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Chemical Structure| 165111-46-6 Chemical Structure| 165111-46-6

Structure of 165111-46-6

Chemical Structure| 165111-46-6

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Product Details of [ 165111-46-6 ]

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

Safety of [ 165111-46-6 ]

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:

Computational Chemistry of [ 165111-46-6 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

50.09 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.23
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

2.05
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

2.09
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

2.02
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

2.73
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.22

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.83
Solubility 0.379 mg/ml ; 0.00149 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-2.73
Solubility 0.473 mg/ml ; 0.00186 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-3.82
Solubility 0.0384 mg/ml ; 0.000151 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.39 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<0.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.25

Application In Synthesis of [ 165111-46-6 ]

* 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 [ 165111-46-6 ]

[ 165111-46-6 ] Synthesis Path-Downstream   1~31

  • 1
  • [ 165111-46-6 ]
  • [ 678992-38-6 ]
  • [ 678992-35-3 ]
YieldReaction ConditionsOperation 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%.
  • 2
  • [ 103261-67-2 ]
  • [ 165111-46-6 ]
YieldReaction ConditionsOperation 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.

  • 3
  • [ 165111-46-6 ]
  • [ 165111-47-7 ]
YieldReaction ConditionsOperation 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.
  • 4
  • [ 165111-46-6 ]
  • [ 99-05-8 ]
  • [ 1134082-50-0 ]
YieldReaction ConditionsOperation 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.
  • 7
  • [ 165111-46-6 ]
  • [ 2393-23-9 ]
  • [ 1440519-96-9 ]
YieldReaction ConditionsOperation 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.

  • 8
  • [ 165111-46-6 ]
  • [ 23386-40-5 ]
  • 9
  • [ 165111-46-6 ]
  • [ 1261869-76-4 ]
YieldReaction ConditionsOperation 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).
  • 10
  • [ 165111-46-6 ]
  • (S)-2-(2,7-dioxoazepan-3-yl)-1-oxoisoindoline-5-carbonitrile [ No CAS ]
  • 11
  • [ 165111-46-6 ]
  • (S)-tert-butyl ((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)methyl)carbamate [ No CAS ]
  • 12
  • [ 165111-46-6 ]
  • (S)-3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)azepane-2,7-dione trifluoroacetic acid [ No CAS ]
  • 13
  • [ 165111-46-6 ]
  • [ 21568-87-6 ]
  • (S)-1-oxo-2-(2-oxoazepan-3-yl)isoindoline-5-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation 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] +.
  • 14
  • [ 165111-46-6 ]
  • (S)-1-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-3-amine [ No CAS ]
  • 2-((S)-1-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperidin-3-yl)-1-oxoisoindoline-5-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation 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).
  • 15
  • [ 165111-46-6 ]
  • [ 1431528-74-3 ]
  • C18H14ClN3O4 [ No CAS ]
YieldReaction ConditionsOperation 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]+.
  • 16
  • [ 165111-46-6 ]
  • (R)-2-((4-(3-aminopiperidin-1-yl)-3-(but-2-yn-1-yl)-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)methyl)-4-cyanobenzoic acid hydrochloride [ No CAS ]
  • 17
  • [ 165111-46-6 ]
  • C27H31N5O6 [ No CAS ]
  • 18
  • [ 165111-46-6 ]
  • C28H33N5O6 [ No CAS ]
  • 19
  • [ 165111-46-6 ]
  • (R)-2-((8-(3-aminopiperidin-1-yl)-7-(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)-4-cyanobenzoic acid hydrochloride [ No CAS ]
  • 20
  • [ 165111-46-6 ]
  • C29H33N7O6 [ No CAS ]
  • 21
  • [ 165111-46-6 ]
  • C30H35N7O6 [ No CAS ]
  • 22
  • [ 666816-98-4 ]
  • [ 165111-46-6 ]
  • C20H16BrN5O4 [ No CAS ]
YieldReaction ConditionsOperation 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%)
  • 23
  • [ 165111-46-6 ]
  • C6H11(2)HN2O*C2HF3O2 [ No CAS ]
  • (S)-2-(3-d-2-oxoazepan-3-yl)-1-oxoisoindoline-5-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation 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]+.
  • 24
  • [ 165111-46-6 ]
  • (S)-2-(3-d-2,7-dioxoazepan-3-yl)-1-oxoisoindoline-5-carbonitrile [ No CAS ]
  • 25
  • [ 165111-46-6 ]
  • (S)-tert-butyl ((2-(3-d-2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)methyl)carbamate [ No CAS ]
  • 26
  • [ 165111-46-6 ]
  • (S)-4-nitrophenyl ((2-(3-d-2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)methyl)carbamate [ No CAS ]
  • 27
  • [ 165111-46-6 ]
  • (S)-N-(tert-butyl)-3-((2-((4-(3-(3-((2-(3-d-2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)propoxy)phenyl)amino)-5-methylpyrimidin-4-yl)amino)benzenesulfonamide [ No CAS ]
  • 28
  • [ 165111-46-6 ]
  • 2-((3-chloro-4-methylphenyl)amino)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)acetamide [ No CAS ]
  • 29
  • [ 165111-46-6 ]
  • tert-butyl N-[[2-(2,6-dioxo-3-piperidyl)-1-oxoisoindolin-5-yl]methyl]carbamate [ No CAS ]
  • 30
  • [ 165111-46-6 ]
  • C14H15N3O3*C2HF3O2 [ No CAS ]
  • 31
  • [ 165111-46-6 ]
  • [ 24666-56-6 ]
  • [ 1010100-27-2 ]
YieldReaction ConditionsOperation 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] +.
 

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