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[ CAS No. 99365-48-7 ] {[proInfo.proName]}

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Chemical Structure| 99365-48-7
Chemical Structure| 99365-48-7
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Product Details of [ 99365-48-7 ]

CAS No. :99365-48-7 MDL No. :MFCD06659911
Formula : C8H6BrNO Boiling Point : -
Linear Structure Formula :- InChI Key :XQQPPAZTHUEMPF-UHFFFAOYSA-N
M.W : 212.04 Pubchem ID :2763190
Synonyms :

Calculated chemistry of [ 99365-48-7 ]

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) : -6.56 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.72
Log Po/w (XLOGP3) : 1.46
Log Po/w (WLOGP) : 1.37
Log Po/w (MLOGP) : 1.87
Log Po/w (SILICOS-IT) : 2.53
Consensus Log Po/w : 1.79

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.48
Solubility : 0.705 mg/ml ; 0.00333 mol/l
Class : Soluble
Log S (Ali) : -1.68
Solubility : 4.46 mg/ml ; 0.021 mol/l
Class : Very 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 : 1.7

Safety of [ 99365-48-7 ]

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:

Application In Synthesis of [ 99365-48-7 ]

* 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.

  • Upstream synthesis route of [ 99365-48-7 ]
  • Downstream synthetic route of [ 99365-48-7 ]

[ 99365-48-7 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 99365-48-7 ]
  • [ 86626-38-2 ]
YieldReaction ConditionsOperation in experiment
45%
Stage #1: With borane-THF In tetrahydrofuran at 20℃;
Stage #2: With hydrogenchloride; methanol; water In tetrahydrofuran at 0 - 20℃; for 1 h;
Stage #3: With sodium hydroxide In tetrahydrofuran; methanol; water
Step 85a: 73/4rt-butyl 4-bromoindoline-l-carboxylate (Compound 0601-177)A mixture of 4-bromooxindole (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 0°C 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 10percent> 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 (10percent). The crude product was dissolved in 10percent 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, 45percent) as an oil. LCMS: 200 [M+l]+. 1H-NMR (400 MHz. OMSO-d6) δ 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 4-bromooxindole (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 10percent 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 (10percent). The crude product was dissolved in 10percent 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, 45percent) as an oil. LCMS: 200 [M+1]+. 1H-NMR (400 MHz. DMSO-d6) δ 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%
Stage #1: With diborane In tetrahydrofuran at 20℃;
Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water at 0 - 20℃; for 1 h;
THF (2M, 40mL) solution of 4-bromo-oxindole (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 10percent 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 (10percent). The crude product was 10percent 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, 45percent) as an oil.
Reference: [1] Patent: WO2011/130628, 2011, A1, . Location in patent: Page/Page column 224-225
[2] Patent: US2013/102595, 2013, A1, . Location in patent: Paragraph 0564; 0565
[3] Patent: JP2015/187145, 2015, A, . Location in patent: Paragraph 0480
  • 2
  • [ 37777-74-5 ]
  • [ 99365-48-7 ]
YieldReaction ConditionsOperation 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 50percent 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, 93percent). MS(ES) M+1 212, M+2 214.
Reference: [1] Patent: US2003/225127, 2003, A1, . Location in patent: Page 16
[2] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 4, p. 1414 - 1418
  • 3
  • [ 20780-72-7 ]
  • [ 99365-48-7 ]
YieldReaction ConditionsOperation in experiment
93% With titanium tetrachloride; zinc In tetrahydrofuran at 20℃; for 0.0833333 h; Inert atmosphere General procedure: TiCl4 (0.7 mL, 6 mmol)was added to a stirred suspension of Zn powder (0.78 g, 12 mmol) in freshlydistilled anhydrous THF (15 mL) at room temperature (rt) under a dry N2atmosphere. After completion of the addition, the mixture was refluxed for 2 h.The suspension of the low-valent titanium reagent thus-formed was cooled tort. A solution of isatin or its derivatives 1 or 3 (2 mmol) in THF (10 mL) wasadded dropwise. The mixture was stirred at room temperature for about 5 minunder N2. After this period, the thin layer chromatography (TLC) analysis of themixture showed the reaction completed. The reaction mixture was quenchedwith 3percent HCl (15 mL) and extracted with CHCl3 (3 50 mL). The combinedextracts were washed with water (3 50 mL) and dried over anhydrousNa2SO4. After evaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography (petroleum ether/ethylacetate = 5:1) to give the pure products 2 or 4.
56% With titanium tetrachloride; zinc In tetrahydrofuran at 20℃; Inert atmosphere A mixture ofZn power (8.64g, 132.13mmol) and TiCl4 (12.60g, 66.42mmol) in THF (100mL) was stirred at 80 °C for 2 hours, then it was cooled to RT, a solution of 4-bromoindoline-2, 3-dione (5.01g, 22.16mmol) in THF (100mL) was added dropwise under N2. After completion of the reaction, Hydrochloric acid solution (100mL, 3M) was added, the mixture was extracted with DCM (50mL3), the organic phase was washed with brine (50mL2), dried over anhydrous Na2SO4, filtered and the solvent was removed under reduced pressure, the residue was purified by column chromatography to afford the compound 9a (2.63g, 56.0percent). MS: 212 (M+H) +.
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 14, p. 2238 - 2242
[2] Patent: WO2017/211303, 2017, A1, . Location in patent: Page/Page column 42
  • 4
  • [ 52488-36-5 ]
  • [ 99365-48-7 ]
YieldReaction ConditionsOperation in experiment
6%
Stage #1: With potassium hydroxide; iodine In DMF (N,N-dimethyl-formamide) at 20℃; for 0.5 h;
Stage #2: With sodium sulfite In DMF (N,N-dimethyl-formamide); water at 20℃; for 0.25 h;
Stage #3: With phosphoric acid In 2-methoxy-ethanol at 100℃; for 48 h; Heating / reflux
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 100°C. 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 20percent to 40percent ethyl acetate/hexanes to afford 121mg (6percent) of the title compound as a tan solid. MS (ES) 212,214 (M+H), 210, 212 (M-H) ; HPLC shows 76percent purity.
Reference: [1] Patent: WO2004/52847, 2004, A2, . Location in patent: Page 258
  • 5
  • [ 1196150-98-7 ]
  • [ 99365-48-7 ]
Reference: [1] Organic Letters, 2009, vol. 11, # 22, p. 5330 - 5333
  • 6
  • [ 55289-35-5 ]
  • [ 99365-48-7 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 4, p. 1414 - 1418
  • 7
  • [ 98592-11-1 ]
  • [ 99365-48-7 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 4, p. 1414 - 1418
  • 8
  • [ 603-83-8 ]
  • [ 99365-48-7 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 4, p. 1414 - 1418
  • 9
  • [ 99365-48-7 ]
  • [ 73183-34-3 ]
  • [ 1150271-44-5 ]
YieldReaction ConditionsOperation 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
Reference: [1] Patent: WO2017/174621, 2017, A1, . Location in patent: Page/Page column 88
[2] Patent: WO2017/202742, 2017, A1, . Location in patent: Page/Page column 42; 43; 97; 98
  • 10
  • [ 99365-48-7 ]
  • [ 885272-46-8 ]
Reference: [1] Patent: WO2011/130628, 2011, A1,
[2] Patent: JP2015/187145, 2015, A,
[3] Patent: US2013/102595, 2013, A1,
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