154477-55-1|Methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoate| Ambeed

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Quality Control of [ 154477-55-1 ] Purity: 95% SDS Specification

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Product Details of [ 154477-55-1 ]

CAS No. :	154477-55-1
Formula :	C₃₃H₃₉NO₄
M.W :	513.67
SMILES Code :	O=C(OC)C(C)(C)C1=CC=C(C(CCCN2CCC(C(C3=CC=CC=C3)(O)C4=CC=CC=C4)CC2)=O)C=C1
MDL No. :	MFCD08063765
InChI Key :	PGQMZSGBFIPEKX-UHFFFAOYSA-N
Pubchem ID :	9958101

Safety of [ 154477-55-1 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 154477-55-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	38
Num. arom. heavy atoms	18
Fraction Csp3	0.39
Num. rotatable bonds	11
Num. H-bond acceptors	5.0
Num. H-bond donors	1.0
Molar Refractivity	155.17
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	66.84 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	5.06
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	5.14
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	5.26
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	3.97
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	6.53
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	5.19

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-5.89
Solubility	0.000666 mg/ml ; 0.0000013 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-6.29
Solubility	0.000264 mg/ml ; 0.000000514 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	-9.27
Solubility	0.000000278 mg/ml ; 0.0000000005 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Poorly soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	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	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	Yes
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	Yes
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.78 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	1.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	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<3.0
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)	4.24

Application In Synthesis of [ 154477-55-1 ]

* 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 [ 154477-55-1 ]

[ 154477-55-1 ] Synthesis Path-Upstream 1~24

1
[ 154825-95-3 ]
[ 154477-55-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: With toluene-4-sulfonic acid In ethanol at 20℃; for 48 h; Stage #2: With sodium hydrogencarbonate In ethyl acetate	The alkyne of formula II (R=Me) (200 mg, 0.40 mmol) is dissolved in absolute ethanol (0.8 ml) and then treated with monohydrate p-toluenesulfonic acid (383 mg, 2.02 mmol). After 10 minutes, Ph₃AuCl (4 mg, 0.0081 mmol, 2percent molar) and AgCF₃SO₃(2 mg, 0.0081 mmol, 2percent molar) are added. After 48 h, at room temperature, the ethanol is evaporated under reduced pressure and the residue is taken up with ethyl acetate and basified till pH 10-11 with a NaHCO₃solution. The phases are separated, and the aqueous one is extracted with ethyl acetate. The organic phases are collected, dried with Na₂SO₄, filtered off and evaporated under reduced pressure. The crude reaction is purified by flash chromatography (acetate/methanol 9:1 as eluent) and 198 mg of title keto compound are obtained as a white solid, with a yield of 95percent.¹H NMR (400 MHz, CDCl₃) δ ppm: 7.94 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.0 Hz, 4H), 7.43 (d, J=8.6 Hz, 2H), 7.34-7.29 (m, 4H), 7.22-7.17 (m, 2H), 3.65 (s, 3H), 3.04-2.95 (m, 4H), 2.49-2.42 (m, 3H), 2.05-1.92 (m, 4H, 1H exchanges with D₂O), 1.62 (s, 6H), 1.52-1.41 (m, 4H).
28.3%	at 55℃; for 3.5 h;	Methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoate To a vial was added the methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)but-1-yn-1-yl)phenyl)-2-methylpropanoate (KSC-335-054) (0.074 g, 0.149 mmol). The mercuric oxide (1.493 ml, 0.045 mmol) was made into a 0.03 M solution in 4percent w/v sulfuric acid and added to the starting material then heated to 55° C. and stirred for 3.5 h. The reaction turned a milky white color upon addition of the mercuric oxide solution. The reaction was removed from heat and diluted with saturated NaHCO₃ (10 mL) and extracted with DCM (3*10 mL). The DCM layers were combined and dried with MgSO₄, filtered and concentrated then purified by reverse-phase MPLC (10-100percent MeCN:water) to produce methyl 2-(4-(4-(4-(hydroxydiphenylmethyl) piperidin-1-yl)butanoyl)phenyl)-2-methylpropanoate (0.0217 g, 0.042 mmol, 28.3percent yield). ¹H NMR (400 MHz, CDCl₃): δ 7.93-7.91 (m, 2H), 7.48-7.45 (m, 4H), 7.42-7.39 (m, 2H), 7.30-7.26 (m, 4H), 7.19-7.14 (m, 2H), 3.63 (s, 3H), 2.96-2.88 (m, 4H), 2.44-2.34 (m, 3H), 2.08 (br s, 1H), 1.60 (s, 6H), 1.62-1.56 (m, 4H), 1.46-1.30 (m, 4H).

References: [1] Patent: US2010/228034, 2010, A1, . Location in patent: Page/Page column 3.
[2] Patent: EP1260505, 2002, A1, . Location in patent: Example 6.
[3] Journal of Organic Chemistry, 1994, vol. 59, # 9, p. 2620 - 2622.
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8540 - 8562.
[5] Patent: US2015/238473, 2015, A1, . Location in patent: Paragraph 0237.

2
[ 115-46-8 ]
[ 154477-54-0 ]
[ 154477-55-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium hydrogencarbonate; potassium iodide In toluene at 80℃; for 30 h; Reflux	1000 mL reaction flask, 55.4 g of diphenylpiperidine methanol was added successively, 42.1 g of potassium bicarbonate, 3.1g potassium iodide, 310 mL of toluene, Heated to 80 ° C, A solution of methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoate (VI) (53.3 g) in toluene (150 ml) was slowly added dropwise, Plus, Reflux reaction about 30h, HPLC monitoring reaction is complete, The reaction solution was cooled to 10 to 15 ° C, filter, The filtrate was concentrated to give 107 g of crude product; With 250mL anhydrous ethanol heated reflux solution, Dropping 80 mL of water, After refluxing for 30 min, Natural cooling to 10 ~ 15 deg C, Insulation stirring 4h, Filtration gave an off-white solid, Drying 90g; And then recrystallized with EA, To obtain 77.4 g of methyl 2- [4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -butanoyl] phenyl] -2-methylpropionate (VII) as a white solid, Purity 99.5percent Yield 80percent. among them, The molar ratio of methyl 2- (4- (4-chlorobutyryl) phenyl) -2-methylpropanoate (VI), potassium iodide and base is 1: 0.1: 2.23.

References: [1] Patent: CN106380441, 2017, A, . Location in patent: Paragraph 0010; 0051; 0052; 0053; 0054; 0055.
[2] Patent: WO2005/19175, 2005, A1, . Location in patent: Page/Page column 26.
[3] Patent: WO2008/12859, 2008, A2, . Location in patent: Page/Page column 4-5.
[4] Patent: WO2009/136412, 2009, A2, . Location in patent: Page/Page column 8.
[5] Patent: US2010/16599, 2010, A1, . Location in patent: Page/Page column 2.

3
[ 43076-33-1 ]
[ 31469-15-5 ]
[ 154477-55-1 ]

Yield	Reaction Conditions	Operation in experiment
62%	With zinc(II) fluoride; tri-tert-butyl phosphine In N,N-dimethyl-formamide at 80℃; for 2 h;	EXAMPLE 8 Two grams of 3, 90 mg of P(tBu)₃, 300 mg of Pd(dba)₂, 250 mg of ZnF₂and 1.1 g of 5 were dissolved in 330 mL of DMF under argon. The mixture was heated to 80° for two hours, cooled to room temperature, diluted with ether and worked up as described in example 1. The resulting product was filtered through silica to provide 1.3 g (62percent) of 6.

References: [1] Patent: US2006/63808, 2006, A1, . Location in patent: Page/Page column 8; 10; 14.

4
[ 154825-96-4 ]
[ 154477-55-1 ]

Yield	Reaction Conditions	Operation in experiment
61%	With magnesium sulfate In acetone	Scheme A, optional step f: Preparation of 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylbenzeneacetic acid methyl ester 4-[4-[4-(Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic acid methyl ester (2.05 g, 0.00398 mol) was dissolved in 100 mL of acetone and chilled in an ice-bath. To the solution was added Jones reagent (Prepared via the method of Feiser and Feiser) dropwise until a red color persisted. The reaction was allowed to warm to room temperature and then stirred for 18 hours at ambient temperature. The mixture was concentrated under vacuum to give a green solid. The residue was partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer was separated, washed with water (3100 mL), brine (1100 mL) and treated with MgSO₄, filtered and concentrated in vacuo to give a light green solid. Purification via column chromatography yielded 1.25 g (61percent yield) of the title compound as a white solid. MH⁺514.6.

References: [1] Patent: US2003/105329, 2003, A1, .

5
[ 1451149-72-6 ]
[ 154477-55-1 ]

Yield	Reaction Conditions	Operation in experiment
5.8 g	With sulfuric acid; water In methanol at 40℃; for 12 h;	EXAMPLE 12 Synthesis of methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanoyl)phenyl)-2-methyl-propanoate (Compound VIII) In a reaction flask 7.0 g methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-1,1-dimethoxybutyl)phenyl)-2-methylpropanoate (0.01 mol), 35 ml methanol, 5 ml water, 1.5 g sulfuric acid 96percent (0.015 mol) were charged, the temperature was brought to 40° C. and the reaction mixture was kept under these conditions for twelve hours. At the end of the reaction, the temperature was brought to 15° C., 20 ml water and ammonia 30percent solution up to pH 8 were added, the resultant solid was filtered and dried in oven at 40° C. under vacuum to give 5.8 g methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butanoyl)phenyl)-2-methyl-propanoate.

References: [1] Patent: US2013/237709, 2013, A1, . Location in patent: Paragraph 0114.

6
[ 115-46-8 ]
[ 154477-55-1 ]

References: [1] Patent: US6348597, 2002, B2, . Location in patent: Page column 98-99.

7
[ 115-46-8 ]
[ 394222-31-2 ]
[ 154477-55-1 ]

Yield	Reaction Conditions	Operation in experiment
7 g	With sodium hydrogencarbonate; potassium iodide In water; toluene for 20 h; Reflux	EXAMPLE 8 Preparation of methyl 2-(4-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-1-oxybutyl)phenyl)-2-methyl-propanoate In a reaction flask 5 g methyl 4-(4-bromo-1-oxybutyl)-α,α-dimethylphenylacetate (0.15 mol), 25 ml toluene, 4.08 g azacyclonol (0.015 mol), 10 ml water, 1.53 g sodium bicarbonate (0018 mol) and 0.25 g potassium iodide (0.0015 mol) were charged, the reaction mixture was brought to the reflux temperature and kept under these conditions for 20 hours. At the end of the reaction, the temperature was brought to 25° C., the separated organic phase was concentrated to residue by distillation under vacuum to give 7 g methyl 2-(4-(4-(4-(hydroxy-diphenylmethyl)piperidin-1-yl)-1-oxybutyl)phenyl)-2-methyl-propanoate.

References: [1] Patent: US2013/237709, 2013, A1, . Location in patent: Paragraph 0106.

8
[ 154825-97-5 ]
[ 154477-55-1 ]

References: [1] Journal of Organic Chemistry, 1994, vol. 59, # 9, p. 2620 - 2622.
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8540 - 8562.

9
[ 154825-93-1 ]
[ 154477-55-1 ]

References: [1] Journal of Organic Chemistry, 1994, vol. 59, # 9, p. 2620 - 2622.
[2] Patent: US2013/237709, 2013, A1, .
[3] Patent: US2013/237709, 2013, A1, .
[4] Patent: US2013/237709, 2013, A1, .
[5] Patent: US2013/237709, 2013, A1, .
[6] Patent: US2013/237709, 2013, A1, .
[7] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8540 - 8562.
[8] Patent: US2015/238473, 2015, A1, .

10
[ 958378-24-0 ]
[ 154477-55-1 ]

References: [1] Patent: WO2007/135693, 2007, A2, . Location in patent: Page/Page column 14-15: 18.

11
[ 154825-94-2 ]
[ 154477-55-1 ]

References: [1] Journal of Organic Chemistry, 1994, vol. 59, # 9, p. 2620 - 2622.
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8540 - 8562.
[3] Patent: US2015/238473, 2015, A1, .

12
[ 115-46-8 ]
[ 154477-54-0 ]
[ 937009-94-4 ]
[ 154477-55-1 ]

References: [1] Patent: WO2007/7347, 2007, A1, . Location in patent: Page/Page column 4-5; 7; 11.
[2] Patent: WO2007/7347, 2007, A1, . Location in patent: Page/Page column 4-5; 8; 11-12.

13
[ 1451149-70-4 ]
[ 154477-55-1 ]

References: [1] Patent: US2013/237709, 2013, A1, .
[2] Patent: US2013/237709, 2013, A1, .

14
[ 394222-31-2 ]
[ 154477-55-1 ]

References: [1] Patent: US2013/237709, 2013, A1, .

15
[ 1451149-71-5 ]
[ 154477-55-1 ]

References: [1] Patent: US2013/237709, 2013, A1, .

16
[ 154477-54-0 ]
[ 154477-55-1 ]

References: [1] Patent: US2013/237709, 2013, A1, .

17
[ 1451149-74-8 ]
[ 154477-55-1 ]

References: [1] Patent: US2013/237709, 2013, A1, .

18
[ 1195-98-8 ]
[ 154477-55-1 ]