40987-24-4|(4-Benzylmorpholin-2-yl)methanol| Ambeed

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Quality Control of [ 40987-24-4 ] Purity: 98% SDS Specification

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Product Details of [ 40987-24-4 ]

CAS No. :	40987-24-4
Formula :	C₁₂H₁₇NO₂
M.W :	207.27
SMILES Code :	OCC1CN(CC2=CC=CC=C2)CCO1
MDL No. :	MFCD02682009
InChI Key :	WQNIKIMRIXHNFF-UHFFFAOYSA-N
Pubchem ID :	2776358

Safety of [ 40987-24-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H317-H319
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 40987-24-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	6
Fraction Csp3	0.5
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	62.39
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	32.7 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.46
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	0.77
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.35
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.	0.86
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	1.72
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.23

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.71
Solubility	4.06 mg/ml ; 0.0196 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.04
Solubility	19.0 mg/ml ; 0.0918 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-2.59
Solubility	0.529 mg/ml ; 0.00255 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	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	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.02 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	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<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.15

Application In Synthesis of [ 40987-24-4 ]

* 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 [ 40987-24-4 ]
Downstream synthetic route of [ 40987-24-4 ]

[ 40987-24-4 ] Synthesis Path-Upstream 1~7

1
[ 40987-25-5 ]
[ 40987-24-4 ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: at 215℃; for 3 h; Inert atmosphere Stage #2: at 50℃; for 2 h; Reflux	Step 3b: Synthesis of (4-benzylmorpholin-2-yl)methanol 20.3 g of 4-benzyl-2-chloromethylmorpholine, previously obtained, 3.5 ml of water and then 45 ml of formamide (75-12-7) are placed in a 250 ml round-bottomed flask with a condenser and a thermometer and under argon. The reaction medium is heated at 215° C. at the reflux of formamide for 3 h and then cooled to 50° C. with a bath of ice-cold water. A further 3.5 ml of water are added and the refluxing is resumed for a further 2 h. After returning to ambient temperature (20° C.), the medium is poured into ice-cold water (150 ml), the resulting mixture is basified with 10M sodium hydroxide (50 ml) at pH=12, extraction is carried out twice with toluene, and the organic phases are combined and washed with a saturated NaCl solution (50 ml), dried over magnesium sulfate and brought to dryness under a vacuum of 3 mbar for 1 h. (4-Benzylmorpholin-2-yl)methanol (13.4 g) is isolated in the form of an amber oil (yield=72percent).

References: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 6, p. 2227 - 2244.
[2] Patent: US2013/274253, 2013, A1, . Location in patent: Paragraph 1825-1826.
[3] Synthetic Communications, 1980, vol. 10, # 1, p. 59 - 74.

2
[ 769087-80-1 ]
[ 40987-24-4 ]

References: [1] Patent: US2010/63022, 2010, A1, . Location in patent: Page/Page column 29.

3
[ 174560-84-0 ]
[ 943443-03-6 ]
[ 40987-24-4 ]

References: [1] Journal of Organic Chemistry, 2008, vol. 73, # 9, p. 3662 - 3665.

4
[ 61636-32-6 ]
[ 40987-24-4 ]

References: [1] Journal of Chemical Research, Miniprint, 1999, # 3, p. 1001 - 1047.

5
[ 174560-84-0 ]
[ 40987-24-4 ]

References: [1] Synthetic Communications, 1980, vol. 10, # 1, p. 59 - 74.
[2] Patent: US2013/274253, 2013, A1, .

6
[ 104-63-2 ]
[ 40987-24-4 ]

References: [1] Synthetic Communications, 1980, vol. 10, # 1, p. 59 - 74.
[2] Patent: US2013/274253, 2013, A1, .

7
[ 40987-24-4 ]
[ 103003-01-6 ]

References: [1] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 9, p. 3766 - 3774.
[2] Journal of Medicinal Chemistry, 1994, vol. 37, # 17, p. 2791 - 2796.
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 6, p. 2227 - 2244.

[ 40987-24-4 ] Synthesis Path-Downstream 1~35

1
[ 40987-25-5 ]
[ 40987-24-4 ]

Yield	Reaction Conditions	Operation in experiment
72%		Step 3b: Synthesis of (4-benzylmorpholin-2-yl)methanol 20.3 g of 4-benzyl-2-chloromethylmorpholine, previously obtained, 3.5 ml of water and then 45 ml of formamide (75-12-7) are placed in a 250 ml round-bottomed flask with a condenser and a thermometer and under argon. The reaction medium is heated at 215 C. at the reflux of formamide for 3 h and then cooled to 50 C. with a bath of ice-cold water. A further 3.5 ml of water are added and the refluxing is resumed for a further 2 h. After returning to ambient temperature (20 C.), the medium is poured into ice-cold water (150 ml), the resulting mixture is basified with 10M sodium hydroxide (50 ml) at pH=12, extraction is carried out twice with toluene, and the organic phases are combined and washed with a saturated NaCl solution (50 ml), dried over magnesium sulfate and brought to dryness under a vacuum of 3 mbar for 1 h. (4-Benzylmorpholin-2-yl)methanol (13.4 g) is isolated in the form of an amber oil (yield=72%).

References: [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 2227 - 2244.
[2]Patent: US2013/274253,2013,A1 .Location in patent: Paragraph 1825-1826.
[3]Synthetic Communications,1980,vol. 10,p. 59 - 74.

2
[ 7206-70-4 ]
[ 40987-24-4 ]
[ 126645-66-7 ]

References: [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 1406 - 1413.

3
[ 40987-24-4 ]
[ 103003-01-6 ]

References: [1]Chemical and Pharmaceutical Bulletin,1985,vol. 33,p. 3766 - 3774.
[2]Journal of Medicinal Chemistry,1994,vol. 37,p. 2791 - 2796.
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 2227 - 2244.

4
[ 40987-24-4 ]
[ 501-53-1 ]
[ 135782-20-6 ]

References: [1]Tetrahedron Letters,1991,vol. 32,p. 2281 - 2284.

5
[ 40987-24-4 ]
[ 98-59-9 ]
[ 40987-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	In pyridine; water;	(1) 4-Benzyl-2-(p-toluenesulfonyloxymethyl)-morpholine: 4-Benzyl-2-hydroxymethylmorpholine (prepared in the same manner as described in Synthetic Communication, Vol. 10, pages 59-73, 1980) (51 g) is dissolved in pyridine (100 ml) and thereto is added p-toluenesulfonyl chloride (51.7 g) under ice cooling, and the mixture is stirred at room temperature for 12 hours. The precipitated crystals are separated by filtration and washed with ethyl acetate to give hydrochloride of the title compound (70 g). The product (50 g) is suspended in water (200 ml) and the mixture is adjusted to pH 10 with 2N aqueous sodium hydroxide, and extracted with ether. The extract is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (43 g). NMR (CDCl3) delta: 1.7-2.9 (4H, m), 2.4 (3H, s), 3.4-4.1 (5H, m), 3.5 (2H, s), 7.2-7.5 (7H, m), 7.8 (2H, d, J=9Hz).

References: [1]Synthetic Communications,1980,vol. 10,p. 59 - 74.
[2]Patent: US5166203,1992,A .

6
[ 24424-99-5 ]
[ 40987-24-4 ]
[ 135065-69-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	palladium-carbon; In methanol;	Step A: 2-Hydroxymethylmorpholine-4-carboxylic acid tert-butyl ester To a solution of (4-benzylmorpholin-2-yl)-methanol (0.66 g, 3.18 mmol, Synth. Comm. 1980, 10, 59-73) in MeOH (20 mL) was added Boc anhydride (0.83 g, 3.82 mmol) followed by Pd/C (0.66 g, 6.20 mmol). The mixture was stirred under hydrogen atmosphere for 60 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to afford the product as colorless oil (0.69 g, 99% yield).
87%		Ammonium formate (3.04 g, 48.2 mmol) and 10% palladium on activated carbon (500 mg) were added to (4-benzylmorpholin-2-yl)methanol (1.00 g, 4.82 mmol) in methanol (50 mL). The mixture was stirred at room temperature for 4 hours. Subsequently, the reaction mixture was filtered through Celite and the solvent was evaporated. The resulting residue was dissolved in acetonitrile (20 mL). While this solution was chilled in an ice bath, ditert-butyl dicarbonate (1.58 g, 7.23 mmol) and triethylamine (1.35 mL, 9.64 mmol) were added and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated and water was added to the residue. The mixture was then extracted with ethyl acetate and the extract was washed with brine, followed by drying over magnesium sulfate and evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane: ethyl acetate = 5:1 -> 1:1) gave 907 mg (87%) of the desired compound as a colorless oil. 1H NMR (400MHz, DMSO-d6) delta 1.40 (9H, s), 2.47-2.66 (1H, m), 2.73-2.92 (1H, m),3.25-3.45 (4H, m), 3.70 (1H, d, J = 13.4 Hz), 3.79 (1H, dd, J = 11.6, 2.4 Hz), 3.85 (1H, d, J = 12.8 Hz), 4.77 (1H, t, J = 5.5 Hz).

References: [1]Patent: US2004/192653,2004,A1 .
[2]Patent: EP1780210,2007,A1 .Location in patent: Page/Page column 55-56.
[3]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4080 - 4083.

7
[ 61636-32-6 ]
[ 40987-24-4 ]

References: [1]Journal of Chemical Research, Miniprint,1999,p. 1001 - 1047.

8
[ 174560-84-0 ]
[ 40987-24-4 ]

References: [1]Synthetic Communications,1980,vol. 10,p. 59 - 74.
[2]Patent: US2013/274253,2013,A1 .

9
[ 104-63-2 ]
[ 40987-24-4 ]

References: [1]Synthetic Communications,1980,vol. 10,p. 59 - 74.
[2]Patent: US2013/274253,2013,A1 .

10
[ 40987-24-4 ]
[ 60929-58-0 ]