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Structure of 165111-46-6
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 165111-46-6 |
Formula : | C10H8BrNO2 |
M.W : | 254.08 |
SMILES Code : | COC(=O)C1=C(CBr)C=C(C=C1)C#N |
MDL No. : | MFCD09864855 |
InChI Key : | QMLVCVLSZNSKJM-UHFFFAOYSA-N |
Pubchem ID : | 23359115 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H302-H314 |
Precautionary Statements: | P264-P270-P271-P280-P303+P361+P353-P304+P340-P305+P351+P338-P310-P330-P331-P363-P403+P233-P501 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅱ |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.2 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 55.27 |
TPSA ? Topological Polar Surface Area: Calculated from |
50.09 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.23 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.05 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.09 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.02 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.73 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.22 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.83 |
Solubility | 0.379 mg/ml ; 0.00149 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.73 |
Solubility | 0.473 mg/ml ; 0.00186 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.82 |
Solubility | 0.0384 mg/ml ; 0.000151 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.39 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.25 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In DMF (N,N-dimethyl-formamide); at 20 - 40℃; for 21h; | Example 6 [5- 5- 5-CYANO-1-OXO-1, 3-DIHYDRO-ISOINDOL-2-YLMETHYL)-3-METHYL-1 H-PYRAZOL-4- VIOXY]-ISOPHTHALONITRILE] Sodium carbonate (401 mg, 3.78 [MMOL)] was added to the amine from preparation 14 (400 mg, 1.6 [MMOL)] in N, N-dimethylformamide (20 ml), followed by <strong>[165111-46-6]2-bromomethyl-4-cyano-benzoic acid methyl ester</strong> (EP 685478, reference example 21) (340 mg, 1.6 [MMOL)] and the reaction stirred at room temperature for 18 hours. The reaction was then warmed to [40C] for a further 3 hours, the mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (25 mi) and water (25 [ML).] The layers were separated, the organic phase dried over magnesium sulphate and evaporated under reduced pressure. The crude product was purified by chromatography using a Bond Elut Si cartridge and [DICHLOROMETHANE] : methanol : 0.88 ammonia (100: 0: 0 to 90: 10: 1) as the eluant. The product was then triturated with hot acetonitrile, the solid filtered and dried to afford the title compound as a white solid (48.5mg).[1H] NMR [(400MHZ,] [DMSO-D6)] : 2.02 (s, 3H), 4.36 (s, 2H), 4.60 (s, 2H), 7.42 (s, 2H), 7.50 (d, 1 H), 7.70 (s, 1 H), 7.82 (m, 1 H), 7.97 (s, 1 H), 12.75 (br s, 1 H). LRMS: m/z ES-393 [[M-H]-.] Microanalysis found: C, 65.55 ; [H.,] 3.57 ; N, 21.03. [C22H14N602] ; [0.] [5H2O] requires C, 65.50 ; H, 3.75 ; N, 20.83%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 20℃; for 4h; | [0131] To a solution of methyl 5-cyano-2-toluate (5.00 g, 28.6 mmol) in CCl4 (185 mL) at RT was added NBS (5.08 g, 28.6 mmol) followed by benzoyl peroxide (830 mg, 3.43 mmol). The mixture was stirred for 4 h then poured into sat. NaHCCh (aq.), and the organic layer was separated and concentrated. Ethyl acetate (EA) was added, and the solution was dried over MgSCri then filtered and concentrated to give methyl 2-(bromomethyl)-4-cyanobenzoate (7.9 g, 100% yield) as a solid. LCMS (ESI) m/z 255 [M+H] +. |
66.9% | [0510] To a solution of methyl 4-cyano-2-methylbenzoate (4.0 g, 22.83 mmol) in CCl4 (150 mL) was added NBS (4.88 g, 27.4 mmol) and the suspension was heated at 80C for 5 min. AIBN (1.88 g, 11.42 mmol) was added and the suspension was stirred at 80C for 16 hrs, cooled to rt and filtered. The filtrate was concentrated providing the crude product, which was purified on silica gel with EA/petroleum ether from 0% to 5% providing methyl 2-(bromomethyl)-4-cyanobenzoate (3.84 g, 66.9% yield) as a white solid | |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; | Reference Example 21 Methyl 2-bromomethyl-4-cyanobenzoate 1.0 g of benzoyl peroxide and 8.0 g of N-bromosuccinimide were added to 7.5 g of methyl 4-cyano-o-toluate obtained in Reference example 20 dissolved in 50 ml of carbon tetrachloride and the mixture was refluxed under heating for 8 hours. During reflux, 3 g of N-bromosuccinimide was added to the mixture. The resulting reaction mixture was filtered and the filtrate was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was removed from the solution to obtain 20 g of a crude product of the title compound. |
With N-Bromosuccinimide; In tetrachloromethane; for 5h;Heating / reflux; | Methyl 2-(bromomethyl)-4-cyanobenzoate (3) The compound 2 (525 mg, 3 mmol) and NBS (594 mg, 3.3 mmol) in CCl4 (20 mL) were refluxed for 5 hours. The reaction was cooled to room temperature. Hexane was added into the reaction and the solid obtained was removed by filtration. The filtrate was concentrated under the reduced pressure to give the crude compound 3, which was used directly in the next step. | |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 3h;Inert atmosphere; Reflux; | A mixture of 4-cyano-2-methyl-benzoic acid methyl ester (12.5 g,71.35 mmol), NBS (12.7 g,71.35 mmol) and di-benzoyl peroxide (BPO) (0.8 g,3.28 mmol) in CCI4 (200 mL) was heated to reflux temperature for 3 hours. After it was cooled to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a crude product (18.2 g) which was used in the next step reaction without further purification. | |
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 48h; | Step 2. methyl 2-(bromomethyl)-4-cyanobenzoate To a stirred solution of methyl 4-cyano-2-methylbenzoate (1 g, 5.7 mmol) in CCl4 (30 mL), was added NBS (1.4 g, 6.2 mmol), and catalytic AIBN. The reaction mixture was stirred for 48 h at 80 C. The reaction progress was monitored by TLC (10% EtOAc in hexanes). The reaction was cooled to room temperature and diluted with water (25 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2*50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated, and purified by column chromatography silica (60-120 mesh silica with 80-100% EtOAc in petroleum ether) as eluent to give the title compound as a colorless solid. 1H NMR (400 MHz, CDCl3): delta 8.05 (d, J=8.0 Hz, 1H), 7.78 (s, 1H), 7.6 (d, J=8.0 Hz, 1H), 4.9 (s, 2H), 4.0 (s, 3H). | |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 3h;Inert atmosphere; Reflux; | A mixture of 4-cyano-2-methyl-benzoic acid methyl ester (12.5 g, 71.35 mmol), NBS (12.7 g, 71.35 mmol) and di-benzoyl peroxide (BPO) (0.8 g, 3.28 mmol) in CC14 (200 mL) was heated to reflux temperature for 3 hours. Then, it was cooled to room temperature and the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a crude product (18.2 g) which was used in the next step reaction without further purification. | |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 3h;Inert atmosphere; Reflux; | A mixture of 4-cyano-2-methyl-benzoic acid methyl ester (12.5 g,71.35 mmol), NBS (12.7 g, 71.35 mmol) and di-benzoyl peroxide (BPO) (0.8 g, 3.28 mmol) in CC14 (200 mL) was heated to reflux temperature for 3 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a crude product (18.2g) which was used in the next step reaction without further purification. | |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 3h;Inert atmosphere; Reflux; | A mixture of 4-cyano-2-methyl-benzoic acid methyl ester (12.5 g, 71.35 mmol), NBS (12.7 g, 71.35 mmol) and di-benzoyl peroxide (BPO) (0.8 g, 3.28 mmol) in CC14 (200 mL) was heated to reflux temperature for 3 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a crudeproduct (18.2 g) which was used in the next step reaction without further purification. | |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 3h;Reflux; Inert atmosphere; | TCI 2-Bromomethyl-4-cyano-benzoic acid methyl ester A mixture of 4-cyano-2-methyl-benzoic acid methyl ester (12.5 g, 71.35 mmol), NBS (12.7 g, 71.35 mmol) and di-benzoyl peroxide (BPO) (0.8 g, 3.28 mmol) in CC14 (200 mL) was heated to reflux temperature for 3 hours. After it was cooled to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give a crude product (18.2 g) which was used in the next step reaction without further purification. | |
With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; at 80℃; for 12h; | General procedure: A mixture of methyl 5-fluoro-2-methylbenzoate (0.5 g, 3.0 mmol),NBS (0.18 g, 3.0 mmol), and di-benzoyl peroxide (BPO) (36 mg, 0.15 mmol) in 1,2-dichloroethane (5 mL) was heated at 80 C for 12 huntil all starting material was consumed. The reaction was cooled to room temperature, and the precipitated solid was removed by filtration and washed with ethers (10 mL). The filtrate was concentrated in vacuo and the residue was partitioned between 2 N NaHCO3 (15 mL) and ethers (15 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to give a crude product (0.65 g, 89%), which was used in the next step reaction without further purification. | |
With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; at 80℃; for 12h; | General procedure: A mixture of methyl 3-bromo-2-methylbenzoate (500 mg, 3.3 mmol), NBS (770.4 mg, 4.3 mmol), and di-benzoyl peroxide (BPO, 80.7 mg, 0.3 mmol) in 1,2-dichloroethane (10 mL) was heated at 80 C for 12 h. The reaction mixture was cooled to room temperature, and the precipitated solid was removed by filtration and washed with ethers (10 mL). The filtrate was concentrated in vacuo and the residue was partitioned between 2 N NaHCO3 (15 mL) and ethers (15 mL). The organic layer was separated, dried over NaSO4, filtered and concentrated to give a crude product (683.2 mg, 89.6%), which was used in the next step reaction without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; hydroquinone;potassium iodide; In N-methyl-acetamide; water; | Reference Example 22 Methyl 4-cyano-2-(4-hydroxyphenoxy)methylbenzoate 5.9 g of potassium carbonate and a catalytic amount of potassium iodide were added to 20 g of <strong>[165111-46-6]methyl 2-bromomethyl-4-cyanobenzoate</strong> obtained in Reference example 21 and 14.2 g of hydroquinone dissolved in 60 ml of dimethylformamide and the mixture was stirred at 90 C. for 3 hours. After the solvent was removed from the reaction mixture under reduced pressure, water was added to the residue, the mixture was extracted with ethyl acetate and the organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed from the solution to obtain 9.5 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 150℃; for 0.0833333h;Microwave irradiation; | 3-(5-Cyano-1-oxoisoindolin-2-yl)benzoic acid (4) A mixture of the compound 3 (310 mg) and 3-amino benzoic acid (217 mg) in DMF (3 mL) was heated under microwave irradiation at 150 C. for 5 minutes. The reaction was cooled to room temperature. White precipitates were collected by filtration to give the compound 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.69 g | In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere; | To a solution of <strong>[165111-46-6]2-bromomethyl-4-cyano-benzoic acid methyl ester</strong> (18.1 g, 71.24 mmol) in THF (300 mL) was added PMBNH2 (23.4 g, 178.1 mmol) at 0 C and the reaction mixture was stirred at room temperature for 16 hours. After vacuum filtration, the filtrate - 166 -was concentrated in vacuo. The residue obtained was re-dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhy. Na2S04, filtered, and concentrated in vacuo to give a crude product which was purified by columnchromatography (11.69 g, 56.0%) as a soild |
56.0 g | In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere; | To a solution of <strong>[165111-46-6]2-bromomethyl-4-cyano-benzoic acid methyl ester</strong> (18.1 g, 71.24 mmol) in THF (300 mL) was added PMBNH2 (23.4 g, 178.1 mmol) at 0 C and the reaction mixture was stilTed at room temperature for 16 hours. After vacuum filtration, the filtratewas concentrated in vacuo. The residue obtained was re-dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product which was purified by column chromatography to give the title compound (11.69 g, 56.0%) as a solid. |
11.69 g | In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere; | To a solution of <strong>[165111-46-6]2-bromomethyl-4-cyano-benzoic acid methyl ester</strong> (18.1 g, 71.24 mmol) in THF (300 mL) was added PMBNH2 (23.4 g, 178.1 mmol) at 0 C and the reactionmixture was stilTed at room temperature for 16 hours. After vacuum filtration, the filtrate was concentrated in vacuo. The residue obtained was re-dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product which was purified by column chromatography to give the title compound as a solid (11.69 g, 56.0%). |
11.69 g | In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere; | To a solution of <strong>[165111-46-6]2-bromomethyl-4-cyano-benzoic acid methyl ester</strong> (18.1 g, 71.24 mmol) in THF (300 mL) was added PMBNH2 (23.4 g, 178.1 mmol) at 0 C and the reaction mixture was stilTed at room temperature for 16 hours. After vacuum filtration, the filtratewas concentrated in vacuo. The residue obtained was re-dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product which was purified by column chromatography to give the title compound (11.69 g, 56.0%) as a solid. |
11.69 g | In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere; | GammaRho1 2-(4-Methoxy-benzyl)- l-oxo-2,3-dihvdro-lH-isoindole-5-carbonitrile To a solution of <strong>[165111-46-6]2-bromomethyl-4-cyano-benzoic acid methyl ester</strong> (18.1 g, 71.24 mmol) in THF (300 mL) was added PMBNH2 (23.4 g, 178.1 mmol) at 0 C and the reaction mixture was stirred at room temperature for 16 hours. After vacuum filtration, the filtrate was concentrated in vacuo. The residue obtained was re-dissolved in EtOAc and washed with water and brine. The organic layer was dried over anhy. Na2S04, filtered, and concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (11.69 g, 56.0%) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonia; In methanol; at 40℃; for 18h;Sealed tube; | Step 3. 1-oxoisoindoline-5-carbonitrile To <strong>[165111-46-6]methyl 2-(bromomethyl)-4-cyanobenzoate</strong> (0.3 g, 1.18 mmol) in a sealed tube, was added 7N NH3 in MeOH (10 mL). The tube was then sealed and the reaction stirred at 40 C. for 18 h. The reaction progress was monitored by TLC (90% EtOAc in hexanes). The reaction was filtered to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 8.95 (s, 1H), 8.1 (s, 1H), 7.9 (d, J=8.0 Hz, 1H), 7.8 (d, J=8.0 Hz, 1H), 4.4 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.2% | With triethylamine; In N,N-dimethyl-formamide; at 20 - 85℃; for 16h; | [0511] To a solution of <strong>[165111-46-6]methyl 2-(bromomethyl)-4-cyanobenzoate</strong> (4.28 g, 16.85 mmol) in DMF (80 mL) at rt was added (S)-3-aminoazepan-2-one (2.59 g, 20.22 mmol), followed by TEA (3.40 g, 33.7 mmol). The suspension was stirred at 85C for 16 hrs, the solvent was removed and the residue was diluted with water (20 mL). The suspension was stirred at rt for 30 min, filtered, and the filter cake was washed with water, dried in vacuum providing (S)-1-oxo-2-(2-oxoazepan-3-yl)isoindoline-5-carbonitrile (2.30 g, 44.2% yield) as a light yellow solid. MS (ESI) m/z 270.1 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.25 g | With triethylamine; In toluene; at 20℃; for 2h;Reflux; | A flask was charged with <strong>[165111-46-6]methyl 2-(bromomethyl)-4-cyanobenzoate</strong> (0.5 g, 0.984 mmol, US5,591,752 Al), (5)-i -(((5)-2,3 -dihydrobenzo[b] [1,4] dioxin-2-yl)methyl)piperidin-3 -amine(0.244 g, 0.984 mmol), toluene (5 mL) and triethylamine (0.206 mL, 1.476 mmol). Reactionis refluxed for 2 h, then cooled to room temperature and filtered. Solvents were evaporatedand residue was purified with silica gel chromatography using EtOAc / heptanes to give 0.25 g of 2-((5)- 1 -(((5)-2,3 -dihydrobenzo[b] - [1,4] dioxin-2-yl)methyl)piperidin-3 -yl)- 1- oxoisoindoline-5-carbonitrile as solids.?H NMR (400 MHz, CDC13) oe ppm 1.61-1.69 (m, 1H), 1.70-1.86 (m, 2H), 1.87-1.99 (m,1H), 2.26-2.34 (m, 1H), 2.35-2.44 (m, 1H), 2.62-2.75 (m, 2H), 2.79-2.89 (m, 1H), 3.04 (dd,1H), 4.03 (dd, 1H), 4.25-4.34 (m, 2H), 4.4 1-4.55 (m, 3H), 6.79-6.90 (m, 4H), 7.72-7.79 (m,2H), 7.95 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h; | General procedure: To a suspension of 3 (8 g, 40.3 mmol) and K2CO3 (16.7 g,120.8 mmol) in DMF (50 mL) was added methyl 2-(bromomethyl)benzoate (9.7 g, 42.3 mmol). The reaction mixture was stirred at r.t. for 10 h. The reaction mixture was poured into water. The precipitate was collected by filtration, washed with water, and dried to give compound 4 as a brown solid (10.5 g, 75%). mp: 140-141 C; 1H NMR (400 MHz,CDCl3) delta 8.10 (s, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.65 (d, J=7.7 Hz,1H), 7.38 (t, J=7.7 Hz, 1H), 5.97 (s, 1H), 5.13 (s, 2H), 4.84-4.67 (m,2H), 3.90 (s, 3H), 1.81 (s, 3H); MS (ESI) m/z: 347.26 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 10h; | General procedure: Compound 11a (385.5 mg, 1.7 mmol) was added to a mixture of compound 5 (500 mg, 1.7 mmol) and K2CO3 (697.7 mg, 5.1 mmol) in DMF (30 mL). After stirring at 50 C. for 10 h, the mixture was poured into water. The precipitate was collected by filtration, washed with water, and dried to give compound 6a as a white solid (703.5 mg, yield: 93.9%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; | To a solution of (ri)-3 -amino-3 -<7-azepan-2-one TFA salt (366.1 mg, 2.838 mmol) in DMF (10 mL) at 0 C was added TEA (598.3 mg, 5.912 mmol) and methyl 2- (bromomethyl)-4-cyanobenzoate (598.3 mg, 2.365 mmol). The mixture was stirred at RT overnight then concentrated. The residue was purified using silica gel eluting with MeOH in DCM (0% to 5%) to give (ri)-2-(3-<7-2-oxoazepan-3-yl)-l-oxoisoindoline-5-carbonitrile (340 mg, 53% yield) as a solid. MS (ESI) m/z = 271 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | [0132] To a solution of 3 -amino-2, 6-piperidinedi one HC1 (648 mg, 3.94 mmol) in DMF (20 mL) at RT was added TEA (1.21 mL, 8.67 mmol) and stirred for 10 min. The mixture was cooled to 0 C then a solution of <strong>[165111-46-6]methyl 2-(bromomethyl)-4-cyanobenzoate</strong> (1.00 g, 3.94 mmol) in DMF was added dropwise. After 10 min, the reaction was warmed to RT and stirred for 2 days then concentrated. The residue was purified by silica gel chromatography eluting with hexanes/EA (1 : 1) to hexanes (100%) to give 2-(2,6-dioxo-3-piperidyl)-l-oxo-5- isoindolinecarbonitrile (230 mg, 22% yield) as a solid. LCMS (ESI) m/z 270 [M+H] +. |