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Chemical Structure| 835616-61-0
Chemical Structure| 835616-61-0
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Product Details of [ 835616-61-0 ]

CAS No. :835616-61-0 MDL No. :MFCD30188075
Formula : C13H9FN2O4 Boiling Point : -
Linear Structure Formula :- InChI Key :MPQLCQKBYRSPNA-UHFFFAOYSA-N
M.W : 276.22 Pubchem ID :70876201
Synonyms :
Chemical Name :2-(2,6-Dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione

Safety of [ 835616-61-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313 UN#:N/A
Hazard Statements:H315-H319 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 835616-61-0 ]

* 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 [ 835616-61-0 ]

[ 835616-61-0 ] Synthesis Path-Downstream   1~29

  • 1
  • [ 835616-61-0 ]
  • [ 88829-82-7 ]
  • tert-butyl (8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
63% With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 90℃; for 19h; 2-(2,6-Dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (294 mg, 1.06 mmol, 1 eq) and tert-butyl (8-aminooctyl)carbamate (286 mg, 1.17 mmol, 1.1 eq) were dissolved in NMP (5.3 mL, 0.2M). DIPEA (369 uL, 2.12 mmol, 2 eq) was added and the mixture was heated to 90 C. After 19 hours, the mixture was diluted with EtOAc, washed with water, and washed three times with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (ISCO, 12 g column, 0-10% MeOH/DCM, 30 minute gradient) afforded the desired product as a brown solid (0.28 g, 0.668 mmol, 63%).
63% With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 90℃; for 19h; 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l,3-dione (294 mg, 1.06 mmol, 1 eq) and fert-butyl (8-aminooctyl)carbamate (286 mg, 1.17 mmol, 1.1 eq) were dissolved in NMP (5.3 mL, 0.2M). DIPEA (369 mu, 2.12 mmol, 2 eq) was added and the mixture was heated to 90 C. After 19 hours, the mixture was diluted with ethyl acetate and washed with water and three times with brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (ISCO, 12 g column, 0-10% MeOH/DCM, 30 minute gradient) gave the desired product as a brown solid (0.28 g, 0.668 mmol, 63%).NMR (500 MHz, Chloroform-i ) delta 8.12 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.02 (s, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.93 (dd, J= 12.3, 5.3 Hz, 1H), 4.51 (s, 1H), 3.21 (t, J = 7.2 Hz, 2H), 3.09 (d, J= 6.4 Hz, 2H), 2.90 (dd, J= 18.3, 15.3 Hz, 1H), 2.82 - 2.68 (m, 2H), 2.16 - 2.08 (m, 1H), 1.66 (p, J= 7.2 Hz, 2H), 1.37 (d, J = 62.3 Hz, 20H).LCMS 501.41 (M+H).
63% With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 90℃; for 19h; 2-(2,6-Dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (294 mg, 1.06 mmol, 1 eq.) and tert-butyl (8-aminooctyl)carbamate (286 mg, 1.17 mmol, 1.1 eq.) were dissolved in NMP (5.3 mL). DIPEA (369 microliters, 2.12 mmol, 2 eq.) was added and the mixture was heated to 90 C. After 19 hours the mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and three times with brine. The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The material was purified by column chromatography (ISCO, 12 g column, 0-10% MeOH/DCM, 30 minute gradient) to give the desired product as a brown solid (0.3345 g, 0.6682 mmol, 63%).NMR (500 MHz, CDCb) delta 8.12 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.02 (s, 1H), 6.81 (d, J= 7.2 Hz, 1H), 4.93 (dd, J= 12.3, 5.3 Hz, 1H), 4.51 (s, 1H), 3.21 (t, J= 7.2 Hz, 2H), 3.09 (d, J= 6.4 Hz, 2H), 2.90 (dd, J= 18.3, 15.3 Hz, 1H), 2.82 - 2.68 (m, 2H), 2.16 - 2.08 (m, 1H), 1.66 (p, J= 7.2 Hz, 2H), 1.37 (d, J= 62.3 Hz, 20H).LCMS 501.41 (M+H)+.
34% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 12h; Compound 2- (2,6-dioxopiperidin-3-yl) -5-fluoroisoindole-1,3-dione (0.20 g, 0.7 mmol)With tert-butyl (8-aminooctyl) carbamate (0.19g, 0.8mmol) dissolved in DMF,Add DIPEA (0.18g, 1.4mmol),After stirring at 90 for 12h,The reaction solution was poured into ice water,Ethyl acetate extraction,Wash with saturated sodium chloride solution,Dry over anhydrous sodium sulfate,Concentrate to get crude product,Purified via silica gel column chromatography (eluent: dichloromethane / methanol = 100: 1)To give a yellow solid tert-butyl (8-((2- (2,6-dioxopiperidin-3-yl) -1,3-dioxoisoindol-5-yl) amino) octyl) carbamic acid ester0.12g,The yield is 34%.
17% With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 90℃; To a stirred solution of 2-(2,6-dioxopiperidin-3 -yl)-5-fluoroisoindoline- 1,3 -dione (3-1,300 mg, 1.09 mmol, 1 equiv) inNMP (5.4 mL, 0.2 M)was added DIPEA (378 jiL, 2.17 mmol, 2 equiv) andN-Boc-1,8-octanediamine (292 mg, 1.19 mmol, 1.1 equiv). The reaction mixture was heated to 90 C overnight and then cooled to room temperature. EtOAc (50 mL) and satd. NaHCO3 (aq) (50 mL) were added. The aqueous phase was extracted with EtOAc (25 mL), and the combined organic layers were washed with water (2 x 30 mL) and brine (3 x 50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (eluting with 0 to 5% MeOH in CH2C12) to give the title compound8-1 as a yellow solid (93 mg, 17%). ?H NIVIR (500 IVIFIz, CDC13) 8.46 (s, 1H), 7.56 (d, J 8.3Hz, 1H), 6.91 (d, J= 2.1 Hz, 1H), 6.70 (dd, J= 8.4, 2.2 Hz, 1H), 4.91 (dd, J 12.2, 5.3 Hz, 1H),4.76 (s, 1H), 4.56 (s, 1H), 3.20-3.11 (m, 2H), 3.13-3.00 (m, 2H), 2.91-2.64 (m, 3H), 2.13-2.04 (m, 1H), 1.62 (p, J= 7.2 Hz, 2H), 1.42 (s, 9H), 1.37 - 1.24 (m, 1OH). MS (ESI) [M+H]:501.4.

  • 2
  • [ 835616-61-0 ]
  • [ 1227382-01-5 ]
  • tert-butyl 6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With N-ethyl-N,N-diisopropylamine; Step 6: tert-butyl 6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate To a mixture of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (300 mg, 1.09 mmol, 1.00 eq) and <strong>[1227382-01-5]tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate; oxalic acid</strong> (317 mg, 0.65 mmol, 0.60 eq) in (methylsulfinyl)methane (5 mL) was added N,N-diisopropylethylamine (561 mg, 4.34 mmol, 4.00 eq) in one portion under nitrogen. The mixture was heated to 120 C. and stirred for 16 hours. The mixture was poured into ice-water (w/w=1/1) (30 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with brine (50 mL*3), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was triturated by Petroleum ether: Ethyl acetate (1:1, 50 mL) to afford tert-butyl 6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (420 mg, 0.92 mmol, 85% yield) as a yellow solid.
  • 3
  • [ 835616-61-0 ]
  • [ 5514-98-7 ]
  • tert-butyl 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
15% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃; 4.1 Step 1. /erf-butyl 6-((2-(2,6-dioxopiperidin-3-yl)-l^-dioxoisoindolin-5-yl)amino)hexanoate (5b) To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l,3-dione (5a, 74 mg, 0.268 mmol, 1 equiv) in NMP (1.3 mL, 0.2 M) was added DIPEA (93.3 uL, 0.536 mmol, 2 equiv) and ierf-butyl 6-aminohexanoate (3b, 55.2 mg, 0.295 mmol, 1.1 equiv). The reaction mixture was heated to 90 °C overnight, and then cooled to room temperature. EtOAc (20 mL) was added. The organic layer was washed with water (20 mL) and brine (3 x 20 mL), dried over Na2S04, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel (eluting with 0 to 5% MeOH in CH2CI2) to give compound 5b as a yellow solid (18 mg, 15%). NMR (400 MHz, CDCh) 6 8.31 (s, 1H), 7.57 (d, J= 8.3 Hz, 1H), 6.91 (d, J= 2.2 Hz, lH), 6.70 (dd, J= 8.3, 2.2 Hz, lH), 4.92 (dd, J= 12.3, 5.3 Hz, lH), 4.71 (t, J = 5.4 Hz, 1H), 3.46 - 3.31 (m, 2H), 3.20 (td, J= 7.0, 5.4 Hz, 2H), 2.94 - 2.63 (m, 3H), 2.25 - 2.19 (m, 2H), 2.15 - 2.06 (m, lH), 1.69 - 1.55 (m, 4H), 1.44 (s, 9H). MS (ESI) [M+H]+: 444.3.
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 130℃; for 0.833333h; Microwave irradiation;
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃; Step 1: To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline- 1,3-dione (1.0 eq.), and tert-butyl 6-aminohexanoate (1.2 eq.) in NMP is added DIPEA (2.0 eq.) and the reaction mixture is heated to 90 °C. Upon completion, the reaction is cooled to rt and diluted with EtOAc. The organic layer is washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by column chromatography (S1O2) to provide tert-butyl 6-((2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)amino)hexanoate (Intermediate 56-1).
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃; Step 1: To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline- 1,3-dione (1.0 eq.), and tert-butyl 6-aminohexanoate (1.2 eq.) in NMP is added DIPEA (2.0 eq.) and the reaction mixture is heated to 90 °C. Upon completion, the reaction is cooled to rt and diluted with EtOAc. The organic layer is washed with water, brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by column chromatography (S1O2) to provide tert-butyl 6-((2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-5-yl)amino)hexanoate (Intermediate 56-1).

  • 4
  • [ 835616-61-0 ]
  • [ 102522-32-7 ]
  • tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃; 6.1 Step 1. tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-13-dioxoisoindolin-5-yl)amino)octanoate (7a) To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l,3-dione (5a, 100 mg, 0.362 mmol, 1 equiv) in NMP (1.8 mL, 0.2 M) was added DIPEA (126.1 uL, 0.724 mmol, 2 equiv) and /erf-butyl 8-aminooctanoate (6b, 78 mg, 0.362 mmol, 1 equiv). The reaction mixture was heated to 90 °C overnight and then cooled to room temperature and taken up in EtOAc (20 mL). The organic layer was washed with water (20 mL) and brine (3 x 20 mL), then dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 0 to 5% MeOH in CH2CI2) to give compound 7a as a yellow solid (56 mg, 33%). NMR (500 MHz, CDCh) δ 8.27 (s, lH), 7.58 (d, J= 8.3 Hz, lH), 6.93 (d, J= 2.1 Hz, 1H), 6.71 (dd, J= 8.3, 2.2 Hz, 1H), 4.94 - 4.88 (m, 1H), 4.59 (s, 1H), 3.19 (t, J= 7.2 Hz, 2H), 2.94 - 2.66 (m, 3H), 2.24 - 2.17 (m, 2H), 2.16 - 2.03 (m, lH), 1.68 - 1.53 (m, 4H), 1.43 (s, 9H), 1.40 - 1.27 (m, 6H).
21% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 90℃; 22.1 Step 1: Preparation of tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoate 5-F-thalidomide (100 mg, 0.362 mmol) and DIPEA (0.094 mL, 0.543 mmol) were added to a solution of tert-butyl 8-aminooctanoate (117 mg, 0.543 mmol) in DMSO and stirred at 90 °C overnight. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and the solvent removed in vacuo to give an oil. The crude mixture was purified by silica gel column chromatography using EtOAc / Hx = 30 % to give the title compound (36 mg, 0.076 mmol, 21 %) as a green solid. 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 2.1 Hz, 1H), 6.71 (dd, J = 8.3, 2.1 Hz, 1H), 5.00-4.89 (m, 1H), 4.69 (t, J = 5.4 Hz, 1H), 3.18 (q, J = 6.5 Hz, 2H), 2.93-2.70 (m, 3H), 2.22 (t, J = 7.4 Hz, 2H), 2.16-2.06 (m, 1H), 1.70-1.52 (m, 4H), 1.44 (s, 9H), 1.42-1.30 (m, 6H).
21% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 90℃; 22.1 Step 1: Preparation of tert-butyl 8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octanoate 5-F-thalidomide (100 mg, 0.362 mmol) and DIPEA (0.094 mL, 0.543 mmol) were added to a solution of tert-butyl 8-aminooctanoate (117 mg, 0.543 mmol) in DMSO and stirred at 90 °C overnight. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and the solvent removed in vacuo to give an oil. The crude mixture was purified by silica gel column chromatography using EtOAc / Hx = 30 % to give the title compound (36 mg, 0.076 mmol, 21 %) as a green solid. 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 2.1 Hz, 1H), 6.71 (dd, J = 8.3, 2.1 Hz, 1H), 5.00-4.89 (m, 1H), 4.69 (t, J = 5.4 Hz, 1H), 3.18 (q, J = 6.5 Hz, 2H), 2.93-2.70 (m, 3H), 2.22 (t, J = 7.4 Hz, 2H), 2.16-2.06 (m, 1H), 1.70-1.52 (m, 4H), 1.44 (s, 9H), 1.42-1.30 (m, 6H).
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 130℃; for 0.833333h; Microwave irradiation;

  • 5
  • [ 932741-19-0 ]
  • [ 835616-61-0 ]
  • 2-(2,6-dioxopiperidin-3-yl)-5-((2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
20% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 90℃; Inert atmosphere; 82.5 5. Step- Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((2-(2-(2-(prop-2-yn-1- yloxy)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione A mixture of 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethanamine(120 mg, 0.31 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (86 mg, 0.31 mmol), and N- ethyl-N-isopropylpropan-2-amine (0.09 ml, 0.5 mmol) in 1-methylpyrrolidin-2-one (2 ml) was stirred at 90°C overnight under nitrogen. TLC showed the reaction was complete. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was collected, washed with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 50% ethyl acetate in dichloromethane) to afford 2-(2,6-dioxopiperidin-3-yl)-5-((2-(2- (2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione (55 mg, yield 20%) as yellow solid. LC_MS: (ES+): m/z 444.2 [M+H]+. tR = 2.135 min
  • 6
  • [ 319-03-9 ]
  • [ 31140-42-8 ]
  • [ 835616-61-0 ]
  • 7
  • [ 835616-61-0 ]
  • [ 88829-82-7 ]
  • (Z)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide [ No CAS ]
  • 8
  • [ 835616-61-0 ]
  • [ 127828-22-2 ]
  • tert-butyl (2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethyl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
22% With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 90℃; To a stirred solution of 2-(2,6-dioxopiperidin-3 -yl)-5-fluoroisoindoline- 1,3 -dione (3-1,100mg, 0.362mmo1, 1 equiv)inNMP(1.8mL, 0.2 M) was added DIPEA (126 jiL, 0.724mmol, 2 equiv) and <strong>[127828-22-2]tert-butyl (2-(2-aminoethoxy)ethyl)carbamate</strong> (74 mg, 0.362 mmol, 1 equiv). The reaction mixture was heated to 90 C overnight and then cooled to room temperature. EtOAc (50 mL) was added. The organic layer was washed with water (30 mL) and brine (3 x 30 mL), dried over Na2504, filtered, and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (eluting with 0 to 5% MeOH in CH2C12) to give the title compound 9-1 as a yellow solid (37 mg, 22%). ?H NIVIR (500 MHz, CDC13) 8.70 (s, 1H), 7.607.47 (m, 1H), 6.99 - 6.85 (m, 1H), 6.74 (d, J= 8.3 Hz, 1H), 5.06 -4.96 (m, 1H), 4.92 (dd, J= 12.0, 5.3 Hz, 1H), 3.72 - 3.63 (m, 2H), 3.58 - 3.48 (m, 2H), 3.33 - 3.24 (m, 4H), 2.95 - 2.66 (m, 3H), 2.09 (ddd, J= 10.5, 6.6, 3.2 Hz, 1H), 1.43 (s, 9H). MS (ESI) [M+H]: 461.2.
  • 9
  • [ 835616-61-0 ]
  • [ 107045-28-3 ]
  • tert-butyl 4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)methyl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
17% With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 90℃; A stirred solution of 2-(2,6-dioxopiperidin-3 -yl)-5-fluoroisoindoline- 1,3 -dione (3-1, 200mg, 0.724 mmol, 1 equiv) in NIVIP (3.6 mL, 0.2 M) was added DIPEA (525 jiL, 1.45 mmol, 2equiv) and <strong>[107045-28-3]tert-butyl 4-(aminomethyl)benzoate</strong> (165 mg, 0.796 mmol, 1.1 equiv). The reaction mixture was heated to 90 C overnight and then cooled to room temperature. EtOAc (50 mL) was added. The organic layer was washed with water (30 mL) and brine (3 x 30 mL), dried over Na2504, filtered, and concentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (eluting with 0 to 5% MeOH in CH2C12) to give the title compound 11-1 as a yellow solid (57 mg, 17%). MS (ESI) [M+H]: 464.6.
  • 10
  • [ 373608-48-1 ]
  • [ 835616-61-0 ]
  • C25H33N5O6 [ No CAS ]
  • 11
  • [ 835616-61-0 ]
  • [ 188646-83-5 ]
  • [ 2241315-64-8 ]
YieldReaction ConditionsOperation in experiment
95.9% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 110℃; for 2h; Inert atmosphere; Sealed tube; Step 3: Synthesis of 5-[4-(dimethoxymethyl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3- yl)isoindole-1,3-dione Into a 30-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed 4-(dimethoxymethyl)piperidine (300 mg, 1.9 mmol, 1.0 equiv), DMSO (20.0 mL), 2- (2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (520.4 mg, 1.9 mmol, 1.0 equiv), DIEA (730.5 mg, 5.7 mmol, 3.0 equiv). The resulting mixture was stirred for 2 hours at 110°C in an oil bath. Then the mixture was diluted with 30 mL of water and extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with brine (30 mL x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:0). This resulted in 750.0 mg (95.9%) of 5-[4-(dimethoxymethyl)piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione as a yellow solid. MS (ES+): m/z 416.25[MH+].
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; 1 Step 1 To a solution of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (300 mg, 1.09 mmol, 1 eq) and 4-(dimethoxymethyl)piperidine (207.52 mg, 1.30 mmol, 1.2 eq) in DMSO (5 mL) was added DIEA (421.11 mg, 3.26 mmol, 567.53 uL, 3 eq) at 25°C, then the reaction was stirred at 100°C for 1 h to give a brown solution. The desired product was detected by TLC (Dichloromethane: Methanol= 10:1, Rf= 0.5). The reaction mixture was poured into H2O (5 mL). The mixture was extracted with ethyl acetate (10 mL*3). The organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=100/1, 1/1) to afford 5-[4- (dimethoxymethyl)-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (326 mg, 580.69 umol, 53.47% yield, 74% purity) as a yellow solid.
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; 1 Step 1 To a solution of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (300 mg, 1.09 mmol, 1 eq) and 4-(dimethoxymethyl)piperidine (207.52 mg, 1.30 mmol, 1.2 eq) in DMSO (5 mL) was added DIEA (421.11 mg, 3.26 mmol, 567.53 uL, 3 eq) at 25°C, then the reaction was stirred at 100°C for 1 h to give a brown solution. The desired product was detected by TLC (Dichloromethane: Methanol= 10:1, Rf= 0.5). The reaction mixture was poured into H2O (5 mL). The mixture was extracted with ethyl acetate (10 mL*3). The organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether/Ethyl acetate=100/1, 1/1) to afford 5-[4- (dimethoxymethyl)-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (326 mg, 580.69 umol, 53.47% yield, 74% purity) as a yellow solid.

  • 12
  • [ 835616-61-0 ]
  • [ 88211-50-1 ]
  • 5-(but-3-ynylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
50% With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 130℃; for 1h; To a mixture of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (650 mg, 2.35 mmol, Intermediate HX), but-3-yn-1-amine (373 mg, HCl, CAS14044-63-4) in DMSO (10 mL) was added DIPEA (3.04 g, 23.5 mmol) and stirred at 130 C. for lhr. On completion, the mixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with brine (2×30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1:1) to give the title compound (386 mg, 50% yield) as a brown solid; LC-MS (ESI+) m/z 326.0 (M+H)+.
  • 13
  • [ 835616-61-0 ]
  • [ 61798-24-1 ]
  • 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2S)-2-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine; trifluoroacetic acid; Example 16 2-(2,6-dioxopiperidin-3-yl)-5-(methyl((1S,2S)-2-(methylamino)cyclohexyl)amino)isoindoline-1,3-dione (I-114) A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (15-4, 200 mg, 0.724 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine ((S,S)-1-5a, 0.24 mL, 1.5 mmol) and DIPEA (0.63 mL, 3.6 mmol) in NMP (3.0 mL) was stirred at 180 C. for 6 h in the microwave. The reaction mixture was concentrated and the resulting residue was purified by reverse phase HPLC eluting with 5-100% water/MeCN with 0.1% TFA as a modifier. The desired fractions were collected, neutralized with sat. aq. sodium bicarbonate solution, extracted with DCM, and then further purified by silica gel chromatography eluting with 0-40% EtOAc:EtOH (v/v=3:7, with 2% Et3N as a modifier) in DCM to afford the desired product 1-114 (230 mg, 0.577 mmol, 80% yield) as a light yellow solid. MS [M+H]+=399.6. 1H NMR (400 MHz, Acetonitrile-d3) delta 7.63 (d, J=8.4 Hz, 1H), 7.25 (d, J=2.5 Hz, 1H), 7.09 (dd, J=8.7, 2.5 Hz, 1H), 4.99-4.91 (m, 1H), 2.93 (s, 3H), 2.82-2.55 (m, 4H), 2.29 (s, 3H), 2.23-2.05 (m, 3H), 1.83-1.56 (m, 4H), 1.53-1.06 (m, 3H).
  • 14
  • [ 835616-61-0 ]
  • [ 61798-24-1 ]
  • 5-(((1R,2R)-2-(dimethylamino)cyclohexyl)(methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ No CAS ]
  • 15
  • [ 835616-61-0 ]
  • [ 894493-95-9 ]
  • 5-(((1S,2S)-2- (dimethylamino)cyclohexyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
9% With triethylamine; trifluoroacetic acid; Step 3. 5-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (I-153) A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (15-4, 30 mg, 0.11 mmol), <strong>[894493-95-9](1S,2S)-N1,N1-dimethylcyclohexane-1,2-diamine</strong> (25-2, 31 mg, 0.22 mmol) and DIPEA (0.095 mL, 0.54 mmol) in i-PrOH (1 mL) was stirred at 170 C. for 4 h in the microwave. The reaction mixture was concentrated and the resulting residue was purified by reverse phase RP-C18 column chromatography eluting with 5 to 100% MeCN in water with 0.1% TFA as a modifier. The fractions containing the desired product were collected and neutralized with sat. aq. sodium bicarbonate solution. The resulting mixture was extracted with DCM, and then further purified by silica gel column chromatography eluting with 0 to 40% EtOAc:EtOH (v/v=3:7, with 2% Et3N as a modifier) in DCM to provide the desired product 1-153 (4 mg, 0.01 mmol, 9% yield) as a light yellow solid. MS [M+H]+=399.4. 1H NMR (400 MHz, Acetonitrile-d3) delta 8.88 (s, 1H), 7.56 (d, J=8.3 Hz, 1H), 6.99 (d, J=2.3 Hz, 1H), 6.88 (dd, J=8.4, 2.1 Hz, 1H), 5.80 (d, J=5.2 Hz, 1H), 5.09-4.82 (m, 1H), 3.35-3.28 (m, 1H), 2.86-2.64 (m, 3H), 2.52-2.45 (m, 1H), 2.36-2.27 (m, 1H), 2.22 (s, 6H), 2.14-2.06 (m, 2H), 1.75-1.68 (m, 1H), 1.50-1.26 (m, 3H), 1.26-1.09 (m, 2H).
  • 16
  • [ 68832-13-3 ]
  • [ 835616-61-0 ]
  • 2-(2,6-dioxopiperidin-3-yl)-5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]isoindole-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 16h; A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-l,3-dione (373 mg, 1.35 mmol), DMF (8 mL) , ethylbis(propan-2-yl)amine (0.94 mL, 5.40 mmol) and prolinol (137 mg, 1.35 mmol) was allowed to stir at 90C for 16 h. CH2CI2 and H2O were added. The organic layer was dried with MgS04, filtered, concentrated and purified by MPLC (0-10% MeOH in CH2CI2) to afford 2-(2,6-dioxopiperidin-3-yl)-5-[(2S)-2- (hydroxymethyl)pyrrolidin-l-yl]isoindole-l,3-dione (386.00 mg, 80.0%).
  • 17
  • [ 835616-61-0 ]
  • [ 1023595-11-0 ]
  • C26H32N4O7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With 1-methyl-pyrrolidin-2-one; diisopropylamine at 20 - 90℃; for 6h; Inert atmosphere; 78.1 Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-[1-oxa-4,9-diazaspiro[5.5]undecan-9-yl]isoindole-1,3- dione (i78-2) To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (1.50 g, 5.430 mmol, 1.00 equiv) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (1.67 g, 6.516 mmol, 1.20 equiv) in NMP (10.00 mL) was added DIEA (1.40 g, 10.861 mmol, 2.00 equiv) dropwise at room temperature. The resulting mixture was stirred for 6 hours at 90 °C under nitrogen atmosphere. The residue was purified by reverse flash chromatography (conditions: column, C18 silica gel; mobile phase, ACN in water, 10% to 50% gradient in 20 minutes; detector, UV 254 nm). This resulted in tert-butyl 9-(2- (2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate (2 g, 72%) as a green oil. LCMS (ESI) m/z: [M+H]+ = 513.
  • 18
  • [ 835616-61-0 ]
  • [ 173405-78-2 ]
  • [ 2476319-06-7 ]
YieldReaction ConditionsOperation in experiment
90% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 90℃; Inert atmosphere; 77.a a) tert-butyl 9-12-12.6-dio\o-3-piperidyl )- 1.3-dio\o-isoindolin-5-yl 1-3.9- diazaspiror5.51undecane-3-carboxylate To a stirred solution of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-l,3-dione (200 mg, 724 pmol, 1.0 eq) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (184 mg, 724 pmol, 1.0 eq) in DMSO (1.5 mL) at room temperature was added DIPEA (187 mg, 253 pL, 1.45 mmol, 2.0 eq). The reaction mixture was stirred at 90 °C overnight. The reaction mixture was then poured into EtOAc/THF (1:1) and extracted sequentially with water and with brine. The organic phase was dried over Na2SC>4 and concentrated in vacuo. The crude material was purified on silica column (heptane/EtOAc 0-100%) to afford the title compound (334 mg, 654 pmol, 90% yield) as a green solid. MS (ESI): 455.4 ([M+H- C4H8]+).
88% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 80℃; for 5h; 77.1 The first step: 9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro [5.5] Undecane-3-carboxylate tert-butyl ester (77b)tert-butyl 9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate Dissolve tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (77a) (850 mg, 3.34 mmol) in 20 mL DMSO,2 mL of DIPEA and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (see WO2017197056 for the synthesis method) (1.38 g, 5.00 mmol) were added, The temperature was raised to 80°C for 5h. The reaction solution was cooled to room temperature, 50 mL of water was added, and the solid was collected by filtration. The filter cake was washed with 50 mL of water, the solid was dissolved in 100 mL of DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane). /methanol (v/v)=20:1) to obtain 77b (1.5 g, yield: 88%).
306 mg With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 65℃; for 2h; 20.1 Step 1 : tert-butyl 9-r2-(2.6-dioxopiperidin-3-yl)-1.3-dioxoisoindol-5-yl1-3.9- diazaspiror5.51undecane-3-carboxylate. A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-l,3-dione (218 mg, 0.79 mmol), z-Pr2NEt (412 pL, 2.37 mmol), and tert-butyl 3,9-diazaspiro[5.5]undecane-3- carboxylate (201 mg, 0.79 mmol) was dissolved in A-methylpyrrolidone (1 mL) and heated to 65 °C for 2 h before being cooled and purified (SiCh, 0 - 100% EtO Ac/Hexanes) to afford tert-butyl 9-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindol-5-yl]-3,9- diazaspiro[5.5]undecane-3-carboxylate (306 mg). LCMS: C27H34N4O6 requires: 510, found: m/z = 511 [M+H]+.
  • 19
  • [ 835616-61-0 ]
  • [ 131922-05-9 ]
  • C18H17F3N4O4 [ No CAS ]
  • 20
  • [ 835616-61-0 ]
  • [ 131922-05-9 ]
  • 2-(2,6-dioxopiperidin-3-yl)-5-(4-(6-((1r,3r)-3-((5-(5-methyl-5H-pyrido[4,3-b]indol-7-yl)pyridin-2-yl)oxy)cyclobutoxy)hexyl)-3-(trifluoromethyl)piperazin-1-yl)isoindoline-1,3-dione [ No CAS ]
  • 21
  • [ 928038-44-2 ]
  • [ 835616-61-0 ]
  • 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-1-yl)isoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine In dimethyl sulfoxide at 120℃; for 2h; 8.3 The third step: 2-(2,6-dioxo-3-piperidinyl)-5-[3-(hydroxymethyl)azetidin-1-yl]isoindoline-1,3- Dione (8c) Combine 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (see WO2017197056 for synthesis method)(0.50g, 1.81mmol) dissolved in 10mL DMSO, add 3-(hydroxymethyl)azetidine hydrochloride(0.3g, 2.42mmol) and triethylamine (0.37g, 3.62mmol) in sequence, and heat to 120 degrees Celsius , Stir for 2h.The reaction solution was cooled to room temperature, 20 mL of water and 20 mL of ethyl acetate were added for extraction, and the organic layer was washed with saturated sodium chloride aqueous solution (20 mL x 4),After concentration under reduced pressure, 2-(2,6-dioxo-3-piperidinyl)-5-[3-(hydroxymethyl)azetidin-1-yl]isoindoline-1,3 -Dione (8c) (0.5 g, yield: 80%).
68% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one for 16h; 12 Step 2: Amine displacement of aryl fluoride General procedure: To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3- dione (1.0 g, 3.62 mmol) in N-methyl pyrrolidone (10 mL) were added RxRyNH (3.60 mmol) and DIEA (1.4 g, 10.83 mmol). The resulting solution was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and purified by reverse phase flash chromatography to afford the corresponding final product. RxRy correspond to any amine R groups defined elsewhere herein. [00326] Step 3: Alcohol oxidation
43% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 80℃; for 3h; 60.1 Step 1: 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (hydroxymethyl) azetidin-1-yl) isoindoline-1, 3-dione Into a 100-mL flask, was placed azetidin-3-ylmethanol hydrochloride (500 mg, 4.05 mmol) , DMSO (8 mL) , 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindole-1, 3-dione (1.23 g, 4.45 mmol) , DIEA (2.61 g, 20.25 mmol) . The resulting solution was stirred for 3 hours at 80 . The reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted with DCM (2 x 50 mL) . The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH = 100: 0 90 : 10 gradient elution) to give the product (600 mg, 43%) . [M+H]+= 344.1.
43% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 80℃; for 3h; 60.1 Step 1: 2- (2, 6-dioxopiperidin-3-yl) -5- (3- (hydroxymethyl) azetidin-1-yl) isoindoline-1, 3-dione Into a 100-mL flask, was placed azetidin-3-ylmethanol hydrochloride (500 mg, 4.05 mmol) , DMSO (8 mL) , 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindole-1, 3-dione (1.23 g, 4.45 mmol) , DIEA (2.61 g, 20.25 mmol) . The resulting solution was stirred for 3 hours at 80 . The reaction mixture was cooled to room temperature. The reaction was quenched with water and extracted with DCM (2 x 50 mL) . The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (DCM: MeOH = 100: 0 90 : 10 gradient elution) to give the product (600 mg, 43%) . [M+H]+= 344.1.

  • 22
  • [ 141449-85-6 ]
  • [ 835616-61-0 ]
  • tert-butyl 2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
45% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 2h; 21.1 The first step: 2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]-1,3,3a,4 ,6,6a-Hexahydropyrrolidine[3,4]-c]pyrrole-5-carboxylic acid ethyl ester (21b) The 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindoline-1,3-dione (4e) (0.065g, 0.2 4mmol)Dissolve in 10ml DMSO,Add 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carboxylic acid tert-butyl ester (21a) (0.05g, 0.24mmol),N,N-diisopropylethylamine 0.5ml, (0.28g, 0.1mmol), stirred at 100°C for 2 hours,After cooling to room temperature, adding 10 mL of water to wash, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography to obtain 2-[2-(2,6-dioxo-3-piper) (Pyridinyl)-1,3-dioxo-isoindolin-5-yl]-1,3,3a,4,6,6a-hexahydropyrrolidine[3,4]-c]pyrrole-5- Ethyl carboxylate (21b) (0.05g, 45%).
  • 23
  • [ 835616-61-0 ]
  • [ 51052-79-0 ]
  • 3-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]propanoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 16h; Inert atmosphere; 12 Ligase 11 : 1- [2-(2,6-dioxo-3-piperidyl)- l,3-dioxo-isoindolin-4-yl] piperidine-4- carboxylic acid General procedure: A mixture of isonipecotic acid (1683 mg, 13.0 mmol, 1.2 eq), 2-(2,6-dioxo-3-piperidyl)- 4-fluoro-isoindoline-l,3-dione (3000 mg, 10.8 mmol, 1 eq), DIPEA (5.68 mL, 32.5 mmol, 3 eq) in DMSO (50 mL) was stirred at 100 °C for 16 h. Water was added, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified on silica gel (PE/EtOAc 10-100%) to afford the title compound (560 mg, 1.4 mmol, 12% yield) as an orange solid.
  • 24
  • [ 1211568-27-2 ]
  • [ 835616-61-0 ]
  • [ 2229725-33-9 ]
YieldReaction ConditionsOperation in experiment
62.1% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃;
520 mg With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 4h; Sealed tube; Step 1: Preparation of tert-butyl 4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate Into a 30 mL sealed tube, was placed tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1- carboxylate (600 mg, 2.117 mmol, 1.0 equiv), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3- dione (584.77 mg, 2.117 mmol, 1.0 equiv), DIEA (820.83 mg, 6.351 mmol, 3.0 equiv) in DMSO (20 ml). The resulting mixture was stirred for 4 hours at 100 °C in an oil bath. The crude product was purified by Prep-HPLC. This resulted in 520 mg of tert-butyl 4-([1-[2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindol-5-yl]piperidin-4-yl]methyl)piperazine-1-carboxylate as a yellow green solid. LC/MS (ESI) m/z: 540.25 [M+1] +.
  • 25
  • [ 845305-83-1 ]
  • [ 835616-61-0 ]
  • tert-butyl 4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)oxy)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
92.6% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 2h;Sealed tube; Into a 30-mL sealed tube, was placed tert-butyl 4-(piperidin-4-yloxy)piperidine-1- carboxylate (500 mg, 1.7 mmol, 1.0 equiv), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3- dione (509.9 mg, 1.8 mmol, 1.05 equiv), DIEA (681.7 mg, 5.3mmol, 3.0 equiv) in DMF (20 mL). The resulting mixture was stirred for 2 hours at 100 C in an oil bath. Then the mixture was diluted with 20 mL of water and extracted with ethyl acetate (20 mL x 2). The organic layers were combined and concentrated under reduced pressure. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (2:1). This resulted in 880 mg (92.6%) of tert-butyl 4-([1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]piperidin-4- yl]oxy)piperidine-1-carboxylate as a yellow solid. LC/MS (ESI) m/z: 541.35 [M+1] +.
  • 26
  • [ 283173-50-2 ]
  • [ 835616-61-0 ]
  • [ 2699130-25-9 ]
YieldReaction ConditionsOperation in experiment
46% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 90℃; for 2h; 34 2-(2,6-dioxopiperidin-3-yl)-5-((4-(8-fluoro-6-oxo-1,3,4,5-tetrahydro-1H-azepino[5,4,3-cd ]indol-2-yl)benzyl)(methyl)amino)isoindoline-1,3-dione 8-Fluoro-1,3,4,5-tetrahydro-2-[4-[(methylamino)methyl]phenyl]-6H-pyrrolo[4,3,2-ef][2]benzazepine-6-one (34A) (120mg, 0.372mmol),2-(2,6-dioxo-3-piperidinyl)-5-fluorodihydroisoindole-1,3-dione (114mg, 0.412mmol) was dissolved in 2mL DMSO,Add N,N-diisopropylethylamine (222mg, 1.72mmol), and react at 90°C for 2 hours after the addition is complete.After the reaction, cool to room temperature, add 10 mL of water, filter, dissolve the filter cake with 20 mL of dichloromethane, wash with 5 mL of saturated sodium chloride, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude silica gel column purification, eluent : DCM-2% MeOH/DCM-5% MeOH/DCM, the crude product was obtained and then sent to liquid phase preparation to obtain compound 34 as a yellow solid (100 mg, 46%).
  • 27
  • [ 835616-61-0 ]
  • [ 64834-63-5 ]
  • 2-(2,6-dioxo-3-piperidyl)-5-(2-hydroxyethyl-((4-methoxyphenyl)methyl)amino)isoindoline-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 120℃; for 16h;
  • 28
  • [ 835616-61-0 ]
  • [ 1251006-64-0 ]
  • tert-butyl 3-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]azetidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 100℃; for 16h; Inert atmosphere; 5 To a solution of tert-butyl 3-(4-piperidyl)azetidine-l-carboxylate (0.4 g, 1.66 mmol, 1 eq) and 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-l,3-dione (413.74 mg, 1.50 mmol, 0.9 eq) and DIEA (1.08 g, 8.32 mmol, 1.45 mL, 5 eq) in DMSO (20. mL). Then the mixture was stirred at 100 °C for 16hr under N2. TLC (Dichloromethane: Methanol=10:l, Rf=0.6) showed no start material and a new spot. The residue was diluted with H20 (50 mL) extracted with ethyl acetate (70 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (0 to 10% Methanol in Dichloromethane) to give tert-butyl 3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]-4-piperidyl]azetidine-l-carboxylate (800 mg, 1.47 mmol, 88.09% yield, 91% purity) as a yellow solid.
  • 29
  • [ 892493-65-1 ]
  • [ 835616-61-0 ]
  • tert‐butyl 1‐[2‐(2,6‐dioxo‐3‐piperidyl)‐1,3‐dioxo‐isoindolin‐5‐yl]piperidine‐4‐carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
56% With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 90℃; for 18h;
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