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[ CAS No. 138564-58-6 ] {[proInfo.proName]}

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Chemical Structure| 138564-58-6
Chemical Structure| 138564-58-6
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Quality Control of [ 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 ]      Expand+

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 ?2

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.

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

[ 138564-58-6 ] Synthesis Path-Downstream   1~17

  • 1
  • [ 1493-27-2 ]
  • [ 138564-58-6 ]
  • [ 138564-59-7 ]
YieldReaction ConditionsOperation in experiment
77% With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃; for 18h;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): delta 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% 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) delta 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) upsilon 3279, 3080, 3027, 2917, 2854, 2226, 1612, 1491, 1402, 1335, 1270, 736 cm-1; MS 258 (M-1).
60% 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): delta 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;N-benzyl-N,N,N-triethylammonium chloride; In DMF (N,N-dimethyl-formamide); at 0 - 25℃; for 5h; 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
With potassium hydroxide; In acetonitrile; at 0 - 5℃; for 3h; Potassium hydroxide (101.4 g) in acetonitrile (150 ml) is taken under nitrogen and cooled to 0-5°C. A solution of <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (100 g) and o-fluoronitrobenzene (122.6 g) in acetonitrile (550 ml) is added. The reaction is then stirred for 3 hours and chilled water is added. The solid thus obtained is filtered off and air-dried. The solid is crystallized from water-methanol mixture and the crystallized solid is dried under vacuum at 40-45°C to obtain the title compound (140 g).
In tetrahydrofuran; 2. 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile To a stirred slurry of sodium hydride (14.4 g, 50percent dispersion in oil, 0.3 mol) in dry tetrahydrofuran (50 mL) under nitrogen was added, dropwise, a solution of 2-fluoronitrobenzene (28.2 g, 0.2 mol) and 2-amino-5-methylthiophene3-carbonitrile (27.6 g, 0.2 mol) in dry tetrahydrofuran (250 mL). The mixture was stirred at 25° C. for 24 hours, poured onto cracked ice and extracted into dichloromethane (3*500 mL). The combined extracts were washed with 2N hydrochloric acid (2*200 mL), water (2*200 mL), dried over magnesium sulphate and the solvent removed under reduced pressure. The residue was crystallized from ethanol to give the title compound, (35.2 g), m.p. 99°-102° C.
In tetrahydrofuran; 2. 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile To a stirred slurry of sodium hydride (14.4 g, 50percent dispersion in oil, 0.3 mol) in dry tetrahydrofuran (50 mL) under nitrogen was added, dropwise, a solution of 2-fluoro-nitrobenzene (28.2 g, 0.2 mol) and <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (27.6 g, 0.2 mol) in dry tetrahydrofuran (250 mL). The mixture was stirred at 25° C. for 24 hours, poured onto cracked ice and extracted into dichloromethane (3*500 mL). The combined extracts were washed with 2N hydrochloric acid (2*200 mL), water (2*200 mL), dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was crystallized from ethanol to give the title compound, (35.2 g), m.p. 99°-102° C.
In tetrahydrofuran; 2. 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile To a stirred slurry of sodium hydride (14.4 g, 50percent dispersion in oil, 0.3 mol) in dry tetrahydrofuran (50 mL) under nitrogen was added, dropwise, a solution of 2-fluoro-nitrobenzene (28.2 g, 0.2 mol) and <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (27.6 g, 0.2 mol) in dry tetrahydrofuran (250 mL). The mixture was stirred at 25° C. for 24 hours, poured onto cracked ice and extracted into dichloromethane (3*500 mL). The combined extracts were washed with 2N hydrochloric acid (2*200 mL) water (2*200 mL), dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was crystallized from ethanol to give the title compound, (35.2 g), m.p. 99°-102° C.
In tetrahydrofuran; 2. (2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile To a stirred slurry of sodium hydride (14.4 g, 50percent dispersion in oil, 0.3 mol) in dry tetrahydrofuran (50 mL) under nitrogen was added, dropwise, a solution of 2-fluoro-nitrobenzene (28.2 g, 0.2 mol) and <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (27.6 g, 0.2 mol) in dry tetrahydrofuran (250 mL). The mixture was stirred at 25° C. for 24 hours, poured onto cracked ice and extracted into dichloromethane (3*500 mL). The combined extracts were washed with 2N hydrochloric acid (2*200 mL), water (2*200 mL), dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was crystallized from ethanol to give the title compound, (35.2 g), m.p. 99°-102° C.
In tetrahydrofuran; 2. 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile To a stirred slurry of sodium hydride (14.4 g, 50percent dispersion in oil, 0.3 mol) in dry tetrahydrofuran (50 mL) under nitrogen was added, dropwise, a solution of 2-fluoro-nitrobenzene (28.2 g, 0.2 mol) and 2-amino-5- methylthiophene-3-carbonitrile (27.6 g, 0.2 mol) in dry tetrahydrofuran (250 mL). The mixture was stirred at 25° C. for 24 hours, poured onto cracked ice and extracted into dichloromethane (3*500 mL). The combined extracts were washed with 2N hydrochloric acid (2 *200 mL), water (2*200 mL), dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was crystallized from ethanol to give the title compound, (35.2 g), m.p. 99°-102° C.
With potassium hydroxide; In isopropyl alcohol; 2-fIuoronitrobenzene is condensed with 5-Amino-4-Cyano-2-Methyl Thiophene in Isopropyl alcohol and Potassium Hydroxide powder give 4-cyano-2-methyl-1-(2-nitrophenyl amino) Thiophene
With potassium hydroxide; In acetonitrile; at 0 - 5℃; for 3h; EXAMPLE 2; Preparation of 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrilePotassium hydroxide (101.4 g) in acetonitrile (150 ml) is taken under nitrogen and cooled to 0-5° C. A solution of <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (100 g) and o-fluoronitrobenzene (122.6 g) in acetonitrile (550 ml) is added. The reaction is then stirred for 3 hours and chilled water is added. The solid thus obtained is filtered off and air-dried. The solid is crystallized from water-methanol mixture and the crystallized solid is dried under vacuum at 40-45° C. to obtain the title compound (140 g).
With potassium hydroxide; In acetonitrile; at 0 - 5℃;Inert atmosphere; Example 2; Preparation of 2-(2-nitroanilino)-5-methylthiophene-3-carbonitrilePotassium hydroxide (101 g) in acetonitrile (150 ml) was taken under nitrogen and cooled to 0-5° C. A solution of <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (100 g) and ortho-fluoronitrobenzene (122 g) in acetonitrile (550 ml) was added. The reaction mixture was then stirred for 3 hours and chilled water was added into the reaction mixture. The solid was separated out. The solid thus obtained was filtered off and air-dried. The solid was crystallized from water-methanol mixture and the crystallized solid was dried under vacuum at 40-45° C. to obtain the title compound (140 g).
With potassium hydroxide; In dimethyl sulfoxide; Step E 5-Methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile To a solution of <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (13.8 g, 100 mmol) and 1-fluoro-2-nitrobenzene (16.92 g, 120 mmol) in dimethylsulfoxide was added potassium hydroxide (11.2 g, 200 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water, and the resulting suspension was filtered. The filtered cake was dried to give 5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile as a red solid used without further purification. 1H NMR: (400 MHz, CDCl3) delta 9.69 (s, 1H), 8.27-8.25 (m, 1H), 7.56-7.52 (m, 1H), 7.23-7.20 (m, 1H), 7.0-6.96 (m, 1H), 6.80 (s, 1H), 2.49 (s, 3H).
With potassium hydroxide; In dimethyl sulfoxide; at 20℃; To a solution of <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (13.8 g, 100mmol) and 1-fluoro-2-nitrobenzene (16.92 g, 120 mmol) in dirnethylsulfoxide wasadded potassium hydroxide (11.2 g, 200 mmol). The reaction mixture was stirred atroom temperature overnight The mixture was diluted with water, and the resultingsuspension was filtered. The filtered cake was dried to give 5-methyl-2-((2-nitropllenyl)amino)thiophene-3-carbonitrile as a red solid used without furtherpurification. 1H NMR: (400 MHz, CDCb) o 9.69 (s, 1 H), 8.27-8.25 (m, 1 H), 7.56-7.52(m, 1 H), 7.23-7.20 (m, 1 H), 7.0-6.96 (m, 1 H), 6.80 (s, 1 H), 2.49(s, 3H).
With potassium hydroxide; In dimethyl sulfoxide; at 20℃; To a solution of <strong>[138564-58-6]2-amino-5-methylthiophene-3-carbonitrile</strong> (13.8 g, 100 mmol) and 1-fluoro-2-nitrobenzene (16.92 g, 120 mmol) in dimethylsulfoxide was added potassium hydroxide (11.2 g, 200 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water, and the resulting suspension was filtered. The filtered cake was dried to give 5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile as a red solid used without further purification. 1H NMR (400 MHz, CDCl3) delta 9.69 (s, 1H), 8.27-8.25 (m, 1H), 7. 56-7.52 (m, 1H), 7.23-7.20 (m, 1H), 7.0-6 .96 (m,1H), 6. 80 (s, 1H) , 2 .49 (s, 3H).

  • 2
  • [ 10298-80-3 ]
  • [ 138564-58-6 ]
  • 2-(4-Methoxy-2-nitro-phenylamino)-5-methyl-thiophene-3-carbonitrile [ No CAS ]
  • 3
  • [ 446-11-7 ]
  • [ 138564-58-6 ]
  • 5-methyl-2-[(4-methyl-2-nitrophenyl)amino]-3-thiophenecarbonitrile, light red modification [ No CAS ]
  • 4
  • [ 123-38-6 ]
  • [ 109-77-3 ]
  • [ 138564-58-6 ]
YieldReaction ConditionsOperation in experiment
86% With sulfur; choline chloride; urea; sodium hydroxide; In water; at 60℃; for 2h;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 60C 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 2h; General procedure: General procedure forpreparation of2-aminothiophenes
78% 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 0C, 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 78%.1H NMR (200 MHz, CDCl3): delta 6.35 (s, IH), 4.15 (br s, 2H), 2.27 (s, 3H). 13C NMR (50 MHz, CDCl3): delta 160.9, 146.3, 124.6, 122.0, 115.7, 14.9.
74% 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 (10% 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, 74%) as an orange solid; Rf = 0.51 (25% EtOAct/hexanes); mp 100-101 C. 1H NMR (CDCl3): delta 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]+, 100%).
62.3% 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 5-10C. The pot was warmed to 18C, 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 182C. After the addition was complete, the mixture was stirred at 18I2C 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 70C, (or fan-dried at 45C) to give 2- amino-5-methylthiophene-3-carbonitrile (58.5 g). Yield: 62.3%.
62% With zinc(II) oxide; sulfur; In ethanol; at 85℃; for 6h; 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 mol%) 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% 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=48%). m.p. 93-95 C. 1H NMR (400 MHz, CDCl3) delta 2.27 (s, 3H), 4.56 (br, exchangeable with D2O, 2H), 6.35 (s, 1H); IR (KBr) upsilon 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 12h;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.
With sulfur; triethylamine; In N,N-dimethyl-formamide; at 5℃; for 0.75h; A mixture of (46.2 g) of sulphur, propionaldehyde (100 g) and dimethylformamide (200 ml) are taken under nitrogen. Triethylamine (113.2 ml) is added at 5C. A solution of malonitrile (95.2 g) in dimethylformamide (200 ml) is added. After addition, the reaction mixture is stirred for 45 minutes. The reaction mixture is then poured onto ice water (2400 ml). The solid thus obtained is isolated by filtration, washed with chilled water and dried to obtain the title compound (139.5 g).
With sulfur; triethylamine; In N,N-dimethyl-formamide; By the reaction of Malononitrile with Propionaldehyde in presence of Sulphur Powder and Triethylamine in N,N-dimethlyformamide to give 5-Amino-4-Cyano-2-Methyl Thiophene as per the procedure described in EP0454436A1

  • 8
  • [ 138564-58-6 ]
  • Olanzapine N-Oxide [ No CAS ]
  • 9
  • [ 138564-58-6 ]
  • 7-methoxy-4'-N-desmethyl-olanzepine [ No CAS ]
  • 10
  • [ 138564-58-6 ]
  • [ 186792-81-4 ]
  • 11
  • [ 138564-58-6 ]
  • 7-Methoxy-2-methyl-10-(4-methyl-4-oxy-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene [ No CAS ]
  • 12
  • [ 138564-58-6 ]
  • 7-Methoxy-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine; hydrochloride [ No CAS ]
  • 13
  • [ 138564-58-6 ]
  • [ 89-61-2 ]
  • [ 660861-93-8 ]
YieldReaction ConditionsOperation in experiment
74.8% With lithium hydroxide; In water; dimethyl sulfoxide; at 20.4 - 30.4℃; for 40h; Stir in a 3 neck 500 mL round bottom flask, 2-amino-5-methyl-thiophene-3- carbonitrile (124.11 g, 0. [898] mol, [1] eauiv. ), 1, 4-dichloro-2-nitro-benzene [(174.] 15 g, 0. 907mol, 1.01 equiv), and DMSO (1.6 L, 13 [VOL)) FOR] 15 min. (dark solution). Charge in one portion, LiOH [H2O] (75.37g, 1.796 mol, 2 equiv). Began to exotherm from 20.4 [C] to 25. [5 C] over 10 minutes. After 30 minutes temp reaches 28. [1 C] and at 1 hour 30. [4 C.] Place tap water in the bath around the flask to control the exotherm. Check HPLC at 23 h, which shows [81.] 2 % of desired product. Let continue to stir at ambient temperature for greater reaction conversion. Check HPLC at 39 h, which shows 83.5 % of one product. Let stir 40 hours total. Cool with ice/water bath to [17 C.] Begin pH adjustment by slowly adding 1 [N HCI] (1020 mL) to reach pH=7.1. Keep exotherm [IS AT 15-22 C] during the addition. Workup includes: pouring reaction mixture into 22 L bottom outlet flask, rinsing in with [CH2CL2] (5.6 [L)] and [5% LICI] solution (3.6 L), stirring about 10 min. , and allowing layers to separate. The lower layer might be darker than upper layer. Back- extract the aqueous layer with [CH2C12] (1.5 L). Combine organic layers and wash with 5% [LICI] solution (3 x 1.3 L). Dry organic layer with [NA2SO4] (800 g) allowing it to stir [1] hour, filter and evaporate to dryness. Wt. = 376 g. Back-extract the combined aqueous layers with [CH2C12] (0.5 L). Check aq layer by [HPLC-2] mL aq layer in 15 mL of eluent for product in aq layer. Wash the organic phase with brine [(2X500] mL) and finally with [5] % LiCl (500 mL). Dry over the weekend with [NAS04] (80 g). Filter and add to other organic layer. For Chromatography, dissolve crude material in methylene chloride (950 g) and charge to a silica gel 60 (2.8 kg pre wetted with heptane) bed on fritted funnel. Some product might crash out on top of silica cake. Rinse flask and add to top of cake with [CH2CL2] [(0. 3] L) until all of the precipitate is dissolve and onto the column. Elute with heptane [(-16] L), then 25 % [CH2C12] in heptane (-8 L), then 37.5 % [CH2C12] in heptane (-8 L), follow by 50 % [CH2C12] in heptane and 100 % [CH2C12.] Early Fractions might contain no product. Identify mix fractions containing product and rundown separately until virtually all methylene chloride is gone leaving the product in heptane, cool to [0 C] and filter. Filtrate analysis shows 5 % product by area % integration. Combine product only fractions and evaporate to dryness. Add cake from mixed fractions. Combined dry weight= 197.4 g. HPLC area percent = 97.0 % NMR is consistent with desired product : Yield 74.8 %.
  • 14
  • [ 611-06-3 ]
  • [ 138564-58-6 ]
  • [ 660861-93-8 ]
YieldReaction ConditionsOperation in experiment
33% With lithium hydroxide; In water; dimethyl sulfoxide; at 20℃; for 18h; Dissolve <strong>[138564-58-6]2-amino-5-methyl-thiophene-3-carbonitrile</strong> (4.14g, 30mmol) and 2,4- dichloronitrobenzene (5.76g, 30mmol) in dimethylsulfoxide (70ml) and stir under nitrogen. Add lithium hydroxide monohydrate (2. [0G,] 47. [7MMOL)] and heat the mixture in an oil bath at room temperature for 18 hours. Pour the mixture into ice water, make acid with 2N HC1, extract into ethyl acetate, dry [(MGS04)] and concentrate under reduced pressure. Crystallize from ethanol to give [2- (4-CHLORO-2-NITRO-PHENYLAMINO)-5-METHYL-] thiophene-3-carbonitrile as a yellow solid (2. 92g, 33%): NMR [(1H,] 300 MHz, CDCl3) : 89. 5 (1H broad), 8.25 (lH, s), 7. 45 [(1H,] d), 7.1 [(LH,] d), 6.25 [(1H,] s), 2.5 (3H, s).
  • 15
  • [ 2105-61-5 ]
  • [ 138564-58-6 ]
  • [ 660862-33-9 ]
YieldReaction ConditionsOperation in experiment
44% With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 8 - 20h; Add sodium hydride, 60% dispersion in mineral oil (55.0 g x 60% = 33.0 g, 1.38 mol) to THF (950 mL) with stirring at [0-5 C] under nitrogen. Add a solution of 2-amino- 5-methyl-thiophene-3-carbonitrile (95.0 g, 0.687 mol) and [1,] 2,4-trifluoro-5-nitro-benzene (121.7 g, 0.687 mol) in THF (1325 mL) dropwise [OVER-1] hour, keeping the temperature below [10 C.] Allow the reaction to warm to ambient temperature and stir for 8-20 hours. Cool to [10-15 C] and add aqueous IN HCl (550 mL) dropwise over 10-15 minutes to adjust the pH to 7.0-7. 2, keeping the pot temperature below [15 C.] Remove most of the organic portion under reduced pressure, and then filter and rinse with water. Dry at 50-60 [C] to obtain the crude product. Purify by flash chromatography, eluting with 1 : 1/methylene chloride: heptane to give 89. [1] g (44%) of the title [COMPOUND. LH] NMR (400 MHz, DMSO-d6) [No. ] 9.77 (bs, 1H), 8.33 (m, 1H), 7.09 (s, 1H), 7.07 (m, 1H), 2.47 (s, 3H). HRMS (ES) exact mass M+H calcd for [C12H7F2N302S] 318.0125 ; found 318. [0133.
  • 16
  • [ 446-35-5 ]
  • [ 138564-58-6 ]
  • [ 660862-12-4 ]
YieldReaction ConditionsOperation in experiment
62% With lithium hydroxide; In water; dimethyl sulfoxide; at 20℃; for 18h; Add <strong>[138564-58-6]2-amino-5-methyl-thiophene-3-carbonitrile</strong> (10.0 g, 72.4 mmol) and 2,4- [DIFLUORO-1-NITRO-BENZENE] (8.00 mL, 73.0 mmol) to DMSO (130 mL) and stir under nitrogen at ambient temperature. Add lithium hydroxide monohydrate (6.10 g, 145 mmol) in one portion and stir at ambient temperature. After 18 hours, add deionized water (390 mL) dropwise at [10-20 C.] Adjust the pH to 7-8 with concentrated [HC1] (-6 mL) and stir for 4 hours. Filter the crude product and rinse with 3: 1/water : DMSO, then water. Dry at [50 C] to constant weight. Purify by flash chromatography, eluting with methylene chloride to give the title compound 10.3 g (62%) [:'H] NMR (400 MHz, [DMSO-D6)] [5] 9.83 (bs, 1H), 8. 28 (m, [1H),] 7.12 (s, 1H), 6.91 (m, [1H),] 6.73 (m, 1H), 2.53 (s, 3H). HRMS (ES) exact mass M+H calcd for [C12H8FN302S] 300.0219 ; found 300.0219.
YieldReaction ConditionsOperation in experiment
1. 2-Amino-5-methylthiophene-3-carbonitrile A mixture of sulfur (217.8 g, 6.79 mol), propional-dehyde (472.5 g, 587 mL, 8.13 mol) and dimethylformamide (1350 m) was placed in a 5 litre flange-necked flask fitted with air stirrer, air condenser, long reach thermometer and dropping funnel. Triethylamine (576 mL, 4.13 mol) was added dropwise over 30 minutes to the cooled stirred reaction mixture whilst maintaining the pot temperature between 5-10 C. with an ice-bath. After addition was complete the pot was allowed to warm up to 18 C. over 50 minutes, keeping the mixture well stirred. Then a solution of malononitrile (450 g, 6.8 mol) in dimethylformamide (900 mL) was added dropwise over 70 minutes keeping the pot temperature around 20 C. throughout the addition. After addition was complete the mixture was stirred at 15-20 C. for a further 45 minutes then sampled for TLC. The mixture was then poured onto ice (4 liters)/water (8 liters) with stirring and this caused the required product to precipitate. After 10 minutes the stirrer was switched off and the solid allowed to settle. The aqueous liquor was decanted away and the solid isolated by filtration. The isolated solid was well washed with water (de-ionized, 4 liters), then dried over night in vacuo at 70-75 C. to give the title compound (585 g), m.p. 100 C.
1. 2-Amino-5-methylthiophene-3-carbonitrile A mixture of sulphur (217.8 g, 6.79 mol), propionaldehyde (472.5 g, 587 mL, 8.13 mol) and dimethylformamide (1350 m) was placed in a 5 liter flange-necked flask fitted with air stirrer, air condenser, long reach thermometer and dropping funnel. Triethylamine (576 mL, 4.13 mol) was added dropwise over 30 minutes to the cooled stirred reaction mixture whilst maintaining the pot temperature between 5-10 C. with an ice-bath. After addition was complete the pot was allowed to warm up to 18 C. over 50 minutes, keeping the mixture well stirred. Then a solution of malononitrile (450 g, 6.8 mol) in dimethylformamide (900 mL) was added dropwise over 70 minutes keeping the pot temperature around 20 C. throughout the addition. After addition was complete the mixture was stirred at 15-20 C. for a further 45 minutes then sampled for TLC. The mixture was then poured onto ice (4 liters)/water (8 liters) with stirring and this caused the required product to precipitate. After 10 minutes the stirrer was switched off and the solid allowed to settle. The aqueous liquor was decanted away and the solid isolated by filtration. The isolated solid was well washed with water (de-ionised, 4 liters), then dried over night in vacuo at 70-75 C. to give the title compound (585 g), m.p. 100 C.
1. 2-Amino-5-methylthiophene-3-carbonitrile A mixture of sulfur (217.8 g, 6.79 mol), propional-dehyde (472.5 g, 587 mL, 8.13 mol) and dimethylformamide (1350 m) was placed in a 5 liter flange-necked flask fitted with air stirrer, air condenser, long reach thermometer and dropping funnel. Triethylamine (576 mL, 4.13 mol) was added dropwise over 30 minutes to the cooled stirred reaction mixture whilst maintaining the pot temperature between 5-10 C. with an ice-bath. After addition was complete the pot was allowed to warm up to 18 C. over 50 minutes, keeping the mixture well stirred. Then a solution of malononitrile (450 g, 6.8 mol) in dimethylformamide (900 mL) was added dropwise over 70 minutes keeping the pot temperature around 20 C. throughout the addition. After addition was complete the mixture was stirred at 15-20 C. for a further 45 minutes then sampled for TLC. The mixture was then poured onto ice (4 liters)/water (8 liters) with stirring and this caused the required product to precipitate. After 10 minutes the stirrer was switched off and the solid allowed to settle. The aqueous liquor was decanted away and the solid isolated by filtration. The isolated solid was well washed with water (de-ionized, 4 liters), then dried over night in vacuo at 70-75 C. to give the title compound (585 g), m.p. 100 C.
1. 2-Amino-5-methylthiophene-3-carbonitrile A mixture of sulfur (217.8 g, 6.79 mol), propional-dehyde (472.5 g, 587 mL, 8.13 mol) and dimethylformamide (1350 m) was placed in a 5 liter flange-necked flask fitted with air stirrer, air condenser, long reach thermometer and dropping funnel. Triethylamine (576 mL, 4.13 mol) was added dropwise over 30 minutes to the cooled stirred reaction mixture whilst maintaining the pot temperature between 5-10 C. with an ice-bath. After addition was complete the pot was allowed to warm up to 18 C. over 50 minutes, keeping the mixture well stirred. Then a solution of malononitrile (450 g, 6.8 mol) in dimethylformamide (900 mL) was added dropwise over 70 minutes keeping the pot temperature around 20 C. throughout the addition. After addition was complete the mixture was stirred at 15-20 C. for a further 45 minutes then sampled for TLC. The mixture was then poured onto ice (4 liters)/water (8 liters) with stirring and this caused the required product to precipitate. After 10 minutes the stirrer was switched off and the solid allowed to settle. The aqueous liquor was decanted away and the solid isolated by filtration. The isolated solid was well washed with water (deionized, 4 liters), then dried over night in vacuo at 70-75 C. to give the title compound (585 g), m.p. 100 C.
1. 2-Amino-5-methylthiophene-3-carbonitrile A mixture of sulfur (217.8 g, 6.79 mol), propional-dehyde (472.5 g, 587 mL, 8.13 mol) and dimethylformamide (1350 m) was placed in a 5 litre flange-necked flask fitted with air stirrer, air condenser, long reach thermometer and dropping funnel. Triethylamine (576 mL, 4.13 mol) was added dropwise over 30 minutes to the cooled stirred reaction mixture whilst maintaining the pot temperature between 5-10 C. with an ice-bath. After addition was complete the pot was allowed to warm up to 18 C. over 50 minutes, keeping the mixture well stirred. Then a solution of malononitrile (450 g, 6.8 mol) in dimethylformamide (900 mL) was added dropwise over 70 minutes keeping the pot temperature around 20 C. throughout the addition. After addition was complete the mixture was stirred at 15-20 C. for a further 45 minutes then sampled for TLC. The mixture was then poured onto ice (4 litres)/water (8 litres) with stirring and this caused the required product to precipitate. After 10 minutes the stirrer was switched off and the solid allowed to settle. The aqueous liquor was decanted away and the solid isolated by filtration. The isolated solid was well washed with water (de-ionized, 4 litres), then dried over night in vacuo at 70-75 C. to give the title compound (585 g), m.p. 100 C.
1. 2-Amino-5-methylthiophene-3-carbonitrile A mixture of sulfur (217.8 g, 6.79 mol), propional-dehyde (472.5 g, 587 mL, 8.13 mol) and dimethylformamide (1350 m) was placed in a 5 liter flange-necked flask fitted with air stirrer, air condenser, long reach thermometer and dropping funnel. Triethylamine (576 mL, 4.13 mol) was added dropwise over 30 minutes to the cooled stirred reaction mixture whilst maintaining the pot temperature between 5-10 C. with an ice-bath. After addition was complete the pot was allowed to warm up to 18 C. over 50 minutes, keeping the mixture well stirred. Then a solution of malononitrile (450 g, 6.8 mol) in dimethylformamide (900 mL) was added dropwise over 70 minutes keeping the pot temperature around 20 C. throughout the addition. After addition was complete the mixture was stirred at 15-20 C. for a further 45 minutes then sampled for TLC. The mixture was then poured onto ice (4 liters)/water (8 liters) with stirring and this caused the required product to precipitate. After 10 minutes the stirrer was switched off and the solid allowed to settle. The aqueous liquor was decanted away and the solid isolated by filtration. The isolated solid was well washed with water (de-ionized, 4 litres), then dried over night in vacuo at 70-75 C. to give the title compound (585 g), m.p. 100 C.

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