4497-04-5|3-Morpholinopropanoic acid| Ambeed

CAS No. :	4497-04-5
Formula :	C₇H₁₃NO₃
M.W :	159.18
SMILES Code :	O=C(O)CCN1CCOCC1
MDL No. :	MFCD02089311
InChI Key :	YUYHRSGXZZVNMS-UHFFFAOYSA-N
Pubchem ID :	410813

Safety of [ 4497-04-5 ]

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

Computational Chemistry of [ 4497-04-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	0
Fraction Csp3	0.86
Num. rotatable bonds	3
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	43.32
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	49.77 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.58
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	-2.89
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	-0.59
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.	-0.5
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	0.35
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	-0.41

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	1.19
Solubility	2480.0 mg/ml ; 15.6 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Highly soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	2.4
Solubility	40200.0 mg/ml ; 253.0 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Highly 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	-0.24
Solubility	92.2 mg/ml ; 0.579 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.	-9.32 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	2.0
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)	1.58

Application In Synthesis of [ 4497-04-5 ]

* 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 [ 4497-04-5 ]

[ 4497-04-5 ] Synthesis Path-Downstream 1~55

1
[ 110-91-8 ]
[ 57-57-8 ]
[ 4497-04-5 ]

References: [1]Patent: US2526558,1948, .

2
[ 33611-43-7 ]
[ 4497-04-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium hydroxide; In ethanol;	The starting material was prepared as follows: Potassium hydroxide (485 mg, 8.6mmol) was added to a solution of methyl 3-morpholinopropionate (1 g, 5.7 mmol) in ethanol (20 ml) and the mixture stirred for 2 hours at 80° C. The solution was allowed to cool and adjusted to pH1 with 6M hydrochloric acid. Insoluble material was removed by filtration and the volatiles removed from the filtrate by evaporation. The resulting oil was triturated with ether, the solid product collected by filtration, washed with methylene chloride and dried under vacuum to give 3-morpholinopropionic acid (993 mg, 89percent) as a white solid. 1H NMR Spectrum: (DMSOd6; CF3COOD) 2.83(t, 2H); 3.13(t, 2H); 3.36(t, 2H); 3.46(d, 2H); 3.73(t, 2H); 3.97(d, 2H) MS-ESI: 159 [MH]+
		Example 17 Preparation of [3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridin-1-yl]-naphthalen-1-yl-methanone To a solution of methyl 4-morpholinepropionate (5.0 g, 28.9 mmol) in MeOH (25 mL) was added 2N NaOH (17.3 mL, 34.6 mmol). The mixture was stirred for 1 h then concentrated in vacuo. The residue was suspended in dichloromethane (125 mL) and DMF (30 muL) was added followed by oxalylchloride (10 mL, 115.6 mmol). The mixture was allowed to stir for 2 h. then concentrated in vacuo. The resulting solid was added portion-wise to a solution of 2-(aminomethyl)pyridine (2.88 mL, 28.2 mmol) and triethylamine (9.0 mL, 64.86 mmol) in dichloromethane (200 mL). The mixture was stirred at ambient temperature for 1 h. then washed with water (300 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to yield 3-morpholin-4-yl-N-pyridin-2-ylmethyl-propionamide (5.56 g, 77percent).

References: [1]Patent: US6184225,2001,B2 .
[2]Journal of Medicinal Chemistry,1993,vol. 36,p. 320 - 330.
[3]Patent: US2008/9491,2008,A1 .Location in patent: Page/Page column 15.
[4]RSC Advances,2017,vol. 7,p. 47297 - 47308.

3
[ 62131-51-5 ]
[ 4497-04-5 ]
[ 108-95-2 ]

References: [1]Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical and Analytical,1982,vol. 21,p. 515 - 516.

4
[ 4497-04-5 ]
[ 134805-50-8 ]
(2S,3R,4R,5S)-2,5-bis<N-<N-<3-(4-morpholinyl)propanoyl>valinyl>amino>-3,4-dihydroxy-1,6-diphenylhexane [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 320 - 330.

5
[ 110-91-8 ]
[ 292638-85-8 ]
[ 4497-04-5 ]

References: [1]Russian Chemical Bulletin,1998,vol. 47,p. 1732 - 1735.

6
[ 4497-04-5 ]
3-morpholino-1-hydroxypropylidenebisphosphonic acid [ No CAS ]

References: [1]Russian Chemical Bulletin,1998,vol. 47,p. 1732 - 1735.

7
tert-butyl 3-morpholinopropanoate [ No CAS ]
[ 4497-04-5 ]

References: [1]Tetrahedron Letters,2000,vol. 41,p. 655 - 658.

Yield	Reaction Conditions	Operation in experiment
		B. 3-(4-Morpholinyl)propanoic Acid A solution of the resultant compound of Example 202A (8.35 g, 48.3 mmol) in 60 ml of dioxane was treated with 40 ml of water and 19.3 ml (58 mmol) of 3N aqueous NaOH. After being stirred for 4 h, the solution was treated with 58 ml (58 mmol) of 1N aqueous HCl and concentrated in vacuo to provide the crude desired compound.
		beta-Morpholino-propionic acid (used for preparing compound No. 32) NMR (60 MHz, delta values in CD3 OD): 2.45 (2H, t, J=6 Hz, --COCH2 --) STR31 3.83 (4H, m, --CH2 OCH2 --)

9
[ 4497-04-5 ]
[ 3282-30-2 ]
C₁₂H₂₁NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%		Example 7; 4-[5-amino- l-(2,6-difluoro-benzoyl)- lH-[ 1 ,2,4]triazol-3- ylamino]-N-(3-morpholin-4-yl-propionyl)-benzenesulfonamide(Cpd 7); 7a; Using the mixed anhydride formation procedure, 1.9 g (100 percent) of Compound7a was generated from morpholinylpropionic acid (1.25 g) and pivaloyl chloride (1.05 g). 1H NMR (300 MHz, CDCl3) delta 3.68 (m, 4 H), 2.75 (t, 2 H), 2.65 (t, 2 H), 2.45 (m, 4 H), 1.21 (s, 9 H).

References: [1]Patent: WO2006/42215,2006,A1 .Location in patent: Page/Page column 37.
[2]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3639 - 3641.

10
[ 4497-04-5 ]
[ 444904-20-5 ]
N-[(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-3-(morpholin-4-yl)propionamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 1781 - 1791.

11
[ 931112-72-0 ]
[ 4497-04-5 ]
N-(5-chloro-3-(4-(2-chloro-5-(trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6-dihydropyridin-2-yl)-2-hydroxybenzyl)-N-methyl-3-(4-morpholinyl)propanamide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3122 - 3129.

12
[ 952658-86-5 ]
[ 4497-04-5 ]
[ 557-21-1 ]
C₂₃H₂₂N₆O₂ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5665 - 5670.

13
[ 4497-04-5 ]
4-[5-amino-1-(2,6-difluoro-benzoyl)-1H-[1,2,4]triazol-3-ylamino]-N-(3-morpholin-4-ylpropionyl)benzenesulfonamide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 3639 - 3641.

18
[ 4497-04-5 ]
[ 186668-40-6 ]
homo-camptothecin-20-O ester of N-morpholine propionic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃; for 20.16h;	[[0158]] B. Homocamptothecin-20-O ester of N-morpholine propionic acid The target molecule is synthesized using the above procedure for this example. The flask is charged with homocamptothecin [(HCPT)] (20 mg,. 05 mmol) and then 7 mL of dry chloroform. The solution is allowed to stir for 10 minutes at ambient temperature. [1- (3-] [DIMETHYLAMINO-PROPYL)-3-ETHYL-CARBODIIMIDE] hydrochloride (EDCI) (61 mg, 0.31 mmol), 4- (dimethylamino) pyridine (DMAP) (12 mg, . 12 mmol) and N-morpholine propionic acid (23 mg, . 15 mmol) is added. The reaction is allowed to stir for 20 hours at ambient temperature and worked up according to the procedure.

References: [1]Patent: WO2003/101998,2003,A1 .Location in patent: Page 58-62.

42
[ 4497-04-5 ]
[ 944343-01-5 ]
[ 944343-02-6 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4896 - 4899.

43
[ 4497-04-5 ]
[ 1204245-57-7 ]
[ 1204244-87-0 ]
[ 1204244-89-2 ]

Yield	Reaction Conditions	Operation in experiment
10%; 5%		Example 99Preparation of N-(2-('difluoro('4-fluorophenvpimethyl')-4-(5-methyl-lH-pyra2psil-3- ylamino)pyrrolo F 1 ,2-f] \\ 1 ,2.4~\|triazin-6-vQ-3 -morpholinopropanamide[00421] A mixture of 2-(difluoro(4-fluorophenyl)methyl)-N-(5-methyl-lH-pyrazol- 3-yl)-6-nitropyrrolo[l,2-f][l,2,4]triazin-4-amine from Example 46 Step F (300 mg, 0.74 mmol), 10percent Pd/C (50 mg), and 10percent HCl (5 mL) in MeOH (15 mL) was stirred under a hydrogen atmosphere for 1.5 h. The mixture was filtered through Celite washing with MeOH. The filtration was concentrated and ethyl ether was added to the residue to form a precipitate, which was collected by filtration and dried under vacuum to afford a solid (292 mg).[00422] To a solution of 3-morpholinopropanoic acid (159 mg, 1 mmol) in DMF (8 mL) was added HATU (456 mg, 1.2 mmol), followed by addition of the above solid and iPr2NEt (1 mL). The mixtrue was stirred at room temperature overnight, then quenched with water and extracted with DCM. Extracts were dried over MgSO4 and concentrated, and the residue was purified by silica gel chromatography using a mixture of EtOAc-hexanes as eluent to afford N-(2-(difluoro(4-fluorophenyl)methyl)- 4-(5-methyl-lH-pyrazol-3-ylamino)pyrrolo[l,2-fj[l,2,4]triazin-6-yl)-3- morpholinopropanamide (0.39 mg, 10 percent) as a solid. 1H NMR (300 MHz, DMSO-^6) delta 12.20 (s, IH), 10.80 (s, IH), 10.50 (s, IH), 8.04 (d, IH), 7.69 (dd, 2H), 7.36 (t, 2H), 7.22 (s, IH), 6.20 (s, IH), 3.56 (t, 4H), 2.63 (t, 2H), 2.50 (overlapping with solvent, 2H), 2.41 (t, 4H), 2.21 (s, 3H); LC-MS (ESI) m/z 515 (M+H)+.

References: [1]Patent: WO2010/2472,2010,A1 .Location in patent: Page/Page column 186-187.

44
[ 4497-04-5 ]
[ 143165-08-6 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 1.75h;Inert atmosphere;	Example 19: Lambda/-(2-(4-(4-(3-(3-terf-Butyl-1 -p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1 - yloxy)pyridin-2-ylamino)-2-oxoethyl)-3-morpholinopropanamide Intermediate G1(COCl)2 / DMF; DIPEA To a suspension of 3-morpholinopropanoic acid (33.9 mg, 213 mumol) in dry DCM (3.0 mL) under nitrogen at 00C was added oxalyl dichloride (21.0 mul_, 248 mumol), followed by 1 drop of DMF and the reaction mixture maintained at 00C for 20 min and the at RT for 1.25 hr. The mixture was cooled to 00C and Intermediate G1 (40 mg, 71 mumol) and DIPEA (61.8 mul_, 355 mumol) were added and the combined reaction mixture was kept at 00C for 30 min and then at RT for 2.25 hr. The reaction was quenched by addition of a 1percent solution of NH3 in MeOH (3.0 mL) and the resulting mixture maintained at RT for 16 hr and was then evaporated in vacuo. The residue was subjected to SCX capture and release and the crude product so obtained was purified by flash column chromatography (SiO2, 12 g, [5percent MeOH in EtOAc] in isohexane, 50- 100percent, gradient elution, then 10percent MeOH in EtOAc) to afford the title compound, Example 19, as a beige solid (20 mg, 39percent); R' 2.00 min (Method 2); m/z 705 (M+H)+ (ES+); 1H NMR (400MHz, DMSO-de) delta: 1.29 (9H, s), 2.29 (2H, t), 2.33 (4H, m), 2.40 (3H, s), 2.47 (2H, m), 3.52 (4H, t), 3.87 (2H, d), 6.40 (1 H, s), 6.72 (1 H, dd), 7.33 (1 H, d), 7.37 (2H, d), 7.47 (2H, m), 7.57- 7.64 (3H, overlapping m), 7.83 (1 H, dd), 7.96 (1 H, d), 8.09 (1 H, d), 8.19 (1 H, d), 8.22 (1 H, t), 8.85 (1 H, br s), 9.16 (1 H, br s), 10.48 (1 H, br s).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane;	Example 198: compound n°198: 4-((4-(2-chlorophenyl)thiazol-2- yl)(methyl)amino)-3-(morpholinomethyl)-4-oxobutanoic acid was synthesized as described in Scheme 18.

References: [1]Patent: WO2010/67130,2010,A1 .Location in patent: Page/Page column 53-54.
[2]Patent: WO2010/66682,2010,A1 .Location in patent: Page/Page column 201; 242.
[3]Journal of Medicinal Chemistry,2013,vol. 56,p. 5757 - 5772.

45
[ 4497-04-5 ]
C₄₂H₄₁N₄O₈Pol [ No CAS ]
[ 143824-78-6 ]
[ 1241875-27-3 ]