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Chemical Structure| 109-11-5 Chemical Structure| 109-11-5

Structure of Morpholin-3-one
CAS No.: 109-11-5

Chemical Structure| 109-11-5

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Product Citations

Product Citations

Rodriguez, Diego F. ; Duran-Osorio, Francisca ; Duarte, Yorley ; Olivares, Pedro ; Moglie, Yanina ; Dua, Kamal , et al.

Abstract: Green chemistry implementation has led to promising results in waste reduction in the pharmaceutical industry. However, the early sustainable development of pharmaceutically active compounds and ingredients remains a considerable challenge. Herein, we wish to report a green synthesis of new pharmaceutically active peptide triazoles as potent factor Xa inhibitors, an important drug target associated with the treatment of diverse cardiovascular diseases. The new inhibitors were synthesized in three steps, featuring cycloaddition reactions (high atom economy), microwave-assisted organic synthesis (energy efficiency), and copper nanoparticle catalysis, thus featuring Earth-abundant metals. The molecules obtained showed FXa inhibition, with IC50-values as low as 17.2 μM and no associated cytotoxicity in HEK293 and HeLa cells. These results showcase the environmental potential and chemical implications of the applied methodologies for the development of new molecules with pharmacological potential.

Keywords: DOACs ; FXa inhibitors ; Ullmann-Goldberg reaction ; click chemistry ; drug discovery ; green chemistry ; microwave synthesis

Purchased from AmBeed: ; ; ;

Alternative Products

Product Details of [ 109-11-5 ]

CAS No. :109-11-5
Formula : C4H7NO2
M.W : 101.10
SMILES Code : O=C1COCCN1
MDL No. :MFCD00631009
InChI Key :VSEAAEQOQBMPQF-UHFFFAOYSA-N
Pubchem ID :66953

Safety of [ 109-11-5 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319
Precautionary Statements:P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313

Computational Chemistry of [ 109-11-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 7
Num. arom. heavy atoms 0
Fraction Csp3 0.75
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 27.23
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

38.33 ?2

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.06
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

-0.8
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

-1.25
Log Po/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.

-1.19
Log Po/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

0.84
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

-0.27

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

0.04
Solubility 110.0 mg/ml ; 1.09 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.

0.47
Solubility 301.0 mg/ml ; 2.98 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

-0.59
Solubility 25.8 mg/ml ; 0.255 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

 Low
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.

-7.48 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)

 1.25

Application In Synthesis of [ 109-11-5 ]

* 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 [ 109-11-5 ]

[ 109-11-5 ] Synthesis Path-Downstream   1~31

  • 1
  • [ 7397-62-8 ]
  • aziridinium tetrafluoroborate [ No CAS ]
  • [ 109-11-5 ]
  • 2
  • [ 109-11-5 ]
  • [ 24424-99-5 ]
  • [ 142929-48-4 ]
YieldReaction ConditionsOperation in experiment
94.21% With dmap; triethylamine; In dichloromethane; at 20℃; for 16h; To a solution of <strong>[109-11-5]morpholin-3-one</strong> (6.4 g, 63.30 mmol, 1.0 eq) in DCM (100 mL) at 20 C was added TEA (19.22 g, 189.90 mmol, 26.4 mL, 3.0 eq), DMAP (1.55 g, 12.66 mmol, 0.2 eq) and then Boc2O (27.63 g, 126.60 mmol, 29.1 mL, 2.0 eq), and the resulting mixture was stirred at 20 C for 16 h. The reaction mixture was concentrated to remove the solvent and the residue was diluted with water (200 mL) and extracted with EA (100 mL *3). The combined organic layers were washed with water (50 mL *3) and then brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give tert-butyl 3-oxomorpholine-4- carboxylate (12.0 g, 59.64 mmol, 94.21% yield) as yellow oil. 1H NMR (400 MHz, CDCI3) δ 4.23 (s, 2H), 3.93 - 3.87 (m, 2H), 3.79 - 3.72 (m, 2H), 1.55 (s, 9H). di-tert-butyl 3-oxomorpholine-2,4-dicarboxylate
76% With dmap; In tetrahydrofuran; at 20℃; for 24h; Step 1: 7?ri-butyl 3-oxomorpholine- -carboxylate [00197] Morpholin-3-one (35g, 346.2 mmol) was slurried in dry THF (350ml). Tert- butoxycarbonyl tert- butyl carbonate (105.8g, 11 1.4 mmol) was added, followed by DMAP (4.2g, 34.6 mmol). The mixture began to degass rapidly over 30 minutes. The resulting orange solution was stirred at ambient temperature for 24hrs. The mixture was then cooled in an ice bath and imidazole (23.57g, 346.2 mmol) was added. After stirring for 30 minutes ethyl acetate (500ml) was added. The organic phase was separated and washed with 1% (v/v) HC1 (500ml), then sat NaHC03 (500ml), then brine (200ml), dried (MgS04), filtered and concentrated. The crude was purified through a plug of silica gel, eluting with ethyl acetate. The filtrate was evaporated to give an oil. 40/60 pet ether (200ml) was added slowly with stirring to generate a white solid. The mixture was aged for 30 minutes, cooled briefly in an ice bath and filtered, washing with 40/60 pet ether. Tert-butyl 3-oxomorpholine-4- carboxylate was obtained as a white solid which was dried under vacuum (52.7g, 76%); lH- NMR (CDCI3) 1.47 (9H, s), 3.68 (2H, m), 3.82 (2H, m), 4.15 (2H, s); MS ES(+) 145.8 (M+ - tBu).
66% With dmap; In tetrahydrofuran; at 20℃;Inert atmosphere; Morpholmn-3-one (8.00 g, 79.2 mmcl) was dissolved in dry THE (100 mL), and then (Boc)20 (25.9 g, 0.119 mol) and DMAP (966 mg, 7.92 mmol) were added. The mixture was stirred at room temperature under N2 atmosphere overnight. Imidazole (5.39 g, 79.2 mmol) was added. After stirred for 30 mm EtOAc (150 mL) was added. The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give oil whichwas solidified after standing. The solid was washed with PE (100 mL)to afford the desired compound (10.5 g, yield 66%) as a white solid.1H NMR (300 MHz, CDCI3): 64.20 (s, 2H), 3.88-3.85 (m, 2H), 3.74-3.70 (m, 2H), 1.51 (s, 9H).LC-MS (mobile phase: from 95% water and 5% CH3CN to 5% water and 95% CH3CN in 3.0mm, purity is >95%, Rt = 1.56 mm; MS Calcd.: 201; MS Found: 202 [M+H] 146 [M-56+H].
  • 3
  • [ 109-11-5 ]
  • [ 945559-61-5 ]
  • 5-chloro-thiophene-2-carboxylic acid-N-({1-[4-(3-oxo-morpholin-4-yl)-phenyl]-1H-imidazol-4-yl}-methyl)-amide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 8-quinolinol; potassium carbonate;copper(l) iodide; In dimethyl sulfoxide; at 130℃; A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 prepared in Example 1 (33 mg, 0.074 mmol), <strong>[109-11-5]3-morpholinone</strong> prepared above (22 mg, 0.218 mmol), 8-hydroxyquinoline (7 mg, 0.048 mmol) and K2CO3 (30 mg, 0.217 mmol) in DMSO (0.5 mL) was degassed before being charged with CuI (14 mg, 0.073 mmol). The mixture in a sealed tube was heated at 130 C. overnight. The mixture was then purified by HPLC to give the title compound (3 mg). MS 417.0 and 419.0 (M+H, Cl pattern).
  • 4
  • [ 109-11-5 ]
  • [ 2363-16-8 ]
  • [ 864296-47-9 ]
YieldReaction ConditionsOperation in experiment
100% With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 95℃; for 16h; 1.00 g (3.85 mmol) methyl 4-bromo-3-nitro-benzoate are dissolved in 6 ml dioxane with 389 mg (3.85 mmol) <strong>[109-11-5]morpholin-3-one</strong> under a nitrogen atmosphere and 36.6 mg (40 μmol) tris-(dibenzylideneacetone)-dipalladium(0), 67.1 mg (116 μmol) xantphos and 1.75 g (5.38 mmol) caesium carbonate are added. Under a nitrogen atmosphere and with stirring, the reaction mixture is heated to 95 C. for 16 hours. Then it is filtered, the solution is evaporated down i. vac. and evaporated with ether. The residue is further reacted without any more purification. Yield: 1.31 g (quantitative). C12H12N2O6 (280.24) Mass spectrum: (M+H)+=281 Rf value: 0.47 (Reversed phase 8; methanol/5% sodium chloride solution=6:4)
  • 5
  • [ 109-11-5 ]
  • [ 540-37-4 ]
  • [ 438056-69-0 ]
YieldReaction ConditionsOperation in experiment
53.45% With copper(l) iodide; 8-quinolinol; potassium carbonate; In dimethyl sulfoxide; at 130℃; for 12h;Inert atmosphere; General procedure: Compound 1 (5g, 22.83mmol) was dissolved in DMSO (120mL), followed by the addition of 2-Piperidinone (4.53g, 45.66mmol), CuI (0.43g, 2.28mmol), 8-hydroxy-quinoline (0.66g, 4.57mmol) and K2CO3 (9.46g, 68.49mmol). The mixture was heated to 130C under N2 for 12h, cooled, and quenched with water (120mL). The organics were extracted with ethyl acetate (2×150mL) and dried (Na2SO4). Purification by silica gel column chromatography (n-hexane/ethyl acetate, 5/1 to 3/1, as eluent) afforded compound 2 as faint yellow (2.80g, 64.47%).
50% With copper(l) iodide; N,N-dimethyl-formamide; at 120℃;Inert atmosphere; Under nitrogen, 8 (21.3 g, 0.21 mol), K3C0349.2 g,Catalytic amount of Cul,P-iodoaniline (35.5 g, 0.16 mil) was added to DMF and heated to 120 C. The color of the reaction solution was gradually changed from yellow to dark brown. Reaction time 30 ~ 40h. The reaction is completed, add anhydrous methanol 142ml, reflux lh, hot filter, evaporated the filtrate, add 355ml water, stirring lh, filter, evaporated the filtrate, add 142ml anhydrous ethanol, activated carbon decolorization, reflux lh, hot Filtration, the filtrate cooling crystallization, pale yellow solid 15.5g, yield 50%.
With potassium carbonate; N,N`-dimethylethylenediamine;copper(l) iodide; In 1,4-dioxane; at 110℃; To a blue solution of 3 -morpholinone (250 mg, 2.48 mmol), 4-iodoaniline (650 mg, 2.97 mmol), CuI (47 mg, 0.25 mmol) and N,N'-dimethylethylenediamine (0.040 mL, 0.372 mmol) in dioxane (5 mL) in a pressure bottle, K2CO3 (683 mg, 4.95 mmol) was added. The mixture was heated at 110 0C overnight. After being cooled to room temperature, the crude dark solution was loaded to two preparative TLC plates, eluted with EtOAc/MeOH (95/5) to give the desired product as off-white solid (240 mg). MS 193.l (M+H).
With potassium carbonate;copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃; B. Preparation of 4-(3-oxo-morpholin-4-yl)phenylamine;[0440] To a blue solution of <strong>[109-11-5]3-morpholinone</strong> (250 mg, 2.48 mmol), 4-iodoaniline (650 mg, 2.97 mmol), CuI (47 mg, 0.25 mmol) and N,N'-dimethylethylenediamine (0.040 mL, 0.372 mmol) in dioxane (5 mL) in a pressure bottle, K2CO3 (683 mg, 4.95 mmol) was added. The mixture was heated at 110 C overnight. After being cooled to room temperature, the crude dark solution was loaded to two preparative TLC plates, eluted with EtOAc/MeOH (95/5) to give the desired product as off-white solid (240 mg). MS 193.1 (M+H).
With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃; A. Preparation of 4-(3-oxo-morpholin-4-yl)phenylamine; [0169] NaH (60%, 3.2 g, 80 mmol) in a flask was washed with hexane. To the flask cooled in an ice-bath, a solution of ethanolamine (4.4 mL, 73 mmol) in dioxane (40 mL) was added. The mixture was heated at reflux for 10 min until no H2 gas evolved. The thick slurry was then cooled in an ice-bath, and a solution of ethyl chloroacetate (8.9 g, 73 mmol) in dioxane (15 mL) was added. The reaction mixture was heated at reflux for Ih. It was then filtered. The filtrate was concentrated in vacuo to give an oil, which was purified by a short flash column, eluted with EtOAc/MeOH (95/5) to give a white solid (1.9 g), as 3-morphorinone.[0170] To a blue solution of <strong>[109-11-5]3-morpholinone</strong> (250 mg, 2.48 mmol), 4-iodoaniline (650 mg, 2.97 mmol), CuI (47 mg, 0.25 mmol) and N,N'-dimethylethylenediamine (0.040 mL, 0.372 mmol) in dioxane (5 mL) in a pressure bottle, K2CO3 (683 mg, 4.95 mmol) was added. The mixture was heated at 110 C overnight. After being cooled to room temperature, the crude dark solution was loaded to two preparative TLC plates, eluted with EtOAc/MeOH (95/5) to give the desired product as off-white solid (240 mg). MS 193.1 (M+H).

  • 6
  • [ 109-11-5 ]
  • [ 19524-06-2 ]
  • [ 887928-36-1 ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate; trans-1,2-cyclohexanediamine;copper(l) iodide; In 1,4-dioxane; at 110℃; A mixture of 4-bromopyridine hydrochloride (778 mg, 4.00 mmol), <strong>[109-11-5]3-morpholinone</strong> (404 mg, 4.00 mmol), K3PO4 (1.70 g, 8.00 mmol) and 1,2-trans-diaminocyclohexane (200 uL, 1.60 mmol) in dioxane (10 mL) was degassed with Ar before being charged with CuI (152 mg, 0.80 mmol). The mixture in a sealed tube was heated at 110 0C overnight. The mixture was applied to a silica gel column, which was then eluted with 2-5% MeOH in CH2Cl2 to give the desired product (85 mg). MS 179.5 (M+H)
With potassium phosphate;copper(l) iodide; trans-1,2-cyclohexanediamine; In 1,4-dioxane; at 110℃;Heating in a sealed tube; EXAMPLE 142 Preparation of (2R) 4-(3-morpholinon-4-yi)piperidin-l-yl-2-phenyl-2-(4- chlorophenylaminocarbonylamino)-acetamide; A. Preparation of 4-(3-morpholinon-4-yl)piperidine; [0509] A mixture of 4-bromopyridine hydrochloride (778 mg, 4.00 mmol), <strong>[109-11-5]3-morpholinone</strong> (404 mg, 4.00 mmol), K3PO4 (1.70 g, 8.00 mmol) and 1,2-trans-diaminocyclohexane (200 uL, 1.60 mmol) in dioxane (10 mL) was degassed with Ar before being charged with CuI (152 mg, 0.80 mmol). The mixture in a sealed tube was heated at 110 0C overnight. The mixture was applied to a silica gel column, which was then eluted with 2-5% MeOH in CH2Cl2 to give the desired product (85 mg). MS 179.5 (M+H).[0510] A solution of the compound (85 mg, 0.48 mmol) and PtO2 (50 mg) in HOAc (8 mL) was hydrogenated under 40 psi on a Parr shaker overnight. The mixture was filtered through Celite. The filtrate was concentrated in vacuo. To the residue, aqueous IN HCl (3 mL) was added. The solution was then concentrated in vacuo to give the desired product as hydrochloride salt (91 mg). MS 185.2 (M+H).
  • 7
  • [ 141-43-5 ]
  • [ 105-39-5 ]
  • [ 109-11-5 ]
YieldReaction ConditionsOperation in experiment
52% To a solution of ethanolamine (197 mmol, 1.1 equiv) in i-PrOH (100 mL) was portionwise added small pieces ofsodium (197 mmol, 1.1 equiv). The mixture was heated at 50 C for 5 h, and the resulting yellow solution was cooled in an ice-water bath. Ethyl chloroacetate (179 mmol, 1.0equiv) was dropwise added at 0 C, and the resulting yellow suspension was heated at 80 C for 2 h. Insoluble materials were removed by paper filtration and washed with i-PrOH. The combined filtrate and washings were concentrated in vacuo, and the resulting brown solids were recrystallized from iPrOH/EtOAc to afford 3-morpholinone in 52% yield.
36% Under nitrogen, Na (45.26 g, 1.97 mol)Was added in portions to a mixed solution of dioxane and isopropanol, and the temperature was raised to 50 C to promote the dissolution of Na(Na dissolves very slowly, generally takes 4 to 5 hours).After all the Na is dissolved,Dropping amino ethanol (98ml, 1.67mo) 1, drop Bi, 50 C stirring 30 ~ 40min.Was transferred to cold water, controlled at -10 C, and ethyl chloroacetate (182 ml, 1.75mo 1) was added dropwise. Drop 10 C stirring 30 ~ 40min.Gradually heated to 80 C, the reaction about 10h, finished, hot filter, the filtrate evaporated to dry yellow oily liquid, dissolved with ethyl acetate, standing, the above clear ethyl acetate layer out of cooling crystallization,To be precipitated after the white needle-like crystals after filtration, to obtain moles of crude ketone. The remaining yellow oil was recrystallized again as described above in a yield of 36%
Ethanolamine is reacted in the presence of sodium hydride with ethyl chloroacetate to give morpholin-3-one (m.p. 100-102 C.) and the desired acid obtained therefrom by heating with barium hydroxide and subsequent treatment with sulphuric acid.
EXAMPLE 95; N-[4-(3-oxo-morpholin-4-yl)phenyl]-2-(2-methylphenyl)-2-(4- chlorophenylaminocarbonylamino)-acetamide; A. Preparation of 3 -morpholinone; EPO <DP n="100"/>[0439] NaH (60%, 3.2 g, 80 mmol) in a flask was washed with hexane. To the flask cooled in an ice-bath, a solution of ethanolamine (4.4 mL, 73 mmol) in dioxane (40 mL) was added. The mixture was heated at reflux for 10 min until no H2 gas evolved. The thick slurry was then cooled in an ice-bath, and a solution of ethyl chloroacetate (8.9 g, 73 mmol) in dioxane (15 mL) was added. The reaction mixture was heated at reflux for Ih. It was then filtered. The filtrate was concentrated in vacuo to give an oil, which was purified by a short flash column, eluted with EtOAc/MeOH (95/5) to give a white solid (1.9 g).
A. Preparation of 4-(3-oxo-morpholin-4-yl)phenylamine; [0169] NaH (60%, 3.2 g, 80 mmol) in a flask was washed with hexane. To the flask cooled in an ice-bath, a solution of ethanolamine (4.4 mL, 73 mmol) in dioxane (40 mL) was added. The mixture was heated at reflux for 10 min until no H2 gas evolved. The thick slurry was then cooled in an ice-bath, and a solution of ethyl chloroacetate (8.9 g, 73 mmol) in dioxane (15 mL) was added. The reaction mixture was heated at reflux for Ih. It was then filtered. The filtrate was concentrated in vacuo to give an oil, which was purified by a short flash column, eluted with EtOAc/MeOH (95/5) to give a white solid (1.9 g), as 3-morphorinone.[0170] To a blue solution of 3-morpholinone (250 mg, 2.48 mmol), 4-iodoaniline (650 mg, 2.97 mmol), CuI (47 mg, 0.25 mmol) and N,N'-dimethylethylenediamine (0.040 mL, 0.372 mmol) in dioxane (5 mL) in a pressure bottle, K2CO3 (683 mg, 4.95 mmol) was added. The mixture was heated at 110 C overnight. After being cooled to room temperature, the crude dark solution was loaded to two preparative TLC plates, eluted with EtOAc/MeOH (95/5) to give the desired product as off-white solid (240 mg). MS 193.1 (M+H).
500 mg under a nitrogen atmosphere, sodium hydride (60 wt %, 1.2 g) and a solution of dioxane (25 ml) was cooled to 0 C, ethanolamine (1.5 ml) was added at room temperature and stirred for 30 minutes. This reaction liquid is cooled to 0 C, after 30 minutes stirring at room temperature ethyl chloroacetate (2.7 ml) was added, this reaction mixture was further stirred and heated for 40 minutes under reflux condition. After cooling the reaction liquid, solid is removed by filtration. Under a reduced pressure by concentrating somas, refining residues is obtained in column chromatography (ethyl acetate: methanol = 19:1), obtained as a colorless solid morpholin-3-one (500 mg).

  • 8
  • [ 109-11-5 ]
  • [ 212267-75-9 ]
  • 4-(8-[(2,6-dimethylphenyl)methyl]amino}-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-3-morpholinone [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; N,N`-dimethylethylenediamine;copper(l) iodide; In 1,4-dioxane; at 140℃; for 12h;Microwave synthesizer; Example 114-(8-[(2,6-Dimethylphenyl)methyl|amino}-2,3-dimethylimidazo[l,2-α]pyridin-6- yl)-<strong>[109-11-5]3-morpholinone</strong> hydrochlorideA mixture of 6-bromo-N-[(2,6-dimethylphenyl)methyl]-2,3-dimethylimidazo[ 1 ,2- α]pyridin-8-amine (100 mg, 0.28 mmol; WO 98/37080), <strong>[109-11-5]3-morpholinone</strong> (56 mg, 0.56 mmol; US 3308121), copper(I) iodide (16 mg, 0.083 mmol), potassium carbonate (138 mg, 1.0 mmol) and ΛζN'-dimethylethylenediamine (7.4 mg, 0.083mmol) in dioxane (2 mL) was heated in an Initiator Microwave Synthesizer at 140C for 12 hours. The cooled mixture was applied to an Isolute SCX cartridge. Elution with methanol, followed by water, then methanol then IM NH3 in methanol gave, after evaporation, the product which was further purified by chromatography on silica gel. Elution with dichloromethane/methanol (0 to 10%) gave a pale yellow solid which was dissolved in methanol (2 mL), Ethereal HCl (IM; 0.3ml) was added and the solvent evaporated to give the title compound as a pale yellow solid; MS (ES+ve): [M+H]+ at m/z 379 (C22H26N4O2 requires [M+H]+ at m/z 379).
  • 9
  • [ 109-11-5 ]
  • [ 910777-46-7 ]
  • 4-[2,3-dimethyl-8-([4-(methyloxy)phenyl]methyl}oxy)imidazo[1,2-a]pyridin-6-yl]-3-morpholinone [ No CAS ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; N,N`-dimethylethylenediamine;copper(l) iodide; In 1-methyl-pyrrolidin-2-one; at 120℃; for 18h;Microwave synthesizer; Description 12 4-[2,3-Dimethyl-8-({ [4-(methyloxy)phenyl] methyI}oxy)imidazo[l,2-α]pyridin-6-A mixture of 6-bromo-2,3-dimethyl-8-([4-(methyloxy)phenyl]methyl} oxy)imidazo[l,2-α]pyridine (589 mg, 1.63 mmol; Description 5), 3-moφholinone (330 mg, 3.27 mmol; US 3308121), cesium carbonate (1.86 g, 5.7 mmol), copper(I) iodide (89 mg, 0.47 mmol) and ΛζN'-dimethylethylenediamine (42 mg, 0.47 mmol) in N-methylpyrrolidinone (10 mL) was heated in an Initiator Microwave Synthesizer at 120C for 18 hours. The mixture was applied to an Isolute SCX cartridge and washed with methanol followed by elution with 2M NH3 in methanol. The basic fractions were combined and evaporated under reduced pressure. This residue was purified by column chromatography on silica eluting with a 50-100% ethyl acetate in hexane gradient to afford the title compound. MS (ES+ve): [M+H]+ at m/z 382 (C2]H23N3O4 requires [M+H]+ at m/z 382).
  • 10
  • [ 109-11-5 ]
  • [ 34662-31-2 ]
  • [ 927870-46-0 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 24h; A suspension of 5-chloro-2-nitrobenzonitrile (2.41 g), <strong>[109-11-5]morpholin-3-one</strong> (2 g), cesium carbonate (6.45 g), tris(dibenzylideneacetone)dipalladium (120 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (230 mg) in 30 ml dioxane was heated for 24 h at 120 C. The reaction mixture was cooled to 25 C., diluted with CH2Cl2 and filtered through decalite. The organic layer was washed with water and brine and purified by chromatography (silica gel, AcOEt) to yield 2-nitro-5-(3-oxo-morpholin-4-yl)-benzonitrile as a yellow solid (1.77 g). MH+=248.3
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; A suspension of 5-chloro-2-nitrobenzonitrile (2.41 g), <strong>[109-11-5]morpholin-3-one</strong> (2 g), cesium carbonate (6.45 g), tris(dibenzylideneacetone)dipalladium (120 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (230 mg) in dioxane (30 ml) was heated overnight at 120 C. The reaction mixture was cooled, diluted with CH2Cl2 and filtered through decalite. Extraction (water and brine) and chromatography (silica gel, AcOEt) delivered 2-nitro-5-(3-oxo-morpholin-4-yl)-benzonitrile as a yellow solid (1.77 g). MS: 248.3 ([M+H]+).
  • 11
  • [ 109-11-5 ]
  • [ 1182728-08-0 ]
  • [ 1182728-10-4 ]
YieldReaction ConditionsOperation in experiment
85% With potassium carbonate;copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 110℃; for 20h;Inert atmosphere; 1.5) 4-(3-Benzylsulfanyl-2-ethyl-phenyl)-<strong>[109-11-5]morpholin-3-one</strong> (Intermediate 5): <n="48"/>Intermediate 4 (1.075 g, 3.5 mmol), <strong>[109-11-5]morpholin-3-one</strong> (389 mg, 3.85 mmol), CuI (67 mg, 0.35 mmol), N,N'-dimethylethylene diamine (75 μl, 0.7 mmol) and K2CO3 (1 ,064 g, 7.7 mmol) were suspended in toluene (30 ml) under argon and heated to 110 C for 2Oh. After cooling to RT the reaction mixture was quenched by addition of 100 ml sat. aq. NH4CI, 150 ml concentrated NH3 in water and 100 ml water and extracted three times with ethyl acetate. The organic layers were combined and washed with water and sat. aq. NaCI-solution, dried with MgSO4, filtered and evaporated to dryness. The resulting011 crystallizes upon standing and was triturated with n-heptane-MTBE (19:1). Yield: 974 mg, 85 %
85% With potassium carbonate;copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 110℃; for 20h;Inert atmosphere; 1.6) 4-(3-Benzylsulfanyl-2-ethyl-phenyl)-<strong>[109-11-5]morpholin-3-one</strong> (Intermediate 6): Intermediate 5 (1.075 g, 3.5 mmol), <strong>[109-11-5]morpholin-3-one</strong> (389 mg, 3.85 mmol), CuI (67 mg, 0.35 mmol), N,N'-dimethylethylene diamine (75 μl, 0.7 mmol) and K2CO3 (1 ,064 g , 7.7 mmol) were suspended in toluene (30 ml) under argon and heated to 1100C for 20 h. After cooling to RT the reaction mixture was quenched by addition of 100 ml sat. aq NH4CI, 150 ml cone. NH3 in water and 100 ml water and extracted three times with ethyl acetate. The organic layers were combined and washed with water and sat. aq NaCI-solution, dried with MgSO4, filtered and evaporated to dryness. The resulting oil crystallizes upon standing and was triturated with n-heptane-MTBE (19:1). Yield: 974 mg, 85 %
  • 12
  • [ 109-11-5 ]
  • [ 420-37-1 ]
  • [ 18596-80-0 ]
YieldReaction ConditionsOperation in experiment
44% In dichloromethane; at 20℃; To a solution of <strong>[109-11-5]3-morpholone</strong> (2.0 g, 20 mmol) in dichloromethane (40 mL) in a 100 mL single neck flask was added trimethyloxonium tetrafluoroborate (4.0 g, 27 mmol), the mixture was stirred at room temperature overnight. The mixture was quenched with saturated aqueous sodium bicarbonate solution (50 mL) under ice bath, and then adjusted pH to neutral. The mixture was extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the title compound as a transparent oil (1.0 g, 44%).‘H NIVIR (400 1VIFIz5 CDC13) 4.01 (d, J 1.2 H4 2H’), 3.65 (d, J 2.3 H4 3H), 3.62 (dd, J 6.5, 3.2 Hz; 2H’), 3.51 (dd, J 6.5, 2.9 Hz, 2H).
Example 9A5 -Methoxy-3 ,6-dihydro-2H- 1 ,4-oxazineA solution of 1.2 g (11.9 mmol) <strong>[109-11-5]morpholine-3-one</strong> in dichloromethane (70 ml) was cooled to 00C and treated with 25 g (238 mmol) dry sodium carbonate. After stirring for 10 min at 00C, 6.14 g (41.5 mmol) trimethyloxonium tetrafluoroborate were added at 00C. The mixture was allowed to warm to room temperature and stirred for 6 h. Water (100 ml) was added, and the organic layer was separated. The aqueous phase was extracted several times with dichloromethane, and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product thus obtained was used in the next step without further purification.GC-MS (method 3): R1 = 3.36 min; MS (ESIpos): m/z = 116 (M+H)+.
A solution of 1.2 g (1 1.9 mmol) <strong>[109-11-5]morpholine-3-one</strong> in dichloromethane (70 ml) was cooled to 0C and treated with 25 g (238 mmol) dry sodium carbonate. After stirring for 10 min at 0C, 6.14 g (41.5 mmol) trimethyloxonium tetrafluorob orate were added at 0C. The mixture was allowed to warm to room temperature and stirred for 6 h. Water (100 ml) was added, and the organic layer was separated. The aqueous phase was extracted several times with dichloromethane, and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product thus obtained was used in the next step without further purification.GC-MS (method 5): Rt = 3.36 min; MS (ESIpos): m/z = 1 16 (M+H)+.
Example 3A5-Methoxy-3,6-dihydro-2H-l ,4-oxazine A solution of 1.2 g (11.9 mmol) <strong>[109-11-5]morpholine-3-one</strong> in dichloromethane (70 ml) was cooled to 00C and treated with 25 g (238 mmol) dry sodium carbonate. After stirring for 10 min at 0C, 6.14 g (41.5 mmol) trimethyloxonium tetrafluoroborate were added at 0C. The mixture was allowed to warm to room temperature and stirred for 6 h. Water (100 ml) was added, and the organic layer was separated. The aqueous phase was extracted several times with dichloromethane, and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product thus obtained was used in the next step without further purification.GC-MS (method 3): R, = 3.36 min; MS (ESIpos): m/z = 116 (M+?)+.

  • 13
  • [ 109-11-5 ]
  • [ 1149752-92-0 ]
  • [ 1217484-43-9 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃; for 0.25h;Microwave irradiation; A microwave vial was charged with methyl 3-bromo-5-(5-methylpyridin-2-yl)benzoate(100 mg, 0.33 mmol), <strong>[109-11-5]morpholin-3-one</strong> (42 mg, 0.41 mmol), palladium acetate (4 mg), cesium carbonate (169 mg, 0.52 mmol), xantphos (3 mg), and 1,4-dioxane (1 mL). The reaction mixture was subjected to microwave irradiation at 1 10 0C for 15 min. The reaction mixture was filtered and the filterate was concentrated under reduced pressure. The resultant residue was purified by preparative HPLC to get the product as a yellow solid.
  • 14
  • [ 109-11-5 ]
  • [ 1093628-67-1 ]
  • [ 1093628-69-3 ]
YieldReaction ConditionsOperation in experiment
98% With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; for 15h;Inert atmosphere; Reflux; 1.5 g (3.59 mmol) of the compound from Example 5A are dissolved in 20 ml of anhydrous dioxane, and 0.45 g (4.49 mmol) of morpholinone, 137 mg (0.719 mmol) of copper(I) iodide, 1.53 g (7.19 mmol) of potassium phosphate and 153 μl (1.44 mmol) of N,N'-dimethylethylenediamine are added in succession. By repeatedly applying a slight vacuum and venting with argon, the reflux apparatus is made inert. The reaction mixture is heated at reflux for 15 hours. After this period, the mixture is allowed to cool to room temperature. Water is added, and the mixture is extracted with ethyl acetate. The organic extract is washed successively with water and saturated sodium chloride solution. The extract is dried over anhydrous magnesium sulphate and then filtered, and the filtrate is freed from the solvent under reduced pressure. The residue is purified by filtration with suction through silica gel using cyclohexane/ethyl acetate 1:1 as mobile phase. This gives 1.38 g (98% of theory) of the title compound. 1H-NMR (400 MHz, DMSO-d6, δ/ppm): 7.32-7.28 (m, 9H), 7.26-7.20 (m, 2H), 7.00-6.92 (m, 2H), 4.33 (s, 4H), 4.15 (s, 2H), 3.91 (dd, 2H), 3.55 (dd, 2H). HPLC (method 1): Rt=4.78 min. MS (DCl, NH3, m/z): 391 (M+H)+.
98% With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; for 15h;Inert atmosphere; Reflux; Example 6A4-[4-(Dibenzylamino)-3-fluorophenyl]<strong>[109-11-5]morpholin-3-one</strong> 1.5 g (3.59 mmol) of the compound from Example 5A were dissolved in 20 ml of anhydrous dioxane, and 0.45 g (4.49 mmol) of morpholinone, 137 mg (0.719 mmol) of copper(I) iodide, 1.53 g (7.19 mmol) of potassium phosphate and 153 μl (1.44 mmol) of N,N'-dimethylethylenediamine were added in succession. The reflux apparatus was inertized by repeated application of a slightly reduced pressure and venting with argon. The reaction mixture was heated at reflux for 15 hours. After this period of time, the mixture was allowed to cool to room temperature. Water was added, and the mixture was extracted with ethyl acetate.The organic extract was washed successively with water and saturated sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was freed from the solvent under reduced pressure. The residue was purified by filtration with suction through silica gel using the mobile phase cyclohexane/ethyl acetate 1:1. This gave 1.38 g (98% of theory) of the title compound.1H-NMR (400 MHz, DMSO-d6, δ/ppm): 7.32-7.28 (m, 9H), 7.26-7.20 (m, 2H), 7.00-6.92 (m, 2H), 4.33 (s, 4H), 4.15 (s, 2H), 3.91 (dd, 2H), 3.55 (dd, 2H).HPLC (Method 1): Rt=4.78 min.MS (DCl, NH3, m/z): 391 (M+H)+.
  • 15
  • [ 109-11-5 ]
  • methyl 4-{(4E)-5-[2-(3-bromopropoxy)phenyl]-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate [ No CAS ]
  • methyl 4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(3-oxomorpholin-4-yl)propoxy]phenyl}pent-4-en-1-yl]benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% Example 23A Methyl 4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(3-oxomorpholin-4-yl)propoxy]phenyl}pent-4-en-1-yl]benzoate (enantiomer 1) A solution of 0.175 g (1.73 mmol) of <strong>[109-11-5]morpholin-3-one</strong> [CAS Reg. No. 109-11-5] is initially charged in 6 ml of dry DMF, and 71 mg (1.78 mmol) of sodium hydride (60% in paraffin oil) are added. The mixture is stirred at room temperature for 45 min. The reaction solution is then cooled to 0 C., and a solution of 0.28 g (0.495 mmol) of methyl 4-{(4E)-5-[2-(3-bromopropoxy)phenyl]-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (Example 22A) in 3 ml of dry DMF is added. The mixture is stirred at room temperature for 1 h. The reaction solution is then carefully poured into 50 ml of ice-cold 10% strength ammonium chloride solution. The mixture is extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and concentrated. This gives 0.29 g (0.495 mmol, 100% of theory) of a colorless oil which is reacted without further purification. LC-MS (Method 7): Rt=3.15 min; m/z=586 (M+H)+.
  • 16
  • [ 109-11-5 ]
  • [ 1238695-54-9 ]
  • [ 1238696-93-9 ]
YieldReaction ConditionsOperation in experiment
59% With potassium phosphate;copper(l) iodide; trans-1,2-cyclohexanediamine; In 1,4-dioxane; for 6h;Inert atmosphere; Reflux; Example 1104-{3-Fluoro-4-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]phenyl}<strong>[109-11-5]morpholin-3-one</strong> A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), <strong>[109-11-5]3-morpholinone</strong> (60.7 mg, 0.6 mmol), CuI (9.5 mg, 0.05 mmol), trans-1,2-diaminocyclohexane (0.012 mL, 0.1 mmol), and K3PO4 (212 mg, 1.0 mmol) in 1,4-dioxane (2 mL) was refluxed for 6 h under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from MeOH/H2O to give the title compound (136 mg, 59% yield) as a white solid: mp 193-195 C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.75-3.79 (2H, m), 3.90 (3H, s), 4.04-4.07 (2H, m), 4.35 (2H, s), 6.41 (1H, t, J=9.0 Hz), 7.00 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.31 (1H, d, J=2.3 Hz), 7.33-7.46 (6H, m), 7.78-7.80 (2H, m). LC-MS (ESI) m/z 462 [M+H]+. Anal. Calcd for C24H20FN5O4: C, 62.47; H, 4.37; N, 15.18. Found: C, 62.31; H, 4.33; N, 15.25.
59% With potassium phosphate; copper(l) iodide; (S,S)-1,2-diaminocyclohexane; In 1,4-dioxane; for 6h;Reflux; Inert atmosphere; A suspension of 1- (2-fluoro-4-iodophenyl) -5-methoxy-3- (1- phenyl-lH-pyrazol-5-yl) pyridazin-4 (1H) -one (244 mg, 0.5 mmol) , <strong>[109-11-5]3-morpholinone</strong> (60.7 mg, 0.6 mmol), Cul (9.5 mg, 0.05 mmol), trans-1, 2-diaminocyclohexane (0.012 mL, 0.1 mmol), and K3PO4 (212 mg, 1.0 mmol) in 1,4-dioxane (2 mL) was refluxed for 6 hr under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgS04, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt and recrystallized from MeOH/H20 to give the title compound (136 mg, 59% yield) as a white solid: mp 193-195C; ? NMR (300 MHz, CDCI3) : δ ppm 3.75-3.79 (2H, m) , 3.90 (3H, s) , 4.04-4.07 (2H, m) , 4.35 (2H, s) , 6.41 (1H, t, J = 9.0 Hz), 7.00 (1H, ddd, J = 1.1, 2.3, 9.0 Hz), 7.31 (1H, d, J = 2.3 Hz), 7.33- 7.46 (6H, m) , 7.78-7.80 (2H, m) . LC-MS (ESI) m/z 462 [M + H]+. Anal. Calcd for C24H20FN5O4 : C, 62.47; H, 4.37; N, 15.18. Found: C, 62.31; H, 4.33; N, 15.25.
  • 17
  • [ 109-11-5 ]
  • [ 455-88-9 ]
  • [ 845729-40-0 ]
YieldReaction ConditionsOperation in experiment
51% (b) 3-methyl-1-nitro-4-(3-oxo-morpholin-4-yl)-benzene 1.00 g (6.45 mmol) 4-fluoro-3-methyl-1-nitro-benzene is combined in 20 ml DMF with 281 mg (6.45 mmol) 55% sodium hydride, dispersed in paraffin, stirred for 5 min at ambient temperature. Then 815 mg (8.06 mmol) <strong>[109-11-5]morpholin-3-one</strong> were added and then stirred for 2 h at ambient temperature. Then the mixture is evaporated down i. vac., water is added to the residue and it is extracted with ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, dried on sodium sulphate, evaporated down i. vac. and the residue is purified by chromatography on silica gel (eluant gradient: cyclohexane/ethyl acetate=1:1→0:1). Yield: 780 mg (51%) Rf value: 0.52 (silica gel, ethyl acetate) C11H12N2O4 (236.22) Mass spectrum: (M+H)+=237
  • 18
  • [ 109-11-5 ]
  • [ 94446-97-6 ]
  • [ 1307249-61-1 ]
YieldReaction ConditionsOperation in experiment
66% With sodium hydride;tetra-(n-butyl)ammonium iodide; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 16h; PREPARATION 484-[(2-Bromo-3-pyridyl)methyl]<strong>[109-11-5]morpholin-3-one</strong>; To a solution of 2-bromo-3-bromomethyl-pyridine (0.68 g, 2.36 mmol) in dimethylformamide (10 mL) are added sodium hydride (0.11 g, 60% suspension, 2.82 mmol), <strong>[109-11-5]morpholin-3-one</strong> (0.20 g, 1.97 mmol) and tetrabutylammonium iodide (catalytic) at 0 C. The mixture is stirred at room temperature for 16 hours. After completion, the reaction mixture is partitioned between ethyl acetate (25 mL) and water (25 mL). The aqueous layer is extracted with ethyl acetate (2×25 mL) and the combined organic extracts are dried over sodium sulfate and concentrated in vacuo. The crude material is purified by column chromatography over silica gel eluting with hexane/ethyl acetate (55:45) to yield 0.35 g (66%) of the title compound. MS (m/z): 271/273 (M+1, M+3).
  • 19
  • [ 109-11-5 ]
  • [ 1295502-03-2 ]
  • [ 1295501-83-5 ]
YieldReaction ConditionsOperation in experiment
54% (0.20 g, 0.96 mmol) (5-Phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) was dissolved in dichloromethane (5 ml) and methanesulfonyl chloride (75 μ, 0.96 mmol, 1.0 equiv.) and triethylamine (270 μ, 1.91 mmol, 2 equiv.) were added at 0-5C. The mixture was stirred for 1 hour at room temperature. The reaction mixture was evaporated, dissolved in 2 ml DMF and added to a suspension of <strong>[109-11-5]morpholin-3-one</strong> (97 mg, 0.96 mmol, 1.0 equiv.) previously treated with sodium hydride (60%) (69 mg, 1.43 mmol, 1.5 equiv.) in 2 ml DMF. The mixture was stirred for 3 hours at room temperature. The reaction mixture was treated with sat. NaHC03 solution and extracted twice with EtOAc. The organic layers were extracted with water, dried over sodium sulfate and evaporated to dryness. The crude material was purified by flash chromatography on silica gel (20gr, ethyl acetate/heptane gradient, 0: 100 to 0: 100). The desired 4-(5 -phenylethynyl-pyridin-2-ylmethyl)-morpho lin-3 -one (150 mg, 54% yield) was obtained as a light brown solid, MS: m/e = 293.1 (M+H+).
  • 20
  • [ 109-11-5 ]
  • [ 1296308-86-5 ]
  • [ 1296309-80-2 ]
YieldReaction ConditionsOperation in experiment
47% With potassium phosphate; N,N`-dimethylethylenediamine;copper(l) iodide; In 1,4-dioxane; at 90℃; for 16h; Step (ii)To a solution of l-(3-iodobenzyl)-N-(l-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d]pyrimidin-6-amine (50mg, 0.12mmol) in dioxane (lmL) were added morpho lin-3 -one (15mg, 1.25eq), copper iodide (4.4mg, 0.2eq), potassium phosphate (49mg, 2eq) and Ν,Ν'- dimethylethylene diamine (5μ1, 0.4eq). After stirring for 16h at 90C, the reaction mixture was partitioned between 0.5M EDTA and DCM. The aqueous phase was extracted with DCM, the combined organic phases dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC to yield the title compound (23mg, 56μιηο1, 47%). 1H NMR (d6-DMSO) δ 9.85 (s, 1H), 8.92 (s, 1H), 8.06 (s, 2H), 7.56 (s, 1H), 7.43 (s, 1H), 7.39 - 7.35 (m, 1H), 7.33 - 7.29 (m, 1H), 7.20 - 7.13 (m, 1H), 5.57 (s, 2H), 4.17 (s, 2H), 3.96 - 3.91 (m, 2H), 3.84 (s, 3H), 3.69 - 3.64 (m, 2H); LC-MS method B, (ES+) 405.1, RT = 6.31min.
  • 21
  • [ 109-11-5 ]
  • [ 20511-12-0 ]
  • [ 1227486-41-0 ]
YieldReaction ConditionsOperation in experiment
100% With potassium phosphate; copper(l) iodide; In 1,4-dioxane; at 110℃; A solution of Example 149a (200 mg, 0.90 mmol), Example 149b (95 mg, 0.91 mmol), Example 149c (26 mg, 0.18 mmol), CuI (18 mg, 0.09 mmol) and K3PO4 (380 mg, 1.82 mmol) in 1,4- dioxane (5 mL) was stirred at 110oC overnight. The reaction was diluted with CH3CN (5 mL), filtered and concentrated to give the crude product Example 149d (210 mg, quant.) as black oil.1H NMR (400 MHz, DMSO-d6) d 7.85 (br, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.43 (d, J = 8.0 Hz, 1H), 5.98 (s, 2H), 4.13 (s, 2H), 3.91 (t, J = 4.0 Hz, 2H), 3.61 (t, J = 4.0 Hz, 2H).
With potassium phosphate;copper(l) iodide; trans-1,2-cyclohexanediamine; In 1,4-dioxane; at 110℃; for 23h; To a suspension of 5-iodopyridin-2-amine (800 mg) in dioxane (6 mL) were added copper (I) iodide (6.9 mg), trans-cyclohexane-1,2-diamine (44 μL), <strong>[109-11-5]morpholin-3-one</strong> (441 mg), and powdery tripotassium phosphate (1.54 g). The resulting reaction mixture was heated and stirred at 110C for 23 hours. After cooling to room temperature, the reaction mixture was filtered through celite, and the solid was washed with CHCl3. The liquid was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (CHCl3/MeOH = from 100/0 to 88/12) to obtain 4-(6-aminopyridin-3-yl)<strong>[109-11-5]morpholin-3-one</strong> (548.3 mg) as a pale yellow solid.
  • 22
  • [ 109-11-5 ]
  • trans-4-({6-[(6-bromo-1,3-benzothiazol-2-yl)amino]-2-pyridinyl}amino)cyclohexanol [ No CAS ]
  • 4-[2-({6-[(trans-4-hydroxycyclohexyl)amino]-2-pyridinyl}amino)-1,3-benzothiazol-6-yl]-3-morpholinone [ No CAS ]
YieldReaction ConditionsOperation in experiment
16% Example 59:4-[2-({6-[(trans-4-hydroxycyclohexyl)amino]-2-pyridinyl}amino)-1 ,3-benzothiazol-6- yl]-<strong>[109-11-5]3-morpholinone</strong>A mixture of trans-4-({6-[(6-bromo-1 ,3-benzothiazol-2-yl)amino]-2- pyridinyl}amino)cyclohexanol [example 3] (150mg, 0.36mmol), <strong>[109-11-5]3-morpholinone</strong> (108mg, 1.07mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (41.4mg, 0.072mmol), tris(benzylidieneacetone)dipalladium (32.8mg, 0.036mmol) and caesium carbonate (350mg, 1 .07mmol) in 1 ,4-dioxane (10mL) was heated at 90C under an atmosphere of nitrogen for 16 hours. No reaction was observed. The mixture was cooled and treated with DMF (3ml_), copper(l) iodide (204mg, 1.07mmol) and Ν,Ν'- dimethylethylenediamine (0.1 14mL, 1 .07mmol). The mixture was then heated at 100C for 3 hours. The cooled mixture was treated with chloroform (30ml_) and water (30ml_) and separated. The organic phase was evaporated to dryness and the product was subjected to purification by mass-directed automated preparative HPLC (formic acid modifier) to afford the title compound (24.6mg, 0.056mmol, 16% yield). LCMS (Method A): Rt 0.66 minutes; m/z 440 (MH+)
  • 23
  • [ 6320-16-7 ]
  • [ 109-11-5 ]
YieldReaction ConditionsOperation in experiment
10% With sodium hydride; In tetrahydrofuran; at 20 - 60℃; for 6h;Inert atmosphere; Cooling with ice; Under an argon atmosphere, to a solution of 2-chloro-N-(2-hydroxyethyl)acetamide (3.2 g, 23 mmol) in tetrahydrofuran (64 ml) was added sodium hydride (1.2 g, 30 mmol) under ice-cooling, and the mixture was stirred for 1 hr. Then, the mixture was stirred at room temperature for 1 hr, and further at 60 C. for 4 hr. After cooling, water (540 μl) was added, and the reaction mixture was dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (232 mg, yield 10%).1H-NMR (400 MHz, DMSO-d6) δ: 3.20-3.23 (m, 2H), 3.70-3.73 (m, 2H), 3.96 (s, 2H), 7.88-8.07 (brs, 1H).
  • 24
  • [ 109-11-5 ]
  • [ 1361311-23-0 ]
  • [ 1361311-32-1 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃;Inert atmosphere; Step A: To a mixture of 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline from Example 35 step B (336 mg, 0.84 mmol), tris(dibenzylideneacetone)dipalladium (73 mg, 0.08 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (144 mg, 0.25 mmol), <strong>[109-11-5]morpholin-3-one</strong> (102 mg, 1 mmol) and Cs2CO3 (383 mg, 1.18 mmol) was added dioxane (5 mL). The reaction vessel was evacuated and flushed with argon (3×), and the mixture was heated at 100 C. overnight. The mixture was diluted with MeOH and DCM and concentrated under reduced pressure onto Celite. The mixture was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to afford 4-(2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazolin-8-yl)<strong>[109-11-5]morpholin-3-one</strong> (203 mg, 57%) as a mixture which was used without further purification. LC-MS (ESI) m/z 421 (M+H)+.
  • 25
  • [ 109-11-5 ]
  • [ 1373489-37-2 ]
  • [ 1373488-85-7 ]
YieldReaction ConditionsOperation in experiment
5% Synthesis of Example 312 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(3-oxo-morpholin-4-yl)-pyridine-3-carboxylic acid amide A solution of 1.0 g (2.95 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2) in propionitrile (20 ml) was treated with 1.33 g (8.87 mmol) NaI and 1.0 ml (8.28 mmol) trichloromethylsilane. Subsequently the solution was heated at 110 C. for 16 h. The mixture was then partitionated between a 2M aq. NaOH sol and EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in dioxane (10 ml) and 2.26 g (7.0 mmol) Cs2CO3 and 114 mg (0.92 mmol) picolinic acid were added. This mixture was degassed for 30 min followed by the addition of 88 mg (0.46 mmol) CuI and 470 mg (4.65 mmol) <strong>[109-11-5]3-morpholinone</strong>. The reaction solution was then heated to 100 C. for 16 h and subsequently concentrated in vacuo. The residue was dissolved in water and was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 60 mg (0.15 mmol, 5%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(3-oxo-morpholin-4-yl)-pyridine-3-carboxylic acid amide (example 312). [M+H]+ 404.1.
5% Synthesis of example 312: 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(3- morpholin-4-yl)-pyridine-3-A solution of 1.0 g (2.95 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl- pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2) in propionitrile (20 ml) was treated with 1.33g (8.87 mmol) Nal and 1.0 ml (8.28 mmol) trichloromethylsilane. Subsequently the solution was heated at 110 C for 16h. The mixture was then partitionated between a 2M aq. NaOH sol and EtOAc. The organic layer was separated, washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was dissolved in dioxane (10 ml) and 2.26 g (7.0 mmol) Cs2C03 and 114 mg (0.92 mmol) picolinic acid were added. This mixture was degassed for 30 min followed by the addition of 88 mg (0.46 mmol) Cul and 470 mg (4.65 mmol) <strong>[109-11-5]3-morpholinone</strong>. The reaction solution was then heated to 100 C for 16 h and subsequently concentrated in vacuo. The residue was dissolved in water and was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2S04 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 60 mg (0.15 mmol, 5%) 2-Ethylsulfanyl-N-[(3-fluorophenyl)- methyl]-4-methyl-6-(3-oxo-morpholin-4-yl)-pyridine-3-carboxylic acid amide (example 312).[M+Hf 404.1.
  • 26
  • [ 109-11-5 ]
  • [ 1380182-99-9 ]
  • [ 1380182-98-8 ]
YieldReaction ConditionsOperation in experiment
78% Example n 1 : Synthesis of 4-(2-(5-methyl-1 -(naphthalen-2-yl)-1 H-pyrazol-3- yloxy)ethyl) <strong>[109-11-5]morpholin-3-one</strong>To a stirred suspension of sodium hydride (65 mg 60% dispersion in mineral oil, 1 ,63 mmol) in DMF (3 ml), cooled to 0-5C, a solution of <strong>[109-11-5]morpholin-3-one</strong> (91 mg, 0,91 m mol) i n DM F (3 m l) was added d ropwise. The m ixture was sti rred at room temperature for 3 hrs. Then, a solution of 3-(2-chloroethoxy)-5-methyl-1-(naphthalen-2- yl)-1 H-pyrazole (200 mg, 0,7 mmol) in DMF (4 ml) was added and the mixture was heated to 50C for 14 hrs. The reaction mixture was cooled, water (2 ml) added dropwise, and it was evaporated to dryness in vacuum. The resulting residue was partitioned between dichloromethane and water. The organic layer was washed with water, dried over Na2S04, filtered and evaporated giving 223 mg of crude residue, which was purified by a silica gel column chromatography (eluent: ethyl acetate) and 4- (2-(5-methyl-1-(naphthalen-2-yl)-1 H-pyrazol-3-yloxy)ethyl) <strong>[109-11-5]morpholin-3-one</strong> (192 mg, 78%) was obtained as an amorphous white solid.Purity determined by HPLC: 100 %1 H-NMR (CDCIa) δ ppm : 7.95-7,8 (m, 4H) , 7,6-7,5 (m, 3H), 5,7 (s, 1 H), 4,45 (t, J=5,2Hz, 2H), 4,2 (s, 2H), 3,85 (t, J=5,3Hz, 2H), 3,8 (t, J=5,3Hz, 2H), 3,6 (t, J=5,4Hz, 2H), 2,35 (s, 3H).
78% EXAMPLES Example n 1: Synthesis of 4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl) <strong>[109-11-5]morpholin-3-one</strong> [Show Image] To a stirred suspension of sodium hydride (65 mg 60% dispersion in mineral oil, 1,63 mmol) in DMF (3 ml), cooled to 0-5C, a solution of <strong>[109-11-5]morpholin-3-one</strong> (91 mg, 0,91 mmol) in DMF (3 ml) was added dropwise. The mixture was stirred at room temperature for 3 hrs. Then, a solution of 3-(2-chloroethoxy)-5-methyl-1-(naphthalen-2-yl)-1H-pyrazole (200 mg, 0,7 mmol) in DMF (4 ml) was added and the mixture was heated to 50C for 14 hrs. The reaction mixture was cooled, water (2 ml) added dropwise, and it was evaporated to dryness in vacuum. The resulting residue was partitioned between dichloromethane and water. The organic layer was washed with water, dried over Na2SO4, filtered and evaporated giving 223 mg of crude residue, which was purified by a silica gel column chromatography (eluent: ethyl acetate) and 4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl) <strong>[109-11-5]morpholin-3-one</strong> (192 mg, 78%) was obtained as an amorphous white solid. Purity determined by HPLC: 100 % 1H-NMR (CDCl3) δ ppm: 7.95-7,8 (m, 4H), 7,6-7,5 (m, 3H), 5,7 (s, 1H), 4,45 (t, J=5,2Hz, 2H), 4,2 (s, 2H), 3,85 (t, J=5,3Hz, 2H), 3,8 (t, J=5,3Hz, 2H), 3,6 (t, J=5,4Hz, 2H), 2,35 (s, 3H).
  • 27
  • [ 109-11-5 ]
  • 4-(2-chloroethyl)-4,5,6,7-tetrahydro-1-phenyl-1H-indazole [ No CAS ]
  • [ 1380243-69-5 ]
YieldReaction ConditionsOperation in experiment
29% NaH (38 mg of 55-65% dispersion, 0.96 mmol) was added to a solution of morpholin-3- one (42.5 mg, 0.42 mmol) in DMF (2 mL) under argon at 0C and the mixture was stirred for 30 minutes and 4-(2-chloroethyl)-1-phenyl-4,5,6,7-tetrahydro-1 H-indazole (100 mg, 0.38 mmol) was added to the previous mixture and allowed to reach room temperature. The mixture was microwave irradiated at 100 C (power set point 150 W; hold time 10 min). The solvent was removed at reduced pressure and the resulting crude was diluted in ethyl acetate. The organic phase was washed with acid water and then with basic water. The organic phase was dried and the solvent was removed at reduced pressure. The crude was purified by flash chromatography to yield 4-(2-(1- phenyl-4,5,6,7-tetrahydro-1 H-indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong> as an orange oil (37 mg, 0.113 mmol, 29%).1 H NMR (400 MHz, CDCI3) δ 7.55 (s, 1 H), 7.52-7.39 (m, 4H), 7.35-7.27 (m, 1 H), 4.18 (s, 2H), 3.90 (t, J= 5.1 Hz, 2H), 3.65 (m, 1 H), 3.51 (m, 1 H), 3.41 (q, J= 5.2 Hz, 2H), 2.77 (m, 1 H), 2.71 (m, 2H), 2.10-1.95 (m, 3H), 1.76-1.65 (m, 2H), 1.47 (m, 1 H).
29% Example 7: Synthesis of 4-(2-(1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong>. NaH (38 mg of 55-65% dispersion, 0.96 mmol) was added to a solution of <strong>[109-11-5]morpholin-3-one</strong> (42.5 mg, 0.42 mmol) in DMF (2 mL) under argon at 0C and the mixture was stirred for 30 minutes and 4-(2-chloroethyl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole (100 mg, 0.38 mmol) was added to the previous mixture and allowed to reach room temperature. The mixture was microwave irradiated at 100 C (power set point 150 W; hold time 10 min). The solvent was removed at reduced pressure and the resulting crude was diluted in ethyl acetate. The organic phase was washed with acid water and then with basic water. The organic phase was dried and the solvent was removed at reduced pressure. The crude was purified by flash chromatography to yield 4-(2-(1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong> as an orange oil (37 mg, 0.113 mmol, 29%). 1H NMR (400 MHz, CDCl3) δ 7.55 (s, 1 H), 7.52-7.39 (m, 4H), 7.35-7.27 (m, 1H), 4.18 (s, 2H), 3.90 (t, J= 5.1 Hz, 2H), 3.65 (m, 1 H), 3.51 (m, 1 H), 3.41 (q, J= 5.2 Hz, 2H), 2.77 (m, 1 H), 2.71 (m, 2H), 2.10-1.95 (m, 3H), 1.76-1.65 (m, 2H), 1.47 (m, 1 H).
  • 28
  • [ 109-11-5 ]
  • [ 1229291-23-9 ]
  • [ 1380243-70-8 ]
YieldReaction ConditionsOperation in experiment
28% The title compound was prepared from (R)-4-(2-chloroethyl)-1 -phenyl-4, 5,6,7- tetrahydro-1 H-indazole (200 mg, 0.77 mmol), NaH (76 mg of 55-65% dispersion, 1.91 mmol) and <strong>[109-11-5]morpholin-3-one</strong> (85 mg, 0.84 mmol) in DMF (2ml_) and the mixture was microwave irradiated at 100 C (power set point 150 W; hold time 10 min). The crude was purified by flash chromatography to yield (R)-4-(2-(1 -phenyl-4, 5, 6, 7-tetrahydro-1 H- indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong> (70.1 mg, 0.21 mmol, 28%).1 H NMR (300 MHz, CDCI3) δ 7.54 (s, 1 H), 7.47 (m, 4H), 7.32 (m, 1 H), 4.18 (s, 2H), 3.90 (t, J= 5.1 Hz, 2H), 3.67 (m, 1 H), 3.55-3.35 (m, 3H), 2.71 (m, 3H), 2.02 (m, 3H), 1.70 (m, 2H), 1.48 (m, 1 H)[a]20D = +1.6 (c=0.5, MeOH)Enantiomeric purity = 92% ee Column: (Chiralcel OD-H)
28% With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 100℃;Microwave irradiation; Example 8: Synthesis of (R)-4-(2-(1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong>. The title compound was prepared from (R)-4-(2-chloroethyl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole (200 mg, 0.77 mmol), NaH (76 mg of 55-65% dispersion, 1.91 mmol) and <strong>[109-11-5]morpholin-3-one</strong> (85 mg, 0.84 mmol) in DMF (2mL) and the mixture was microwave irradiated at 100 C (power set point 150 W; hold time 10 min). The crude was purified by flash chromatography to yield (R)-4-(2-(1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong> (70.1 mg, 0.21 mmol, 28%). 1H NMR (300 MHz, CDCl3) δ 7.54 (s, 1 H), 7.47 (m, 4H), 7.32 (m, 1 H), 4.18 (s, 2H), 3.90 (t, J= 5.1 Hz, 2H), 3.67 (m, 1 H), 3.55-3.35 (m, 3H), 2.71 (m, 3H), 2.02 (m, 3H), 1.70 (m, 2H), 1.48 (m, 1 H) [α]20D = +1.6 (c=0.5, MeOH) Enantiomeric purity = 92% ee Column: (Chiralcel OD-H)
  • 29
  • [ 109-11-5 ]
  • [ 1229291-26-2 ]
  • [ 1380243-71-9 ]
YieldReaction ConditionsOperation in experiment
19% The title compound was prepared from (S)-4-(2-chloroethyl)-1 -phenyl-4, 5,6,7- tetrahydro-1 H-indazole (200 mg, 0.77 mmol), NaH (76 mg of 55-65% dispersion, 1.91 mmol) and <strong>[109-11-5]morpholin-3-one</strong> (85 mg, 0.84 mmol) in DMF (2ml_) and the mixture was microwave irradiated at 100 C (power set point 150 W; hold time 10 min). The crude was purified by flash chromatography to yield (S)-4-(2-(1 -phenyl-4, 5, 6, 7-tetrahydro-1 H- indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong> (47mg, 0.14 mmol, 19%).1 H NMR spectroscopic data are identical to those of the example 8[a]20D = -0.9 (c=0.5, MeOH)Enantiomeric purity = 99% eeColumn: (Chiralcel OD-H)
19% With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 100℃; for 0.166667h;Microwave irradiation; Example 9: Synthesis of (S)-4-(2-(1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong>. The title compound was prepared from (S)-4-(2-chloroethyl)-1-phenyl-4,5,6,7-tetrahydro-1H-indazole (200 mg, 0.77 mmol), NaH (76 mg of 55-65% dispersion, 1.91 mmol) and <strong>[109-11-5]morpholin-3-one</strong> (85 mg, 0.84 mmol) in DMF (2mL) and the mixture was microwave irradiated at 100 C (power set point 150 W; hold time 10 min). The crude was purified by flash chromatography to yield (S)-4-(2-(1-phenyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)ethyl)<strong>[109-11-5]morpholin-3-one</strong> (47mg, 0.14 mmol, 19%). 1H NMR spectroscopic data are identical to those of the example 8 [α]20D = -0.9 (c=0.5, MeOH) Enantiomeric purity = 99% ee Column: (Chiralcel OD-H)
  • 30
  • [ 109-11-5 ]
  • [ 106-37-6 ]
  • [ 634905-12-7 ]
YieldReaction ConditionsOperation in experiment
67.6% With dipotassium hydrogenphosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 105℃; for 15h;Inert atmosphere; Sealed tube; Example 144-(((lR,3S)-3-amino-2,2,3-trimethylcyclopentyl)amino)-6-(4-(3-oxo-4- morpholinyl)phenyl)pyrrolo [ 1 ,2-b]pyridazine-3 -carboxamide Step 1 : 4-(4-brom henyl)<strong>[109-11-5]morpholin-3-one</strong>[00234] A solution of 1,4-dibromobenzene (283 mg, 1.200 mmol), morpholin-3- one (101 mg, 1 mmol), dibasic potassium phosphate (348 mg, 2 mmol), copper (I) iodide (38.1 mg, 0.20 mmol) and N,N'-dimethylethylenediamine (0.043 ml, 0.40 mmol) in dioxane (3 ml) was purged with nitrogen for 2 min, sealed in a reaction vial and heated in a heating block at 105 C for 15 h. The crude product mixture was filtered, and charged to a 12 g silica gel cartridge which was eluted with 0-50% EtOAc in hexanes to give the title compound (173 mg, 0.676 mmol, 67.6 % yield) as a white solid. XH NMR (400 MHz, CDC13) δ ppm 10.56 (1 H, none), 7.55 (2 H, d, J=8.80 Hz), 7.24 (2 H, d, J=8.58 Hz), 4.04 (2 H, dd, J=5.83, 4.29 Hz), 3.73-3.79 (2 H, m). HPLC (condition G): ret. time 2.213 min. LC/MS [m/z, (M+H)] 258.0.
  • 31
  • [ 109-11-5 ]
  • 7-bromo-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine [ No CAS ]
  • [ 51323-43-4 ]
  • 4-(3-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)benzyl)morpholin-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
11% To a suspension of morpholin-3-one (29 mg, 0.288 mmol) in THF (2 mL) was added NaH (16.14 mg, 0.336 mmol). After stirring the mixture for 5 mi (3- (bromomethyl)phenyl)boronic acid (41.3 mg, 0.192 mmol) was added and the resulting mixture was stirred at room temperature for 2 h. Water (1 mL) was added, followed byphosphoric acid, potassium salt (61.2 mg, 0.288 mmol) and 7-bromo-5-(1-(tetrahydro-2H-pyran-4-yl)- 1 H- 1,2,3 -triazol-5-yl)pyrrolo[2, 1 -f] [1 ,2,4]triazin-4-amine (35 mg, 0.096 mmol). The reaction vessel was evacuated, backfilled with N2 and then degassed by bubbling N2 while being sonicated. Tetrakis triphenylphosphine (11.11 mg, 9.61 .imol) was added and the degassing process was repeated. The reaction mixture was heated at140 C in a microwave for 1 h. The reaction mixture was cooled, filtered, washed with water and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, dried and concentrated. The residue purified by preparative LCMS method C to obtain 4-(3 -(4-amino-5-( 1 -(tetrahydro-2H-pyran-4-yl)- 1 H- 1,2,3 -triazol-5 -yl)pyrrolo[2, 1 -f] [1,2,4] triazin-7-yl)benzyl)morpholin-3-one (5.3 mg, 11% yield). LC/MS (M+H) =475.15. ?H NMR (500 MHz, DMSO-d6) oe 2.0 (m, 2H), 2.16 (m, 2H), 3.32 (t, 2H), 3.37 (m, 2H), 3.85 (t, 2H), 3.93 (m, 3H), 4.14(s, 2H), 4.64 (s, 2H), 7.27 (m, 2H), 7.50 (t, 1H), 7.87 (s, 1H), 7.96 (m, 2H), 8.10 (m, 1H).
 

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