[ CAS No. 198479-63-9 ] {[proInfo.proName]}

Name: 198479-63-9|5-(Benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indole|97%
Brand: Ambeed
SKU: A100829
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Quality Control of [ 198479-63-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 198479-63-9 ]

CAS No. :	198479-63-9	MDL No. :	MFCD04004106
Formula :	C₂₉H₂₅NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KRIJKJMYOVWRSJ-UHFFFAOYSA-N
M.W :	419.51	Pubchem ID :	3824745
Synonyms :

Calculated chemistry of [ 198479-63-9 ]

Physicochemical Properties

Num. heavy atoms :	32
Num. arom. heavy atoms :	27
Fraction Csp3 :	0.1
Num. rotatable bonds :	7
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	130.66
TPSA :	34.25 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-3.88 cm/s

Lipophilicity

Log Po/w (iLOGP) :	4.31
Log Po/w (XLOGP3) :	7.01
Log Po/w (WLOGP) :	7.0
Log Po/w (MLOGP) :	4.68
Log Po/w (SILICOS-IT) :	7.52
Consensus Log Po/w :	6.1

Druglikeness

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

Water Solubility

Log S (ESOL) :	-7.02
Solubility :	0.0000401 mg/ml ; 0.0000000956 mol/l
Class :	Poorly soluble
Log S (Ali) :	-7.54
Solubility :	0.000012 mg/ml ; 0.0000000285 mol/l
Class :	Poorly soluble
Log S (SILICOS-IT) :	-11.42
Solubility :	0.0000000016 mg/ml ; 0.0 mol/l
Class :	Insoluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	3.05

Safety of [ 198479-63-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302-H317	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 198479-63-9 ]

* 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 [ 198479-63-9 ]
Downstream synthetic route of [ 198479-63-9 ]

[ 198479-63-9 ] Synthesis Path-Upstream 1~14

1
[ 35081-45-9 ]
[ 51388-20-6 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
94.6%	With triethylamine In N,N-dimethyl-formamide at 115℃; for 4 h;	10 g of 4 '-benzyloxy-2-bromophenylacetone (II-a) 15 g of p-benzyloxyaniline hydrochloride (II-b), 50 mL of N, N-dimethylformamide and 8 mL of triethylamine at 115 ° C for 4 hours. The reaction solution was completely purified by thin layer chromatography (TLC). The reaction solution was poured into 250 mL of ice water to precipitate a solid. The crude product was stirred with 20 mL of methanol and dried at 40 ° C for 24 h to give 12.5 g of a yellowish brown solid product, 5-benzyloxy-2-[(4-benzyloxy)phenyl]-3-methyl-1H-indole (Intermediate II) in a yield of 94.6percent
90.5%	Stage #1: With triethylamine In butan-1-ol at 118℃; for 3 h; Stage #2: With hydrogenchloride In water; butan-1-ol at 118℃; for 7 h;	2-bromo- (4-benzyloxyphenyl) acetone (12. 7 g, 0.04 mol)Benzyloxyaniline hydrochloride (11. lg, 0.04 mol) was added to n-butanol (120 ml)Triethylamine (12.2 ml) was added and the temperature was raised to 118 ° (after refluxing, 3 hours later,2_ bromo- (4-benzyloxyphenyl) acetone was completely reacted; concentrated hydrochloric acid (1. 0 ml) was added,The temperature was raised to 118 ° C for 7 hours.The reaction solution was cooled, suction filtered and dried to give a white solid 15. 2 g, HPLC purity: 98percent yield 90.5percent.
65.14%	With triethylamine In N,N-dimethyl-formamide at 100 - 125℃;	4'-Benzyloxy-2-bromophenylpropiophenone (50 g), 4-benzyloxyaniline hydrochloride (40.5 g), triethylamine (50 mL) and N,N-dimethylformamide (300 mL) are mixed and heated to about 100⁰C, and maintained at that temperature for 3-3.5 hours until reaction completion as verified using thin layer chromatography (TLC). The mixture is cooled to 50-55⁰C and additional 4-benzyloxyaniline hydrochloride (40.5 g) is added and stirred. The temperature is raised to 120- 125°C and maintained for 5-5.5 hours, with completion of the reaction verified using TLC. After completion of the reaction, the mixture is allowed to cool to room temperature, then the mixture is added to a solution of 5percent acetic acid (1000 mL) in water, followed by mixing with ethyl acetate (2000 mL). The organic layer is separated and washed with 5percent sodium bicarbonate solution (1000 mL) and brine solution (1000 mL). The organic layer is distilled completely under vacuum and the residue is cooled to 45°C, then methanol (400 ml_) is added and the mixture is stirred for 1 -1.5 hours. The formed solid is filtered and washed with methanol (300 ml_), then dried under vacuum at 65°C for 4 hours to afford the title compound in 65.14percent yield.

Reference： [1] Patent: CN106810487, 2017, A, . Location in patent: Paragraph 0078-0083; 0096; 0110; 0117
[2] Patent: CN104098499, 2016, B, . Location in patent: Paragraph 0035-0037
[3] Chemico-Biological Interactions, 2012, vol. 197, # 1, p. 8 - 15
[4] Patent: WO2011/22596, 2011, A2, . Location in patent: Page/Page column 4; 21; 22
[5] Journal of Medicinal Chemistry, 2001, vol. 44, # 11, p. 1654 - 1657
[6] Patent: EP1212335, 2006, B1, . Location in patent: Page/Page column 22-23

2
[ 4495-66-3 ]
[ 52068-30-1 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With acetic acid In ethanol at 75 - 80℃;	Example-2 4-Benzyloxy phenyl hydrazine hydrochloride (10 g, 40 mmol), 4-benzyloxy propiophenone (9.6 g, 40 mmol) and acetic acid (0.1 ml, 1.7 mmol) were suspended in 140 ml of ethanol and the mixture was refluxed for 12 hrs at a temperature of 75-80° C. During said period the product precipitates. After cooling the mixture at 10-15° C. the crystallized product was isolated by filtration and washed with chilled ethanol (30 ml) and water (50 ml). 5-Benzyloxy-2-(4-benzyloxy)-3-methyl-1H-indole melting at 152-153° C. was obtained in a yield of 15.7 g (94percent). ¹H-NMR (DMSO) δ 10.65 (s, 1H); 7.55 (d, 2H); 7.50 (d, 4H); 7.30-7.45 (m, 6H); 7.21 (d, 1H); 7.10 (d, 1H); 7.10 (d, 1H); 6.91 (dd, 1H); 5.16 (s, 2H); 5.11 (s, 2H); 2.33 (s, 3H)
94%	at 75 - 80℃; for 12 h;	Example-2 4-Benzyloxy phenyl hydrazine hydrochloride (10 g, 40 mmol), 4-benzyloxy propiophenone (9.6 g, 40 mmol) and acetic acid (0.1 ml, 1.7 mmol) were suspended in 140 ml of ethanol and the mixture was refluxed for 12 hrs at the temperature of 75 to 80°C. During said period the product precipitates. After cooling the mixture at 10 to 15°C the crystallized product was isolated by filtration and washed with chilled ethanol (30 ml) and water (50 ml). 5-Benzyloxy-2-(4-benzyloxy)-3-methyl-1H-indole melting at 152 to 153°C was obtained in a yield of 15.7 g (94percent). ¹H-NMR (DMSO) δ 10.65 (s, 1H); 7.55 (d, 2H); 7.50(d, 4H); 7.30-7.45(m, 6H); 7.21(d, 1H); 7.10(d, 1H); 7.10(d, 1H); 6.91(dd, 1H); 5.16(s, 2H); 5.11(s, 2H); 2.33(s, 3H)
84%	With hydrogenchloride In ethanol for 2 h; Reflux	1-(4-(Benzyloxy)phenyl)propan-1-one (2) (1.9 g, 8.0 mmol) and1-(4-(benzyloxy)phenyl)hydrazine hydrochloride (4) (2.0 g,8.0 mmol) were dissolved in EtOH (50 mL) and 5 drops of conc.HCl was added and the mixture was refluxed for 2 h. The reaction mixture was then allowed to cool and was stirred for 1 h. The mixturewas filtered to afford an pale pink solid. The solid was washedwith cold EtOH (10 mL) followed by n-hexane (20 mL). (2.8 g, 84percent).Mp: 149–152 C.50 IR: mmax (KBr) cm1: 3470 (N–H), 2880, 2820,1620 (CC). 1H NMR (CDCl3, 400 MHz) d 7.86 (br s, 1H, NH),7.48–7.58 (m, 6H, Ar-H), 7.33–7.47 (m, 6H, Ar-H), 7.25–7.31 (m,1H, Ar-H), 7.14–7.18 (m, 1H, Ar-H), 7.07–7.13 (m, 2H, Ar-H), 6.97(d, J = 7.53 Hz, 1H, Ar-H), 5.18 (s, 2H, CH2), 5.15 (s, 2H CH2), 2.43(s, 3H, CH3) 13C NMR (CDCl3, 100 MHz) d 157.7 (BnO–C), 157.3(BnO–C), 143.6 (Ar-C–CH2), 137.3 (Cq), 136.3 (Cq), 136.0 (Cq),129.9 (ArC), 128.5 (ArC), 128.2 (ArC), 128.2 (ArC), 127.7 (ArC),127.6 (Ar-C), 127.1 (ArC), 120.4 (ArC), 114.7 (ArC), 114.6 (ArC),114.3 (ArC), 112.2 (Cq), 110.8 (CC), 108.8 (ArC), 102.0 (ArC),70.0 (CH2), 69.6 (CH2), 9.3 (CH3). HRMS (EI): Found 442.1797 (M+Na)+, C29H25NNaO2 requires 442.1783.

Reference： [1] Patent: US7968732, 2011, B1, . Location in patent: Page/Page column 3-4
[2] Patent: EP2426105, 2012, A1, . Location in patent: Page/Page column 3-4
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4075 - 4099

3
[ 6373-46-2 ]
[ 4495-66-3 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
23%	With triethylamine In N,N-dimethyl-formamide at 125℃; for 6 h;	In a 250 mL round bottom flask, 4-(benzyloxy)aniline (8.8 g, 44.34 mmol, 3.00 equiv) was added to a solution of 1-[4-(benzyloxy)phenyl]propan-1-one (4.3 g, 17.89 mmol, 1.00 equiv) in DMF/TEA (40/4.3 mL). The resulting solution was stirred for 6 hours at 125° C. The reaction was then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate (20 mL*3) and the organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure and the residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:5). This resulted in 1.7 g (23percent) of 5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole as a light brown solid.

Reference： [1] Patent: US2018/72711, 2018, A1, . Location in patent: Paragraph 0432; 0435

4
[ 6373-46-2 ]
[ 198479-63-9 ]

Reference： [1] Patent: US6583170, 2003, B1,
[2] Patent: US5985910, 1999, A,
[3] Patent: US6005102, 1999, A,
[4] Patent: US5780497, 1998, A,
[5] Patent: EP802184, 1997, A1,
[6] Patent: EP802184, 1997, A1,

5
[ 1048697-94-4 ]
[ 6373-46-2 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
80.5%	for 6 h; Reflux	1- (4-benzyloxyphenyl) -2- (4-benzyloxy-phenylamino) -1-propanone (12.3g, 0.028mol), 4- benzyloxyaniline (14.0g, 0.070mol) placed in 500mL flask, ethylene glycol monomethyl ether as a solvent, refluxed 6h. The solvent was distilled off under reduced pressure, the residue was stirred with ethanol, suction filtered to give 9.5 g of a brown solid, yield 80.5percent. m.p.151-152 . ESI-MS: m / z420 ([M + H] +). 1H-NMR (400MHz, CDCl3) δ7.89 (s, 1H), 7.45 (m, 14H), 7.28 (d, J = 2.6Hz, 1H), 7.11 (d, J = 8.4Hz, 2H), 6.97 ( dd, J1 = 8.5Hz, J2 = 1.5Hz, 1H), 5.18 (s, 2H), 5.15 (s, 2H), 2.43 (s, 3H).

Reference： [1] Patent: CN105801564, 2016, A, . Location in patent: Paragraph 0026; 0030; 0041; 0042

6
[ 1048697-94-4 ]
[ 51388-20-6 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	at 110 - 115℃; for 5 h;	2) The starting iV-(4-benzyloxyphenyl)-α-amino-4-benzyloxypropiophenone (22) (30.4 g; 69.7 mmol) and 4-benzyloxyaniline hydrochloride (3.3 g; 13.9 mmol) were suspended in propan-2- ol (380 ml) and the mixture was heated up to 110-115°C under an inert atmosphere in a pressure vessel. After 5 hours the heating was disconnected and the reaction mixture was stirred overnight. The crystallized beige product was filtered and washed with a small quantity of propan-2-ol. 24.2 g (82 percent) of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole (3b) with the melting temperature of 152.0-153.2°C were obtained.
79%	at 110 - 115℃; for 5 h;	Preparation of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-li7-indole (1)1) The starting N-(4-benzyloxyphenyl)-α-amino-4-benzyloxypropiophenone (22) (30.4 g; 69.7 mmol) and 4-benzyloxyaniline hydrochloride (3.3 g; 13.9 mmol) were suspended in ethanol (380 ml) and the mixture was heated to 110-115⁰C under an inert atmosphere in a pressure vessel. After 5 hours the heating was disconnected and the reaction mixture was stirred overnight. The crystallized white product was filtered and washed with ethanol. 23.3 g (79percent) of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole (3b) with the melting temperature of 152.4-153.4°C were obtained. ¹H-NMR (DMSO) δ 10.65 (s, IH); 7.55 (d, 2H); 7.50 (d, <n="11"/>4H); 7.30-7.45 (m, 6H); 7.21(d, IH); 7.10 (d, 2H); 7.10 (d, IH); 6.91 (dd, IH); 5.16 (s, 2H); 5.11 (s, 2H); 2.33 (s, 3H). MS el m/z 419.

Reference： [1] Patent: WO2008/98527, 2008, A1, . Location in patent: Page/Page column 5; 8; 9; 12
[2] Patent: WO2008/98527, 2008, A1, . Location in patent: Page/Page column 5; 8-9

7
[ 6373-46-2 ]
[ 198479-63-9 ]

Reference： [1] Patent: US5880137, 1999, A,

8
[ 70-70-2 ]
[ 198479-63-9 ]

Reference： [1] Chemico-Biological Interactions, 2012, vol. 197, # 1, p. 8 - 15
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4075 - 4099
[3] Patent: CN105801564, 2016, A,
[4] Patent: US2018/72711, 2018, A1,

9
[ 4495-66-3 ]
[ 198479-63-9 ]

Reference： [1] Chemico-Biological Interactions, 2012, vol. 197, # 1, p. 8 - 15
[2] Patent: CN105801564, 2016, A,

10
[ 100-39-0 ]
[ 198479-63-9 ]

Reference： [1] Chemico-Biological Interactions, 2012, vol. 197, # 1, p. 8 - 15
[2] Patent: US2018/72711, 2018, A1,

11
[ 100-44-7 ]
[ 198479-63-9 ]

Reference： [1] Patent: CN105801564, 2016, A,
[2] Patent: CN105801564, 2016, A,

12
[ 35081-45-9 ]
[ 198479-63-9 ]

Reference： [1] Patent: CN105801564, 2016, A,

13
[ 100-02-7 ]
[ 198479-63-9 ]

Reference： [1] Patent: CN105801564, 2016, A,

14
[ 1145-76-2 ]
[ 198479-63-9 ]

Reference： [1] Patent: CN105801564, 2016, A,

[ 198479-63-9 ] Synthesis Path-Downstream 1~88

1
[ 35081-45-9 ]
[ 51388-20-6 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
94.6%	With triethylamine; In N,N-dimethyl-formamide; at 115℃; for 4h;	10 g of 4 '-benzyloxy-2-bromophenylacetone (II-a) 15 g of p-benzyloxyaniline hydrochloride (II-b), 50 mL of N, N-dimethylformamide and 8 mL of triethylamine at 115 C for 4 hours. The reaction solution was completely purified by thin layer chromatography (TLC). The reaction solution was poured into 250 mL of ice water to precipitate a solid. The crude product was stirred with 20 mL of methanol and dried at 40 C for 24 h to give 12.5 g of a yellowish brown solid product, 5-benzyloxy-2-[(4-benzyloxy)phenyl]-3-methyl-1H-indole (Intermediate II) in a yield of 94.6%
90.5%		2-bromo- (4-benzyloxyphenyl) acetone (12. 7 g, 0.04 mol)Benzyloxyaniline hydrochloride (11. lg, 0.04 mol) was added to n-butanol (120 ml)Triethylamine (12.2 ml) was added and the temperature was raised to 118 (after refluxing, 3 hours later,2_ bromo- (4-benzyloxyphenyl) acetone was completely reacted; concentrated hydrochloric acid (1. 0 ml) was added,The temperature was raised to 118 C for 7 hours.The reaction solution was cooled, suction filtered and dried to give a white solid 15. 2 g, HPLC purity: 98% yield 90.5%.
65.14%	With triethylamine; In N,N-dimethyl-formamide; at 100 - 125℃;	4'-Benzyloxy-2-bromophenylpropiophenone (50 g), 4-benzyloxyaniline hydrochloride (40.5 g), triethylamine (50 mL) and N,N-dimethylformamide (300 mL) are mixed and heated to about 1000C, and maintained at that temperature for 3-3.5 hours until reaction completion as verified using thin layer chromatography (TLC). The mixture is cooled to 50-550C and additional 4-benzyloxyaniline hydrochloride (40.5 g) is added and stirred. The temperature is raised to 120- 125C and maintained for 5-5.5 hours, with completion of the reaction verified using TLC. After completion of the reaction, the mixture is allowed to cool to room temperature, then the mixture is added to a solution of 5% acetic acid (1000 mL) in water, followed by mixing with ethyl acetate (2000 mL). The organic layer is separated and washed with 5% sodium bicarbonate solution (1000 mL) and brine solution (1000 mL). The organic layer is distilled completely under vacuum and the residue is cooled to 45C, then methanol (400 ml_) is added and the mixture is stirred for 1 -1.5 hours. The formed solid is filtered and washed with methanol (300 ml_), then dried under vacuum at 65C for 4 hours to afford the title compound in 65.14% yield.

With triethylamine; In N,N-dimethyl-formamide; at 120 - 150℃; for 4.66667h;

The bromoketone CAS No. [66414-19-5] (50.0 g, 0.16 mol) in 200 mL DMF was treated with the 4-benzyloxyaniline hydrochloride CAS No. [51145-58-5] (44 g, 0.22 mol) and the reaction purged with nitrogen for about 10 minutes. The triethylamine (54.6 mL) was added and the reaction was heated at 120C for 2 hours. TLC analysis (EtOAc/hexanes) shows the starting material disappeared forming a more polar spot. The reaction mixture was allowed to cool down and an additional 48 g of the aniline hydrochloride was added. The reaction was heated to 150C for 2 hours. An additional 5 grams of the aniline hydrochloride was added and the reaction was heated at 150C for an additional 30 minutes. The reaction mixture was allowed to cool to room temperature and then poured into approximately 1.5 liters of water and extracted with 2 liters of ethyl acetate. Solids are dissolved with additional ethyl acetate as necessary. The ethyl acetate layer is washed with 1 liter of 1 N NaOH solution aq., 1 liter of water, brine, then dried over magnesium sulfate and filtered. The organic layers were concentrated down to yield a crude solid which was stirred with 500 mL of methanol and filtered. This solid was then stirred with 500 mL of ethyl ether and filtered. The solid was stirred alternatively with methanol and ether until it is of whitish color. Reaction yields 36 g of product: Mp = 150-152C; 1H NMR (DMSO) delta 10.88 (s, 1 H), 7.56 (d, 2 H, J = 8.8 Hz), 7.48 (d, 4 H, J = 7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J = 7.0 Hz), 7.13 (d, 2 H, J = 8.8 Hz), 7.08 (d, 1 H, J = 2.2 Hz), 6.94 (dd, 1 H, J = 8.8, 2.4 Hz), 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419.

Reference： [1]Patent: CN106810487,2017,A .Location in patent: Paragraph 0078-0083; 0096; 0110; 0117
[2]Patent: CN104098499,2016,B .Location in patent: Paragraph 0035-0037
[3]Chemico-Biological Interactions,2012,vol. 197,p. 8 - 15
[4]Patent: WO2011/22596,2011,A2 .Location in patent: Page/Page column 4; 21; 22
[5]Journal of Medicinal Chemistry,2001,vol. 44,p. 1654 - 1657
[6]Patent: EP1212335,2006,B1 .Location in patent: Page/Page column 22-23

2
[ 80494-75-3 ]
[ 198479-63-9 ]
[ 198479-82-2 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1654 - 1657
[2]Chemico-Biological Interactions,2012,vol. 197,p. 8 - 15

3
[ 869006-43-9 ]
[ 198479-63-9 ]
[ 869006-49-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5124 - 5128

4
[ 869006-41-7 ]
[ 198479-63-9 ]
[ 869006-47-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5124 - 5128

5
[ 198479-63-9 ]
pipendoxifene [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1654 - 1657

6
[ 198479-63-9 ]
[ 198481-32-2 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1654 - 1657
[2]Patent: WO2011/22596,2011,A2
[3]Chemico-Biological Interactions,2012,vol. 197,p. 8 - 15

7
[ 198479-63-9 ]
[ 198479-95-7 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1654 - 1657
[2]Chemico-Biological Interactions,2012,vol. 197,p. 8 - 15

8
[ 198479-63-9 ]
[ 198480-07-8 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1654 - 1657
[2]Chemico-Biological Interactions,2012,vol. 197,p. 8 - 15

9
[ 198479-63-9 ]
[ 198480-20-5 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1654 - 1657

10
[ 198479-63-9 ]
[ 198480-21-6 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1654 - 1657
[2]Chemico-Biological Interactions,2012,vol. 197,p. 8 - 15

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 22 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole (39) The bromoketone CAS No. [66414-19-5] (50.0 g, 0.16 mol) in 200 mL DMF was treated with the 4-benzyloxyaniline hydrochloride CAS No. [51145-58-5] (44 g, 0.22 mol) and the reaction purged with nitrogen for about 10 minutes. The triethylamine (54.6 mL) was added and the reaction was heated at 120 C. for 2 hours. TLC analysis (EtOAc/hexanes) shows the starting material disappeared forming a more polar spot. The reaction mixture was allowed to cool down and an additional 48 g of the aniline hydrochloride was added. The reaction was heated to 150 C. for 2 hours. An additional 5 grams of the aniline hydrochloride was added and the reaction was heated at 150 C. for an additional 30 minutes. The reaction mixture was allowed to cool to room temperature and then poured into approximately 1.5 liters of water and extracted with 2 liters of ethyl acetate. Solids are dissolved with additional ethyl acetate as necessary. The ethyl acetate layer is washed with 1 liter of 1 N NaOH solution aq., 1 liter of water, brine, then dried over magnesium sulfate and filtered. The organic layers were concentrated down to yield a crude solid which was stirred with 500 mL of methanol and filtered. This solid was then stirred with 500 mL of ethyl ether and filtered. The solid was stirred alternatively with methanol and ether until it is of whitish color. Reaction yields 36 g of product: Mp=150-152 C.; 1H NMR (DMSO) delta 10.88 (s, 1 H), 7.56 (d, 2 H, J=8.8 Hz), 7.48 (d, 4 H, J=7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J=7.0 Hz), 7.13 (d, 2 H, J=8.8 Hz), 7.08 (d, 1 H, J=2.2 Hz), 6.94 (dd, 1 H, J=8.8, 2.4 Hz), 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419.
		When this reaction is complete, the mixture can be quenched with water. The resulting precipitate can be collected, washed with dilute acetic acid, water and heptane, and dried. STR38 The 4'-(benzyloxy)-2-bromopropiophenone product of Scheme X can be heated with 4-benzyloxyaniline hydrochloride in the presence of N,N-diisopropylethylamine and toluene under reflux with the azeotropic removal of water, as shown in Scheme XI. When the reaction is complete, the mixture can be cooled and diluted with methanol. The resulting solids of 3-methyl-2-(4-benzyloxy)phenyl-5-benzyloxyindole can be collected, washed with methanol and dried. STR39

12
4'-benzyloxy-2-bromophenylpropiophenone [ No CAS ]
[ 6373-46-2 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
33%	In dichloromethane; ethyl acetate; N,N-dimethyl-formamide;	EXAMPLE 1 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole A flask was charged with 4-benzyloxyaniline (45 g, 0.23 mol), 4'-benzyloxy-2-bromophenylpropiophenone (21 g, 0.066 mol), and DMF (50 mL). The reaction was heated at reflux for 30 minutes and then cooled to rt and then partitioned between EtOAc (250 mL) and 1N HCl (aq) (100 mL). The EtOAc was washed with NaHCO3 (aq) and brine, dried over MgSO4. The solution was concentrated and the residue taken up in CH2Cl2 and hexanes added to precipitate out 25 g of a crude solid. The solid was dissolved in CH2Cl2 and evaporated onto silica gel and chromatographed using CH2Cl2/Hexane (1:5) to yield 9.2 g of a tan solid (33%): Mpt=150-152 C.; 1H NMR (DMSO) 10.88 (s, 1 H), 7.56 (d, 2 H, J=8.8 Hz), 7.48 (d, 4 H, J=7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J=7.0 Hz), 7.13 (d, 2 H, J=8.8 Hz), 7.08 (d, 1 H, J=2.2 Hz), 6.94 (dd, 1 H, J=8.8, 2.4 Hz), 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419.
33%	In dichloromethane; ethyl acetate; N,N-dimethyl-formamide;	EXAMPLE 1 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole A flask was charged with 4-benzyloxyaniline (45 g, 0.23 mol), 4'-benzyloxy-2-bromophenylpropiophenone (21 g, 0.066 mol), and DMF (50 mL). The reaction was heated at reflux for 30 minutes and then cooled to rt and then partitioned between EtOAc (250 mL) and 1 N HCl (aq) (100 mL). The EtOAc was washed with NaHCO3 (aq) and brine, dried over MgSO4. The solution was concentrated and the residue taken up in CH2 Cl2 and hexanes added to precipitate out 25 g of a crude solid. The solid was dissolved in CH2 Cl2 and evaporated onto silica gel and chromatographed using CH2 Cl2 /Hexane (1:5) to yield 9.2 g of a tan solid (33%): Mpt=150-152 C.; 1 H NMR (DMSO) 10.88 (s, 1 H), 7.56 (d, 2 H, J=8.8 Hz), 7.48 (d, 4 H, J=7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J=7.0 Hz), 7.13 (d, 2 H, J=8.8 Hz), 7.08 (d, 1 H, J=2.2 Hz), 6.94 (dd, 1 H, J=8.8, 2.4 Hz), 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419.
33%	In dichloromethane; ethyl acetate; N,N-dimethyl-formamide;	EXAMPLE 14 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole STR40 A flask was charged with 4-benzyloxyaniline (45 g, 0.23 mol), 4'-benzyloxy-2-bromophenylpropiophenone (66414-19-5) (21g, 0.066 mol), and 50 mL DMF. The reaction was heated at reflux for 30 minutes and then cooled to rt and then partitioned between 250 mL EtOAc and 100 mL 1N HCl (aq). The EtOAc was washed with NaHCO3 (aq) and brine, dried over MgSO4. The solution was concentrated and the residue taken up in CH2 Cl2 and hexanes added to precipitate out 25 g of a crude solid. The solid was dissolved in CH2 Cl2 and evaporated onto silica gel and chromatographed using CH2 Cl2 /Hexane (1:5) to yield 9.2 g of a tan solid (33%): Mpt=150-152 C.; 1 H NMR (DMSO) 10.88 (s, 1 H), 7.56 (d, 2 H, J=8.8 Hz), 7.48 (d, 4 H, J=7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J=7.0 Hz), 7.13 (d, 2 H, J=8.8 Hz), 7.08 (d, 1 H, J=2.2 Hz), 6.94 (dd, 1 H, J=8.8, 2.4 Hz), 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419.

33%	In dichloromethane; ethyl acetate; N,N-dimethyl-formamide;	EXAMPLE 1 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole A flask was charged with 4-benzyloxyaniline (45 g, 0.23 mol), 4'-benzyloxy-2-bromophenylpropiophenone (21 g, 0.066 mol), and DMF (50 mL). The reaction was heated at reflux for 30 minutes and then cooled to rt and then partitioned between EtOAc (250 mL) and 1N HCl (aq) (100 mL). The EtOAc was washed with NaHCO3 (aq) and brine, dried over MgSO4. The solution was concentrated and the residue taken up in CH2 Cl2 and hexanes added to precipitate out 25 g of a crude solid. The solid was dissolved in CH2 Cl2 and evaporated onto silica gel and chromatographed using CH2 Cl2 /Hexane (1:5) to yield 9.2 g of a tan solid (33%): Mpt=150-152 C.; 1 H NMR (DMSO) 10.88 (s, 1H), 7.56 (d, 2H, J=8.8 Hz), 7.48 (d, 4H, J=7.9 Hz), 7.42-7.29 (m, 6H), 7.21 (d, 1H, J=7.0 Hz), 7.13 (d, 2H, J=8.8 Hz), 7.08 (d, 1H, J=2.2 Hz), 6.94 (dd, 1H, J=8.8, 2.4 Hz), 5.16 (s, 2H), 5.11 (s, 2H), 2.33 (s, 3H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419.
33%	In hydrogenchloride; CH2Cl2and; ethyl acetate; N,N-dimethyl-formamide;	EXAMPLE 1 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole A flask was charged with 4-benzyloxyaniline (45 g, 0.23 mol), 4'-benzyloxy-2-bromophenylpropiophenone (21g, 0.066 mol), and DMF (50 mL). The reaction was heated at reflux for 30 minutes and then cooled to rt and then partitioned between EtOAc (250 mL) and IN HCl (aq) (100 mL). The EtOAc was washed with NaHCO3(aq) and brine, dried over MgSO4. The solution was concentrated and the residue taken up in CH2Cl2and hexanes added to precipitate out 25g of a crude solid. The solid was dissolved in CH2Cl2and evaporated onto silica gel and chromatographed using CH2Cl2/Hexane (1:5) to yield 9.2 g of a tan solid (33%): Mpt = 150-152C; 1H NMR (DMSO) 10.88 (s, 1 H), 7.56 (d, 2 H, J = 8.8 Hz), 7.48 (d, 4 H, J = 7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J = 7.0 Hz), 7.13 (d, 2 H, J = 8.8 Hz), 7.08 (d, 1 H, J = 2.2 Hz), 6.94 (dd, 1 H, J = 8.8, 2.4 Hz), 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419.
33%	In CH2Cl2and; ethyl acetate; N,N-dimethyl-formamide;	EXAMPLE 18 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole A flask was charged with 4-benzyloxyaniline (45 g, 0.23 mol), 4'-benzyloxy-2-bromophenylpropiophenone (21g, 0.066 mol), and DMF (50 mL). The reaction was heated at reflux for 30 minutes and then cooled to rt and then partitioned between EtOAc (250 mL) and 1N HCl (aq) (100 mL). The EtOAc was washed with NaHCO3(aq) and brine, dried over MgSO4. The solution was concentrated and the residue taken up in CH2Cl2and hexanes added to precipitate out 25g of a crude solid. The solid was dissolved in CH2Cl2and evaporated onto silica gel and chromatographed using CH2Cl2/Hexane (1:5) to yield 9.2 g of a tan solid (33%): Mpt = 150-152C; 1H NMR (DMSO) 10.88 (s, 1 H), 7.56 (d, 2 H, J = 8.8 Hz), 7.48 (d, 4 H, J = 7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J = 7.0 Hz), 7.13 (d, 2 H, J = 8.8 Hz), 7.08 (d, 1 H, J = 2.2 Hz), 6.94 (dd, 1 H, J = 8.8, 2.4 Hz), 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419.

Reference： [1]Patent: US6583170,2003,B1
[2]Patent: US5985910,1999,A
[3]Patent: US6005102,1999,A
[4]Patent: US5780497,1998,A
[5]Patent: EP802184,1997,A1
[6]Patent: EP802184,1997,A1

13
[ 198479-63-9 ]
[ 198479-82-2 ]

Yield	Reaction Conditions	Operation in experiment
	In ethyl acetate; N,N-dimethyl-formamide;	{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-acetic Acid Ethyl Ester A solution of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole (indole example No. 7) (32 g, 77 mmol) in DMF (0.15 L) was cooled to 0 C. and treated with sodium hydride (2.2 g, 89 mmol). The reaction was stirred for 20 minutes and then the benzyl chloride CAS No. (80494-75-3] (29 g, 127 mmol) was added and the reaction stirred for 18 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was washed with brine and dried over magnesium sulfate. The ethyl acetate was concentrated and triturated with ether to obtain 21 g of a white solid. The filtrate was concentrated and triturated with ether to give an additional 7 g of white solid for a total yield of 28 g: Mp=129-131 C.; 1H NMR (DMSO) 7.47 (d, 4H, J=7.2 Hz), 7.39 (q, 4H, J=7.9 Hz), 7.36-7.32 (m, 1H), 7.29 (d, 2H, J=8.8 Hz), 7.19 (d, 1H, J=9.0 Hz), 7.13-7.09 (m, 4H), 6.80 (dd, 1H, J=8.8, 2.4 Hz), 6.73 (s, 4H), 5.16 (s, 2H), 5.13 (s, 2H), 5.11 (s, 2H), 4.66 (s, 2H), 4.11 (q, 2H, J=7.2 Hz), 2.15 (s, 3H), 1.16 (t, 3H, J=7.2 Hz); MS eI m/z 612.
	In ethyl acetate; N,N-dimethyl-formamide;	{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-acetic acid ethyl ester A solution of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole (indole example No. 7) (32 g, 77 mmol) in DMF (0.15 L) was cooled to 0 C. and treated with sodium hydride (2.2 g, 89 mmol). The reaction was stirred for 20 minutes and then the benzyl chloride CAS No. [80494-75-3] (29 g, 127 mmol) was added and the reaction stirred for 18 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was washed with brine and dried over magnesium sulfate. The ethyl acetate was concentrated and triturated with ether to obtain 21 g of a white solid. The filtrate was concentrated and triturated with ether to give an additional 7 g of white solid for a total yield of 28 g: Mp=129-131 C.; 1 H NMR (DMSO) 7.47 (d, 4H, J=7.2 Hz), 7.39 (q, 4H, J=7.9 Hz), 7.36-7.32 (m, 1H), 7.29 (d, 2H, J=8.8 Hz), 7.19 (d, 1H, J=9.0 Hz), 7.13-7.09 (m, 4H), 6.80 (dd, 1H, J=8.8, 2.4 Hz), 6.73 (s, 4H), 5.16 (s, 2H), 5.13 (s, 2H), 5.11 (s, 2H), 4.66 (s, 2H), 4.11 (q, 2H, J=7.2 Hz), 2.15 (s, 3H), 1.16 (t, 3H, J=7.2 Hz); MS eI m/z 612.
	In ethyl acetate; N,N-dimethyl-formamide;	{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-acetic acid ethyl ester A solution of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole (indole example No. 7) (32g, 77 mmol) in DMF (0.15 L) was cooled to 0C and treated with sodium hydride (2.2 g, 89 mmol). The reaction was stirred for 20 minutes and then the benzyl chloride CAS No. [80494-75-3] (29g, 127 mmol) was added and the reaction stirred for 18 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was washed with brine and dried over magnesium sulfate. The ethyl acetate was concentrated and triturated with ether to obtain 21 g of a white solid. The filtrate was concentrated and triturated with ether to give an additional 7 g of white solid for a total yield of 28 g: Mp = 129-131C; 1H NMR (DMSO) 7.47 (d, 4 H, J = 7.2 Hz), 7.39 (q, 4 H, J = 7.9 Hz), 7.36-7.32 (m, 1 H), 7.29 (d, 2 H, J = 8.8 Hz), 7.19 (d, 1 H, J = 9.0 Hz), 7.13-7.09 (m, 4 H), 6.80 (dd, 1 H, J = 8.8, 2.4 Hz), 6.73 (s, 4 H), 5.16 (s, 2 H), 5.13 (s, 2 H), 5.11 (s, 2 H), 4.66 (s, 2 H), 4.11 (q, 2 H, J = 7.2 Hz), 2.15 (s, 3 H), 1.16 (t, 3 H, J = 7.2 Hz); MS eI m/z 612.

Reference： [1]Patent: US6479535,2002,B1
[2]Patent: US5998402,1999,A
[3]Patent: EP1076558,2003,B1

14
[ 198481-40-2 ]
[ 198479-63-9 ]
[ 198481-21-9 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; ethyl acetate; N,N-dimethyl-formamide;	5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-chloro-propoxy)-benzyl]-3-methyl-1H-indole A solution consisting of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole No. 7 (6.5 g, 15.5 mmol) in DMF (60 mL) was cooled to 0 C. and treated with addition of sodium hydride (0.68 g, 17.0 mmol) and stirred for 20 minutes. A solution of 4-(3-chloropropoxy)-benzyl bromide No. 163 in DMF (10 mL) was then added slowly. The reaction was allowed to come to rt and stirred for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The ethyl acetate was washed with water, brine and dried over magnesium sulfate and concentrated. The concentrate was treated with methanol and 5 g of the desired product precipitated as a white solid with a melting point of 130-132 C.

Reference： [1]Patent: US5998402,1999,A

15
4-benzyloxy-2-bromophenylpropiophenone [ No CAS ]
[ 6373-46-2 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
33%	In dichloromethane; ethyl acetate; N,N-dimethyl-formamide;	EXAMPLE 1 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole A flask was charged with 4-benzyloxyaniline (45 g, 0.23 mol), 4-benzyloxy-2-bromophenylpropiophenone (21 g, 0.066 mol), and DMF (50 mL). The reaction was heated at reflux for 30 minutes and then cooled to rt and then partitioned between EtOAc (250 mL) and 1N HCl (aq) (100 mL). The EtOAc was washed with NaHCO3 (aq) and brine, dried over MgSO4. The solution was concentrated and the residue taken up in CH2 Cl2 and hexanes added to precipitate out 25 g of a crude solid. The solid was dissolved in CH2 Cl2 and evaporated onto silica gel and chromatographed using CH2 Cl2 /Hexane (1:5) to yield 9.2 g of a tan solid (33%): Mpt=150-152 C.; 1 H NMR (DMSO) 10.88 (s, 1 H), 7.56 (d, 2 H, J=8.8 Hz), 7.48 (d, 4 H, J=7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J=7.0 Hz), 7.13 (d, 2 H, J=8.8 Hz), 7.08 (d, 1 H, J=2.2 Hz), 6.94 (dd, 1 H, J=8.8, 2.4 Hz), 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419.

Reference： [1]Patent: US5880137,1999,A

16
[ 1048697-94-4 ]
[ 51388-20-6 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	In isopropyl alcohol; at 110 - 115℃; for 5h;Product distribution / selectivity;	2) The starting iV-(4-benzyloxyphenyl)-alpha-amino-4-benzyloxypropiophenone (22) (30.4 g; 69.7 mmol) and 4-benzyloxyaniline hydrochloride (3.3 g; 13.9 mmol) were suspended in propan-2- ol (380 ml) and the mixture was heated up to 110-115C under an inert atmosphere in a pressure vessel. After 5 hours the heating was disconnected and the reaction mixture was stirred overnight. The crystallized beige product was filtered and washed with a small quantity of propan-2-ol. 24.2 g (82 %) of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole (3b) with the melting temperature of 152.0-153.2C were obtained.
79%	In ethanol; at 110 - 115℃; for 5h;Product distribution / selectivity;	Preparation of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-li7-indole (1)1) The starting N-(4-benzyloxyphenyl)-alpha-amino-4-benzyloxypropiophenone (22) (30.4 g; 69.7 mmol) and 4-benzyloxyaniline hydrochloride (3.3 g; 13.9 mmol) were suspended in ethanol (380 ml) and the mixture was heated to 110-1150C under an inert atmosphere in a pressure vessel. After 5 hours the heating was disconnected and the reaction mixture was stirred overnight. The crystallized white product was filtered and washed with ethanol. 23.3 g (79%) of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole (3b) with the melting temperature of 152.4-153.4C were obtained. 1H-NMR (DMSO) delta 10.65 (s, IH); 7.55 (d, 2H); 7.50 (d, <n="11"/>4H); 7.30-7.45 (m, 6H); 7.21(d, IH); 7.10 (d, 2H); 7.10 (d, IH); 6.91 (dd, IH); 5.16 (s, 2H); 5.11 (s, 2H); 2.33 (s, 3H). MS el m/z 419.

Reference： [1]Patent: WO2008/98527,2008,A1 .Location in patent: Page/Page column 5; 8; 9; 12
[2]Patent: WO2008/98527,2008,A1 .Location in patent: Page/Page column 5; 8-9

17
[ 223251-25-0 ]
[ 198479-63-9 ]
[ 198480-21-6 ]

Yield	Reaction Conditions	Operation in experiment
93.7%	With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 10h;	Weigh 3g of 60% NaH, 5-benzyloxy-2-[(4-benzyloxy) phenyl]-3-methyl-111-indole (Intermediate II), 7 g of 1-[2-(4-(chloromethyl)phenoxy)ethyl] azepane hydrochloride (II-c) and 100 mL of N, N-dimethylformamide were stirred at room temperature for 10 h. , And 100 mL of purified water was added dropwise to the filtrate, stirred for 1 h, filtered and wetted with 40 (vacuum drying 241 To give white product 11.68, 1- (4- (2- Yl) ethoxy) benzyl) -5- (benzyloxy) -2- (4- (benzyloxy) phenyl) -3-methyl-1H-indole (Intermediate III) 93.7%
91.8%		In a 1000-L reactor, 90 kg of DMSO was added, and 30 kg of 5-(benzyloxy)-2-(4-(benzyloxy) was added at room temperature.Phenyl)-3-methyl-1H-indole was stirred until dissolution, 50 kg sodium hydroxide solids and 12 kg water were added,After activation for 1 h, a solution of compound 4 in DMSO (24 kg of compound 4 dissolved in 210 kg DMF) was added,After reacting for 1 hour at room temperature, the reaction is completed, 600 kg of purified water is added, and the crystals are stirred for 8 hours, filtered, and dried.This gave 42.8 kg of an off-white solid, yield: 91.8%, HPLC purity: 99.5%. .
82.6%	With sodium hydride; In N,N-dimethyl acetamide; at 0 - 10℃; for 0.5h;Large scale;	60% sodium hydride (6.0 Kg; 0.15 moles) and N,N-dimethylacetamide (10.0 Kg) are loaded into a neutralised reactor. The temperature is adjusted to 0-10 C., and a separately prepared solution of 3-methyl-5-(benzyloxy)-2-(4-benzyloxyphenyl)-1H-indole (25.0 Kg, 0.0596 moles) and N,N-dimethylacetamide (37.5 Kg) is dripped in. A solution prepared separately by dissolving 1-{2-[4-(chloromethyl)phenoxy]ethyl}hexahydro-1H-azepine hydrochloride (20.0 Kg; 0.0657 moles) and N,N-dimethylacetamide is then poured in. After pouring, the mass is maintained at 0-10 C. for 30 min, and toluene (50 Kg) and water are then added. The mass is heated to 70 C., and the lower aqueous phase is then separated and eliminated. Methanol (175 Kg) is added, and the mixture is cooled to 20-25 C. and centrifuged, washing with methanol (50 Kg). After drying, about 32.0 kg of 1-{4-[2-(azepan-1-yl)ethoxy]benzyl}-5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indole is obtained. Yield: 82.6%.

80.5%		Example 1 Preparation of 1-[4-(2-azepan-1-yl-ethoxy)benzyl]-2-(4-benzyloxyphenyl)-5-benzyloxy-3-methyl-1H-indole (benzylated bazedoxifene) In an inert atmosphere NaH (2.7 g; 112 mmol) was suspended in DMF (80 ml). At 0-5 C. <strong>[198479-63-9]5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole</strong> (11 g; 26 mmol) was added and the suspension was stirred for 30 minutes. Then a solution of 4-(2-azepan-1-yl-ethoxy)benzyl chloride (8 g; 26 mmol) in DMF (30 ml) was added dropwise within 1 hour. The cooling was shut down and the reaction mixture was stirred for another 2.5 hours. Then, water (1.2 ml) was carefully added dropwise to the reaction mixture and the reaction mixture was filtered through a thin layer of celite. Another 35 ml of water were added dropwise to the brightly yellow filtrate under intensive stirring. The separated white product was filtered and washed with methanol. The yield of the crude product was 13.7 g (81%). The crude product was dissolved in 70 ml of ethyl acetate with a small quantity of activated charcoal and filtered while hot. 100 ml of methanol were added to the filtrate. The yield of crystallization was 80.5%. Melt. point=109-112 C. HPLC content 99.8%.
76%		To a slurry of NaH (20.0 g, 60% oil dispersion, 0.5 mol, 2.5 eq.) solution of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole (84 g, 0.2 mol, 1.0 eq.) in DMF (100 mL) was added at 0 / + 10 C over 1 h. The reaction mixture was stirred for 30 min. A solution of the benzylchloride (synthesis shown in scheme 7 and details given in the following experimental) (67 g, 0.22 mol, 1.1 eq.) in DMF (200 mL) was added dropwise at 0 / + 10 C over 2 h. The reaction mixture was stirred at 25C for 2 h. TLC at this point showed no starting material, mostly product (EtOAc/hexane 1:5). The reaction mixture was diluted with water (1 L), extracted with EtOAc (3 x 1L), and dried over MgSO4. The solution was concentrated to 150 mL, poured in MeOH (750 mL), and stirred overnight. The precipitate was filtered and dried to give the title compound (99 g, 76 %): Mp = 106 - 107C; 1H NMR (DMSO) delta 7.47 (d, 4 H, J = 8.3 Hz), 7.41 - 7.36 (m, 4 H), 7.36 - 7.30 (m, 2 H), 7.29 (d, 2 H, J = 8.8 Hz), 7.19 (d, 1 H, J = 8.8 Hz), 7.14 - 7.10 (m, 3 H), 6.80 (dd, 1 H, J = 8.8 Hz), 6.73 (s, 4 H), 5.15 (s, 2 H), 5.13 (s, 2 H), 5.11 (s, 2 H), 3.90 (t, 2 H, J = 5.9 Hz), 2.76 (t, 2 H, J = 5.9 Hz), 2.64 - 2.56 (m, 4 H), 2.15 (s, 3 H), 1.58 - 1.44 (m, 8 H); MS FAB m/z 651 (M+H+).
		To a chilled mixture of sodium hydride (2.28 g) in N,N-dimethylformamide(10 mL) and toluene (10 mL), a solution of 5-benzyloxy-2-(4-benzyloxy-phenyl)-3- methyl-1 H-indole (10 g) in N,N-dimethylformamide (20 mL) is added at -5 to -1 C. The mixture is stirred for 30-45 minutes at the same temperature and then a solution of 1 -[2-(4-chloromethyl-phenoxy)-ethyl]-azepane hydrochloride (7.97 g) in N,N-dimethylfor?nannide (50 mL) is added over 30 minutes, below 5C. The mixture is stirred at or below 5C for -2-3 hours and reaction progress is monitored using TLC. Acetic acid (0.8 mL) is added, followed by addition of ethyl acetate (100 mL) and water (100 mL). The mixture is filtered and the aqueous layer is extracted with ethyl acetate (100 mL, then 50 mL). The combined organic layer is washed with 10% brine solution (2*100 mL). The organic layer is separated and distilled under vacuum at 500C to form a residue. Methanol (120 mL) is added to the residue and the mixture is stirred for 30 minutes at 25-300C. The solid is filtered and washed with methanol (40 mL). Methanol (90 mL) is added and the mixture is stirred for 30 minutes at 25-30C, the solid is filtered and washed with methanol (50 mL). The solid is dried under vacuum at 500C for -1.5 hours, to afford the title compound.

Reference： [1]Patent: CN106810487,2017,A .Location in patent: Paragraph 0078-0080; 0086; 0087; 0098; 0112; 0119
[2]Patent: CN107793344,2018,A .Location in patent: Paragraph 0016; 0023; 0052-0057
[3]Patent: US2019/389842,2019,A1 .Location in patent: Paragraph 0080
[4]Patent: US2010/240888,2010,A1 .Location in patent: Page/Page column 3
[5]Patent: EP1212335,2006,B1 .Location in patent: Page/Page column 23
[6]Patent: WO2011/22596,2011,A2 .Location in patent: Page/Page column 4; 24; 25

18
[ 5457-30-7 ]
[ 198479-63-9 ]
[ 1165802-14-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 485 - 488

19
[ 198479-63-9 ]
[ 1124291-88-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 485 - 488

20
[ 198479-63-9 ]
[ 1165802-20-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 485 - 488

21
[ 198479-63-9 ]
[ 1124291-89-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 485 - 488

22
[ 198479-63-9 ]
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol hydrochloride [ No CAS ]

Reference： [1]Patent: WO2011/22596,2011,A2
[2]Patent: WO2011/22596,2011,A2

23
[ 198479-63-9 ]
bazedoxifene acetate [ No CAS ]

Reference： [1]Patent: WO2011/22596,2011,A2
[2]Patent: WO2011/22596,2011,A2
[3]Patent: WO2011/22596,2011,A2

24
[ 198479-63-9 ]
[ 1266685-11-3 ]

Reference： [1]Patent: WO2011/22596,2011,A2

25
[ 198479-63-9 ]
[ 1266685-12-4 ]

Reference： [1]Patent: WO2011/22596,2011,A2

26
[ 4495-66-3 ]
[ 52068-30-1 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With acetic acid; In ethanol; at 75 - 80℃;Product distribution / selectivity;	Example-24-Benzyloxy phenyl hydrazine hydrochloride (10 g, 40 mmol), 4-benzyloxy propiophenone (9.6 g, 40 mmol) and acetic acid (0.1 ml, 1.7 mmol) were suspended in 140 ml of ethanol and the mixture was refluxed for 12 hrs at a temperature of 75-80° C.During said period the product precipitates.After cooling the mixture at 10-15° C. the crystallized product was isolated by filtration and washed with chilled ethanol (30 ml) and water (50 ml).5-Benzyloxy-2-(4-benzyloxy)-3-methyl-1H-indole melting at 152-153° C. was obtained in a yield of 15.7 g (94percent).1H-NMR (DMSO) delta 10.65 (s, 1H); 7.55 (d, 2H); 7.50 (d, 4H); 7.30-7.45 (m, 6H); 7.21 (d, 1H); 7.10 (d, 1H); 7.10 (d, 1H); 6.91 (dd, 1H); 5.16 (s, 2H); 5.11 (s, 2H); 2.33 (s, 3H)
94%	acetic acid; In ethanol; at 75 - 80℃; for 12h;Product distribution / selectivity;	Example-24-Benzyloxy phenyl hydrazine hydrochloride (10 g, 40 mmol), 4-benzyloxy propiophenone (9.6 g, 40 mmol) and acetic acid (0.1 ml, 1.7 mmol) were suspended in 140 ml of ethanol and the mixture was refluxed for 12 hrs at the temperature of 75 to 80°C.During said period the product precipitates.After cooling the mixture at 10 to 15°C the crystallized product was isolated by filtration and washed with chilled ethanol (30 ml) and water (50 ml).5-Benzyloxy-2-(4-benzyloxy)-3-methyl-1H-indole melting at 152 to 153°C was obtained in a yield of 15.7 g (94percent).1H-NMR (DMSO) delta 10.65 (s, 1H); 7.55 (d, 2H); 7.50(d, 4H); 7.30-7.45(m, 6H); 7.21(d, 1H); 7.10(d, 1H); 7.10(d, 1H); 6.91(dd, 1H); 5.16(s, 2H); 5.11(s, 2H); 2.33(s, 3H)
84%	With hydrogenchloride; In ethanol; for 2h;Reflux;	1-(4-(Benzyloxy)phenyl)propan-1-one (2) (1.9 g, 8.0 mmol) and1-(4-(benzyloxy)phenyl)hydrazine hydrochloride (4) (2.0 g,8.0 mmol) were dissolved in EtOH (50 mL) and 5 drops of conc.HCl was added and the mixture was refluxed for 2 h. The reaction mixture was then allowed to cool and was stirred for 1 h. The mixturewas filtered to afford an pale pink solid. The solid was washedwith cold EtOH (10 mL) followed by n-hexane (20 mL). (2.8 g, 84percent).Mp: 149?152 C.50 IR: mmax (KBr) cm1: 3470 (N?H), 2880, 2820,1620 (CC). 1H NMR (CDCl3, 400 MHz) d 7.86 (br s, 1H, NH),7.48?7.58 (m, 6H, Ar-H), 7.33?7.47 (m, 6H, Ar-H), 7.25?7.31 (m,1H, Ar-H), 7.14?7.18 (m, 1H, Ar-H), 7.07?7.13 (m, 2H, Ar-H), 6.97(d, J = 7.53 Hz, 1H, Ar-H), 5.18 (s, 2H, CH2), 5.15 (s, 2H CH2), 2.43(s, 3H, CH3) 13C NMR (CDCl3, 100 MHz) d 157.7 (BnO?C), 157.3(BnO?C), 143.6 (Ar-C?CH2), 137.3 (Cq), 136.3 (Cq), 136.0 (Cq),129.9 (ArC), 128.5 (ArC), 128.2 (ArC), 128.2 (ArC), 127.7 (ArC),127.6 (Ar-C), 127.1 (ArC), 120.4 (ArC), 114.7 (ArC), 114.6 (ArC),114.3 (ArC), 112.2 (Cq), 110.8 (CC), 108.8 (ArC), 102.0 (ArC),70.0 (CH2), 69.6 (CH2), 9.3 (CH3). HRMS (EI): Found 442.1797 (M+Na)+, C29H25NNaO2 requires 442.1783.

Reference： [1]Patent: US7968732,2011,B1 .Location in patent: Page/Page column 3-4
[2]Patent: EP2426105,2012,A1 .Location in patent: Page/Page column 3-4
[3]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 4075 - 4099

27
[ 4495-66-3 ]
[ 198479-63-9 ]

Reference： [1]Chemico-Biological Interactions,2012,vol. 197,p. 8 - 15
[2]Patent: CN105801564,2016,A
[3]Patent: US2019/389842,2019,A1

28
[ 100-39-0 ]
[ 198479-63-9 ]

Reference： [1]Chemico-Biological Interactions,2012,vol. 197,p. 8 - 15
[2]Patent: US2018/72711,2018,A1

29
[ 198479-63-9 ]
[ 91444-54-1 ]

Reference： [1]Chemico-Biological Interactions,2012,vol. 197,p. 8 - 15
[2]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 4075 - 4099
[3]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 4075 - 4099
[4]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 4075 - 4099

30
[ 70-70-2 ]
[ 198479-63-9 ]

Reference： [1]Chemico-Biological Interactions,2012,vol. 197,p. 8 - 15
[2]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 4075 - 4099
[3]Patent: CN105801564,2016,A
[4]Patent: US2018/72711,2018,A1
[5]Patent: US2019/389842,2019,A1

31
[ 112772-83-5 ]
[ 198479-63-9 ]
[ 1251936-40-9 ]

Yield	Reaction Conditions	Operation in experiment
80%		2-substituted indole derivative (Formula IV) (80 g g, 0.19 mole) was dissolved in N,N-dimethyl formamide (DMF) (400 ml), cooled to 10-15 C. Sodamide (22.4 g, 0.57 moles) was added and stirred for 15 min. (4-chloromethyl phenoxy)acetonitrile (Formula III) of example 2 (44 g, 0.24 mole) in DMF (160 ml) was added drop wise completion, and stirred for 2-3 h at 10-15 C. (TLC, 30% EtOAc-hexane-absence of starting material). After reaction was quenched with ice-cold water (1400 ml), extracted with toluene (800 ml) and aqueous layer extracted with toluene (200 ml). Combined toluene layers were washed with saturated brine solution (2150 ml) and Toluene was recovered under vacuum to get an off-white material. It was suspended in 800 ml Methanol and stirred for 1 hour at room temperature and filtered, washed with methanol 100 ml2 and dried under vacuum to get an off white intermediate (Formula V). (84 g, Yield: 80%) HPLC Purity: 95.1% 1H NMR (CDCl3) delta 2.24 (s, 3H), 4.70 (s, 2H), 5.10 (s, 2H), 5.12 (s, 2H), 5.13 (s, 2H), 6.82 (d, 2H, J=4 Hz), 6.90 (m, 3H), 7.03 (m, 4H), 7.14 (d, 1H, J=4 Hz), 7.21 (m, 2H), 7.22-7.50 (m, 9H). MS (ESI) 565.5 (M+1)+.

Reference： [1]Patent: US2012/253038,2012,A1 .Location in patent: Page/Page column 7

32
[ 1343413-04-6 ]
[ 198479-63-9 ]
C₄₅H₄₁NO₆S [ No CAS ]
[ 1343413-11-5 ]

Yield	Reaction Conditions	Operation in experiment
60%		Example 10 Preparation of 2-(4-[5-(benzyloxy)-2-[4-(benzyloxy)phenyl]-3-methyl-1H-indol-1-yl]methyl}phenoxy)ethyl-4-methylbenzenzene-1-sulfonate (formula 2a) A solution of <strong>[198479-63-9]5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole</strong> of formula 3 (25 g, 59.6 mmol) in dimethyl formamide (DMF, 100 ml) was cooled to -10 to -5 C. and treated with sodium hydride (4.8 g, 120 mmol). Reaction mixture was stirred for 30 min and then 2-(4-bromomethyl)phenoxy ethyl-4-methyl benzene sulfonate of formula 18a (27.5 g, 71.5 mmol) in DMF (100 ml) was added and stirred for 3 hrs at -5 to 0 C. The reaction mixture was quenched with acetic acid, poured into water (200 ml) and extracted with dichloromethane (2*200 ml). The dichloromethane layer was separated and washed with water (200 ml) and brine (100 ml), dried over MgSO4 and concentrated under vacuum to afford the crude material. This was found to contain 25-30% of C-alkyl impurity of formula-24. The crude material was dissolved in 150 ml of methanol-ethyl acetate mixture (5:2) at 50 C. and stirred for 30 min at ambient temperature. A white precipitate fell out of solution almost immediately. The precipitate was filtered, washed with 50 ml methanol and dried under vacuum to give 25.8 g (60%) of 2a as a white solid. M.R: 147-149 C. Purity by HPLC: 98% (Area) H1-NMR (CDCl3): delta 7.77 (d, 2H); 7.50-7.29 (m, 12H); 7.20 (d, 2H); 7.13 (d, 1H); 7.06-6.93 (m, 3H); 6.89 (dd, 1H); 6.80 (d, 2H); 6.61 (d, 2H); 5.13 (s, 2H); 5.09 (s, 4H); 4.30 (t, 2H); 4.05 (t, 2H); 2.41 (s, 3H), 2.24 (s, 3H)

Reference： [1]Patent: US2012/330008,2012,A1 .Location in patent: Page/Page column 8-9

33
[ 110-52-1 ]
[ 198479-63-9 ]
5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-1-(4-bromobutyl)-3-methyl-1H-indole [ No CAS ]
6-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-(4-bromobutyl)-3-methyl-3H-indole [ No CAS ]
1,4-bis(5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)butane [ No CAS ]