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Chemical Structure| 655225-01-7 Chemical Structure| 655225-01-7

Structure of 655225-01-7

Chemical Structure| 655225-01-7

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Product Details of [ 655225-01-7 ]

CAS No. :655225-01-7
Formula : C11H21BrN2O2
M.W : 293.20
SMILES Code : BrCCN1CCN(C(OC(C)(C)C)=O)CC1
MDL No. :MFCD07367890
InChI Key :IWSFZKCIZFXAFT-UHFFFAOYSA-N
Pubchem ID :15946441

Safety of [ 655225-01-7 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302+H312+H332-H315-H319-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 655225-01-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 0
Fraction Csp3 0.91
Num. rotatable bonds 5
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 76.08
TPSA ?

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

32.78 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

3.38
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

1.68
Log Po/w (WLOGP)?

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

1.17
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.

1.57
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

1.39
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.84

Water Solubility

Log S (ESOL):?

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

-2.39
Solubility 1.2 mg/ml ; 0.00411 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.

-1.98
Solubility 3.05 mg/ml ; 0.0104 mol/l
Class?

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

Very 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

-2.21
Solubility 1.79 mg/ml ; 0.0061 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

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.

-6.9 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)

2.73

Application In Synthesis of [ 655225-01-7 ]

* 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 [ 655225-01-7 ]

[ 655225-01-7 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 77279-24-4 ]
  • [ 655225-01-7 ]
YieldReaction ConditionsOperation in experiment
83.7% With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃;Cooling with ice; Carbon tetrabromide (1.681 g, 5.07 mmol) was dissolved in dichloromethane (17 ml), cooled with ice.thereTertiary butyl 4- (2-hydroxyMethyl) piperazine-1-carboxylate (1.062 g, 4.61 mmol), triphenylphosphine (1.329 g, 5.07 mmol), and stirred overnight at room temperature was added dichloromethane (11 ml). After the reaction, the solvent was evaporated. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, hexane / ethyl acetate) to give the title compound (1.131 g, 83.7percent) as a yellow solid.
78% With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 20h; STEP A: A solution of tetrabromomethane (1.58 g, 4.7 mmol) in DCM (10 mL) is added dropwise (30 min) to the solution of N-Boc-piperazin-4-ethanol (1 g, 4.34 mmol) and triphenylphosphine (1.23 g, 4.7 mmol) in DCM (10 mL) at 0°C. The reaction is left at RT for 20 h. The organic solvent is removed under reduced pressure and the crude is purified by flash column chromatography (eluent petroleum ether/EtOAc) to give the expected compound (1 g, 3.38 mmol, Yield 78percent) as colourless oil. H1-NMR (CDCI3) delta (ppm): 3.41-3.47 (m, 6H); 2.81 (t, J=6.00 Hz, 2H); 2.48 (t, J=6.00 Hz, 4H); 1.46 (s, 9H)
With carbon tetrabromide; triphenylphosphine; In tetrahydrofuran; Example 63; l-{2-[4-(3,5-dimethoxybenzyl)piperazin-l-yl]ethyl}-3,3-bis(4-fluorophenyl)pyrrolidin-2- one; Example 63A; tert-butyl 4-(2-bromoethyl)piperazine-l-carboxylate; tert-Butyl 4-(2-hydroxyethyl)piperazine-l-carboxylate (5.76 g, 25.0 mmol) was dissolved in dry tetrahydrofuran (100 mL) and carbon tetrabromide (9.12 g, 27.5 mmol). A solution of triphenyl phosphine (6.62 g, 25.3 mmol) in dry tetrahydrofuran (25 mL) was added dropwise, and the mixture was stirred for 20 hours. The reaction was diluted with n- hexane (100 mL) and washed with a saturated NaHCO3 solution, water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexanes 1 :4 gave the title compound. MS (DCI) m/z 295(M+H)+.
  • 2
  • [ 655225-01-7 ]
  • [ 655225-03-9 ]
  • 3
  • [ 106-93-4 ]
  • [ 57260-71-6 ]
  • [ 655225-01-7 ]
YieldReaction ConditionsOperation in experiment
36% With N-ethyl-N,N-diisopropylamine; at 30℃; for 72h;Inert atmosphere; Example 24 tert-Butyl 4-(2-bromoethyl)piperazine-1-carboxylate A mixture of tert-butyl piperazine-1-carboxylate (5.0 g, 26.9 mmol), 1,2-dibromoethane (25 mL), DIPEA (3.5 g, 26.9 mmol) was stirred at 30° C. under argon for 72 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (1-2percent methanol/dichloroethane) to afford the desired product (2.8 g, 36percent yield) as a solid. ESI-MS m/z: 293.1[M+1]+.
  • 4
  • [ 655225-01-7 ]
  • 1-(2-nitrooxyethyl)piperazine hydrochloride [ No CAS ]
  • 5
  • [ 655225-01-7 ]
  • prednisolone 21-[4-(2-nitrooxyethyl)piperazin-1-yl]acetate [ No CAS ]
  • 6
  • 4-[4-(2-methoxy-2-oxoethyl)phenyl]piperazin-1-ium chloride [ No CAS ]
  • [ 655225-01-7 ]
  • [ 198627-14-4 ]
YieldReaction ConditionsOperation in experiment
45% (1) 4-[2-(1-tert-Butyloxycarbonylpiperazin-4-yl)ethyl]-1-(4-methoxycarbonylmethylphenyl)piperazine Prepared from 1-(4-methoxycarbonylmethylphenyl)piperazine hydrochloride and <strong>[655225-01-7]2-(1-tert-butyloxycarbonylpiperazin-4-yl)ethyl bromide</strong>. Yield: 45percent of theory, Melting point: 161-180° C. (dec.) Mass spectrum: M+ =446
  • 7
  • [ 57260-71-6 ]
  • [ 655225-01-7 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In methanol; 1,2-dibromomethane; EXAMPLE X 2-(1-tert-Butyloxycarbonylpiperazin-4-yl)ethyl bromide A solution of 1.0 g of 1-tert-butyloxycarbonylpiperazine and 0.7 g (0.005 mol) of N-ethyldiisopropylamine in 5 ml of 1,2-dibromomethane is allowed to stand at room temperature for 3 days and then concentrated to dryness in vacuo. The residue is purified by means of chromatography on a silica gel column, methylene chloride which initially contains 1percent and then 2percent of methanol being used as eluent. Yield: 0.6 g (38percent of theory), Mass spectrum: (M+H)+ =293/295
  • 8
  • [ 866268-32-8 ]
  • [ 655225-01-7 ]
  • [ 1207679-26-2 ]
YieldReaction ConditionsOperation in experiment
Intermediate 22: 1 ,1-Dimethylethyl 4-{2-r6-amino-2-(butyloxy)-8-(methyloxy)-9H- purin-9-yl1ethyl)-1-piperazinecarboxylate; 2-(Butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate (131 mg, 0.373mmole) and potassium carbonate (185mg, 0.41 mmole) in DMF (1 ml) was stirred and heated at 60°C for 1 hour. A solution of 1 ,1-dimethylethyl 4-(2-bromoethyl)-1- piperazinecarboxylate (120mg, 0.41 mmole) in DMF (0.6ml) was added and the mixture stirred at 500C for 2.5 hours and then left at room temperature overnight. The mixture was heated at 500C for a further 4 hours and then quenched with water (10ml) and extracted with ethyl acetate (3x1 OmI). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting initially with chloroform:methanol 90:1 then 80:1 then 75:1 and finaly 60:1. Product-containing fractions were combined and evaporated to give the title compound as a yellow oily solid (168mg). 1H NMR (CDCI3): delta 5.66 (2H, d), 4.25 (2H, t), 4.05 (2H, t), 4.10 (3H, s), 3.35 (4H, broad s), 2.71 (2H, t), 2.46 (4H, broad s) 1.76 (2H, q) 1.48 (2H, q), 1.45 (9H, s) and 0.96 (3H, t).
  • 9
  • [ 1219624-43-7 ]
  • [ 655225-01-7 ]
  • [ 1219624-52-8 ]
YieldReaction ConditionsOperation in experiment
With potassium tert-butylate; In tetrahydrofuran; at 75℃; for 18h; Example 63B; tert-butyl 4-(2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-l-yl)ethyl)piperazine-l- carboxylate; To a solution of 3,3-bis(4-fluorophenyl)pyrrolidin-2-one (Example 58B, 1.37 g, 5.00 mmol) in tetrahydrofuran (30 mL) was added potassium t-butoxide (1.0 M in tetrahydrofuran) (7.5 mL, 7.5 mmol) followed by the product from Example 63A (1.47 g, 5.00 mmol). The reaction mixture was heated at 75 0C for 18 hours. The reaction was concentrated, diluted with ethyl acetate, washed with water and brine, dried with MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography eluting with 3percent methanol/dichloromethane to give the title compound. MS (DCI) m/z 486.3(M+H)+.
  • 10
  • [ 302-01-2 ]
  • [ 655225-01-7 ]
  • [ 1280725-93-0 ]
YieldReaction ConditionsOperation in experiment
In ethanol;Reflux; Step 1 : A mixture of lb (4.85g, 16.5mmol) and 9a (16.5g, 0.33mol) in ethanol (50mL) was heated under reflux overnight, then evaporated under high vacuum. The residue was re-dissolved in ethanol and the resulting precipitate was filtered off. The filtrate was concentrated and dried to give crude 9b (4.02g, ca. 100percent).
  • 11
  • [ 655225-01-7 ]
  • [ 1204412-31-6 ]
  • 12
  • [ 655225-01-7 ]
  • [ 1204411-44-8 ]
  • 13
  • [ 655225-01-7 ]
  • [ 1204475-20-6 ]
  • 14
  • [ 655225-01-7 ]
  • [ 1204412-32-7 ]
  • 15
  • [ 5451-40-1 ]
  • [ 655225-01-7 ]
  • [ 1204412-23-6 ]
YieldReaction ConditionsOperation in experiment
67.4% Step 1: To a solution of la in DMF was added NaH with ice-bath. The resulting mixture was stirred for 15min. at 0-5 °C and was added lb. The reaction mixture was stirred at r.t. for 2h and evaporated to remove DMF. The residue was purified by column chromatography (PE:EA=8:1) to give lc (1.74g, 67.4percent).
  • 16
  • [ 1313409-30-1 ]
  • [ 655225-01-7 ]
  • C32H39N9O3 [ No CAS ]
  • [ 1313409-32-3 ]
YieldReaction ConditionsOperation in experiment
With caesium hydroxide hydrate; In N,N-dimethyl-formamide; for 0.5h;Inert atmosphere; To a solution of N-(l-((lH-pyrazol-3-yl)methyl)-3-ethyl-lH-indazol-4-yl)imidazo[l,2- a]pyridine-3-carboxamide (40.0 mg; 0.104 mmol) in dry DMF (0.5 mL) was added tert-butyl4- (2-bromoethyl)piperazine-l -carboxylate (30.4 mg; 0.104 mmol) and cesium hydroxide hydrate (17.4 mg; 0.104 mmol). The mixture was stirred under a nitrogen atmosphere for 30 minutes. The mixture was filtered, washing with methanol and ethyl acetate, and the solvent was removed under reduced pressure. The residue (a mixture of two regioisomers) was purified by preparative thin layer chromatography on silica, eluting with 10percent methanol in dichloromethane. The desired isomer tert-butyl 4-(2-(3-((3-ethyl-4-(imidazo[l,2-a]pyridine- 3-carboxamido)- lH-indazol- 1 -yl)methyl)- lH-pyrazol- 1 -yl)ethyl)piperazine- 1 -carboxylate was isolated (21.5 mg) along with some of the alternate isomer.
  • 17
  • [ 1313409-30-1 ]
  • [ 655225-01-7 ]
  • N-(3-ethyl-1-((1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-3-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide trihydrochloride [ No CAS ]
  • 18
  • [ 79-16-3 ]
  • [ 655225-01-7 ]
  • C14H27N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.341 g of 60percent NaH in oil is added to a solution of 0.748 g of N-methylacetamide in 80 ml of THF and stirred for 10 minutes at RT. Then 2 g of <strong>[655225-01-7]tert-butyl 4-(2-bromoethyl)piperazinecarboxylate</strong> is added and stirred for 16 hours at RT. Water is added to the reaction mixture, it is decanted and the organic solvent is evaporated under vacuum. The residue is dissolved in DCM, filtered through a Chem Elut.(R). cartridge, eluting with DCM and the solvents are evaporated under vacuum. The residue is purified by preparative HPLC and a white solid is obtained.
Preparation 7.3N-Methyl-N-[2-(piperazin-1 -yl)ethyl]acetamide ditrifluoroacetate. 0.341 g of 60percent NaH in oil is added to a solution of 0.748 g of N- methylacetamide in 80 ml of THF and stirred for 10 minutes at RT. Then 2 g of fe/f-butyl 4-(2-bromoethyl)piperazinecarboxylate is added and stirred for 16 hours at RT. Water is added to the reaction mixture, it is decanted and the organic solvent is evaporated under vacuum. The residue is dissolved in DCM, filtered through a Chem Elut.(R). cartridge, eluting with DCM and the solvents are evaporated under vacuum. The residue is purified by preparative HPLC and a white solid is obtained. The solid is dissolved in 5 ml of DCM, 1 .2 ml of TFA is added and it is stirred for 16 hours at RT. The reaction mixture is diluted by adding 100 ml of toluene and the solvents are concentrated under vacuum.1 .5 g of the expected compound is obtained.
  • 19
  • [ 655225-01-7 ]
  • N-methyl-N-[2-(piperazin-1-yl)ethyl]acetamide ditrifluoroacetate [ No CAS ]
  • 20
  • [ 1433605-21-0 ]
  • [ 655225-01-7 ]
  • [ 1433605-57-2 ]
YieldReaction ConditionsOperation in experiment
99% Sodium hydride (60percent mineral oil dispersion) (19.16 mg, 0.82 mmol) in anhydrous DMF (5 mL) is added at 0°C under nitrogen to the solution of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4- methyl-7,8-dihydro-6H-quinazolin-5-one oxime (Intermediate 1) (0.25 g, 0.684 mmol) in anhydrous DMF (5 mL). After 5 min, <strong>[655225-01-7]N-Boc-4-(2-bromoethyl)piperazine</strong> (0.24 g, 0.82 mmol) dissolved in anhydrous DMF (5 mL) is added and the mixture is stirred at RT for 3 h. Ice is added to the suspension and the mixture is extracted with DCM (3 x 10 mL). The organic phase is dried over Na2S04, filtered and concentrated under reduced pressure to give the expected compound (0.395 g, 0.677 mmol, Yield: 99percent) as light brown solid. 1H-NMR (CDCl3) delta (ppm): 8.60-8.61 (m, 1H); 8.55 (m, 1H); 7.58-7.61 (m, 1H); 7.33-7.42 (m, 1H); 7.13-7.19 (m, 1H); 6.95 (dd, J=2.70, 9.00 Hz, 1H); 5.02 (s, 2H); 4.25 (t, J=6.00 Hz, 2H); 3.43 (t, J=6.00 Hz, 4H); 2.83-3.22 (m, 6H); 2.58 (s, 3H); 2.50-2.54 (m, 1H); 2.45 (t, J=3.00 Hz, 4H); 1.46 (s, 9H)
70% STEP A: Sodium hydride (60percent mineral oil dispersion) (13.21 mg, 0.330 mmol) is added under nitrogen to the solution of (E)-2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H- quinazolin-5-one oxime (Intermediate 1) (0.1 g, 0.275 mmol) in anhydrous DMF (4 mL). After 5 min, <strong>[655225-01-7]N-Boc-4-(2-bromoethyl)piperazine</strong> (161 mg, 0.550 mmol) is added and the mixture is heated at 50°C for 1.5 h. The suspension is diluted with H20 and extracted with EtOAc. The organic phase is dried over Na2S04, filtered and concentrated under reduced pressure. The beige-orange residue is purified by flash column chromatography (eluent DCM/MeOH from 99/1 to 95/5) to give the expected compound (0.111 g, 0.193 mmol, Yield: 70percent). LC-MS: method A, rt=1.60 min; (ES+), M+H+= 576.5 1H-NMR (DMSO-d6) delta (ppm): 8.57 (dd, J=4.84, 1.61 Hz, 1 H); 8.53 (dd, J=2.2Q, 0.73 Hz, 1 H): 7.76 (ddd, J=7.92, 2.35, 1.76 Hz, 1 H); 7.66 (dd, J=8.80, 5.87 Hz, 1 H); 7.45 (ddd, J=7.78, 4.84, 0.88 Hz, 1 H); 7.31 (td, J=8.73, 2.79 Hz, 1 H); 7.1 1 (dd, J=9.68, 2.93 Hz, 1 H); 6.76 (s, 2 H); 4.15 (t, J=5.87 Hz, 2 H); 3.24-3.28 (m, 4 H); 2.94-3.08 (m, 2 H); 2.82-2.94 (m, 1 H); 2.54-2.66 (m, 4 H); 2.45 (s, 3 H); 2.32-2.39 (m, 4 H); 1.39 (s, 9 H)
  • 21
  • [ 1609390-23-9 ]
  • [ 655225-01-7 ]
  • [ 1609390-44-4 ]
YieldReaction ConditionsOperation in experiment
62% With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; To a solution of compound 3 (240 mg, 0.55 mmol) in DMF was added compound 4 (300 mg, 0.82 mmol). NaH (133 mg, 5.5 mmol) was added at 0° C. at which point the reaction mixture was warmed to r.t. and stirred overnight. The reaction was quenched with H2O, extracted with EA (2×20 ml) and the combined organic layers were purified by gel chromatography (DCM:MeOH=20:1) to afford the desired product, compound 5 (190 mg, 62percent)
  • 22
  • 4-chloro-5-iodo-2-methoxybenzenamine [ No CAS ]
  • [ 655225-01-7 ]
  • tert-butyl 4-(2-((4-chloro-5-iodo-2-methoxyphenyl)amino)ethyl)piperazine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
21% tert-Butyl 4-(2-((4-chloro-5-iodo-2-methoxyphenyl)amino)ethyl)piperazine-1-carboxylate To a stirred solution of 4-chloro-5-iodo-2-methoxyaniline (968 mg, 3.42 mmol) in anhydrous THF (20 mL) at 0° C., NaH (60percent in mineral oil, 205.2 mg, 5.13 mmol) was added and the resulting mixture was stirred at reflux under nitrogen for 1 h. To this mixture, tert-butyl-4-(2-bromoethyl)piperazine-1-carboxylate (500 mg, 1.71 mmol) was added and the resulting mixture was stirred at room temperature for 15 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-30percent ethyl acetate/petroleum ether) to afford the desired product (180 mg, 21percent yield) as a solid.
  • 23
  • 4-chloro-5-iodo-2-methoxybenzenamine [ No CAS ]
  • [ 655225-01-7 ]
  • tert-butyl-4-(2-((2',5',6-trichloro-4-methoxy-[1,1'-biphenyl]-3-yl)amino)ethyl)piperazine-1-carboxylate [ No CAS ]
  • 24
  • 1’-[(5-chloro-1H-indol-2-yl)methyl]spiro[cyclopropane-1,3’-pyrrolo[2,3-c]pyridin]-2’(1‘H)-one [ No CAS ]
  • [ 655225-01-7 ]
  • tert-butyl 4-(2-{5-chloro-2-[(2'-oxospiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-1'(2'H)-yl)methyl]-1H-indol-1-yl}ethyl)piperazine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
130 mg With potassium carbonate; for 48h;Reflux; To a solution of tert-butyl 4-(2-bromoethyl)piperazine-l-carboxylate (130 mg, 0.44 mmol) in acetone (20 mL) was added l'-[(5-chloro-lH-indol-2-yl)methyl]spiro[cyclopropane-l,3'- pyrrolo[2,3-c]pyridin]-2'(l 'H)-one (142 mg, 0.44 mmol) and potassium carbonate (182 mg, 1.32 mmol). The reaction was heated under reflux for 48 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (10percent methanol in dichloromethane) to afford 130 mg of fert-butyl 4-(2-{5-chloro-2-[(2'- oxospiro [cyclopropane- 1 ,3 '-pyrrolo [2, 3 -c]pyridin] - 1 '(2'H)-yl)methyl] - 1 H-indol- 1 - yl} ethyl )piperazine-l -carboxylate.
  • 25
  • [ 655225-01-7 ]
  • 1'-({5-chloro-1-[2-(piperazin-1-yl)ethyl]-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one [ No CAS ]
  • 26
  • [ 655225-01-7 ]
  • 1'-({1-[2-(4-acetylpiperazin-1-yl)ethyl]-5-chloro-1H-indol-2-yl}methyl)spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one [ No CAS ]
  • 27
  • [ 655225-01-7 ]
  • 1'-[(5-chloro-1-{2-[4-(methylsulfonyl)piperazin-1-yl]ethyl}-1H-indol-2-yl)methyl]spiro[cyclopropane-1,3'-pyrrolo[2,3-c]pyridin]-2'(1'H)-one [ No CAS ]
  • 28
  • 5-bromo-1-(4-methoxybenzyl)-1H-imidazo[4,5-h][1,6]naphthyridin-(3H)-one [ No CAS ]
  • [ 655225-01-7 ]
  • C28H33BrN6O4 [ No CAS ]
  • 29
  • 5-bromo-4-(cyclobutylmethoxy)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one [ No CAS ]
  • [ 655225-01-7 ]
  • C24H35BrN4O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; Step 1. 5-Bromo-4-(cyclobutylmethoxy)-1-methyl-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one A solution of 5-bromo-4-(cyclobutylmethoxy)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (250 mg, 0.803 mmol) in N,N-dimethylformamide (7.96 mL) was treated with cesium carbonate (1.31 g, 4.02 mmol) followed by the addition of <strong>[655225-01-7]tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate</strong> (471 mg, 1.61 mmol), and the resultant reaction mixture was stirred at 60° C. overnight, after which time the LCMS analysis of the reaction mixture indicated complete conversion of the starting materials. The reaction mixture was diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give the crude intermediate tert-butyl carboxylate, which was used in further step without purification.
  • 30
  • [ 655225-01-7 ]
  • 5-bromo-4-(cyclobutylmethoxy)-1-methyl-3-(2-piperazin-1-ylethyl)-1,3-dihydro-2H-benzimidazol-2-one [ No CAS ]
  • 31
  • [ 655225-01-7 ]
  • 3-[2-(4-acetylpiperazin-1-yl)ethyl]-5-bromo-4-(cyclobutylmethoxy)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one [ No CAS ]
  • 32
  • [ 655225-01-7 ]
  • 5-bromo-4-(cyclobutylmethoxy)-1-methyl-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-dihydro-2H-benzimidazol-2-one [ No CAS ]
  • 33
  • N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-{1-[(4-methylpiperidin-4-yl)methyl]-1H-pyrazol-4-yl}thiophene-2-carboxamide [ No CAS ]
  • [ 655225-01-7 ]
  • N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-[1-({4-methyl-1-[2-(piperazin-1-yl)ethyl]piperidin-4-yl}methyl)-1H-pyrazol-4-yl]thiophene-2-carboxamide hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 1163 N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-[1-({4-methyl-1-[2-(piperazin-1-yl)ethyl]piperidin-4-yl}methyl)-1H-pyrazol-4-yl]thiophene-2-carboxamide (5912) A solution of N-(imidazo[1,2-a]pyridin-7-ylmethyl)-5-{1-[(4-methylpiperidin-4-yl)methyl]-1H-pyrazol-4-yl}thiophene-2-carboxamide (0.100 g, 0.197 mmol) in N,N-dimethylformamide (2 ml) was added <strong>[655225-01-7]tert-butyl 4-(2-bromoethyl)piperazine-1-carboxylate</strong> (0.058 g, 0.197 mmol) followed by N,N-diisopropylethylamine (0.138 ml, 0.788 mmol) and the reaction was stirred overnight. The reaction mixture was purified directly using normal phase chromatography and the resulting material was treated with HCl in dioxane (4M) for 2 hours then concentrated to give the title compound as a hydrochloride salt. 1H NMR (500 MHz, DMSO-d6) delta 14.64 (s, 1H), 10.40 (s, 1H), 9.72 (s, 1H), 9.54 (t, J=6.0 Hz, 1H), 8.89 (d, J=6.9 Hz, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.22 (s, 1H), 8.16 (d, J=2.1 Hz, 1H), 7.91 (d, J=3.9 Hz, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.50 (dd, J=7.0, 1.4 Hz, 1H), 7.28 (d, J=3.8 Hz, 1H), 4.64 (d, J=5.8 Hz, 2H), 4.23-3.54 (m, 10H), 3.35 (d, J=38.3 Hz, 8H), 1.72 (d, J=77.7 Hz, 4H), 0.98 (s, 3H); MS (ESI(+)) m/e 547 (M+H)+.
  • 34
  • 4-methoxybenzo[d]oxazole-7-ol [ No CAS ]
  • [ 655225-01-7 ]
  • tert-butyl 4-(2-((4-methoxybenzo[d]oxazol-7-yl)oxy)ethyl)piperazine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; The compound obtained in Example 102-1 (45 mg, 0.27 mmol) in DMF (1 ml) solution of, tertiary butyl 4- (2-bromoethyl) piperazine-1-carboxylate (88 mg, 0.30 mmol) , it was added cesium carbonate (107 mg, 0.33 mmol). And stirred overnight at 70 , was solidified after the completion of the reaction was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (95 mg, 92percent).
  • 35
  • 2-(5-(pyridin-3-ylethynyl)-1,3,4-oxadiazol-2-yl)phenol [ No CAS ]
  • [ 655225-01-7 ]
  • tert-butyl 4-(2-(2-(5-(pyridin-3-ylethynyl)-1,3,4-oxadiazol-2-yl)phenoxy)ethyl)piperazine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
95.8% With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; The compound obtained in Example 138-5 (141 mg, 0.54 mmol) was dissolved in DMF (2.8 ml). Thereto cesium carbonate (209 mg, 0.64 mmol), tert-butyl 4- (2-bromomethyl) piperazine-1-carboxylate (317 mg, 1.08 mmol), potassium iodide (179 mg, 1.08 mmol) was added to 70 and the mixture was stirred overnight at . After the reaction, the solvent was evaporated. The residue was purified by silica gel column chromatography (Chromatorex NH 10 g, hexane / ethyl acetate) to give the title compound (246 mg, 95.8percent) as a yellow oil.
 

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Technical Information

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