[ CAS No. 5486-55-5 ] {[proInfo.proName]}

Name: 5486-55-5|2,6-Dimethoxynaphthalene|98%
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SKU: A443071
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Quality Control of [ 5486-55-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 5486-55-5 ]

Product Details of [ 5486-55-5 ]

CAS No. :	5486-55-5	MDL No. :	MFCD00004063
Formula :	C₁₂H₁₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AHKDVDYNDXGFPP-UHFFFAOYSA-N
M.W :	188.22	Pubchem ID :	79627
Synonyms :

Calculated chemistry of [ 5486-55-5 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.17
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	56.93
TPSA :	18.46 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.01 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.58
Log Po/w (XLOGP3) :	3.44
Log Po/w (WLOGP) :	2.86
Log Po/w (MLOGP) :	2.45
Log Po/w (SILICOS-IT) :	2.97
Consensus Log Po/w :	2.86

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.57
Solubility :	0.0506 mg/ml ; 0.000269 mol/l
Class :	Soluble
Log S (Ali) :	-3.51
Solubility :	0.0584 mg/ml ; 0.00031 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.33
Solubility :	0.0088 mg/ml ; 0.0000468 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.0

Safety of [ 5486-55-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 5486-55-5 ]

* 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 [ 5486-55-5 ]
Downstream synthetic route of [ 5486-55-5 ]

[ 5486-55-5 ] Synthesis Path-Upstream 1~14

1
[ 581-43-1 ]
[ 74-88-4 ]
[ 5486-55-5 ]

Reference： [1] Canadian Journal of Chemistry, 1987, vol. 65, p. 2397 - 2404
[2] CrystEngComm, 2017, vol. 19, # 11, p. 1464 - 1469
[3] Chinese Journal of Chemistry, 2017, vol. 35, # 8, p. 1289 - 1293
[4] Journal of Organic Chemistry, 2016, vol. 81, # 19, p. 8744 - 8758
[5] Journal of Chemical Research, 2012, vol. 36, # 11, p. 675 - 677

2
[ 581-43-1 ]
[ 77-78-1 ]
[ 5486-55-5 ]

Reference： [1] Israel Journal of Chemistry, 2014, vol. 54, # 5-6, p. 796 - 816
[2] Chemische Berichte, 1907, vol. 40, p. 1413
[3] Journal of Medicinal Chemistry, 1993, vol. 36, # 20, p. 2891 - 2898
[4] Bulletin of the Chemical Society of Japan, 1989, vol. 62, # 2, p. 545 - 550
[5] Journal of Medicinal Chemistry, 2007, vol. 50, # 22, p. 5293 - 5300
[6] Journal of Medicinal Chemistry, 2012, vol. 55, # 12, p. 5720 - 5733

3
[ 5111-66-0 ]
[ 75-57-0 ]
[ 5486-55-5 ]

Reference： [1] Tetrahedron, 2008, vol. 64, # 51, p. 11618 - 11624

4
[ 581-43-1 ]
[ 77-78-1 ]
[ 5486-55-5 ]
[ 5111-66-0 ]

Reference： [1] Tetrahedron, 1982, vol. 38, # 15, p. 2347 - 2354
[2] Patent: US6365775, 2002, B1, . Location in patent: Page column 11

5
[ 5111-65-9 ]
[ 5486-55-5 ]

Reference： [1] Journal of the American Chemical Society, 1948, vol. 70, p. 1279

6
[ 5111-66-0 ]
[ 77-78-1 ]
[ 5486-55-5 ]

Reference： [1] Journal of the American Chemical Society, 1948, vol. 70, p. 1279

7
[ 135-76-2 ]
[ 5486-55-5 ]

Reference： [1] Journal of Medicinal Chemistry, 1964, vol. 7, p. 519 - 524

8
[ 582-17-2 ]
[ 77-78-1 ]
[ 5486-55-5 ]

Reference： [1] Journal of Organic Chemistry, 1986, vol. 51, # 26, p. 5252 - 5258

9
[ 581-43-1 ]
[ 80-48-8 ]
[ 5486-55-5 ]

Reference： [1] Journal of Medicinal Chemistry, 1964, vol. 7, p. 519 - 524

10
[ 613-20-7 ]
[ 5486-55-5 ]

Reference： [1] Chemische Berichte, 1907, vol. 40, p. 1413

11
[ 74-83-9 ]
[ 581-43-1 ]
[ 5486-55-5 ]

Reference： [1] Journal of Fluorine Chemistry, 2014, vol. 168, p. 193 - 197

12
[ 67-56-1 ]
[ 581-43-1 ]
[ 5486-55-5 ]

Reference： [1] Chemische Berichte, 1903, vol. 36, p. 570

13
[ 5486-55-5 ]
[ 5111-66-0 ]

Reference： [1] Journal of Organic Chemistry, 1997, vol. 62, # 12, p. 4097 - 4104

14
[ 581-43-1 ]
[ 77-78-1 ]
[ 5486-55-5 ]
[ 5111-66-0 ]

Reference： [1] Tetrahedron, 1982, vol. 38, # 15, p. 2347 - 2354
[2] Patent: US6365775, 2002, B1, . Location in patent: Page column 11

[ 5486-55-5 ] Synthesis Path-Downstream 1~88

1
[ 123-51-3 ]
[ 5486-55-5 ]
[ 65472-33-5 ]

Reference： [1]Journal of the Chemical Society,1941,p. 386,389

2
[ 5486-55-5 ]
[ 39077-18-4 ]

Reference： [1]Journal of the Chemical Society,1937,p. 1859,1861
[2]Journal of the Chemical Society,1937,p. 1859,1861

3
[ 5486-55-5 ]
[ 25315-06-4 ]

Reference： [1]CrystEngComm,2017,vol. 19,p. 1464 - 1469
[2]Chinese Journal of Chemistry,2017,vol. 35,p. 1289 - 1293
[3]Journal of the Chemical Society,1937,p. 1859,1861

4
[ 5486-55-5 ]
[ 25314-97-0 ]

Reference： [1]Journal of the Chemical Society,1937,p. 1859,1861
[2],1929,vol. 6,p. 1524
Chemisches Zentralblatt,1930,vol. 101,p. 2411

5
[ 5486-55-5 ]
[ 4785-56-2 ]

Reference： [1]Journal of the Indian Chemical Society,1933,vol. 10,p. 693,696

6
[ 5486-55-5 ]
(2-carboxy-4-methoxy-phenyl)-glyoxylic acid [ No CAS ]

Reference： [1]Journal of the Indian Chemical Society,1933,vol. 10,p. 693,696
[2]Journal of the Indian Chemical Society,1933,vol. 10,p. 693,696

7
[ 5486-55-5 ]
[ 326018-78-4 ]

Reference： [1]Journal of the American Chemical Society,1935,vol. 57,p. 1459,1463

8
[ 67-56-1 ]
[ 5486-55-5 ]
[ 55218-06-9 ]
[ 77746-25-9 ]
[ 77746-24-8 ]
[ 77746-23-7 ]

Reference： [1]Journal of the American Chemical Society,1981,vol. 103,p. 2361 - 2371

9
[ 5486-55-5 ]
[ 86748-23-4 ]
[ 105501-40-4 ]

Reference： [1]Angewandte Chemie,1986,vol. 98,p. 1127 - 1129

10
[ 5486-55-5 ]
[ 581-43-1 ]

Reference： [1]Journal of Organic Chemistry,1990,vol. 55,p. 5987 - 5991

11
[ 5486-55-5 ]
[ 58046-83-6 ]

Reference： [1]Canadian Journal of Chemistry,1987,vol. 65,p. 2397 - 2404
[2]Bulletin de l'Academie Polonaise des Sciences, Serie des Sciences Chimiques,1961,vol. 9,p. 507 - 513

12
[ 5486-55-5 ]
[ 25315-09-7 ]
[ 25315-05-3 ]

Reference： [1]Tetrahedron,1982,vol. 38,p. 2347 - 2354

13
[ 5486-55-5 ]
[ 2472-22-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In ethanol; water;	EXAMPLE 207 (6-Methoxy-3,4-dihydro-1H-naphthalen-2-ylidene)-acetic acid ethyl ester A suspension of <strong>[5486-55-5]2,6-dimethoxynaphthalene</strong> (20.0 g, Aldrich) in 200 mL of anhydrous EtOH was heated to reflux under a stream of nitrogen. Sodium spheres (18 g, Aldrich) were added gradually to the hot suspension over a period of 2 hours. Additional ETOH (50 ml) was added and the reaction was heated until all of the sodium had dissolved. The solution was cooled to room temperature and placed in an ice bath. The addition of 6 N HCl brought the solution to pH 6, and additional HCl (10 mL) was added. The solution was heated to reflux for 0.5 h. The golden mixture was cooled to room temperature, H2O (200 mL) was added, and the solution was extracted with ET2O. The combined ET2O extracts were dried (Na2SO4), filtered, and concentrated to afford 6-methoxy-2-tetra-lone as a red oil (23.5 g).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2632 - 2634
[2]Journal of Medicinal Chemistry,1993,vol. 36,p. 2891 - 2898
[3]Journal of Medicinal Chemistry,2007,vol. 50,p. 5293 - 5300
[4]Journal of Medicinal Chemistry,1964,vol. 7,p. 519 - 524
[5]Patent: US6429214,2002,B1
[6]Journal of Medicinal Chemistry,2012,vol. 55,p. 5720 - 5733
[7]Journal of Medicinal Chemistry,2015,vol. 58,p. 2538 - 2546

14
[ 5486-55-5 ]
2,6-Dimethoxy-naphthalene-1-sulfonic acid [ No CAS ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1992,vol. 111,p. 499 - 506

15
[ 5486-55-5 ]
2,6-Dimethoxy-naphthalene-1,5-disulfonic acid [ No CAS ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1992,vol. 111,p. 499 - 506

16
[ 5486-55-5 ]
2,6-dimethoxynaphtalene-1-sulfinyl chloride [ No CAS ]

Reference： [1]Australian Journal of Chemistry,1985,vol. 38,p. 1209 - 1221

17
[ 5486-55-5 ]
[ 141-97-9 ]
[ 64-19-7 ]
[ 134255-38-2 ]
[ 134255-37-1 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1991,vol. 64,p. 851 - 856

18
[ 108-13-4 ]
[ 5486-55-5 ]
[ 64-19-7 ]
[ 134255-29-1 ]
[ 134255-28-0 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1991,vol. 64,p. 851 - 856

19
[ 5486-55-5 ]
[ 166975-76-4 ]
[ 648905-80-0 ]

Yield	Reaction Conditions	Operation in experiment
~ 68%	With aluminum (III) chloride; In dichloromethane; at 0 - 20℃;	In a dry round bottom flask equipped with stir bar, temperature probe and N2 line, dissolve <strong>[5486-55-5]2,6-dimethoxynaphthalene</strong> (1.0 eq) in [CH2C12] (5 volume equivalents) at ambient temperature. Cool the solution to [0 °C] in with an ice bath, and add [4- (2-PIPERIDIN-1-YL-] ethoxy) -benzoyl chloride [(1.] [1] eq). Add aluminum chloride (2.0 eq). Once the reaction is [DETERMINED] to be complete, quench the reaction slowly with 1 N [NAOH] and dilute with additional water and [CH2CL2. WASH] the aqueous layer with [(1] x 20 mL) [OF CH2C12.] Combine the organic extracts and wash with brine and dry [(NA2SO4).] Recrystallize the crude product from methanol to give (2, [6-DIMETHOXY-NAPHTHALEN-1-YL)- [4- (2-PIPERIDIN-1-] yl-ethoxy) -phenyl] -methanone (average yield 68percent).
68%	aluminum (III) chloride; In dichloromethane; at 0℃;	In a dry round bottom flask equipped with stir bar, temperature probe and N2 line, dissolve <strong>[5486-55-5]2,6-dimethoxynaphthalene</strong> (1.0 eq) in [CH2CI2] (5 volume equivalents) at ambient temperature. Cool the solution to [0 °C] in with an ice bath, and add [4- (2-PIPERIDIN-1-YL-] [ETHOXY) -BENZOYL CHLORIDE (1.1 EQ) ADD ALUMINUM CHLORIDE (2.0 EQ). ONCE THE REACTION IS] determined to be complete, quench the reaction slowly with 1 N [NAOH] and dilute with additional water and [CH2C12. WASH] the aqueous layer with [(1] x 20 mL) [OF CH2CL2.] Combine the organic extracts and wash with brine and dry (Na2SO4). Recrystallize the crude product from methanol to give (2, [6-DIMETHOXY-NAPHTHALEN-1-YL)- [4- (2-PIPERIDIN-1-] [YL-ETHOXY)-PHENYL]-METHANONE] (average yield 68percent).
68%		In a dry round bottom flask equipped with stir bar, temperature probe and N2 line, dissolve <strong>[5486-55-5]2,6-dimethoxynaphthalene</strong> (1.0 eq) in CH2CI2 (5 volume equivalents) at ambient temperature. Cool the solution to 0 °C in with an ice bath, and add 4- (2-piperidin-1-yl- ethoxy) -benzoyl chloride (1. 1 eq). Add aluminum chloride (2.0 eq). Once the reaction is determined to be complete, quench the reaction slowly with 1 N NaOH and dilute with additional water and CH2Cl2. Wash the aqueous layer with (1 x 20 mL) of CH2C12. Combine the organic extracts and wash with brine and dry (Na2SO4). Recrystallize the crude product from methanol to give (2, 6-dimethoxy-naphthalen-1-yl)-[4-(2-piperidin-1- yl-ethoxy) -phenyl] -methanone (average yield 68percent). Dissolve (2,6-dimethoxy-naphthalen-1-yl)- [4- (2-piperidin-1-yl-ethoxy)-phenyl]- methanone in CH2C12 (10 volume equivalents) in a 3-neck round bottom flask equipped with a pressure equalizing addition funnel, stirbar, and N2 source. Cool the flask in an ice/brine bath and add 1.0 M BC13 solution in CH2C12 (1.2 equivalents) dropwise. The reaction solution turns dark red and the temperature initially increases to 5 °C. Within one hour, all starting material is consumed, as determined by TLC (1 : 1, Ether: Petroleum Ether). Quench the reaction with methanol (5 equivalents) and allow to warm to room temperature. Dilute the organic solution with CH2C12 (one volume equivalent) and add to a 1.0 M NaHCO3 solution (5 volume equivalents) and stir for one hour. Separate the aqueous and organic layers. Wash the aqueous layer with CH2C12 (one volume) and the combine organic layers, wash with saturated NH4CI and dry over Na2SO4. Purify the product via column chromatography (50/1 silica gel) eluting with CH2C12/Hexanes (3/1) to yield (2-hydroxy-6-methoxy-naphthalen-1-yl)- [4- (2-piperidin-1-yl-ethoxy)-phenyl]- methanone (typical yield 87 percent). Dissolve (2-hydroxy-6-methoxy-naphthalen-1-yl)- [4- (2-piperidin-1-yl-ethoxy)- phenyl] -methanone in CH2C12 (10 volumes) in a three neck round bottom flask equipped with a stir bar and N2 source and chill to 0°C in an ice/brine bath. Add pyridine (1.3 equivalents). Add trifluoromethane sulfonyl chloride (1.2 equivalents) via syringe over 15 minutes. After 15 minutes, quench the reaction with H20 (10 volumes), wash with 1 N HC1 (5 volumes), wash with 1.0 N NaHCO3, and dry over Na2SO4. Concentrate to give the title compound in quantitative yield. Use the product without further purification.

~ 68%	With aluminum (III) chloride; In dichloromethane; at 0 - 20℃;	In a dry round bottom flask equipped with stir bar, temperature probe and N2 line, dissolve <strong>[5486-55-5]2,6-dimethoxynaphthalene</strong> (1.0 [EQ)] in [CH2C12] (5 volume equivalents) at ambient temperature. Cool the solution to [0 °C] in with an ice bath, and add 4- (2-piperidin-1-yl- ethoxy) -benzoyl chloride [(1.] [1] [EQ).] Add aluminum chloride (2.0 [EQ).] Once the reaction is determined to be complete, quench the reaction slowly with 1 N NaOH and dilute with additional water and [CH2CIZ. WASH THE] aqueous layer with [(1] x 20 mL) [OFCH2CL2.] Combine the organic extracts and wash with brine and dry [(NA2S04).] Recrystallize the crude product from methanol to give (2, [6-DIMETHOXY-NAPHTHALEN-1-YL)- [4- (2-PIPERIDIN-1-] [YL-ETHOXY)-PHENYL]-METHANONE] (average yield 68percent).
		Dissolve 2, 6-dimethoxynaphthalene (1.0 eq. ) in CH2C12 (5 volume eq. ) at ambient temperature in a dry round bottom flask equipped with stir bar, temperature probe and N2 line. Cool the solution to 0 °C with an ice bath, and add 4-(2-piperidin-1-yl-ethoxy)- benzoyl chloride (1. 1 eq.). Add aluminum chloride (2. 0 eq.). Once the reaction is determined to be complete, quench the reaction slowly with 1 N NaOH and dilute with additional water and CH2C12. Wash the aqueous layer with CH2C12 (20 mL). Combine the organic extracts and wash with brine and dry (Na2SO4). Recrystallize the crude product from methanol to give (2, 6-dimethoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl- ethoxy)-phenyl]-methanone. Dissolve (2, 6-dimethoxy-naphthalen-1-yl)- [4- (2-piperidin-1-yl-ethoxy)-phenyl]- methanone in CH2C12 (10 volume eq. ) in a 3-neck round bottom flask equipped with a pressure equalizing addition funnel, stirbar, and N2 source. Cool the flask in an ice/brine bath and add 1.0 M BC13 solution in CH2C12 (1.2 eq. ) dropwise. The reaction solution turns dark red and the temperature initially increases to 5 °C. After about 1 hour, quench the reaction with methanol (5 eq. ) and allow to warm to room temperature. Dilute the organic solution with CH2C12 (one volume eq. ) and add a 1.0 M NaHC03 solution (5 volume eq.) and stir for one hour. Separate the aqueous and organic layers. Wash the aqueous layer with CH2C12 (one volume) and combine the organic layers. Wash with saturated NH4C1 and dry over Na2SO4. Purify the product via column chromatography (50/1 silica gel) eluting with CH2Cl2/hexanes (3/1) to yield (2-hydroxy-6-methoxy- naphthalen-1-yl)- [4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone. Dissolve (2-hydroxy-6-methoxy-naphthalen-1-yl)- [4- (2-piperidin-1-yl-ethoxy)- phenyl] -methanone in CH2C12 (10 volumes) in a three neck round bottom flask equipped with a stir bar and N2 source and chill to 0°C in an ice/brine bath. Add pyridine (1.3 eq. ). Add trifluoromethanesulfonyl chloride (1.2 eq. ) via syringe over 15 minutes. After about 15 minutes, quench the reaction with H20 (10 volumes), wash with 1 N aqueous HC1 (5 volumes) and 1.0 N aqueous NaHCO3, and dry over Na2SO4. Obtain the title compound in quantitative yield after concentration.
	With aluminum (III) chloride; In dichloromethane; at 0 - 20℃;	Dissolve <strong>[5486-55-5]2,6-dimethoxynaphthalene</strong> (1.0 eq) in CH2Cl2 (5 volume equivalents) at ambient temperature in a dry round bottom flask equipped with stir bar, temperature probe and N2 line. Cool the solution to 0 °C with an ice bath, and add 4- (2-piperidin-1-yl- ethoxy) -benzoyl chloride (1.1 eq). Add aluminum chloride (2.0 eq). Once the reaction is determined to be complete, quench the reaction slowly with 1 N NaOH and dilute with additional water and CH2Cl2. Wash the aqueous layer with CH2Cl2 (20 mL). Combine the organic extracts and wash with brine and dry (Na2S04). Recrystallize the crude product from methanol to give (2, 6-dimethoxy-naphthalen-1-yl)- [4- (2-piperidin-1-yl- ethoxy)-phenyl]-methanone. Dissolve (2, 6-dimethoxy-naphthalen-1-yl)- [4- (2-piperidin-1-yl-ethoxy)-phenyl]- methanone in CH2C12 (10 volume equivalents) in a 3-neck round bottom flask equipped with a pressure equalizing addition funnel, stirbar, and N2 source. Cool the flask in an ice/brine bath and add 1.0 M BC13 solution in CH2Cl2 (1.2 equivalents) dropwise. The reaction solution turns dark red and the temperature initially increases to 5 °C. After about 1 hour, quench the reaction with methanol (5 equivalents) and allow to warm to room temperature. Dilute the organic solution with CH2Cl2 (one volume equivalent) and add a 1.0 M NaHC03 solution (5 volume equivalents) and stir for one hour. Separate the aqueous and organic layers. Wash the aqueous layer with CH2C12 (one volume) and combine the organic layers. Wash with saturated NH4C1 and dry over Na2SO4. Purify the product via column chromatography (50/1 silica gel) eluting with CH2Cl2/hexanes (3/1) to yield (2-hydroxy-6-methoxy-naphthalen-1-yl)- [4- (2-piperidin-1-yl-ethoxy)-phenyl]- methanone. Dissolve (2-hydroxy-6-methoxy-naphthalen-1-yl)- [4- (2-piperidin-1-yl-ethoxy)- phenyl] -methanone in CH2C12 (10 volumes) in a three neck round bottom flask equipped with a stir bar and N2 source and chill to 0°C in an ice/brine bath. Add pyridine (1.3 equivalents). Add trifluoromethanesulfonyl chloride (1.2 equivalents) via syringe over 15 minutes. After about 15 minutes, quench the reaction with H20 (10 volumes), wash with 1 N aqueous HCl (5 volumes) and 1.0 N aqueous NaHC03, and dry over Na2S04. Obtain the title compound in quantitative yield after concentration.
		Dissolve <strong>[5486-55-5]2,6-dimethoxynaphthalene</strong> (1.0 equivalent (eq) ) in CH2C12 (5 volume equivalents) at ambient temperature in a dry round bottom flask equipped with stir bar, temperature probe and N2 line. Cool the solution to 0°C with an ice bath, and add 4- (2- piperidin-l-yl-ethoxy)-benzoyl chloride (1.1 eq). Add aluminum chloride (2.0 eq). Once the reaction is determined to be complete, quench the reaction slowly with 1 N NaOH and dilute with additional water and CH2C12. Wash the aqueous layer with CH2C12 (20 mL). Combine the organic extracts and wash with brine and dry (Na2SO4). Recrystallize the crude product from methanol to give (2, 6-dimethoxy-naphthalen-1-yl)- [4- (2-piperidin-1- yl-ethoxy)-phenyl]-methanone. Dissolve (2, 6-dimethoxy-naphthalen-1-yl)- [4- (2-piperidin-1-yl-ethoxy)-phenyl]- methanone in CH2C12 (10 volume equivalents) in a 3-neck round bottom flask equipped with a pressure equalizing addition funnel, stir bar, and N2 source. Cool the flask in an ice/brine bath and add 1.0 M BC13 solution in CH2C12 (1.2 eq) dropwise. After about 1 hour, quench the reaction with methanol (5 eq) and allow the reaction to warm to room temperature. Dilute the organic solution with CH2C12 (one volume eq) and add a 1.0 M NaHC03 solution (5 volume eq) and stir for one hour. Separate the aqueous and organic layers. Wash the aqueous layer with CH2C12 (one volume) and combine the organic layers. Wash with saturated NILtCl and dry over Na2SO4. Purify the product via column chromatography (50/1 silica gel) eluting with CH2Cl2/hexanes (3/1) to yield (2-hydroxy- 6-methoxy-naphthalen-1-yl)- [4- (2-piperidin-1-yl-ethoxy)-phenyl]-methanone. Dissolve (2-hydroxy-6-methoxy-naphthalen-1-yl)- [4- (2-piperidin-1-yl-ethoxy)- phenyl] -methanone in CH2CI2 (10 volumes) in a three neck round bottom flask equipped with a stir bar and N2 source and chill to 0°C in an ice/brine bath. Add pyridine (1.3 equivalents) and trifluoromethanesulfonyl chloride (1.2 equivalents) via syringe over 15 minutes. After about 15 minutes, quench the reaction with H20 (10 volumes), wash with 1 N aqueous HC1 (5 volumes) and 1.0 N aqueous NaHCO3, and dry over Na2S04. Obtain the title compound in quantitative yield after concentration.

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 6772 - 6775
[2]Patent: WO2004/29047,2004,A1 .Location in patent: Page 23
[3]Patent: WO2004/9603,2004,A1 .Location in patent: Page 23
[4]Patent: WO2005/73204,2005,A1 .Location in patent: Page/Page column 32-34
[5]Patent: WO2004/9578,2004,A2 .Location in patent: Page 25
[6]Patent: WO2004/9086,2004,A1 .Location in patent: Page/Page column 68
[7]Patent: WO2005/73205,2005,A1 .Location in patent: Page/Page column 47-48
[8]Patent: WO2005/73244,2005,A1 .Location in patent: Page/Page column 11-12

20
[ 5486-55-5 ]
[ 166975-76-4 ]
[ 649724-98-1 ]

Yield	Reaction Conditions	Operation in experiment
75.5%	With aluminum (III) chloride; In dichloromethane; for 5h;	Dissolve <strong>[5486-55-5]2,6-dimethoxynaphthalene</strong> 37.6 g (0.20 mol) and 4-(2-(piperidin-1- yl) ethoxy) benzoyl chloride 64.0 g (0.21 mol) in 800 mL of dichloromethane. Add aluminum chloride 133 g (1.00 mol) portionwise and slowly (the first 30 to 50 g must be added slowly to keep the acylation reaction under control so the solvent does not boil off). After all the aluminum chloride has been added, stir the reaction until no more undemethylated compound can be detected either by TLC or HPLC (about 5 hours). Slowly pour the reaction mixture into 1 L of ice/water with vigorous stirring. Decant the top layer water into a separation funnel. Wash the dichloromethane solution and the precipitate with 2N HCl and decant the aqueous layer again into the separation funnel. Extract the aqueous layer with dichloromethane. Adjust the combined dichloromethane solution and the precipitate pH to 8 first with IN NaOH then with saturated NaHCO3. Filter the mixture. Slurry the solid repeatedly with dichloromethane. Separate the layers of the filtrate and extract the aqueous phase with dichloromethane. Wash the combined organic with brine and dry over MgS04. Treat the dichloromethane solution with charcoal and filter through a prepackaged"suppelco"silica gel funnel. Evaporate the solvent to give 61.2 g (75.5percent) of 6-methoxy-1- [4- (2-piperidin-1-yl-ethoxy)-benzoyl]- naphthalen-2-ol. Couple 6-methoxy-1- [4- (2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-ol and 2,4-dibenzyloxyphenyl boronic acid to provide 2- (2, 4-dibenzyloxyphenyl)-6-methoxy-l- [4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalene by the procedure analogous to that described above in the procedure for 5- {6-benzyloxy-1- [4- (2-piperidin-1-yl-ethoxy)- phenoxy]-naphthalen-2-yl}-2-methyl-isoindole-1, 3-dione. Dissolve 10.5 g (20.0 mmol) 2- (2, 4-dibenzyloxyphenyl)-6-methoxy-l- [4- (2- piperidin-1-yl-ethoxy)-benzoyl]-naphthalene in 150 mL of THF. Add LAH 1.5 g (37.0 mmol) portionwise with vigorous stirring at 0 °C. After the addition, allow the reaction to warm up to room temperature and then stir for 3 hours. Cool the reaction in an ice bath and slowly quench with saturated Na2SO4. Filter off the solid A1203 and wash the filter cake with THF (2x50mL). Combine the filtrates, concentrate and purify the residue by flash chromatography on silica gel using CH2Cl2 : MeOH (9: 1) as eluent to afford 2- methoxy-5- {hydroxy- [4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-6-(2, 4- benzyloxyphenyl)-naphthalene. Heat 2-methoxy-5- {hydroxy- [4- (2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-6- (2, 4- benzyloxyphenyl) -naphthalene to 60°C in THF containg 10percent (by weight) of Pd/C (30percent) catalyst, overnight under 50 psi of hydrogen atmosphere to afford 2-methoxy-5- {hydroxy- [4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-6-(2-hydroxy-4-benzyloxyphenyl)- naphthalene. Treat the THF solution of 2-methoxy-5- {hydroxy- [4- (2-piperidin-1-yl- ethoxy)-phenyl]-methyl}-6- (2-hydroxy-4-benzyloxyphenyl)-naphthalene with 10percent (by mol) of concentrated HCl to give I-12- [4- (8-benzyloxy-2-methoxy-5H-6-oxa-chrysen-5- yl)-phenoxy]-ethyl}-piperidine. Dissolve 1- {2- [4- (8-benzyloxy-2-methoxy-5H-6-oxa-chrysen-5-yl)-phenoxy]- ethyl}-piperidine (680 mg) in a mixture of 250 ml ethanol and 150 ml THF with warming. Add a slurry of 300 mf 10 percent Pd/C in ethanol and react under 1 atmosphere of hydrogen for 18 hours. Filter the catalyst and evaporate the solvent to yield 465 mg of 2- methoxy-5- [4- (2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-8-ol. Dissolve 2-methoxy-5- [4- (2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-oxa-chrysen-8- ol (118 mg. , 0.245 mmoles) in 20 ml methylene chloride and add N- phenyltrifluoromethanesulfonimide (400 mg, . 1.12 mmoles) followed by 1.0 ml of diisopropylethyl amine and stir for 72 hours. Evaporate the solution to a paste and purify by running through an SCX column in methanol (elute with 2N ammonia/methanol) to give 125 mg of the title compound: 125 mg (83percent).

Reference： [1]Patent: WO2005/73205,2005,A1 .Location in patent: Page/Page column 40-42
[2]Journal of Medicinal Chemistry,2006,vol. 49,p. 843 - 846

21
[ 5486-55-5 ]
[ 861930-70-3 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 843 - 846

22
[ 5486-55-5 ]
[ 651326-69-1 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 843 - 846

23
[ 5486-55-5 ]
[ 861931-20-6 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 843 - 846

24
[ 5486-55-5 ]
[ 861930-75-8 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 843 - 846

25
[ 5486-55-5 ]
[ 874486-74-5 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 843 - 846

26
[ 5486-55-5 ]
[ 648905-79-7 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 843 - 846
[2]Journal of Medicinal Chemistry,2005,vol. 48,p. 6772 - 6775

27
[ 5486-55-5 ]
[ 649724-98-1 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 6772 - 6775

28
[ 5486-55-5 ]
[ 736926-06-0 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 6772 - 6775

29
[ 5486-55-5 ]
[ 648905-84-4 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 6772 - 6775

30
[ 5486-55-5 ]
[ 648905-81-1 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 6772 - 6775

31
[ 5486-55-5 ]
[ 648905-83-3 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 6772 - 6775

32
[ 5486-55-5 ]
[ 70312-05-9 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2891 - 2898

33
[ 5486-55-5 ]
[ 744174-28-5 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2891 - 2898

34
[ 5486-55-5 ]
Benzyl-[6-methoxy-3,4-dihydro-1H-naphthalen-(2E)-ylidene]-amine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2891 - 2898

35
[ 5486-55-5 ]
2,6-dimethoxynaphtalene-1-sulfinamide [ No CAS ]

Reference： [1]Australian Journal of Chemistry,1985,vol. 38,p. 1209 - 1221

36
[ 5486-55-5 ]
[ 148228-82-4 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1993,vol. 32,p. 328 - 333

37
[ 5486-55-5 ]
N-<<(1-methyl-6-methoxy)naphth>ethenyl>pyruvoyl amide [ No CAS ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1993,vol. 32,p. 328 - 333

38
[ 5486-55-5 ]
[ 148228-83-5 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1993,vol. 32,p. 328 - 333

39
[ 5486-55-5 ]
[ 6223-33-2 ]

Reference： [1]Journal of the American Chemical Society,1981,vol. 103,p. 2361 - 2371
[2]Journal of the American Chemical Society,1981,vol. 103,p. 2361 - 2371

40
[ 5486-55-5 ]
[ 77746-25-9 ]

Reference： [1]Journal of the American Chemical Society,1981,vol. 103,p. 2361 - 2371

41
[ 5486-55-5 ]
[ 77746-24-8 ]

Reference： [1]Journal of the American Chemical Society,1981,vol. 103,p. 2361 - 2371

42
[ 5486-55-5 ]
[ 77746-23-7 ]

Reference： [1]Journal of the American Chemical Society,1981,vol. 103,p. 2361 - 2371

43
[ 5486-55-5 ]
[ 86539-78-8 ]

Reference： [1]European Journal of Medicinal Chemistry,1983,vol. 18,p. 175 - 180

44
[ 5486-55-5 ]
[ 86539-79-9 ]

Reference： [1]European Journal of Medicinal Chemistry,1983,vol. 18,p. 175 - 180

45
[ 5486-55-5 ]
2,6-dimethoxy-[1]naphthylamine [ No CAS ]

Reference： [1]Journal of the Chemical Society,1937,p. 1859,1861

46
[ 5486-55-5 ]
2,6-dimethoxy-naphthalene-1,5-diyldiamine [ No CAS ]

Reference： [1]Journal of the Chemical Society,1937,p. 1859,1861

47
[ 5111-65-9 ]
[ 5486-55-5 ]

Reference： [1]Journal of the American Chemical Society,1948,vol. 70,p. 1279

48
[ 613-20-7 ]
[ 5486-55-5 ]

Reference： [1]Chemische Berichte,1907,vol. 40,p. 1413

49
[ 5486-55-5 ]
4-(2,6-dimethoxy-[1]naphthyl)-butyric acid [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1936,vol. 58,p. 2382,2384

50
[ 5486-55-5 ]
[ 856206-84-3 ]

Reference： [1]Journal of the American Chemical Society,1935,vol. 57,p. 1459,1463

51
[ 5486-55-5 ]
2,6-diacetoxy-1,5-dibenzyl-naphthalene [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1935,vol. 57,p. 1459,1463

52
[ 5486-55-5 ]
[ 20915-75-7 ]