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Chemical Structure| 138564-58-6
Chemical Structure| 138564-58-6
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Product Details of [ 138564-58-6 ]

CAS No. :138564-58-6 MDL No. :MFCD01626055
Formula : C6H6N2S Boiling Point : -
Linear Structure Formula :- InChI Key :YGXADLPRHBRTPG-UHFFFAOYSA-N
M.W : 138.19 Pubchem ID :689056
Synonyms :

Calculated chemistry of [ 138564-58-6 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.17
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 38.4
TPSA : 78.05 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.77 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.55
Log Po/w (XLOGP3) : 1.93
Log Po/w (WLOGP) : 1.52
Log Po/w (MLOGP) : 0.09
Log Po/w (SILICOS-IT) : 2.2
Consensus Log Po/w : 1.46

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.32
Solubility : 0.656 mg/ml ; 0.00474 mol/l
Class : Soluble
Log S (Ali) : -3.19
Solubility : 0.0886 mg/ml ; 0.000641 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.75
Solubility : 2.45 mg/ml ; 0.0177 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.15

Safety of [ 138564-58-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P501-P261-P270-P271-P264-P280-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330-P302+P352+P312-P304+P340+P312 UN#:N/A
Hazard Statements:H302+H312+H332-H315-H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 138564-58-6 ]

* 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 [ 138564-58-6 ]
  • Downstream synthetic route of [ 138564-58-6 ]

[ 138564-58-6 ] Synthesis Path-Upstream   1~6

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YieldReaction ConditionsOperation in experiment
69%
Stage #1: at 20℃; for 20 h;
Stage #2: With sodium hydroxide In water at 0℃;
EXAMPLE 8 : iV-(3-hydroxyphenethyl)-2,6-dimethylthieno[2,3-d]pyriinidin-4- amine (Final Compound 22). a) 2-amino-5-methylthiophene-3-carboxamide; According to Scheme 5 Step 1: 2-amino5-methylthiophene-3-carbonitrile (4.0Og, 28.9mmol) in concentrated sulfuric acid (38.8ml) was stirred at r.t. for 20 hours. The mixture was poured onto ice-water (25Og) and neutralized to pH=7 with a concentrated sodium hydroxide solution. The mixture was extracted with ethyl acetate and the organic layer was dried over MgSO4, filtered and evaporated till dryness. The residue was purified by chromatography over silica gel (Flashmart Pack: 85g/60-40um, eluent: ethyl acetate) yielding title compound (3.10g, 69percent) as a brown solid.
Reference: [1] Patent: WO2006/30031, 2006, A1, . Location in patent: Page/Page column 57
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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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  • [ 138564-59-7 ]
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
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YieldReaction ConditionsOperation in experiment
86% With sulfur; choline chloride; urea; sodium hydroxide In water at 60℃; for 2 h; Green chemistry General procedure: A mixture of 0.070 g 4-propylcyclohexanone (0.5 mmol),0.030 g malononitrile (0.5 mmol), 0.019 g sulfur powder(0.6 mmol), and 0.1 cm3 NaOH (4 mol dm-3 aqueoussolution) in 1 cm3 choline chloride/urea was stirred at 60°C for 2–3 h. After completion of the reaction, indicated by TLC monitoring, 5 cm3 water was added. The solid product was separated by filtration and if necessary the precipitate recrystallized from EtOH to afford the corresponding pure product
79% With sulfur In neat (no solvent) at 60℃; for 2 h; General procedure: General procedure forpreparation of2‑aminothiophenes
78%
Stage #1: With sulfur; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 1 h;
Stage #2: at 20℃;
For a general synthesis see He, X.; Griesser, U. J.; Stowell, J. G.; Borchrdt, T. B.; Byrn, S. R. J. Pharm. Sci. 2001, 90, 371.A Sulfur (S8, 0.9 g, 0.0 27 mmol), propionalaldehyde (2 ml, 0.027 mmol) and DMF (6 ml) were transferred to a three-necked round-bottomed flask equipped with a dropping funnel and condenser. The resulting mixture was cooled to 0°C, and EPO <DP n="34"/>triethylamine (2.3 ml) was added in a dropwise manner via the dropping funnel. The resulting dark solution was then warmed to room temperature over a period of 1 h. A solution of malononitrile (1.71 ml, 1.8 g, 0.027 mmol) in DMF (3.2 ml) was transferred to the addition funnel and added in a dropwise manner. The resulting brownish mixture was stirred overnight at room temperature. Then the mixture was poured over 80 ml of ice and water to yield an orange precipitate. The solid A was filtered, washed with chilled water, and dried in vacuo; yield 78percent.1H NMR (200 MHz, CDCl3): δ 6.35 (s, IH), 4.15 (br s, 2H), 2.27 (s, 3H). 13C NMR (50 MHz, CDCl3): δ 160.9, 146.3, 124.6, 122.0, 115.7, 14.9.
74%
Stage #1: With sulfur; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 2.66667 h;
Stage #2: at 20℃; for 1.33333 h; Cooling with ice
Triethylamine (33.3 g, 0.33 mol) was added dropwise to a mixture of sulfur (16.0 g, 0.50 mol) and propionaldehyde (34.8 g, 0.60 mol) in DMF (100 mL) under vigorous stirring in an ice bath. The reaction mixture was stirred for 40 min at 0 °C, and stirred another 120 min at 15–20 °C. Then malononitrile (33.7 g, 0.51 mol) in DMF (66 mL) was added dropwise in an ice bath. The reaction mixture was stirred for additional 80 min at 15–20 °C, and was poured into an ice-water (300 mL) with stirring. The resulted precipitate was filtered, washed with ice-water, and dried in vacuo to obtain an orange solid product (37.0 g). The resulted solution was extracted with EtOAc (200 mL × 3), washed with water, dried over Na2SO4, and concentrated to give a crude product, which was purified by column chromatography (10percent EtOAc/hexanes) on silica gel to obtain another portion of the solid product (14.2 g). The work-up totally afforded 1 (51.2 g, 74percent) as an orange solid; Rf = 0.51 (25percent EtOAct/hexanes); mp 100–101 °C. 1H NMR (CDCl3): δ 2.27 (d, J = 1.0 Hz, 3H, CH3), 4.60 (s, 2H, NH2), 6.35 (q, J = 1.0 Hz, 1H, Ar-H). MS(ESI): 139 ([M+H]+, 100percent).
62.3%
Stage #1: With sulfur; triethylamine In DMF (N,N-dimethyl-formamide) at 0 - 18℃; for 1.33333 h;
Stage #2: at 18℃; for 0.75 h;
A mixture of sulfur (21.8 g), propionaldehyde (47.3 g) and N, N- DIMETHYLFORMAMIDE (135 mL) was placed in a 500 mL flask and cooled in an ice bath. Triethylamine (57.6 mL) was added dropwise over 30 minutes to the stirred reaction mixture and the temperature was maintained between 5-10°C. The pot was warmed to 18°C, and stirred at 182 C over 50 minutes. A solution of malononitrile (45 g) in N, N-DIMETHYLFORMAMIDE (90 mL) was added dropwise at a temperature of 182°C. After the addition was complete, the mixture was stirred at 18I2°C for 45 minutes. The mixture was poured onto ice/water (1.2 L) while stirring. A solid precipitate was collected by filtration, washed thoroughly with water, and dried overnight in vacuo at 70°C, (or fan-dried at 45°C) to give 2- amino-5-methylthiophene-3-carbonitrile (58.5 g). Yield: 62.3percent.
62% With zinc(II) oxide; sulfur In ethanol at 85℃; for 6 h; General procedure: 10 mmol of ketone or aldehyde, 10 mmol of malonodinitrile, and 10 mmol of sulfur powder were mixed. Then, 0.02 g (2.5 molpercent) of ZnO nano-particles was added and the mixture was heated to 100 °C with good stirring for the required time. After 6 h, the reaction was stopped and the corresponding product was worked up by 10 ml of ethanol and ZnO was separated by a simple filtration. Thereafter, the reaction mixture was cooled to room temperature and poured into 150 ml of ice-water. The precipitate was filtered off, washed with cold water and dried. To further purification, the crude product was purified by silica gel column chromatography with 10:1 hexane:ethyl acetate as eluent.
48%
Stage #1: With sulfur; triethylamine In N,N-dimethyl-formamide at 18℃;
Stage #2: at 18℃; for 1.83333 h;
EXAMPLE 1; 2-Methyl-4-(4-methylpiperazin-1-yl)-10H-benzo[b]thieno[2,3-e][1,4]diazepine Step 1 2-Amino-5-methylthiophene-3-carbonitrile: At about -5° C. and over a period of about 15 minutes, triethylamine (22.97 g, 227 mmol) was added dropwise to a mixture of sulphur powder (12.13 g, 378.35 mmol), propionaldehyde (26.34 g, 454.1 mmol) and N,N-dimethylformamide (100 mL). The mixture was stirred at about 18° C. for about 2 hours, and then a solution of malononitrile (25 g, 378.44 mmol) and N,N-dimethylformamide (50 mL) was added dropwise over a period of about 20 minutes. The mixture was stirred at about 18° C. for about 90 minutes, and then poured into ice-cold water. The resulting precipitant was collected and dried to give the title product as a cream color solid (25 g, yield=48percent). m.p. 93-95° C. 1H NMR (400 MHz, CDCl3) δ 2.27 (s, 3H), 4.56 (br, exchangeable with D2O, 2H), 6.35 (s, 1H); IR (KBr) υ 3416, 3329, 3222, 2914, 2196, 1624, 1516, 1382, 1272, 1104, 895, 811 cm-1; MS 139 (M+1).
37% With 1H-imidazole; sulfur In N,N-dimethyl-formamide at 50℃; for 12 h; Inert atmosphere General procedure: A mixture of carbonyl compounds 4a-r (3.0 mmol), dicyanomethane (3.3 mmol), sulfur (4.5 mmol), and imidazole (0.3 mmol) in DMF (3.0 mL) was stirred at 60 °C under nitrogen atmosphere for 10-18 h. The crude materials were directly purified through flash chromatography to give the desired products 5a-r.

Reference: [1] Monatshefte fur Chemie, 2017, vol. 148, # 4, p. 711 - 716
[2] Research on Chemical Intermediates, 2018, vol. 44, # 3, p. 2195 - 2213
[3] Patent: WO2008/50341, 2008, A2, . Location in patent: Page/Page column 32; 33
[4] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 7, p. 1953 - 1956
[5] Journal of Pharmaceutical Sciences, 2001, vol. 90, # 3, p. 371 - 388
[6] Patent: WO2004/94390, 2004, A1, . Location in patent: Page 13
[7] Journal of Molecular Catalysis A: Chemical, 2013, vol. 368-369, p. 16 - 23
[8] Russian Journal of Bioorganic Chemistry, 2005, vol. 31, # 4, p. 378 - 382
[9] Applied Organometallic Chemistry, 2017, vol. 31, # 11,
[10] Patent: US2010/266711, 2010, A1, . Location in patent: Page/Page column 14
[11] Tetrahedron, 2011, vol. 67, # 34, p. 6202 - 6205
[12] Applied Organometallic Chemistry, 2018, vol. 32, # 5,
[13] Tetrahedron, 2010, vol. 66, # 41, p. 8203 - 8209
[14] Patent: WO2006/6180, 2006, A1, . Location in patent: Page/Page column 10
[15] Patent: WO2006/25065, 2006, A1, . Location in patent: Page/Page column 7
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Reference: [1] Patent: US2009/5556, 2009, A1, . Location in patent: Page/Page column 5
[2] Patent: US2010/317849, 2010, A1, . Location in patent: Page/Page column 4
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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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