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Chemical Structure| 2207541-30-6 Chemical Structure| 2207541-30-6

Structure of Lenalidomide-I
CAS No.: 2207541-30-6

Chemical Structure| 2207541-30-6

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Product Details of [ 2207541-30-6 ]

CAS No. :2207541-30-6
Formula : C13H11IN2O3
M.W : 370.14
SMILES Code : N1C(=O)C(N2C(=O)C3=C(C(=CC=C3)I)C2)CCC1=O
English Name :3-(4-Iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione
MDL No. :MFCD32862119
InChI Key :BKIUJJLYXXEGFT-UHFFFAOYSA-N
Pubchem ID :134348132

Safety of [ 2207541-30-6 ]

Application In Synthesis of [ 2207541-30-6 ]

* 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 [ 2207541-30-6 ]

[ 2207541-30-6 ] Synthesis Path-Downstream   1~12

  • 1
  • [ 191732-72-6 ]
  • [ 2207541-30-6 ]
YieldReaction ConditionsOperation in experiment
85% Stage #1: Lenalidomide With sulfuric acid; sodium nitrite In methanol; water at 0 - 20℃; for 0.333333h; Stage #2: With potassium iodide In methanol; water at 80℃; for 3h; 13 Synthesis of 3 -(4-(5-(6-((4-(4-chlorophenyl)-3 ,9-dimethyl-6H-thieno [3 ,2-fj [1 ,2,4j triazolo [4,3 -aj [1 ,4j diazepin-2-yl)ethynyl)pyridin-3 -yl)pent- 1 -yn- 1-yl)- 1 -oxoisoindolin-2-yl)piperidine-2,6-dione (Cpd. No. 13) To a suspended solution of lenalidomide (1.04 g, 4.0 mmol, 1.0 eq) and NaNO2 (0.83 g, 12.0 mmol, 3.0 eq) in 40 mL of water at 0 °C was added diluted sulfuric acid (4.0 mL in 10 mL of water). Then the solution was stirred at room temperature for 20 mm. Then a solution of KI (3.32 g, 20.0 mmol, 5.0 eq) in 20 mL of water was added and the solution was heated to 80 °C to stir for 3 h. After cooling to room temperature, NaOH (aq) was added to neutralize the solution and the concentrated residue was purified by flash column chromatography with DCM/ MeOH to afford the compound S38 as a slightly yellow solid (1.26 g, 85% yield). UPLC-MS calculated for C,3H,21N203 [M+1j:370.99, found 370.95.
68% With tert.-butylnitrite; diiodomethane In acetonitrile Inert atmosphere; Cooling with ice; Reflux; 1.1 (1) Synthesis of Compound 1 Dissolve lenalidomide (8.87 mmol, 1.0 equiv.) and CH2I2 (1.0 equiv.) in 20 mL of acetonitrile, replace the system with nitrogen three times, add tert-butyl nitrite (4.5 equiv.) to the solution under ice bath, and reflux until lenalidomide disappears. After the reaction is completed, cool to room temperature, evaporate the solvent under reduced pressure, add 10 mL of water to the residue, extract three times with 20 mL of ethyl acetate, and combine the organic phases. Wash the organic phase with 10 mL of saturated brine, and treat it with silica gel column chromatography (DCM/EtOAc=3:1) to obtain brown solid compound 1 (6.03 mmol).
67% Stage #1: Lenalidomide With hydrogenchloride; sodium nitrite In water at -5℃; for 1h; Stage #2: With potassium iodide In water at 20℃; 1 Take S1 (260mg, 1mmol) and dissolve it in concentrated hydrochloric acid/water (5mL/5mL), and slowly add aqueous sodium nitrite solution dropwise at -5°C(138 mg, 2 mmol, dissolved in 1 mL of water), continue stirring for 1 hour, and then dropwise add potassium iodide aqueous solution (332 mg, 2 mmol, dissolved in 1 mL of water)water), move to room temperature and stir overnight after adding dropwise, after TLC (dichloromethane/methanol=15/1) monitoring raw material reaction is complete, filter waterWash three times to get brown solid S11 (250mg, 67%
72 % Stage #1: Lenalidomide With sulfuric acid; sodium nitrite In water at 20℃; Stage #2: With potassium iodide In water at 80℃; Cooling with ice; 1.5.1 Step 1: UBI-1237 (V1782-042) A1 (5.2 g, 20 mmol), and NaNO 2 (4.15 g, 60 mmol) were added to water (200 mL), diluted H 2SO 4 (20 mL of concentrated sulfuric acid plus 50 mL of water) was slowly added dropwise over about 75 minutes. Then after reacting at room temperature for 30 minutes, 100 mL aqueous solution of KI (16.6 g, 100 mmol) was added dropwise in ice bath, then the mixture was reacted at 80°C. for 3 hours, and stood till cooling down. The mixture was filtered. The filter cake was washed repeatedly with petroleum ether and water. The solid was recrystallized with ethanol to obtain product UBI-1237 (5.4 g, yield 72%) as a brownish yellow solid. LCMS [M+H] +=371 1H NMR (400 MHz, DMSO-d 6) δ 11.01 (s, 1H), 8.04 (d, J=7.7 Hz, 1H), 7.77 (t, J=5.6 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 5.15 (m, 1H), 4.29 (d, J=17.5 Hz, 1H), 4.14 (d, J=17.5 Hz, 1H), 2.91 (m, 1H), 2.66-2.55 (m, 1H), 2.49-2.42 (m, 1H), 2.02 (m, 1H).
72 % Stage #1: Lenalidomide With sulfuric acid; sodium nitrite In water at 20℃; Stage #2: With potassium iodide In water at 80℃; Cooling with ice; 1.5.1 Step 1: UBI-1237 (V1782-042) A1 (5.2 g, 20 mmol), and NaNO 2 (4.15 g, 60 mmol) were added to water (200 mL), diluted H 2SO 4 (20 mL of concentrated sulfuric acid plus 50 mL of water) was slowly added dropwise over about 75 minutes. Then after reacting at room temperature for 30 minutes, 100 mL aqueous solution of KI (16.6 g, 100 mmol) was added dropwise in ice bath, then the mixture was reacted at 80°C. for 3 hours, and stood till cooling down. The mixture was filtered. The filter cake was washed repeatedly with petroleum ether and water. The solid was recrystallized with ethanol to obtain product UBI-1237 (5.4 g, yield 72%) as a brownish yellow solid. LCMS [M+H] +=371 1H NMR (400 MHz, DMSO-d 6) δ 11.01 (s, 1H), 8.04 (d, J=7.7 Hz, 1H), 7.77 (t, J=5.6 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 5.15 (m, 1H), 4.29 (d, J=17.5 Hz, 1H), 4.14 (d, J=17.5 Hz, 1H), 2.91 (m, 1H), 2.66-2.55 (m, 1H), 2.49-2.42 (m, 1H), 2.02 (m, 1H).
45.2 g With copper(l) iodide; tert.-butylnitrite In acetonitrile at 60℃; for 12h; Inert atmosphere; 1.1 Intermediate 26: 3-(4-iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione To a solution of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (CAS No 191732-72-6, 25.0 g, 96.41 mmol) in acetonitrile (300 mL) was added copper(I) iodide (28.10 g, 144.6 mmol). The reaction mixture was purged with argon gas for 20 min then tert-butyl nitrite (16.57 g, 144.6 mmol) was added and the reaction mixture was heated at 60°C for 12h. The reaction mixture was poured then into water (300 mL), a solid precipitate formed, which was filtered and dried under vacuum to afford 3-(4-iodo-1-oxoisoindolin-2-yl) piperidine-2, 6-dione (Intermediate 26, 45.2 g) as an off white solid, which was used for the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.98-2.04 (m, 2H), 2.82-2.98 (m, 2H), 4.11-4.32 (m, 2H), 5.13 (m, 1H), 7.31-7.42 (m, 1H), 7.71-7.80 (m, 1H), 7.98-8.06 (m, 1H), 10.99 (br s, 1H). Mass spec: m/z [M+H]+371.0.

  • 2
  • [ 2207541-30-6 ]
  • [ CAS Unavailable ]
  • [ 2207541-23-7 ]
YieldReaction ConditionsOperation in experiment
79% With copper(l) iodide; trans-bis(triphenylphosphine)palladium dichloride; triethylamine In N,N-dimethyl-formamide at 80℃; for 4h; 7 Synthesis of 4-(2-(2,6-dioxopiperidin-3-yl)- 1-oxoisoindolin-4-yl)but-3-yn- 1-yl 4-(4-((3- benzyl-9-methyl-4H,6H-thieno [2,3 -e][1 ,2,4] triazolo [3 ,4-c][1 ,4]oxazepin-2-yl)ethynyl)-1H-pyrazol- 1 -yl)butano ate Step 1: To compound 6 (370 mg, 1 mmol) in 10 mL DMF, L12 (317 mg) andmL TEA were added Pd(PPh3)2C12 (30 mg) and CuT (20 mg). After degassing, themixture was stirred at 80 °C for 4 h. After distilling solvent under vacuum, the residuewas purified via Combi-Flash column using DCM and MeOH to give 7 as a white solid(246 mg, 79%). ESI-MS:3 13.11.
54 % With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide In N,N-dimethyl-formamide at 80℃; Inert atmosphere; 1.4.7.4 Step 4: UBI-1309f (V2127-024) UBI-1309d (500 mg, 1.35 mmol), 3-butyne-1-ol (94 mg, 1.35 mmol), Pd(PPh3)2Cl2 (94 mg, 0.135 mmol) and cuprous iodide (51 mg, 0.27 mmol) were added to DMF (2 mL), the mixture was reacted at 80°C. for 16 hours under N 2 protection. The mixture was purified by reversed-phase chromatography column (MeOH/H2O=5%-95%, 45 min), collected at 60% to obtain compound UBI-1309f (215 mg, yield 54%) as a white solid.
54 % With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide In N,N-dimethyl-formamide at 80℃; Inert atmosphere; 1.4.7.4 Step 4: UBI-1309f (V2127-024) UBI-1309d (500 mg, 1.35 mmol), 3-butyne-1-ol (94 mg, 1.35 mmol), Pd(PPh3)2Cl2 (94 mg, 0.135 mmol) and cuprous iodide (51 mg, 0.27 mmol) were added to DMF (2 mL), the mixture was reacted at 80°C. for 16 hours under N 2 protection. The mixture was purified by reversed-phase chromatography column (MeOH/H2O=5%-95%, 45 min), collected at 60% to obtain compound UBI-1309f (215 mg, yield 54%) as a white solid.
  • 3
  • [ 1338564-53-6 ]
  • [ 2207541-30-6 ]
  • [ 2408797-43-1 ]
YieldReaction ConditionsOperation in experiment
81% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 75℃; for 6.5h; Inert atmosphere; h?/7-Butyl 2-(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)prop-2-yn-l- yl)oxy)ethoxy)ethoxy)acetate (SR3-072) SM2-081 (0.050 g, 0.135 mmol) and the alkyne SR3-066 (0.042 g, 0.162 mmol) were added into a solution of PdCl2(PPli3)2 (0.009 g, 0.014 mmol) and Cul (0.005 g, 0.027 mmol) in DMF (1.75 mL) under Ar. The mixture was heated at 75 °C for 6.5 h. The reaction mixture was cooled and filtered through Celite. The Celite bed was rinsed with EtOAc (20 mL). The filtrate and ethyl acetate wash was concentrated under reduced pressure and purified by flash column chromatography using MeOH:DCM (0-10%) as eluent to afford SR3-072 as an off-white solid (0.055 g, 81%). 1 H NMR (500 MHz, DMSO-de) d 11.00 (s, 1H), 7.77 (dd, J = 7.6, 1.1 Hz, 1H), 7.73 (dd, J = 7.6, 1.0 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 5.15 (dd, 7 = 13.3, 5.1 Hz, 1H), 4.50 (d, J = 17.7 Hz, 1H), 4.46 (s, 2H), 4.35 (d, J = 17.7 Hz, 1H), 3.98 (s, 2H), 3.68-3.64 (m, 2H), 3.61-3.46 (m, 6H), 2.91 (ddd, J = 17.2, 13.6, 5.4 Hz, 1H), 2.65-2.55 (m, 1H), 2.44 (m, 1H), 2.01 (ddd, J = 9.5, 5.4, 2.7 Hz, 1H), 1.41 (s, 9H). 13C NMR (126 MHz, DMSO) d 172.8, 170.9, 169.3, 167.5, 143.9, 134.4, 132.1, 128.7, 123.5, 117.5, 91.3, 81.3, 80.6, 72.3, 69.8, 69.7, 69.5, 68.8, 68.1, 60.2, 58.1, 51.6, 46.9, 31.2, 27.7, 22.3. HRMS (ESI+): m/z calcd for C26H33N2O8 (M+H)+ 501.2231, found 501.2240, m/z calcd for C26H32N208Na (M+Na)+ 523.2051, found 523.2069. HPLC-MS (ESI+): m/z 523.2 [100%, (M+Na)+] HPLC-MS (ESI-): m/z 499.3 [40%, M-H ]
81% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 75℃; for 6.5h; Inert atmosphere; tert-Butyl 2-(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethoxy)acetate(SR3-072): SM2-081(0.050 g,0.135 mmol)and the alkyne SR3-066(0.042 g,0.162 mmol)were added into a solution of PdCl2(PPh3)2(0.009 g,0.014 mmol)and CuI(0.005 g,0.027 mmol)in DMF(1.75 mL)under Ar. The mixture was heated at 75 °C for 6.5 h. The reaction mixture was c00led and filtered through Celite. The Celite bed was rinsed with EtOAc(20 mL). The filtrate and ethyl acetate wash was concentrated under reduced pressure and purified by flash column chromatography using MeOH:DCM(0-10%)as eluent to afford SR3-072 as an off-white solid(0.055 g,81%).1H NMR(500 MHz,DMSO-d6)δ 11.00(s,1H),7.77(dd,J = 7.6,1.1 Hz,1H),7.73(dd,J = 7.6,1.0 Hz,1H),7.56(t,J = 7.6 Hz,1H),5.15(dd,J = 13.3,5.1 Hz,1H),4.50(d,J = 17.7 Hz,1H),4.46(s,2H),4.35(d,J = 17.7 Hz,1H),3.98(s,2H),3.68-3.64(m,2H),3.61-3.46(m,6H),2.91(ddd,J = 17.2,13.6,5.4 Hz,1H),2.65-2.55(m,1H),2.44(m,1H),2.01(ddd,J = 9.5,5.4,2.7 Hz,1H),1.41(s,9H).13C NMR(126 MHz,DMSO)δ 172.8,170.9,169.3,167.5,143.9,134.4,132.1,128.7,123.5,117.5,91.3,81.3,80.6,72.3,69.8,69.7,69.5,68.8,68.1,60.2,58.1,51.6,46.9,31.2,27.7,22.3. HRMS(ESI+): m/z calcd for C26H33N2O8(M+H)+501.2231,found 501.2240,m/z calcd for C26H32N2O8Na(M+Na)+523.2051,found 523.2069. HPLC-MS(ESI+): m/z 523.2 [100%,(M+Na)+]. HPLC-MS(ESI-): m/z 499.3 [40%,M-H-].
  • 4
  • [ 2207541-30-6 ]
  • [ 74-88-4 ]
  • [ 2241014-55-9 ]
YieldReaction ConditionsOperation in experiment
71% With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 0 - 25℃; for 2h; 19 Synthesis of 3-(4-iodo-1-oxo-3H-isoindol-2-yl)-1 -methylpiperidine-2, 6-dione: Into a 100 mL roundbottom flask, were placed 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (1.5 g, 4.1 mmol, 1.0 eq), N,N- dimethylformamide (20 mL), CH3I (1.2 g, 8.1 mmol, 2.0 eq). After that, DBU (1.2 g, 8.1 mmol, 2.0 eq) was added at 0°C. The reaction mixture was stirred for 2 hours at 25°C. The resulting mixture was concentrated under vacuum. The residue was diluted with water (100 mL) and extracted with ethyl acetate (2x80 mL). The combined organic phase was washed with brine (2x80 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether= (0:1 to 1 :1) to give 3-(4-iodo-1 -oxo-3H-isoindol-2-yl)-1 - methylpiperidine-2, 6-dione (1.1 g, 71%) as a purple solid. LC-MS (ESI, m/z) M+1 : 385. 1HNMR (400 MHz, DMSO-cfc) 5 8.04 (dd, J=7.4, 2.0 Hz, 1H), 7.78 (dd, J=7.6, 3.4 Hz, 1 H), 7.36 (t, J=7.8 Hz, 1 H), 5.30-5.12 (m, 1 H), 4.34-4.23 (m, 1 H), 4.15 (d, J=17.4 Hz, 1 H), 3.02 (s, 3H), 2.98 (dd, J=12.8, 4.6 Hz, 1 H), 2.79 (dd, J=4.6, 2.4 Hz, 1H), 2.45 (dd, J=13.2, 4.6 Hz, 1 H), 2.10-1.97 (m, 1H).
71% With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 0 - 25℃; for 2h; 19 Synthesis of 3-(4-iodo-1-oxo-3H-isoindol-2-yl)-1 -methylpiperidine-2, 6-dione: Into a 100 mL roundbottom flask, were placed 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (1.5 g, 4.1 mmol, 1.0 eq), N,N- dimethylformamide (20 mL), CH3I (1.2 g, 8.1 mmol, 2.0 eq). After that, DBU (1.2 g, 8.1 mmol, 2.0 eq) was added at 0°C. The reaction mixture was stirred for 2 hours at 25°C. The resulting mixture was concentrated under vacuum. The residue was diluted with water (100 mL) and extracted with ethyl acetate (2x80 mL). The combined organic phase was washed with brine (2x80 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether= (0:1 to 1 :1) to give 3-(4-iodo-1 -oxo-3H-isoindol-2-yl)-1 - methylpiperidine-2, 6-dione (1.1 g, 71%) as a purple solid. LC-MS (ESI, m/z) M+1 : 385. 1HNMR (400 MHz, DMSO-cfc) 5 8.04 (dd, J=7.4, 2.0 Hz, 1H), 7.78 (dd, J=7.6, 3.4 Hz, 1 H), 7.36 (t, J=7.8 Hz, 1 H), 5.30-5.12 (m, 1 H), 4.34-4.23 (m, 1 H), 4.15 (d, J=17.4 Hz, 1 H), 3.02 (s, 3H), 2.98 (dd, J=12.8, 4.6 Hz, 1 H), 2.79 (dd, J=4.6, 2.4 Hz, 1H), 2.45 (dd, J=13.2, 4.6 Hz, 1 H), 2.10-1.97 (m, 1H).
62% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 3h; 3-(4-Iodo-l-oxoisoindolin-2-yl)-l-methylpiperidine-2,6-dione (SM3-098) The K2CO3 (448.1 mg, 3.24 mmol) and Mel (0.25 mL, 4.05 mmol) were added to a solution of SM2-081 (1.00 g, 2.70 mmol) in DMF (8.0mL), and the mixture was stirred at 60 °C for 3 h. Water and EtOAc were added to the mixture. The aqueous layer was extracted with EtOAc (3x20 mL), combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated. The title compound was obtained by triturating from EtO Ac/hexane and MeOH as a white solid (0.65 g, 62%). lH NMR (500 MHz, DMSO-i 6) d 8.04 (dd, J = 0.9, 7.8 Hz, 1H), 7.78 (dd, J = 0.9, 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 5.22 (dd, J = 5.1, 13.5 Hz, 1H), 4.28 (d, J = 17.4 Hz, 1H), 4.14 (d, J = 17.4 Hz, 1H), 3.03 - 2.95 (m, 4H), 2.78 -2.73 (m, 1H), 2.48 - 2.41 (m, 1H), 2.00 - 2.05 (m, 1H). 13C NMR (126 MHz, CDCb) d 171.20, 169.99, 168.97, 146.28, 140.99, 133.52, 130.23, 124.00, 90.57, 52.65, 51.36, 32.16, 27.35, 22.88. HPLC-MS (ESI+): m/z 791.0 [100%, (2M+Na)+], 385.0 [50%, (M+H)+] HRMS (ESI+): m/z calcd for C14H13IN2O3 (M+H)+ 385.0044, found 385.0039.
62% With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 3h; 3-(4-Iodo-1-oxoisoindolin-2-yl)-1-methylpiperidine-2,6-dione(SM3-098): The K2CO3(448.1 mg,3.24 mmol)and MeI(0.25 mL,4.05 mmol)were added to a solution of SM2-081(1.00 g,2.70 mmol)in DMF(8.0mL),and the mixture was stirred at 60 °C for 3 h. Water and EtOAc were added to the mixture. The aqueous layer was extracted with EtOAc(3×20 mL),combined organic layers were washed with brine,dried(Na2SO4),filtered and concentrated. The title compound was obtained by triturating from EtOAc/hexane and MeOH as a white solid(0.65 g,62%).1H NMR(500 MHz,DMSO-d6)δ 8.04(dd,J = 0.9,7.8 Hz,1H),7.78(dd,J = 0.9,7.6 Hz,1H),7.35(t,J = 7.6 Hz,1H),5.22(dd,J = 5.1,13.5 Hz,1H),4.28(d,J = 17.4 Hz,1H),4.14(d,J = 17.4 Hz,1H),3.03 - 2.95(m,4H),2.78-2.73(m,1H),2.48 - 2.41(m,1H),2.00 - 2.05(m,1H).13C NMR(126 MHz,CDCl3)δ 171.20,169.99,168.97,146.28,140.99,133.52,130.23,124.00,90.57,52.65,51.36,32.16,27.35,22.88. HPLC-MS(ESI+): m/z 791.0 [100%,(2M+Na)+],385.0 [50%,(M+H)+]. HRMS(ESI+): m/z calcd for C14H13IN2O3(M+H)+385.0044,found 385.0039.
70 % With potassium carbonate In N,N-dimethyl-formamide at 60℃;

  • 5
  • [ 312747-81-2 ]
  • [ 2353-44-8 ]
  • [ 2207541-30-6 ]
YieldReaction ConditionsOperation in experiment
80% With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; 6 To a stirred solution of methyl-2-(bromomethyl)-3-iodobenzoate (4.66 g, 13.2 mmol) and 3-aminopiperidine-2,6-dione (2.59 g, 15.7 mmol) in ACN (20 mL) was added DIPEA (8.39 g, 65.5 mmol). After stirred at 90 °C overnight, the mixture was poured into water and filtered to give 3-(4-iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3.9 g) in 80% yield. MS (ESI) m/z: 370.1 [M+H]+
66% With triethylamine In acetonitrile at 80℃; for 14h; INT-6 Synthesis of 3-(4-iodo-1 -oxo-3H-isoindol-2-yl)piperidine-2, 6-dione: A mixture of methyl 2- (bromomethyl)-3-iodobenzoate (16.0 g, 45.1 mmol, 1.0 eq), 3-aminopiperidine-2, 6-dione (8.7 g, 67.6 mmol, 1.5 eq) and triethylamine (13.7 g, 135.2 mmol, 3.0 eq) in acetonitrile (150 mL) was stirred for 14 hours at 80°C. The resulting mixture was concentrated under vacuum, diluted with ethyl acetate (100 mL) and water (100 mL). The precipitated solids were collected by filtration and washed with water (50 mL). Finally, 3-(4-iodo-1-oxo-3H- isoindol-2-yl)piperidine-2, 6-dione (11.0 g, 66%) was obtained as a blue solid. 1HNMR (300 MHz, DMSO-ofc) 8 11.02 (bs, 1 H), 7.88 (d, J=7.8 Hz, 1 H), 7.78 (d, J=7.5 Hz, 1H), 7.52 (t, J=7.8 Hz, 1 H), 5.16 (dd, J=13.2, 5.1 Hz, 1 H), 4.43 (d, J=17.7 Hz, 1 H), 4.27 (d, J=17.7 Hz, 1H), 2.93 (ddd, J=18.3, 13.5, 5.4 Hz, 1 H), 2.66-2.52 (m, 1 H), 2.44 (dd, J=13.5, 4.5 Hz, 1H), 2.11-1.96 (m, 1 H).
66% With triethylamine In acetonitrile at 80℃; for 14h; INT-6 Synthesis of 3-(4-iodo-1 -oxo-3H-isoindol-2-yl)piperidine-2, 6-dione: A mixture of methyl 2- (bromomethyl)-3-iodobenzoate (16.0 g, 45.1 mmol, 1.0 eq), 3-aminopiperidine-2, 6-dione (8.7 g, 67.6 mmol, 1.5 eq) and triethylamine (13.7 g, 135.2 mmol, 3.0 eq) in acetonitrile (150 mL) was stirred for 14 hours at 80°C. The resulting mixture was concentrated under vacuum, diluted with ethyl acetate (100 mL) and water (100 mL). The precipitated solids were collected by filtration and washed with water (50 mL). Finally, 3-(4-iodo-1-oxo-3H- isoindol-2-yl)piperidine-2, 6-dione (11.0 g, 66%) was obtained as a blue solid. 1HNMR (300 MHz, DMSO-ofc) 8 11.02 (bs, 1 H), 7.88 (d, J=7.8 Hz, 1 H), 7.78 (d, J=7.5 Hz, 1H), 7.52 (t, J=7.8 Hz, 1 H), 5.16 (dd, J=13.2, 5.1 Hz, 1 H), 4.43 (d, J=17.7 Hz, 1 H), 4.27 (d, J=17.7 Hz, 1H), 2.93 (ddd, J=18.3, 13.5, 5.4 Hz, 1 H), 2.66-2.52 (m, 1 H), 2.44 (dd, J=13.5, 4.5 Hz, 1H), 2.11-1.96 (m, 1 H).
65.9% With triethylamine In acetonitrile at 80℃; for 14h; 23 Synthesis of 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione: Into a 500 mL round-bottom flask, were placed methyl 2-(bromomethyl)-3-iodobenzoate (16.0 g, 45.1 mmol, 1.0 eq), 3-aminopiperidine-2,6- dione (8.7 g, 67.6 mmol, 1.5 eq), triethylamine (13.7 g, 135.2 mmol, 3.0 eq) and CH3CN (150 mL). The reaction mixture was stirred for 14 hours at 80°C. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with ethyl acetate (100 mL) and water (100 mL). The precipitated solids were collected by filtration and washed with water (2x50 mL). Finally, 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione was obtained as a blue solid (11.0 g, 65.9%). 1HNMR (300 MHz, DMSO-d6) 6 11 .02 (br, 1 H), 7.88 (d, J=7.8 Hz, 1 H), 7.78 (d, J=7.5 Hz, 1 H), 7.52 (t, J=7.8 Hz, 1 H), 5.16 (dd, J=13.2, 5.1 Hz, 1 H), 4.43 (d, J=17.7 Hz, 1 H), 4.27 (d, J=17.7 Hz, 1 H), 3.01-2.93 (m, 2H), 2.66-2.52 (m, 1 H), 2.11-1.96 (m, 1H).
65.9% With triethylamine In acetonitrile at 80℃; for 14h; 23 Synthesis of 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione: Into a 500 mL round-bottom flask, were placed methyl 2-(bromomethyl)-3-iodobenzoate (16.0 g, 45.1 mmol, 1.0 eq), 3-aminopiperidine-2,6- dione (8.7 g, 67.6 mmol, 1.5 eq), triethylamine (13.7 g, 135.2 mmol, 3.0 eq) and CH3CN (150 mL). The reaction mixture was stirred for 14 hours at 80°C. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with ethyl acetate (100 mL) and water (100 mL). The precipitated solids were collected by filtration and washed with water (2x50 mL). Finally, 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione was obtained as a blue solid (11.0 g, 65.9%). 1HNMR (300 MHz, DMSO-d6) 6 11 .02 (br, 1 H), 7.88 (d, J=7.8 Hz, 1 H), 7.78 (d, J=7.5 Hz, 1 H), 7.52 (t, J=7.8 Hz, 1 H), 5.16 (dd, J=13.2, 5.1 Hz, 1 H), 4.43 (d, J=17.7 Hz, 1 H), 4.27 (d, J=17.7 Hz, 1 H), 3.01-2.93 (m, 2H), 2.66-2.52 (m, 1 H), 2.11-1.96 (m, 1H).
66 % With triethylamine In acetonitrile at 80℃; Synthesis of 3-(4-iodo-1 -oxo-3H-isoindol-2-yl)piperidine-2, 6-dione: A mixture of methyl 2-(bromomethyl)-3-iodobenzoate (16.0 g, 45.1 mmol, 1.0 eq), 3-aminopiperidine-2, 6-dione (8.7 g, 67.6 mmol, 1.5 eq) and triethylamine (13.7 g, 135.2 mmol, 3.0 eq) in acetonitrile (150 mL) was stirred for 14 hours at 80°C. The resulting mixture was concentrated under vacuum, diluted with ethyl acetate (100 mL) and water (100 mL). The precipitated solids were collected by filtration and washed with water (50 mL). Finally, 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (11.0 g, 66%) was obtained as a blue solid.1HNMR (300 MHz, DMSO-d6) 5 11.02 (bs, 1 H), 7.88 (d, J=7.8 Hz, 1 H), 7.78 (d, J=7.5 Hz, 1 H), 7.52 (t, J=7.8 Hz, 1 H), 5.16 (dd, J=13.2, 5.1 Hz, 1 H), 4.43 (d, J=17.7 Hz, 1 H), 4.27 (d, J=17.7 Hz, 1 H), 2.93 (ddd, J=18.3, 13.5, 5.4 Hz, 1 H), 2.66-2.52 (m, 1 H), 2.44 (dd, J=13.5, 4.5 Hz, 1 H), 2.11-1.96 (m, 1 H).

  • 6
  • [ 2207541-30-6 ]
  • [ 287192-97-6 ]
  • [ 2415160-55-1 ]
YieldReaction ConditionsOperation in experiment
75% With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); copper (I) iodide; triethylamine In tetrahydrofuran at 65℃; for 6h; Inert atmosphere; 6.3 To a solution of 3-(4-iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 2.7 mmol) in THF (20 mL) were added tert-butyl 4-ethynylpiperidine-1-carboxylate (520 mg, 2.46 mmol), CuI (50 mg, 0.25 mmol), and TEA (2.48 g, 24.6 mmol), followed by addition of Pd(PPh3)2Cl2 (180 mg, 0.25 mmol) under N2. After stirred at 65 °C for 6 h, the mixture was filtered, concentrated, and purified using silica gel eluting with DCM in EtOAc from 10% to 50% to give tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethynyl)piperidine-1-carboxylate (1.01 g) in 75% yield. MS (ESI) m/z: 452.2 [M+1]+.
53% With copper (I) iodide; tetrakis-(triphenylphosphine)-palladium; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 6h; Inert atmosphere; 20 Synthesis of tert-butyl 4-{2- [2-(2, 6-dioxop i peri di n-3-y I )-1 -oxo-3H-isoindol-4- yl]ethynyl}piperidine-1 -carboxylate: To a stirred mixture of tert-butyl 4-ethynylpiperidine-1 -carboxylate (950 mg, 4.5 mmol, 1.0 eq) and 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (1680 mg, 4.5mmol, 1.0 eq) in N,N-dimethylformamide (20 mL), DIEA (4 mL) were added Pd(PPh3)4 (524 mg, 0.5 mmol, 0.1 eq) and Cui (86 mg, 0.5 mmol, 0.1 eq) in portions at 25°C under nitrogen atmosphere. The reaction mixture was stirred for 6 hours at 25°C. The resulting mixture was diluted with water (60 mL) and then extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with water (3x20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether= (0:1 to 1 :1) to give tert-butyl 4-{2-[2-(2,6- dioxopiperidin-3-yl)-1 -oxo-3H-isoindol-4-yl]ethynyl}piperidine-1 -carboxylate (1.1 g, 53%) as a brown solid. LC- MS (ESI, m/z) M+1 -tBu: 396.
53% With copper (I) iodide; tetrakis-(triphenylphosphine)-palladium; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 25℃; for 6h; Inert atmosphere; 20 Synthesis of tert-butyl 4-{2- [2-(2, 6-dioxop i peri di n-3-y I )-1 -oxo-3H-isoindol-4- yl]ethynyl}piperidine-1 -carboxylate: To a stirred mixture of tert-butyl 4-ethynylpiperidine-1 -carboxylate (950 mg, 4.5 mmol, 1.0 eq) and 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (1680 mg, 4.5mmol, 1.0 eq) in N,N-dimethylformamide (20 mL), DIEA (4 mL) were added Pd(PPh3)4 (524 mg, 0.5 mmol, 0.1 eq) and Cui (86 mg, 0.5 mmol, 0.1 eq) in portions at 25°C under nitrogen atmosphere. The reaction mixture was stirred for 6 hours at 25°C. The resulting mixture was diluted with water (60 mL) and then extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with water (3x20 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether= (0:1 to 1 :1) to give tert-butyl 4-{2-[2-(2,6- dioxopiperidin-3-yl)-1 -oxo-3H-isoindol-4-yl]ethynyl}piperidine-1 -carboxylate (1.1 g, 53%) as a brown solid. LC- MS (ESI, m/z) M+1 -tBu: 396.
  • 7
  • [ 2207541-30-6 ]
  • [ 149990-27-2 ]
  • [ 2727151-46-2 ]
YieldReaction ConditionsOperation in experiment
70% With copper(l) iodide; Pd(PPh3)2Cl2; triethylamine In N,N-dimethyl-formamide at 85℃; for 5h; Inert atmosphere; 1 Take the above S11 (370mg, 1mmol), cuprous iodide (380mg, 5mmol), bis(triphenylphosphine) palladium dichloride(105mg, 0.15mmol), triethylamine (696uL, 5mmol) was dissolved in anhydrous N,N-dimethylformamide, after nitrogen replacement 3 times, tert-butyl 3-butynecarbamate (519uL, 3mmol) was added , 85 of stirring reaction 5 hours, after the reaction is complete, ethyl acetate is dilutedreleased, washed with water for three times, and after concentration, dichloromethane/methanol=20/1 column chromatography gave brown solid product S12 (290 mg, 70%),
56.2 % With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 80℃; 7 Step 7: UB-180925i (V2031-121) UBI-1237 (400 mg, 1.08 mmol), UB-180925h (274 mg, 1.62 mmol), PdCl2(PPh3)2 (38 mg, 0.05 mmol), copper iodide (21 mg), and triethylamine (491 mg) was added to anhydrous DMF (5 mL). The reaction system was stirred at 80°C. for 2 hours, the reaction was cooled down to room temperature after completion. The mixture was added into water, extracted with dichloromethane, brine (30 mL), dried over sodium sulfate, filtered, and concentrated, then isolated by silica gel column chromatography (dichloromethane/methanol=10%) to obtain UB-180925i (250 mg, yield 56.2%) as a yellow solid. LCMS: [M+H] +=412.2 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.71 (dd, J=7.6, 1.1Hz, 1H), 7.64 (dt, J=8.1, 1.9 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.11-6.97 (m, 1H), 5.15 (dd, J=13.3, 5.1Hz, 1H), 3.18 (q, J=6.6 Hz, 2H), 3.04 (q, J=6.6 Hz, 1H), 2.98-2.89 (m, 1H), 2.62 (s, 1H), 2.61-2.54 (m, 2H), 2.45 (dd, J=13.1, 4.4 Hz, 1H), 2.39 (t, J=6.7 Hz, 1H), 2.02 (dd, J=8.9, 3.6 Hz, 1H), 1.37 (d, J=4.7 Hz, 9H).
56.2 % With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 80℃; 7 Step 7: UB-180925i (V2031-121) UBI-1237 (400 mg, 1.08 mmol), UB-180925h (274 mg, 1.62 mmol), PdCl2(PPh3)2 (38 mg, 0.05 mmol), copper iodide (21 mg), and triethylamine (491 mg) was added to anhydrous DMF (5 mL). The reaction system was stirred at 80°C. for 2 hours, the reaction was cooled down to room temperature after completion. The mixture was added into water, extracted with dichloromethane, brine (30 mL), dried over sodium sulfate, filtered, and concentrated, then isolated by silica gel column chromatography (dichloromethane/methanol=10%) to obtain UB-180925i (250 mg, yield 56.2%) as a yellow solid. LCMS: [M+H] +=412.2 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.71 (dd, J=7.6, 1.1Hz, 1H), 7.64 (dt, J=8.1, 1.9 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.11-6.97 (m, 1H), 5.15 (dd, J=13.3, 5.1Hz, 1H), 3.18 (q, J=6.6 Hz, 2H), 3.04 (q, J=6.6 Hz, 1H), 2.98-2.89 (m, 1H), 2.62 (s, 1H), 2.61-2.54 (m, 2H), 2.45 (dd, J=13.1, 4.4 Hz, 1H), 2.39 (t, J=6.7 Hz, 1H), 2.02 (dd, J=8.9, 3.6 Hz, 1H), 1.37 (d, J=4.7 Hz, 9H).
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 85℃; Inert atmosphere; 15.a Synthesis of Int. 114 Into a 40 mL vial were added 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (racemic) (500 mg, 1.35 mmol, 1 eq.), DMF (5 mL), tert-butyl but-3-yn-1-ylcarbamate (274 mg, 1.62 mmol, 1.2 eq.), TEA (683 mg, 6.76 mmol, 5 eq.), Pd(PPh3)2Cl2 (95 mg, 0.14 mmol, 0.1 eq.) and CuI (10 mg, 0.054 mmol, 0.04 eq.) at 18 °C. The reaction was stirred for 5 h at 85 °C under nitrogen. The mixture was allowed to cool to 18 °C, quenched with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue purified by reversed-phase flash chromatography on a C18 column using a 40 to 70% gradient of MeCN in water (containing 0.1% formic acid) over 20 min to afford tert-butyl (4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)but-3-yn-1-yl)carbamate (racemic) (400 mg, yield = 69%) as a brown solid. LCMS: (ES, m/z): [MC4H8]+ = 356 (LCMS condition: Column: HALO 90A C18; Mobile phase A: water (containing 0.1% formic acid); Mobile phase B: MeCN (containing 0.1% formic acid); Flow rate: 1.5 mL/min.; RT: 0.775 min)

  • 8
  • [ 10160-87-9 ]
  • [ 2207541-30-6 ]
  • [ 2807573-50-6 ]
YieldReaction ConditionsOperation in experiment
89.9% With copper (I) iodide; tetrakis-(triphenylphosphine)-palladium; triethylamine In N,N-dimethyl-formamide at 70℃; for 2h; Inert atmosphere; INT-7 Synthesis of 3-[4-(3,3-diethoxyprop-1 -yn-1 -yl)-1-oxo-3H-isoindol-2-yl]piperidine-2, 6-dione: Into a 100 mL round flask purged and maintained under an inert atmosphere of nitrogen, were placed 3-(4-iodo-1 - oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (2.0 g, 5.4 mmol, 1.0 eq), 3,3-diethoxy-propyne (830 mg, 6.4 mmol, 1.2 eq), Pd(PPh3)4 (620 mg, 0.5 mmol, 0.1 eq), Cui (100 mg, 0.5 mmol, 0.1 eq), triethylamine (1.6 g, 16.2 mmol, 3.0 eq) and N,N-dimethylformamide (20 mL). The reaction mixture was stirred for 2 hours at 70°C. The resulting mixture was diluted with water (150 mL) and extracted with ethyl acetate (2x100 mL). The combined organic phase was washed with brine (2x100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether=1 :0 to give 3-[4-(3,3-diethoxyprop-1 -yn-1 -yl)-1 -oxo-3H-isoindol-2- yl]piperidine-2, 6-dione (1 .8 g, 89.9%) as light yellow solid. LC-MS (ESI, m/z) M+1 : 371 . 1H NMR (300 MHz, DMSO-ofe) 6 11.01 (s, 1 H), 7.79 (ddd, J=11.7, 7.5, 1.2 Hz, 2H), 7.68-7.51 (m, 2H), 5.60 (s, 1 H), 5.15 (dd, J=13.2, 5.1 Hz, 1 H), 4.51 (d, J=17.7 Hz, 1 H), 4.36 (d, J=17.7 Hz, 1H), 3.77-3.55 (m, 4H), 3.01-2.83 (m, 2H), 2.63 (s, 1 H), 2.11 -1 .97 (m, 1 H), 1 .19 (t, J=7.1 Hz, 6H).
89.9% With copper (I) iodide; tetrakis-(triphenylphosphine)-palladium; triethylamine In N,N-dimethyl-formamide at 70℃; for 2h; Inert atmosphere; INT-7 Synthesis of 3-[4-(3,3-diethoxyprop-1 -yn-1 -yl)-1-oxo-3H-isoindol-2-yl]piperidine-2, 6-dione: Into a 100 mL round flask purged and maintained under an inert atmosphere of nitrogen, were placed 3-(4-iodo-1 - oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (2.0 g, 5.4 mmol, 1.0 eq), 3,3-diethoxy-propyne (830 mg, 6.4 mmol, 1.2 eq), Pd(PPh3)4 (620 mg, 0.5 mmol, 0.1 eq), Cui (100 mg, 0.5 mmol, 0.1 eq), triethylamine (1.6 g, 16.2 mmol, 3.0 eq) and N,N-dimethylformamide (20 mL). The reaction mixture was stirred for 2 hours at 70°C. The resulting mixture was diluted with water (150 mL) and extracted with ethyl acetate (2x100 mL). The combined organic phase was washed with brine (2x100 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether=1 :0 to give 3-[4-(3,3-diethoxyprop-1 -yn-1 -yl)-1 -oxo-3H-isoindol-2- yl]piperidine-2, 6-dione (1 .8 g, 89.9%) as light yellow solid. LC-MS (ESI, m/z) M+1 : 371 . 1H NMR (300 MHz, DMSO-ofe) 6 11.01 (s, 1 H), 7.79 (ddd, J=11.7, 7.5, 1.2 Hz, 2H), 7.68-7.51 (m, 2H), 5.60 (s, 1 H), 5.15 (dd, J=13.2, 5.1 Hz, 1 H), 4.51 (d, J=17.7 Hz, 1 H), 4.36 (d, J=17.7 Hz, 1H), 3.77-3.55 (m, 4H), 3.01-2.83 (m, 2H), 2.63 (s, 1 H), 2.11 -1 .97 (m, 1 H), 1 .19 (t, J=7.1 Hz, 6H).
  • 9
  • [ 2207541-30-6 ]
  • [ 2807574-73-6 ]
  • [ 2807574-77-0 ]
YieldReaction ConditionsOperation in experiment
91% With copper (I) iodide; tetrakis-(triphenylphosphine)-palladium; triethylamine In N,N-dimethyl-formamide at 25℃; for 14h; Inert atmosphere; 36 Synthesis of 3-(4-{4-[(2R)-1 -(3-methoxy-4-nitrobenzoyl)piperidin-2-yl]but-1 -yn-1 -y I}- 1 -oxo-3H- isoindol-2-yl)piperidine-2,6-dione(assumed): To a stirred mixture of (2R)-2-(but-3-yn-1-yl)-1-(3-methoxy-4- nitrobenzoyl)piperidine (180 mg, 0.6 mmol, 1.0 eq) and 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (210 mg, 0.6 mmol, 1.0 eq) in N,N-dimethylformamide (6 mL) and triethylamine (2 mL) were added Cui (11 mg, 0.1 mmol, 0.1 eq) and Pd(PPhs)4 (66 mg, 0.1 mmol, 0.1 eq) in portions at 25°C under nitrogen atmosphere. The reaction mixture was stirred for 14 hours at 25°C. The resulting mixture was diluted with water (20 mL) and then extracted with ethyl acetate (3x15 mL). The combined organic layers were washed with water (2x10 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The residue was purified by a flash column (silica gel, dichloromethane/CH30H=100:0 to 100:5) to give 3-(4-{4-[(2R)-1-(3- methoxy-4-nitrobenzoyl)piperidin-2-yl]but-1 -yn-1 -yl}-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (400 mg, 91%) as a brown solid. LC-MS (ESI, m/z) M+1 : 559.
91% With copper (I) iodide; tetrakis-(triphenylphosphine)-palladium; triethylamine In N,N-dimethyl-formamide at 25℃; for 14h; Inert atmosphere; 36 Synthesis of 3-(4-{4-[(2R)-1 -(3-methoxy-4-nitrobenzoyl)piperidin-2-yl]but-1 -yn-1 -y I}- 1 -oxo-3H- isoindol-2-yl)piperidine-2,6-dione(assumed): To a stirred mixture of (2R)-2-(but-3-yn-1-yl)-1-(3-methoxy-4- nitrobenzoyl)piperidine (180 mg, 0.6 mmol, 1.0 eq) and 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (210 mg, 0.6 mmol, 1.0 eq) in N,N-dimethylformamide (6 mL) and triethylamine (2 mL) were added Cui (11 mg, 0.1 mmol, 0.1 eq) and Pd(PPhs)4 (66 mg, 0.1 mmol, 0.1 eq) in portions at 25°C under nitrogen atmosphere. The reaction mixture was stirred for 14 hours at 25°C. The resulting mixture was diluted with water (20 mL) and then extracted with ethyl acetate (3x15 mL). The combined organic layers were washed with water (2x10 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The residue was purified by a flash column (silica gel, dichloromethane/CH30H=100:0 to 100:5) to give 3-(4-{4-[(2R)-1-(3- methoxy-4-nitrobenzoyl)piperidin-2-yl]but-1 -yn-1 -yl}-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (400 mg, 91%) as a brown solid. LC-MS (ESI, m/z) M+1 : 559.
  • 10
  • [ 2207541-30-6 ]
  • [ 2807574-75-8 ]
  • [ 2807574-81-6 ]
YieldReaction ConditionsOperation in experiment
86% With copper (I) iodide; tetrakis-(triphenylphosphine)-palladium; triethylamine In N,N-dimethyl-formamide at 25℃; for 14h; Inert atmosphere; 38 Synthesis of 3-(4-{4-[(2S)-1 -(3-methoxy-4-nitrobenzoyl)piperidin-2-yl]but-1 -yn-1 -y I}- 1 -oxo-3H- isoindol-2-yl)piperidine-2, 6-dione: To a stirred mixture of (2S)-2-(but-3-yn-1-yl)-1-(3-methoxy-4- nitrobenzoyl)piperidine (180 mg, 0.6 mmol, 1 eq) and 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (210 mg, 0.6 mmol, 1.0 eq) in N,N-dimethylformamide (6 mL) and triethylamine (2 mL) were added Pd(PPhs)4 (66 mg, 0.1 mmol, 0.1 eq) and Cui (11 mg, 0.1 mmol, 0.1 eq) in portions at 25°C under nitrogen atmosphere. The reaction mixture was stirred for 14 hours at 25°C. The resulting mixture was diluted with water (20 mL) and then extracted with ethyl acetate (3x15 mL). The combined organic layers were washed with water (2x10 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The residue was purified by a flash column (silica gel, dichloromethane/CH30H=100:0 to 100:5) to give 3-(4-{4-[(2S)-1-(3- methoxy-4-nitrobenzoyl)piperidin-2-yl]but-1 -yn-1 -yl}-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (370 mg, 86%) as a brown solid. LC-MS (ESI, m/z) M+1 : 559.
86% With copper (I) iodide; tetrakis-(triphenylphosphine)-palladium; triethylamine In N,N-dimethyl-formamide at 25℃; for 14h; Inert atmosphere; 38 Synthesis of 3-(4-{4-[(2S)-1 -(3-methoxy-4-nitrobenzoyl)piperidin-2-yl]but-1 -yn-1 -y I}- 1 -oxo-3H- isoindol-2-yl)piperidine-2, 6-dione: To a stirred mixture of (2S)-2-(but-3-yn-1-yl)-1-(3-methoxy-4- nitrobenzoyl)piperidine (180 mg, 0.6 mmol, 1 eq) and 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (210 mg, 0.6 mmol, 1.0 eq) in N,N-dimethylformamide (6 mL) and triethylamine (2 mL) were added Pd(PPhs)4 (66 mg, 0.1 mmol, 0.1 eq) and Cui (11 mg, 0.1 mmol, 0.1 eq) in portions at 25°C under nitrogen atmosphere. The reaction mixture was stirred for 14 hours at 25°C. The resulting mixture was diluted with water (20 mL) and then extracted with ethyl acetate (3x15 mL). The combined organic layers were washed with water (2x10 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The residue was purified by a flash column (silica gel, dichloromethane/CH30H=100:0 to 100:5) to give 3-(4-{4-[(2S)-1-(3- methoxy-4-nitrobenzoyl)piperidin-2-yl]but-1 -yn-1 -yl}-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (370 mg, 86%) as a brown solid. LC-MS (ESI, m/z) M+1 : 559.
  • 11
  • [ 2207541-30-6 ]
  • [ 2807573-56-2 ]
  • [ 2807573-57-3 ]
YieldReaction ConditionsOperation in experiment
86.2% With copper (I) iodide; tetrakis-(triphenylphosphine)-palladium; triethylamine In N,N-dimethyl-formamide at 70℃; for 2h; Inert atmosphere; Sealed tube; INT-10 Synthesis of tert-butyl (1 S)-1 -{2-[2-(2, 6-d ioxopiperid i n -3-y I)- 1 -oxo-3H-isoindol-4-yl]ethynyl}-6- azaspiro[2.5]octane-6-carboxylate: Into a 40-mL sealed-tube purged and maintained with an inert atmosphere of nitrogen, were palced tert-butyl (1S)-1-ethynyl-6-azaspiro[2.5]octane-6-carboxylate (800 mg, 3.4 mmol, 1.0 eq), 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (1.4 g, 3.7 mmol, 1.1 eq), Cui (65 mg, 0.3 mmol, 0.1 eq), Pd(PPhs)4 (393 mg, 0.3 mmol, 0.1 eq), EtsN (1.0 g, 10.2 mmol, 3.0 eq), DMF (10 mL). The resulting solution was stirred for 2 hours at 70°C. The resulting mixture was then quenched by the addition of water (100 mL) and then was extracted with ethyl acetate (2x100 mL). The combined organics were washed with brine (2x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether=1 :1 to give tert-butyl (1 S)-1 -{2-[2-(2,6-dioxopiperidin-3-yl)-1 -oxo-3H-isoindol-4-yl]ethynyl}-6- azaspiro[2.5]octane-6-carboxylate as a light yellow solid (1.4 g, 86.2%). LC-MS (ESI, m/z) M+1 : 478. 1HNMR (400 MHz, DMSO-ofe) 6 11.00 (d, J=2.6 Hz, 1 H), 7.70 (d, J=7.6 Hz, 1 H), 7.66-7.48 (m, 2H), 5.13 (dd, J=13.4, 5.2 Hz, 1H), 4.43 (dd, J=17.8, 8.8 Hz, 1 H), 4.31 (dd, J=17.8, 3.0 Hz, 1 H), 3.54-3.45 (m, 2H), 3.40-3.31 (m, 2H), 3.00-2.86 (m, 1 H), 2.60 (dd, J=17.4, 3.8 Hz, 1 H), 2.49-2.41 (m, 1 H), 2.04 (dd, J=12.2, 6.0 Hz, 1H), 1.67-1.56 (m, 3H), 1.51-1.43 (m, 1H), 1.41 (s, 9H), 1.34-1.25 (m, 1H), 1.03 (dd, J=8.6, 4.2 Hz, 1 H), 0.80-0.77 (m, 1 H).
86.2% With copper (I) iodide; tetrakis-(triphenylphosphine)-palladium; triethylamine In N,N-dimethyl-formamide at 70℃; for 2h; Inert atmosphere; Sealed tube; INT-10 Synthesis of tert-butyl (1 S)-1 -{2-[2-(2, 6-d ioxopiperid i n -3-y I)- 1 -oxo-3H-isoindol-4-yl]ethynyl}-6- azaspiro[2.5]octane-6-carboxylate: Into a 40-mL sealed-tube purged and maintained with an inert atmosphere of nitrogen, were palced tert-butyl (1S)-1-ethynyl-6-azaspiro[2.5]octane-6-carboxylate (800 mg, 3.4 mmol, 1.0 eq), 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (1.4 g, 3.7 mmol, 1.1 eq), Cui (65 mg, 0.3 mmol, 0.1 eq), Pd(PPhs)4 (393 mg, 0.3 mmol, 0.1 eq), EtsN (1.0 g, 10.2 mmol, 3.0 eq), DMF (10 mL). The resulting solution was stirred for 2 hours at 70°C. The resulting mixture was then quenched by the addition of water (100 mL) and then was extracted with ethyl acetate (2x100 mL). The combined organics were washed with brine (2x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether=1 :1 to give tert-butyl (1 S)-1 -{2-[2-(2,6-dioxopiperidin-3-yl)-1 -oxo-3H-isoindol-4-yl]ethynyl}-6- azaspiro[2.5]octane-6-carboxylate as a light yellow solid (1.4 g, 86.2%). LC-MS (ESI, m/z) M+1 : 478. 1HNMR (400 MHz, DMSO-ofe) 6 11.00 (d, J=2.6 Hz, 1 H), 7.70 (d, J=7.6 Hz, 1 H), 7.66-7.48 (m, 2H), 5.13 (dd, J=13.4, 5.2 Hz, 1H), 4.43 (dd, J=17.8, 8.8 Hz, 1 H), 4.31 (dd, J=17.8, 3.0 Hz, 1 H), 3.54-3.45 (m, 2H), 3.40-3.31 (m, 2H), 3.00-2.86 (m, 1 H), 2.60 (dd, J=17.4, 3.8 Hz, 1 H), 2.49-2.41 (m, 1 H), 2.04 (dd, J=12.2, 6.0 Hz, 1H), 1.67-1.56 (m, 3H), 1.51-1.43 (m, 1H), 1.41 (s, 9H), 1.34-1.25 (m, 1H), 1.03 (dd, J=8.6, 4.2 Hz, 1 H), 0.80-0.77 (m, 1 H).
  • 12
  • [ 287193-01-5 ]
  • [ 2207541-30-6 ]
  • [ 2807575-60-4 ]
YieldReaction ConditionsOperation in experiment
51.3% With copper (I) iodide; tetrakis-(triphenylphosphine)-palladium; triethylamine In N,N-dimethyl-formamide at 25℃; for 14h; Inert atmosphere; 55 Synthesis of tert-butyl 3-{2-[2-(2, 6-d ioxopiperid i n -3-y l)-1 -oxo-3H-isoindol-4-yl]ethynyl}azetidine-1 -carboxylate: To a stirred mixture of tert-butyl 3-ethynylazetidine-1 -carboxylate (1.0 g, 5.5 mmol, 1.0 eq) and 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (2.5 g, 6.6 mmol, 1.2 eq) in Dimethyl Formamide (20 mL) and triethylamine (5 mL) was added Cui (0.3 g, 1.6 mmol, 0.3 eq) and Pd(PPh3)4 (0.6 g, 0.6 mmol, 0.1 eq) in portions at 25°C under nitrogen atmosphere. The reaction mixture was stirred for 14 hours at 25°C under nitrogen atmosphere. The resulting mixture was diluted with water (60 mL) and then extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with water (3x30 mL) and brine (30 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The crude residue was purified by a flash column (silica gel, ethyl acetate/petroleum ether=3: 1 ) to give tert-butyl 3-{2-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]ethynyl}azetidine-1-carboxylate (1.2 g, 51.3%) as a brown solid. LC- MS (ESI, m/z) M+1 : 368.
51.3% With copper (I) iodide; tetrakis-(triphenylphosphine)-palladium; triethylamine In N,N-dimethyl-formamide at 25℃; for 14h; Inert atmosphere; 55 Synthesis of tert-butyl 3-{2-[2-(2, 6-d ioxopiperid i n -3-y l)-1 -oxo-3H-isoindol-4-yl]ethynyl}azetidine-1 -carboxylate: To a stirred mixture of tert-butyl 3-ethynylazetidine-1 -carboxylate (1.0 g, 5.5 mmol, 1.0 eq) and 3-(4-iodo-1-oxo-3H-isoindol-2-yl)piperidine-2, 6-dione (2.5 g, 6.6 mmol, 1.2 eq) in Dimethyl Formamide (20 mL) and triethylamine (5 mL) was added Cui (0.3 g, 1.6 mmol, 0.3 eq) and Pd(PPh3)4 (0.6 g, 0.6 mmol, 0.1 eq) in portions at 25°C under nitrogen atmosphere. The reaction mixture was stirred for 14 hours at 25°C under nitrogen atmosphere. The resulting mixture was diluted with water (60 mL) and then extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with water (3x30 mL) and brine (30 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The crude residue was purified by a flash column (silica gel, ethyl acetate/petroleum ether=3: 1 ) to give tert-butyl 3-{2-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]ethynyl}azetidine-1-carboxylate (1.2 g, 51.3%) as a brown solid. LC- MS (ESI, m/z) M+1 : 368.
 

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