (2 mL) was degassed and heated at 90° C. under N2 for 14 hours. The volatiles were evaporated and the residue was partitioned (EtOAc-H2O). The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, hexanes-ethyl acetate) to give the title compound as a light yellow solid (0.122 g, 60% purity). ESIMS m/z=673.29 [M+H]+.; Example 476 The title compound was obtained as an impurity in the compound of example 474. ESIMS m/z=675.30 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.8 g | With tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 90℃; for 4h; Inert atmosphere; | 17.3 Step 3: Tert-butyl (S)-2-(5-(4-((2R,5R)-1-(4-(4,4-dimethyl-1,4-azasilinan-1-yl)-3,5-difluorophenyl))-5-(4-nitrophenyl)pyrrolidin-2-yl)phenyl)-1H-imidazol-2-yl) pyrrolidine-1-carboxylate 1 -(2,6-Difluoro-4-((2R,5R)-2-(4-nitrophenyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyri din-2-yl)phenyl)pyrrolidin-1-yl)phenyl)-4,4-dimethylazasilinane (1.3 g, 2.05 mmol), tert-butyl (S)-2-(5-bromo-1H-imidazol-2-yl) pyrrolidine-1-carboxylate (0.71 g, 2.26 mmol), potassium carbonate (0.85 g, 6.15 mmol) and tetrakis(triphenylphosphine)palladium (0.12 g, 0.103 mmol) were added in sequence into a reaction flask, and then dioxane (65 mL) and water (13 mL) were added to the flask under nitrogen gas protection. The mixture was heated to 90° C. and stirred for 4 h. After the completion of the reaction, the reaction mixture was poured into water (100 mL) and then extracted with ethyl acetate (200 mL). The organic phase was washed with water (100 mL) and a saturated saline solution (100 mL), respectively, and then dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1) to give tert-butyl (S)-2-(5-(4-((2R,5R)-1-(4-(4,4-dimethyl-1,4-azasilinan-1-yl)-3,5-difluorophenyl))-5-(4-nitrophenyl)pyrrolidin-2-yl) phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.8 g). MS (ESI): m/z 743.2. |
Tags: 1007882-59-8 synthesis path| 1007882-59-8 SDS| 1007882-59-8 COA| 1007882-59-8 purity| 1007882-59-8 application| 1007882-59-8 NMR| 1007882-59-8 COA| 1007882-59-8 structure
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P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
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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