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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
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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 :
Chemical Name :5-Methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile

Calculated chemistry of [ 138564-59-7 ]      Expand+

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 ?2

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:Ⅲ
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.

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

[ 138564-59-7 ] Synthesis Path-Downstream   1~11

  • 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
  • [ 138564-59-7 ]
  • 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With hydrogenchloride; tin; In ethanol; water; at 85℃; for 4h;Green chemistry; In a 500 mL round-bottom flask fitted with a mechanical stirrer and a thermometer was placed 10.0 g (0.0386 mol) of <strong>[138564-59-7]5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile</strong>(1) and 100 mL ethanol. The mixture was stirred at 50?C for 0.5 h. Then 7.4 g(0.062 mol) of tin powder and 84 mL of 4M hydrochloric acid were added. The temperature of the reaction mixture was raised to 85?C and stirring was continued for 4 additional hours. Then the mixture was cooled to 25?C and stirred for another 8 h, which led to the precipitation of a solid. The precipitated crystals were collected, washed with 20 mL ethanol,and dried in vacuo to afford 9.8 g (96percent) of the hydrochloride of 2 as a pale yellowsolid, mp. above 3008 (HPLC > 98.5percent). 1H NMR (DMSO-d6): d 2.38 (3 H, s), 6.18 (1H, s), 6.51 (1 H, b), 6.91 (2 H, b), 6.95 (1 H, d, J D 8.4 Hz), 7.18 (3 H, m).
95% With hydrogenchloride; tin(ll) chloride; In ethanol; water; for 3h;Heating / reflux; For a general synthesis see Chakrabarti, J. K.; Hotten, T. M.; Pullar, I. A.; Steggles, D. J. J. Med. Chem. 1989, 32, 2375.BTo a slurry of B (100 mg, 0.4 mmol) in ethanol (ImI) was added tin(II)- chloride-dihydrate (260 mg, 1.16 mmol) in concentrated HCl (ImI), the solution was heated to reflux for 3 h and cooled overnight, and the solid C was filtered, washed with chilled DCM, and dried in vacuo; yield 95percent.1H NMR (200 MHz, DMSOd6): delta 11.05 (s, IH), 9.53 (s, IH), 9.08 (br s, IH), 8.82 (br s, IH), 6.80 - 7.14 (m, 4H), 6.78 (s, IH), 2.23 (s, 3H).
95% With hydrogenchloride; tin(II) chloride dihdyrate; In ethanol; water; for 20.25h;Reflux; Step 3; 2-Methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-amine hydrochloride: Over a period of 15 minutes, a solution of stannous chloride dihydrate (14.63 g, 64.84 mmol) and 5N hydrochloric acid (50 mL) was added to suspension of 5-methyl-2-(2-nitrophenylamino)thiophene-3-carbontrile (5 g, 19.30 mmol) and ethanol (50 mL). The resulting mixture was heated at reflux for about 20 hours, and then concentrated in vacuo. The resuting residue was slowly poured into stirred ice-cold water.The resulting precipitant was collected, washed with water, and dried to give the title compound as a brown color solid (4.2 g, yield=95percent). m.p. 160-162° C. 1H NMR (400 MHz, DMSO-d6) delta 2.25 (s, 3H), 6.79 (s, 1H), 6.85 (d, J=7.6 Hz, 1H) 6.94 (d, J=7.6 Hz, 1H) 7.02 (t, J=7.2 Hz, 1H), 7.10 (t, 7.4 Hz, 1H), 8.76 (br, exchangeable with D2O, 1H), 9.06 (br, exchangeable with D2O, 1H), 9.50 (br, exchangeable with D2O, 1H), 11.0 (br, exchangeable with D2O, 1H); IR (KBr) upsilon 3326, 3180, 2953, 2904, 1653, 1543, 1483, 1244, 751 cm-1; MS 230 (M+1).
86% With hydrogenchloride; tin(II) chloride dihdyrate; In ethanol; water; for 1h;Reflux; To a stirred suspension of compound 2 (10.0?g, 38.6?mmol) in ethanol (75?mL) at 50?°C was added a solution of stannous chloride dihydrate (30.5?g, 135?mmol) in hydrochloric acid (6?N, 65?mL, 386?mmol). The reaction mixture was stirred under reflux for 1?h, concentrated under reduced pressure and allowed to crystallize at 5?°C. The salt was filtered, washed with a small amount of cold water, and dried to afford 3 (8.8?g, 86percent) as a yellow solid; Rf?=?0.12 (10percent MeOH/CH2Cl2); mp: >250?°C. 1H NMR (DMSO-d6): delta 2.25 (d, J?=?1.0?Hz, 3H, CH3), 6.80 (d, J?=?1.5?Hz, 1H, Ar-H), 6.85 (dd, J?=?1.5, 8.0?Hz, 1H, Ph-H), 6.94 (dd, J?=?1.5, 8.0?Hz, 1H, Ph-H), 7.00 (dt, J?=?1.5, 8.0?Hz, 1H, Ph-H), 7.08 (dt, J?=?1.5, 8.0?Hz, 1H, Ph-H), 8.91 (br s, 1H, NHH), 9.11 (br s, 1H, NHH), 9.58 (s, 1H, NH), 11.19 (br s, 1H, HCl). MS (ESI): 230 ([M+H]+, 100percent).
2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile (100 g) is taken in ethyl acetate (1000 ml). 5percent Pd/C (15 g) is added and hydrogenated at 50°C for 15 hours. Ethyl acetate is distilled off to get the solid. The solid is taken in isopropyl alcohol (500 ml), concentrated hydrochloric acid (102 ml) is added at room temperature and the mixture is heated upto 80-82°C for 12 hours under stirring. The solution is cooled to precipitate the solid, filtered and dried under vacuum at 55-60°C to give the title compound (80g).
With stannous chloride; In hydrogenchloride; ethanol; 3. 4-Amino-2-methyl-10H-thieno[2.3-b][1,5]benzodiazepine, hydrochloride To a stirred slurry of <strong>[138564-59-7]2-(2-nitroanilino)-5-methyl-thiophene-3-carbonitrile</strong> (3 g, 0.011 mol) in ethanol (35 mL) at 50° C. was added, over 10 minutes, a solution of anhydrous stannous chloride (6.95 g, 0.037 mol) in hydrochloric acid (26 mL, 5M). The mixture was stirred under reflux for 1 hour, concentrated under reduced pressure and allowed to crystallize over night at 5° C. The salt was filtered, washed with a small amount of water, dried (4.3 g) m.p. >250° C., and used without further purification in the next stage.
With stannous chloride; In hydrogenchloride; ethanol; 3. 4-Amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine, hydrochloride To a stirred slurry of <strong>[138564-59-7]2-(2-nitroanilino)-5-methylthiophene-3-carbonitrile</strong> (3 g, 0.011 mol) in ethanol (35 mL) at 50° C. was added, over 10 minutes, a solution of anhydrous stannous chloride (6.95 g, 0.037 mol) in hydrochloric acid (26 mL, 5M). The mixture was stirred under reflux for 1 hour, concentrated under reduced pressure and allowed to crystallise over night at 5° C. The salt was filtered, washed with a small amount of water, dried (4.3 g) m.p. >250° C., and used without further purification in the next stage.
With stannous chloride; In hydrogenchloride; ethanol; 3. 4-Amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine, hydrochloride To a stirred slurry of <strong>[138564-59-7]2-(2-nitroanilino)-5-methyl-thiophene-3-carbonitrile</strong> (3 g, 0.011 mol) in ethanol (35 mL) at 50° C. was added, over 10 minutes, a solution of anhydrous stannous chloride (6.95 g, 0.037 mol) in hydrochloric acid (26 mL, 5M). The mixture was stirred under reflux for 1 hour, concentrated under reduced pressure and allowed to crystallize over night at 5° C. The salt was filtered, washed with a small amount of water, dried (4.3 g) m.p. >250° C., and used without further purification in the next stage.
With stannous chloride; In hydrogenchloride; ethanol; 3. 4-Amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine, hydrochloride To a stirred slurry of <strong>[138564-59-7]2-(2-nitroanilino)-5-methyl-thiophene-3-carbonitrile</strong> (3 g, 0.011 mol) in ethanol (35 mL) at 50° C. was added, over 10 minutes, a solution of anhydrous stannous chloride (6.95 g, 0.037 mol) in hydrochloric acid (26 mL, 5M). The mixture was stirred under reflux for 1 hour, concentrated under reduced pressure and allowed to crystallize over night at 5° C. The salt was filtered, washed with a small amount of water, dried (4.3 g) m.p.>250° C., and used without further purification in the next stage.
With hydrogenchloride; tin(ll) chloride; In isopropyl alcohol; Reduction of 4-cyano-2-methyl-1-(2-nitrophenyl amino) Thiophene with Stannous Chloride and Hydrochloric acid in Isopropyl Alcohol and followed by cyclization to get 4-Amino-2-Methyl-10H-Thieno [2,3,-b][1,5] Benzodiazepine using the same procedure as described in EP 0454436A1 but using Isopropyl alcohol in place of Ethanol
EXAMPLE 9; Preparation of 4-amino-2-methyl-10H-thieno[2,3-b][1,5] benzodiazepine hydrochloride2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile (100 g) is taken in ethyl acetate (1000 ml). 5percent Pd/C (15 g) is added and hydrogenated at 50° C. for 15 hours. Ethyl acetate is distilled off to get the solid. The solid is taken in isopropyl alcohol (500 ml), concentrated hydrochloric acid (102 ml) is added at room temperature and the mixture is heated up to 80-82° C. for 12 hours under stirring. The solution is cooled to precipitate the solid, filtered and dried under vacuum at 55-60° C. to give the title compound (80 g).

  • 3
  • [ 138564-59-7 ]
  • [ 132539-06-1 ]
  • 5
  • [ 138564-59-7 ]
  • Olanzapine N-Oxide [ No CAS ]
  • 6
  • [ 100-39-0 ]
  • [ 138564-59-7 ]
  • 2-[2-nitrophenyl-(N-benzyl)amino]-5-methylthiophene-3-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
55 - 60% With potassium hydroxide;N-benzyl-N,N,N-triethylammonium chloride; In dichloromethane; water; at 25 - 30℃; for 5h; A mixture OF 2-(2-NITROANILINO)-5-METHYLTHIOPHENE-3-CARBONITRILE (100 g), dichloromethane (915 mL), benzyl bromide (69. 8 g), and benzyltriethylammonium chloride (BTEA) (1.8 g) was stirred in a 2L flask. A solution of 50percent potassium hydroxide (200 g) was added slowly at a temperature below 25°C. After the addition was complete, the mixture was stirred between 25-30°C for 5 hours. Water (300g) was added, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (200 mlX2), and the organic layers were combined, washed with water (400 mlX2), and removed under reduced pressure. Toluene (110 mL) was added to the residue, the mixture was heated, and activated carbon was added. The mixture was filtered, allowed to cool, and crystallization occurred (6 g). The crystals were filtrated, washed with ethanol, and dried at 45°C to give THE 2- [2-NITROPHENYL- (N-BENZYL) amino] -5-methylthiophene-3-carbonitrile. Yield: 55-60percent.
  • 7
  • [ 138564-59-7 ]
  • [ 873895-41-1 ]
YieldReaction ConditionsOperation in experiment
With hydrogen;5%-palladium/activated carbon; In ethyl acetate; at 50 - 55℃; 2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile (100 g) is taken in ethyl acetate (1000 ml). The reaction mixture is then hydrogenated by 5 percent Pd/C (15 g) at 50-55°C at 10-12 Kg pressure. The reaction mixture is filtered, and ethyl acetate is distilled off to get the title compound.
With hydrogen;5%-palladium/activated carbon; In ethyl acetate; at 50 - 55℃; under 7355.72 - 8826.87 Torr; EXAMPLE 3; Preparation of 2-(2-aminoanilino)-5-methylthiophene-3-carbonitrile2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile (100 g) is taken in ethyl acetate (1000 ml). The reaction mixture is then hydrogenated by 5percent Pd/C (15 g) at 50-55° C. at 10-12 Kg pressure. The reaction mixture is filtered, and ethyl acetate is distilled off to get the title compound.
With hydrogen;5% Pd(II)/C(eggshell); In ethyl acetate; at 50 - 55℃; under 7355.72 - 8826.87 Torr; Example 3; Preparation of 2-(2-aminoanilino)-5-methylthiophene-3-carbonitrile2-(2-Nitroanilino)-5-methylthiophene-3-carbonitrile (100 g) was taken in ethyl acetate (1000 ml). The reaction mixture was then hydrogenated by 5percent Pd/C (15 g) at 50-55° C. and at 10-12 Kg pressure. The reaction mixture was filtered, and ethyl acetate was distilled off to get the title compound.
In ethyl acetate; Step F 2-((2-Aminophenyl)amino)-5-methylthiophene-3-carbonitrile To a solution of <strong>[138564-59-7]5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile</strong>, prepared as described in the previous step, (43.3 g, 0.157 mol) in ethyl acetate (500 mL) was added 10percent palladium on carbon (8 g). The black mixture was stirred at room temperature overnight under an atmosphere of hydrogen gas. When LCMS showed that most of <strong>[138564-59-7]5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile</strong> was consumed completely, the mixture was filtered and the filtrate was concentrated to provide 2-((2-aminophenyl)amino)-5-methylthiophene-3-carbonitrile. 1H NMR (400 MHz, CDCl3) delta 7.29-7.21 (m, 1H), 7.11-7.10 (m, 1H), 6.86-6.79 (m, 2H), 6.48-6.47 (m, 1H), 6.42 (brs, 1H), 3.75-3.70 (br, 2H), 2.28 (s, 3H).
With palladium 10% on activated carbon; hydrogen; In ethyl acetate; at 20℃; To a solution of <strong>[138564-59-7]5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile</strong>, prepared as described in the previous step, (43.3 g, 0.157 mol) in ethylacetate (500 mL) was added 10percent palladium on carbon (8 g). The black mixture \Nasstirred at room temperature overnight under an atmosphere of hydrogen gas. WhenLCMS showed that most of <strong>[138564-59-7]5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile</strong>was consumed completely, the mixture was filtered and the filtrate was concentratedto provide 2-((2-aminophenyl)amino)-5-methylthiophene-3-carbonitrile. 1 H NMR(400MHz, CDCI3) o 7.29-7.21 (m, 1H), 7.11-7.10 (m, 1H), 6.86-6.79 (m, 2H), 6.48-6.47 (rn, 1 H), 6.42 (brs, 1 H), 3.75-3.70 (br, 2H), 2.28 (s, 3H).
With palladium 10% on activated carbon; hydrogen; In ethyl acetate; at 20℃; To a solution of <strong>[138564-59-7]5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile</strong>, prepared as described in the previous step, (43.3 g, 0.157 mol) in ethyl acetate (500 mL) was added 10percent palladium on carbon (8 g). The black mixture was stirred at room temperature overnight under an atmosphere of hydrogen gas. When LCMS showed that most of <strong>[138564-59-7]5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile</strong> was consumed completely, the mixture was filtered and the filtrate was concentrated to provide 2-((2-aminophenyl)arnino)-5-methylthiophene-3-carbonitrile. 1H NMR (400MHz, CDCI3) delta 7.29-7.21 (m, 1H), 7.11-7.10 (m. 1H}, 6.86-6.79 (m, 2H), 6.48-6.47 (m, 1H), 6.42 (brs, 1H), 3.75-3.70 (br, 1H). 2.28 (s, 3H).

  • 8
  • [ 109-01-3 ]
  • [ 138564-59-7 ]
  • [ 873895-41-1 ]
  • [ 132539-06-1 ]
  • 2-methyl-5,10-dihydro-4H-benzo[b]thieno[2,3-e][1,4]diazepin-4-one [ No CAS ]
  • 9
  • [ 109-01-3 ]
  • [ 138564-59-7 ]
  • [ 132539-06-1 ]
  • 10
  • [ 109-01-3 ]
  • [ 138564-59-7 ]
  • [ 132539-06-1 ]
  • 2-methyl-5,10-dihydro-4H-benzo[b]thieno[2,3-e][1,4]diazepin-4-one [ No CAS ]
  • 11
  • [ 138564-59-7 ]
  • [ 1428146-26-2 ]
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