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Product Details of [ 1241377-74-1 ]

CAS No. :1241377-74-1 MDL No. :MFCD21496290
Formula : C10H9BrN2 Boiling Point : -
Linear Structure Formula :- InChI Key :XTONHEFSOWWNHK-UHFFFAOYSA-N
M.W : 237.10 Pubchem ID :22097071
Synonyms :

Safety of [ 1241377-74-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P501-P261-P273-P272-P202-P201-P264-P280-P302+P352-P308+P313-P337+P313-P305+P351+P338-P362+P364-P333+P313-P405 UN#:N/A
Hazard Statements:H315-H319-H351 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1241377-74-1 ]

* 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 [ 1241377-74-1 ]

[ 1241377-74-1 ] Synthesis Path-Downstream   1~50

  • 1
  • 6-bromo-naphthalene-1,2-diamine [ No CAS ]
  • [ 15761-39-4 ]
  • [ 1309945-26-3 ]
YieldReaction ConditionsOperation in experiment
90% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 9h; 6.F To a solution of Compound Int-6e (40.5 g, 171 mmol), iY-Boc-proline (45.0 g, 209 mmol) and N N-diisopropylethylamine (90 mL, 517 mmol) in anhydrous- MF (1 L) at 0 °C was added HATU (78 g, 205 mmol). The resulting reaction was warmed to room temperature then stirred at this temperature for 9 hours. Water (1.5 L) was added to the reaction mixture and the resulting solution was extracted with MTBE (3 x 1.5 L). The combined organic extracts were washed with brine (3 1 L), dried over Na2S0 filtered and concentrated in vacuo. The residue obtained was dissolved in MeOH (75 mL) and water (1.5 L) was added. The resulting heterogeneous mixture was allowed to stir vigorously for 2 hours, then filtered. The filter cake was washed with water (1 L) and dried in vacuo at 55 °C to provide Compound Int-6f as an off-white solid (66.5 g, 90%), which was-used without further purification. 1H NMR (DMSO-i¾) δ 9.4.5-9.42 (m, 1H), 8.12- 8.09 (m, 1H), 8.00 (s, 1H), 7.52-7.47 (m, 1H), 7.36-7.33 (m, 1H-), 7.19-7:08 (m, 1), 5.58 (s, 1H), 5.45 (s, 1H), 4.35-4.21 (m, 1H), 3.45-3.31 (m, 2H), 2.33-2.13 (m, IE), 2.0-1.75 (m, 3H), 1.46-1.38 (ms 9H).
90% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 9h;
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 9h; 1.F Step F - Preparation of Compound IFIFTo a solution of compound IE (40.5 g, 171 mmol),. ;V-Boc-proiine (45.0 g, 209 mmol) and N,N-diisopropylethylamine (90 mL, 517 mmol) in anhydrous DMF (1 L) at 0 °C was added HATU (78 g, 205 mmol). The resulting mixture was wanned to room temperature then stirred at this temperature for 9 hours. Water (1.5 L) was added to the reaction mixture and the resulting aqueous solution was extracted with MTBE (3 χ 1.5 L). The combined organics were washed with brine (3 x 1 L), dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was dissolved in MeOH (75 mL) and water (1.5 L) was added. The resulting heterogeneous mixture was stirred vigorously for 2 hours and filtered. The filter cake was washed with water (1 L) and dried in vacuo at 55 °C to provide Compound IF as an off-white solid (66.5 g, 90%). 1H NMR (DMSO-^) δ 9.45-9.42 (m, 1H), 8.12-8.09 (m, 1H), 8.00 (s, 1H), 7.52-7.47 (m, 1H), 7.36-7.33 (m, 1H), 7.19-7.08 (m, 1H), 5.58 (s, 1H), 5.45 (s, 1R), 4.35-4.21- (m, 1H), 3.45-3.31 (m, 2H), 2.33-2.13 (m, 1H), 2.0-1.75 (m, 3H), 1.46-1.38 (m, 9H-).
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 9h; 17.F Step F - Syntheses of Intermediate Compound Int-17f Step F - Syntheses of Intermediate Compound Int-17f (0338) (0339) To a solution of Compound Int-17e (40.5 g, 171 mmol), N-Boc-proline (45.0 g, 209 mmol) and diisopropylethylamine (90 mL, 517 mmol) in anhydrous DMF (1 L) at 0 °C was added HATU (78 g, 205 mmol). The resulting reaction was warmed to room temperature then allowed to stir at this temperature for 9 hours. Water (1.5 L) was added to the reaction mixture and the resulting solution was extracted with MTBE (3 × 1.5 L). The combined organic extracts were washed with brine (3 × 1 L), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was dissolved in MeOH (75 mL) and water (1.5 L) was added. The resulting heterogeneous mixture was allowed to stir vigorously for 2 hours, then filtered. The filter cake was washed with water (1 L) and dried in vacuo at 55 °C to provide Compound Int-17f as an off-white solid (66.5 g, 90%), which was used without further purification. 1H NMR (DMSO-d6) δ 9.45-9.42 (m, 1H), 8.12-8.09 (m, 1H), 8.00 (s, 1H), 7.52-7.47 (m, 1H), 7.36-7.33 (m, 1H), 7.19-7.08 (m, 1H), 5.58 (s, 1H), 5.45 (s, 1H), 4.35-4.21 (m, 1H), 3.45-3.31 (m, 2H), 2.33-2.13 (m, 1H), 2.0-1.75 (m, 3H), 1.46-1.38 (m, 9H).
Stage #1: 1-(tert-butoxycarbonyl)-L-proline With chloroformic acid ethyl ester; triethylamine In dichloromethane at -10℃; for 0.166667h; Stage #2: 6-bromo-naphthalene-1,2-diamine In dichloromethane at -5 - 20℃; for 2h; 6.5 Synthesis of compound 7-6A To a solution of (S) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (9.06 g , 42.17 mmol, 1.00 eq) , ethyl carbonochloridate (4.58 g, 42.17 g, 1.00 eq) in DCM (100 mL) was added dropwise Et3N (8.8 mL, 63.26 mmol, 1.50 eq) at -10 . After the addition, the mixture was maintained at -10 for 10 min, then filtered. The filter cake was washed with DCM (10 mL ×2) , and the filtrate was collected and reserved for the later use. To a solution of compound 7-5A (10 g, 42.17 mmol, 1.00 eq) in DCM (80 mL) was added dropwise the filtrate at -5 . After the addition, the resulting mixture was stirrd at rt for 2 h. After the reaction was completed, 100 mL of water was added, then the mixture was partitioned. The aqueous layer was extracted with DCM (50 mL × 2) . The combined organic layers were dried and concentrated to give the crude product as a brown black solid (18.00 g, 95.18) . 1H NMR (400 MHz, CDCl3) : δ 7.90 (s, 1H) , 7.65 (d, J 9.0 Hz, 1H) , 7.47 (d, J 8.1 Hz, 1H) , 7.40 (d, J 8.6 Hz, 1H) , 7.16 (d, J 8.6 Hz, 1H) , 4.61 -4.34 (m, 3H) , 4.00 (d, J 5.1 Hz, 1H) , 2.43 (s, 2H) , 2.13 (dd, J 12.8, 7.1 Hz, 2H) , 1.90 -1.63 (m, 2H) , 1.54 (s, 9H) ppm MS-ESI, m/z: 434.2 [M+H]+.

  • 2
  • [ 71590-32-4 ]
  • [ 1241377-74-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: nitric acid; acetic anhydride / acetic acid / 6.5 h / 0 - 20 °C 2: hydrogenchloride; methanol / 6 h / 75 °C 3: water; iron / ammonium chloride / tetrahydrofuran / 3 h / 60 °C
Multi-step reaction with 3 steps 1: acetic anhydride; acetic acid; nitric acid / 6.5 h / 0 - 20 °C 2: hydrogenchloride; water / methanol / 6 h / 75 °C 3: ammonium chloride; iron / water; tetrahydrofuran / 3 h / 60 °C
Multi-step reaction with 3 steps 1: nitric acid / acetic acid / 6.5 h / 0 - 20 °C 2: hydrogenchloride / methanol; water / 6 h / 75 °C 3: iron; ammonium chloride / water; tetrahydrofuran / 3 h / 60 °C
Multi-step reaction with 3 steps 1: potassium nitrate; sulfuric acid / acetic acid / 7 h / 20 - 30 °C 2: hydrogenchloride / tetrahydrofuran / 7 h / 80 °C 3: sodium carbonate; sodium dithionite / 1,4-dioxane / 5 h / 0 - 20 °C
Multi-step reaction with 3 steps 1: nitric acid; acetic anhydride / acetic acid / 4.5 h / 0 - 20 °C 2: hydrogenchloride / methanol; water / 6 h / 75 °C 3: iron; ammonium chloride / tetrahydrofuran; water / 3 h / 60 °C
Multi-step reaction with 3 steps 1: nitric acid / acetic anhydride; acetic acid / 11 h / 35 - 45 °C / Industrial scale 2: ammonium chloride; water; iron / tetrahydrofuran / 6 h / 55 - 65 °C / Industrial scale 3: hydrogenchloride / methanol / 5 h / 55 - 65 °C / Industrial scale

  • 3
  • [ 1241377-74-1 ]
  • [ 1180668-98-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: pH 7
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8
  • 4
  • [ 1241377-74-1 ]
  • [ 1309945-27-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: pH 7 3.1: potassium acetate / tricyclohexylphosphine; bis(dibenzylideneacetone)-palladium(0) / 1,4-dioxane / 4 h / 100 °C
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate / bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine / 1,4-dioxane / 4 h / 100 °C
  • 5
  • [ 1241377-74-1 ]
  • [ 1315625-52-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate / bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine / 1,4-dioxane / 4 h / 100 °C 4.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 15 h / 100 °C
  • 6
  • [ 1241377-74-1 ]
  • [ 1315625-54-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate / bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine / 1,4-dioxane / 4 h / 100 °C 4.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 15 h / 100 °C 5.1: trifluoroacetic acid / dichloromethane / 1.5 h / 20 °C
  • 7
  • [ 1241377-74-1 ]
  • [ 1315624-38-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate / bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine / 1,4-dioxane / 4 h / 100 °C 4.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 15 h / 100 °C 5.1: trifluoroacetic acid / dichloromethane / 1.5 h / 20 °C 6.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 15 h / 0 - 20 °C
  • 8
  • [ 1241377-74-1 ]
  • [ 1315624-44-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate / bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine / 1,4-dioxane / 4 h / 100 °C 4.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 4 h / 100 °C / Inert atmosphere; Sealed tube
  • 9
  • [ 1241377-74-1 ]
  • [ 1315625-57-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate / bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine / 1,4-dioxane / 4 h / 100 °C 4.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 4 h / 100 °C / Inert atmosphere; Sealed tube 5.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
  • 10
  • [ 1241377-74-1 ]
  • [ 1315624-46-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate / bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine / 1,4-dioxane / 4 h / 100 °C 4.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 4 h / 100 °C / Inert atmosphere; Sealed tube 5.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 16 h / 0 - 20 °C
  • 11
  • [ 1241377-74-1 ]
  • [ 1315624-66-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate / bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine / 1,4-dioxane / 4 h / 100 °C 4.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 4 h / 100 °C / Inert atmosphere; Sealed tube 5.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 16 h / 0 - 20 °C 7.1: hydrogenchloride / water / 2 h / 90 °C
  • 12
  • [ 1241377-74-1 ]
  • [ 1241379-01-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate / bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine / 1,4-dioxane / 4 h / 100 °C 4.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 4 h / 100 °C / Inert atmosphere; Sealed tube 5.1: trifluoroacetic acid / dichloromethane / 1 h / 20 °C 6.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 16 h / 0 - 20 °C 7.1: hydrogenchloride / water / 2 h / 90 °C 8.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 16 h / 0 - 20 °C
  • 13
  • [ 1241377-74-1 ]
  • [ 1315624-53-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate / bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine / 1,4-dioxane / 4 h / 100 °C 4.1: sodium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane; water / 7 h / Inert atmosphere; Reflux
  • 14
  • [ 1241377-74-1 ]
  • [ 1315625-59-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate / bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine / 1,4-dioxane / 4 h / 100 °C 4.1: sodium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane; water / 7 h / Inert atmosphere; Reflux 5.1: trifluoroacetic acid / dichloromethane / 17 h / 20 °C
  • 15
  • [ 1241377-74-1 ]
  • [ 1315624-57-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate / bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine / 1,4-dioxane / 4 h / 100 °C 4.1: sodium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane; water / 7 h / Inert atmosphere; Reflux 5.1: trifluoroacetic acid / dichloromethane / 17 h / 20 °C 6.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0 - 20 °C
  • 16
  • [ 1241377-74-1 ]
  • [ 1315624-50-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate / bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine / 1,4-dioxane / 4 h / 100 °C 4.1: sodium carbonate / dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,4-dioxane / 7 h / Inert atmosphere; Reflux
  • 17
  • [ 1241377-74-1 ]
  • [ 1315625-62-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate; bis(pinacol)diborane / tris(dibenzylideneacetone)dipalladium(0) chloroform complex; XPhos / 1,4-dioxane / 16 h / 110 °C / sealed tube 3.2: 1 h / 100 °C
  • 18
  • [ 1241377-74-1 ]
  • [ 1315625-64-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate; bis(pinacol)diborane / tris(dibenzylideneacetone)dipalladium(0) chloroform complex; XPhos / 1,4-dioxane / 16 h / 110 °C / sealed tube 3.2: 1 h / 100 °C 4.1: hydrogenchloride / water / 2 h / 90 °C
  • 19
  • [ 1241377-74-1 ]
  • [ 1315624-49-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: 20 °C / pH 8 3.1: potassium acetate; bis(pinacol)diborane / tris(dibenzylideneacetone)dipalladium(0) chloroform complex; XPhos / 1,4-dioxane / 16 h / 110 °C / sealed tube 3.2: 1 h / 100 °C 4.1: hydrogenchloride / water / 2 h / 90 °C 5.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 3 h / 20 °C
  • 20
  • [ 5773-80-8 ]
  • [ 1241377-74-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: triethylamine; diphenylphosphoranyl azide / toluene / 4 h / 100 °C 2: nitric acid; acetic acid / 2.33 h 3: tin(II) chloride dihdyrate / methanol / 18 h / 70 °C
Multi-step reaction with 5 steps 1.1: triethylamine; diphenyl phosphoryl azide / <i>tert</i>-butyl alcohol / 15 h / Reflux 1.2: 0.5 h 1.3: 15 h / -78 - 20 °C 2.1: triethylamine / dichloromethane / 1.5 h / 0 - 20 °C 3.1: nitric acid; acetic anhydride / acetic acid / 6.5 h / 0 - 20 °C 4.1: hydrogenchloride; methanol / 6 h / 75 °C 5.1: water; iron / ammonium chloride / tetrahydrofuran / 3 h / 60 °C
Multi-step reaction with 3 steps 1: triethylamine; diphenyl phosphoryl azide / 16 h / 80 °C 2: acetic acid; nitric acid 3: tin(II) chloride dihdyrate / methanol / 16 h / Reflux
Multi-step reaction with 5 steps 1.1: triethylamine; diphenyl phosphoryl azide / <i>tert</i>-butyl alcohol / 15 h / Reflux 1.2: 15 h / -78 °C 2.1: triethylamine / dichloromethane / 1.5 h / 0 - 20 °C 3.1: acetic anhydride; acetic acid; nitric acid / 6.5 h / 0 - 20 °C 4.1: hydrogenchloride; water / methanol / 6 h / 75 °C 5.1: ammonium chloride; iron / water; tetrahydrofuran / 3 h / 60 °C
Multi-step reaction with 5 steps 1.1: diphenyl phosphoryl azide; triethylamine / <i>tert</i>-butyl alcohol / 15 h / Reflux 1.2: 15 h / 20 °C 2.1: triethylamine / dichloromethane / 1.5 h / 20 °C 3.1: nitric acid / acetic acid / 6.5 h / 0 - 20 °C 4.1: hydrogenchloride / methanol; water / 6 h / 75 °C 5.1: iron; ammonium chloride / water; tetrahydrofuran / 3 h / 60 °C
Multi-step reaction with 5 steps 1.1: diphenyl phosphoryl azide; triethylamine / <i>tert</i>-butyl alcohol / 15 h / Reflux 1.2: 15 h / -78 - 20 °C 2.1: triethylamine / dichloromethane / 1.5 h / 0 - 20 °C 3.1: nitric acid; acetic anhydride / acetic acid / 4.5 h / 0 - 20 °C 4.1: hydrogenchloride / methanol; water / 6 h / 75 °C 5.1: iron; ammonium chloride / tetrahydrofuran; water / 3 h / 60 °C

  • 22
  • [ 855930-17-5 ]
  • [ 1241377-74-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: hydrogenchloride; methanol / 6 h / 75 °C 2: water; iron / ammonium chloride / tetrahydrofuran / 3 h / 60 °C
Multi-step reaction with 2 steps 1: hydrogenchloride; water / methanol / 6 h / 75 °C 2: ammonium chloride; iron / water; tetrahydrofuran / 3 h / 60 °C
Multi-step reaction with 2 steps 1: hydrogenchloride / methanol; water / 6 h / 75 °C 2: iron; ammonium chloride / water; tetrahydrofuran / 3 h / 60 °C
Multi-step reaction with 2 steps 1: hydrogenchloride / tetrahydrofuran / 7 h / 80 °C 2: sodium carbonate; sodium dithionite / 1,4-dioxane / 5 h / 0 - 20 °C
Multi-step reaction with 2 steps 1: hydrogenchloride / methanol; water / 6 h / 75 °C 2: iron; ammonium chloride / tetrahydrofuran; water / 3 h / 60 °C

  • 23
  • [ 1309945-25-2 ]
  • [ 1241377-74-1 ]
YieldReaction ConditionsOperation in experiment
95% With iron; ammonium chloride In tetrahydrofuran; water at 60℃; for 3h; 6.E To a^olution of Compound Int-6d (47.9 g, 179 mmol) and ammonium chloride (14.4 g, 269 mmol) in water (100 mL) and THF (250 mL) was added iron powder (50 g, 895 mmol). The resulting reaction was. heated to 60 °C and allowed to stir vigorously at this temperature for 3 hours, then cooled to room temperature. The reaction mixture was filtered through a Celite pad and rinsed with MeOH until the Celite was colorless. The combined filtrate and rinsings were concentrated in vacuo and the resulting residue was purified immediately on a silica gel plug (18 cm L 14 cm W) eluting with 1%MeOH/Cl¾Cl2 (7 L) to provide Compound Int-6e as a brown solid (40.5 g^95%). 1H N R (DMSO-i¾) 5 7.85-7.79 (m, 2H), 7.32-7.29 (m, 1H), 7.03-6.96 (m, 2H), 4.86 (br s, 4H). LRMS: (M+H)+ = 238.
With water; iron In tetrahydrofuran at 60℃; for 3h; 1.E Step E - Preparation of Compound I E1ETo a solution of Compound ID (47.9 g, 179 mmol) and ammonium chloride (14.4 g, 269 mmol) in water (100 mL) and THF (250 mL) was added iron powder (50 g, 895 mmol). The resulting mixture wa&heated to 60 °C and allowed to stir vigorously at this temperature for 3. hours, then cooled to room temperature. The reaction mixture was filtered over Celite and rinsed with MeOH until the Celite was colorless. The filtrate was concentrated in vacuo and purified immediately on a silica gel plug (18 cm L χ 14 cm W) eluting with 1% MeOH/CH2Cl2 (7 L) to provide Compound-IE as a crude brown solid (40.5 g, 95%). 1H NMR (DMSO-d6) δ 7.85-7.79 (m, 2H), 7.32-7.29 (m, 1H), 7.03-6.96 (m, 2H), 4.86 (br s, 4H). LRMS: (M+H)+ = 238.
40.5 g With iron; ammonium chloride In tetrahydrofuran; water at 60℃; for 3h; 17.E Step E - Synthesis of Intermediate Compound Int-17e Step E - Synthesis of Intermediate Compound Int-17e (0336) (0337) To a solution of Compound Int-17d (47.9 g, 179 mmol) and ammonium chloride (14.4 g, 269 mmol) in water (100 mL) and THF (250 mL) was added iron powder (50 g, 895 mmol). The resulting reaction was heated to 60 °C and allowed to stir vigorously at this temperature for 3 hours, then cooled to room temperature. The reaction mixture was filtered through a Celite pad and rinsed with MeOH until the Celite was colorless. The combined filtrate and rinsings were concentrated in vacuo and the resulting residue was purified immediately on a silica gel plug (17 cm L × 14 cm W) eluting with 1% MeOH/CH2Cl2 (7 L) to provide Compound Int-17e as a brown solid (40.5 g, 95%). 1H NMR (DMSO-d6) δ 7.85-7.79 (m, 2H), 7.32-7.29 (m, 1H), 7.03-6.96 (m, 2H), 4.86 (br s, 4H). LRMS: (M+H)+ = 238
  • 24
  • [ 334769-80-1 ]
  • 6-bromo-naphthalene-1,2-diamine [ No CAS ]
  • [ 1241377-70-7 ]
YieldReaction ConditionsOperation in experiment
EEDQ (1.67 g, 6.75 mmol) was added to a solution of Example J.9g2 (1.6 g,6.75 mmol) and M.4a (1.55 g, 6.75 mmol) in DCM (100 mL) and stirred for 6h.(Note: The dianiline was not completely soluble). The reaction mixture was diluted with DCM (1 vol) and washed with half sat'd NaHC03 soln. Concentration gave a solid (2.5 g). LC/MS (Cond. J2): RT = 3.07 min. LC/MS Anal. Calcd. for[M+H]+ C2iH27BrN303: 448.13; found 448.11. The crude solid (2.5 g, 5.58 mmol) was taken up in AcOH (200 mL) and stirred for 18 h at 60 °C. Concentration under high vacuum removed the solvent. The residue was taken up in DCM, washed with sat'd aHC03 soln, and concentrated. The residue was charged (DCM) to a 80 g Thompson silica gel cartridge and gradient elution was performed from 15percent to 100percent B over 750 mL. (A/B Hex/EtOAc) to give Example J.9g (2.6 g). XH NMR (MeOD, 500 MHz, delta): 8.36-8.35 (m, 2H), 8.0 (d, J = 9Hz, 1H), 7.91 (dd, J = 9, 2 Hz, 1H), 7.87 (d, J = 9 Hz, 1H), 5.31-5.28 (m, 1H), 4.17 (br. s, 1H), 2.59-2.56 (m, 1H), 2.39-2.31 (m, 2H) 1.86-1.83 (m, 1H), 1.52-1.19 (m, 12H). LC/MS (Cond. J2): RT = 2.57 min.LC/MS Anal. Calcd. for [M+H]+ 430.12; found 430.09.
  • 25
  • [ 869114-68-1 ]
  • 6-bromo-naphthalene-1,2-diamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: nitric acid; acetic acid / 2.33 h 2: tin(II) chloride dihdyrate / methanol / 18 h / 70 °C
Multi-step reaction with 2 steps 1: acetic acid; nitric acid 2: tin(II) chloride dihdyrate / methanol / 16 h / Reflux
  • 26
  • [ 1241377-72-9 ]
  • [ 1241377-74-1 ]
YieldReaction ConditionsOperation in experiment
With tin(II) chloride dihdyrate In methanol at 70℃; for 18h; J.9g2 Tin(II)chloride dehydrate (3 g, 16.34 mmol) was added to a solution of tert- butyl 6-bromo-l-nitronaphthalen-2-ylcarbamate (2 g, 5.47 mmol) in MeOH (100 mL) and the solution was stirred for 18 h at 70 °C. The solvent was removed by rotary evaporation and Example J.9g2 (assume theoretical 1.25 g) was dried under high vacuum. LC/MS (Cond. J2): RT = 1.49 min. LC/MS Anal. Calcd. for [M+H]+ Ci0H9BrN2: 237.00; found 236.96.
With tin(II) chloride dihdyrate In methanol for 16h; Reflux; 11.3 Step 3: 6-bromonaphthalene-1 ,2-diamine Step 3: 6-bromonaphthalene-1 ,2-diamine To a cooled solution of of the product of step 2 (75 g, 0.2 mol) in methanol (400ml_), SnC ^HbO (212 g, 0.61 mol) was added. The reaction mixture was stirred at reflux for 16 h. The reaction mixture was then concentrated to dryness, diluted with water and adjusted to an alkaline pH with aqueous NaHC03 than NaOH solutions and extracted with EtOAc. The organic layer was dried (MgSC ) and concentrated to give 6- bromonaphthalene-1 ,2-diamine (35 g) which was used without further purification in the next step.
  • 27
  • [ 1241377-74-1 ]
  • [ 1309945-32-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: pH 7 3.1: potassium acetate / tricyclohexylphosphine; bis(dibenzylideneacetone)-palladium(0) / 1,4-dioxane / 4 h / 100 °C 4.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 4 h / 100 °C
  • 28
  • [ 1241377-74-1 ]
  • [ 1309945-33-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: pH 7 3.1: potassium acetate / tricyclohexylphosphine; bis(dibenzylideneacetone)-palladium(0) / 1,4-dioxane / 4 h / 100 °C 4.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 4 h / 100 °C 5.1: hydrogenchloride; water / 4 h / 90 °C
  • 29
  • [ 1241377-74-1 ]
  • [ 1309944-65-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2.1: acetic acid / 1 h / 60 °C 2.2: pH 7 3.1: potassium acetate / tricyclohexylphosphine; bis(dibenzylideneacetone)-palladium(0) / 1,4-dioxane / 4 h / 100 °C 4.1: sodium carbonate / tetrakis(triphenylphosphine) palladium(0) / 1,2-dimethoxyethane; water / 4 h / 100 °C 5.1: hydrogenchloride; water / 4 h / 90 °C 6.1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 1 h / 0 °C / Inert atmosphere
  • 30
  • 6-bromo-naphthalene-1,2-diamine [ No CAS ]
  • [ 268224-29-9 ]
  • [ 1334313-77-7 ]
YieldReaction ConditionsOperation in experiment
96% With N-ethyl-N,N-diisopropylamine; HATU; at 0℃; for 6.5h; Step 1 - Synthesis of intermediate Int-25aA solution of compound Int-25a (2.7g, 11.4 mmol), compound Int- 8f (2.2 g, 7.77 mmol), Hunig's base (2 mL, 15 mmol), and HATU (3.0 g, 7.89 mmol) was cooled to 0 C and allowed to stir at this temperature for The resulting 6.5 hours. The reaction mixture was then diluted with water (150 mL) and filtered. The collected solid was purified using a 330 g ISCO silica column on Combi-Flash Rf with elution of 0-5% methanol in dichloromethane to provide compound Int- 25b as a foam (3.55 g, 96%).
96% With N-ethyl-N,N-diisopropylamine; HATU; at 0℃; for 6.5h; Step 1 - Synthesis of intermediate Int-25a A solution of compound Int-25a (2.7g, 11.4 mmol), compound Int- 8f (2.2 g, 7.77 mmol), Hunig's base (2 mL, 15 mmol), and HATU (3.0 g, 7.89 mmol) was cooled to 0 C and allowed to stir at this temperature for The resulting 6.5 hours. The reaction mixture was then diluted with water (150 mL) and filtered. The collected solid was purified using a 330 g ISCO silica column on Combi-Flash Rf with elution of 0-5% methanol in dichloromethane to provide compound Int- 25b as a foam (3.55 g, 96%).
96% With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; at 0 - 20℃; for 6.5h; Step A - Synthesis of Intermediate Compound Int-27a (0389) A 100 mL round bottomed flask was charged with Int-17e (2.7g, 11.4 mmol), Int-25d (2.2 g, 7.77 mmol), anhydrous THF, and diisopropylethylamine (2 mL, 15 mmol), and cooled to 0 C. HATU (3.0 g, 7.89 mmol) was then added and the resulting reaction was allowed to stir at 0 C for 6.5 hours, during which time the reaction warmed to room temperature, and then the reaction mixture was diluted with water (150 mL). After filtration, the crude solid was purified using a 330 g ISCO silica column on Combi-Flash system (eluted with 0-5% methanol in dichloromethane) to provide Compound Int-27a as a foam (3.55 g, 96%).
  • 31
  • [ 364750-81-2 ]
  • 6-bromo-naphthalene-1,2-diamine [ No CAS ]
  • [ 1476720-74-7 ]
YieldReaction ConditionsOperation in experiment
1.6 g With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; (a) (2S,4S)-2-(2-Amino-6-bromo-naphthalen-1-ylcarbamoyl)-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester To a solution of 6-bromo-naphthalene-1,2-diamine (2.0 g, 8.5 mmol) in DMF (150 mL) was added <strong>[364750-81-2](2S,4S)-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester</strong> (2.14 g, 10.2 mmol), DIPEA (3.29 g, 25.5 mmol), and HATU (4.84 g, 12.7 mmol). The reaction mixture was stirred at RT overnight and extracted with EtOAc/H2O (150 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (2:1 EtOAc:petroleum ether) to provide the title intermediate (1.6 g)
1.6 g With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; To a solution of 6-bromo-naphthalene-1,2-diamine (2.0 g, 8.5 mmol) in DMF (150 mL) was added <strong>[364750-81-2](2S,4S)-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester</strong> (2.14 g, 10.2 mmol), DIPEA (3.29 g, 25.5 mmol), and HATU (4.84 g, 12.7 mmol). The reaction mixture was stirred at RT overnight and extracted with EtOAc/H2O (150 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (2:1 EtOAc:petroleum ether) to provide the title intermediate (1.6 g)
  • 32
  • [ 1241377-74-1 ]
  • [ 1476720-75-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: acetic acid / 1 h / 60 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 5 h / 20 °C / Inert atmosphere
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: acetic acid / 1 h / 60 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 5 h / 20 °C / Inert atmosphere
  • 33
  • [ 1241377-74-1 ]
  • [ 1326303-51-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: acetic acid / 1 h / 60 °C / Inert atmosphere
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: acetic acid / 1 h / 60 °C / Inert atmosphere
  • 34
  • [ 1241377-74-1 ]
  • [ 1378391-12-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: acetic acid / 1 h / 60 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 5 h / 20 °C / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine; HATU / dichloromethane / 4 h / 20 °C / Inert atmosphere 5: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 90 °C / Inert atmosphere
Multi-step reaction with 5 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: acetic acid / 1 h / 60 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 5 h / 20 °C / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 4 h / 20 °C / Inert atmosphere 5: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 90 °C / Inert atmosphere
  • 35
  • [ 1241377-74-1 ]
  • [ 1476720-76-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: acetic acid / 1 h / 60 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 5 h / 20 °C / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine; HATU / dichloromethane / 4 h / 20 °C / Inert atmosphere
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 2: acetic acid / 1 h / 60 °C / Inert atmosphere 3: trifluoroacetic acid / dichloromethane / 5 h / 20 °C / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 4 h / 20 °C / Inert atmosphere
  • 36
  • [ 64-18-6 ]
  • [ 1241377-74-1 ]
  • [ 1646193-46-5 ]
YieldReaction ConditionsOperation in experiment
30 mg at 80℃; for 3h; 11.4 Step 4: 7-bromo-3H-benzo[e]benzimidazole Step 4: 7-bromo-3H-benzo[e]benzimidazole The product of step 3 (35 g, 0.15 mol) in formic acid (350ml_) was heated to 80°C for 3 h. The reaction mixture was then concentrated to dryness, diluted with water and the yellow precipitate was filtered and washed with water and oven-dried. The filtrate was purified by column chromatography eluting with a gradient of cyclohexane/EtOAc to afford 7-bromo-3H-benzo[e]benzimidazole (30 g, 82% combined yield). LC/MS (method 1 ): Rt = 0.873 min; MS: m / z = 247 (M+).
  • 37
  • 6-bromo-naphthalene-1,2-diamine [ No CAS ]
  • [ 109523-13-9 ]
  • C24H28BrN3O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
95% Intermediate F7. Step F7a. To a solution of (25,,3aS,7a5)-l-(tert-butoxycarbonyl)octahydro-lH-indole-2- carboxylic acid (3.18 g, 11.8 mmol) and commercially available 6-bromonaphthalene-l,2- diamine (3.08 g, 13.0 mmol) in acetonitrile (100 mL) was added EDC-HC1 (2.96 g, 15.5 mmol), followed by DMAP (144 mg, 1.18 mmol). The mixture was stirred at rt overnight and concentrated to afford a dark syrup, which was purified by chromatography (silica, EtOAc-hexanes) to afford the desired compounds (a mixture of regio-isomers) as a dark brown oil (5.42 g, 94%). ESIMS m/z = 488.14, 490.14 [M+H]+. Step F7b. A solution of the compounds from step F7a in acetic acid (50 mL) was heated at 60 C for 1 hour before cooling. It was concentrated before being partitioned between H20 and EtOAc. The organic phase was washed with aqueous aHC03, brine, dried ( a2S04), and concentrated. The residue was purified by chromatography (silica, EtOAc- hexanes) to afford the desired compound as a yellow solid (5.42 g, 95%). ESIMS m/z = 470.18, 472.18 [M+H]+.
  • 38
  • 6-bromo-naphthalene-1,2-diamine [ No CAS ]
  • [ 109523-13-9 ]
  • C24H30BrN3O3 [ No CAS ]
  • C24H30BrN3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; Step F7a. To a solution of (25,,3aS,7a5)-l-(tert-butoxycarbonyl)octahydro-lH-indole-2- carboxylic acid (3.18 g, 11.8 mmol) and commercially available 6-bromonaphthalene-l,2- diamine (3.08 g, 13.0 mmol) in acetonitrile (100 mL) was added EDC-HC1 (2.96 g, 15.5 mmol), followed by DMAP (144 mg, 1.18 mmol). The mixture was stirred at rt overnight and concentrated to afford a dark syrup, which was purified by chromatography (silica, EtOAc-hexanes) to afford the desired compounds (a mixture of regio-isomers) as a dark brown oil (5.42 g, 94%). ESIMS m/z = 488.14, 490.14 [M+H]+.
  • 39
  • [ 1241377-74-1 ]
  • [ 124002-32-0 ]
  • [ 1653966-14-3 ]
YieldReaction ConditionsOperation in experiment
98% Stage #1: 6-bromo-naphthalene-1,2-diamine; (2S,3aS,6aS)-1-[(tert-butoxy)carbonyl]octahydrocyclopenta[b]pyrrole-2-carboxylic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; Stage #2: With acetic acid at 60℃; for 1h; F9.F9c; F9.F9d Step F9c. To a solution of the compound from step F9b (2.50 g, 9.79 mmol) and 6- bromonaphthalene-l,2-diamine (2.44 g, 10.3 mmol) in acetonitrile (100 mL) was added EDC-HC1 (2.44 g, 12.7 mmol) and DMAP (119 mg, 0.979 mmol). The solution was stirred at rt overnight and concentrated to afford a dark syrup, which was purified by chromatography (silica, EtOAc-hexanes) to afford the desired compounds (a mixture of regio-isomers) as a dark brown oil (4.18 g, 90%). ESIMS m/z = 474.12, 476.12 [M+H] +. Step F9d. A solution of compounds (mixture of regio-isomers) from step F9c in acetic acid (50 mL) was heated at 60 °C for 1 h before being allowed to cool down. The mixture was concentrated before being partitioned between Ι0 and EtOAc. The organic phase was separated, and washed with aqueous aHC03 (*3), brine, dried (Na2S04), and concentrated to afford a brown slurry, which was purified by chromatography (silica, EtOAc-hexanes) to afford the desired compound as a yellow foam (3.98 g, 98%). ESIMS m/z = 478.16, 480.16 [M+Na]+.
  • 40
  • [ 1241377-74-1 ]
  • [ 124002-32-0 ]
  • [ 1653967-18-0 ]
  • [ 1653966-15-4 ]
YieldReaction ConditionsOperation in experiment
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; Overall yield = 90 %; Overall yield = 4.18 g; F9.F9c Step F9c. To a solution of the compound from step F9b (2.50 g, 9.79 mmol) and 6- bromonaphthalene-l,2-diamine (2.44 g, 10.3 mmol) in acetonitrile (100 mL) was added EDC-HC1 (2.44 g, 12.7 mmol) and DMAP (119 mg, 0.979 mmol). The solution was stirred at rt overnight and concentrated to afford a dark syrup, which was purified by chromatography (silica, EtOAc-hexanes) to afford the desired compounds (a mixture of regio-isomers) as a dark brown oil (4.18 g, 90%). ESIMS m/z = 474.12, 476.12 [M+H] +.
  • 41
  • 6-bromo-naphthalene-1,2-diamine [ No CAS ]
  • [ 84348-39-0 ]
  • [ 74-88-4 ]
  • C22H26BrN3O3 [ No CAS ]
  • C22H26BrN3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: (S)-1-tert-butyl 2-methyl 4-methylenepyrrolidine-1,2-dicarboxylate With 9-bora-bicyclo[3.3.1]nonane In tetrahydrofuran at 20℃; for 5h; Stage #2: With sodium perborate monohydrate In tetrahydrofuran at 20℃; Stage #3: 6-bromo-naphthalene-1,2-diamine; methyl iodide Further stages; F19; F20 Intermediate F19. Step F19a. A solution of (S)-l-tert-butyl 2-methyl 4-methylenepyrrolidine-l,2- dicarboxylate (5.7 g, 23.6 mmol) in THF (50mL) was treated with 9-BBN (0.5 M in THF, 71 mL, 35.5 mmoL) at rt for 5 hours before H20 (50 mL) was added at 0 °C. Sodium perborate (NaB03-Fi20, 12.3 g, 80 mmol) was added and the mixture was stirred overnight at rt. It was filtered through Celite and the filtrate was partitioned (EtOAc-H20). The organics were dried ( a2S04), filtered and evaporated. The crude was purified by chromatography (silica, hexanes-ethyl acetate) to give the desired compounds as an diastereomeric mixture and as a colorless oil (4.20 g, 68%). Step F19b. A solution of the compounds from step F19a (1.45 g, 5.6 mmol) in THF (15 mL) and FLO (15 mL) was treated with LiOH (161 mg, 6.7 mmol) at rt for 4 hours before concentration. The residue was dissolved in water and acidified to pH 2 by HC1 (4 M). It was extracted with EtOAc. The organics were dried (Na2S04), filtered and evaporated to give the desired compounds as a white solid (1.30 g, 95%), which was used directly in the next step. Step F19c. A solution of the compounds from step F19b (1.30 g, 5.3 mmol) in DMF (10 mL) was treated with NaH (60 % w/w, 466 mg, 11.7 mmol) at 0 °C for 30 minutes before Mel (0.36 mL, 5.83 mmol) was added. It was stirred 1.5 hours at rt before being quenched with ice-water and extraction with MTBE. The aqueous was acidified to pH 2 by HC1 (4 M) and extracted with EtOAc. The extracts were dried (Na2S04), filtered and evaporated to give the desired compounds as an orange syrup (0.94 g, 68%), which is a mixture of inseparable diastereomers. Step F19c. The desired compound was prepared and separated as a major product (more polar) from the compounds of step F19c and 6-bromo-naphthalene-l,2-diamine following the procedures similar to that described in Intermediate F7. ESIMS m/z = 460.17, 462.17 [M+H]+. Intermediate F20. The desired compound was prepared and separated as a minor product (less polar) in step F19c. ESIMS m/z = 460.13, 462.13 [M+H]+.
  • 42
  • [ 1241377-74-1 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; Overall yield = 81 %; Overall yield = 0.3 g; F21.F21d Step F21d. A solution of the compound from step F21c (0.20 g, 0.78 mmol) and 6- bromonaphthalene-l,2-diamine (0.19 g, 0.81 mmol) in acetonitrile (8 mL) was treated with EDC.HC1 (0.19 g, 1.0 mmol) and DMAP (9.4 mg, 0.08 mmol) at rt overnight. It was concentrated to afford a dark syrup, which was purified by chromatography (silica, EtOAc-hexanes) to afford the desired compounds (mixture of regio-isomers and diastereomers) as a dark brown oil (0.30 g, 81%). ESIMS m/z = 498.34, 500.34 [M+Na] +.
  • 43
  • [ 1241377-74-1 ]
  • [ CAS Unavailable ]
  • [ 1653966-31-4 ]
YieldReaction ConditionsOperation in experiment
71% Stage #1: 6-bromo-naphthalene-1,2-diamine; C13H23NO4 With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; Stage #2: With acetic acid at 60℃; for 1h; F21.F21d; F21.F21e Step F21d. A solution of the compound from step F21c (0.20 g, 0.78 mmol) and 6- bromonaphthalene-l,2-diamine (0.19 g, 0.81 mmol) in acetonitrile (8 mL) was treated with EDC.HC1 (0.19 g, 1.0 mmol) and DMAP (9.4 mg, 0.08 mmol) at rt overnight. It was concentrated to afford a dark syrup, which was purified by chromatography (silica, EtOAc-hexanes) to afford the desired compounds (mixture of regio-isomers and diastereomers) as a dark brown oil (0.30 g, 81%). ESIMS m/z = 498.34, 500.34 [M+Na] +. Step F21e. A solution of the compounds from step F21d (0.29 g, 0.61 mmol) in acetic acid (4 mL) was heated at 60 °C for 1 hour. It was concentrated and the residue was partitioned between H20 and EtOAc. The organic phase was separated, washed with aqueous aHC03 and brine, and dried (Na2S04). It was concentrated to afford a brown slurry, which was purified by chromatography (silica, EtOAc-hexanes) to afford the desired compound as a major isomer (yellow solid, 0.20 g, 71%). ESIMS m/z = 458.38, 460.38 [M+H]+.
  • 44
  • [ 1241377-74-1 ]
  • [ 15761-39-4 ]
  • [ 1309945-26-3 ]
  • [ 1653966-19-8 ]
YieldReaction ConditionsOperation in experiment
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 3h; Overall yield = 95 %; Overall yield = 0.74 g; F13.F13a Step F13a. Into a solution of N-Boc-L-Proline (0.386 g, 1.79 mmol) and 6-bromo- naphthalene- 1,2-diamine (0.425 g, 1.79 mmol) in acetonitrile (18 mL) was added EDC-HCl (0.447 g, 2.33 mmol) and DMAP (21.9 mg, 0.179 mmol). It was stirred at rt for 3 hours and concentrated to afford a dark syrup, which was purified by chromatography (silica, EtOAc-hexanes) to afford the desired compounds (a mixture of regio-isomers) as a dark brown oil (0.74 g, 95%). ESIMS m/z = 434.07.14, 436.07 [M+H]+.
  • 45
  • [ 1241377-74-1 ]
  • [ 15761-39-4 ]
  • [ 1180668-98-7 ]
YieldReaction ConditionsOperation in experiment
100% Stage #1: 6-bromo-naphthalene-1,2-diamine; 1-(tert-butoxycarbonyl)-L-proline With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 3h; Stage #2: With acetic acid at 60℃; for 2h; F13.F13a; F13.F13b Step F13a. Into a solution of N-Boc-L-Proline (0.386 g, 1.79 mmol) and 6-bromo- naphthalene- 1,2-diamine (0.425 g, 1.79 mmol) in acetonitrile (18 mL) was added EDC-HCl (0.447 g, 2.33 mmol) and DMAP (21.9 mg, 0.179 mmol). It was stirred at rt for 3 hours and concentrated to afford a dark syrup, which was purified by chromatography (silica, EtOAc-hexanes) to afford the desired compounds (a mixture of regio-isomers) as a dark brown oil (0.74 g, 95%). ESIMS m/z = 434.07.14, 436.07 [M+H]+. Step F13b. A solution of the compounds (a mixture of regio-isomers) from step F 13a in acetic acid (8 mL) was heated at 60 °C for 2 hours before being cooled. It was concentrated before partition between H2O, EtOAc and DCM. The organic phase was washed with aqueous aHC03 (*2), brine, dried (Na2S04), and concentrated. The residue was purified by chromatography (silica, EtOAc-hexanes) to afford the desired compound as a yellow solid (0.71 g, 100%). ESIMS m/z = 438.14, 440.14 [M+Na] +.
  • 46
  • [ 1241377-74-1 ]
  • [ 1180668-98-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2: acetic acid / 1 h / 60 °C
Multi-step reaction with 2 steps 1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 9 h / 20 °C 2: acetic acid / 1 h / 60 °C
Multi-step reaction with 2 steps 1.1: triethylamine; chloroformic acid ethyl ester / dichloromethane / 0.17 h / -10 °C 1.2: 2 h / -5 - 20 °C 2.1: acetic acid / 5 h / 50 °C
  • 47
  • [ 1241377-74-1 ]
  • [ 1309945-27-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 9 h / 0 - 20 °C 2: acetic acid / 1 h / 60 °C 3: potassium acetate; bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine / 1,4-dioxane / 4 h / 100 °C
Multi-step reaction with 3 steps 1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 9 h / 20 °C 2: acetic acid / 1 h / 60 °C 3: bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine; potassium acetate / 1,4-dioxane / 4 h / 100 °C
  • 48
  • [ 131707-40-9 ]
  • [ 1241377-74-1 ]
YieldReaction ConditionsOperation in experiment
95% With iron; ammonium chloride In tetrahydrofuran; water at 60℃; for 3h;
91.01% With sodium dithionite; sodium carbonate In 1,4-dioxane at 0 - 20℃; for 5h; 6.4 Synthesis of compound 7-5A To a solution of compound 7-4A (4.00 g, 14.97 mmol, 1.00 eq) in 1, 4-dioxane (30 mL) were added dropwise Na2S2O4(8.68 g, 44.93mmol, 3.00 eq) and Na2CO3(1.58g, 14.97 mmol, 1.00 eq) under ice-bath condition. After the addition, the mixture was stirred at rt for 5 h. After the reaction was completed, the reaction mixture was poured into 30 mL of water, then there was a cinerous solid precipitated. The resulting mixture was filterd. The filter cake was washed with water (15 mL × 3) and dried to give the product as a cinerous solid (3.2 g, 91.01) . 1H NMR (400 MHz, CDCl3) : δ 7.89 (d, J 1.4 Hz, 1H) , 7.60 (d, J 9.0 Hz, 1H) , 7.49 (dd, J 9.0, 1.7 Hz, 1H) , 7.22 (d, J 8.5 Hz, 1H) , 7.05 (d, J 8.5 Hz, 1H) , 3.70 (d, J 18.9 Hz, 4H) ppm MS-ESI, m/z: 237.2 [M+H]+.
  • 50
  • [ 721929-18-6 ]
  • [ 1241377-74-1 ]
YieldReaction ConditionsOperation in experiment
85.2% With hydrogenchloride In methanol at 55 - 65℃; for 5h; Industrial scale; 4 Example 4: Add 500 kg of methanol to the oil obtained in the previous step, add 36 kg of concentrated hydrochloric acid dropwise, warm the reaction kettle to 55-65°C, and vigorously stir the reaction for 5 h. After the reaction is completed under HPLC control, it is concentrated under reduced pressure to half the original volume. Then, add 300kg of toluene to the reactor, continue to concentrate, azeotropically take away a large amount of methanol and toluene, continue to concentrate to half, then add 300kg of toluene, continue to concentrate to half of the original volume, a large amount of solids precipitate, and then cool to 15-25 It was kept at temperature for 2h, and then filtered to obtain 36.5 kg of off-white solid as compound 8: 6-bromonaphthalene-1,2-diamine, purity 99.3%, yield 85.2%.
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