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[ CAS No. 201940-08-1 ]

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CAS No. :201940-08-1MDL No. :MFCD09953049
Formula : C13H16BrNO2 Boiling Point : 354.7°C at 760 mmHg
Linear Structure Formula :-InChI Key :-
M.W :298.18Pubchem ID :16102683
Synonyms :

Computed Properties of [ 201940-08-1 ]

TPSA : 29.5 H-Bond Acceptor Count : 2
XLogP3 : 2.9 H-Bond Donor Count : 0
SP3 : 0.46 Rotatable Bond Count : 2

Safety of [ 201940-08-1 ]

Signal Word:WarningClass:N/A
Precautionary Statements:P261-P305+P351+P338UN#:N/A
Hazard Statements:H315-H319-H335Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 201940-08-1 ]

  • Upstream synthesis route of [ 201940-08-1 ]
  • Downstream synthetic route of [ 201940-08-1 ]

[ 201940-08-1 ] Synthesis Path-Upstream   1~9

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Reference: [1] Journal of the American Chemical Society, 2016, vol. 138, # 41, p. 13493 - 13496
[2] Angewandte Chemie - International Edition, 2018, vol. 57, # 7, p. 1968 - 1972[3] Angew. Chem., 2018, vol. 130, p. 1986 - 1990,5
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YieldReaction ConditionsOperation in experiment
100% With sodium carbonate In tetrahydrofuran at 20℃; for 2 h; To a solution of 4b (6 g, 30 mmol) in THF (100 mE) was added saturated Na2CO3 solution (25 mE), followed by 13oc20 (33 g, 151 mmol). The mixture was stirred at room temperature for 2 hours and evaporated under reduced pressure. The residue was extracted with ethyl acetate (50 mEx3). The combined organic phase was washed with brine, dried over anhydrous Na2504 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA1O:1, v: v) to provide 4c (9 g, ca. 100percent yield). EC-MS: 298 [M+1].
85% With sodium carbonate In dichloromethane; water for 4 h; Cooling with ice 5-Bromoisoindoline (10.36 g, 52.3 mmol) was dissolved in 80 mL dichloromethane, and cooled in an ice bath.
Boc anhydride (22.8 g, 104.6 mmol) was added dropwise followed by the addition of sodium carbonate (16.6 g, 156.9 mmol) and water (150 mL), and stirred in an ice bath for 4 hours.
The organic phase was separated, washed with brine, and concentrated, and then the residue was purified by silica gel column chromatography to give the product 5-bromo-2-tert-butoxycarbonylisoindoline (13.3 g). Yield: 85 percent. MS m/z [ESI]: 298.0[M+1].
1H-NMR (400 MHz, CDCl3): δ= 7.37 (2H, m) , 7.11 (1H, m), 4.62 (4H, m), 1.51 (9H, s).
83.4% With dmap In N,N-dimethyl-formamide at 25℃; for 10 h; To a solution of 5-bromoisoindoline (3.98 g, 20.2 mmol) in DMF (20 ml) was added DMAP (40.0 mg) and BOC2O (8.81 g, 40.4 mmol). The mixture was stirred at 25°C for 10 h. After LC-MS showed the reaction was completed. The reaction mixture was concentrated to give the crude product, which was washed with pe to give the title compound(5.00 g, 83.4percent). ‘HNMR(400 MHz, CDC13) ö7.39-7.43 (2H,m) 7.09-7.18(1 H, m) 4.61- 4.68(4 H, m) 1.53(9 H, s).
64%
Stage #1: With triethylamine In dichloromethane at 20℃; for 2.5 h; Cooling with ice
Stage #2: With N,N-dimethyl-ethanamine In dichloromethane at 20℃; for 1 h; Cooling with ice
Example 7 [1-(pyridin-4-yl)piperidin-4-yl]methyl 2-[amino(imino)methyl]isoindoline-5-carboxylate ditrifluoroacetate; step 1 Synthesis of tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate; To a solution (45 mL) of 5-bromoisoindoline (1.78 g, 9.00 mmol) in dichloromethane were added triethylamine (1.25 mL, 9.00 mmol) and di-tert-butyl dicarbonate (1.96 g, 9.00 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2.5 hr. N,N-Dimethylethylamine (0.988 mL, 9.00 mmol) was added under ice-cooling, the mixture was stirred at room temperature for 1 hr, and 1 N hydrochloric acid was added to the reaction mixture. The mixture was extracted with dichloromethane, and the extract was washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate 100:0 - 92:8) to give the title compound. yield (1.72 g, 5.76 mmol, 64percent) MS (ESI, m/z) 284 [(M-Me)+H]+ 1H-NMR (CDCl3)δ1.51 (s, 9H), 4.59-4.67 (m, 4H), 7.08-7.15 (m, 1H), 7.36-7.42 (m, 2H).
61% With sodium hydrogencarbonate In tetrahydrofuran at 20℃; To a solution of 5-bromoisoindoline (1.3 g, 6.6 mmol) in THF (30 mL) were added NaHCC (1.66 g, 19.8 mmol) and (Boc)20 (4.3 g, 19.8 mmol). The reaction was stirred at rt overnight, then concentrated in vacuo. The residue was partitioned between H20 (40 mL) and DCM (40 mL), and the aqueous phase was extracted with DCM (60 mL x 2). The combined organic phases were dried over anhydrous a2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a pale yellow solid (1.2 g, 61percent). MS (ESI, pos. ion) m/z: 244.0 [M-56+l]+; NMR (400 MHz, CDC13) δ (ppm): 7.35-7.41 (m, 2H), 7.07-7.14 (m, 1H), 4.58-4.66 (m, 4H), 1.51 (s, 9H).
61% With sodium hydrogencarbonate In tetrahydrofuran at 20℃; 5-bromoisoindoline (1.3 g, 6.6 mmol)Was dissolved in tetrahydrofuran (30 mL)To this was added sodium bicarbonate (1.66 g, 19.8 mmol) andBoc anhydride (4.3 g, 19.8 mmol).The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure.The residue was partitioned between dichloromethane (40 mL) and water (40 mL) and the separated aqueous phase was extracted with dichloromethane (60 mL x 2).There are mergersThe organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5/1) to give the title compound as a pale yellow solid (1.2 g, 61percent).
53% With dmap In tetrahydrofuran at 20℃; for 3 h; To a solution of 5-bromo-2,3-dihydro-lH-isoindole (8.75 g; 1.0 equiv) in THF (126 mL) are added di-fert-butyldicarbonate (10.8 g; 1.12 equiv) and 4-dimethylaminopyridine (5.4 g; 1.0 equiv) and the reaction is stirred at room temperature for 3 h. The reaction is quenched with saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic extracts are dried (MgSO4), filtered, and concentrated to afford crude product, which is purified by silica gel chromatography to yield 7.0 g 5-bromo-l,3-dihydro- isoindole-2-carboxylic acid tert-butyl ester (23.49 mmol; 53percent yield over two steps). 1H NMR (400 MHz, CD3OD): δ 7.39 (dd, J= 4.0, 16.0 Hz, 1 H), 7.26 (s, 1 H), 7.12 (dd, J = 20.0, 4.0 Hz), 4.67 (s, 1 H), 4.62 (s, 2 H), 4.59 (s, 1 H), 1.51 (s, 9 H).

Reference: [1] Patent: US2017/275301, 2017, A1, . Location in patent: Paragraph 0226; 0228
[2] Patent: EP3257857, 2017, A1, . Location in patent: Paragraph 0102; 0104
[3] Journal of Organic Chemistry, 2012, vol. 77, # 24, p. 11296 - 11301
[4] Patent: WO2015/54317, 2015, A1, . Location in patent: Paragraph 0272; 0273
[5] Patent: EP2311810, 2011, A1, . Location in patent: Page/Page column 24
[6] Patent: WO2014/89324, 2014, A1, . Location in patent: Paragraph 0236
[7] Patent: CN104016979, 2017, B, . Location in patent: Paragraph 0602; 0603; 0604; 0605
[8] Patent: WO2008/76954, 2008, A2, . Location in patent: Page/Page column 54
[9] Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 199 - 210
[10] Patent: US2008/171754, 2008, A1, . Location in patent: Page/Page column 103
[11] Patent: WO2008/44029, 2008, A1, . Location in patent: Page/Page column 235
[12] Patent: WO2008/44041, 2008, A1, . Location in patent: Page/Page column 257
[13] Patent: WO2008/44045, 2008, A1, . Location in patent: Page/Page column 310
[14] Patent: WO2008/44054, 2008, A2, . Location in patent: Page/Page column 154
[15] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 14, p. 4159 - 4162
[16] Patent: US2010/152184, 2010, A1, . Location in patent: Page/Page column 97
[17] Journal of Medicinal Chemistry, 2010, vol. 53, # 16, p. 5956 - 5969
[18] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912
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YieldReaction ConditionsOperation in experiment
88% With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1 h; A solution of 5-bromoisoindoline, HC1 (255 mg, 1.00 mmol) in DCM (5 mL) was treated with DIEA (0.570 mL, 3.26 mmol) and (Boc)20 (0.290 mL, 1.25 mmol). The mixture was stirred at rt for 1 h. The reaction was quenched with brine and extracted withDCM (2x). The combined organic extracts were dried over MgSO4, filtered, and concentrated to afford the crude product, which was purified by silica gelchromatography to provide 176A (0.28 g, 88percent yield). MS(ESI) m/z 243.9 (M+H-tBu)t ‘H NMR (500MHz, CDC13)ö 7.45-7.35 (m, 2H), 7.17-7.08 (m, 1H), 4.68-4.60(m, 4H), 1.52 (s, 9H).
Reference: [1] Patent: WO2017/40449, 2017, A1, . Location in patent: Paragraph 00449
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YieldReaction ConditionsOperation in experiment
70% at 10 - 35℃; for 15 h; Boc2O (2.58 g, 11.82 mmol) was added to a mixture of 5-bromoisoindoline-1,3-dione (2.23 g, 11.26 mmol) in THF (35 mL) at room temperature, and the mixture was stirred at room temperature for 15 hr.
The reaction mixture was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (solvent gradient; 0→14percent ethyl acetate/hexane) to give tert-butyl 5-bromoisoindoline-2-carboxylate (2.35 g, 7.88 mmol, 70.0percent) as a white solid.
1H NMR (300 MHz, CDCl3):δ 1.51(9H,s), 4.58-4.68(4H,m), 7.07-7.17(1H,m), 7.35-7.44(2H,m).
57.6%
Stage #1: With borane-THF In tetrahydrofuran at 0℃; for 36.5 h; Reflux
Stage #2: for 4 h; Reflux
Stage #3: With dmap In tetrahydrofuran at 20℃; for 4 h;
General procedure: Toa solution of 4a (10.0 g, 35.3 mmol)in MeOH (200 mL) was added 8M KOH solution (20 mL) and then heated to reflux.After 36 h, the reaction mixture was concentrated under reduced pressure.The mixture was diluted with H2O (100 mL), extracted with EA (75 mL×2), dried over Na2SO4 and concentrated under reducedpressure. The residue was dissolved in THF (100 mL). Di-tert-butyldicarbonate (9.0 g, 41.2 mmol) and DMAP (0.5 g, 4.0 mmol) was added and thenthe reaction mixture was stirred at room temperature for 4 h. Afterconcentration, the residue was purified by silica gel column chromatography(PET/EA = 15:1, v/v) to affordcompound 5a as colorless oil (8.3 g,75.5percent).
Reference: [1] Patent: EP3192791, 2017, A1, . Location in patent: Paragraph 0599
[2] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 18, p. 3050 - 3056
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  • [ 6941-75-9 ]
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Reference: [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 199 - 210
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4909 - 4912
[3] Journal of Organic Chemistry, 2012, vol. 77, # 24, p. 11296 - 11301
[4] Patent: WO2014/89324, 2014, A1,
[5] Patent: WO2015/54317, 2015, A1,
[6] Patent: CN104016979, 2017, B,
[7] Patent: US2017/275301, 2017, A1,
[8] Patent: EP3257857, 2017, A1,
  • 6
  • [ 24424-99-5 ]
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Reference: [1] Patent: US2010/119479, 2010, A1,
  • 7
  • [ 86-90-8 ]
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Reference: [1] Patent: WO2014/89324, 2014, A1,
[2] Patent: CN104016979, 2017, B,
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  • [ 201940-08-1 ]
  • [ 73183-34-3 ]
  • [ 905273-91-8 ]
YieldReaction ConditionsOperation in experiment
73% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In dimethyl sulfoxide at 90℃; for 12 h; Inert atmosphere To a suspension of tert-butyl 5-bromo-2-(tert-butoxycarbonyl)isoindoline (1.2 g, 4 mmol) and bis(pinacolato)diboron (2 g, 8 mmol) in DMSO (20 mL) was added AcOK (1.6 g, 16 mmol), followed by Pd(dppf)Cl2-CH2Cl2 (327 mg, 0.4 mmol) under N2 atmosphere. The reaction was heated at 90 °C for 12 h, then cooled to rt and poured into EtOAc/H20 (300 mL/100 mL). The separatedorganic phase was washed with brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) =20/1) to give the title compound as yellow oil (1 g, 73percent). MS (ESI, pos. ion) m/z: 290.2 [M-56+l ; NMR (400 MHz, CDC13) δ (ppm): 7.68-7.74 (m, 2H), 7.23-7.30 (m, 1H), 4.64-4.70 (m, 4H), 1.53 (s, 9H), 1.36 (s, 12H).
73% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In dimethyl sulfoxide at 90℃; for 12 h; Inert atmosphere Under nitrogen protection,A solution of 5-bromo-2- (tert-butoxycarbonyl) isoindoline (1.2 g, 4 mmol)And boronic acid pinacol ester (2 g, 8 mmol)Was dissolved in dimethylsulfoxide (20 mL)To this was added potassium acetate (1.6 g, 16 mmol) andPd (dppf) Cl2CH2Cl2 (327 mg, 0.4 mmol).The reaction solution was heated and stirred at 90 ° C for 12 hours,Cool to room temperature and pour into acetic acidEthyl acetate / water (300 mL / 100 mL), the separated organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate,Filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 20/1)The title compound was obtained as a yellow oil (1 g, 73percent).
72% With potassium acetate In N,N-dimethyl-formamide at 85℃; for 4 h; Step 2:
tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-isoindole-2-carboxylate
A solution of tert-butyl 5-bromo-1,3-dihydro-2H-isoindole-2-carboxylate (0.80 mmol), bis(pinacolato)diboron (0.96 mmol) and potassium acetate (2.5 mmol) in DMF (4 mL) was degassed.
To this solution was added PdCl2dppf (1:1 complex with DCM, 0.04 mmol).
The reaction mixture was heated at 85° C. for 4 hr and then allowed to cool to rt and diluted with EtOAc.
The solution was washed with water and brine, dried over Na2SO4, filtered and concentrated.
The residue was purified by column chromatography (10-30percent EtOAc in hexane) to give tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-isoindole-2-carboxylate (0.57 mmol, 72percent) as a white solid. LCMS: (FA) ES+346.
Reference: [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 2, p. 199 - 210
[2] Patent: WO2014/89324, 2014, A1, . Location in patent: Paragraph 0237
[3] Patent: CN104016979, 2017, B, . Location in patent: Paragraph 0606; 0607; 0608; 0609
[4] Patent: US2008/171754, 2008, A1, . Location in patent: Page/Page column 103
[5] Patent: WO2010/10186, 2010, A1, . Location in patent: Page/Page column 58
[6] Patent: WO2010/145202, 2010, A1, . Location in patent: Page/Page column 59
[7] Patent: WO2015/112441, 2015, A1, . Location in patent: Page/Page column 56
[8] Patent: US2016/333021, 2016, A1, . Location in patent: Paragraph 0345
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Reference: [1] Journal of Organic Chemistry, 2012, vol. 77, # 24, p. 11296 - 11301
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