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[ CAS No. 138564-59-7 ] {[proInfo.proName]}

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Chemical Structure| 138564-59-7
Chemical Structure| 138564-59-7
Structure of 138564-59-7 * Storage: {[proInfo.prStorage]}
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Product Details of [ 138564-59-7 ]

CAS No. :138564-59-7 MDL No. :MFCD06408054
Formula : C12H9N3O2S Boiling Point : -
Linear Structure Formula :- InChI Key :NPXUFPFFHANGDL-UHFFFAOYSA-N
M.W : 259.28 Pubchem ID :395460
Synonyms :

Calculated chemistry of [ 138564-59-7 ]

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 11
Fraction Csp3 : 0.08
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 72.37
TPSA : 109.88 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : No
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.06 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.16
Log Po/w (XLOGP3) : 3.98
Log Po/w (WLOGP) : 3.58
Log Po/w (MLOGP) : 0.9
Log Po/w (SILICOS-IT) : 1.65
Consensus Log Po/w : 2.45

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.21
Solubility : 0.016 mg/ml ; 0.0000618 mol/l
Class : Moderately soluble
Log S (Ali) : -5.99
Solubility : 0.000266 mg/ml ; 0.00000103 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -4.09
Solubility : 0.0209 mg/ml ; 0.0000807 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.06

Safety of [ 138564-59-7 ]

Signal Word:Danger Class:9
Precautionary Statements:P501-P273-P260-P270-P264-P280-P391-P314-P337+P313-P305+P351+P338-P301+P312+P330 UN#:3077
Hazard Statements:H302-H319-H372-H410 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 138564-59-7 ]

* 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 [ 138564-59-7 ]
  • Downstream synthetic route of [ 138564-59-7 ]

[ 138564-59-7 ] Synthesis Path-Upstream   1~7

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YieldReaction ConditionsOperation in experiment
77% With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 18 h; Inert atmosphere; Cooling with ice A solution of 1-fluoro-2-nitrobenzene (34.5 g, 244 mmol) and compound 1 (33.1 g, 240 mmol) in dry THF (160 mL) was added dropwise under N2 atmosphere to a vigorously stirred suspension of NaH (13.5 g, 60percent dispersion in oil, 336 mmol) in dry THF (100 mL) in an ice bath. After the reaction mixture was stirred at room temperature (RT) for 10 h, additional NaH (1.53 g, 95percent, 72 mmol) was slowly added to above reaction mixture. The mixture was stirred for another 8 h at rt, and poured into cracked ice, adjusted pH value to 8 with saturated NH4Cl. The resulting precipitate was filtered, and dried; and the crude product was purified by column chromatography (10percent EtOAc/hexanes) on silica gel to obtain 2 (47.9 g, 77percent) as a darkened solid; Rf = 0.62 (25percent EtOAc/hexanes); mp 105–107 °C. 1H NMR (CDCl3): δ 2.47 (d, J = 1.0 Hz, 3H, CH3), 6.78 (q, J = 1.0 Hz, 1H, Ar-H), 6.95 (ddd, J = 1.0, 7.0, 8.5 Hz, 1H, Ph-H), 7.18 (dd, J = 1.0, 8.5 Hz, 1H, Ph-H), 7.50 (ddd, J = 1.5, 7.0, 8.5 Hz, 1H, Ph-H), 8.24 (dd, J = 1.5, 8.5 Hz, 1H, Ph-H), 9.61 (s, 1H, NH). MS (ESI): 258 ([M−H], 100percent).
64%
Stage #1: With sodium hydride In tetrahydrofuran at -10 - 20℃; for 7.25 h;
Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0℃;
Step 2; 5-Methyl-2-(2-nitrophenylamino) thiophene-3-carbontrile: At about -10° C. and over a period of 15 minutes, a solution of 2-fluoro-nitro benzene (10.23g, 72.36 mmol), 2-amino -5-methylthiophene-3-carbonitrile (10 g, 72.36 mmol), and tetrahydrofuran (100 mL) was added dropwise to a suspension of sodium hydride (4.35 g, 108.69 mmol) and dry tetrahydrofuran. The resulting mixture was stirred for about 7 hours at ambient temperature and then cooled to about 0° C. Ice-cold water (100 mL) was slowly added, and then 5 N hydrochloric acid was added. Following standard extractive workup with dichloromethane (2.x.100 mL), the resulting residue was triturated with a mixture of n-pentane and diethyl ether (10:1), filtered, and dried to give the title compound as a dark brown color solid (12.0 g, yield=64percent). m.p. 100-103° C. 1H NMR (400 MHz, CDCl3) δ 2.47 (s, 3H), 6.78 (s, 1H), 6.96 (t, J=7.8 Hz, 1H), 7.2 (d, J=8.4 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H) 8.25 (d, J=8.4 Hz, 1H), 9.61 (s, exchangeable with D2O, 1H); IR (KBr) υ 3279, 3080, 3027, 2917, 2854, 2226, 1612, 1491, 1402, 1335, 1270, 736 cm-1; MS 258 (M-1).
60%
Stage #1: With sodium hydride In tetrahydrofuran at 30℃;
Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0℃;
For a general synthesis see He, X.; Griesser, U. J.; Stowell, J. G.; Borchrdt, T. B.; Byrn, S. R. J. Pharm. Sd. 2001, 90, 371.B To NaH (3 equivalents, from 55percent suspension in oil, rendered oil-free by washing with hexane) was added 1 ml of dry THF. 2-amino-5-methyl-3- thiophenecarbonitrile (A, as prepared above, 0.5 g, 3.6 mmol) and 4-fluoro-3- nitotoluene (0.51 g, 3.6 mmol) were dissolved in dry THF (1.5 ml) and added in a dropwise manner to the suspension while the temperature was maintained below 30°C. The reaction mixture was allowed to stir overnight under N2 purge. The mixture was then poured into 11 ml of ice- water mixture, neutralized with concentrated HCl, and extracted with 36 ml of DCM. The DCM solution was dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel (elution with 1 :9 EtOAc/ Hexanes) to give compound B (yield 60percent).1H NMR (200 MHz, CDCl3): δ 9.61 (br s, IH), 8.25 (dd, J = 8.5 Hz, J = 1.5 Hz, IH), 7.52 (dt, J = 7.8 Hz, J = 1.4 Hz, IH), 7.19 (dd, J = 8.5 Hz, J = 1.1 Hz, IH)5 6.97 (dt, J = 7.8 Hz, J = 1.2 Hz5 IH), 6.78 (d, J = 1.1 Hz, IH), 2.48 (s, 3H).
60% With potassium hydroxide In DMF (N,N-dimethyl-formamide) at 0 - 25℃; for 5 h; To a stirred mixture of potassium hydroxide (59.1 g), benzyltriethylammonium chloride (1.2 g) and N,N-dimethylformamide (70 mL) in a 250 mL flask was added dropwise a solution of 2-amino-5-methylthiophene-3- carbonitrile (73 g) and 1-fluoro-2-nitrobenzene (74.5 g) in N,N dimethylformamide (175 mL) while maintaining the temperature between at 20-25 °C with an ice/salt bath. After the addition was complete, the mixture was stirred between 20-25°C for 5 hours, then poured onto ice/water (400 mL), and extracted with dichloromethane (480 mL). The organic layer was separated, and the aqueous layer was extracted twice with dichloromethane (240 mLx2). Water (400 mL) was added to the combined organic extracts, and the pH was adjusted between 8-9 with 2N hydrochloric acid. The organic layer was separated and washed with water (400 mL). The solvent was removed under reduced pressure to afford a residue that was crystallized from ethanol (300 mL) to give 2- (2-nitroanilino)-5-methylthiophene-3- carbonitrile (82.2 g). Yield: 60percent

Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 7, p. 1953 - 1956
[2] Patent: US2010/266711, 2010, A1, . Location in patent: Page/Page column 14
[3] Patent: WO2008/50341, 2008, A2, . Location in patent: Page/Page column 33
[4] Patent: WO2004/94390, 2004, A1, . Location in patent: Page 13-14
[5] Russian Journal of Bioorganic Chemistry, 2005, vol. 31, # 4, p. 378 - 382
[6] Tetrahedron, 2010, vol. 66, # 41, p. 8203 - 8209
[7] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 1, p. 25 - 30
[8] Patent: WO2006/6180, 2006, A1, . Location in patent: Page/Page column 10
[9] Patent: US5229382, 1993, A,
[10] Patent: US5605897, 1997, A,
[11] Patent: US5627178, 1997, A,
[12] Patent: US5817655, 1998, A,
[13] Patent: US5817657, 1998, A,
[14] Patent: US5817656, 1998, A,
[15] Patent: WO2006/25065, 2006, A1, . Location in patent: Page/Page column 7-8
[16] Patent: US2009/5556, 2009, A1, . Location in patent: Page/Page column 5
[17] Patent: US2010/317849, 2010, A1, . Location in patent: Page/Page column 4
[18] Patent: US2014/57303, 2014, A1, . Location in patent: Page/Page column
[19] Patent: WO2014/31656, 2014, A1, . Location in patent: Paragraph 00189; 00190
[20] Patent: WO2014/31587, 2014, A1, . Location in patent: Page/Page column 57
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Reference: [1] Journal of Organic Chemistry, 2016, vol. 81, # 23, p. 11788 - 11801
[2] Angewandte Chemie - International Edition, 2013, vol. 52, # 37, p. 9813 - 9817[3] Angew. Chem., 2013, vol. 125, # 37, p. 9995 - 9999,5
  • 3
  • [ 3320-86-3 ]
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Reference: [1] RSC Advances, 2016, vol. 6, # 64, p. 59808 - 59815
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  • [ 109-01-3 ]
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Reference: [1] Tetrahedron, 2010, vol. 66, # 41, p. 8203 - 8209
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Reference: [1] Russian Journal of Bioorganic Chemistry, 2005, vol. 31, # 4, p. 378 - 382
[2] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 1, p. 25 - 30
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 7, p. 1953 - 1956
[4] Journal of Organic Chemistry, 2016, vol. 81, # 23, p. 11788 - 11801
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  • [ 109-01-3 ]
  • [ 138564-59-7 ]
  • [ 132539-06-1 ]
Reference: [1] Tetrahedron, 2010, vol. 66, # 41, p. 8203 - 8209
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  • [ 873895-41-1 ]
  • [ 132539-06-1 ]
Reference: [1] Tetrahedron, 2010, vol. 66, # 41, p. 8203 - 8209
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[ 138564-59-7 ]

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Chemical Structure| 138564-58-6

[ 138564-58-6 ]

2-Amino-5-methylthiophene-3-carbonitrile