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Product Details of [ 125328-80-5 ]

CAS No. :125328-80-5 MDL No. :MFCD08059123
Formula : C9H9BrClNO Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 262.53 Pubchem ID :-
Synonyms :

Safety of [ 125328-80-5 ]

Signal Word:Warning Class:
Precautionary Statements:P280-P305+P351+P338 UN#:
Hazard Statements:H302 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 125328-80-5 ]

* 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 [ 125328-80-5 ]

[ 125328-80-5 ] Synthesis Path-Downstream   1~53

  • 1
  • [ 7463-35-6 ]
  • [ 125328-80-5 ]
YieldReaction ConditionsOperation in experiment
96% With bromine; acetic acid for 2h;
96% With bromine In acetic acid at 15℃; for 2h; 4.4B To a suspension of acetamide 4A (2.00 g, 10.9 mmol) in 15 mL of glacialAcOH cooled to approximately15 C was added bromine (1.67mL, 32.7 mmol) over 20 min. The ice bath was removed and the solution was stirred for 2 h, poured into ice water with stirring, and the solid was then filtered and dried to give 2.75 g (96%) of the desiredbromide. 1H NMR (DMSO-d6) 8 2.05 (s, 3H), 2.28 (s, 3H), 7.29 (d,J= 8.3,1H), 7.56 (d,J= 8.8,1H), 9.60 (s,1H) ; 13C NMR(DMSO-d6) # 16.7, 23.1, 118.1, 125.5, 130.4, 132.7, 133.4, 137.1, 168.4 ; HPLC a) column: PhenominexODS C18 4.6 x 50 mm, 4 min gradient,, 10% MeOH/90%H20/0.1% TFA to90% MeOH/10% H2O/0. 1% TFA,1 min hold, 4mL/min, UV detection at 220nm, 2.95 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6 x 50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4mL/min, UV detection at 220 nm, 2.87 min retention time (98%); MS (ES)mAz 263 [M+H] +.
96% With bromine; acetic acid at 0 - 15℃; for 2.33333h; 1B To a suspension of acetamide 1A (2.00 g, 10.9 mmol) in 15 mL of glacial AcOH cooled to approximately 15° C. was added bromine (1.67 mL, 32.7 mmol) over 20 min. The ice bath was removed and the solution was stirred for 2 h, poured into ice water with stirring, and the solid was then filtered and dried to give 2.75 g (96%) of the desired bromide. 1H NMR (DMSO-d6) δ 2.05 (s, 3H), 2.28 (s, 3H), 7.29 (d, J=8.3, 1H), 7.56 (d, J=8.8, 1H), 9.60 (s, 1H); 13C NMR (DMSO-d6) δ 16.7, 23.1, 118.1, 125.5, 130.4, 132.7, 133.4, 137.1, 168.4; HPLC a) column: Phenominex ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.95 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.87 min retention time (98%); MS (ES) m/z 263 [M+H]+.
96% With bromine; acetic acid at 15℃; for 2.33h; 1.B 1B. 4-Bromo-3-chloro-2-methylphenylacetamide; To a suspension of acetamide 1A (2.0 g, 10.9 mmol) in 15 mL of glacial AcOH cooled to approximately 15° C. was added bromine (1.67 mL, 32.7 mmol) over 20 min. The ice bath was removed and the solution was stirred for 2 h, poured into ice water with stirring, and the solid was then filtered and dried to give 2.75 g (96%) of the desired bromide. 1H NMR (DMSO-d6) δ 2.05 (s, 3H), 2.28 (s, 3H), 7.29 (d, J=8.3, 1H), 7.56 (d, J=8.8, 1H), 9.60 (s, 1H); 13C NMR (DMSO-d6) δ 16.7, 23.1, 118.1, 125.5, 130.4, 132.7, 133.4, 137.1, 168.4; HPLC a) column: Phenominex ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.95 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.87 min retention time (98%); MS (ES) m/z 263 [M+H]+.
93.6% With bromine; acetic acid at 0℃; for 17.5h; 24 N-(4-Bromo-3-chloro-2-methyl-phenyl)-acetamideDissolve N-(3-chloro-2-methyl-phenyl)-acetamide (120.0 g, 0.653 mol) in acetic acid and cool to 0 °C. Add bromine (313.3 g, 1.96 mol) dropwise over 30 min via an addition funnel. Stir for 17 h while allowing the reaction to warm to room temperature. Pour the reaction into IL of ice, and filter. Rinse the filter cake with 4L of water. The title product is isolated in 93.6% yield (160.6 g) as a white solid. MS: MS (ESI-): 262 (M-I)". MS (ESI+): 263 (M+l)+.
90% With bromine In acetic acid at 0 - 20℃; for 24h; b b) N-(4-bromo-3-chloro-2-methylphenyl)acetamide b) N-(4-bromo-3-chloro-2-methylphenyl)acetamideTo a suspension of N-(3-chloro-2-methylphenyl)acetamide (35 g, 0.19 mol) in 350 mL of glacial AcOH cooled to 0 °C was added bromine (29.5 mL, 0.57 mol) dropwise. The ice bath was removed and the solution was stirred for 24 h and then poured into ice water with stirring. The solid was then filtered and dried to give the title compound (45 g, 90%) which was used for the next step without any further purification.1H NMR (400 MHz, DMSO-d6): δ 9.60 (bs, 1 H), 7.58 (d, J = 8.8 Hz, 1 H), 7.30 (d, J = 8.7 Hz, 1 H), 2.29 (s, 3H), 2.06 (s, 3H); MS (ES): m/z 261 .9 (M + 1 ).
90% With bromine; acetic acid at 0 - 20℃; for 24h; A1.b b) N-(4-bromo-3-chloro-2-methylphenyl)acetamide To a suspension of N-(3-chloro-2-methylphenyl)acetamide (35 g, 0.19 mol) in 350 mL of glacial AcOH cooled to 0°C. was added bromine (29.5 mL, 0.57 mol) dropwise. The ice bath was removed and the solution was stirred for 24 h and then poured into ice water with stirring. The solid was then filtered and dried to give the title compound (45 g, 90%) which was used for the next step without any further purification. 1H NMR (400 MHz, DMSO-d6): δ 9.60 (bs, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.30 (d, J=8.7 Hz, 1H), 2.29 (s, 3H), 2.06 (s, 3H); MS (ES): m/z 261.9 (M+1).
77.4% With bromine; acetic acid at -5 - 0℃; for 4h; 1.2; 2.4 The second step is to dissolve 14 grams of bromine in 42 grams of glacial acetic acid and drop it into another three-necked flask (containing 3-chloro-2-methylacetanilide) at a rate of one drop per minute. Acetic acid solution), use an ice water bath to control the temperature in the three-necked flask between -5 0 , after 4 hours, the addition is complete, followed by TLC, after the reaction is completed, pour into 1000ml of ice water, stir,There is light yellow flocculent precipitation, filtering, drying,Recrystallization gave 23 g of white powdery solid. (The comprehensive yield of the first and second steps is 77.4%)
70% With bromine; acetic acid at 0 - 20℃; for 4h;
With bromine; nitrobenzene
With bromine
With bromine In acetic acid at 15 - 20℃; for 2.5h; Step B: N-(4-bromo-3 -chloro-2-methylphenyl)acetamide Step B: N-(4-bromo-3 -chloro-2-methylphenyl)acetamideTo a solution of N-(3-chloro-2-methylphenyl)acetamide (13.00 g, 70.8 mmol) in AcOH (100 mL) was added Br2 (10.9 mL, 0.212 mol) at 15 °C dropwise over 30 mm. The solution was thenstirred at room temperature for 2 h. The mixture was poured into ice water and stirred, filtered and dried to afford the title compound. LC/MS [M+1] =262; 264. ‘H NIVIR (400 MHz, MeOD) 7.54-7.52 (d, J 8.8 Hz, 1H), 7.22-7.19 (d, J 8.4 Hz, 1H), 2.35 (s, 3H), 2.16 (s, 3H).
With bromine; acetic acid for 14h; 20 A solution of N-(4-bromo-3-chloro-2-methyl-phenyl)-acetamide (10.00 g, 54.50 mmol) and Br2 (2.80 mL, 54.40 mmol) in HOAc was stirred for 14 hours. The resulting solution was then quenched in H2O and the precipitate was filtered. The precipitate was purified by column chromatography using hex:EtOAc (1:1) as the eluant to afford the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3.) δ 2.19 (s, 3H), 2.35 (s, 3H), 7.06 (br s, 1H), 7.43-7.55 (m, 2H).

Reference: [1]Li, James J.; Sutton, James C.; Nirschl, Alexandra; Zou, Yan; Wang, Haixia; Sun, Chongqing; Pi, Zulan; Johnson, Rebecca; Krystek Jr., Stanley R.; Seethala, Ramakrishna; Golla, Rajasree; Sleph, Paul G.; Beehler, Blake C.; Grover, Gary J.; Fura, Aberra; Vyas, Viral P.; Li, Cindy Y.; Gougoutas, Jack Z.; Galella, Michael A.; Zahler, Robert; Ostrowski, Jacek; Hamann, Lawrence G. [Journal of Medicinal Chemistry, 2007, vol. 50, # 13, p. 3015 - 3025]
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2005/49580, 2005, A1 Location in patent: Page/Page column 43
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2005/197367, 2005, A1 Location in patent: Page/Page column 17
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2007/4717, 2007, A1 Location in patent: Page/Page column 16-17
[5]Current Patent Assignee: ELI LILLY & CO - WO2006/124447, 2006, A2 Location in patent: Page/Page column 64
[6]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2013/14627, 2013, A1 Location in patent: Page/Page column 45; 46
[7]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2014/329876, 2014, A1 Location in patent: Paragraph 0429; 0432; 0433
[8]Current Patent Assignee: HUNAN HENGTAI BIOPHARMACEUTICAL - CN110683981, 2020, A Location in patent: Paragraph 0018; 0020
[9]Boettcher, Stephan; Hederos, Markus; Champion, Elise; Dekany, Gyula; Thiem, Joachim [Organic Letters, 2013, vol. 15, # 14, p. 3766 - 3769]
[10]Current Patent Assignee: BASF - DE217896, 1800, C [Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 10, p. 135][Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 10, p. 135]
[11]Hamann, Lawrence G.; Manfredi, Mark C.; Sun, Chongqing; Krystek Jr., Stanley R.; Huang, Yanting; Bi, Yingzhi; Augeri, David J.; Wang, Tammy; Zou, Yan; Betebenner, David. A.; Fura, Aberra; Seethala, Ramakrishna; Golla, Rajasree; Kuhns, Joyce E.; Lupisella, John A.; Darienzo, Celia J.; Custer, Laura L.; Price, Jennifer L.; Johnson, James M.; Biller, Scott A.; Zahler, Robert; Ostrowski, Jacek [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 7, p. 1860 - 1864]
[12]Current Patent Assignee: MERCK & CO INC - WO2016/8064, 2016, A1 Location in patent: Page/Page column 56
[13]Current Patent Assignee: ABBVIE INC - US2008/194650, 2008, A1 Location in patent: Page/Page column 24-25
  • 2
  • [ 125328-80-5 ]
  • [ 544-92-3 ]
  • [ 627531-48-0 ]
YieldReaction ConditionsOperation in experiment
67% In DMF (N,N-dimethyl-formamide) at 150℃; for 4h; 1C A suspension of bromide 1B (2.70 g, 10.3 mmol) and copper cyanide (0.92 g, 10.3 mmol) in DMF (30 mL) was heated to 150° C. for 4 h. The suspension was cooled, poured into water with stirring, and the solid was filtered and dried to give 1.44 g (67%) of the desired nitrile. 1H NMR (DMSO-d6) δ 2.12 (s, 3H), 2.29 (s, 3H), 7.72 (d, J=8.8, 1H), 7.75 (d, J=8.2, 1H), 9.73 (s, 1H); 13C NMR (DMSO-d6) δ 15.3, 23.5, 107.7, 116.5, 123.0, 130.1, 131.5, 135.7, 142.3, 168.8; HPLC a) column: Phenominex ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.23 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C1 8 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.13 min retention time (95%); MS (ES) m/z 209 [M+H]+.
67% In N,N-dimethyl-formamide at 150℃; for 4h; 1.C 1C. 3-Chloro-4-cyano-2-methylphenylacetamide; A suspension of bromide 1B (2.7 g, 10.3 mmol) and copper cyanide (0.92 g, 10.3 mmol) in DMF (30 mL) was heated to 150° C. for 4 h. The suspension was cooled, poured into water with stirring, and the solid was filtered and dried to give 1.44 g (67%) of the desired nitrile. 1H NMR (DMSO-d6) δ 2.12 (s, 3H), 2.29 (s, 3H), 7.72 (d, J=8.8, 11H), 7.75 (d, J=8.2, 11H), 9.73 (s, 1H); 13C NMR (DMSO-d6) δ 15.3, 23.5, 107.7, 116.5, 123.0, 130.1, 131.5, 135.7, 142.3, 168.8; HPLC a) column: Phenominex ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.23 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.13 min retention time (95%); MS (ES) m/z 209 [M+H]+.
In N,N-dimethyl-formamide
  • 3
  • [ 125328-80-5 ]
  • copper(l) cyanide [ No CAS ]
  • [ 627531-48-0 ]
YieldReaction ConditionsOperation in experiment
70% In N,N-dimethyl-formamide at 150℃; for 24h; c c) N-(3-chloro-4-cyano-2-methylphenyl)acetamide c) N-(3-chloro-4-cyano-2-methylphenyl)acetamide A suspension of N-(4-bromo-3-chloro-2-methylphenyl)acetamide (45 g, 0.17 mol) and copper cyanide (34 g, 0.34 mol) in DMF (450 mL) was heated to 150 °C for 24 h. The suspension was cooled, poured into water with stirring. The solid was filtered and dried to give 25 g (70%) of the title compound which was used for the next step without further purification.1H NMR (400 MHz, DMSO-d6): δ 9.73 (bs, 1 H), 7.78 - 7.73 (m, 2H), 2.31 (s, 3H), 2.13 (s, 3H); IR (KBr): 3307, 3097, 3014, 2235, 1930, 1674, 1514 cm"1; MS (ES): m/z 207 (M - 1 ).
70% In N,N-dimethyl-formamide at 150℃; for 24h; A1.c c) N-(3-chloro-4-cyano-2-methylphenyl)acetamide A suspension of N-(4-bromo-3-chloro-2-methylphenyl)acetamide (45 g, 0.17 mol) and copper cyanide (34 g, 0.34 mol) in DMF (450 mL) was heated to 150°C. for 24 h. The suspension was cooled, poured into water with stirring. The solid was filtered and dried to give 25 g (70%) of the title compound which was used for the next step without further purification.1H NMR (400 MHz, DMSO-d6): δ 9.73 (bs, 1H), 7.78-7.73 (m, 2H), 2.31 (s, 3H), 2.13 (s, 3H); IR (KBr): 3307, 3097, 3014, 2235, 1930, 1674, 1514 cm-1; MS (ES): m/z 207 (M-1).
67% In N,N-dimethyl-formamide at 150℃; for 4h;
67% In DMF (N,N-dimethyl-formamide) at 150℃; for 4h; 4.4C A suspension of bromide 4B (2.70 g, 10.3 mmol) and copper cyanide (0.92 g, 10.3 mmol) in DMF (30 mL) was heated to150 C for 4 h. The suspension was cooled, poured into water with stirring, and the solid was filtered and dried to give 1.44g (67%) of the desirednitrile.'H NMR (DMSO-d6)8 2.12(s, 3H), 2.29 (s, 3H), 7.72 (d,J= 8.8, 1H), 7.75 (d,J= 8.2, 1H), 9.73 (s, 1H); 13C NMR (DMSO-d6)# 15. 3, 23.5, 107.7, 116.5, 123.0, 130.1, 131.5, 135.7, 142.3, 168.8 ; HPLC a) column: Phenominex ODS C18 4.6 x 50 mm, 4 min gradient, 10%MeOH/90%H20/0. 1% TFA to90% MeOH/10%H2O/0. 1% TFA, 1 min hold, 4mL/min, UV detection at 220 nm, 2.23 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6 x 50 mm, 4 min gradient, 10% MeOH/90% H2O/0. 1% TFA to 90% MeOH/10%H20/0-1 % TFA,1 min hold, 4 mL/min, UV detection at 220 nm, 2.13 min retention time (95%); MS (ES)m/z 209 [M+H] +.

  • 6
  • [ 125328-80-5 ]
  • [ 864361-79-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: 67 percent / dimethylformamide / 4 h / 150 °C 2.1: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3.1: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4.1: NaH / dioxane / 0.5 h / 20 °C 4.2: 82 percent / CuI / dioxane / 72 h / 100 °C
  • 7
  • [ 125328-80-5 ]
  • [ 864361-80-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: 67 percent / dimethylformamide / 4 h / 150 °C 2.1: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3.1: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4.1: NaH / dioxane / 0.5 h / 20 °C 4.2: 82 percent / CuI / dioxane / 72 h / 100 °C 5.1: aq. NaOH / methanol / 5 h / 20 °C 5.2: 93 percent / conc. HCl / ethyl acetate / 24 h / 60 °C
  • 8
  • [ 125328-80-5 ]
  • [ 864661-63-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: 21 percent / K3PO4 / CuI; 1,2-cyclohexyldiamine / dioxane / 14 h / 110 °C
  • 9
  • [ 125328-80-5 ]
  • [ 864661-53-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: 21 percent / K3PO4 / CuI; 1,2-cyclohexyldiamine / dioxane / 14 h / 110 °C 5: 88 percent / KOH / tetrahydrofuran; methanol / 3 h / 0 °C
  • 10
  • [ 125328-80-5 ]
  • [ 945469-30-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: 21 percent / Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C
  • 11
  • [ 125328-80-5 ]
  • C21H34ClN3OSi [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: 21 percent / Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C
  • 12
  • [ 125328-80-5 ]
  • [ 945469-31-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: 21 percent / Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C 6: 130 mg / i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C
  • 13
  • [ 125328-80-5 ]
  • [ 757247-59-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: 21 percent / Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C 6: 130 mg / i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C 7: 68 percent / Bu4NF / tetrahydrofuran / 1 h / 20 °C
  • 14
  • [ 125328-80-5 ]
  • [ 757247-76-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C
  • 15
  • [ 125328-80-5 ]
  • [ 757247-77-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C
  • 16
  • [ 125328-80-5 ]
  • [ 757247-78-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C 6: i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C
  • 17
  • [ 125328-80-5 ]
  • [ 757247-34-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C 6: i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C 7: Bu4NF / tetrahydrofuran / 1 h / 20 °C
  • 18
  • [ 125328-80-5 ]
  • [ 757248-19-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C
  • 19
  • [ 125328-80-5 ]
  • [ 757248-20-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C
  • 20
  • [ 125328-80-5 ]
  • [ 757248-21-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C 6: i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C
  • 21
  • [ 125328-80-5 ]
  • 2-chloro-4-((1R,7S,7aR)-7-hydroxy-1-methyl-3-oxo-tetrahydro-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)-3-methylbenzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C 6: i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C 7: Bu4NF / tetrahydrofuran / 1 h / 20 °C
  • 22
  • [ 125328-80-5 ]
  • [ 945469-37-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C
  • 23
  • [ 125328-80-5 ]
  • C21H34ClN3OSi [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C
  • 24
  • [ 125328-80-5 ]
  • [ 945469-41-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C 6: i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C
  • 25
  • [ 125328-80-5 ]
  • [ 757247-60-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C 6: i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C 7: Bu4NF / tetrahydrofuran / 1 h / 20 °C
  • 26
  • [ 125328-80-5 ]
  • [ 757248-23-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: 21 percent / Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C 6: 130 mg / i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C 7: 68 percent / Bu4NF / tetrahydrofuran / 1 h / 20 °C 8: 94 percent / PPh3; diisopropyl azodicarboxylate / tetrahydrofuran / 2 h / 20 °C
  • 27
  • [ 125328-80-5 ]
  • 2-chloro-4-((1S,7R,7aR)-1-ethyl-7-hydroxy-3-oxo-tetrahydro-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)-3-methylbenzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: 21 percent / Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C 6: 130 mg / i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C 7: 68 percent / Bu4NF / tetrahydrofuran / 1 h / 20 °C 8: 94 percent / PPh3; diisopropyl azodicarboxylate / tetrahydrofuran / 2 h / 20 °C 9: 88 percent / KOH / tetrahydrofuran; methanol / 2 h / 20 °C
  • 28
  • [ 125328-80-5 ]
  • C22H20ClN3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C 6: i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C 7: Bu4NF / tetrahydrofuran / 1 h / 20 °C 8: PPh3; diisopropyl azodicarboxylate / tetrahydrofuran / 2 h / 20 °C
  • 29
  • [ 125328-80-5 ]
  • 2-chloro-4-((1S,7R,7aR)-7-hydroxy-1-methyl-3-oxo-tetrahydro-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)-3-methylbenzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C 6: i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C 7: Bu4NF / tetrahydrofuran / 1 h / 20 °C 8: PPh3; diisopropyl azodicarboxylate / tetrahydrofuran / 2 h / 20 °C 9: KOH / tetrahydrofuran; methanol / 2 h / 20 °C
  • 30
  • [ 125328-80-5 ]
  • C23H22ClN3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C 6: i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C 7: Bu4NF / tetrahydrofuran / 1 h / 20 °C 8: PPh3; diisopropyl azodicarboxylate / tetrahydrofuran / 2 h / 20 °C
  • 31
  • [ 125328-80-5 ]
  • 2-chloro-4-((1R,7R,7aR)-1-ethyl-7-hydroxy-3-oxo-tetrahydro-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)-3-methylbenzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 9 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C 4: Cs2CO3 / Pd2(dba)3; chiral ferrocenyl catalyst / toluene; dimethylsulfoxide / 48 h / 100 °C 5: TFA / CH2Cl2 / 3 h / 20 °C 6: i-Pr2NEt / tetrahydrofuran; toluene / 1.17 h / 0 - 20 °C 7: Bu4NF / tetrahydrofuran / 1 h / 20 °C 8: PPh3; diisopropyl azodicarboxylate / tetrahydrofuran / 2 h / 20 °C 9: KOH / tetrahydrofuran; methanol / 2 h / 20 °C
  • 32
  • [ 125328-80-5 ]
  • [ 757247-81-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 85 percent / Na2CO3 / CH2Cl2; toluene / 130 h / 0 - 20 °C 4: 93 percent / i-Pr2NEt / CH2Cl2 / -78 - 20 °C
  • 33
  • [ 125328-80-5 ]
  • [ 757247-82-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 85 percent / Na2CO3 / CH2Cl2; toluene / 130 h / 0 - 20 °C 4: 93 percent / i-Pr2NEt / CH2Cl2 / -78 - 20 °C 5: 69 percent / t-BuOK; p-toluenesulfonyl chloride / tetrahydrofuran / 5.5 h / 20 - 60 °C
  • 34
  • [ 125328-80-5 ]
  • 2-chloro-4-((1S,7R,7aR)-7-hydroxy-3-oxo-1-(trifluoromethyl)-tetrahydro-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)-3-methylbenzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 85 percent / Na2CO3 / CH2Cl2; toluene / 130 h / 0 - 20 °C 4: 93 percent / i-Pr2NEt / CH2Cl2 / -78 - 20 °C 5: 69 percent / t-BuOK; p-toluenesulfonyl chloride / tetrahydrofuran / 5.5 h / 20 - 60 °C 6: 86 percent / Bu4NF / tetrahydrofuran / 2 h / 20 °C
  • 35
  • [ 125328-80-5 ]
  • (2R,3S)-3-(tert-butyldimethylsilanyloxy)-2-[(1S)-(2,2,2-trifluoro-1-hydroxyethyl)]-pyrrolidine-1-carboxylic acid (3-chloro-4-cyano-2-methyl-phenyl)-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 85 percent / Na2CO3 / CH2Cl2; toluene / 130 h / 0 - 20 °C 4: i-Pr2NEt / CH2Cl2 / -78 - 20 °C
  • 36
  • [ 125328-80-5 ]
  • C21H27F3ClN3O2Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 85 percent / Na2CO3 / CH2Cl2; toluene / 130 h / 0 - 20 °C 4: i-Pr2NEt / CH2Cl2 / -78 - 20 °C 5: t-BuOK; p-toluenesulfonyl chloride / tetrahydrofuran / 5.5 h / 20 - 60 °C
  • 37
  • [ 125328-80-5 ]
  • 2-chloro-4-((1R,7S,7aR)-7-hydroxy-3-oxo-1-(trifluoromethyl)-tetrahydro-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)-3-methylbenzonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 85 percent / Na2CO3 / CH2Cl2; toluene / 130 h / 0 - 20 °C 4: i-Pr2NEt / CH2Cl2 / -78 - 20 °C 5: t-BuOK; p-toluenesulfonyl chloride / tetrahydrofuran / 5.5 h / 20 - 60 °C 6: Bu4NF / tetrahydrofuran / 2 h / 20 °C
  • 38
  • [ 125328-80-5 ]
  • [ 757248-02-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 85 percent / Na2CO3 / CH2Cl2; toluene / 130 h / 0 - 20 °C 4: i-Pr2NEt / CH2Cl2 / -78 - 20 °C
  • 39
  • [ 125328-80-5 ]
  • [ 757247-75-9 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: 67 percent / dimethylformamide / 4 h / 150 °C 2: 95 percent / conc. HCl; EtOH / 0.5 h / Heating 3: 39 percent / CuI; tert-butylnitrite / acetonitrile / 3 h / 65 °C
Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 24 h / 150 °C 2: hydrogenchloride; water / ethanol / Reflux 3: copper(l) iodide; tert.-butylnitrite / acetonitrile / 3 h / Inert atmosphere; Heating
Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 24 h / 150 °C 2: hydrogenchloride / ethanol / 2 h / Reflux 3: copper(l) iodide; tert.-butylnitrite / acetonitrile / 3 h / 65 °C / Inert atmosphere
  • 40
  • [ 87-60-5 ]
  • [ 125328-80-5 ]
YieldReaction ConditionsOperation in experiment
96% 22.A 22A. 22A. N-(4-Bromo-3-chloro-2-methylphenyl)acetamide The title compound was prepared (2.75 g, 96% yield) from commercially available 3-chloro-2-methylaniline by procedures analogous to those described in Experiment 2A and 2B.
Multi-step reaction with 2 steps 1: 100 percent / ethanol / 2 h / 20 °C 2: 96 percent / bromine; glacial acetic acid / 2 h
Multi-step reaction with 2 steps 1: AcOH; NaOH 2: Br2
Multi-step reaction with 2 steps 1: ethanol / 2 h / 20 °C 2: bromine / acetic acid / 24 h / 0 - 20 °C
Multi-step reaction with 2 steps 1: dichloromethane / 20.5 h / 0 - 20 °C 2: bromine; acetic acid / 4 h / 0 - 20 °C
Multi-step reaction with 2 steps 1: ethanol / 20 °C 2: acetic acid; bromine / 24 h / 0 - 20 °C
Multi-step reaction with 2 steps 1: ethanol / 2 h 2: bromine / acetic acid / 2.5 h / 15 - 20 °C
Multi-step reaction with 2 steps 1: 12 h / 5 °C 2: acetic acid; bromine / 4 h / -5 - 0 °C

Reference: [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2004/19063, 2004, A1 Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2004/181064, 2004, A1
[2]Li, James J.; Sutton, James C.; Nirschl, Alexandra; Zou, Yan; Wang, Haixia; Sun, Chongqing; Pi, Zulan; Johnson, Rebecca; Krystek Jr., Stanley R.; Seethala, Ramakrishna; Golla, Rajasree; Sleph, Paul G.; Beehler, Blake C.; Grover, Gary J.; Fura, Aberra; Vyas, Viral P.; Li, Cindy Y.; Gougoutas, Jack Z.; Galella, Michael A.; Zahler, Robert; Ostrowski, Jacek; Hamann, Lawrence G. [Journal of Medicinal Chemistry, 2007, vol. 50, # 13, p. 3015 - 3025]
[3]Hamann, Lawrence G.; Manfredi, Mark C.; Sun, Chongqing; Krystek Jr., Stanley R.; Huang, Yanting; Bi, Yingzhi; Augeri, David J.; Wang, Tammy; Zou, Yan; Betebenner, David. A.; Fura, Aberra; Seethala, Ramakrishna; Golla, Rajasree; Kuhns, Joyce E.; Lupisella, John A.; Darienzo, Celia J.; Custer, Laura L.; Price, Jennifer L.; Johnson, James M.; Biller, Scott A.; Zahler, Robert; Ostrowski, Jacek [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 7, p. 1860 - 1864]
[4]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2013/14627, 2013, A1
[5]Boettcher, Stephan; Hederos, Markus; Champion, Elise; Dekany, Gyula; Thiem, Joachim [Organic Letters, 2013, vol. 15, # 14, p. 3766 - 3769]
[6]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2014/329876, 2014, A1
[7]Current Patent Assignee: MERCK & CO INC - WO2016/8064, 2016, A1
[8]Current Patent Assignee: HUNAN HENGTAI BIOPHARMACEUTICAL - CN110683981, 2020, A
  • 43
  • [ 125328-80-5 ]
  • [ 544-92-3 ]
  • [ 573768-09-9 ]
YieldReaction ConditionsOperation in experiment
79% With 1-methyl-pyrrolidin-2-one; copper(l) iodide; at 130℃; for 72h; Dissolve N-(4-bromo-3-chloro-2-methyl-phenyl)-acetamide (10 g, 38 mmol) in N-methylpyrrolidinone (60 mL) and sparge with nitrogen. Add copper cyanide (10.2 g, 114 mol) and copper iodide (21.8 g, 1 i4 mol) and stir under nitrogen at 130 C for 72 h. Cool the reaction and add ethylene diamine (100 mL), along with water (300 mL). Extract the reaction mixture with EtOAc. Separate and dry the organic portion over Na2SO4, filter, and concentrate. Dissolve the resulting residue in 1 : 1 EtOH/concentrated HCl. Stir at reflux temperature for 30 min, cool and concentrate to half of the volume. Add water (500 mL) and filter. Rinse the filter cake with water and isolate 5.0 g (79%) of the title compound as a white solid. MS: MS (ESI-): 207 (M-I)". MS (ESI+): 209 (M+l)+.
  • 44
  • [ 125328-80-5 ]
  • [ 627531-47-9 ]
YieldReaction ConditionsOperation in experiment
95% With hydrogenchloride; In ethanol; water; at 80℃; for 5h; 100ml flask-N (4-bromo-3 - chloro-2-methylphenyl) Oh theta mid 10g (38.09mmol) and the mixture was stirred into a 38ml ethanol. To the reaction mixture into a 38ml HCl 12N (27eq) it was refluxed at 80 for 5 hours. After the completion of the reaction was concentrated under reduced pressure to give the title compound 8.5g (95%).
With hydrogenchloride; In ethanol;Reflux; Step C: 4-bromo-3 -chloro-2-methylaniline To a solution of N-(4-bromo-3-chloro-2-methylphenyl)acetamide (18.50 g, 70.5 mmol) in EtOH(70 mL) was added cone. HC1 (70 mL) at room temperature, and the soluation was heated atreflux overnight. The mixture was adjusted to pH7 with solid Na2CO3, and then extracted byEtOAc, dried and concentrated to afford the title compound. LC/MS [M+1] =220; 222. ?HNIVIR (400 IVIFIz, CDC13) 7.24-7.22 (d, J 8.4 Hz, 1H), 6.48-6.46 (d, J 8.4 Hz, 1H), 2.26 (s,3H).
A solution of N-(4-bromo-3-chloro-2-methyl-phenyl)-acetamide (3.37 g, 12.80 mmol) in H2SO4: H2O (1:1) was refluxed for 3 hours. The reaction mixture was cooled to room temperature and neutralized with NaOH and extracted with Et2O (3×150 mL). The combined organic phases were washed with H2O (3×100 mL) and brine (1×100 mL), then dried over MgSO4 and concentrated. Purification by column chromatography using hex:EtOAc (4:1) as the eluant afforded the title aniline. Spectroscopic data: 1H NMR (300 MHz, CDCl3) delta 2.31 (s, 3H), 3.93 (br s, 2H), 6.47 (d, J=8.79 Hz, 1H), 7.24 (d, J=7.91 Hz, 1H).
  • 46
  • [ 125328-80-5 ]
  • [ 1447125-22-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: magnesium sulfate heptahydrate; potassium permanganate / water / 3 h / Reflux 2.1: sodium hydroxide / water / 5 h / Reflux 3.1: pyridine / dichloromethane; acetonitrile / 3 h / 50 °C 4.1: sodium hydride / N,N-dimethyl-formamide; paraffin oil / 0.75 h / Cooling with ice 4.2: 5 h / 20 °C
Multi-step reaction with 4 steps 1.1: potassium permanganate; magnesium sulfate / water / 5.5 h / Reflux 2.1: sodium hydroxide; water / 4 h / Reflux 3.1: pyridine / dichloromethane; acetonitrile / 3.5 h / 45 °C / Inert atmosphere 4.1: sodium hydride / N,N-dimethyl-formamide / 0.75 h / Inert atmosphere; Cooling with ice 4.2: Inert atmosphere
  • 47
  • [ 125328-80-5 ]
  • [ 1447125-25-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: magnesium sulfate heptahydrate; potassium permanganate / water / 3 h / Reflux 2.1: sodium hydroxide / water / 5 h / Reflux 3.1: pyridine / dichloromethane; acetonitrile / 3 h / 50 °C 4.1: sodium hydride / N,N-dimethyl-formamide; paraffin oil / 0.75 h / Cooling with ice 4.2: 5 h / 20 °C 5.1: sodium hydride / paraffin oil / 6.5 h / 20 °C
Multi-step reaction with 5 steps 1.1: potassium permanganate; magnesium sulfate / water / 5.5 h / Reflux 2.1: sodium hydroxide; water / 4 h / Reflux 3.1: pyridine / dichloromethane; acetonitrile / 3.5 h / 45 °C / Inert atmosphere 4.1: sodium hydride / N,N-dimethyl-formamide / 0.75 h / Inert atmosphere; Cooling with ice 4.2: Inert atmosphere 5.1: sodium hydride / 6.5 h / 20 °C / Inert atmosphere
  • 48
  • [ 125328-80-5 ]
  • [ 1447125-28-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: magnesium sulfate heptahydrate; potassium permanganate / water / 3 h / Reflux 2.1: sodium hydroxide / water / 5 h / Reflux 3.1: pyridine / dichloromethane; acetonitrile / 3 h / 50 °C 4.1: sodium hydride / N,N-dimethyl-formamide; paraffin oil / 0.75 h / Cooling with ice 4.2: 5 h / 20 °C 5.1: sodium hydride / paraffin oil / 6.5 h / 20 °C 6.1: potassium <i>tert</i>-butylate / diethyl ether / 2 h / 40 - 45 °C / Inert atmosphere
Multi-step reaction with 6 steps 1.1: potassium permanganate; magnesium sulfate / water / 5.5 h / Reflux 2.1: sodium hydroxide; water / 4 h / Reflux 3.1: pyridine / dichloromethane; acetonitrile / 3.5 h / 45 °C / Inert atmosphere 4.1: sodium hydride / N,N-dimethyl-formamide / 0.75 h / Inert atmosphere; Cooling with ice 4.2: Inert atmosphere 5.1: sodium hydride / 6.5 h / 20 °C / Inert atmosphere 6.1: potassium <i>tert</i>-butylate / diethyl ether / 2 h / 40 - 45 °C / Inert atmosphere
  • 49
  • [ 125328-80-5 ]
  • [ 125328-77-0 ]
YieldReaction ConditionsOperation in experiment
76.1% With dihydrogen peroxide In water at 50℃; for 4h; 1.3; 23 The third step is to add 200ml of water in a 500ml three-necked flask, and then add 11g of 4-bromo-3-chloro-2-methylphenylacetamide. When the temperature is raised to 50 ° C, add 3g of hydrogen peroxide dropwise within 4 hours , Follow up with TLC, when 4-bromo-3-chloro-2-methylacetanilide is reacted, drop it with sodium bisulfite (20% solution) until no bubbles appear in the reaction system, cool to normal temperature and use again When the pH value of the acidified hydrochloric acid reaches 2.0, a white solid is precipitated, filtered, dried, and recrystallized to obtain 8.5 g of white solid 6-chloro-5-bromo-2-acetamidobenzoic acid. (The yield of this part is 76.1%)
70% With potassium permanganate; magnesium sulfate heptahydrate In water for 3h; Reflux;
With potassium permanganate; magnesium sulfate In water for 5.5h; Reflux;
  • 50
  • [ 125328-80-5 ]
  • [ 943138-45-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: magnesium sulfate heptahydrate; potassium permanganate / water / 3 h / Reflux 2: sodium hydroxide / water / 5 h / Reflux 3: pyridine / dichloromethane; acetonitrile / 3 h / 50 °C
Multi-step reaction with 3 steps 1: potassium permanganate; magnesium sulfate / water / 5.5 h / Reflux 2: sodium hydroxide; water / 4 h / Reflux 3: pyridine / dichloromethane; acetonitrile / 3.5 h / 45 °C / Inert atmosphere
  • 51
  • [ 125328-80-5 ]
  • [ 7240-90-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 10 steps 1.1: potassium permanganate; magnesium sulfate / water / 5.5 h / Reflux 2.1: sodium hydroxide; water / 4 h / Reflux 3.1: pyridine / dichloromethane; acetonitrile / 3.5 h / 45 °C / Inert atmosphere 4.1: sodium hydride / N,N-dimethyl-formamide / 0.75 h / Inert atmosphere; Cooling with ice 4.2: Inert atmosphere 5.1: sodium hydride / 6.5 h / 20 °C / Inert atmosphere 6.1: potassium <i>tert</i>-butylate / diethyl ether / 2 h / 40 - 45 °C / Inert atmosphere 7.1: tetra(n-butyl)ammonium hydrogensulfate; potassium carbonate / water; dichloromethane / 20 °C 8.1: tetrakis(triphenylphosphine) palladium(0); morpholine / tetrahydrofuran / 20 °C 9.1: potassium carbonate; silver(I) acetate / 0.33 h / 90 - 100 °C 10.1: sodium methylate / methanol / 20 °C
  • 52
  • [ 125328-80-5 ]
  • [ 1044256-89-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: sulfuric acid; water / 3 h / Heating / reflux 1.2: 20 °C 2.1: hydrogenchloride; sodium nitrite / ethanol; water / 2 h / 70 °C 3.1: N-Bromosuccinimide / 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 0.5 h / Heating / reflux
  • 53
  • [ 125328-80-5 ]
  • [ 97329-43-6 ]
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Aryls

Chemical Structure| 1607828-43-2

[ 1607828-43-2 ]

N-(4-Bromo-5-chloro-2-methylphenyl)acetamide

Similarity: 0.95

Chemical Structure| 116010-06-1

[ 116010-06-1 ]

N-(2-Bromo-5-chloro-4-methylphenyl)acetamide

Similarity: 0.85

Chemical Structure| 1864015-01-9

[ 1864015-01-9 ]

N-(4-Bromo-5-chloro-2-methylphenyl)formamide

Similarity: 0.84

Chemical Structure| 1607828-43-2

[ 1607828-43-2 ]

N-(4-Bromo-5-chloro-2-methylphenyl)acetamide

Similarity: 0.95

Chemical Structure| 116010-06-1

[ 116010-06-1 ]

N-(2-Bromo-5-chloro-4-methylphenyl)acetamide

Similarity: 0.85

Bromides

Chemical Structure| 1607828-43-2

[ 1607828-43-2 ]

N-(4-Bromo-5-chloro-2-methylphenyl)acetamide

Similarity: 0.95

Chemical Structure| 116010-06-1

[ 116010-06-1 ]

N-(2-Bromo-5-chloro-4-methylphenyl)acetamide

Similarity: 0.85

Chemical Structure| 1864015-01-9

[ 1864015-01-9 ]

N-(4-Bromo-5-chloro-2-methylphenyl)formamide

Similarity: 0.84

Chemical Structure| 1607828-43-2

[ 1607828-43-2 ]

N-(4-Bromo-5-chloro-2-methylphenyl)acetamide

Similarity: 0.95

Chemical Structure| 116010-06-1

[ 116010-06-1 ]

N-(2-Bromo-5-chloro-4-methylphenyl)acetamide

Similarity: 0.85

Chlorides

Chemical Structure| 1607828-43-2

[ 1607828-43-2 ]

N-(4-Bromo-5-chloro-2-methylphenyl)acetamide

Similarity: 0.95

Chemical Structure| 116010-06-1

[ 116010-06-1 ]

N-(2-Bromo-5-chloro-4-methylphenyl)acetamide

Similarity: 0.85

Chemical Structure| 1864015-01-9

[ 1864015-01-9 ]

N-(4-Bromo-5-chloro-2-methylphenyl)formamide

Similarity: 0.84

Chemical Structure| 1607828-43-2

[ 1607828-43-2 ]

N-(4-Bromo-5-chloro-2-methylphenyl)acetamide

Similarity: 0.95

Chemical Structure| 116010-06-1

[ 116010-06-1 ]

N-(2-Bromo-5-chloro-4-methylphenyl)acetamide

Similarity: 0.85

Amides

Chemical Structure| 1607828-43-2

[ 1607828-43-2 ]

N-(4-Bromo-5-chloro-2-methylphenyl)acetamide

Similarity: 0.95

Chemical Structure| 116010-06-1

[ 116010-06-1 ]

N-(2-Bromo-5-chloro-4-methylphenyl)acetamide

Similarity: 0.85

Chemical Structure| 22459-81-0

[ 22459-81-0 ]

N-(4-Bromo-3-chlorophenyl)acetamide

Similarity: 0.82

Chemical Structure| 1607828-43-2

[ 1607828-43-2 ]

N-(4-Bromo-5-chloro-2-methylphenyl)acetamide

Similarity: 0.95

Chemical Structure| 116010-06-1

[ 116010-06-1 ]

N-(2-Bromo-5-chloro-4-methylphenyl)acetamide

Similarity: 0.85

Amines

Chemical Structure| 1607828-43-2

[ 1607828-43-2 ]

N-(4-Bromo-5-chloro-2-methylphenyl)acetamide

Similarity: 0.95

Chemical Structure| 116010-06-1

[ 116010-06-1 ]

N-(2-Bromo-5-chloro-4-methylphenyl)acetamide

Similarity: 0.85

Chemical Structure| 1864015-01-9

[ 1864015-01-9 ]

N-(4-Bromo-5-chloro-2-methylphenyl)formamide

Similarity: 0.84

Chemical Structure| 1607828-43-2

[ 1607828-43-2 ]

N-(4-Bromo-5-chloro-2-methylphenyl)acetamide

Similarity: 0.95

Chemical Structure| 116010-06-1

[ 116010-06-1 ]

N-(2-Bromo-5-chloro-4-methylphenyl)acetamide

Similarity: 0.85