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[ CAS No. 99365-40-9 ] {[proInfo.proName]}

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Chemical Structure| 99365-40-9
Chemical Structure| 99365-40-9
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Product Details of [ 99365-40-9 ]

CAS No. :99365-40-9 MDL No. :MFCD02179605
Formula : C8H6BrNO Boiling Point : -
Linear Structure Formula :- InChI Key :JARRYVQFBQVOBE-UHFFFAOYSA-N
M.W : 212.04 Pubchem ID :2773289
Synonyms :
6-Bromo-2-oxindole
Chemical Name :6-Bromoindolin-2-one

Calculated chemistry of [ 99365-40-9 ]      Expand+

Physicochemical Properties

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 : 29.1 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.28 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.78
Log Po/w (XLOGP3) : 1.85
Log Po/w (WLOGP) : 1.37
Log Po/w (MLOGP) : 1.87
Log Po/w (SILICOS-IT) : 2.53
Consensus Log Po/w : 1.88

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.72
Solubility : 0.401 mg/ml ; 0.00189 mol/l
Class : Soluble
Log S (Ali) : -2.08
Solubility : 1.76 mg/ml ; 0.00828 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.75
Solubility : 0.0379 mg/ml ; 0.000179 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.63

Safety of [ 99365-40-9 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 99365-40-9 ]

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

  • Upstream synthesis route of [ 99365-40-9 ]
  • Downstream synthetic route of [ 99365-40-9 ]

[ 99365-40-9 ] Synthesis Path-Upstream   1~9

  • 1
  • [ 99365-40-9 ]
  • [ 6326-79-0 ]
  • [ 1147124-21-7 ]
Reference: [1] Chemical Communications, 2018, vol. 54, # 59, p. 8265 - 8268
  • 2
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  • [ 63839-24-7 ]
Reference: [1] Patent: WO2010/128152, 2010, A1, . Location in patent: Page/Page column 106-107
  • 3
  • [ 557-21-1 ]
  • [ 99365-40-9 ]
  • [ 199327-63-4 ]
YieldReaction ConditionsOperation in experiment
81% at 80℃; for 15 h; Commercially available 6-bromoxindole (656 mg), zinc cyanide (288 mg) and tetrakis triphenylphosphine palladium(0) (175 mg) were suspended in dry N,N-dimethylformamide (6 mL). The resulting mixture was degassed by three pump/vent cycles with argon and then placed in a preheated oil bath (80° C.). After stirring at this temperature for 15 h the mixture was cooled to room temperature, diluted with water (60 mL) and extracted with ethyl acetate (3.x.60 mL). The combined organic layers were washed with water (2.x.60 mL), dried (MgSO4), filtered and concentrated. The remaining residue was purified by flash chromatography (silica, dichloromethane/methanol) to afford the title compound (385 mg; 81percent). [MH]+=159.
Reference: [1] Patent: US2006/173183, 2006, A1, . Location in patent: Page/Page column 105
  • 4
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  • [ 199327-63-4 ]
YieldReaction ConditionsOperation in experiment
80% With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 80℃; for 16 h; bl .l) 2-Oxoindoline-6-carbonitrile A mixture of palladium-tetrakis(triphenylphosphine) (10.90 g, 9.43 mmol), 6- bromoindolin-2-one (10 g, 47.2 mmol) and dicyanozinc (7.75 g, 66.0 mmol) in DMF (80 mL) was heated to 80 °C for 16 h. The reaction mixture was cooled to rt and water was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel column and elution with 5percent MeOH/CfLC^) to give 2-oxoindoline-6-carbonitrile (5.97 g, 37.7 mmol, 80 percent yield) as a brown solid. RT=1.15 min (3 min).
Reference: [1] Patent: WO2015/173393, 2015, A1, . Location in patent: Page/Page column 69
  • 5
  • [ 99365-40-9 ]
  • [ 73183-34-3 ]
  • [ 893441-85-5 ]
YieldReaction ConditionsOperation in experiment
75% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,2-dimethoxyethane at 80℃; Four microwave vials were loaded as follows: 6-bromoindolin-2-one(500 mg, 2.36 mmol), bis(pinacolato)diboron (898 mg, 3.54 mmol),potassium acetate (694 mg, 7.07 mmol) and Pd(dppf)C12CH2C12 (96.0mg, 0.118 mmol) were dissolved in DME (17 mL). The reaction was heated at 80 °C overnight. The content of the four vials was then combined, concentrated and purified bycolumn chromatography (CyHex/EtOAc) to afford the title compound as a white solid (2.27 g, 75percent, purity 80percent). IH NMR (500 MHz, CDCI3) ppm = 8.57 (bs, IH), 7.48 (d, J7.3, IH), 7.31 (5, 1H), 7.23 (d, J=7.3, IH), 3.55 (s, 2H), 1.33 (s, 12H); LC — MS (ESI, mlz) Rt = 2.75 mm — 260 (M+H) (H PLC method E).
55% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In dimethyl sulfoxide at 90℃; for 18 h; 6-Brornoindohn-2-one 27) (2 00 u, 9 40 mmol) bispmacolatodiboron (6 00 g 23 60 mniol), potassium acetate (2.76g. 28.2 mmol) and diehloro[i,i’bis(dipheuylphosphino)feuocenrJj palladrum (11) dichloromethane addutt (0 40 g 0 55 rnniol) in DM80 (30 niL) were stirred at 90 °C tbr 18 hours, The reaction mixture was cooled to ambient temperature., then partitioned between water and ethyl acetate. Thelayers were separated and the aqueous layer extracted again with ethyl acetate (2x). The combined organic layers were washed with water and brine and concentrated to give a purple solid. The crude material was pre-absorbed onto Celite and chroniatographed (‘DCVC) eluting with a gradient of ethyl acetate in heptane (0 50percent ethyl. acetate.) Like fractions were combined and recrystallised from DCM and PE to give 6-(4,5,5-tetrainethyi—l,3,2—dioxahorolan—2yi)indoiin—2—one (24) as a colourless solid in 2 crops (1.33 g, 55percent); nip 178.5 181.4 °C. ‘H NMR (200 MHz, CDCI3) 8 8.61 (br s, 1H), 7.46 (d, 111. J7,4 Hz), 7.30 (s, lH), 7.21 (d. lH,J7.4 Hz), 3.53 (s, 2H). 1.32 (s. 1211).
40% With potassium acetate In N,N-dimethyl-formamide at 95℃; for 18 h; Inert atmosphere; Sealed flask 6-bromoindolin-2-one (0.424 g; 2 mmol), potassium acetate (0.687 g; 7.0 mmol) and bis[pinacolato]diborane (0.762 g; 3.0 mmol) were placed in a 20 mL microwave vial, dissolved in dry DMF (13 mL) and the flask was purged with nitrogen. The catalyst [1 ,1 '- Bis(diphenylphosphino)ferrocene]palladium(ll) chloride, complex with dichloromethane (0.169 g; 0.20 mmol) was added, the flask was again purged with argon, sealed and the reaction was heated at 950C for 18 h. The reaction mixture was diluted with water and the suspension was extracted twice with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (10 - 80 percent) in heptane furnished 0.390 g (40 percent) of the title compound.ESI/APCI(+): 260 (M+H);1H NMR (DMSO-d6) δ 10.40 (s, 1 H), 7.27 (dd, J= 7,3, 0,8 Hz, 1 H), 7.21 (m, 1 H), 7.07 (s, 1 H), 3.50 (s, 2 H), 1.28 (s, 12 H).
39% With potassium acetate In N,N-dimethyl-formamide at 90℃; for 16 h; Inert atmosphere a) 6-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2- l)-1 ,3-dihydro-indol-2-one6-Bromo-1 ,3-dihydro-2H-indol-2-one (150 mg, 0.71 mmol), bis(pinacolato)diboron (233 mg, 0.92 mmol), KOAc (104 mg, 1.07 mmol) and Pd(dppf)CI2 (29 mg) in anhydrous DMF (3 mL) were heated under N2 at 90°C for 16 h. The mixture was diluted with EtOAc (40 mL) and washed with water (30 mL) then brine (30 mL). The organic layer was dried (Na2S04) and concentrated in vacuo. Purification by column chromatography (MeOH-DCM gradient) gave a yellow solid (72 mg, 39percent); 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1 H), 7.27 (dd, J=7.3, 0.9 Hz, 1 H), 7.23 (d, J=7.3 Hz, 1 H), 7.07 (s, 1 H), 3.49 (s, 2H), 1.29 (s, 12H); m/z (ES+APCI)+: 260 [M+H]+.
22% With potassium acetate In 1-methyl-pyrrolidin-2-one at 130℃; for 3 h; To a solution of 6-bromo-2-oxindole (1 equiv) in NMP (0.05 M) were added bispinacolato diboron (2.4 equiv), potassium acetate (1.5 equiv), dppf (0.05 equiv) and PdCl2(dppf) (0.05 equiv). The reaction mixture was stirred at 130°C for 3 hours and then concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The organic phase was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel eluting with EtOAc/hexane (9 / 1), yielding the desired product as a red solid. 6-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-l,3-dihydro-indol-2-one: (22 percent yield, 51 percent purity main impurity being the boronic acid 28 percent) m/z (LC-MS, ESP): 260 [M+H]+ R/T = 3.51 min

Reference: [1] Patent: WO2015/144290, 2015, A1, . Location in patent: Page/Page column 85
[2] Patent: WO2015/39172, 2015, A1, . Location in patent: Page/Page column 60
[3] Patent: WO2011/15641, 2011, A1, . Location in patent: Page/Page column 128
[4] Patent: WO2011/101640, 2011, A1, . Location in patent: Page/Page column 106
[5] Patent: WO2008/23161, 2008, A1, . Location in patent: Page/Page column 120
[6] Patent: WO2006/66172, 2006, A1, . Location in patent: Page/Page column 77
[7] Patent: WO2014/63778, 2014, A1, . Location in patent: Page/Page column 46
  • 6
  • [ 5414-19-7 ]
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  • [ 1190861-43-8 ]
YieldReaction ConditionsOperation in experiment
31%
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -40℃; for 0.75 h;
Stage #2: at 20℃; for 16 h;
n-BuLi (2M in hexane, 22.6 mL, 45.27 mmol) was added drop wise at -40°C to a solution of 6-bromo-indolin-2-one (3 g, 14.14 mmol) and diisopropylamine (6.3 mL, 45.27 mmol) in THF (60 mL). The mixture was stirred for 45 min at -40°C, 1-bromo-2-(2-bromoethoxy)ethane was added drop wise at this temperature and stirring was continued at RT for 16 h. The reaction mixture was quenched with 4N hydrogen chloride solution (40 mL) and the aqueous phase was separated and extracted with EtOAc (3x 60 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04 and concentrated. The raw product was triturated with hexane (20 mL) and filtered. The filter was washed with hexane/EtOAc = 4:1 (100 mL) affording the target compound as light brown solid. Yield: 1.2 g (31 percent). HPLC (method 1 ): Rt = 2.94 min, m/z [M+H]+ = 282.1 (MW calc. 282.13).
Reference: [1] Patent: WO2017/108204, 2017, A1, . Location in patent: Page/Page column 133
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5270 - 5273
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Reference: [1] Chemistry Letters, 2014, vol. 43, # 12, p. 1870 - 1872
[2] Patent: CN107739374, 2018, A,
  • 9
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  • [ 77-78-1 ]
  • [ 897957-06-1 ]
Reference: [1] Patent: WO2010/142985, 2010, A1, . Location in patent: Page/Page column 22
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