[ CAS No. 4497-04-5 ] {[proInfo.proName]}

Name: 4497-04-5|3-Morpholinopropanoic acid|98%
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Quality Control of [ 4497-04-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 4497-04-5 ]

Product Details of [ 4497-04-5 ]

CAS No. :	4497-04-5	MDL No. :	MFCD02089311
Formula :	C₇H₁₃NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YUYHRSGXZZVNMS-UHFFFAOYSA-N
M.W :	159.18	Pubchem ID :	410813
Synonyms :

Calculated chemistry of [ 4497-04-5 ]

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 :	49.77 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-9.32 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.58
Log Po/w (XLOGP3) :	-2.89
Log Po/w (WLOGP) :	-0.59
Log Po/w (MLOGP) :	-0.5
Log Po/w (SILICOS-IT) :	0.35
Consensus Log Po/w :	-0.41

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	1.19
Solubility :	2480.0 mg/ml ; 15.6 mol/l
Class :	Highly soluble
Log S (Ali) :	2.4
Solubility :	40200.0 mg/ml ; 253.0 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-0.24
Solubility :	92.2 mg/ml ; 0.579 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.58

Safety of [ 4497-04-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

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.

Upstream synthesis route of [ 4497-04-5 ]
Downstream synthetic route of [ 4497-04-5 ]

[ 4497-04-5 ] Synthesis Path-Upstream 1~4

1
[ 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]⁺

Reference： [1] Patent: US6184225, 2001, B2,
[2] Journal of Medicinal Chemistry, 1993, vol. 36, # 3, p. 320 - 330
[3] Patent: US2008/9491, 2008, A1, . Location in patent: Page/Page column 15
[4] RSC Advances, 2017, vol. 7, # 75, p. 47297 - 47308

2
[ 110-91-8 ]
[ 292638-85-8 ]
[ 4497-04-5 ]

Reference： [1] Russian Chemical Bulletin, 1998, vol. 47, # 9, p. 1732 - 1735

3
[ 110-91-8 ]
[ 57-57-8 ]
[ 4497-04-5 ]

Reference： [1] Patent: US2526558, 1948, ,
[2] Journal of the American Chemical Society, 1951, vol. 73, p. 3168,3171

4
[ 62131-51-5 ]
[ 4497-04-5 ]
[ 108-95-2 ]

Reference： [1] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical & Analytical, 1982, vol. 21, # 5, p. 515 - 516

[ 4497-04-5 ] Synthesis Path-Downstream 1~73

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).

Reference： [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 ]

Reference： [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 ]

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

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

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

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

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

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

Reference： [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).

Reference： [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 ]

Reference： [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 ]

Reference： [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 ]

Reference： [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 ]

Reference： [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.

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

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

Reference： [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)+.

Reference： [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.

Reference： [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 ]

Reference： [1]Journal of Combinatorial Chemistry,2010,vol. 12,p. 676 - 686

46
[ 4497-04-5 ]
C₄₂H₄₁N₄O₈Pol [ No CAS ]
[ 35661-60-0 ]
[ 1241876-11-8 ]

Reference： [1]Journal of Combinatorial Chemistry,2010,vol. 12,p. 676 - 686

47
[ 4497-04-5 ]
C₄₂H₄₁N₄O₈Pol [ No CAS ]
N-(9-fluorenylmethoxycarbonyl)-3-(β-naphthyl)-L-alanine [ No CAS ]
[ 1241875-69-3 ]

Reference： [1]Journal of Combinatorial Chemistry,2010,vol. 12,p. 676 - 686

48
[ 4497-04-5 ]
C₃₉H₄₃N₄O₈Pol [ No CAS ]
[ 35661-40-6 ]
[ 1241876-55-0 ]

Reference： [1]Journal of Combinatorial Chemistry,2010,vol. 12,p. 676 - 686

49
[ 4497-04-5 ]
C₃₉H₄₃N₄O₈Pol [ No CAS ]
[ 86123-10-6 ]
[ 1241876-46-9 ]

Reference： [1]Journal of Combinatorial Chemistry,2010,vol. 12,p. 676 - 686

50
[ 4497-04-5 ]
C₅₈H₅₉N₁₃O₁₆S₅ [ No CAS ]
C₆₅H₇₀N₁₄O₁₈S₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 366 - 369

51
[ 4497-04-5 ]
14-dehydroxy-11,12-didehydroandrographolide [ No CAS ]
C₂₇H₃₉NO₆ [ No CAS ]
C₃₄H₅₀N₂O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%; 24%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃;	General procedure: Compound 2 (100 mg, 0.30 mmol) and pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester (194 mg, 0.90 mmol) were dissolved in dry dichloromethane. EDCI (239 mg, 1.20 mmol) and a catalytic amount of DMAP were then added, and the reaction mixture was stirred at 25 for 3-10 h. The solvent wasevaporated under reduced pressure to afford white powder. The white powder was dissolved in CH2Cl2 and was then washed with dilute hydrochloric acid, aq NaHCO3,brine, and water successively. The CH2Cl2 phase was driedover anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silicagel column chromatography (gradient elution, EtOAc/PE = 1:5to 1:2) to afford 3b (white powder, 50 mg, 0.071 mmol, 23.7%) and 3c (white powder, 40 mg, 0.077 mmol, 25.7%).Compounds 3d-k were prepared with similar protocols.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4056 - 4060

52
[ 4497-04-5 ]
[ 1446981-14-1 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5757 - 5772

53
[ 4497-04-5 ]
C₅₀H₅₀N₁₀O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 5757 - 5772

54
[ 4497-04-5 ]
[ 1972-05-0 ]
3-methoxy-2-((6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylphenyl 3-morpholinopropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With 2-pyrrolidinopyridine; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;	3-Methoxy-2-((6R)-3-methyl-6-(prop-l-en-2-yl)cyc 1 ohex-2-enyl)-5- pentyiphenyl 3-morpholinopropanoate (HU-435) was prepared from plant-derived cannabidiol which was converted to mono-methoxy CBD. Dicyclohexylcarbodiimide (DCC, 3.2 mmoles) was added to 4-morpholino propionic acid (3.2 mmoles), monomethoxy CBD (1.6 mmoles) and pyrrolidinopyridine (0.32 mmoles) in dry CH2C12 (20 ml). The reaction mixture was stirred at room temperature overnight (precipitation of dicyclohexylurea, DCU, was seen within 10 minutes). The DCU was filtered and the solution was concentrated and purified on silica gel column using 50 % ether in petroleum ether as eluent. HU-435 was afforded at a 28 % yield. NMR (500 MHz, in CDC13): ppm: 6.52 (1H, s), 6.41 (1H, s), 5.20 (1H, s), 4.47 (1H, s). 4.39, (1H, s), 3.72- 3.67 (7H, m), 2.85-2.40 (9H, m), 2.20-1.95, (2H, m), 1.65, (3H, s), 1.59, (3H, s), 1.30-1.22, (6H, m), 0.86, (3H, t).

Reference： [1]Patent: WO2015/162610,2015,A1 .Location in patent: Page/Page column 16

55
[ 4497-04-5 ]
1-(4-(4-aminopiperidin-1-yl)-3-(trifluoromethyl)phenyl)-3-(3-(6,7-dimethoxyquinolin-4-yloxy)phenyl)urea hydrochloride [ No CAS ]
N-(1-(4-(3-(3-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)ureido)-2-(trifluoromethyl)phenyl)piperidin-4-yl)-3-morpholinopropanamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 8456 - 8472

56
[ 4497-04-5 ]
C₂₂H₂₉FN₃O₉P [ No CAS ]
methyl ((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-4-methyl-3-((3-morpholinopropanoyl)oxy)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-valinate [ No CAS ]

Reference： [1]Patent: WO2016/123905,2016,A1 .Location in patent: Paragraph 066; 069

57
[ 4497-04-5 ]
[ 19333-10-9 ]
bis[3-(Ν-morpholine)propylester]silicon phthalocyanine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	Reflux; Inert atmosphere;	Under nitrogen, silicon phthalocyanine dichloride (244.7mg, 0.4mmol), 3-(N-morpholino)propanoic acid 1.2 - 2.4mmol (preferably 2.0 mmol) were added to toluene or xylene or dioxane 20 - 50 ml (preferably toluene, 30 ml) and refluxed for 20-36 hours (preferably 24 hours). The solvent was removed by vacuum rotary evaporation, dissolved in 100 ml of dichloromethane and centrifuged The solution was extracted with water (3 x 100 ml). The organic layer was collected and then extracted with dilute hydrochloric acid (0.1 - 0.5 mmol) and the aqueous layer was collected. The aqueous layer was neutralized with 1 M sodium hydroxide, precipitated as a blue precipitate, centrifuged, washed with water and dried in vacuo to give a blue product in 43percent yield. The maximum absorption peak of the product in DMF is at 681 nm and the maximum absorption wavelength in the aqueous solution is at 691-700 nm.

Reference： [1]Patent: CN104650129,2017,B .Location in patent: Paragraph 0046-0049

58
[ 4497-04-5 ]
C₇H₁₂ClNO₂*ClH [ No CAS ]

Reference： [1]RSC Advances,2017,vol. 7,p. 47297 - 47308

59
[ 4497-04-5 ]
C₃₄H₃₈N₁₀O₆*2ClH [ No CAS ]

Reference： [1]RSC Advances,2017,vol. 7,p. 47297 - 47308

60
[ 4497-04-5 ]
6-(3-isopropyl-5-(piperidin-4-yl)-1H-indol-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine trifluoroacetate [ No CAS ]
1-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)-3-morpholinopropan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine; HATU; In acetonitrile; at 20℃;	To a two dram vial were added the TFA salt of (2480) 6-(3-isopropyl-5-(piperidin-4-yl)-lH-indol-2-yl)-7-methyl-[l,2,4]triazolo[l,5-a]pyridine (0.025 g, 0.053 mmol), CH3CN, HATU (1.0 equiv.), TEA (3.0 equiv.), and (2481) 3-morpholinopropanoic acid (0.250 g, 1.570 mmol). The reaction vial was capped and stirred overnight at room temperature. The mixture was diluted with solvent (90: 10:0.1 CH3CN: Water: TF A) and filtered. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge CI 8, 19 x 200 mm, 5-muiotaeta particles; Mobile Phase A: 5 :95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95 :5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-70percent B over 19 minutes, then a 3-minute hold at 100percent B; Flow: 20 mL/min. (2482) Fractions containing the product were combined and dried via centrifugal evaporation to afford (2483) l-(4-(3-isopropyl-2-(8-methyl-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-lH-indol-5-yl)piperidi n-l-yl)-3-morpholinopropan-l-one (21.2 mg, 0.041 mmol, 78 percent yield). LCMS MH+: 515.2 HPLC Ret. Time 1.52 min. Method QC-ACN-AA-XB. NMR (500 MHz, DMSO-de) delta 8.85-8.72 (m, 1H), 8.55-8.48 (m, 1H), 7.63-7.50 (m, 2H), 7.36-7.22 (m, 1H), 7.06-6.94 (m, 1H), 4.63-4.51 (m, 1H), 4.06-3.98 (m, 1H), 3.63-3.56 (m, 5H), 3.30-3.20 (m, 1H), 2.70-2.53 (m, 1 1H), 2.46-2.39 (m, 3H), 1.89-1.79 (m, 2H), 1.70-1.59 (m, 1H), 1.53-1.46 (m, 1H), 1.45-1.39 (m, 6H).

Reference： [1]Patent: WO2018/5586,2018,A1 .Location in patent: Page/Page column 343; 344

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3α,7α-dihydroxy-6α-ethyl-5β-cholanic acid benzyl ester [ No CAS ]
C₄₀H₆₁NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.12 g	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	Intermediate 3-1 (0.250 g, 0.49 mmol, 1.0 eq),3-morpholinepropionic acid (0.078 g, 0.49 mmol, 1.0 eq) and4-dimethylaminopyridine (0.180 g, 1.47 mmol, 3.0 eq), 10 mLDichloromethane, added in batchesEDCI (0.189g,0.98 mmol, 2.0 eq), stirred at room temperature overnight. TLC showed that after the conversion of the starting material was completed, it was quenched with water, and the crude product was obtained by DCM, and silica gel column chromatography (PE/EA=5/1) gave 0.120 g of pale yellow oil.

Reference： [1]Patent: CN108218946,2018,A .Location in patent: Paragraph 0096; 0099; 0102-0103

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1-(2-(aminomethyl)-6-(tert-butyl)pyrimidin-4-yl)-3-((1S,4R)-4-((3-(tert-butyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)urea [ No CAS ]
N-((4-(tert-butyl)-6-(3-((1S,4R)-4-((3-(tert-butyl)[1,2,4]-triazolo[4,3-a]pyridin-6-yl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)ureido)pyrimidin-2-yl)methyl)-3-morpholinopropanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1h;	A solution of Intermediate (Table 1, 1 eq), HOBt (1.2 eq) and EDC (1.2 eq) in DCM (3-5 ml) was treated with the relevant acid (Reagent, Table 1, 1.2 eq). The reaction mixture was stirred at RT for 1 hour. The reaction mixture was diluted with DCM and 1120and the two phases were separated. The aqueous phase was extracted with DCM (x 3) and the combined organic phases were passed through a phase separator and the solvent was removed under reduced pressure. Purification by FCC, eluting with 0-10percent 2N NH3 in MeOH/DCM afforded the title compound (10percent - 50percent). Where necessary further purification by, for example, trituration, crystallisation, HPLC, MDAP or SFC could beundertaken.

Reference： [1]Patent: WO2018/224423,2018,A1 .Location in patent: Page/Page column 210; 229

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methyl (S)-4-(5,5,8a-trimethyl-2-(4-phenylpiperidin-4-carbonyl)-1,2,3,5,8,8a-hexahydroisoquinolin-6-yl)benzoate [ No CAS ]
C₃₈H₄₇N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Prepared a solution of HATU (821 mg, 2.16 mmol) in DMF (24 mL). To each of the 48 carboxylic acids weighed into 16 x 48 mm threaded vials was added 0.5 mL of the HATU solution. The reactions were agitated at 350 rpm on an Innova platform shaker at room temperature for 10 minutes. Prepared a solution of the (S)-methyl 4-(5,5,8a-trimethyl-2- (4-phenylpiperidine-4-carbonyl) 1,2,3,5, 8, 8a-hexahydroisoquinolin-6-yl)benzoate (720 mg, 1.44 mmol) and DIPEA (1.0 mL, 5.8 mmol) in DMF (24 mL). Added 0.5 mL of the (S)-methyl 4-(5,5,8a-trimethyl-2-(4-phenylpiperidine-4-carbonyl) 1,2,3, 5, 8,8a- hexahydroisoquinolin-6-yl)benzoate/ DIPEA solution to each of the reaction vials. Capped vials and agitated at 350 rpm on an Innova platform shaker at room temperature for 18 hrs. Samples were blown down in the Zymark tabletop dryer at 35 C for 3 hours. Prepared a solution of Lithium Hydroxide Monohydrate (483 mg, 11.5 mmol) in water (9.6 mL). To each of the reaction vials was added 0.8 mL dioxane and 0.2 mL of the lithium hydroxide solution. Capped vials and agitated at 350 rpm on an Innova platform shaker at 70 C for 18 hrs. Added 100 glacial acetic acid to each vial. Samples were blown down in the Zymark tabletop dryer at 35 C for 3 hours. Added 1.0 mL DMF to each vial. Transferred contents to a 96 well 2-mL filter plate, collecting into a 96 well deepwell plate. Rinsed reaction vials w/ 500 DMF each and transferred rinses to the appropriate wells of the filter plate. Transferred contents to 16x48 mm threaded vials. Submitted for HPLC purification, and LCMS analyses, results are shown in the spreadsheet. See Table 12.

Reference： [1]Patent: WO2018/2848,2018,A1 .Location in patent: Page/Page column 45; 119-120; 121

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N-(4-(aminomethyl)benzyl)-2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzamide [ No CAS ]
2-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-N-(4-((3-morpholinopropanamido)methyl)benzyl)benzamide [ No CAS ]