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Chemical Structure| 54540-58-8 Chemical Structure| 54540-58-8

Structure of 54540-58-8

Chemical Structure| 54540-58-8

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Product Details of [ 54540-58-8 ]

CAS No. :54540-58-8
Formula : C10H12ClF
M.W : 186.65
SMILES Code : FC1=CC=C(CCCCCl)C=C1
English Name :1-(4-Chlorobutyl)-4-fluorobenzene
MDL No. :MFCD11935101
InChI Key :QMDPGDCZIVOKNA-UHFFFAOYSA-N
Pubchem ID :3016889

Safety of [ 54540-58-8 ]

Computational Chemistry of [ 54540-58-8 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.4
Num. rotatable bonds 4
Num. H-bond acceptors 1.0
Num. H-bond donors 0.0
Molar Refractivity 50.58
TPSA ?

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

0.0 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.62
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

3.59
Log Po/w (WLOGP)?

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

3.81
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.

4.26
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

4.23
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.7

Water Solubility

Log S (ESOL):?

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

-3.36
Solubility 0.0806 mg/ml ; 0.000432 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.

-3.28
Solubility 0.0987 mg/ml ; 0.000529 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

-4.91
Solubility 0.00229 mg/ml ; 0.0000122 mol/l
Class?

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

Moderately soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

Low
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

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

Yes
CYP2C19 inhibitor?

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

No
CYP2C9 inhibitor?

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

No
CYP2D6 inhibitor?

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

Yes
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.

-4.89 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

1.0
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

2.0
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<2.0
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)

1.45

Application In Synthesis of [ 54540-58-8 ]

* 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 [ 54540-58-8 ]

[ 54540-58-8 ] Synthesis Path-Downstream   1~14

  • 1
  • [ 3874-54-2 ]
  • [ 54540-58-8 ]
YieldReaction ConditionsOperation in experiment
89% With triethylsilane; trifluoroacetic acid at 0℃; for 2h;
With hydrogen In ethanol
With hydrogenchloride; mercury dichloride; zinc In toluene for 5h; Reflux;
With triethylsilane In trifluoroacetic acid 1-(4-chloro-butyl)-4-fluoro-benzene 1-(4-chloro-butyl)-4-fluoro-benzene Triethylsilane (22.5 ml; 0.141 mol) was added dropwise to a cold (~0° C.) stirring mixture of 4-chloro-4'-fluoro-butyrophenone (10 ml; 0.0613 mol) in trifluoroacetic acid (47 ml). The reaction mixture was stirred at room temperature under nitrogen for 6 hours. The reaction was quenched with brine and extracted with diethyl ether. The organic extract was dried (MgSO4) and evaporated under vacuum giving the desired compound as an oil. Following the above described process and using the appropriate acyl halide the following compound can be prepared:

  • 2
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
  • [ 28593-14-8 ]
  • [ 54540-58-8 ]
YieldReaction ConditionsOperation in experiment
In various solvent(s) at 100℃; CIDNP, thermolyse;
  • 3
  • [ 54540-58-8 ]
  • [ 138625-87-3 ]
  • [ 569350-89-6 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; sodium iodide In acetonitrile for 18h; Heating;
  • 4
  • [ 160419-40-9 ]
  • [ 54540-58-8 ]
  • [ 160418-83-7 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate In <i>N</i>-methyl-acetamide; methanol 5 (Compound 14) EXAMPLE 5 5-methoxy-3-[N-(4-(4-fluoro-phenyl)-butyl)-1,2,5,6-tetrahydro-pyridin-3-ylmethyl]-1H-indole (Compound 14) A mixture of compound of Description 5 [5-methoxy-3-(1,2,5,6-tetrahydro-pyridin-3-ylmethyl)-1H-indole] (1.4 g; 0.0058 mol), potassium carbonate (4 g; 0.0029 mol), a catalytic amount of potassium iodide (0.030 g) and compound of Description 9 [1-(4-chloro-butyl)-4-fluoro-benzene] (5.4 g; 0.029 mol) in dimethylformamide (40 ml) was heated at 80° C. for 6 hours. The reaction mixture was cool down to room temperature. quenched with water and then extracted with ethyl acetate. The organic extract was dried (MgSO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent methylene chloride/methanol/ammonia (95/5/0,5), the desired compound was obtained as an oil. A solution of this oil in methanol was saturated with gaseous hydrogen chloride. A solid was precipitated. The title compound hydrochloride was collected by filtration, washed with hexane and dried under vacuum (0.66 g). Mp 65°-70° C. 1 H NMR (DMSO+CDCl3) δ=12.42 (b, 1H), 8.28 (b, 1H), 7.3-6.8 (8H), 5.87 (b, 1H), 3.82 (s, 3H), 3.7-2.3 (12H), 1.8-1.2 (4H); MS (C.I.): [M+H]+ 393 m/z Following the above described process and using the appropriate halide synthesised according to Description 5, the following compound was prepared
  • 5
  • [ CAS Unavailable ]
  • [ 54540-58-8 ]
  • [ CAS Unavailable ]
  • [ 87789-49-9 ]
  • [ 133982-12-4 ]
YieldReaction ConditionsOperation in experiment
With Ki In ethyl acetate; acetonitrile 9 1-(4-(4-Fluorophenyl)butyl)-4-(5-fluoro-2-pyrimidinyl) piperazine Example 9 1-(4-(4-Fluorophenyl)butyl)-4-(5-fluoro-2-pyrimidinyl) piperazine A mixture of 4-(5-fluoro-2-pyrimidinyl)piperazine (1.66 g, 9.1 mmol), 1-chloro-4-(4-fluorophenyl)butane1 (1.68 g, 9.0 mmol), K2 CO3 (2.48 g, 17.9 mmol), KI (0.15 g, 0.9 mmol) and MeCN (90 mL) was refluxed under N2 atm. for 40 h and then allowed to cool at 23° C. and filtered; the solids were washed with MeCN (2*20 mL). The filtrates were combined and concentrated under reduced pressure to a gum which was dissolved in EtOAc (200 mL). The organic solution was washed with water (20 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was passed through a silica gel pad using EtOAc acetate as eluding solvent. The appropriate fractions were combined and concentrated; the resulting solid was recrystallized from ethanol to afford analytical sample; mp 59°-61° C.; 1 H NMR (CDCl3, 200 MHz) δ: 1.4-1.8 (m, 4H), 2.2-2.5 (m, 6H), 2.45 (t, J=5.1 Hz), 2.5-2.7 (m, 2H), 3.74 (t, J=5.1 Hz, 4H), 6.9-7.0 (m, 2H), 7.0-7.2 (m, 2H), 8.17 (s, 2H); IR (KBr) ν: 610, 1555, 1511, 1485, 1455, 1445, 1360 cm-1;
  • 6
  • [ 98460-38-9 ]
  • [ 54540-58-8 ]
  • [ CAS Unavailable ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
5.1 g (77%) With Ki; oxalic acid In water; N,N-dimethyl-formamide 7 11-[1-(4-bis-4-Fluorophenyl)butyl]piperidin-4-yl}-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine EXAMPLE 7 11-[1-(4-bis-4-Fluorophenyl)butyl]piperidin-4-yl}-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine To 40 ml DMF were added 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (3.0 g, 0.011 mole), 4-chloro-1-bis-(p-fluorophenyl)butane (3.0 g, 0.0106 mole), milled K2 CO3 (10 g) and 0.01 g KI. After stirring at 90° C. for two hours, the mixture was filtered, and the filtrate evaporated to an oil. This oil was stirred with 100 ml water for five minutes and then extracted with ether. The ether solution was washed twice with water and dried (saturated NaCl, anhydrous MgSO4). After filtering, the filtrate was acidified to pH 1 with an ethereal solution of oxalic acid. The resultant precipitate was collected and dried to yield 5.1 g (77%), m.p. 90°-120° C. This material was recrystallized twice from ethyl acetate/methanol/ether (10:1:5) to yield 3.5 g, m.p. 145°-147° C. ANALYSIS: Calculated for C33 H34 F2 N2 O.(CO2 H)2: 69.75% C; 6.02% H; 4.65% N; Found: 69.41% C; 6.02% H; 4.57% N.
5.1 g (77%) With Ki; oxalic acid In water; N,N-dimethyl-formamide 7 11-[1-(4-bis-4-Fluorophenyl)butyl]piperidin-4-yl}-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine EXAMPLE 7 11-[1-(4-bis-4-Fluorophenyl)butyl]piperidin-4-yl}-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine To 40 ml DMF were added 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (3.0 g, 0.011 mole), 4-chloro-1-bis-(p-fluorophenyl)butane (3.0 g, 0.0106 mole), milled K2 CO3 (10 g) and 0.01 g KI. After stirring at 90° C. for two hours, the mixture was filtered, and the filtrate evaporated to an oil. This oil was stirred with 100 ml water for five minutes and then extracted with ether. The ether solution was washed twice with water and dried (saturated NaCl, anhydrous MgSO4). After filtering, the filtrate was acidified to pH 1 with an ethereal solution of oxalic acid. The resultant precipitate was collected and dried to yield 5.1 g (77%), m.p. 90°-120° C. This material was recrystallized twice from acetate/methanol/ether (10:1:5) to yield 3.5 g, m.p. 145°-147° C.
  • 7
  • [ 99579-21-2 ]
  • [ 54540-58-8 ]
  • [ 88144-45-0 ]
YieldReaction ConditionsOperation in experiment
30.78% With potassium iodide; potassium carbonate In N,N-dimethyl-formamide 14 1'-[4-(4-Fluorophenyl)butyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride EXAMPLE 14 1'-[4-(4-Fluorophenyl)butyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride The compound 2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride (5 g, 18.6 mmole) was dissolved in 100 ml of DMF and stirred under nitrogen at 90° C. with 5 g of potassium carbonate (milled, anhydrous), 15 mg of potassium iodide, and 3.80 g of 4-(4-fluorophenyl)butyl chloride (20.4 mmole) overnight. The reaction was determined to be complete by TLC. The mixture was cooled to ambient temperature, quenched with water and extracted into ether. The ether extracts were backwashed with saturated brine and the solvent was removed under vacuum. The residue was loaded onto a 100 g alumina column packed in ether and 50 ml fractions were eluted. The desired material was found in fractions 2-4, which were subsequently combined. The hydrochloride was precipitated and recrystallized from methanol-water resulting in 2.4 g of 1'-[4-(4-fluorophenyl)butyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride (5.7 mmole, 30.78%) which appeared pure by TLC on silica gel in chloroform:methanol (9:1), Rf =0.8, and in dichloromethane:2-propanol (1:1), Rf =0.7. MS (MH+ =384), NMR-DMSO-d6 and IR-KBr are consistent with the structure, m.p.=212°-213° C.
With potassium iodide; potassium carbonate In N,N-dimethyl-formamide 14 1'-[4-(4-Fluorophenyl)butyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride EXAMPLE 14 1'-[4-(4-Fluorophenyl)butyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride The compound 2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride (5 g, 18.6 mmole) was dissolved in 100 ml of DMF and stirred under nitrogen at 90° C. with 5 g of potassium carbonate (milled, anhydrous), 15 mg of potassium iodide, and 3.80 g of 4-(4-fluorophenyl)butyl chloride (20.4 mmole) overnight. The reaction was determined to be complete by TLC. The mixture was cooled to ambient temperature, quenched with water and extracted into ether. The ether extracts were backwashed with saturated brine and the solvent was removed under vacuum. The residue was loaded onto a 100 g alumina column packed in ether and 50 ml fractions were eluted. The desired material was found in fractions 2-4, which were subsequently combined. The hydrochloride was precipitated and recrystallized from methanol-water resulting in 2.4 g of 1'-[4-(4-fluorophenyl) butyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]-hydrochloride (5.7
  • 8
  • [ 2934996-24-2 ]
  • [ 54540-58-8 ]
  • [ 99579-51-8 ]
YieldReaction ConditionsOperation in experiment
With potassium iodide In acetic acid butyl ester 78 1'-[4-(4-Fluorophenyl)butyl]-7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride EXAMPLE 78 1'-[4-(4-Fluorophenyl)butyl]-7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride The compound 7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride (5.0 g, 16.4 mmole) was suspended in 100 ml of n-butylacetate along with 5.0 g of milled anhydrous potassium carbonate, 15 mg of potassium iodide and 3.2 g of 4-(4-fluorophenyl)butylchloride (17.2 mmole). The mixture was stirred at reflux for 48 hr. under nitrogen. The reaction mixture was cooled to ambient temperature, filtered and the solvent removed under vacuum. The oily residue was loaded onto a 100 g alumina column packed in ether. Fractions of 50 ml were collected and the desired product was found in numbers 2-4. These were combined and taken to dryness under vacuum. The residual oil was dissolved in anhydrous ether and the hydrochloride salt precipitated. The solids were recrystallized from ethyl acetate/ethanol yielding 5.3 g of 1'-[4-(4-fluorophenyl)butyl]-7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride (11.7
  • 9
  • [ 2934600-96-9 ]
  • [ 54540-58-8 ]
  • [ 99579-50-7 ]
YieldReaction ConditionsOperation in experiment
With potassium iodide In acetic acid butyl ester 77 1'-[4-(4-Fluorophenyl)butyl]-7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride EXAMPLE 77 1'-[4-(4-Fluorophenyl)butyl]-7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride The compound 7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride (5.0 g, 17.4 mmole) was suspended in 100 ml of n-butylacetate, along with 5.0 g of milled, anhydrous potassium carbonate, 15 mg of potassium iodide and 3.3 g of 4-(4-fluorophenyl)butyl chloride (17.4 mmole). The mixture was heated at reflux with stirring for 48 hr. under nitrogen. The reaction mixture was cooled, filtered and taken to dryness under vacuum. The residual oil was loaded onto a 100 g alumina column packed in ether. Fractions of 50 ml were collected and the desired product was found in numbers 2-4. These were combined and taken to dryness under vacuum. The oily residue was dissolved in anhydrous ether and the hydrochloride precipitated. The solids were recrystallized from ethyl acetate/ethanol yielding 4.0 g of 1'-[4-(4-fluorophenyl)butyl]-7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride (9.2 mmole, 52.6%) which appeared pure by TLC on silica gel in hexane:ethyl acetate:methanol:ammonium hydroxide (10:10:1:0.1), Rf =0.5 and by HPLC (Water's-C18 μ-Bondapak, 65%, acetonitrile/35% 0.05M ammonium citrate, flow=2.0 ml/min, tR =3.1 min, UV detection λ=265 nm). MS (ci MH+ =402), NMR-DMSOd6 and IR-CHCl3 are consistent with the structure, mp=201°-205° C.
  • 10
  • [ 6940-78-9 ]
  • [ 352-13-6 ]
  • [ 54540-58-8 ]
YieldReaction ConditionsOperation in experiment
76% With N,N,N,N,-tetramethylethylenediamine; [((Me)NN2)NiCl] In tetrahydrofuran at 20℃; for 2h; Inert atmosphere;
  • 11
  • [ 41885-98-7 ]
  • [ 54540-58-8 ]
  • [ 1366348-92-6 ]
YieldReaction ConditionsOperation in experiment
83.2% Stage #1: 1-(4-chlorophenyl)homopiperazine; 1-(4-chlorobutyl)-4-fluorobenzene With potassium carbonate; potassium iodide In 1,2-dimethoxyethane for 16h; Reflux; Inert atmosphere; Stage #2: With hydrogenchloride 4.6.1. 3-(4-Chlorophenyl)-8-(3-(4-fluorophenoxy)propyl)-8-azabicyclo[3.2.1]octan-3-ol (7) General procedure: A mixture of 3-(4-fluorophenoxy)propylmethanesulfonate 26 (0.73 g, 3.1 mmol), 3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol 44 (1.0 g, 2.56 mmol), KI (0.2 g), and K2CO3 (1.10 g, 7.69 mmol) in DME (25 ml) was heated to reflux under N2 for 16 h. The mixture was diluted with EtOAc (450 mL), followed by washing with saturated NaHCO3 (100 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to dry followed by column chromatography on silica gel affording 3-(4-chlorophenyl)-8-(3-(4-fluorophenoxy)propyl)-8-azabicyclo[3.2.1]octan-3-ol 7 in an off white semi-solid form. The product was converted to the HCl salt, followed by recrystallization in EtOAc-Et2O to give its HCl salt (722 mg), in a yield of 72.3%.
  • 12
  • [ 54540-58-8 ]
  • [ 1159155-92-6 ]
  • [ 1366348-85-7 ]
YieldReaction ConditionsOperation in experiment
79.5% Stage #1: 1-(4-chlorobutyl)-4-fluorobenzene; 3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol With potassium carbonate; potassium iodide In 1,2-dimethoxyethane for 16h; Reflux; Inert atmosphere; Stage #2: With hydrogenchloride 4.6.1. 3-(4-Chlorophenyl)-8-(3-(4-fluorophenoxy)propyl)-8-azabicyclo[3.2.1]octan-3-ol (7) General procedure: A mixture of 3-(4-fluorophenoxy)propylmethanesulfonate 26 (0.73 g, 3.1 mmol), 3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol 44 (1.0 g, 2.56 mmol), KI (0.2 g), and K2CO3 (1.10 g, 7.69 mmol) in DME (25 ml) was heated to reflux under N2 for 16 h. The mixture was diluted with EtOAc (450 mL), followed by washing with saturated NaHCO3 (100 mL). The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to dry followed by column chromatography on silica gel affording 3-(4-chlorophenyl)-8-(3-(4-fluorophenoxy)propyl)-8-azabicyclo[3.2.1]octan-3-ol 7 in an off white semi-solid form. The product was converted to the HCl salt, followed by recrystallization in EtOAc-Et2O to give its HCl salt (722 mg), in a yield of 72.3%.
  • 13
  • [ 91-21-4 ]
  • [ 54540-58-8 ]
  • [ 1954688-98-2 ]
YieldReaction ConditionsOperation in experiment
75% Stage #1: 1,2,3,4-tetrahydroisoquinoline; 1-(4-chlorobutyl)-4-fluorobenzene With potassium carbonate; potassium iodide In 1,2-dimethoxyethane at 120℃; for 1h; Microwave irradiation; Sealed tube; Stage #2: With hydrogenchloride In diethyl ether 3 4.7. general alkylation procedure for compounds 6-8, 10-12a,14, and 16 General procedure: A mixture of alkylating agent (1 equiv), THIQ (1.1 equiv) K2CO3(1.1 equiv), and KI (catalytic) in DME (10 mL) was placed in a20 mL microwave vial with a stirrer and tightly sealed. The mixture was subjected to microwave heating at 120 °C for 60 min. The mixture was directly purified on silica by flash chromatography (gradient up to 70% EtOAc in hexanes) to afford compound 7. The free base where necessary, was converted to the HCl salt and crystallized out of a MeOH-Et2O solvent mixture.
  • 14
  • [ 54540-58-8 ]
  • [ 87394-65-8 ]
  • [ 2328073-98-7 ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate; potassium iodide In isopropyl alcohol for 12h; Inert atmosphere; Reflux; 1 5.3. Synthesis of homopiperazine analogs 2, 3, 4 and piperazine analogs (8and 10) General procedure: General Procedure I: A mixture of 4-chloro-1-(4-fluorophenyl)butan-1-one (1.0 g, 5.0 mmol), 1-(5-chloropyridin-2-yl)-1,4-diazepane (1.2 g,5.7 mmol), KI (250 mg), NaHCO3 (1.0 g, 11.9 mmol) in iPrOH (10 mL)was heated to reflux under N2 for 12 h. After cooling to rt, the mixturewas diluted with EtOAc (500 mL) and washed with water (2×300 mL).The organic layer was dried over Na2SO4, filtered and the filtrate wasconcentrated in vacuo to dryness to obtain a residue which was purifiedby column chromatography on silica gel to afford 4-(4-(5-chloropyridin-2-yl)-1,4-diazepan-1-yl)-1-(4-fluoro-phenyl)butan-1-one 2 as a freebase.
 

Historical Records

Technical Information

• Alkyl Halide Occurrence • Baeyer-Villiger Oxidation • Barbier Coupling Reaction • Baylis-Hillman Reaction • Benzylic Oxidation • Birch Reduction • Blanc Chloromethylation • Bucherer-Bergs Reaction • Clemmensen Reduction • Corey-Bakshi-Shibata (CBS) Reduction • Corey-Chaykovsky Reaction • Fischer Indole Synthesis • Friedel-Crafts Reaction • General Reactivity • Grignard Reaction • Henry Nitroaldol Reaction • Hiyama Cross-Coupling Reaction • Horner-Wadsworth-Emmons Reaction • Hydride Reductions • Hydrogenolysis of Benzyl Ether • Kinetics of Alkyl Halides • Kumada Cross-Coupling Reaction • Lawesson's Reagent • Leuckart-Wallach Reaction • McMurry Coupling • Meerwein-Ponndorf-Verley Reduction • Passerini Reaction • Paternò-Büchi Reaction • Petasis Reaction • Peterson Olefination • Pictet-Spengler Tetrahydroisoquinoline Synthesis • Preparation of Aldehydes and Ketones • Preparation of Alkylbenzene • Preparation of Amines • Prins Reaction • Reactions of Aldehydes and Ketones • Reactions of Alkyl Halides with Reducing Metals • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reformatsky Reaction • Robinson Annulation • Schlosser Modification of the Wittig Reaction • Schmidt Reaction • Specialized Acylation Reagents-Ketenes • Stille Coupling • Stobbe Condensation • Substitution and Elimination Reactions of Alkyl Halides • Suzuki Coupling • Tebbe Olefination • Ugi Reaction • Vilsmeier-Haack Reaction • Wittig Reaction • Wolff-Kishner Reduction

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