101376-26-5|(R)-(4-Benzylmorpholin-3-yl)methanol| Ambeed

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Quality Control of [ 101376-26-5 ] Purity: 95% SDS Specification

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Product Details of [ 101376-26-5 ]

CAS No. :	101376-26-5
Formula :	C₁₂H₁₇NO₂
M.W :	207.27
SMILES Code :	OC[C@H]1N(CC2=CC=CC=C2)CCOC1
MDL No. :	MFCD06799481
InChI Key :	CPLXVETYMUMERG-GFCCVEGCSA-N
Pubchem ID :	1514271

Safety of [ 101376-26-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 101376-26-5 ] 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.	2.26
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	1.19

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)	2.14

Application In Synthesis of [ 101376-26-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 101376-26-5 ]

[ 101376-26-5 ] Synthesis Path-Downstream 1~35

1
[ 100-44-7 ]
[ 101376-26-5 ]
[ 101376-22-1 ]

References: [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 1288 - 1290.

2
[ 106973-37-9 ]
[ 101376-26-5 ]

Yield	Reaction Conditions	Operation in experiment
86%		Intermediate 65(R)-(4-Benzylmorpholin-3-yl)methanol[0351][Chemical Formula 96]To a solution of intermediate 66 (12.6 g, 53.6 mmol) in tetrahydrofuran (200 mL) was added borane-tetrahydrofuran-complex (1.0 M, 348 mL). After stirring for 6 hours at room temperature, to the mixture was added methanol, and after heated to 80C, stirred for 2 hours. To the mixture were added saturated sodium bicarbonate water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified with silica gel column (hexane/ethyl acetate = 90/10 to 10/90) to give the title compound (9.60 g, 46.0 mmol, 86%).MS (ESI+) 208 (IVT+l, 100%)

References: [1]Patent: WO2011/111875,2011,A1 .Location in patent: Page/Page column 90-91.
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 8609 - 8630.
[3]Journal of the Chemical Society. Perkin transactions I,1985,p. 2577 - 2580.
[4]Helvetica Chimica Acta,2004,vol. 87,p. 90 - 105.

3
[ 101376-26-5 ]
[ 681851-29-6 ]

References: [1]Helvetica Chimica Acta,2004,vol. 87,p. 90 - 105.

4
[ 106973-40-4 ]
[ 101376-26-5 ]

References: [1]Helvetica Chimica Acta,2004,vol. 87,p. 90 - 105.

5
[ 106910-76-3 ]
[ 101376-26-5 ]

References: [1]Helvetica Chimica Acta,2004,vol. 87,p. 90 - 105.
[2]Journal of the Chemical Society. Perkin transactions I,1985,p. 2577 - 2580.
[3]Patent: WO2011/111875,2011,A1 .
[4]Journal of Medicinal Chemistry,2019,vol. 62,p. 8609 - 8630.

6
[ 101376-26-5 ]
[ 681851-35-4 ]

References: [1]Helvetica Chimica Acta,2004,vol. 87,p. 90 - 105.

7
[ 101376-26-5 ]
[ 681851-31-0 ]

References: [1]Helvetica Chimica Acta,2004,vol. 87,p. 90 - 105.

8
[ 101376-26-5 ]
[ 681851-33-2 ]

References: [1]Helvetica Chimica Acta,2004,vol. 87,p. 90 - 105.

9
[ 101376-26-5 ]
[ 101376-28-7 ]

References: [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 1288 - 1290.

10
[ 101376-26-5 ]
[ 101376-24-3 ]

References: [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 1288 - 1290.

11
[ 100-52-7 ]
[ 101376-26-5 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1985,p. 2577 - 2580.
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 8609 - 8630.

12
[ 18162-48-6 ]
[ 101376-26-5 ]
[ 211053-43-9 ]

Yield	Reaction Conditions	Operation in experiment
99.3%	With 1H-imidazole; In DMF (N,N-dimethyl-formamide); at 20℃; for 1.5h;	A solution of 1.00 g (4. 82 mmol) (R)- (4-BENZYL-MORPHOLIN-3-YL)-METHANOL, 0.80 g (5.3 mmol) tert-butyl-chloro-dimethyl-silane and 0.72 g (0.11 mmol) imidazole in 10 ml N, N-dimethylformamide was stirred at room temperature for 90 min. Consecutive addition of water and 1 M aqueous sodium hydroxide solution was followed by extraction with three portions of tert-butyl methyl ether. The combined organic layers were washed with 1 M aqueous sodium hydroxide solution, dried over sodium sulphate and concentrated in vacuo to give 1.54 g (99.3%) of the crude title compound as a colorless oil.

References: [1]Patent: WO2005/2577,2005,A1 .Location in patent: Page 204.

13
[ 288-32-4 ]
[ 18162-48-6 ]
[ 101376-26-5 ]
[ 211053-43-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	In dichloromethane;	STR31 <strong>[101376-26-5](3R)-4-Benzylmorpholine-3-methanol</strong> (1.04 g, 5.0 mmol), t-butyldimethylchlorosilane (0.83 g, 5.5 mol), and imidazole (0.41 g, 6.0 mmol) were allowed to react in 5 mL of dichloromethane at room temperature overnight. The reaction product was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain (3S)-3-(t-butyldimethylsilyloxy)methyl-4-benzylmorpholine (1.53 g, 95%) as a colorless oil.

References: [1]Patent: US6080859,2000,A .

14
[ 101376-26-5 ]
[ 2937-50-0 ]
(R)-allyl 3-(hydroxymethyl)morpholine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	palladium; In ethanol; hexane; ethyl acetate;	Preparation 43 The mixture of <strong>[101376-26-5](3R)-4-benzyl-3-hydroxymethylmorpholine</strong> (2.23 g) and 10% palladium on carbon (wet, 1.11 g) and ethanol was stirred under hydrogen atmosphere for 2 hours. The catalyst was filtrated and the filtrate was evaporated. The oily residue was taken up in ethyl acetate (50 ml) and water (50 ml). The mixture was treated with allyl chloroformate (1.23 ml) at pH 9-10 and stirred for 30 minutes. The separated organic layer was washed with brine (50 ml*2) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica gel (40 ml) eluding with ethyl acetate in hexane (5-50%) to give (3R)-4-allyloxycarbonyl-3-hydroxymethylmorpholine (1.22 g). NMR (CDCl3, delta): 2.75 (1H, br. s), 2.9-4.4 (9H, m), 4.4-4.7 (2H, m), 4.9-5.4 (2H, m), 5.6-6.2 (1H, m)

References: [1]Patent: US4923857,1990,A .

15
[ 101376-26-5 ]
[ 211053-49-5 ]

Yield	Reaction Conditions	Operation in experiment
57%		(a) (3R)-Morpholin-3-ylmethanol; A solution of [(3i?)-4-benzylmorpholin-3-yl]methanol (see J. Med. Chem.; 29; 1986; 1288- 1290; 1.1 g, 5.4 mmol) in ethanol (25 mL) was mixed with palladium hydroxide (20% on carbon, 0.7 g) and acetic acid (0.5 mL). The mixture was stirred under hydrogen overnight20 at 1.2 bar and RT. The catalyst was filtered off and the solvent was removed by evaporation. The residue (except 200 mg) was dissolved in ether (1 mL) and THF (10 mL). The solution was filtered through a strong cation exchange column (Isolute SCX-2, 10 g). The column was washed with THF and then the product was eluted with ammonia- saturated methanol. The solvent was removed by evaporation and there was obtained 0.3625 g (57%) of (3i?)-morpholin-3-ylmethanol as an oil. 1H NMR (500 MHz, CD3OD): 2.9 (m, 3H), 3.3 (t, IH)5 3.5 (m, 3H), 3.7-3.9 (m, 2H).

References: [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 8609 - 8630.
[2]Patent: WO2006/137790,2006,A1 .Location in patent: Page/Page column 35.
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 2227 - 2244.

16
[ 101376-26-5 ]
[ 917572-28-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; for 2.5h;Heating / reflux;	(a) (3S)-4-Benzyl-3-(chloromethyl)morpholine; To a solution of [(3i?)-4-benzykciotaorpholin-3-yl]methanol (see J. Med. Chem.; 29; 1986; 0 1288-1290; 1.83 g, 8.8 mmol) in dry methylene chloride (15 mL) was added thionyl chloride (3.15 g, 26.5 mmol) and DMF (2 drops). The mixture was heated to reflux for 2 h 30 min and then the solvent was removed by evaporation. The residue was treated with aqueous NaHCO3 and the solution was extracted with ethyl acetate. The organic solution was separated and the solvent was removed by evaporation. There was obtained 1.88 g s (94%) of (31S)-4-benzyl-3-(chloromethyl)morpholine as an oil. 1H NMR (500 MHz, CDCl3): 2.3-2.4 (m, IH), 2.7 (m, IH), 2.8 (m, IH), 3.5 (d, IH), 3.6-3.9 (m, 5H), 4.0 (d, IH), 7.3 (m, IH), 7.4 (m, 4H); LCMS: m/z 226 (M+l)+.
94%	With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; for 2.5h;Heating / reflux;	(a) (3S)-4-Benzyl-3-(chloromethyl)morpholineTo a solution of [(3i?)-4-benzylmorpholin-3-yl]methanol (see J. Med. Chem.; 29; 1986; 1288-1290; 1.83 g, 8.8 mmol) in dry methylene chloride (15 mL) was added thionyl chloride (3.15 g, 26.5 mmol) and DMF (2 drops). The mixture was heated to refluxed for 2 h 30 min and then the solvent was removed by evaporation. The residue was treated with aqueous NaHCO3 and the solution was extracted with ethyl acetate. The organic solution was separated and the solvent was removed by evaporation. There was obtained 1.88 g (94%) of (3S)-4-berLzyl-3-(chloromethyl)morpholine as an oil. 1H NMR (500 MHz, CDCl3): 2.3-2.4 (m, IH), 2.7 (m, IH), 2.8 (m, IH), 3.5 (d, IH), 3.6-3.9 (m, 5H), 4.0 (d, IH), 7.3 (m, IH), 7.4 (m, 4H); LCMS: m/z 226 (M+l)+.
	With thionyl chloride; In dichloromethane; for 15h;	Intermediate 64(S)-4-Benzyl-3-(chloromethyl)morpholine[0349][Chemical Formula 95]To a solution of intermediate 65 (9.60 g, 46.3 mmol) in dichloromethane (230 mL) was added thionyl chloride (60.0 mL, 69.5 mmol). After stirring for 15 hours, to the mixture was added aqueous sodium hydroxide solution. The aqueous layer was neutralized with 2N hydrochloric acid, and then extracted with dichloromethane. The organic layer was washed with water and brine, and then dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (10.4 g, 46.3 mmol, quant.).MS (ESI+) 226 (M++l, 100%)

References: [1]Patent: WO2006/137790,2006,A1 .Location in patent: Page/Page column 32.
[2]Patent: WO2006/137791,2006,A1 .Location in patent: Page/Page column 43.
[3]Patent: WO2011/111875,2011,A1 .Location in patent: Page/Page column 90.
[4]Journal of Medicinal Chemistry,2017,vol. 60,p. 2227 - 2244.

17
[ 714971-27-4 ]
[ 101376-26-5 ]

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 6527 - 6530.

18
[ 24424-99-5 ]
[ 101376-26-5 ]
[ 215917-99-0 ]

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 6527 - 6530.

19
[ 211053-49-5 ]
[ 100-39-0 ]
[ 101376-26-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 2h;	Benzyl bromide (1.2 g, 7.06 mmol) was added in one portion to a stirred solution of (R)- morpholin-3-ylmethanol (986 mg, 6.42 mmol) and DIPEA (1.66 g, 12.8 mmol) in MeCN (50 ml) and the resulting solution was stirred at rt for 2h, whereafter the mixture was then concentrated under reduced pressure. The afforded residue was dissolved in DCM (50ml) was and washed sequentially with sat. aq. NaHC03 (50 ml) and 1 M KOH (10 ml). The aqueous phase was extracted with DCM (25 ml) and the combined organic layers were dried over Na2S04, filtered and concentrated which gave the title compound (1.19 g, 89%). MS (ESI): 208 [M+H]+.

References: [1]Patent: WO2013/95275,2013,A1 .Location in patent: Page/Page column 48; 49.

20
[ 101376-26-5 ]
[ 1266238-75-8 ]

Yield	Reaction Conditions	Operation in experiment
70%	With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; for 3h;	Step 1 (S)-4-benzyl-3-(fluoromethyl)morpholine To a solution of Int. N (6.81 g, 3.28 mmol) in CH2Cl2 (50 mL) at 0 C. was added diethylaminosulfur trifluoride (6.26 mL, 4.9 mmol) dropwise and the resulting mixture was stirred at RT for 3 h. The reaction mixture was added dropwise to ice-water, aq. sat. NaHCO3 was added to adjust to pH=8, and the aqueous layer was extracted with CH2Cl2 (3*50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (90% EtOAc in hexanes) to afford the title compound (5.18 g, 70% yield) as a yellow liquid. MS (ES+) Cl2H16FNO requires: 209, found: 210 [M+H]+.
		Hexafluoropropene diethylamine complex (1.25 ml, 6.89 mmol) was added dropwise at -30 under N2 to a solution of BB14-a (1.19 g, 5.74 mmol) in dry DCM (100 ml) and the resulting reaction mixture was stirred at rt for 3h. The solution was then washed with water and sat. aq. NaHC03, dried over Na2S04 and evaporated in vacuo. The residue was dissolved in methanol (100 ml) and the solution was added to a 30% CH3ONa solution in methanol (209 ml). After 30 min of stirring, acetic acid (0.9 ml) was added and the mixture was concentrated in vacuo. DCM and water were added to the residue and the organic phase was separated, dried over Na2S04 and concentrated in vacuo. The residue was purified by column chromatography on silica which gave a crude mixture (1.014 g) containing mainly the title compound and 4-benzyl-6- fluoroperhydro-1 ,4-ixazepine. The crude mixture was used in the next step without further purification. MS (ESI): 210 [M+H]+.

References: [1]Patent: US2019/16713,2019,A1 .Location in patent: Paragraph 0738-0741.
[2]Patent: WO2013/95275,2013,A1 .Location in patent: Page/Page column 49.

21
[ 101376-26-5 ]
[ 1266323-76-5 ]

References: [1]Patent: WO2013/95275,2013,A1 .
[2]Patent: US2019/16713,2019,A1 .

22
[ 101376-26-5 ]
((1,2-trans)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)cyclopentyl)((S)-3-(fluoromethyl)morpholino)methanone [ No CAS ]

References: [1]Patent: WO2013/95275,2013,A1 .

23
[ 75-03-6 ]
[ 101376-26-5 ]
(R)-4-benzyl-3-(ethoxymethyl)morpholine [ No CAS ]