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Chemical Structure| 489446-42-6 Chemical Structure| 489446-42-6

Structure of 489446-42-6

Chemical Structure| 489446-42-6

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Product Details of [ 489446-42-6 ]

CAS No. :489446-42-6
Formula : C12H18BNO4
M.W : 251.09
SMILES Code : O=C(NCC1=CC=C(B(O)O)C=C1)OC(C)(C)C
MDL No. :MFCD04115637
InChI Key :MUBGEKQUCSEECZ-UHFFFAOYSA-N
Pubchem ID :3863163

Safety of [ 489446-42-6 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 489446-42-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 18
Num. arom. heavy atoms 6
Fraction Csp3 0.42
Num. rotatable bonds 6
Num. H-bond acceptors 4.0
Num. H-bond donors 3.0
Molar Refractivity 69.78
TPSA ?

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

78.79 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.0
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

1.33
Log Po/w (WLOGP)?

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

0.24
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.

0.7
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

-0.47
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.36

Water Solubility

Log S (ESOL):?

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

-2.09
Solubility 2.06 mg/ml ; 0.00822 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.

-2.59
Solubility 0.651 mg/ml ; 0.00259 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

-2.65
Solubility 0.562 mg/ml ; 0.00224 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

No
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

No
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.

-6.89 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)

2.06

Application In Synthesis of [ 489446-42-6 ]

* 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 [ 489446-42-6 ]

[ 489446-42-6 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 489446-42-6 ]
  • [ 945244-49-5 ]
  • C30H32N2O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate;Pd-FibreCat 1007; In N,N-dimethyl-formamide; at 150℃; for 0.166667h;Microwave irradiation; Preparation 19 N-(4'-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide 1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide (37 mg, 0.10 mmol), <strong>[489446-42-6]4-((tert-butoxycarbonylamino)methyl)phenylboronic acid</strong> (37 mg, 0.15 mmol), 1 M K2CO3 (0.2 mL, 0.2 mmol), Pd-FibreCat 1007 (8 mg, 0.1 mmol), and N,N-dimethylformamide (1 mL) were combined. The mixture was irradiated in the microwave at 150 C. for 10 minutes. The reaction was filtered and purified by reverse phase HPLC. The obtained material was dissolved in dichloromethane (2 mL) containing trifluoroacetic acid (2 mL) and stirred at 25 C. for 1 hour. The reaction was filtered and purified by reverse phase HPLC to yield N-(4'-(aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as the TFA salt (8.1 mg, 20%). ESI-MS m/z calc. 400.2, found 401.5 (M+1)+; retention time 2.55 minutes.
With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 0.166667h;Microwave irradiation; 1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide (37 mg, 0.10 mmol), <strong>[489446-42-6]4-((tert-butoxycarbonylamino)methyl)phenylboronic acid</strong> (37 mg, 0.15 mmol), 1 M K2CO3 (0.2 mL, 0.2 mmol), Pd-FibreCat 1007 (8 mg, 0.1 mmol), and N,N-dimethylformamide (1 mL) were combined. The mixture was irradiated in the microwave at 150 C. for 10 minutes. The reaction was filtered and purified by reverse phase HPLC. The obtained material was dissolved in dichloromethane (2 mL) containing trifluoroacetic acid (2 mL) and stirred at 25 C. for 1 hour. The reaction was filtered and purified by reverse phase HPLC to yield N-(4'-(aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as the TFA salt (8.1 mg, 20%). ESI-MS m/z calc. 400.2. found 401.5 (M+1)+; retention time 2.55 minutes.
  • 2
  • [ 51239-46-4 ]
  • [ 489446-42-6 ]
YieldReaction ConditionsOperation in experiment
For compounds (2-6) the commercially available 4-aminomethylphenylboronic acid and 3-aminomethylphenylboronic acid were BOC protected under standard conditions (Wei et al., 2000) and the appropriate boronic acid was used at the Suzuki coupling stage in the synthesis of compounds (2-6). The BOC group was removed with 4 M HCl in dioxane at RT after hydrazone coupling;
  • 3
  • [ 864132-33-2 ]
  • [ 489446-42-6 ]
  • 4-bromo-5-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-3-ethoxycarbonylmethoxy-thiophene-2-carboxylic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
58% With potassium fluoride;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 150℃; for 0.666667h;microwave; The first step of Scheme 7: To a microwave tube was added 4-benzyl-carbamic acid tert-butyl ester boronic acid (75 mg, 0.3 mmol), 4,5-Dibromo-3-ethoxycarbonylmethoxy-thiophene-2-carboxylic acid methyl ester (80 mg, 0.2 mmol), potassium fluoride (46 mg, 0.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol). The vessel was purged with argon and then diluted with THF (2 mL). The reaction was heated in the microwave at 150 C. for 40 minutes. The reaction was diluted with ethyl acetate (10 mL) and filtered through a layer of silica gel. Purification of the material by CombiFlash column chromatography eluting with a 10-35% ethyl acetate-hexane gradient to yield 61 mg of 4-Bromo-5-[4-(tert-butoxycarbonylamino-methyl)-phenyl]-3-ethoxycarbonylmethoxy-thiophene-2-carboxylic acid methyl ester as a white solid (58%). 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.32 (t, J=7.07 Hz, 3H) 1.47 (s, 9H) 3.88 (s, 3H) 4.30 (q, J=7.16 Hz, 2H) 4.37 (d, J=5.81 Hz, 2H) 4.91 (s, 2H) 7.38 (d, J=8.34 Hz, 3H) 7.63 (m, 2H).
  • 4
  • [ 887147-33-3 ]
  • [ 489446-42-6 ]
  • C21H24N6O2S [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; ethanol; water; at 100℃; for 0.833333h; Example A82-[4-("aminomethyl')phenyll-N,8-dimethyl-8H-imida2or4,5-d1thiazolo[4,5-b1pyridin-5- amine A8A3.3 (20mg, 0.067 mmol), 4-(t-butyloxycarbonylaminomethyl)phenylboronic acid (18.6mg 0.074 mmol) and tetrakis(triphenylphosphine)palladium (0) (7.74 mg, 0.007 mmol) was added to a mixture of 2M aqueous sodium carbonate (0.14 mL) dioxane (0.35 mL) and ethanol (0.35 mL). The reaction mixture was heated under an argon74 EPO <DP n="76"/>atomosphere for 50 min. at 100 0C. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. Dichloromethane (1 mL) was added and the suspension cooled in an ice bath. Trifluoroacetic acid (1 mL) was added and the reaction mixture stirred at 0 0C for 45 min. The solvent was removed under reduced pressure and the crude product was dissolved in methanol and purified by automated reverse phase chromatography. The appropriate fractions were combined and the solvent removed under reduced pressure with the aid of heptane as an azeotroping agent to yield 19.8 mg of product as a pale yellow solid. M+H+ = 325.27. NMR 400 MHz J6DMSO delta 8.29 s, IH, 8.28-8.20 br s, 2H, 8.17 d, J = 8.2 hz, 2H, 7.65 d, J = 8.2 Hz, 2 H, 4.20-4.10 apparent quartet, 2H, 4.03, s, 3H, 3.06, s, 3H.
  • 5
  • [ 489446-42-6 ]
  • [ 928650-17-3 ]
  • [ 928650-19-5 ]
YieldReaction ConditionsOperation in experiment
38% With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃; for 1h;Microwave irradiation; 4-[6-(Cvclopropylmethyl-amino)-pyrimidin-4-yll-iV*-(tert-butoxycarbonyl)-benzylamine; In a microwave reaction vessel, slurry 6-chloro-4-(cyclopropylmethyl-amino)-pyrimidine (560 mg, 3 mmol), [4-(N-tert-butoxycarbonyl-aminomethyl)phenyl]boronic acid (1.1 g, 4 mmol), and tetrakis(triphenylphosphine)palladium(0) (190 mg, 0.15 mmol) in toluene (4 mL). Add ethanol (1 mL) followed by potassium carbonate (0.9 g, 6 mmol) dissolved in water (300 DL). Irradiate in microwave (300 watts) at 120 0C for 60 min. Cool to room temperature, pour reaction mixture into IN NaOH (250 mL) and extract with DCM (3x100 mL). Wash the combined organic extracts with brine, dry over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with hexane/EtOAc (4: 1 to 2:3 over 45 min; 40 mL/min) to obtain the desired intermediate (450 mg, 38%) as a yellow solid. MS (ES+) m/z: 355 (M+H)+.
  • 6
  • [ 489446-42-6 ]
  • (2-chloropyrimidin-4-yl)cyclopropylmethylamine [ No CAS ]
  • [ 928650-25-3 ]
YieldReaction ConditionsOperation in experiment
20% With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃; for 1.5h;Microwave irradiation; 4-r4-(Cvclopropylmethyl-amino)-pyrimidin-2-yll-N-(?grt-butoxycarbonyl)-benzylamine; Slurry 2-chloro-4-(cyclopropylmethyl-amino)-pyrimidine (370 mg, 2 mmol), [4-(N-tert- butoxycarbonyl-aminomethyl)phenyl]boronic acid (710 mg, 2.83 mmol), and tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.10 mmol) in toluene (3 mL). Add ethanol (0.5 mL) followed by potassium carbonate (550 mg, 4 mmol) dissolved in water (300 muL). Irradiate in microwave (300 watts) at 120 C for 90 min. Cool to room temperature, pour reaction mixture into water (100 mL) containing IN NaOH (25 mL) and extract with DCM (3x50 mL). Wash the combined organic extracts with brine, dry over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with hexane/EtOAc (4:1 to 1:4 over 45 min; 40 mL/min) to obtain the desired intermediate (105 mg, 20%) as a yellow solid. MS (ES+) m/z: 355 (M+H)+. Additionally recovered unreacted 2-chloro-4-(cyclopropylmethyl-amino)-pyrimidine (100 mg).
  • 7
  • [ 489446-42-6 ]
  • [ 928650-29-7 ]
  • [ 928650-31-1 ]
YieldReaction ConditionsOperation in experiment
90% With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃; for 1h;Microwave irradiation; 4-r2-(Cvclopropylmethyl-amino)-pyrimidin-4-yll-N-(fert-butoxycarbonyl)-benzylamine; Slurry 4-chloro-2-(cyclopropylmethyl-amino)-pyrimidine (155 mg, 0.62 mmol), [4-(N- fert-butoxycarbonyl-ammomethyl)phenyl]boronic acid (160 mg, 0.86 mmol), and tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.031 mmol) in toluene (3 mL). Add ethanol (0.5 mL) followed by potassium carbonate (175 mg, 1.24 mmol) dissolved in water (300 muL). Irradiate in microwave (300 watts) at 120 C for 60 min. Cool to room temperature, pour reaction mixture into water (100 mL) containing IN NaOH (25 mL) and extract with DCM (3x50 mL). Wash the combined organic extracts with brine, dry over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (12 g) eluting with hexane/EtOAc (4:1 to 3:7 over 30 min; 30 mL/min) to obtain the desired intermediate (200 mg, 90%) as a light yellow solid. MS (ES+) m/z: 355 (M+H)+.
  • 8
  • [ 489446-42-6 ]
  • [ 928650-35-5 ]
  • [ 928650-36-6 ]
YieldReaction ConditionsOperation in experiment
63% With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; N-(tgrt-Butoxycarbonyl')-4-r5-(3,3-dimethylbutyryl)tiophen-2-vn-benzylamine; To a solution of 2-bromo-5-(3,3-dimethylbutyryl)-thiophene (187 mg, 0.7 mmol) in dioxane (7 mL) add a solution of aqueous 2M Na2CO3 (0.9 mL), [4-(iV-t£rt-butoxycarbonyl- aminomethyl)phenyl]boronic acid (216 mg, 0.8 mmol) and tetrakis(triphenylphosphine)- palladium(O) (41 mg, 0.03 mmol). Heat the mixture at 90 0C overnight. Cool at room temperature, add water and extract with EtOAc. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate (174 mg, 63%).
  • 9
  • [ 24424-99-5 ]
  • [ 51239-46-4 ]
  • [ 489446-42-6 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In tetrahydrofuran; for 1h;Heating / reflux; 3,5-Dimethyl-isoxazole-4-sulfonic acid 4-(5-fluoro-2-methoxy-pyridin-3-yl) benzylamide Di-tert-butyl dicarbonate (3.5 g, 16 mmol) and triethylamine (13 ml, 9.4 mmol) were added to a stirred solution of 4-aminomethylphenylboronic acid (3 g, 16 mmol) in tetrahydrofuran (100 ml). The reaction was stirred under reflux for 1 hour, then the solvent evaporated and the residue partitioned between water and ethyl acetate. The organic phase was concentrated under reduced pressure to give tert-butoxycarbonylaminomethyl-4-phenyl-boronic acid (2.67 g, 10.6 mmol) as a white solid. Toluene (16 ml), ethanol (4 ml), 2M sodium carbonate solution and tetrakis(triphenylphosphine) palladium (0) were added to tert-butoxycarbonylaminomethyl-4-phenyl-boronic acid (1.349 g, 5.4 mmol) and 3-bromo-5-fluoro-2-methoxy-pyridine (0.505 g, 2.45 mmol) and the mixture stirred under reflux for 24 h. Water was added and the mixture extracted with ethyl acetate. The organic phase was separated and the solvent evaporated. The residue was purified on silica gel eluting with 3:1 heptane/ethyl acetate to give [4-(5-fluoro-2-methoxy-pyridin-3-yl-benzyl]-carbamic acid-tert-butyl ester as a yellow oil. Trifluoroacetic acid (2 ml, 0.026 mmol) was added to a solution of [4-(5-fluoro-2-methoxy-pyridin-3-yl-benzyl]-carbamic acid-tert-butyl ester (0.8 g, 2.41 mmol) in dichloromethane (4 ml) and the reaction mixture stirred for 2 h. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic phase was separated and the solvent evaporated to give 4-(5-fluoro-2-methoxy-pyridin-3-yl)-benzylamine. The title compound was prepared in a similar manner to N-[1-(2-allyl-5'-fluoro-2'-methoxy-biphenyl-4-yl)-ethyl]-3,4-difluoro-benzenesulfonamide (Example 34) using 4-(5-fluoro-2-methoxy-pyridin-3-yl)-benzylamine and 3,5-dimethyl-isoxazole-4-sulfonyl chloride. MS (ESI) m/z: 392 [M+H]+.
With triethylamine; In tetrahydrofuran; at 20℃; for 1h; To a solution of 4-aminomethylphenylboronic acid (2.65 mmol) in THF (10 mL) were added di-tert-butyl dicarbonate (3.97 mmol) and triethylamine (1 mL). The mixture was stirred at room temperature for 1 h. After completion of the reaction, excess solvent was evaporated to dryness under reduced pressure. The residue was diluted with water (30 mL) and ethyl acetate (15 mL). The organic phase was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. The NHBoc-protected boronic acid was then used for Suzuki coupling as described in compound 6 to afford compound 9.
  • 10
  • [ 489446-42-6 ]
  • [ 884494-81-9 ]
  • [ 943153-49-9 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 24h;Heating / reflux; 3,5-Dimethyl-isoxazole-4-sulfonic acid 4-(5-fluoro-2-methoxy-pyridin-3-yl) benzylamide Di-tert-butyl dicarbonate (3.5 g, 16 mmol) and triethylamine (13 ml, 9.4 mmol) were added to a stirred solution of 4-aminomethylphenylboronic acid (3 g, 16 mmol) in tetrahydrofuran (100 ml). The reaction was stirred under reflux for 1 hour, then the solvent evaporated and the residue partitioned between water and ethyl acetate. The organic phase was concentrated under reduced pressure to give tert-butoxycarbonylaminomethyl-4-phenyl-boronic acid (2.67 g, 10.6 mmol) as a white solid. Toluene (16 ml), ethanol (4 ml), 2M sodium carbonate solution and tetrakis(triphenylphosphine) palladium (0) were added to tert-butoxycarbonylaminomethyl-4-phenyl-boronic acid (1.349 g, 5.4 mmol) and 3-bromo-5-fluoro-2-methoxy-pyridine (0.505 g, 2.45 mmol) and the mixture stirred under reflux for 24 h. Water was added and the mixture extracted with ethyl acetate. The organic phase was separated and the solvent evaporated. The residue was purified on silica gel eluting with 3:1 heptane/ethyl acetate to give [4-(5-fluoro-2-methoxy-pyridin-3-yl-benzyl]-carbamic acid-tert-butyl ester as a yellow oil. Trifluoroacetic acid (2 ml, 0.026 mmol) was added to a solution of [4-(5-fluoro-2-methoxy-pyridin-3-yl-benzyl]-carbamic acid-tert-butyl ester (0.8 g, 2.41 mmol) in dichloromethane (4 ml) and the reaction mixture stirred for 2 h. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic phase was separated and the solvent evaporated to give 4-(5-fluoro-2-methoxy-pyridin-3-yl)-benzylamine. The title compound was prepared in a similar manner to N-[1-(2-allyl-5'-fluoro-2'-methoxy-biphenyl-4-yl)-ethyl]-3,4-difluoro-benzenesulfonamide (Example 34) using 4-(5-fluoro-2-methoxy-pyridin-3-yl)-benzylamine and 3,5-dimethyl-isoxazole-4-sulfonyl chloride. MS (ESI) m/z: 392 [M+H]+.
  • 11
  • [ 489446-42-6 ]
  • [ 55052-28-3 ]
  • [4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-benzyl]-carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
[249] A mixture of 4-chloro-7-azaindole (1.516g, 10 mmole) in 1,4-dioxane (48mL) and water ?(12mL) in a 25OmL, two-necked round bottomed flask was charged with K2CO3 (0.82Og, 5.9mmole), [4- (N-BOC-aminornethyl)phenylboronic acid (2.88g, 11.5mmole), Pd(dppf)2Cl2-CH2Cl2 catalyst (371mg, 0.45mmole). Nitrogen was bubbled into the reaction mixture for 15min at rt and then heated at 1000C overnight under nitrogen atmosphere. The reaction mixture was cooled to rt and added triethylamine (3mL) and evaporated to dryness and purified by column chromatography. The crude was taken in methylene chloride and loaded onto the column. The column was eluted with 20-40% ethyl acetate in methylene chloride, the desired fractions from column were collected and the resulting solid was triturated with hot isopropyl ether, cooled to rt and filtered to give the title compound as a pale yellow solid. 1H NMR (CDCl3): delta 1.49 (s, 9H), 4.41 (d, 2H, J = 6.3 Hz), 4.98 (brs, IH), 6.79 (m, IH), 7.17 (d, IH, J = 4.8 Hz), 7.39 (t, IH, J = 3.0 Hz), 7.44 (d, 2H, J = 8.4 Hz), 7.73 (d, 2H, J = 8.4 Hz), 8.37 (d, IH5 J = 5.1 Hz), 10.01 (brs, IH); MS (ES+): m/z 324.09 [MH+].
  • 12
  • [ 489446-42-6 ]
  • [ 1082066-21-4 ]
  • [ 1082066-47-4 ]
YieldReaction ConditionsOperation in experiment
91% With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ISOPROPYLAMIDE; water; at 120℃; for 20h; Stir 3'-chloro-4-(l,5-dimethyl-lH-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H- [l,2']bipyrazinyl (921 mg, 3.00 mmol), potassium carbonate (996 mg, 7.20 mmol), 4-benzyl (carbamic acid tert-butyl ester) boronic acid (940 mg, 3.60 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.015 mmol) in N,N-dimethylacetamide (6 mL). Add water (3 mL), degas for 5 min., and then heat at 120 0C for 20 hr. Cool to room temperature, add water (10 mL) and extract with DCM (3 x 10 mL). Pass the combined DCM extracts through an 1ST Phase Separator Frit.Concentrate the filtrate and purify by SCX-2 chromatography washing with methanol then eluting with 2 M ammonia in methanol. Further purify (silica gel chromatography, eluting with 5:95 to 15:85 methanol: DCM), to give N-{4-[4-(l,5-dimethyl-lH-pyrazol-4- ylmethyl)-3,4,5,6-tetrahydro-2H-[l,2']bipyrazinyl-3'-yl]-benzyl} -carbamic acid tert-butyl ester as an oil (1.3 g, 91%). MS (ES): m/z = 478 [M+H]+.
  • 13
  • [ 489446-42-6 ]
  • [ 1258547-10-2 ]
  • C33H31N3O4 [ No CAS ]
  • 14
  • [ 489446-42-6 ]
  • [ 1003933-82-1 ]
  • C34H33N3O4 [ No CAS ]
  • 15
  • [ 489446-42-6 ]
  • [ 1258547-33-9 ]
  • tert-butyl ((4'-((1-(benzyloxy)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)methyl)-[1,1'-biphenyl]-4-yl)methyl)carbamate [ No CAS ]
  • 16
  • [ 489446-42-6 ]
  • [ 81290-20-2 ]
  • [ 1264670-40-7 ]
  • 17
  • [ 489446-42-6 ]
  • [ 945241-81-6 ]
  • 18
  • [ 489446-42-6 ]
  • [ 945240-16-4 ]
  • 19
  • [ 489446-42-6 ]
  • [ 945244-49-5 ]
  • [ 945235-39-2 ]
YieldReaction ConditionsOperation in experiment
With K2CO3; trifluoroacetic acid; In dichloromethane; N,N-dimethyl-formamide; Preparation 19 N-(4'-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide 1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-methylphenyl)cyclopropanecarboxamide (37 mg, 0.10 mmol), <strong>[489446-42-6]4-((tert-butoxycarbonylamino)methyl)phenylboronic acid</strong> (37 mg, 0.15 mmol), 1 M K2CO3 (0.2 mL, 0.2 mmol), Pd-FibreCat 1007 (8 mg, 0.1 mmol), and N,N-dimethylformamide (1 mL) were combined. The mixture was irradiated in the microwave at 150 C. for 10 minutes. The reaction was filtered and purified by reverse phase HPLC. The obtained material was dissolved in dichloromethane (2 mL) containing trifluoroacetic acid (2 mL) and stirred at 25 C. for 1 hour. The reaction was filtered and purified by reverse phase HPLC to yield N-(4'-(aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as the TFA salt (8.1 mg, 20%). ESI-MS m/z calc. 400.2, found 401.5 (M+1)+; retention time 2.55 minutes.
  • 20
  • [ 489446-42-6 ]
  • C29H45BrN6O6 [ No CAS ]
  • C41H61N7O8 [ No CAS ]
  • 21
  • [ 489446-42-6 ]
  • 1-methylethyl [(cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate [ No CAS ]
  • C28H37N3O5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 100℃; for 1.33333h;Inert atmosphere; Example 551 -methylethyl {(cis)-1 -acetyl-6-[4-(aminomethyl)phenyl]-2-methyl-1 ,2,3,4-tetrahydro- 4-quinolinyl}carbamate hydrochloride1 -Methylethyl [(cis)-1 -acetyl-6-bromo-2-methyl-1 ,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 61 )(212 mg, 0.574 mmol) , potassium carbonate (159 mg, 1 .148 mmol), tetrakis(triphenylphosphine)palladium(0) (33.2 mg, 0.029 mmol) and {4- [([(1 ,1 -dimethylethyl)oxy]carbonyl}amino)methyl]phenyl}boronic acid (173 mg, 0.689 mmol, available from Apollo) were dissolved in ethanol (1 .5 mL) and toluene (1.5 ml_). The reaction mixture was degassed for 20min then stirred and heated under nitrogen for 1 hr at 100 C. The reaction mixture was concentrated under vacum. The residue was partitioned between dichloromethane (10ml) and water (10ml). The organic layer was dried through a hydrophobic frit and concentrated in vacuo, then dissolved in DCM and purified by SP4 on a 25+M silica cartridge using a gradient of 0-50% EtOAc in cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the boc-protected product (250 mg). This was dissolved with 5ml of methanol and treated with 1 ml of acetyl chloride. After 1 h the reaction mixture was loaded on a 20g NH2 cartridge, which was previously conditioned with methanol. Column was washed with methanol (3CV). The appropriate fractions were combined and evaporated in vacuo to give the free base product (197mg). The product was dissolved with 3ml of methanol and treated with 1.1 eq of 2M HCI in to give a yellow solid (181 mg)LCMS (Method B): Rt = 0.63, MH+ = 396
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 100℃; for 1h;Inert atmosphere; 1-Methylethyl [(cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 61) (212 mg, 0.574 mmol), potassium carbonate (159 mg, 1.148 mmol), tetrakis(triphenylphosphine)palladium(0) (33.2 mg, 0.029 mmol) and {4-[([(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]phenyl}boronic acid (173 mg, 0.689 mmol, available from Apollo) were dissolved in ethanol (1.5 mL) and toluene (1.5 mL). The reaction mixture was degassed for 20 min then stirred and heated under nitrogen for 1 hr at 100 C. The reaction mixture was concentrated under vacuum. The residue was partitioned between dichloromethane (10 ml) and water (10 ml). The organic layer was dried through a hydrophobic frit and concentrated in vacuo, then dissolved in DCM and purified by SP4 on a 25+M silica cartridge using a gradient of 0-50% EtOAc in cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the boc-protected product (250 mg). This was dissolved with 5 ml of methanol and treated with 1 ml of acetyl chloride. After 1 h the reaction mixture was loaded on a 20 g NH2 cartridge, which was previously conditioned with methanol. Column was washed with methanol (3 CV). The appropriate fractions were combined and evaporated in vacuo to give the free base product (197 mg). The product was dissolved with 3 ml of methanol and treated with 1.1 eq of 2M HCl in to give a yellow solid (181 mg)LCMS (Method B): Rt=0.63, MH+=396
  • 22
  • [ 489446-42-6 ]
  • [ 1132610-04-8 ]
  • [ 1216894-51-7 ]
YieldReaction ConditionsOperation in experiment
48% With sodium carbonate;PdCl2[dppf]; In quinoclamine; water; Tert-butyl 3-(1-(tert-butoxycarbonyl)-4-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-6-(4-((tert-butoxycarbonylamino)methyl)phenyl)-1H-indazole-1-carboxylate (6b) Tert-butyl 6-bromo-3-(1-(tert-butoxycarbonyl)-4-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-indazole-1-carboxylate (5, 800 mg, 1.308 mol) was dissolved in ACN:H2O (20 mL:2 mL), and <strong>[489446-42-6]4-((tert-butoxycarbonylamino)methyl)phenylboronic acid</strong> (985 mg, 3.92 mol), PdCl2(dppf) (0.3 eq) and Na2CO3 (415 mg, 3.924 mol) were added. The reaction mixture was stirred for 15 hours at room temperature. After evaporation, the reaction mixture was extracted with methylene chloride and water. The organic layer was washed with brine, dried with Mg2SO4, filtered, and then concentrated under reduced pressure. Purification by silica gel column chromatography (MC:MeOH=30:1) yielded a fluorescent solid substance (6b, 455 mg; yield=48%).
  • 23
  • [ 489446-42-6 ]
  • [ 1021918-69-3 ]
  • [ 1021918-70-6 ]
YieldReaction ConditionsOperation in experiment
With potassium dihydrogenphosphate; 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex; In water; N,N-dimethyl-formamide; at 85 - 95℃;Inert atmosphere; General procedure: Substrate (1 equiv) and boronic acid (1.2 equiv) were dissolved in DMF (15 mL). Nitrogen was bubbled through the solution for 2 min. An appropriate base in water (5 mL) and Pd catalyst (0.1 equiv) were added. The solution was then heated to 85-95 C under nitrogen. Upon consumption of the starting material, the solution was condensed under reduced pressure. The resulting material was diluted with ethyl acetate and filtered through celite or flushed through a Bakerbond SPE SiOH disposable extraction column. The filtrate was condensed under reduced pressure to afford the crude product.
  • 24
  • [ 489446-42-6 ]
  • [ 1355152-77-0 ]
  • C38H36N4O3 [ No CAS ]
  • 25
  • [ 489446-42-6 ]
  • [ 1374262-88-0 ]
  • [ 1374262-89-1 ]
YieldReaction ConditionsOperation in experiment
40% With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate; In ethanol; water; toluene; at 100℃;Inert atmosphere; Step 4: Preparation of tert-butyl 4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)benzylcarbamate To a suspension of 3-bromo-2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.250 g, 1 eq.) in a mixture of toluene (5 mL), ethanol (5 mL), and saturated sodium bicarbonate (1 mL) was added <strong>[489446-42-6](4-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid</strong> (0.1 g, 1.5 eq.). The reaction was degassed (nitrogen) for 5 minutes and tetrakis (triphenylphosphine) palladium (0) added (0.025 g). The reaction was again degassed for 5 minutes and stirred at 100 C. overnight. The reaction mixture was cooled to room temperature and poured onto water (50 mL). The aqueous phase was extracted with dichloromethane (2*50 mL) and the organic extracts were combined and washed with water (1*50 mL), brine (1*50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (25-75% ethyl acetate in hexanes) gave the product which was triturated with ether to give tert-butyl 4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)benzylcarbamate (0.133 g, 40%). LCMS: 516 [M+H].
  • 26
  • [ 489446-42-6 ]
  • [ 1374452-33-1 ]
  • [ 1374452-35-3 ]
YieldReaction ConditionsOperation in experiment
48% With N-ethyl-N,N-diisopropylamine;copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 144h;Molecular sieve; To a stirred mixture of 4.8 g (20 mmol) of 3-chloro-5-methoxy-lH-indole-2- carboxylic acid methyl ester, 7.53 g (30 mmol) of 4-(tert-butoxycarbonylamino- methyl)phenylboronic acid and 6.0 g (40 mmol) of copper(II) acetate in 150 mL of N f- dimethylformamide 14 mL (80 mmol) of N^V-diisopropylethylamine and 10 g of 3 A molecular sieves were added. The reaction mixture was vigorously stirred at room temperature with air bubbling for 6 days. The mixture was filtered through Celite. The filtrate was diluted with 500 mL of ethyl acetate and washed with 2 x 200 mL of 25% ammonium hydroxide solution. The organic layer was washed with 200 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with 2-propanol, the crystalline solid was filtered off and dried to yield 4.28 g (48%) of the title compound. MS (EI) 467.2 [M+Na]+.
48% With copper diacetate; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 20℃; for 144h;Molecular sieve; c) 1-[4-(tert-Butoxycarbonylamino-methyl)-phenyl]-3-chloro-5-methoxy-1H-indole-2-carboxylic acid methyl ester To a stirred mixture of 4.8 g (20 mmol) of 3-chloro-5-methoxy-1H-indole-2-carboxylic acid methyl ester, 7.53 g (30 mmol) of 4-(tert-butoxycarbonylamino-methyl)phenylboronic acid and 6.0 g (40 mmol) of copper(II) acetate in 150 mL of N,N-dimethylformamide 14 mL (80 mmol) of N,N-diisopropylethylamine and 10 g of 3 A molecular sieves were added. The reaction mixture was vigorously stirred at room temperature with air bubbling for 6 days. The mixture was filtered through Celite. The filtrate was diluted with 500 mL of ethyl acetate and washed with 2*200 mL of 25% ammonium hydroxide solution. The organic layer was washed with 200 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with 2-propanol, the crystalline solid was filtered off and dried to yield 4.28 g (48%) of the title compound. MS (EI) 467.2 [M+Na]+.
  • 27
  • [ 489446-42-6 ]
  • [ 1374452-55-7 ]
  • [ 1374452-57-9 ]
YieldReaction ConditionsOperation in experiment
57.6% With N-ethyl-N,N-diisopropylamine;copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 144h;Molecular sieve; To a solution of 1 g (3.79 mmol) of 3-chloro-5-methoxy-2-(5-methyl- [ l,2,4]oxadiazol-3-yl)-lH-indole in 50 mL of N^V-dimethylformamide 1.14 g (4.55 mmol) of 4-(tert-butoxycarbonylaminomethyl)phenylboronic acid, 1.2 g (7.58 mmol) of copper(II) acetate, 2.6 mL (15.2 mmol) of N V-diisopropylethylamine and 2 g 3 A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 6 h. The mixture was filtered through Celite. The filter cake was washed with N,N-dimethylformamide and chloroform, the combined filtrates were concentrated in vacuo. The residue was taken up in chloroform and subsequently washed with concentrated aqueous ammonium hydroxide solution, water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent (Merck) and hexane:ethyl acetate = 2: 1 as eluent to yield 0.98 g (57.6%) of the title compound. MS (EI) 491.1 (M+Na)+.
57.6% With copper diacetate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 6h;Molecular sieve; f) {4-[3-Chloro-5-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-indol-1-yl]-benzyl}-carbamic acid tert-butyl ester To a solution of 1 g (3.79 mmol) of 3-chloro-5-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-1H-indole in 50 mL of N,N-dimethylformamide 1.14 g (4.55 mmol) of 4-(tert-butoxycarbonylaminomethyl)phenylboronic acid, 1.2 g (7.58 mmol) of copper(II) acetate, 2.6 mL (15.2 mmol) of N,N-diisopropylethylamine and 2 g 3 A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 6 h. The mixture was filtered through Celite. The filter cake was washed with N,N-dimethylformamide and chloroform, the combined filtrates were concentrated in vacuo. The residue was taken up in chloroform and subsequently washed with concentrated aqueous ammonium hydroxide solution, water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent (Merck) and hexane:ethyl acetate=2:1 as eluent to yield 0.98 g (57.6%) of the title compound. MS (EI) 491.1 (M+Na)+.
  • 28
  • [ 489446-42-6 ]
  • [ 1374452-59-1 ]
  • [ 1374452-60-4 ]
YieldReaction ConditionsOperation in experiment
49% With N-ethyl-N,N-diisopropylamine;copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 36h;Molecular sieve; To a solution of 0.75 g (3.3 mmol) of 3-chloro-4-fluoro-lH-indole-2-carboxylic acid methyl ester in 30 mL of N,N-dimethylformamide 1.1 g (4.4 mmol) of 4-(tert- butoxycarbonylaminomethyl)phenylboronic acid, 1.0 g (6.4 mmol) of copper(II) acetate, 2.2 mL (12.7 mmol) of N,N-diisopropylethylamine and 1.4 g of 3A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 36 h. The mixture was filtered through Celite. The filter cake was washed with N^V-dimethylformamide and chloroform and the combined filtrates were concentarted in vacuo. The residue was taken up in chloroform and subsequently washed with concentrated aqueous ammonium hydroxide solution, water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent and hexane: ethyl acetate = 2:1 as eluent to yield 0.695 g (49%) of the title compound. MS (EI) 453.2 (M+Na)+.
49% With copper diacetate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 36h;Molecular sieve; b) 1-[4-(tert-Butoxycarbonylamino-methyl)-phenyl]-3-chloro-4-fluoro-1H-indole-2-carboxylic acid methyl ester To a solution of 0.75 g (3.3 mmol) of 3-chloro-4-fluoro-1H-indole-2-carboxylic acid methyl ester in 30 mL of N,N-dimethylformamide 1.1 g (4.4 mmol) of 4-(tert-butoxycarbonylaminomethyl)phenylboronic acid, 1.0 g (6.4 mmol) of copper(II) acetate, 2.2 mL (12.7 mmol) of N,N-diisopropylethylamine and 1.4 g of 3 A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 36 h. The mixture was filtered through Celite. The filter cake was washed with N,N-dimethylformamide and chloroform and the combined filtrates were concentrated in vacuo. The residue was taken up in chloroform and subsequently washed with concentrated aqueous ammonium hydroxide solution, water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent and hexane:ethyl acetate=2:1 as eluent to yield 0.695 g (49%) of the title compound. MS (EI) 453.2 (M+Na)+.
  • 29
  • [ 489446-42-6 ]
  • [ 1253493-31-0 ]
  • [ 1374452-62-6 ]
YieldReaction ConditionsOperation in experiment
50% With N-ethyl-N,N-diisopropylamine;copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 120h;Molecular sieve; To a solution of 1.5 g (6.9 mmol) of 5-fluoro-2-(3-methyl-[l,2,4]oxadiazol-5- yl)-lH-indole in 80 mL of N^V-dimethylformamide, 2.6 g (10 mmol) of 4-(tert- butoxycarbonylaminomethyl)phenylboronic acid, 2.1 g (13.8 mmol) of copper(II) acetate, 4.8 mL (27.6 mmol) of N^V-diisopropylethylamine and 3 g of 3 A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 120 h. The mixture was filtered through Celite. The filter cake was washed with N^V-dimethylformamide and chloroform and the combined filtrates were concentrated in vacuo. The residue taken up in ethyl acetate and subsequently washed with concentrated aqueous ammonium hydroxide solution, water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent and hexane: ethyl acetate as eluent to yield 1.456g (50%) of the title compound.
50% With copper diacetate; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 20℃; for 120h;Molecular sieve; b) {4-[5-Fluoro-2-(3-methyl-[1,2,4]oxadiazol-5-yl)-indol-1-yl]-benzyl}-carbamic acid tert-butyl ester To a solution of 1.5 g (6.9 mmol) of 5-fluoro-2-(3-methyl-[1,2,4]oxadiazol-5-yl)-1H-indole in 80 mL of N,N-dimethylformamide, 2.6 g (10 mmol) of 4-(tert-butoxycarbonylaminomethyl)phenylboronic acid, 2.1 g (13.8 mmol) of copper(II) acetate, 4.8 mL (27.6 mmol) of N,N-diisopropylethylamine and 3 g of 3 A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 120 h. The mixture was filtered through Celite. The filter cake was washed with N,N-dimethylformamide and chloroform and the combined filtrates were concentrated in vacuo. The residue taken up in ethyl acetate and subsequently washed with concentrated aqueous ammonium hydroxide solution, water, 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as absorbent and hexane:ethyl acetate as eluent to yield 1.456 g (50%) of the title compound.
  • 30
  • [ 489446-42-6 ]
  • [ 1374454-10-0 ]
  • [ 1374454-11-1 ]
YieldReaction ConditionsOperation in experiment
57% With N-ethyl-N,N-diisopropylamine;copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 96h;Molecular sieve; To a solution of 1.9 g (7.55 mmol) of 3-chloro-5-fluoro-2-(5-methyl- [l ,3,4]oxadiazol-2-yl)-lH-indole in 40 mL of N,N-dimethylformamide 2.85 g (1 1.33 mmol) of 4-(tert-butoxycarbonylamino-methyl)-boronic acid, 2.75 g (15.1 mmol) of copper(II) acetate, 5.3 mL (30.2 mmol) of N,N-diisopropylethylamine and 4 g 3A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 96 h. The mixture was filtered through Celite. The filter cake was washed with N^ V-dimethylformamide and chloroform and the combined filtrates were concentrated in vacuo. The residue was treated with 300 mL of chloroform and extracted with 2x50 mL of 25% ammonium hydroxide solution and 2x50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and hexane:ethyl acetate = 3:1 as eluent and rechromatographed in chloroform: acetone = 5:1 to yield 1.99 g (57 %) of the title compound as a yellow foam. MS (EI) 457.1 [M+Na]+.
  • 31
  • [ 489446-42-6 ]
  • [ 1374454-16-6 ]
  • [ 1374454-18-8 ]
YieldReaction ConditionsOperation in experiment
89% With N-ethyl-N,N-diisopropylamine;copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 144h;Molecular sieve; To a solution of 0.1 g (0.42 mmol) of 3-chloro-2-(5-methyl-oxazol-2-yl)-indole in 4 mL of N^V-dimethylformamide 0.16 g (0.63 mmol) of 4-(tert- butoxycarbonylamino-methyl)-boronic acid, 0.16 g (0.84 mmol) of copper(II) acetate, 0.3 mL (1.68 mmol) of N^V-diisopropylethylamine and 0.4 g of 3A molecular sieves were added. The reaction mixture was vigorously stirred and bubbled with a stream of dry air at room temperature for 6 days. The mixture was filtered through Celite, the filter cake was washed with N^V-dimethylformamide and concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.040-0.063 mm) as adsorbent (Merck) and hexane:ethyl acetate = 4: 1 as eluent to yield 0.16 g (89 %) of the title compound as a yellow foam. MS (EI) 438.2 (MH+).
  • 32
  • [ 489446-42-6 ]
  • [ 74960-46-6 ]
  • [ 1374452-11-5 ]
YieldReaction ConditionsOperation in experiment
56% With N-ethyl-N,N-diisopropylamine;copper diacetate; In dimethyl sulfoxide; at 20℃; for 144h; To a stirred mixture of 0.353 g (2.0 mmol) of 3-chloro-lH-indole-2-carbonitrile (Reference Example 4c), 0.753 g (3 mmol) of 4-(tert-butoxycarbonylamino- methyl)phenylboronic acid and 0.606 g (4 mmol) of copper(II) acetate in 24 mL of DMSO 1.4 mL (8 mmol) of N^V-diisopropylethylamine was added. The reaction mixture was vigorously stirred at room temperature with air bubbling for 6 days. The mixture was diluted with 60 mL of ethyl acetate and washed with 2 x 50 mL of 25% ammonium hydroxide solution. The organic layer was washed with 50 mL of 1M citric acid, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and hexane:ethyl acetate = 4:1 as eluent to yield 0428 g (56 %) of the title compound. MS (EI) 404.1 [M+Na]+.
56% With copper diacetate; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; for 144h; a) [4-(3-Chloro-2-cyano-indol-1-yl)-benzyl]-carbamic acid tert-butyl ester To a stirred mixture of 0.353 g (2.0 mmol) of 3-chloro-1H-indole-2-carbonitrile (Reference Example 4c), 0.753 g (3 mmol) of 4-(tert-butoxycarbonylamino-methyl)phenylboronic acid and 0.606 g (4 mmol) of copper(II) acetate in 24 mL of DMSO 1.4 mL (8 mmol) of N,N-diisopropylethylamine was added. The reaction mixture was vigorously stirred at room temperature with air bubbling for 6 days. The mixture was diluted with 60 mL of ethyl acetate and washed with 2*50 mL of 25% ammonium hydroxide solution. The organic layer was washed with 50 mL of 1M citric acid, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was submitted to column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and hexane:ethyl acetate=4:1 as eluent to yield 0428 g (56%) of the title compound. MS (EI) 404.1 [M+Na]+.
  • 33
  • [ 489446-42-6 ]
  • [ 1374451-86-1 ]
  • [ 1374451-87-2 ]
YieldReaction ConditionsOperation in experiment
With copper diacetate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 72h;Molecular sieve; A mixture of 5.85 g (25 mmol) of 3-chloro-2-(2-methyl-2H-tetrazol-5-yl)-lH- indole, 9.4 g (37.4 mmol) of 4-(tert-butoxycarbonylaminomethyl)phenylboronic acid, 7.6 g (50 mmol) of copper(II) acetate, 17.6 mL (100 mmol) of NJV- diisopropylethylamine, 12.2 g of 3 A molecular sieves in 200 mL of Nfl- dimethylformamide was vigorously stirred at room temperature with air bubbling for 24 h, and additional 2.0 g (7.9 mmol) of 4-(tert-butoxycarbonylaminomethyl)- phenylboronic acid was added. The mixture was stirred at room temperature with air bubbling for 48 h, then filtered through Celite. The filtrate was concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015- 0.040 mm) as adsorbent (Merck) and hexane:ethyl acetate = 4:1 as eluent to yield 11.8 g of the title compound as a yellow oil.
11.8 g With copper diacetate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 72h;Molecular sieve; e) {4-[3-Chloro-2-(2-methyl-2H-tetrazol-5-yl)-indol-1-yl]-benzyl}-carbamic acid tert-butyl ester A mixture of 5.85 g (25 mmol) of 3-chloro-2-(2-methyl-2H-tetrazol-5-yl)-1H-indole, 9.4 g (37.4 mmol) of 4-(tert-butoxycarbonylaminomethyl)phenylboronic acid, 7.6 g (50 mmol) of copper(II) acetate, 17.6 mL (100 mmol) of N,N-diisopropylethylamine, 12.2 g of 3 A molecular sieves in 200 mL of N,N-dimethylformamide was vigorously stirred at room temperature with air bubbling for 24 h, and additional 2.0 g (7.9 mmol) of 4-(tert-butoxycarbonylaminomethyl)-phenylboronic acid was added. The mixture was stirred at room temperature with air bubbling for 48 h, then filtered through Celite. The filtrate was concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and hexane:ethyl acetate=4:1 as eluent to yield 11.8 g of the title compound as a yellow oil.
  • 34
  • [ 489446-42-6 ]
  • [ 1374452-03-5 ]
  • [ 1374452-04-6 ]
YieldReaction ConditionsOperation in experiment
88.7% To a stirred mixture of 10.0 g (42.7 mmol) of 3-chloro-2-(5-methyl-[l,2,4]oxadiazol-3-yl)-lH-indole, 21.49 g (85.5 mmol) of 4-(tert-butoxycarbonylamino- methyl)phenylboronic acid and 12.98 g (85.5 mmol) of copper(II) acetate in 520 mL of DMSO 29.8 mL (310 mmol) of N^V-diisopropylethylamine and 20 g of 3 A molecular sieves were added. The reaction mixture was vigorously stirred at room temperature with air bubbling for 6 days. The mixture was filtered through Celite. The filtrate was diluted with 1000 mL of ethyl acetate and washed with 2 x 500 mL of 25% ammonium hydroxide solution. The organic layer was washed with 500 mL of 1M citric acid, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 350 mL of 10 % hydrogen chloride in ethyl acetate and stirred at room temperature for 2 h. The precipitated crude product was filtered off, washed with cold ethyl acetate and recrystallized from 2-propanol to yield 14.2 g (88.7%) of the title compound.
88.7% With copper diacetate; N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; ethyl acetate; at 20℃; for 144h;Molecular sieve; c) 4-[3-Chloro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-indol-1-yl]-benzylamine hydro-chloride To a stirred mixture of 10.0 g (42.7 mmol) of 3-chloro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-1H-indole, 21.49 g (85.5 mmol) of 4-(tert-butoxycarbonylamino-methyl)phenylboronic acid and 12.98 g (85.5 mmol) of copper(II) acetate in 520 mL of DMSO 29.8 mL (310 mmol) of N,N-diisopropylethylamine and 20 g of 3 A molecular sieves were added. The reaction mixture was vigorously stirred at room temperature with air bubbling for 6 days. The mixture was filtered through Celite. The filtrate was diluted with 1000 mL of ethyl acetate and washed with 2*500 mL of 25% ammonium hydroxide solution. The organic layer was washed with 500 mL of 1M citric acid, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in 350 mL of 10% hydrogen chloride in ethyl acetate and stirred at room temperature for 2 h. The precipitated crude product was filtered off, washed with cold ethyl acetate and recrystallized from 2-propanol to yield 14.2 g (88.7%) of the title compound.
  • 35
  • [ 489446-42-6 ]
  • [ 169749-89-7 ]
  • [ 508224-95-1 ]
 

Historical Records

Technical Information

• Acyl Group Substitution • Baeyer-Villiger Oxidation • Barbier Coupling Reaction • Baylis-Hillman Reaction • Bouveault-Blanc Reduction • Bucherer-Bergs Reaction • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Catalytic Hydrogenation • Chan-Lam Coupling Reaction • Clemmensen Reduction • Complex Metal Hydride Reductions • Corey-Bakshi-Shibata (CBS) Reduction • Corey-Chaykovsky Reaction • Ester Cleavage • Fischer Indole Synthesis • Grignard Reaction • Henry Nitroaldol Reaction • Horner-Wadsworth-Emmons Reaction • Hydride Reductions • Lawesson's Reagent • Leuckart-Wallach Reaction • Mannich Reaction • McMurry Coupling • Meerwein-Ponndorf-Verley Reduction • Nomenclature of Ethers • Passerini Reaction • Paternò-Büchi Reaction • Petasis Reaction • Peterson Olefination • Pictet-Spengler Tetrahydroisoquinoline Synthesis • Preparation of Aldehydes and Ketones • Preparation of Amines • Preparation of Ethers • Prins Reaction • Reactions of Aldehydes and Ketones • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reactions of Ethers • Reactions with Organometallic Reagents • Reformatsky Reaction • Robinson Annulation • Schlosser Modification of the Wittig Reaction • Schmidt Reaction • Specialized Acylation Reagents-Carbodiimides and Related Reagents • Specialized Acylation Reagents-Ketenes • Specialized Acylation Reagents-Vilsmeier Reagent • Stobbe Condensation • Tebbe Olefination • Ugi Reaction • Wittig Reaction • Wolff-Kishner Reduction

Categories

Related Functional Groups of
[ 489446-42-6 ]

Organoborons

Chemical Structure| 1150114-76-3

A614036 [1150114-76-3]

(4-(4-(tert-Butoxycarbonyl)piperazine-1-carbonyl)phenyl)boronic acid

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tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate

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(4-Boc-Aminophenyl)boronic acid

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Chemical Structure| 380430-68-2

A118028 [380430-68-2]

(3-((tert-Butoxycarbonyl)amino)phenyl)boronic acid

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Aryls

Chemical Structure| 1150114-76-3

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(4-(4-(tert-Butoxycarbonyl)piperazine-1-carbonyl)phenyl)boronic acid

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tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate

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Amides

Chemical Structure| 1150114-76-3

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(4-(4-(tert-Butoxycarbonyl)piperazine-1-carbonyl)phenyl)boronic acid

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(4-Boc-Aminophenyl)boronic acid

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Chemical Structure| 380430-68-2

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Amines

Chemical Structure| 330794-35-9

A114471 [330794-35-9]

tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate

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(3-((tert-Butoxycarbonyl)amino)phenyl)boronic acid

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tert-Butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate

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Chemical Structure| 108468-00-4

A215531 [108468-00-4]

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