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Chemical Structure| 133446-99-8 Chemical Structure| 133446-99-8

Structure of 133446-99-8

Chemical Structure| 133446-99-8

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Product Details of [ 133446-99-8 ]

CAS No. :133446-99-8
Formula : C9H8BrNO4
M.W : 274.07
SMILES Code : O=C(OC)C1=CC=C([N+]([O-])=O)C=C1CBr
MDL No. :MFCD11505948
InChI Key :PGNKFDOPHHNVNF-UHFFFAOYSA-N
Pubchem ID :15088701

Safety of [ 133446-99-8 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H302-H314
Precautionary Statements:P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501
Class:8
UN#:3261
Packing Group:

Computational Chemistry of [ 133446-99-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 15
Num. arom. heavy atoms 6
Fraction Csp3 0.22
Num. rotatable bonds 4
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 59.38
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

72.12 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.89
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

2.16
Log Po/w (WLOGP)?

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

2.12
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.

1.61
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

0.6
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.68

Water Solubility

Log S (ESOL):?

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

-2.93
Solubility 0.321 mg/ml ; 0.00117 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.

-3.31
Solubility 0.135 mg/ml ; 0.000493 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

-3.11
Solubility 0.213 mg/ml ; 0.000776 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

Yes
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.

-6.44 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

3.0 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)

2.2

Application In Synthesis of [ 133446-99-8 ]

* 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 [ 133446-99-8 ]

[ 133446-99-8 ] Synthesis Path-Downstream   1~55

  • 1
  • [ 62621-09-4 ]
  • [ 133446-99-8 ]
YieldReaction ConditionsOperation in experiment
100% With N-Bromosuccinimide; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In tetrachloromethane; at 85℃; for 12h; To a solution of methyl 2-methyl-4-nitro-benzoate (3.00 g, 15.4 mmol) in CCl4 (60.0 mL) was added NBS (3.28 g, 18.4 mmol) and BOP (68.0 mg, 154 umol). The reaction mixture was stirred at 85 C. for 12 hrs. On completion, the mixture was washed with saturated NaHCO3 (20.0 mL) and brine (50.0 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:AcOEt=3:1) to give the title compound (4.21 g, 100% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) delta 8.30 (d, J=2.0 Hz, 1H), 8.20 (dd, J=2.0, 6.4 Hz, 1H), 8.10 (d, J=6.4 Hz, 1H), 4.96 (s, 2H), 4.00 (s, 3H).
96% With N-Bromosuccinimide; In tetrachloromethane; for 2h;Reflux; U) 2-Bromomethyl-4-nitro-benzoic acid methyl esterN-Bromosuccinimide (2.18 g, 12.30 mmol) was added to a stirred solution of 2- methyl-4-nitro-benzoic acid methyl ester (2 g, 10.25 mmol) and ABCN (626 mg, 2.56 mmol) in carbon tetra-chloride (80 ml) at room temperature. The reaction was heated at reflux for 2 hrs and then allowed to cool to room temperature and stirred for 15 hrs. The solvent was evaporated in vacuo and the resulting residue filtered through a pad of silica (eluting with dichloromethane). The solvent was evaporated in vacuo to afford the title compound as a yellow solid (2.70 g, 96%). HPLC retention time 4.49min. Mass spectrum (ES+) m/z 256 (M+H).
88.8% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 70℃;Reflux; Irradiation; EXAMPLE 76 2-Bromomethyl-4-nitro-benzoic acid methyl ester (2) In accordance with general method T, 4.70 g (24.00 mmol) of (1) are dissolved in 30 ml of carbon tetrachloride, with heating, and 5.00 g (28.00 mmol) of N-bromosuccinimide and 2 spatula tips of azobisisobutyronitrile are then added. The mixture is refluxed for 6 h with irradiation with a 500 W spotlight. On cooling to room temperature, succinimide separates out, and is filtered off. The filtrate is evaporated on a rotary evaporator in order to obtain the product as a yellow oil. Yield: 5.85 g (88.8%) C9H8BrNO4 (Mr=274.07); GC (method 3) 7.98 min 1H-NMR (CDCl3) in ppm: 4.96 (s, 2H, -CH2-Br), 2.71 (s, 3H, -CH3) MS m/z (%): 274 (100), 193 (38), 178 (46), 147 (12), 132 (18), 88 (9). General Method TThe substance to be halogenated is dissolved in carbon tetrachloride in a 250 ml three-necked flask with a reflux condenser and drying tube at approx. 70 C. and the stated amounts of N-bromosuccinimide and azobisisobutyronitrile are added. The mixture is refluxed for 5 h, if necessary with irradiation with a 500 W spotlight. At the end of the reaction, the N-bromosuccinimide has dissolved and has been converted into succinimide, which settles on the surface. After cooling to room temperature, the mixture is filtered with suction. The filtrate is evaporated on a rotary evaporator in order to obtain the product as a yellow - orange oil.
78.7% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 20h;Reflux; In a 500 mL, 3-neck round-bottomed flask, the intermediate (1) (20 g, 88.01 mmol) was charged with CC14 (100 mL). N-bromosuccinimide (39.16g, 220.03 mmol) and AIBN (2.16 g, 13.20 mmol) were added and the resulting mixture was refluxed for 20 h. The reaction mixture was quenched with water (500 mL), extracted with dichloromethane (200 mL X 3), and the combined organic layer was washed with saturated brine solution followed by drying over anhydrous sodium sulphate. The organic layer was evaporated under reduced pressure and the crude product obtained was purified by silica gel column chromatography to obtain pure methyl 2-(bromomethyl)-4-nitrobenzoate (2), 19 g; Yield: 78.7%; Eta NMR (400 MHz, OMSO-de) : delta 8.52 (s, 1H), 8.27-8.3(dd, 1H), 8.07-8. l(d, 1H), 5.1 (s, 2H), 3.94 (s, 1H).
65% With N-Bromosuccinimide; 1,1'-azobis(1-cyanocyclohexanenitrile); In tetrachloromethane; for 5h;Reflux; To a solution of 2-methyl-4-nitrobenzoic acid methyl ester (2.0 g, 10.36 mmol) in carbon tetrachloride (80 mL) and l , azobis(cyclohexanecarbonitrile) (0.63 g, 2.56 mmol) was added N-bromosuccinimide (2.18 g, 12.25 mmol) and the resulting solution was heated at reflux for 5h and allowed to sit at room temperature overnight. The reaction was concentrated under reduced pressure and to the resulting residue was added DCM. The solid was filtered off and washed several times with DCM. The combined filtrate and washes were loaded onto a silica column and eluted with 10% EtOAc/hexane to provide slightly impure methyl 2-(bromomethyl)-4-nitrobenzoate (1.82 g, 65% yield) which was carried on as is to the next step.
53% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 15h; Compound methyl 2-methyl-4-nitrobenzoate 52a (5 g, 25.6 mmol) was dissolved in carbon tetrachloride (150 mL),Then N-bromosuccinimide (5.02 g, 28.2 mmol) and azobisisobutyronitrile (419 mg, 2.56 mmol) were added, heated to 80 C and stirred for 15 hours.After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100/1 to 5/1).The target product methyl 2- (bromomethyl) -4-nitrobenzoate 52b (3.7 g, white solid) was obtained, yield: 53%.
49% With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 85℃; for 21h; A solution of Intermediate 58 (9.57 g, 49 mmol), NBS (9.6g, 54 mmol), benzoyl peroxide (121 mg,0.5 mmol) in carbon tetrachloride was heated at 85C for 18 h. The reaction was concentrated under vaccum, analysed by TLC and 1H NMR and found to have some remaining starting material. <n="103"/>The residues were added to CCl4 (40 ml) with NBS (4.4 g) and benzoyl peroxide (60 mg) then stirred at 85C for 3h. The reaction was concentrated, taken up in DCM then washed with aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated under vacuum. The residues were purified by flash chromatography using a Biotage SP4. The desired product was isolated as an orange solid (6.58 g, 49%). 1H NMR (400 MHz, DMSO-^6) delta ppm 3.93 (s, 3 H), 5.10 (s, 2 H), 8.08 (d, 7=8.24 Hz, 1 H), 8.25 - 8.30 (m, 1 H), 8.51 (d, /=2.29 Hz, 1 H).
48.2% With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; for 48h;Reflux; A solution of 19 (2.57 g, 13.19 mmol) in 1,2-dichloroethane (100 mL) was treated with N-bromosuccinimide (2.3 g, 13.19 mmol) and benzoyl peroxide (0.26 g), and the mixture was kept at reflux for 2 days, then cooled, washed with water, and evaporated to a yellow oil (3.52 g). The oil was dissolved in acetone and silica gel (4.0 g) was added. A dry silica gel plug was obtained after evaporation of the solvent. The plug was loaded on to a silica gel column and eluted with 10% ethyl acetate in hexane to afford 20 (1.73 g, 48.2%) as a yellow oil; Rf 0.53 (hexane/EtOAc 3:1); 1H NMR (CDCl3) delta 3.89 (s, 3H, COOCH3), 4.86 (s, 2H, CH2Br), 7.98-8.23 (m, 3H, C6H3).
44% With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 7h;Inert atmosphere; Heating; 2 - methyl-4-nitrobenzoate (. 200mg, 1 OmmoL), benzoyl peroxide (48.5mg,0.2mmoL), N_-bromosuccinimide (213mg, 1.2mmoL) was added to the CCl4 (15mL), and under protection of Ar gas, the reaction was heated at reflux for 7 hours, cooled, washed with saturated sodium bicarbonate (3 X20mL ), saturated brine (20 mL), dried and the solvent was distilled off under reduced pressure, the residue was purified by flash column chromatography, eluent PE: EpsilonAlpha = 20: 1, to give a white solid 124mg, 44% yield
39% With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; Azobisisobutyronitrile (AIBN) (0.17 g, 1.02 mmol) was added to the solution of methyl 2-methyl-4-nitrobenzoate (61.2) (2.0 g, 10.2 mmol) and N-bromosuccinimide (NBS) (2.7 g, 15.2 mmol) in CCl4 (50 mL). The mixture was stirred at 80 C overnight. After cooling to room temperature, the reaction mixture was filtered and, the filtrate was concentrated to afford methyl 2-(bromomethyl)-4-nitrobenzoate (61.3) as a white solid (1.1 g, 39%). [00869] LCMS: 314.0 [M+CH3CN]+.
With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 22h; 5-Nitro-2,3-dihydroisoindol-l-one02N; [695] AIBN (58.6mg, 0.357mmol), NBS (785mg, 4.46mmol), and 2-methyl-4-nitrobenzoic acid methyl ester (696mg, 3.57mmol) were suspended in CC14 (35mL) in asealed tube. The above mixture was flushed with N2 for 5min and heated at 80C for 22h.After cooling, the solid was filtered off and the filtrate was concentrated to dryness to obtain acrude light-brown solid. To above solid was added NH3 (7 N in MeOH, 5mL), and themixture was stirred at rt for 2h and concentrated in vacua to obtain a yellow solid. This crudesolid was triturated with EtOAc (15mL) and was then cooled at -20 C. The mixture wasfiltered to obtain the title compound as yellow solid. 'H NMR (DMSO-^, 400 MHz): 5 =4.51 (s, 2 H), 7.13 (bra, 2 H), 7.91 (d, 1 H, J= 8.4 Hz), 8.25 (dd, 1 H, J= 2.0 & 8.4 Hz), 8.48(d, 1 H, J= 2.0 Hz), 9.04 (brs, 1 H). MS (ES+): m/z 179.22 (100) [MH1]. HPLC: fe = 2.14min (ZQ2000, polar_5 min).
With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane; at 85℃; for 9h;Reflux; Step b:[00294] A mixture of 2-methyl-4-nitro-benzoic acid methyl ester (leq.), NBS (1.1 eq.), benzoyl peroxide (0.01 eq.), and 20 mL of carbon tetrachloride is heated at 85C for 8hrs. Further NBS (0.1 eq.) is added and the whole is is refluxed 1 hrs. The mixture is washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated. The residue is purified by flash chromatography to afford the compound.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 85℃; Step A: Methyl 2-(bromomethyl)-4-nitrobenzoate: Methyl 2-methyl-4-nitrobenzoate (4.2 g, 21.5 mmol) was dissolved in 100 mL CCl4 under nitrogen. N-bromosuccinimide (6.13 g, 34.4 mmol) was added, followed by benzoyl peroxide (0.104 g, 0.430 mmol). The reaction mixture was heated overnight at 85 C. Added 1 g NBS followed by 100 mg benzoyl peroxide and continued heating the reaction for 6 hours. The reaction mixture was cooled to ambient temperature, poured into 1M HCl, extracted with dichloromethane, dried over magnesium sulfate, filtered and concentrated to an oil. Purification was carried out using column chromatography (5-10% EtOAc/hexanes).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 4h;Reflux; Inert atmosphere; A degassed solution of methyl 2-methyl-4-nitrobenzoate (3.5 g, 18.19 mmol), N- bromosuccinimide (3.9 g, 21.91 mmol, 1.2 eq) and benzoyl peroxide (3.63 mmoi, 0.2eq.) in 100 ml CCWwas heated at reflux for 4 hr. it was concentrated to dryness, dissolved in ether, washed 2x with water, aq. Na2S2theta3, brine, dried over MgSO4, filtered, concentrated and purified by chromatography using 15% ethyl acetate in hexanes to provide 4.11g of methyl 2-bromomethyl-4-nitrobenzoate.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 79℃;Inert atmosphere; Preparative Example 46aPreparation of 5-amino-2-cyclopropylisoindolin-1-oneStep 1: 2-cvclopropyl-5-nitroisoindoliii-1-oneAIBN (28 mg, 0.17), NBS (0.37 gram, 2.1 mmol), and the methyl 2-methyl-4-nitrobenzoate (334 g, 1.7 mmol, as prepared in Step 1, Example 44) were suspended in CCI4 (4.2 ml), the vessel evacuated and backfilled with N2 (2x) and the mixture heated under N2 at 79 C overnight. The solution was filtered, and concentrated in vacuum. The residue was dissolved in 7 N cyclopropyl amine (2.1 g, 35.9 mmol, in methanol, 18 ml), and the solution stirred for 2 hours at RT. The volatiles were removed in vacuum and the product purified by chromatography on Sitheta2 eluting with 10% acetone : DCM to give the titled compound.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 22h;Inert atmosphere; Sealed tube; ^nierrrsedsaie B6 S-amsnoisoindoIin-i -one Step A: methyl 2-(bromomethyl)-4-nitrobenzoate 2-methyl-4-nitrobenzoic acid methyl ester (896 mg, 3.57 mmoi), azobisisbufyronifrile (58.6 mg, 0.357 mmol) and N-bromosuccinimide (785 mg, 4.48 mmol) were suspended in carbon tetrachloride (35 mL) in a sealed tube. The above mixture was flushed with nitrogen for 5 minutes and heated at 80 C for 22 hours. After cooling, the solid was filtered off and the filtrate was concentrated to dryness to obtain the crude product methyl 2-(bromomethyl)-4-nitrobenzoate as a light-brown solid, which was used for the next step without purification.
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 70℃; for 15h; To solution of methyl 2-methyl-4-nitrobenzoate (350 mg, 1.8 mmol) in carbon tetrachloride (6 mL) was added NBS (500 mg, 2.8 mmol) and benzoyl peroxide (13 mg, 0.054 mmol). The reaction was then heated to 70 C for 15 hours and then cooled to ambient temperature. Once cooled, water (5 mL) was added and the aqueous layer was extracted with dichloromethane (3 X 10 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified via MPLC (0- 30% EtO Ac/Hex gradient) to afford methyl 2-(bromomethyl)-4-nitrobenzoate. NMR (500 MHz, DMSO-d6): 9 (s, 1H), 8.3 (d, 1H), 8.1 (d, 1H), 7.9 (s, 1H), 4.9 (s, 2H), 4.0 (s, 3H).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 60℃; for 4h; To a solutionof compound 7B (50g, 0.26 mol) in CC14 (500 mL), N-bromosuccinimide (45.8g, 0.26 mol)and benzoyl peroxide(0.12 g, 0.5 mmol) were added. The reactionmixture wasstirred 4 hr at 60C. The mixturewas cooled to RT and was washed with IN NaOHand water and it was dried overNa2S04. The solvent was evaporated to affordcrude7C (71g) as yellow oil.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 22h;Reflux; Step 2: Synthesis of 2-bromomethyl-4-nitro-benzoic acid methyl ester To a solution of 2-Methyl-4-nitro-benzoic acid methyl ester (3.08 g, 15.79 mmole) in 125 ml carbontetrachloride was added NBS (3.1 g, 17.38 mmole) and AIBN (390 mg, 2.38 mmole). The reaction mixture was heated at reflux under light for 22 hours. The reaction mixture was cooled down, concentrated to half, filtered off, solid was washed with 25 ml carbontetrachloride. The filtrate was concentrated to give 4 g crude product, containing about 20% unreacted starting material. This was used for next step without purification.
1.9 g With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 10h;Reflux; 2-Methyl-4-nitro - benzoic acid methyl ester (3.0 g, 15 mmol) wasdissolved in carbon tetrachloride (50 mL), and then were added N- bromosuccinimide (3.0 g, 17 mmol) and benzoyl peroxide (100mg, 0.4 mmol), the addition was complete the reaction was refluxed for 10hours. Completion of the reaction, the reaction solution was cooled toroom temperature, filtered, and the filtrate was washed with saturated sodiumbicarbonate solution and water, dried over anhydrous sodium sulfate, filteredand concentrated. Was purified by silica gel column chromatography usingconcentrated to give the intermediate 2-bromomethyl-4-nitro - benzoic acidmethyl ester (pale yellow solid, 1.9 g).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 2h;Reflux; Compound I (1.95 g, 10.0 mmol) was dissolved in carbon tetrachloride (20 mL), and NBS (2.14 g, 12.0 mmol, 1.2 eq) and benzoyl peroxide (0. 024 g, 0.1 mmol, 0.1 eq) was added and the mixture was heated to reflux for 2 h. At the end of the reaction, the temperature was lowered and the solid was removed by suction filtration. The mother liquor was evaporated to dryness to give Compound II in a yield of 95%.
With N-Bromosuccinimide; dibenzoyl peroxide; In chloroform; at 65℃; for 5h;Inert atmosphere; Schlenk technique; Reflux; General procedure: To a solution of 6.0 g (0.04 mol) of methyl 2-methylbenzoate derivatives in 38 mL of chloroform, 7.5 g (0.042 mol) of N-bromosuccinimide and 0.078 g of benzoyl peroxide were added and carefully warmed up to 65 C until reaction started. Then the mixture was refluxed for 5 h. After cooling down to room temperature, the deposit of succinimide was filtered. The solvent was removed under reduced pressure and the crude product was used in the next step without further purification. To a solution of functionalized methyl 2-(bromomethyl)benzoate (6.55 mmol), substituted phenol (8.5 mmol), K3PO4 (16.4 mmol) and toluene 20 mL were added to Schlenk under argon. The resulting solution was stirred to 110 C for 5 h. The progress of the reaction was monitored by TLC. The mixture was extracted with EtOAc, washed with water, brine and the combined organic layers were dried over anhydrous Na2SO4and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification. To the solution of the ester (0.015 mol) in MeOH (73 mL), was added 13 mL aqueous KOH (20%) and refluxed at 80C for 5 h. MeOH was removed and the aqueous phase was washed with DCM. After acidifying with HCl (10%) the deposit was collected and washed with water.

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  • 2
  • [ 1118-89-4 ]
  • [ 133446-99-8 ]
  • [ 133447-00-4 ]
YieldReaction ConditionsOperation in experiment
55.7% With potassium carbonate; In 2,4-dichlorophenoxyacetic acid dimethylamine; for 16h;Inert atmosphere; The oil 20 (0.85 g, 3.1 mmol) was stirred for 16 h with diethyl glutamate hydrochloride (1.54 g, 6.4 mmol) and powdered K2CO3 (1.7 g, 12 mmol) in DMA (3 mL) under argon. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined ethyl acetate solutions were washed twice with brine, dried, and evaporated to an orange oil. The oil was dissolved in methanol and silica gel was added. A dry silica gel plug was obtained after evaporation of the solvent. The plug was loaded on to a silica gel column and eluted with 25% ethyl acetate in hexane to afford 21 (0.63 g, 55.7%) as an orange oil; Rf 0.44 (hexane/EtOAc 1:1); 1H NMR (CDCl3) delta 1.17-1.22 (t, 3H, COOCH2CH3), 1.26-1.31 (t, 3H, COOCH2CH3), 2.19-2.49 (m, 4H, CHCH2CH2COOEt), 4.02-4.23 (2q, 4H, COOCH2CH3), 4.51-4.83 (dd, 2H, -CH2-), 5.09-5.14 (m, 1H, CHCH2CH2COOEt), 8.00-8.03 (d, 1H, C6H3), 8.36 (br s, 2H, C6H3).
  • 3
  • [ 24666-56-6 ]
  • [ 133446-99-8 ]
  • 3-(5-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
48% With triethylamine; In N,N-dimethyl-formamide; at 75℃; for 12h; To a solution of 3-aminopiperidine-2,6-dione (2.00 g, 12.2 mmol, HCl) and <strong>[133446-99-8]methyl 2-(bromomethyl)-4-nitro-benzoate</strong> (4.21 g, 15.4 mmol) in DMF (10.0 mL) was added TEA (3.07 g, 30.4 mmol). The reaction mixture was stirred at 75 C. for 12 hrs. On completion, the reaction mixture was diluted with water (200 mL), filtered. The filtered cake was collected. The reaction mixture was concentrated in vacuo. The residue was triturated EA:H2O=1:1 (50 mL) to give the title compound (1.7 g, 48% yield) as a blue solid. 1H NMR (400 MHz, DMSO-d6) delta 11.04 (s, 1H), 8.53 (d, J=1.2 Hz, 1H), 8.36 (dd, J=2.0, 8.4 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 5.17 (dd, J=5.2, 13.2 Hz, 1H), 4.69-4.45 (m, 1H), 3.01-2.86 (m, 1H), 2.68-2.59 (m, 1H), 2.48-2.35 (m, 1H), 2.13-2.02 (m, 1H).
1.50 g With potassium carbonate; In N,N-dimethyl-formamide; at 25 - 45℃; for 6h; Preparation of <strong>[133446-99-8]methyl <strong>[133446-99-8]2-(bromomethyl)-4-nitrobenzoate</strong></strong> (23-1) (2.5 g, 9.12 mmol) and 3- aminopiperidine-2,6-dione (1-2) (1.74 g, 13.6 mmol) were added to DMF (12.5 ml) at 25C. Potassium carbonate (3.15 g, 22.8 mmol) was added to the reaction mixture at 25C and the temperature was raised to 42C. The reaction mixture was stirred for 6 hours at 42C and cooled to 20C to 25C. De-ionized water (12.5 ml) was added to the reaction mixture at 20C and stirred for 20 minutes. The solid obtained was filtered, washed with de-ionized water (2 x 25 ml) and dried under vacuum at 40C to 45C for 20 hours to obtain the title compound.Then the crude material was slurried with PE/EA(1/1) 20 mL to give 3-(5-nitro-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (23-2) (1.50 g, 5.18 mmol, ) as gray-green solid. LC/MS (ES+): m/z 290 [M + H]+
  • 4
  • [ 62631-17-8 ]
  • [ 133446-99-8 ]
  • [ 246545-29-9 ]
  • 5
  • [ 133446-99-8 ]
  • [ 100-46-9 ]
  • [ 807343-00-6 ]
  • 6
  • [ 133446-99-8 ]
  • [ 108-95-2 ]
  • [ 924266-46-6 ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate; In toluene; at 110℃; for 5h;Inert atmosphere; Schlenk technique; General procedure: To a solution of 6.0 g (0.04 mol) of methyl 2-methylbenzoate derivatives in 38 mL of chloroform, 7.5 g (0.042 mol) of N-bromosuccinimide and 0.078 g of benzoyl peroxide were added and carefully warmed up to 65 C until reaction started. Then the mixture was refluxed for 5 h. After cooling down to room temperature, the deposit of succinimide was filtered. The solvent was removed under reduced pressure and the crude product was used in the next step without further purification. To a solution of functionalized methyl 2-(bromomethyl)benzoate (6.55 mmol), substituted phenol (8.5 mmol), K3PO4 (16.4 mmol) and toluene 20 mL were added to Schlenk under argon. The resulting solution was stirred to 110 C for 5 h. The progress of the reaction was monitored by TLC. The mixture was extracted with EtOAc, washed with water, brine and the combined organic layers were dried over anhydrous Na2SO4and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification. To the solution of the ester (0.015 mol) in MeOH (73 mL), was added 13 mL aqueous KOH (20%) and refluxed at 80C for 5 h. MeOH was removed and the aqueous phase was washed with DCM. After acidifying with HCl (10%) the deposit was collected and washed with water.
  • 8
  • [ 133446-99-8 ]
  • [ 915034-92-3 ]
  • 9
  • [ 133446-99-8 ]
  • 8-(2-aminophenylamino)-6H-dibenzo[b,e]oxepin-11-one [ No CAS ]
  • 10
  • [ 133446-99-8 ]
  • 8-(4-amino-phenylamino)-6,11-dihydro-dibenzo[b,e]oxepin-11-one [ No CAS ]
  • 11
  • [ 133446-99-8 ]
  • [ 924266-47-7 ]
  • 12
  • [ 133446-99-8 ]
  • 8-(4-amino-2-fluoro-phenylamino)-6,11-dihydro-dibenzo[b,e]oxepin-11-one [ No CAS ]
  • 13
  • [ 133446-99-8 ]
  • [ 924266-51-3 ]
  • 15
  • [ 133446-99-8 ]
  • [ 732936-23-1 ]
  • 17
  • [ 133446-99-8 ]
  • [ 914646-60-9 ]
  • 18
  • [ 133446-99-8 ]
  • [ 914646-62-1 ]
  • 19
  • [ 133446-99-8 ]
  • [ 914646-63-2 ]
  • 20
  • [ 133446-99-8 ]
  • [ 914646-61-0 ]
  • 21
  • [ 133446-99-8 ]
  • 3-(2-benzyl-1-oxo-2,3-dihydro-1<i>H</i>-isoindol-5-yl)-<i>N</i>-hydroxy-acrylamide [ No CAS ]
  • 22
  • [ 133446-99-8 ]
  • [ 914646-64-3 ]
  • 23
  • [ 99584-16-4 ]
  • [ 133446-99-8 ]
  • 24
  • [ 89001-53-6 ]
  • [ 133446-99-8 ]
  • 26
  • [ 133446-99-8 ]
  • [ 246545-30-2 ]
  • 27
  • [ 133446-99-8 ]
  • 5-amino-2-{5-[(2-amino-4-oxo-3,4-dihydro-pyrido[2,3-<i>d</i>]pyrimidin-6-ylmethyl)-amino]-1-oxo-1,3-dihydro-isoindol-2-yl}-pentanoic acid [ No CAS ]
  • 28
  • [ 133446-99-8 ]
  • 2-{5-[(2-amino-4-oxo-3,4-dihydro-pyrido[2,3-<i>d</i>]pyrimidin-6-ylmethyl)-amino]-1-oxo-1,3-dihydro-isoindol-2-yl}-pentanedioic acid [ No CAS ]
  • 29
  • [ 133446-99-8 ]
  • 5-amino-2-{5-[(2-amino-4-oxo-3,4,5,6,7,8-hexahydro-pyrido[2,3-<i>d</i>]pyrimidin-6-ylmethyl)-amino]-1-oxo-1,3-dihydro-isoindol-2-yl}-pentanoic acid [ No CAS ]
  • 30
  • [ 133446-99-8 ]
  • 2-{5-[(2-amino-4-oxo-3,4,5,6,7,8-hexahydro-pyrido[2,3-<i>d</i>]pyrimidin-6-ylmethyl)-amino]-1-oxo-1,3-dihydro-isoindol-2-yl}-pentanedioic acid [ No CAS ]
  • 31
  • [ 133446-99-8 ]
  • (S)-2-(5-[1-(2-Acetylamino-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-meth-(E)-ylidene]-amino}-1-oxo-1,3-dihydro-isoindol-2-yl)-pentanedioic acid diethyl ester [ No CAS ]
  • 32
  • [ 133446-99-8 ]
  • [ 246545-28-8 ]
  • 33
  • [ 133446-99-8 ]
  • 2-{5-[(2-acetylamino-4-oxo-3,4-dihydro-pyrido[2,3-<i>d</i>]pyrimidin-6-ylmethyl)-amino]-1-oxo-1,3-dihydro-isoindol-2-yl}-pentanedioic acid diethyl ester [ No CAS ]
  • 34
  • [ 133446-99-8 ]
  • 2-{5-[(2-acetylamino-4-oxo-3,4,5,6,7,8-hexahydro-pyrido[2,3-<i>d</i>]pyrimidin-6-ylmethyl)-formyl-amino]-1-oxo-1,3-dihydro-isoindol-2-yl}-pentanedioic acid diethyl ester [ No CAS ]
  • 35
  • [ 133446-99-8 ]
  • (S)-2-(5-[1-(2-Acetylamino-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-meth-(E)-ylidene]-amino}-1-oxo-1,3-dihydro-isoindol-2-yl)-5-benzyloxycarbonylamino-pentanoic acid methyl ester [ No CAS ]
  • 36
  • [ 133446-99-8 ]
  • 2-{5-[(2-acetylamino-4-oxo-3,4-dihydro-pyrido[2,3-<i>d</i>]pyrimidin-6-ylmethyl)-amino]-1-oxo-1,3-dihydro-isoindol-2-yl}-5-benzyloxycarbonylamino-pentanoic acid methyl ester [ No CAS ]
  • 37
  • [ 133446-99-8 ]
  • [ 246545-31-3 ]
  • 38
  • [ 133446-99-8 ]
  • 2-{5-[(2-acetylamino-4-oxo-3,4,5,6,7,8-hexahydro-pyrido[2,3-<i>d</i>]pyrimidin-6-ylmethyl)-formyl-amino]-1-oxo-1,3-dihydro-isoindol-2-yl}-5-benzyloxycarbonylamino-pentanoic acid methyl ester [ No CAS ]
  • 39
  • [ 99-52-5 ]
  • [ 133446-99-8 ]
  • 40
  • [ 133446-99-8 ]
  • 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ No CAS ]
  • 41
  • [ 133446-99-8 ]
  • [ 133447-02-6 ]
  • 42
  • [ 133446-99-8 ]
  • (S)-2-[5-(Di-prop-2-ynyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-pentanedioic acid diethyl ester [ No CAS ]
  • 43
  • [ 133446-99-8 ]
  • [ 133446-41-0 ]
  • 44
  • [ 133446-99-8 ]
  • [ 133446-42-1 ]
  • 45
  • [ 133446-99-8 ]
  • [ 133446-95-4 ]
  • 46
  • [ 133446-99-8 ]
  • [ 133447-04-8 ]
  • 47
  • [ 133446-99-8 ]
  • [ 133447-03-7 ]
  • 48
  • [ 133446-99-8 ]
  • [ 133447-05-9 ]
  • 49
  • [ 133446-99-8 ]
  • [ 133447-06-0 ]
  • 50
  • [ 133446-99-8 ]
  • [ 110568-64-4 ]
YieldReaction ConditionsOperation in experiment
92% With ammonia; In methanol; at 20℃; for 2h; 2- (bromomethyl) -4-nitrobenzoate (250mg, 0.92 mmol) was added to a saturated methanolic ammonia (NH3) in (5mL red, stirred at room temperature for 2 hours, TLC the reaction was complete. Save the solvent was distilled off pressure, to the residue was added ethyl acetate (7mL) and sonicated for 3 minutes, placed in -20 C freezer for 3 minutes, a large number of solid, filtered and dried under high vacuum to give a pale yellow solid 150mg, yield 92%
With ammonia; In methanol; at 20℃; for 2h; 5-Nitro-2,3-dihydroisoindol-l-one02N; [695] AIBN (58.6mg, 0.357mmol), NBS (785mg, 4.46mmol), and 2-methyl-4-nitrobenzoic acid methyl ester (696mg, 3.57mmol) were suspended in CC14 (35mL) in asealed tube. The above mixture was flushed with N2 for 5min and heated at 80C for 22h.After cooling, the solid was filtered off and the filtrate was concentrated to dryness to obtain acrude light-brown solid. To above solid was added NH3 (7 N in MeOH, 5mL), and themixture was stirred at rt for 2h and concentrated in vacua to obtain a yellow solid. This crudesolid was triturated with EtOAc (15mL) and was then cooled at -20 C. The mixture wasfiltered to obtain the title compound as yellow solid. 'H NMR (DMSO-^, 400 MHz): 5 =4.51 (s, 2 H), 7.13 (bra, 2 H), 7.91 (d, 1 H, J= 8.4 Hz), 8.25 (dd, 1 H, J= 2.0 & 8.4 Hz), 8.48(d, 1 H, J= 2.0 Hz), 9.04 (brs, 1 H). MS (ES+): m/z 179.22 (100) [MH1]. HPLC: fe = 2.14min (ZQ2000, polar_5 min).
With ammonia; In methanol; at 20℃; for 2h; Step B: 5-nitroisoindoiin-1 -one A suspension of <strong>[133446-99-8]methyl <strong>[133446-99-8]2-(bromomethyl)-4-nitrobenzoate</strong></strong> in ammonium solution (7 N in methanol, 5 mL) was stirred at room temperature for 2 hours and concentrated in vacuum to obtain a yellow solid. This crude solid was triturated with ethyl acetate (15 mL) and was then cooled at -20 C. The mixture was filtered to obtain the product 5-nitroisoindolin-1 -one as yellow solid. N R (400 MHz, DMSO-d6) delta ppm 9.04 (br s, 1 H), 8.48 (d, 1 H, J = 2.0 Hz), 8.25 (dd, 1 H, J = 2.0 Hz, 8.4 Hz), 7.91 (d, 1 H, J = 8.4 Hz), 4.51 (s, 2 H).
With ammonium hydroxide; ammonia; In methanol; at 20℃; Crude 7C (70 g, 0.26 mol) was suspended in 2M NH3inMeOH (700 mL) and concentratedammonium hydroxide (250 mL) at room temperature overnight. The mixturewasfilteredto affordcrude 7D (35g) as a white solid.
With ammonia; In methanol; at 20℃; Step 3: Synthesis of 5-Nitro-2,3-dihydro-isoindol-1-one The crude from the previous step (4 g) was placed in a 100 ml round bottom flask, then a solution of 7N NH3 in MeOH was added. The mixture was stirred at room temperature, overnight. The mixture was concentrated down to a solid residue, then triturated with 75 ml ethylacetate. The suspension was filtered off, solid was dried to give 1.8 g product, pure by HNMR, 64% over 2 steps yield.

  • 51
  • [ 593-51-1 ]
  • [ 133446-99-8 ]
  • [ 1190380-36-9 ]
YieldReaction ConditionsOperation in experiment
9% With triethylamine; In methanol; for 24h;Inert atmosphere; Reflux; A solution of Intermediate 59 (1 g, 3.7 mmol), methylamine hydrochloride (124 mg, 4 mmol) andEt3N (404 mg, 4 mmol) were refluxed in MeOH for 24 h under N2. During this time an additional 0.5eq of methylamine hydrochloride was added, twice, to compensate for the volatility of methylamine. The mixture was diluted with EtOAc, washed sequentially with IM HCl and brine., and the organic phase was dried over Na2SO4 and concentrated under vacuum. The residues were purified by silica gel chromatography, eluting first with 20% EtOAc in petroleum ether and then with 30% MeOH in DCM. Further purification by preparative LCMS gave the title compound (62 mg, 9%). 1H NMR (400 MHz, DMSO-^6) delta ppm 3.12 (s, 3 H), 4.60 (s, 2 H), 7.90 (d, J=8.24 Hz, 1 H), 8.26 - 8.36 (m, 1 H), 8.51 (s, 1 H); m/z (ES+APCI)+ : 193 [M+H]+.
  • 52
  • [ 133446-99-8 ]
  • [ 141-43-5 ]
  • [ 1190380-37-0 ]
YieldReaction ConditionsOperation in experiment
14% With triethylamine; In methanol; for 24h;Inert atmosphere; Reflux; A solution of Intermediate 59 (1 g, 3.7 mmol), 2-hydroxy ethylamine (242 mul, 4 mmol) and Et3N (404 mg, 4 mmol) were refluxed in MeOH for 24 h under N2. The mixture was diluted in DCM, <n="104"/>washed with IM HCl and brine. The organic fractions were dried over Na2SO4 and concentrated under vacuum. The residues were purified by preparative LCMS to give the title compound (114 mg, 14%). 1H NMR (400 MHz, DMSO-^6) delta ppm 3.55 - 3.69 (m, 4 H), 4.68 (s, 2 H), 4.86 - 4.95 (m, 1 H), 7.91 (d, /=8.24 Hz, 1 H), 8.33 (dd, /=8.47, 2.06 Hz, 1 H), 8.52 (s, 1 H); m/z (ES+APCI)+ : 223 [M+H]+.
  • 53
  • [ 133446-99-8 ]
  • [ 110568-64-4 ]
YieldReaction ConditionsOperation in experiment
With ammonia; triethylamine; In methanol; for 24h;Reflux; Step c:[00295] A mixture of 2-Bromomethyl-4-nitro-benzoic acid methyl ester (leq.) an appropriate amine (1.1 eq.), Et3N (l.leq), and 10 mL of methanol is refluxed for 24hrs. The mixture is diluted with EtOAc, washed with HCl (IN) and brine, dried over MgSO4, and evaporated. The residue is purified by flash chromatography. to afford the expected compound.
  • 54
  • [ 20781-20-8 ]
  • [ 133446-99-8 ]
  • [ 1214900-77-2 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; To a solution of the above product in 40 ml DMF at rt was added 2,4- dimethoxybenzyl amine (2.7 ml, 17.98 mmol, 1.2 eq.), potassium carbonate (4.1 g, 30.12 mmol, 2 eq.) and the mixture stirred overnight at rt. It was diluted with ethyl acetate, washed 2x with water, 1 N HCI, brine, dried over MgSO4, filtered, concentrated and purified by chromatography using 5% ethyl acetate in dichloromethane to provide 2.43 g of P29.
  • 55
  • [ 133446-99-8 ]
  • [ 75-31-0 ]
  • [ 1219825-25-8 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In methanol; at 100℃; for 2h;Sealed tube; REFERENCE EXAMPLE 16; 5-Amino-2-isopropyfisoindofin-1-one; a) 2-isopropyi-5-nitroisoindolin-1-one; 0.23 mL (1.64 mmoi) of TEA, and 65 mg (1.09 mmol) of isopropyl amine were added to a solution of methyl 2-bromomethyl-4-nitrobenzenecarboxylate (300 mg, 1.09 mmol) in methanol (2.25 mL). The reaction mixture was stirred in a seaied tube at 100 0C for 2 h. After cooling the reaction mixture, the solid formed was filtered, washed with diethyl ether and dried. The desired compound was obtained and used in next step without further purification.
 

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