460746-47-8|4'-Hydroxy-3'-iodo-[1,1'-biphenyl]-4-carbonitrile| Ambeed

Structure of 460746-47-8

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Quality Control of [ 460746-47-8 ] Purity: 95% SDS Specification

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Product Details of [ 460746-47-8 ]

CAS No. :	460746-47-8
Formula :	C₁₃H₈INO
M.W :	321.11
SMILES Code :	N#CC1=CC=C(C2=CC=C(O)C(I)=C2)C=C1
MDL No. :	MFCD06796628
InChI Key :	GGJLASJZXUIMAG-UHFFFAOYSA-N
Pubchem ID :	10358676

Safety of [ 460746-47-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 460746-47-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	12
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	71.33
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	44.02 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.38
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	3.56
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.54
Log P_o/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.	3.13
Log P_o/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	3.96
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.31

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.56
Solubility	0.00879 mg/ml ; 0.0000274 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-4.17
Solubility	0.0217 mg/ml ; 0.0000676 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	-5.35
Solubility	0.00142 mg/ml ; 0.00000443 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	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	Yes
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	Yes
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.	-5.73 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<1.0
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)	2.29

Application In Synthesis of [ 460746-47-8 ]

* 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.

Upstream synthesis route of [ 460746-47-8 ]
Downstream synthetic route of [ 460746-47-8 ]

[ 460746-47-8 ] Synthesis Path-Upstream 1~2

1
[ 19812-93-2 ]
[ 460746-47-8 ]

Yield	Reaction Conditions	Operation in experiment
53%	With sodium hydroxide; sodium hypochlorite; sodium iodide In methanol	4'-hydroxy-3'-iodo [1,1'-biphenyl]-4-carbonitrile To a solution of 4-hydroxy-4'-cyanobiphenyl (6.00 g, 30.8 mmol), sodium iodide (4.61 g, 30.8 mmol) and sodium hydroxide (1.23 g, 30.8 mmol) in methanol (90 mL) at 0° C. was added an aqueous solution of sodium hypochlorite (47 mL of 5.25percent Clorox.(TM)., 2.29 g, 30.8 mmol) over 45 minutes. The mixture was stirred cold for 1 hour, warmed to ambient temperature and diluted with sodium thiosulfate solution (10 mL), water (80 mL) and adjusted to a pH of 7 by addition of sodium dihydrogen phosphate. The mixture was extracted with dichloromethane (2*90 mL). The combined organic extracts were dried (Na₂SO₄), filtered and concentrated under reduced pressure to give a white powder. The solid was crystallized from dichloroethane/hexane and chromatographed on silica with dichloromethane to give the titled compound (5.19 g, 53percent). MS (DCI) m/z 339[M+NH₄⁺]⁺.
53%	With sodium hydroxide; sodium hypochlorite; sodium iodide In methanol	EXAMPLE 1A 4'-hydroxy-3'-iodo[1,1'-biphenyl]-4-carbonitrile To a solution of 4-hydroxy-4'-cyanobiphenyl (6.00 g, 30.8 mmol), sodium iodide (4.61 g, 30.8 mmol) and sodium hydroxide (1.23 g, 30.8 mmol) in methanol (90 mL) at 0° C. was added an aqueous solution of sodium hypochlorite (47 mL of 5.25percent Clorox.(TM)., 2.29 g, 30.8 mmol) over 45 minutes. The mixture was stirred cold for 1 hour, warmed to ambient temperature and diluted with sodium thiosulfate solution (10 mL), water (80 mL) and adjusted to a pH of 7 by addition of sodium dihydrogen phosphate. The mixture was extracted with dichloromethane (2*90 mL). The combined organic extracts were dried (Na₂SO₄), filtered and concentrated under reduced pressure to give a white powder. The solid was crystallized from dichloroethane/hexane and chromatographed on silica with dichloromethane to give the titled compound (5.19 g, 53percent). MS (DCI) m/z 339[M+NH₄⁺]⁺.
53%	With sodium hydroxide; sodium hypochlorite; sodium iodide In methanol	Example 1A 4'-hydroxy-3'-iodo[1,1'-biphenyl]-4-carbonitrile To a solution of 4-hydroxy-4'-cyanobiphenyl (6.00 g, 30.8 mmol), sodium iodide (4.61 g, 30.8 mmol) and sodium hydroxide (1.23 g, 30.8 mmol) in methanol (90 mL) at 0° C. was added an aqueous solution of sodium hypochlorite (47 mL of 5.25percent Clorox.(TM)., 2.29 g, 30.8 mmol) over 45 minutes. The mixture was stirred cold for 1 hour, warmed to ambient temperature and diluted with sodium thiosulfate solution (10 mL), water (80 mL) and adjusted to a pH of 7 by addition of sodium dihydrogen phosphate. The mixture was extracted with dichloromethane (2*90 mL). The combined organic extracts were dried (Na₂SO₄), filtered and concentrated under reduced pressure to give a white powder. The solid was crystallized from dichloroethane/hexane and chromatographed on silica with dichloromethane to give the titled compound (5.19 g, 53percent). MS (DCI) m/z 339[M+NH₄^+]⁺;

53%

With sodium hydroxide; sodium hypochlorite; sodium iodide In methanol

Example 1A
4'-hydroxy-3'-iodo[1,1'-biphenyl]-4-carbonitrile
To a solution of 4-hydroxy-4'-cyanobiphenyl (6.00 g, 30.8 mmol), sodium iodide (4.61 g, 30.8 mmol) and sodium hydroxide (1.23 g, 30.8 mmol) in methanol (90 mL) at 0° C. was added an aqueous solution of sodium hypochlorite (47 mL of 5.25percent Clorox.(TM)., 2.29 g, 30.8 mmol) over 45 minutes.
The mixture was stirred cold for 1 hour, warmed to ambient temperature and diluted with sodium thiosulfate solution (10 mL), water (80 mL) and adjusted to a pH of 7 by addition of sodium dihydrogen phosphate.
The mixture was extracted with dichloromethane (2*90 mL).
The combined organic extracts were dried (Na₂SO₄), filtered and concentrated under reduced pressure to give a white powder.
The solid was crystallized from dichloroethane/hexane and chromatographed on silica with dichloromethane to give the titled compound (5.19 g, 53percent). MS (DCI) m/z 339[M+NH4⁺]⁺;

References: [1] Organic Process Research and Development, 2005, vol. 9, # 1, p. 45 - 50.
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 3, p. 689 - 693.
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 38 - 55.
[4] Patent: US2003/153548, 2003, A1, .
[5] Patent: US2003/134835, 2003, A1, .
[6] Patent: US2002/169188, 2002, A1, .
[7] Patent: US2002/183309, 2002, A1, .
[8] Patent: US2004/54185, 2004, A1, . Location in patent: Page 9.

2
[ 19812-93-2 ]
[ 460746-47-8 ]

Yield	Reaction Conditions	Operation in experiment
40%	With sodium hydroxide; sodium iodide In methanol	EXAMPLE 169A 4'-hydroxy-3'-iodo-1,1'-biphenyl-4-carbonitrile 4'-Hydroxy-1,1'-biphenyl-4-carbonitrile (25.0 g, 128 mmol), purchased commercially, NaI (19.19 g, 128 mmol), and sodium hydroxide (5.12g, 128 mmol) were combined in methanol (500 mL) at 0° C. and treated with bleach (5.25percent, 181.0 g) dropwise over 1 hour. After stirring at 0° C. for 1 hour, the mixture was treated with 10percent aqueous sodium thiosulfate (250 mL). The mixture was adjusted to pH 6.8 with 10percent aqueous HCl and then the mixture was filtered. The filter cake was crystallized from hot CH₂Cl₂/hexane to provide the title compound (40percent yield). ¹H-NMR (300 MHz, CDCl₃) δ 5.40 (s, 1H), 7.10 (m, 1H), 7.50 (m, 1H), 7.60 (m, 2H), 7.77(m, 2H), 7.90 (m, 1H); MS (CDI) m/z 339 (M+NH₄)⁺.
40%	With sodium hydroxide; sodium iodide In methanol	EXAMPLE 169A 4'-hydroxy-3'-iodo-1,1'-biphenyl-4-carbonitrile 4'-Hydroxy-1,1'-biphenyl-4-carbonitrile (25.0 g, 128 mmol), purchased commercially, NaI (19.19 g, 128 mmol), and sodium hydroxide (5.12g, 128 mmol) were combined in methanol (500 mL) at 0° C. and treated with bleach (5.25percent, 181.0 g) dropwise over 1 hour. After stirring at 0° C. for 1 hour, the mixture was treated with 10percent aqueous sodium thiosulfate (250 mL). The mixture was adjusted to pH 6.8 with 10percent aqueous HCl and then the mixture was filtered. The filter cake was crystallized from hot CH₂Cl₂/hexane to provide the title compound (40percent yield). ¹H-NMR (300 MHz, CDCl₃) δ5.40 (s, 1H), 7.10 (m, 1H), 7.50 (m, 1H), 7.60 (m, 2H), 7.77(m, 2H), 7.90 (m, 1H); MS (CDI) m/z 339 (M+NH₄)⁺.

References: [1] Patent: US2002/137931, 2002, A1, .
[2] Patent: US6620839, 2003, B2, .

[ 460746-47-8 ] Synthesis Path-Downstream 1~29

1
[ 19812-93-2 ]
[ 460746-47-8 ]

Yield	Reaction Conditions	Operation in experiment
53%	With sodium hydroxide; sodium hypochlorite; sodium iodide; In methanol;	4'-hydroxy-3'-iodo [1,1'-biphenyl]-4-carbonitrile To a solution of 4-hydroxy-4'-cyanobiphenyl (6.00 g, 30.8 mmol), sodium iodide (4.61 g, 30.8 mmol) and sodium hydroxide (1.23 g, 30.8 mmol) in methanol (90 mL) at 0 C. was added an aqueous solution of sodium hypochlorite (47 mL of 5.25% Clorox, 2.29 g, 30.8 mmol) over 45 minutes. The mixture was stirred cold for 1 hour, warmed to ambient temperature and diluted with sodium thiosulfate solution (10 mL), water (80 mL) and adjusted to a pH of 7 by addition of sodium dihydrogen phosphate. The mixture was extracted with dichloromethane (2*90 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give a white powder. The solid was crystallized from dichloroethane/hexane and chromatographed on silica with dichloromethane to give the titled compound (5.19 g, 53%). MS (DCI) m/z 339[M+NH4+]+.
53%	With sodium hydroxide; sodium hypochlorite; sodium iodide; In methanol;	EXAMPLE 1A 4'-hydroxy-3'-iodo[1,1'-biphenyl]-4-carbonitrile To a solution of 4-hydroxy-4'-cyanobiphenyl (6.00 g, 30.8 mmol), sodium iodide (4.61 g, 30.8 mmol) and sodium hydroxide (1.23 g, 30.8 mmol) in methanol (90 mL) at 0 C. was added an aqueous solution of sodium hypochlorite (47 mL of 5.25% Clorox, 2.29 g, 30.8 mmol) over 45 minutes. The mixture was stirred cold for 1 hour, warmed to ambient temperature and diluted with sodium thiosulfate solution (10 mL), water (80 mL) and adjusted to a pH of 7 by addition of sodium dihydrogen phosphate. The mixture was extracted with dichloromethane (2*90 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give a white powder. The solid was crystallized from dichloroethane/hexane and chromatographed on silica with dichloromethane to give the titled compound (5.19 g, 53%). MS (DCI) m/z 339[M+NH4+]+.
53%	With sodium hydroxide; sodium hypochlorite; sodium iodide; In methanol;	Example 1A 4'-hydroxy-3'-iodo[1,1'-biphenyl]-4-carbonitrile To a solution of 4-hydroxy-4'-cyanobiphenyl (6.00 g, 30.8 mmol), sodium iodide (4.61 g, 30.8 mmol) and sodium hydroxide (1.23 g, 30.8 mmol) in methanol (90 mL) at 0 C. was added an aqueous solution of sodium hypochlorite (47 mL of 5.25% Clorox, 2.29 g, 30.8 mmol) over 45 minutes. The mixture was stirred cold for 1 hour, warmed to ambient temperature and diluted with sodium thiosulfate solution (10 mL), water (80 mL) and adjusted to a pH of 7 by addition of sodium dihydrogen phosphate. The mixture was extracted with dichloromethane (2*90 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give a white powder. The solid was crystallized from dichloroethane/hexane and chromatographed on silica with dichloromethane to give the titled compound (5.19 g, 53%). MS (DCI) m/z 339[M+NH4+]+;

53%	With sodium hydroxide; sodium hypochlorite; sodium iodide; In methanol;	Example 1A 4'-hydroxy-3'-iodo[1,1'-biphenyl]-4-carbonitrile To a solution of 4-hydroxy-4'-cyanobiphenyl (6.00 g, 30.8 mmol), sodium iodide (4.61 g, 30.8 mmol) and sodium hydroxide (1.23 g, 30.8 mmol) in methanol (90 mL) at 0 C. was added an aqueous solution of sodium hypochlorite (47 mL of 5.25% Clorox, 2.29 g, 30.8 mmol) over 45 minutes. The mixture was stirred cold for 1 hour, warmed to ambient temperature and diluted with sodium thiosulfate solution (10 mL), water (80 mL) and adjusted to a pH of 7 by addition of sodium dihydrogen phosphate. The mixture was extracted with dichloromethane (2*90 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give a white powder. The solid was crystallized from dichloroethane/hexane and chromatographed on silica with dichloromethane to give the titled compound (5.19 g, 53%). MS (DCI) m/z 339[M+NH4+]+;
	With N-iodo-succinimide; sulfuric acid; In water; acetic acid; at 20 - 30℃; for 1.0h;	4'-Hydroxy-1,1'-biphenyl-4-carbonitrile (2.15 kg, 10.90 mol), purchased from Takeda Chemical Industries, Tokyo, Japan, and N-iodosuccinimide (2.4 kg, 97% pure, 10.36 mmol) were combined in acetic acid (17.2 L) at room temperature under nitrogen.The suspension was treated with sulfuric acid (290 ML) slowly maintaining the temperature below 27 C. The reaction was stirred at room temperature and the reaction progress was monitored by HPLC. The reaction mixture was treated with distilled water (35 L) while maintaining the temperature below 30 C. After stirring at room temperature for 1 hour, the solid was filtered and the filter cake was washed with distilled water (32 L) to afford a solid.The solid was dried under reduced pressure at 60 C. for 48 hours to provide the title compound. MS (ESI-) (M-H)-320; 1H-NMR (DMSO-d6) delta10.75 (1H, s), 8.05 (1H, d, J=2.3 Hz), 7.83 (2H, m), 7.80 (2H, m), 7.62 (1H, dd, J=6.1, 8.5 Hz), 7.00 (1H, d, J=8.5 Hz); 13C-NMR (DMSO-d6) delta156.84, 142.55, 136.63, 132.27, 130.52, 127.91, 126.36, 118.54, 114.96, 108.89, 85.32.

References: [1]Organic Process Research and Development,2005,vol. 9,p. 45 - 50.
[2]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 689 - 693.
[3]Journal of Medicinal Chemistry,2005,vol. 48,p. 38 - 55.
[4]Patent: US2003/153548,2003,A1 .
[5]Patent: US2003/134835,2003,A1 .
[6]Patent: US2002/169188,2002,A1 .
[7]Patent: US2002/183309,2002,A1 .
[8]Patent: US2004/54185,2004,A1 .Location in patent: Page 9.

2
[ 927-74-2 ]
[ 460746-47-8 ]
[ 460746-48-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With diisopropylamine;copper(l) iodide; palladium diacetate; triphenylphosphine; In Isopropyl acetate; at 15 - 40℃; for 10.5h;	The product from Example 1A (3.1 kg, 9.68 mol) in isopropyl acetate (49.2 kg) was purged with N2 for about 10 minutes and then cooled to about 15 C. The mixture was treated with palladium(II) acetate (22 g, 0.10 mol), triphenylphosphine, (51 g, 0.19 mol), copper(I) iodide (38 g, 0.19 mol), and 3-butyn-1-ol (0.91 kg, 12.59 moles) while continuing to purge with N2.The mixture was then treated with diisopropylamine (1.97 kg, 19.37 mol), by addition over about 30 minutes.After 2 hours, the suspension was heated to about 40 C. After about 8 hours, the reaction mixture was cooled to room temperature and filtered through a pad of Celite.The pad was washed with isopropyl acetate (12 kg) and the filtrate was washed with 5% NaHCO3 solution and then washed with water.The organic layer was then distilled to dryness.The residue (2.03 kg, 80% assayed yield) was carried onto the tosylation step.A small sample was purified by silica gel chromatography. 1H NMR (CDCl3 at 400 MHz) delta1.81 (t, 1H), 3.07 (t, 2H), 4.01 (q, 2H), 6.56 (s, 1H) 7.41-7.50 (m, 2H), 7.67 (m, 5H); 13C NMR (CDCl3 at 100 MHz) delta32.3, 60.6, 103.6, 110.1, 111.2, 118.8, 119.0, 122.8, 127.6, 129.3, 132.2, 133.8, 145.8, 154.6, 157.0 with 2 peaks overlapping.

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 689 - 693.
[2]Journal of Medicinal Chemistry,2005,vol. 48,p. 38 - 55.
[3]Patent: US2004/54185,2004,A1 .Location in patent: Page 9.
[4]Organic Process Research and Development,2005,vol. 9,p. 45 - 50.

3
[ 460746-47-8 ]
[ 460747-73-3 ]
[ 460746-46-7 ]

Yield	Reaction Conditions	Operation in experiment
	With diisopropylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In acetonitrile; at 20℃;	The solution from Example 2A (3.02 g, 22.0 mmol) in CH3CN (49.5 ML) was purged with nitrogen and treated with the product from Example 1A (3.21 g, 10.0 mmol), CuI (38 mg, 0.2 mmol), PdCl2 (Ph3P)2 (70 mg, 0.2 mmol), and diisopropylamine (8.4 ml, 60 mmol).The mixture was stirred at room temperature under nitrogen until reaction was near complete by HPLC. The reaction mixture was concentrated to about 30 ML, treated with toluene (100 ML), washed with 5% NaHCO3 (2100 ML), and 10% NH4Cl (2100 ML).The organic layer was separated, filtered through a pad of Celite, and extracted with (CH3SO3H:N-methylpyrrolidinone:H2O, 10:20:70) (2100 ML).The aqueous layer was extracted with IPAC (2100 ML), basified with 50% NaOH, and extracted with IPAC (2100).The organic layer was washed with 5% NaHCO3 (2100 ML), 25% brine (100 ML), and treated with active carbon, silica gel (6.0 g), and Na2SO3 (1.0 g).The mixture was stirred at room temperature for 1 hour and filtered. The filtrate was concentrated to dryness to provide the title compound.

References: [1]Tetrahedron,2006,vol. 62,p. 4584 - 4589.
[2]Patent: US2004/54185,2004,A1 .Location in patent: Page 10.

4
[ 460746-47-8 ]
[ 460746-49-0 ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 38 - 55.
[2]Journal of Medicinal Chemistry,2005,vol. 48,p. 38 - 55.
[3]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 689 - 693.

5
[ 460746-47-8 ]
[ 460746-46-7 ]

6
[ 460746-47-8 ]
4-(2-{2-[(2S)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)benzonitrile [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 38 - 55.
[2]Journal of Medicinal Chemistry,2005,vol. 48,p. 38 - 55.

7
[ 460746-47-8 ]
cyclopropyl[4-(2-{2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)phenyl]methanone [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 38 - 55.
[2]Journal of Medicinal Chemistry,2005,vol. 48,p. 38 - 55.

8
[ 460746-47-8 ]
4-{2-[2-(1H-imidazol-1-yl)ethyl]-1-benzofuran-5-yl}benzonitrile [ No CAS ]