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Chemical Structure| 198479-63-9

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Product Details of [ 198479-63-9 ]

CAS No. :198479-63-9
Formula : C29H25NO2
M.W : 419.51
SMILES Code : CC1=C(C2=CC=C(OCC3=CC=CC=C3)C=C2)NC4=C1C=C(OCC5=CC=CC=C5)C=C4
MDL No. :MFCD04004106
InChI Key :KRIJKJMYOVWRSJ-UHFFFAOYSA-N
Pubchem ID :3824745

Safety of [ 198479-63-9 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H317
Precautionary Statements:P280

Computational Chemistry of [ 198479-63-9 ] Show Less

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 ?

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

34.25 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

4.31
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

7.01
Log Po/w (WLOGP)?

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

7.0
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

4.68
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

7.52
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

6.1

Water Solubility

Log S (ESOL):?

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

-7.02
Solubility 0.0000401 mg/ml ; 0.0000000956 mol/l
Class?

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

Poorly soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-7.54
Solubility 0.000012 mg/ml ; 0.0000000285 mol/l
Class?

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

Poorly 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

-11.42
Solubility 0.0000000016 mg/ml ; 0.0 mol/l
Class?

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

Insoluble

Pharmacokinetics

GI absorption?

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

Low
BBB permeant?

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

No
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

Yes
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

No
CYP2D6 inhibitor?

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

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

Yes
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-3.88 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

1.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

1.0
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

1.0
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

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<2.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

3.05

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.

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

[ 198479-63-9 ] Synthesis Path-Downstream   1~2

  • 2
  • [ 223251-25-0 ]
  • [ 198479-63-9 ]
  • [ 198480-21-6 ]
YieldReaction ConditionsOperation 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. 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (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) δ 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+).
46.6% S81: in a 20L kettle, under the condition of feeding nitrogen, put in 155g sodium hydride, 1342mL DMF, and cool to -5-5C; S82: under the condition that the temperature is 30-40 C, add 608g of BAZ-A to 1824 mL of DMF, stir to dissolve completely, obtain the DMF solution of BAZ-A, the temperature is controlled at -5-5 C, dropwise add BAZ to the kettle The DMF solution of -A is controlled to be added dropwise for 2-3h. After the dropwise addition is completed, the temperature is kept at -5-5C for activation for 30min;S83: under the condition that the temperature is 30-40 , add 618g of BAZ-B to 5600 mL of DMF, stir to dissolve completely, obtain the DMF solution of BAZ-B, the temperature is controlled at -5-5 , dropwise add BAZ to the kettle The DMF solution of -B, the control drop time is 2-3h; S84: after the dropwise addition is completed, the temperature is controlled at -5-5C for the insulation reaction, the reaction is completed, the temperature is controlled below 20C, 6080 mL of purified water is added dropwise, the dropwise addition is completed, the nitrogen supply is stopped, 6080 mL of ethyl acetate is added, and stirring To dissolve completely, let stand for 30min, an emulsification layer appears, suction filtration to obtain a filter cake, the filter cake is dissolved in ethyl acetate to obtain an ethyl acetate solution of the filter cake, the filtrate is allowed to stand for 30min, and the liquid is separated to obtain a light yellow water layer e , the orange organic layer f;The temperature was controlled at 20-30C, put into the light yellow aqueous layer e and 1824 mL of ethyl acetate, stirred for 20 min, stood for 30 min, and separated the liquid to obtain the light yellow water layer g and the light yellow organic layer h;The temperature is controlled at 20-30C, the light yellow water layer g, 1824 mL of ethyl acetate are stirred for 20 minutes, and allowed to stand for 30 minutes, and the liquids are separated to obtain a light yellow water layer i and a light yellow organic layer j; The temperature was controlled at 20-30C, put into the orange organic layer f, the light yellow organic layer h, the light yellow organic layer j, the filter cake ethyl acetate solution, and 2432 mL of saturated sodium chloride solution, stirred for 20 min, stood for 30 min, and separated. The organic layer k was obtained, and the aqueous layer was discarded.The temperature was controlled at 20-30C, put into the organic layer k, 2432 mL of saturated sodium chloride solution, stirred for 20 min, stood for 30 min, and separated to obtain the organic layer 1, and the aqueous layer was discarded;The temperature was controlled at 20-30C, put into the organic layer 1, 2432mL of saturated sodium chloride solution, stirred for 20min, stood for 30min, and separated the liquid to obtain the organic layer m, and the aqueous layer was discarded;S85: the organic layer m is concentrated under reduced pressure under the condition that the temperature is below 60C and the vacuum degree is -0.08MPa to obtain a brownish yellow viscous substance;S86: control the temperature at 20-25C, put 1400 mL of ethyl acetate into the brownish-yellow viscous substance, stir, slowly add 4200 mL of ethanol dropwise, complete the dropwise addition, stir until a light yellow precipitate is precipitated, continue to stir for 1 h, centrifuge, add 700 mL of ethanol Washed to get light yellow crude product;S87: put in the light yellow crude product, 1400 mL of ethyl acetate, and 2800 mL of ethanol, heat up until the solid dissolves completely, cool down to 20-25 C., crystallize for 1 h, centrifuge, and wash with 700 mL of ethanol to obtain a light yellow fine product; S88: be below 40 with light yellow fine product at drying temperature,Dry to a moisture content below 0.5% under the condition of vacuum degree of -0.08MPa,506g of light yellow powder were obtained, which was BAZ-C, and the yield was 46.6%;
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-dimethylforϖnannide (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.

 

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Technical Information

Categories

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