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Chemical Structure| 77199-09-8
Chemical Structure| 77199-09-8
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Product Details of [ 77199-09-8 ]

CAS No. :77199-09-8 MDL No. :MFCD00234415
Formula : C8H8BrNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :MVJPVDSRSXLJNQ-UHFFFAOYSA-N
M.W :230.06 Pubchem ID :12686158
Synonyms :

Calculated chemistry of [ 77199-09-8 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.25
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 48.02
TPSA : 39.19 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) : -5.76 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.34
Log Po/w (XLOGP3) : 2.74
Log Po/w (WLOGP) : 2.02
Log Po/w (MLOGP) : 1.4
Log Po/w (SILICOS-IT) : 2.2
Consensus Log Po/w : 2.14

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.16
Solubility : 0.157 mg/ml ; 0.000685 mol/l
Class : Soluble
Log S (Ali) : -3.22
Solubility : 0.139 mg/ml ; 0.000606 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.37
Solubility : 0.099 mg/ml ; 0.000431 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.83

Safety of [ 77199-09-8 ]

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 [ 77199-09-8 ]

* 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 [ 77199-09-8 ]
  • Downstream synthetic route of [ 77199-09-8 ]

[ 77199-09-8 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 77199-09-8 ]
  • [ 30766-11-1 ]
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1011 - 1020
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  • [ 75754-04-0 ]
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1011 - 1020
  • 3
  • [ 77199-09-8 ]
  • [ 88139-91-7 ]
YieldReaction ConditionsOperation in experiment
80%
Stage #1: With sodium tetrahydroborate In methanol at 20 - 70℃; for 0.833333 h;
Stage #2: With hydrogenchloride In water
Example 593-(((5-(l-(4-(2,3-Dimethylphenoxy)butanoyl)-l,2,3,4-tetrahydroquinolin-5-yl)pyridin-2- yl)methoxy)carbonylamino)propanoic acid[00204] To a solution of NaBH4 (0.822 g, 21.73 mmol) in MeOH (25 mL) was added ethyl 5-bromopicolinate (1.0 g, 4.35 mmol) portion-wise over a period of 10 min at room temperature. The mixture was stirred at room temperature for 10 min and then heated to 70 °C for 30 min. The solvent was removed in vacuo, and the resulting residue was diluted with EtOAc and water. The aqueous phase was adjusted to pH 7 with 1 N aq. HCl, and extracted with EtOAc. The combined organic layer was dried over MgS04, filtered, and concentrated in vacuo to afford the title compound (0.65 g, 80percent yield) as a white solid. LCMS, [M+H]+ = 187.9.
Reference: [1] Patent: WO2012/149236, 2012, A1, . Location in patent: Page/Page column 162
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YieldReaction ConditionsOperation in experiment
100% at 20℃; for 18 h; (a) Preparation of ethyl 5-bromopyridine-2-carboxylate 2:To a suspension of 5-bromopyridine-2-carboxylic acid 1 (2.02 g, 10 mmol) in 50 mL of EtOH was added thionyl chloride (5 mL). The mixture was stirred at ambient temperature for 18 h. After removal of all solvent, the residue was purified by column (2: 1 of hexane/ethyl acetate) to give 2.3 g of ethyl 5-bromopyridine-2-carboxylate 2 as an oil. Yield: 2.3g, quantitative yield. .HNMR (CDCIB) δ (ppm): 8.80 (d, 1 H), 8.00 (m, 2 H), 4.50 (m, 2 H), 1.44 (t, 3 H).
86% at 75℃; for 2 h; Reference Example 255
Production of ethyl 5-bromopyridine-2-carboxylate
A mixture of 5-bromopyridine-2-carboxylic acid (35.0 g, 173 mmol), sulfuric acid (12.0 mL) and ethanol (300 mL) was stirred at 75°C for 2 hr.
After cooling to 0°C, the mixture was neutralized with sodium hydrogen carbonate and diluted with water (150 mL).
Ethanol was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (300 mL).
The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure.
The obtained solid was collected by filtration, washed with hexane, and dried to give the title compound (34.5 g, 86percent) as a white solid.
1H NMR (300 MHz, DMSO-d6) δ:1.33 (3 H, t, J = 7.1 Hz), 4.35 (2 H, q, J = 7.1 Hz), 7.99 (1 H, d, J = 8.3 Hz), 8.27 (1 H, dd, J = 2.3, 8.3 Hz), 8.86 (1 H, d, J = 2.3 Hz).
28%
Stage #1: for 2 h; Heating / reflux
Stage #2: Heating / reflux
Stage #3: With sodium carbonate In water; toluene
Pyridine (22) is obtained in two steps from 5-bromo-2-methyl-pyridine (20) by oxidation to 5-bromo-2-pyridinecarboxylic acid (21) as described in G. M. Sanders, M. van Dijk and H. C. van der Plas, Heterocycles 1981, 15, 213-223, and chlorination with SOCl2 followed by reaction with EtOH (see Scheme 6). 1.17 g of 5-bromo-2-pyridinecarboxylic acid (21), prepared according to G. M. Sanders, M. van Dijk and H. C. van der Plas, Heterocycles 1981, 15, 213-223, are placed in SOCl2(6 ml) and the mixture is heated 2 h under reflux. After evaporation of SOCl2 the residue is treated under reflux with a mixture of toluene (3 ml) and absolute EtOH (6 ml). The pH is adjusted to 8 by addition of sat. aq. Na2CO3 sol. and the product is extracted with Et2O. The organic layer is washed to neutral pH with H2O portions, dried over Na2SO4 and the solvent is evaporated to obtain 377 mg of 5-bromo-pyridine-2-carboxylic acid ethyl ester (22) as a white powder, MS (ESI) 232.0 (M+H)+.
15 g at 70℃; for 3 h; Compound d-1-1 of 21g was dissolved in EtOH (ethanol) 300ml and 15ml of sulfuric acid was added, and the mixture was stirred for 3 hours at 70 . Then, by cooling the resulting solution, and then was neutralized with aqueous sodium hydrogen carbonate and ethyl acetate was added to extract fractions, it was carried out the concentration of the organic layer. Purification of the resultant concentrate by silica gel column chromatography to obtain 15g of the compound d-1-2.

Reference: [1] Patent: WO2012/76898, 2012, A1, . Location in patent: Page/Page column 58
[2] Patent: EP2471789, 2012, A1, . Location in patent: Page/Page column 115
[3] Patent: US2005/113374, 2005, A1, . Location in patent: Page/Page column 8; 12-13
[4] Heterocycles, 1981, vol. 15, # 1, p. 213 - 223
[5] Patent: WO2009/5645, 2009, A1, . Location in patent: Page/Page column 153
[6] Patent: WO2009/5646, 2009, A2, . Location in patent: Page/Page column 155
[7] Patent: WO2005/44814, 2005, A1, . Location in patent: Page/Page column 26
[8] Patent: KR2015/129778, 2015, A, . Location in patent: Paragraph 0567-570; 0574-0576
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YieldReaction ConditionsOperation in experiment
81%
Stage #1: With copper In dimethyl sulfoxide at 20℃; for 1 h;
Stage #2: at 20℃; for 15 h;
SYNTHESIS OF INTERMEDIATE KETONE B2-(5-Bromopyridin-2-yl)- 1-(2,4-difluorophenyl)-2,2-difluoroethanone (B) To a suspension of copper powder (2.68 grams (g), 42.2 millimoles (mmol)) in dimethyl sulfoxide(DMSO; 35 milliliters (mL)) was added ethyl 2-bromo-2,2-difluoroacetate (2.70 mL, 21.10mmol), and the mixture was stirred for 1 hour (h) at room temperature (RT). 2,5-Dibromopyridine(2.50 g, 10.55 mmol) was then added, and stirring was continued for 15 h at RT. The reactionmixture was quenched with aqueous (aq) ammonium chloride (NH4C1) and extracted withdichloromethane (CH2C12 3 x 25 mL). The combined organic layers were washed with water (H20), washed with brine, dried over anhydrous sodium sulfate (Na2SO4), and concentrated under reduced pressure to afford the crude product mixture. Purification by column chromatography (eluting with ethyl acetate (EtOAc)/hexane) afforded the ethyl ester intermediate (2.40 g, 8.57mmol, 81percent) as a pale yellow oil. ‘H NMR (500 MHz, CDC13): ö 8.71 (s, 1H), 8.00 (d, J 9.0 Hz,1H), 7.64 (d, J= 9.0 Hz, 1H), 4.42-4.35 (m, 2H), 1.39-1.3 1 (m, 3H).
Reference: [1] Patent: WO2014/43376, 2014, A1, . Location in patent: Page/Page column 46; 47
  • 6
  • [ 624-28-2 ]
  • [ 109-94-4 ]
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YieldReaction ConditionsOperation in experiment
46%
Stage #1: With trimethylsilylmethyllithium In toluene at -78 - 0℃; for 0.5 h;
Stage #2: for 3 h;
Stage #3: With iodine; potassium carbonate In toluene at 20℃; for 18 h;
General procedure: N,N-Dimethylaminoethanol (0.85 ml, 8.5 mmol, 1 equiv.) and(trimethylsilyl)methyllithium 1 M (25.3 ml, 25.3 mmol, 3 equiv.)was added dropwise to 25 ml of dry toluene at 0 °C and the solutionwas stirred for 30 min to form TMSCH2Li-LiDMAE (in situ). Then, Asolution of 2,5-dibromopyridine 1 (2 g, 8.5 mmol, 1 equiv.) in 9 mlof dry toluene was added dropwise. The reaction mixture wasstirred for 30 min, cooled to 78 °C and added methyl formate(5.2 ml, 85 mmol, 10 equiv.) or ethyl formate (6.9 ml, 85 mmol,10 equiv.) in 10 ml of toluene. The reaction mixture stirred for 3 h,and I2 (6.4 g, 25.5 mmol, 3 equiv.), K2CO3 (5.8 g, 42.5 mmol, 5 equiv.)and 20 ml methanol or ethanol were added. The mixture wasstirred at room temperature for 18 h and added 10 ml of a sat.aqueous Na2SO3 solution.Water (10 ml)was added and the mixtureextracted with dichloromethane (3x40 ml), washed with water(1 x 25 ml) and brine (1 x 25 ml). The residue was purified bysilica-gel flash column chromatography (eluent: heptane/diethylether 2: 1) to obtain 2a-b
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1011 - 1020
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Reference: [1] Patent: US2010/41642, 2010, A1, . Location in patent: Page/Page column 25
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  • [ 201230-82-2 ]
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Reference: [1] Synthetic Communications, 1997, vol. 27, # 3, p. 515 - 520
[2] Dalton Transactions, 2011, vol. 40, # 29, p. 7534 - 7540
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Reference: [1] Organic Letters, 2009, vol. 11, # 16, p. 3690 - 3693
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Reference: [1] Heterocycles, 1981, vol. 15, # 1, p. 213 - 223
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