Structure of 99365-48-7
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CAS No. : | 99365-48-7 |
Formula : | C8H6BrNO |
M.W : | 212.04 |
SMILES Code : | C2=C1NC(CC1=C(Br)C=C2)=O |
MDL No. : | MFCD06659911 |
InChI Key : | XQQPPAZTHUEMPF-UHFFFAOYSA-N |
Pubchem ID : | 2763190 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 49.43 |
TPSA ? Topological Polar Surface Area: Calculated from | 29.1 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 1.72 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 1.46 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 1.37 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 1.87 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 2.53 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 1.79 |
Log S (ESOL):? ESOL: Topological method implemented from | -2.48 |
Solubility | 0.705 mg/ml ; 0.00333 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -1.68 |
Solubility | 4.46 mg/ml ; 0.021 mol/l |
Class? Solubility class: Log S scale | Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -3.75 |
Solubility | 0.0379 mg/ml ; 0.000179 mol/l |
Class? Solubility class: Log S scale | Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg | High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg | Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) | No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) | Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) | No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) | No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) | No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) | No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from | -6.56 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from | 0.0 |
Ghose? Ghose filter: implemented from | None |
Veber? Veber (GSK) filter: implemented from | 0.0 |
Egan? Egan (Pharmacia) filter: implemented from | 0.0 |
Muegge? Muegge (Bayer) filter: implemented from | 0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat | 0.55 |
PAINS? Pan Assay Interference Structures: implemented from | 0.0 alert |
Brenk? Structural Alert: implemented from | 0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from | No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) | 1.7 |
* 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 |
---|---|---|
74% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 110℃; for 2 h; Sealed tube; Microwave irradiation | Intermediate 114: 4-(4,4,5,5-Tetramethyl-1 ,2-dioxaborolan-2-yl)indolin-2-one (0793) A mixture of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.903 g, 7.49 mmol, commercially available from, for example, Fluorochem), 4-bromoindolin-2-one (1.038 g, 4.90 mmol, commercially available from, for example, Fluorochem), [1,1'- 7 s(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [Pd(dppf)Cl2.DCM] (0.601 g, 0.73 mmol) and potassium acetate (1.480 g, 15.08 mmol) in 1,4-dioxane (30 mL) was stirred at 110 °C for 2 h. The mixture was allowed to cool to rt before being filtered through a 10 g celite cartridge. The cartridge was washed through with ethyl acetate (3 x 30 mL) and the combined filtrates were evaporated in vacuoto give a brown liquid which was re-dissolved in DCM (ca. 10 mL), loaded onto a 100 g SNAP silica cartridge and purified by Biotage SP4 semi-automated flash column chromatography eluting with a gradient of 20 to 50percent ethyl acetate in cyclohexane. The required fractions were combined and evaporated in vacuo, this was re-dissolved in DCM (ca. 10 mL), transferred to a tarred vial and the solvent evaporated under a stream of nitrogen. The residue was triturated with ether (5 x 5 mL), decanting away the mother liquor each time, and the residue dried under a stream of nitrogen and in vacuo to give the desired product 4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)indolin-2-one (941.8 mg, 3.63 mmol, 74 percent yield) as a cream solid. (0794) LCMS (2 min Formic): Rt = 0.93 min, [MH]+ = 260.3. |
74.2% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 110℃; for 2 h; | A mixture of 4,4,4T,4T,5,5,5T,5T-octamethyl-2,2T-bi( 1,3, 2-d ioxaborolane) (1.9025 g, 7.49 mmol), 4-bromoindolin-2-one (1.0383 g, 4.90 mmol), [1,1’-Bis(d iphenylphosphino)ferrocene]dichloropallad ium(II), complex with dichloromethane (0.6005 g,0.734 mmol) and potassium acetate (1.4802 g, 15.08 mmol) in 1,4-Dioxane (30 mL) was stirred at110 °C for 2 hr. The mixture was allowed to cool to room temperature before being filtered througha lOg celite cartridge. The cartridge was washed through with ethyl acetate (3 x 30 mL) and thecombined filtrates were evaporated in vacuo to give to give a brown liquid, which was redissolved indichloromethane (ca. 10 mL), loaded onto a bOg SNAP silica cartridge and purified by Biotage 5P4semi-automated flash column chromatography eluting with a gradient of 20 to 50percent ethyl acetate incyclohexane. The required fractions were combined and evaporated in vacuo, the residue (which was on the verge of crystallisation) was re-dissolved in dichloromethane (ca. 10 mL), transferred to a tared vial, the solvent evaporated under a stream of nitrogen. The residue was triturated with ether (5 x 5 mL), decanting away the mother liquor each time, and the residue dried under a stream of nitrogen and in vacuoto give the desired product as a cream solid (941.8 mg, 3.63 mmol, 74.2 percent yield)LCMS (2 mm Formic): Rt = 0.93 mi [MH]+ = 260 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sulfuric acid; zinc; In ethanol; water; at 90℃; | To a stirred solution of 2-bromo-6-nitro-phenyl acetic acid (0.66 g, 2.54 mmol) dissolved in 50% H2SO4 (6.0 mL)/EtOH (10.0 mL) was added Zn dust (0.66 g, 10.1 mmol) at 90 C. under N2. The reaction mixture was then treated in a manner analogous to preparation 5 to provide the intermediate title compound (0.50 g, 93%). MS(ES) M+1 212, M+2 214. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In DMF (N,N-dimethyl-formamide); water; at 20 - 80℃; for 80h; | 2-[4-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2yl)-phenyl]propyl-2-propanesulfonamide (0.367, 1.0 mmol), 4-bromo-1,3-dihydro-indol-2-one (0.200 g, 0.94 mmol), PdCl2(dppf).CH2Cl2 (0.033 g, 0.40 mmol), and 2 M Na2CO3 (3.5 mL, 7.0 mmol) were combined in dry DMF (25.0 mL) and heated at 80 C. under nitrogen for 8 h. The reaction mixture turned a dark bown color after 4 h. It was then stirred at ambient temperature for 72 h. The reaction mixture was poured into H2O and extracted with EtOAc. The organic layer was separated and extracted several times with H2O, washed with brine and dried (MgSO4), filtered and evaporated in vacuo. Chromatography on the chromatron using a 4 mm plate and eluting with a gradient EtOAc/hexane 4:6 to 6:4 gave the final title compound, (0.086 g, 25%) as a brown solid. MS(ES) 372 M+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | Add a solution of I2 (2.62g, 10. 30MMOL) in DMF (lOmL) dropwise to a solution of 4- bromoindole (2. 00G, 10. 20MMOL) and KOH (1.43g, 25. 5MMOL) in DMF (40ML). Stir for 30min at room temperature and add saturated aqueous NA2S03. STIR at room temperature for 15MIN, then dilute reaction mixture with ethyl acetate (LOOML). Wash organics three times with H20, dry organics (MGS04) and concentrate to a brown oil. Dissolve oil in 2- methoxyethanol (40ML) and heat to 100C. Add H3PO4 (9ML) and heat to reflux for 48H. Cool to room temperature and dilute with H20 (75mL). Extract into ethyl acetate, dry (MGS04) and concentrate organics to a dark brown oil. Chromatograph on silica gel (90g), eluting with 20% to 40% ethyl acetate/hexanes to afford 121mg (6%) of the title compound as a tan solid. MS (ES) 212,214 (M+H), 210, 212 (M-H) ; HPLC shows 76% purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sulfuric acid; nitric acid; at -5℃; for 1h; | A mixture of concentrated sulfuric acid (3.6 mL) and concentrated nitric acid (0.7 mL) was added slowly to a solution of 4-bromo-1,3-dihydro -2H-indol-2-one (2 g, 9.48 mmol) (prepared according to T. Kosuge et al., Chem. Pharm. Bull.33(4):1414-1418 (1985)) in concentrated sulfuric acid (20 mL) at -5 C, with stirring. The mixture was stirred for an additional 1 h at -5 C, then poured in ice. After standing for 1 h, precipitate formed was collected by filtration and washed with water, and dried in a vacuum oven to give 4-bromo-1,3-dihydro-5-nitro-2H-indol-2-one. (Yield 2.33 g, 96%). |
With nitric acid; In sulfuric acid; | 4-Bromo-1,3-dihydro-5-nitro-2H-indol-2-one A mixture of concentrated sulfuric acid (3.6 mL) and concentrated nitric acid (0.7 mL) was added slowly to a solution of <strong>[99365-48-7]4-bromo-1,3-dihydro-2H-indol-2-one</strong> (2 g, 9.48 mmol) (see Kosuge et al., supra) in concentrated sulfuric acid (20 mL) at -5 C. with stirring. The mixture was stirred for an additional 1 h at -5 C. then poured into ice. After standing for 1 h, precipitate formed was collected by filtration and washed with water, and dried in a vacuum oven to give the above product. (Yield 2.33 g, 96%). | |
With nitric acid; In sulfuric acid; | Example 4 Synthesis of 4-Bromo-1,3-dihydro-5-nitro-2H-indol-2-one (C) A mixture of concentrated sulfuric acid (3.6 mL) and concentrated nitric acid (0.7 mL) was added slowly to a solution of 4-bromo-1,3-dihydro -2H-indol-2-one (2 g, 9.48 mmol) (prepared according to T. Kosuge et al., Chem. Pharm. Bull. 33(4):1414-1418 (1985)) in concentrated sulfuric acid (20 mL) at -5 C., with stirring. The mixture was stirred for an additional 1 h at -5 C., then poured in ice. After standing for 1 h, precipitate formed was collected by filtration and washed with water, and dried in a vacuum oven to give 4-bromo-1,3-dihydro-5-nitro-2H-indol-2-one. (Yield 2.33 g, 96%). |
With nitric acid; In sulfuric acid; | C. Synthesis of 4-Bromo-1,3-dihydro-5-nitro-2H-indol-2-one STR32 A mixture of concentrated sulfuric acid (3.6 mL) and concentrated nitric acid (0.7 mL) was added slowly to a solution of 4-bromo-1,3-dihydro -2H-indol-2-one (2 g, 9.48 mmol) (see below) in concentrated sulfuric acid (20 mL) at -5 C. with stirring. The mixture was stirred for an additional 1 h at -5 C. then poured in ice. After standing for 1 h, precipitate formed was collected by filtration and washed with water, and dried in a vacuum oven to give 4-bromo-1,3-dihydro-5-nitro-2H-indol-2-one. (Yield 2.33 g, 96%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With piperidine; In isopropyl alcohol; at 85℃; for 2h; | A mixture of <strong>[99365-48-7]4-bromo-1,3-dihydro-2H-indol-2-one</strong> (100 mg, 0.47 mmol) (prepared according to T. Kosuge et al., Chem. Pharm. Bull. 33(4):1414-1418 (1985)), and excess 3-methoxy-2-pyrrolecarboxyaldehyde (70.8 mg, 0.57 mmol) (prepared according to F. Bellamy, J. Chem. Research (S) (1979) 18-19; J. Chem. Research (M) (1979) 0106-0116) in 1% piperidine in 2-propanol (1 mL) was heated at 85 C for 2 h. Hot water (1 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.13 g, 83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With piperidine; In isopropyl alcohol; at 85℃; for 2h; | A mixture of <strong>[99365-48-7]4-bromo-1,3-dihydro-2H-indol-2-one</strong> (0.2 g, 0.94 mmol) (see T. Kosuge et. al., Chem. Pharm. Bull. 33(4):1414-1418 (1985)), and excess pyrrole-2-carboxaldehyde (0.11 g, 1.13 mmol) (Aldrich) in 1% piperidine in 2-propanol (2 mL) was heated at 85 C for 2 h. Hot water (2 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.26 g, 96%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In piperidine; water; isopropyl alcohol; | (Z)-4-Bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one A mixture of <strong>[99365-48-7]4-bromo-1,3-dihydro-2H-indol-2-one</strong> (100 mg, 0.47 mmol) (see Kosuge et al., supra) and excess 3-methoxy-2-pyrrolecarboxyaldehyde (70.8 mg, 0.57 mmol) (see Bellamy et al., supra) in 1% piperidine in 2-propanol (1 mL) was heated at 85 C. for 2 h. Hot water (1 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.13 g, 83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In piperidine; water; isopropyl alcohol; | (Z)-4-Bromo-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one A mixture of <strong>[99365-48-7]4-bromo-1,3-dihydro-2H-indol-2-one</strong> (0.2 g, 0.94 mmol) (see Kosuge et al., supra), and excess pyrrole-2-carboxaldehyde (0.11 g, 1.13 mmol) (Aldrich) in 1% piperidine in 2-propanol (2 mL) was heated at 85 C. for 2 h. Hot water (2 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.26 g, 96%). | |
In piperidine; water; isopropyl alcohol; | Starting Material 9: (Z)-4-Bromo-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one A mixture of <strong>[99365-48-7]4-bromo-1,3-dihydro-2H-indol-2-one</strong> (0.2 g, 0.94 mmol) (see T. Kosuge et. al., Chem. Pharm. Bull. 33(4):1414-1418 (1985)), and excess pyrrole-2-carboxaldehyde (0.11 g, 1.13 mmol) (Aldrich) in 1% piperidine in 2-propanol (2 mL) was heated at 85 C. for 2 h. Hot water (2 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.26 g, 96%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In piperidine; water; isopropyl alcohol; | Starting Material 1: (Z)-4-Bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one A mixture of <strong>[99365-48-7]4-bromo-1,3-dihydro-2H-indol-2-one</strong> (100 mg, 0.47 mmol) (prepared according to T. Kosuge et al., Chem. Pharm. Bull. 33(4):1414-1418 (1985)), and excess 3-methoxy-2-pyrrolecarboxyaldehyde (70.8 mg, 0.57 mmol) (prepared according to F. Bellamy, J. Chem. Research (S) (1979) 18-19; J. Chem. Research (M) (1979) 0106-0116) in 1% piperidine in 2-propanol (1 mL) was heated at 85 C. for 2 h. Hot water (1 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.13 g, 83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In piperidine; water; isopropyl alcohol; | Starting Material 1: (Z)-4-Bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one STR23 A mixture of <strong>[99365-48-7]4-bromo-1,3-dihydro-2H-indol-2-one</strong> (100 mg, 0.47 mmol) (see Kosuge et al., Chem. Pharm. Bull. 33(4):1414-1418 (1985)) and excess 3-methoxy-2-pyrrolecarboxyaldehyde (70.8 mg, 0.57 mmol) (see Bellamy et al., J. Chem. Research(S), 18-19 (1979) and Chem. Research (M) 0101-0116 (1979)) in 1% piperidine in 2-propanol (1 mL) was heated at 85 C. for 2 h. Hot water (1 mL) was added. On cooling, the crystallized product was filtered off, washed with aqueous 2-propanol and dried. (Yield 0.13 g, 83%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | Step 1: sec-Butyl lithium (25.3 mL, 35.4 mmol) was added into a solution of tert-butyl 1-pyrrolidinecarboxylate (6.2 mL, 35.4 mmol) and (-)-spartiene (8.29 g, 35.4 mmol) in MTBE (100 mL) at -78C. The mixture was stirred for 1 hour at -78C. Zinc chloride solution (35.4 mL, 35.4 mmol) was added, and the reaction was stirred for 15 minutes at -78C. The reaction was allowed to warm up to room temperature. 4- Bromoindolin-2-one (5.00 g, 23.6 mmol), palladium (II) acetate (0.53 g, 2.4 mmol) and tri- tert-butylphosphine tetrafluoroborate (0.68 g, 2.4 mmol) was added into the reaction mixture. The reaction was stirred for 12 hours at room temperature. The reaction mixture was poured into EtOAc (200 mL), and the suspension was filtered with a pad of celite. The filtrate was concentrated, and the residue was purified by flash chromatography (silica gel eluted with 4:1 hexanes : ethyl acetate) to give (R)-tert-butyl 2-(2-oxoindolin-4-yl)pyrrolidine-l-carboxylate (1.9 g, 27%) as a solid. 1H NMR (CDCl3, 400 MHz) delta 7.80 (s, IH), 7.10-7.20 (m, IH), 6.75- 6.82 (m, IH), 6.62-6.78 (m, IH), 4.65-4.93 (m, IH), 3.34-3.73 (m, 4H), 2.20-2.40 (m, IH), 1.84-2.00 (m, 2H), 1.68-1.83 (m, IH), 1.45 (2, 4H), 1.14 (s, 5H). MS (APCI+) [M+H]+ 303. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Step 1: A stirred solution of <strong>[99365-48-7]4-bromoindolin-2-one</strong> (13.0 g, 61.3 mmol) inTHF (500 mL) was treated by the dropwise addition of a l.OM THF solution of NaHMDS (306 mL, 306 mmol) at -780C under nitrogen. After stirring at -78C for 30 minutes, N- benzylbis(2-chloroethyl)amine hydrochloride (18.05 g, 67.4 mmol) was added as a solid. The reaction mixture was stirred at -78C for 30 minutes and then allowed to warm to room temperature. The reaction mixture was then heated to reflux for 12 hours. After cooling to 00C, the reaction was quenched by the addition of saturated aqueous NH4Cl solution. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3 X 200 mL). The combined organics layers were washed with brine, dried with MgSO4 and concentrated under reduced pressure. The resulting solid was triturated with DCM/EtOAc to give r-benzyl-4-bromospiro[indoline-3,4'-piperidin]-2-one (19.3 g, 85%) as a solid. LCMS (APCI+) m/z 371/373 [M+H]+; Rt = 2.71 min. | |
General procedure: To a suspension of 5-methoxy-1H-pyffolo[3,2-b]pyridin-2(3H)-one (1.85 g, 11.3 mmol, CAS RN 178393-14-1) in THF (80 mL) at -78C was added dropwise LiHMDS (50.3 mL, 50.3 mmol, 1M solution in THF) and the brown solution was stirred at this temperature over 30 mm. before N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (3 g, 11.2 mmol, CAS RN 10429-82-0) was added in one portion. The cooling bath was then removed and the mixture wasallowed to warm up to RT. Heating was installed and the light brown suspension was stuffed at reflux for 24 hours. The light brown reaction mixture was poured on saturated aqueous NH4C1 solution and EtOAc and the layers were separated. The aqueous layer was twice extracted with EtOAc. The organic layer was dried over Mg504, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 40 g column using an MPLCsystem eluting with a gradient of n-heptane : EtOAc (100: 0 to 0: 100). The product containing fractions were combined. The precipitate formed during evaporation was filtered off to afford the title product as a light brown solid (0.288 g; 8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | A suspension of sodium hydride (331mg, 8.63mmol, 60% in oil) and xylenes (17.3mL) was heated to reflux, and <strong>[99365-48-7]4-bromo-1,3-dihydro-2-oxindole</strong> (14) (1.83g, 8.63mmol) was added in ?10 equal portions over 5min. The resulting light orange suspension was heated under reflux for 1h, whereupon dimethylsulfate (1.09g, 818muL, 8.63mmol) was added slowly dropwise at reflux. After heating at reflux for an additional 1h, the reaction was cooled and diluted with EtOAc (30mL). The organic layer was washed with water (3×15mL), brine (15mL), dried (MgSO4) and concentrated to provide a yellow solid that was purified by flash column chromatography eluting with a solvent gradient (CH2Cl2 to 10% Et2O in CH2Cl2) to give 1.29g (66%) of 13 as a fluffy light yellow solid: mp 138-139C; 1H NMR (500MHz) delta 7.15-7.10 (comp, 2H), 6.73-6.69 (m, 1H), 3.43 (s, 2H), 3.17 (s, 3H); 13C NMR (126MHz) delta 173.7, 146.0, 129.4, 125.4, 125.3, 119.0, 106.8, 37.0, 26.5; IR 3054, 2939, 1717, 1611, 1458, 1340, 1296, 1106, 925, 770, 708cm-1; HRMS (CI) m/z calcd for C9H9B79rNO+C9H9B79rNO+ (M+1), 225.9868; found, 225.9875. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;chloro(di-2-norbornylphosphino)(2'-dimethylamino-1,1'-biphenyl-2-yl)palladium(II); In 1,4-dioxane; water; at 120℃; for 0.666667h;Microwave irradiation; | Example 1261 -(1 -Methylethyl)-N-[6-(2-oxo-2,3-dihydro-1 H-indol-4-yl)-1 H-indazol-4-yl]-1 H- pyrazole-5-carboxamide A microwave vial was charged with 1-(1-methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6- (4,4,6,6-tetramethyl-1 ,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1 H-pyrazole-5-carboxamide (70mg), Solvias catalyst (8mg), tripotassium phosphate (90mg) and 4-bromo-1 ,3-dihydro- 2H-indol-2-one (available from Apollo, 33mg), 1 ,4-dioxane (0.5ml) and water (0.1 ml). The reaction was heated under microwave irradiation for a total of 30min at 1200C). Further tripotassium phosphate (60mg) and Solvias catalyst (8mg) were added and the reaction was heated under microwave irradiation for 10min at 120C. The reaction was passed <n="202"/>through a silica cartridge, dried, then extracted with DCM and water before drying the DCM under a stream of nitrogen. The residue was purified as follows: Column: Supelco ABZ+ Plus, 5 mum, 100x21.2mm i.d. Solvent A: 0.1% formic acid in water Solvent B: 1 % formic acid in wate?acetonitrile (5:95, v/v) Flow rate: 20 ml/min. Gradient: 30 - 65% B over 12min.Appropriate fractions were dried. The residue was dissolved in methanol and a few drops of 2M HCI (aq) were added. The solution was dried, dissolved in methanol and passed through an aminopropyl cartridge preconditioned with methanol, washing with methanol. The solvent was dried to give title compound, 10mg. LC/MS (method B) 0.77min m/z 386 [MH+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With piperidine; In ethanol; at 20 - 45℃; | Example 81 (S,Z)-2-((4-bromo-2-oxoindolin-3-ylidene)methyl)-5-(2-hydroxy-3-morpholinopropyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one (S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (40 mg, 0.12 mmol) and 4-bromo-1,3-dihydro-indol-2-one (25 mg, 0.12 mmol) were dissolved in 1.5 ml of ethanol, and added with 6 mul of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at 45 C. for 16 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (1 ml*2) and dried to obtain the title compound (S,Z)-2-((4-bromo-2-oxoindolin-3-ylidene)methyl)-5-(2-hydroxy-3-morpholinopropyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 81 (34 mg, yield 54%) as a yellow solid. |
54% | With piperidine; In ethanol; at 20 - 45℃; | (S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahyd ro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (40 mg, 0.12 mmol) and 4-bromo-1,3-dihydro-indol-2-one (25 mg, 0.12 mmol) were dissolved in 1.5 ml of ethanol, and added with 6mul of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at 45C for 16 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled down to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (1 ml×2) and dried to obtain the title compound (S,Z)-2-((4-bromo-2-oxoindolin-3-ylidene)methyl)-5-(2-hydroxy-3-morpholinopropyl )-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 81 (34 mg, yield 54%) as a yellow solid. MS m/z (ESI): 529.3(M+1) 1HNMR(400 MHz, DMSO-d6) delta13.647(s, 1H, pyrrole-NH),11.185 (s, 1H, indole-NH),8.588(s, 1H, -CH=C), 7.238?7.218(d, 1H, -ArH), 7.095?7.055(t, 1H, -ArH), 6.956?6.936(d, 1H, -ArH), 4.739?4.726(d, 1H, -OH), 3.90(m, 1H, -CHOH), 3.800?3.757(dd, 1H, seven membered ring outer amide-NCH2), 3.593?3.570(t, 4H, morpholin2×-CH2O), 3.446(m, 2H, seven membered ring -NCH2), 3.192(dd, 1H, seven membered ring outer amide-NCH2), 2.956(t, 2H, -CH2C=C), 2.447?2.428(m, 4H, morpholin intra2×-CH2N), 2.411(s, 3H, pyrrole-CH3), 2.301(m, 2H, morpholin outer-NCH2), 2.08(m, 2H, seven membered ring CH2-CH2-CH2) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | In xylenes;Reflux; | Example 39; STEP A; A solution of <strong>[99365-48-7]4-bromoindolin-2-one</strong> (1.7 g, 8 mmol) and acetic anhydride (2 mL) in xylenes (20 ml_) was heated at reflux for overnight. The mixture was concentrated. The residue was dissolved in EtOAc. The EtOAc layer was washed with aqueous NaHCO3 solution, and then concentrated. The residue was purified by silica gel column chromatography (10% EtOAc in Hexanes) to give compound 39-1 (0.87 g, 43% yield) as white solid. |
39% | In 5,5-dimethyl-1,3-cyclohexadiene; for 72h;Reflux; | A solution of <strong>[99365-48-7]4-bromoindolin-2-one</strong> (1 .12 g, 5.32 mmol) and acetic anhydride (1.3 mL, 13.83 mmol) in xylene (12 mL) was heated at reflux for 3 days. Additional acetic anhydride (0.5 mL, 5.32 mmol) was added after 24 h and 48 h of reaction. Then, the mixture was concentrated to dryness and the residue was dissolved in EtOAc. The organic phase was washed with NaHCC>3 sat. sol. dried over MgSC>4 and concentrated to dryness. The crude product was purified by flash chromatography, silica gel, gradient CH/EtOAc 100:0 to 0:100 to give the title compound (522 mg, 39% yield). Step 2. 1 -Acetyl-4-bromo-3,3-dimethylindolin-2-one: Following the experimental procedure described for the preparation of Step 3 of Intermediate 10, using the product obtained in Step 1 and iodomethane as staring materials, the title compound was obtained (488 mg, 36% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Step 85a: 7¾rt-butyl 4-bromoindoline-l-carboxylate (Compound 0601-177)A mixture of <strong>[99365-48-7]4-bromooxindole</strong> (2.77 g, 0.01 mol) and a solution of BH3 in THF (2M, 40 mL) was stirred at room temperature overnight. The mixture was cooled to 0C and diluted with 30 mL of methanol, followed by addition of 12 N HC1 (7.5 mL). The resulting mixture was stirred at room temperature for 1 hour, adjusted to pH 8-9 with 10%> aqueous NaOH. Water was added to the mixture and extracted with ethyl acetate (3 x 100 mL). The organic layer was dried and concentrated to get the crude product which was washed through a silica gel column (ethyl acetate in petroleum ether (10%). The crude product was dissolved in 10% HC1 (3 x 10 mL). The aqueous layer was adjusted to pH7 with NaHC03, extracted with ethyl acetate (3 x 20 mL). The organic layer was dried and concentrated to get 4-bromoindoline (1.16 g, 45%) as an oil. LCMS: 200 [M+l]+. 1H-NMR (400 MHz. OMSO-d6) delta 2.90 (t, J= 8.8 Hz, 2H), 3.46 (t, J= 8.8 Hz, 2H), 5.86 (s, 1H), 6.43 (m, 1H), 6.64 (m, 1H), 6.83 (t, J= 8.0 Hz, 1H). | |
45% | With borane-THF; In tetrahydrofuran; at 20℃; | Step 85a: Tert-butyl 4-bromoindoline-1-carboxylate (Compound 0601-177)[0565]A mixture of <strong>[99365-48-7]4-bromooxindole</strong> (2.77 g, 0.01 mol) and a solution of BH3 in THF (2 M, 40 mL) was stirred at room temperature overnight. The mixture was cooled to 0 C. and diluted with 30 mL of methanol, followed by addition of 12 N HCl (7.5 mL). The resulting mixture was stirred at room temperature for 1 hour, adjusted to pH 8-9 with 10% aqueous NaOH. Water was added to the mixture and extracted with ethyl acetate (3×100 mL). The organic layer was dried and concentrated to get the crude product which was washed through a silica gel column (ethyl acetate in petroleum ether (10%). The crude product was dissolved in 10% HCl (3×10 mL). The aqueous layer was adjusted to pH7 with NaHCO3, extracted with ethyl acetate (3×20 mL). The organic layer was dried and concentrated to get 4-bromoindoline (1.16 g, 45%) as an oil. LCMS: 200 [M+1]+. 1H-NMR (400 MHz. DMSO-d6) delta 2.90 (t, J=8.8 Hz, 2H), 3.46 (t, J=8.8 Hz, 2H), 5.86 (s, 1H), 6.43 (m, 1H), 6.64 (m, 1H), 6.83 (t, J=8.0 Hz, 1H). |
45% | THF (2M, 40mL) solution of <strong>[99365-48-7]4-bromo-oxindole</strong> (2.77g, 0.01mol) A mixture of and BH3 solution was stirred at room temperature overnight. The mixture was cooled to 0 diluted with methanol 30 mL, followed by addition of 12N HCl (7.5mL). The resulting mixture was stirred for 1 hour at room temperature and adjusted to pH 8 ~. 9 with 10% aqueous NaOH. With the addition of water to the mixture, and the mixture was extracted with ethyl acetate (3x100mL). The organic layer was dried and concentrated to give the crude product, which was dissolved in a silica gel column (washing through petroleum ether in ethyl acetate (10%). The crude product was 10% HCl (3 × 10 mL). Water adjust to the layer with NaHCO3 pH 7, and extracted with ethyl acetate (3 × 20 mL). the organic layer was dried and concentrated to give 4-bromo-indoline (1.16g, 45%) as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(diphenylphosphin)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 140℃; for 2h;Inert atmosphere; | . Pre1.1 Preparation of 4-cyanooxindole (method A). 4-bromoxindole (2.0 g, 9.43 mmol), zinc cyanide (680 mg, 5.68 mmol), tris(bisbenzylideneacetone)dipalladium (250 mg, 0.27 mmol) and 1 ,1'-diphenylphosphineferrocene (300 mg, 0.54 mmol) are stirred in anhydrous DMF (10 mL) for 2 h at 140C under argon. The reaction mixture is cooled and poured onto 30 % aqueous ethanol. The precipitate is filtered off, digested with water and EtOH and dried. |
Tags: 99365-48-7 synthesis path| 99365-48-7 SDS| 99365-48-7 COA| 99365-48-7 purity| 99365-48-7 application| 99365-48-7 NMR| 99365-48-7 COA| 99365-48-7 structure
A148054 [20870-90-0]
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